Cognitive frailty and its association with disability among Chinese community-dwelling older adults: a cross-sectional study.

BACKGROUND: There are a variety of determinants that are key to functional disability of older adults. However, little is known regarding the relationship between cognitive frailty and disability among older people. The aims of this study were to examine the associations between cognitive frailty and its six components with instrumental activities of daily living (IADL) functioning in community-dwelling older adults. METHODS: A total of 313 community-dwelling older adults (aged ≥ 65 years) were recruited from eight community centers in central China. Cognitive frailty was operationalized using the Mini-Mental State Examination for the evaluation of cognitive status and the Fried criteria for the evaluation of physical frailty. The outcome was functional disability assessed by the IADL scale. The association between cognitive frailty, as well as its components, and IADL limitations was identified by conducting binary logistic regression analysis. RESULTS: The prevalence of cognitive frailty was 8.9% in this study. The results showed that cognitive frailty (OR = 22.86) and frailty without cognitive impairment (OR = 8.15) were associated with IADL limitations. Subdimensions of cognitive frailty, exhaustion, weakness, low physical activity and cognitive impairment components were independently associated with IADL limitations. CONCLUSION: Cognitive frailty was associated with a higher prevalence of disability. Interventions for improving cognitive frailty should be developed to prevent IADL disability among community-dwelling older adults in China.

Loureirin B Reduces Insulin Resistance and Chronic Inflammation in a Rat Model of Polycystic Ovary Syndrome by Upregulating GPR120 and Activating the LKB1/AMPK Signaling Pathway.

Polycystic ovary yndrome (PCOS) is a common metabolic disorder in women, which is usually associated with insulin resistance (IR) and chronic inflammation. Loureirin B (LrB) can effectively improve insulin resistance and alleviate chronic inflammation, and in order to investigate the therapeutic effect of LrB on polycystic ovary syndrome with insulin resistance (PCOS-IR), we conducted animal experiments. A PCOS-IR rat model was established by feeding a high-fat diet combined with letrozole (1 mg/kg·d for 21 days). The rats were treated with the GPR120 agonists TUG-891 and LrB for 4 weeks. Biochemical parameters (fasting blood glucose, total cholesterol, triglycerides, high- and low-density lipoprotein), hormone levels (serum insulin, E2, T, LH, and FSH), and inflammatory cytokines (TNF-α, IL-1ß, IL-6, and IL-18) were analyzed. Histopathological analyses of ovaries were performed using hematoxylin/eosin (H&E) staining. Real-time PCR and western blotting were used to assess GPR120, NLRP3, and caspase-1 expression in ovaries, and immunohistochemistry was used to evaluate LKB1 and AMPK protein expression. LrB reduced body weight, Lee's index, ovarian index, ovarian area, and volume in PCOS-IR rats. It lowered fasting blood glucose, serum insulin, and HOMA-IR. LrB decreased total serum cholesterol, triglyceride, and LDL levels and increased HDL levels. It reduced serum T, LH, and LH/FSH and raised serum E2 and FSH levels. LrB downregulated the mRNA and protein expression levels of NLRP3 and Caspase-1, increased the protein and mRNA expression levels of GPR120 in rat ovaries, and increased LKB1 and AMPK protein expression in ovaries, ameliorating ovarian histopathological changes in PCOS-IR rats. Taken together, LrB upregulated GPR120, LKB1, and AMPK protein expression, downregulated NLRP3 and Caspase-1 protein expression, reduced insulin resistance and chronic inflammation, and ameliorated histopathological changes in ovarian tissues in PCOS rats, suggesting its potential as a treatment for PCOS.

Non-traditional lipid profiles and the risk of stroke: A systematic review and meta-analysis.

AIMS: An increasing number of studies on non-traditional lipid profiles have been investigated in recent years. However, the associations between non-traditional lipid profiles and the risk of stroke remained inconsistent. Therefore, this meta-analysis aimed to evaluate the associations between non-traditional lipid profiles and the risk of stroke and clarify the dose-response relations. DATA SYNTHESIS: We performed a systematic literature search in PubMed, Embase, and Web of Science databases until 1 November 2022 for relevant studies. Relative risks and 95% confidence intervals were pooled by random-effects or fixed-effects models. A total of 26 full-text studies with 676678 participants and 18057 stroke cases were eligible for the final study. We found a positive association between the risk of stroke and total cholesterol to high-density lipoprotein cholesterol (TC/HDL-C) ratio (RR = 1.19,95%CI = 1.00-1.40, I2 = 74.6%), triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio (RR = 1.24,95%CI = 1.10-1.41, I2 = 62.8%) or low-density lipoprotein cholesterol to high-density lipoprotein cholesterol (LDL-C/HDL-C) ratio (RR = 1.24, 95%CI = 1.11-1.39, I2 = 49.4%). When focusing on the stroke subtype, a more significant association was observed between the risk of ischemic stroke and four non-traditional lipid profiles. In dose-response analysis, we found a linear association between TC/HDL-C ratio and the risk of stroke (RR = 1.16,95%CI = 1.07-1.26). CONCLUSIONS: Elevated non-traditional lipid profiles were associated with an increased risk of ischemic stroke. The linear association showed the risk of stroke increased by 16% when the pooled RR of TC/HDL-C ratio per 1-unit increased. REGISTRATION NUMBER IN PROSPERO: CRD42022321251.

To validate the integral conceptual model of frailty among community-dwelling older adults in China: a cross-sectional study.

PURPOSE: The integral conceptual model of frailty (ICFM) integrates physical, psychological, social aspects of individuals and stresses that frailty is a dynamic state evolving over time. This study aimed to validate the ICMF among community-dwelling older adults in China. METHODS: The study recruited 341 older community-dwelling adults by convenient sampling method between June 1 and August 30, 2019 in Hubei province, China. The data was collected by questionnaire-based survey. Frailty was assessed by the Chinese version of the Tilburg Frailty Index. Participants were assessed for life-course determinants, disease and adverse health outcomes. Hierarchical regression analyses, Bootstrap method and the structural equation model were conducted in data analysis. RESULTS: Both linear and logistic hierarchical regression models were statistically significant. Life-course determinants, disease, and three domains of frailty together explained 35.6% to 50.6% of the variance of disability and all domains of quality of life. The mediation effect of frailty between disease and all adverse outcomes was significant, excluding hospitalization. The structural equation model guided by the ICMF fits the data well. CONCLUSIONS: The ICMF is valid among community-dwelling older adults in China. Therefore, the multidimensional concept of frailty should be widely used in Chinese communities.

Sedentary behavior and the risk of stroke: A systematic review and dose-response meta-analysis.

BACKGROUND AND AIMS: The sedentary behavior in people's daily life has continued to increase in recent years, causing many studies to focus on its relationship with diseases. Several studies have shown that sedentary behavior is an independent risk factor for cardiovascular disease and metabolic disease. Therefore, we performed a meta-analysis to assess the association between sedentary behavior and the risk of stroke. METHODS AND RESULTS: Two independent investigators searched for prospective cohort studies on the association between sedentary behavior and stroke risk, published before February 2022. We pooled adjusted effect size and performed the dose-response analysis by random-effect model. Seven studies with 677,614 participants and 15,135 stroke events during a median follow-up of 12.2 years were included. The pooled hazard ratio (HR) of stroke was 1.16 (95% confidence interval [CI]: 1.09-1.24) with no significant heterogeneity (I2 = 0.0%, p for heterogeneity = 0.983). In dose-response analysis, a nonlinear association between sedentary behavior and stroke risk was discovered. Stroke risk began to increase when sedentary time exceeded 3.7 h/d (HR, 1.01; 95% CI, 0.97-1.05). And when reached 11 h/d, a significantly increased risk of stroke was observed (HR, 1.21; 95% CI 1.12-1.31). CONCLUSION: A nonlinear association was found in the dose-response analysis, with increased risk only when sedentary time exceeded a certain level. Further research is needed to explain the biological mechanisms by which sedentary time above a certain threshold significantly increases stroke risk. (PROSPERO registration number: CRD42022311544).

Errate: Promoting Role of Long Non-Coding RNA Small Nucleolar RNA Host Gene 15 (SNHG15) in Neuronal Injury Following Ischemic Stroke via the MicroRNA-18a/CXC Chemokine Ligand 13 (CXCL13)/ERK/MEK Axis.

The figure 3D was published as figure 3E. The correct figure 3E is provided below. Reference: Tiezhu Guo, Yueting Liu, Xinliang Ren, Wei Wang, Hanrui Liu. Promoting Role of Long Non-Coding RNA Small Nucleolar RNA Host Gene 15 (SNHG15) in Neuronal Injury Following Ischemic Stroke via the MicroRNA-18a/CXC Chemokine Ligand 13 (CXCL13)/ERK/MEK Axis. Med Sci Monit 2020; 26:e923610; DOI: 10.12659/MSM.923610.

Association of insomnia and multidimensional frailty in community-dwelling older adults: A cross-sectional survey.

OBJECTIVE: To evaluate the relationship between insomnia and multidimensional frailty. BACKGROUND: Frailty has major implications on adverse health outcomes of older adults. In recent years, multidimensional nature of frailty has been increasingly recognised. Many frail older adults also suffer from insomnia. METHODS: This was a cross-sectional observational study including 454 community-dwelling adults aged 60 and older. Insomnia was defined as a subjective experience of inadequate sleep duration or quality that affects social functioning during the day, based on the Athens Insomnia Scale (AIS), and multidimensional frailty was based on Tilburg Frailty Indicator (TFI). The STROBE checklist was used to guide the submission. RESULTS: Mean age was 69.1 years old, 211 (46.5%) of participants suffered from insomnia, and 185 (40.7%) of participants were frail. There was a significant relationship between insomnia and multidimensional frailty (physical, psychological and social dimensions). Insomnia was associated with frailty, adjusting for sociodemographic characteristics and comorbidity OR of 6.863 (95% CI: 4.237-11.116). CONCLUSION: Frailty was independently predicted by insomnia. Future researches should determine whether there is a causal relationship between insomnia and multidimensional frailty, with the ultimate goal of providing interventions to reverse or prevent frailty. RELEVANCE TO CLINICAL PRACTICE: This study emphasises the importance of assessment and treatment of insomnia, potentially contributing to the reversion and prevention of frailty in community-dwelling older adults.

Parameters Indicating Development of Influenza-Associated Acute Necrotizing Encephalopathy: Experiences from a Single Center.

BACKGROUND Influenza-associated acute necrotizing encephalopathy (IANE) can be lethal and disabling and have a sudden onset and deteriorate rapidly but lacks early diagnostic indicators. We aimed to examine the early clinical diagnostic indicators in children with IANE. MATERIAL AND METHODS Acute influenza patients were grouped according to their clinical manifestations: flu alone (FA), flu with febrile seizure (FS), influenza-associated encephalopathy (IAE), and IANE. The clinical features, biomarkers, neuroelectrophysiological results, and neuroimaging examination results were compared. RESULTS A total of 31 patients were included (FA (n=4), FS (n=8), IAE (n=14), and IANE (n=5)). The IANE group, whose mean age was 3.7 years, was more likely to show rapid-onset seizure, acute disturbance of consciousness (ADOC), Babinski's sign, and death/sequela. More patients in the IANE group required tracheal intubation mechanical ventilation and received intravenous immunoglobulins (IVIG) and glucocorticoids. The alanine aminotransferase (ALT), aspartate transaminase (AST), and lactate dehydrogenase (LDH) levels in the IANE group were significantly higher than in the FS and IAE groups. The aquaporin-4 (AQP-4) antibody and malondialdehyde (MDA) levels in the serum and cerebrospinal fluid (CSF) were notably higher in IANE patients in the acute stage compared with FS and IAE patients. All patients in the IANE group had positive neuroimaging findings. CONCLUSIONS Early clinical warning factors for IANE include rapid-onset seizures in patients under 4 years of age, ADOC, and pathological signs. Increased AQP-4 antibodies and MDA levels in CSF might contribute to early diagnosis. Early magnetic resonance venography (MRV) and susceptibility-weighted imaging (SWI) sequences, or thrombelastography to identify deep vein thrombosis, might indicate clinical deterioration.

Tumor-associated macrophage interleukin-ß promotes glycerol-3-phosphate dehydrogenase activation, glycolysis and tumorigenesis in glioma cells.

Tumor-immune crosstalk within the tumor microenvironment (TME) occurs at all stages of tumorigenesis. Tumor-associated M2 macrophages play a central role in tumor development, but the molecular underpinnings have not been fully elucidated. We demonstrated that M2 macrophages produce interleukin 1ß (IL-1ß), which activates phosphorylation of the glycolytic enzyme glycerol-3-phosphate dehydrogenase (GPD2) at threonine 10 (GPD2 pT10) through phosphatidylinositol-3-kinase-mediated activation of protein kinase-delta (PKCδ) in glioma cells. GPD2 pT10 enhanced its substrate affinity and increased the catalytic rate of glycolysis in glioma cells. Inhibiting PKCδ or GPD2 pT10 in glioma cells or blocking IL-1ß generated by macrophages attenuated the glycolytic rate and proliferation of glioma cells. Furthermore, human glioblastoma tumor GPD2 pT10 levels were positively correlated with tumor p-PKCδ and IL-1ß levels as well as intratumoral macrophage recruitment, tumor grade and human glioblastoma patient survival. These results reveal a novel tumorigenic role for M2 macrophages in the TME. In addition, these findings suggest possible treatment strategies for glioma patients through blockade of cytokine crosstalk between M2 macrophages and glioma cells.

Promoting Role of Long Non-Coding RNA Small Nucleolar RNA Host Gene 15 (SNHG15) in Neuronal Injury Following Ischemic Stroke via the MicroRNA-18a/CXC Chemokine Ligand 13 (CXCL13)/ERK/MEK Axis.

BACKGROUND Long-non-coding RNA (lncRNA) SNHG15 has been reported to be an aberrantly expressed lncRNA in patients with ischemic stroke, but its role in neuronal injury following ischemic stroke remains unclear. We hypothesized that this lncRNA is associated with the pathogenesis of ischemic stroke. MATERIAL AND METHODS A mouse model of ischemic stroke was established by middle cerebral artery occlusion (MCAO). A neurogenic mouse cell line Neuro-2a (N2a) was subjected to oxygen-glucose deprivation (OGD) for in vitro experiments. Expression of SNHG15, microRNA-18a (miR-18a), and CXCL13 in mouse brain and in OGD-treated N2a cells was determined. Altered expression of SNHG15 and miR-18a was introduced to detect their roles in N2a cell viability and apoptosis. Targeting relationships between miR-18a and SNHG15 or CXCL13 were validated by luciferase assays. Cells were treated with the ERK/MEK antagonist U0126 to assess the role of the ERK/MEK signaling pathway in N2a cell growth. RESULTS SNHG15 and CXCL13 were overexpressed and miR-18a was underexpressed in MCAO-induced mice and OGD-treated N2a cells. Silencing of SNHG15 or overexpression of miR-18a promoted cell viability, while decreased cell apoptosis induced by OGD; however, subsequent disruption of the ERK/MEK signaling pathway reversed these effects. SNHG15 was found to bind to miR-18a, which could further target CXCL13. CONCLUSIONS Silencing of SNHG15 led to CXCL13 upregulation through sequestering miR-18a and the following ERK/MEK activation, thus enhancing viability while reducing apoptosis of N2a cells. SNHG15 may serve as a novel target for ischemic stroke treatment.

Psychometric properties of a Chinese version of the Fraboni scale of ageism: evidence from medical students sample.

BACKGROUND: The increasing of older adults has led to enormous demand for medical care. However, as a group with unique needs and characteristics, older adults are often discriminated against in the medical field. In this paper, we aimed to translate the Fraboni Scale of Ageism (FSA) into Chinese and examine its construct validity, content validity, and reliability in Chinese mainland medical students. In order to evaluate the prevalence of ageism in Chinese medical students and prompt medical college to adopt necessary teaching methods to mitigate ageism in medical students. METHODS: By Brislin's translation guidelines, FSA was translated to Chinese. The convenient sampling method was used to select samples for this survey, including 1,974 students from two medical schools in central and north China. Construct validity was verified by the exploratory and confirmatory factor analysis. The content validity index (CVI) was used to assess content validity. The Cronbach's alpha coefficients and intraclass correlation coefficient (ICC) were used to estimate reliability. RESULTS: The alpha coefficients for FSA (Chinese version) was 0.81 and ICC was 0.87. The CVI was 0.93. Three factors were identified by exploratory factor analysis explaining 34.84% of the total variance and a three-factor model was confirmed to fit by confirmatory factor analysis. CONCLUSIONS: FSA (Chinese version) is a reliable and valid scale for measuring discrimination degree against older adults in Chinese medical students.

MiR-9 Regulates the Expression of BACE1 in Dementia Induced by Chronic Brain Hypoperfusion in Rats.

BACKGROUND/AIMS: MicroRNA-9 (miR-9) plays important roles in nervous system diseases such as glioblastoma and neurodegenerative disorders. However, how miR-9 contributes to dementia requires further study. In this study, we evaluated the role of miR-9 in dementia and the molecular mechanisms underlying its effects. METHODS: A rat model of dementia was created by occlusion of the bilateral common carotid artery (2VO) for 8 weeks. Learning and memory were assessed using the Morris Water Maze (MWM). MicroRNA expression profiling was performed according to a protocol provided by LC Sciences, and quantitative real-time PCR (qRT-PCR) was used to detect the level of miR-9. Transmission electron microscopy (TEM) and hematoxylin-eosin (HE) staining were used to assess pathological changes in brain tissue. Western blot and immunofluorescence were employed to detect the expression of ß-site APP cleaving enzyme 1 (BACE1) and c-AMP response element-binding protein (CREB). RESULTS: Learning and memory were significantly impaired in 2VO rats, and these changes were accompanied by neuronal loss and glial activation in brain tissues. miR-9 was greatly upregulated in both the hippocampus and cortex of rats following 2VO. Knockdown of endogenous miR-9 via lentiviral vector-mediated delivery of its antisense molecule (lenti-pre-AMO-miR-9) reduced the vulnerability to dementia, reversed the increase in BACE1 expression, and ameliorated the reduction in CREB expression triggered by 2VO. BACE1 protein levels were significantly increased, but CREB protein levels were significantly decreased in the presence of miR-9 in cultured neonatal rat neurons (NRNs). AMO-miR-9 rescued the upregulation of BACE1 and downregulation of CREB elicited by miR-9 in rats. Dual luciferase assay experiments showed that overexpression of miR-9 inhibited the expression of CREB by targeting its 3'UTR domain. CREB protein was downregulated by miR-9 overexpression which was reversed by miR-9 inhibition in cultured NRNs. TEM imaging showed that miR-9 caused damage to NRNs, which was reversed by addition of AMO-miR-9. CONCLUSION: We conclude that miR-9 plays an important role in regulating the process of dementia induced by 2VO in rats by increasing BACE1 expression via downregulation of CREB.

Combined Blockade of T Cell Immunoglobulin and Mucin Domain 3 and Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 Results in Durable Therapeutic Efficacy in Mice with Intracranial Gliomas.

BACKGROUND Glioblastoma multiforme (GBM) evades immune surveillance by inducing immunosuppression via receptor-ligand interactions between immune checkpoint molecules. T cell immunoglobulin and mucin domain 3 (Tim-3) is a key checkpoint receptor responsible for exhaustion and dysfunction of T cells and plays a critical role in immunosuppression. Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) has been recently identified as a heterophilic ligand for Tim-3. MATERIAL AND METHODS We established an intracranial GBM model using C57BL/6 mice and GL261 cells, and treated the mice with single or combined monoclonal antibodies (mAbs) against Tim-3/CEACAM1. The CD4+, CD8+, and regulatory T cells in brain-infiltrating lymphocytes were analyzed using flow cytometry, and the effector function of T cells was assessed using ELISA. We performed a rechallenge by subcutaneous injection of GL261 cells in the "cured" (>90 days post-orthotopic tumor implantation) and naïve mice. RESULTS The mean survival time in the control, anti-Tim-3, anti-CEACAM1, and combined treatment groups was 29.8, 43.4, 42.3, and 86.0 days, respectively, with 80% of the mice in the combined group becoming long-term survivors showing immune memory against glioma cells. Infiltrating CD4+ and CD8+ T cells increased and immunosuppressive Tregs decreased with the combined therapy, which resulted in a markedly elevated ratio of CD4+ and CD8+ cells to Tregs. Additionally, plasma IFN-γ and TGF-ß levels were upregulated and downregulated, respectively. CONCLUSIONS Our data indicate that combined blockade of Tim-3 and CEACAM1 generates robust therapeutic efficacy in mice with intracranial tumors, and provides a promising option for GBM immunotherapy.

"Off-on" electrochemiluminescence system for sensitive detection of ATP via target-induced structure switching.

An "off-on" electrochemiluminescence (ECL) strategy was constructed for highly sensitive and selective detection of adenosine 5'-triphosphate (ATP) with a quantum dots (QDs) modified electrode and a DNAzyme signal probe. The immobilized QDs were functionalized with a DNA sequence (DNA1) and then aptamer for recognition of target analyte. The signal probe was prepared by assembling another DNA sequence (DNA2) and G-quadruplex on gold nanoparticle via Au-S chemistry, which was used to bind the probe to electrode surface through a hybridization reaction with aptamer and hemin for forming G-quadruplex/hemin DNAzyme, respectively. Upon the sandwich hybridization of DNA1-aptamer-DNA2, the signal probe could be captured on the aptasensor to catalyze the reduction of dissolved oxygen, the coreactant for cathodic ECL emission of QDs, leading to a decrease of ECL intensity and thus the "off" state. In the presence of target, its recognition by aptamer led to the release of aptamer from electrode surface and decreased the amount of captured signal probe, thus the ECL emission was in its "on" state. The "off-on" strategy resulted from the target-induced structure switching could be used for specific detection of ATP with a linear range of 8-2000 nM and a detection limit of 7.6 nM. The proposed aptasensor could be successfully applied in the ECL detection of ATP in human serum. This method could resist environmental interfering agents and be extended for sensitive and reliable detection of a wide range of analytes in complex sample.

[Multi Scenario Carbon Peak Prediction and Emission Reduction Path Analysis of Xi'an Hi-tech Zone].

The fifth session of the 13th National People's Congress proposed to be committed to promoting carbon peaking and carbon neutrality, promoting the comprehensive green and low-carbon transformation of the economy and society and achieving high-quality development. As an important scientific and technological innovation and industrial cluster in Shaanxi Province, the economic development of the Xi'an Hi-tech Zone largely relies on energy consumption, making the task of carbon reduction particularly challenging. Firstly, taking the Xi'an Hi-tech Zone as the research object, through systematic accounting of carbon emissions within the park, we analyzed the current carbon emission status of enterprises in different energy types and industries. Then, using the Kaya model, multiple independent carbon peak scenarios were set up to predict the total carbon emissions and peak time under different scenarios. Finally, based on the development characteristics of the Xi'an Hi-tech Zone, we scientifically selected corresponding carbon emission reduction paths and provided reasonable emission reduction suggestions. The results showed that the proportion of carbon emissions consumed by electricity was currently the highest, and the share was increasing yearly. Industrial carbon emissions had always been dominant, and the development of the tertiary industry was becoming increasingly prosperous. In the scenario prediction, the carbon emission factor scenario, energy intensity scenario, and economic level scenario could reach the carbon peak by 2030. Among them, the economic development level had the greatest impact on the peak and time of the future carbon peak in the Xi'an Hi-tech Zone, whereas the industrial structure scenario, energy source structure scenario, and population size scenario had no peak before 2030. The future emission reduction path mainly started from decarbonization of the power sector, stable and high-quality economic development, green upgrading of energy and industrial structure, and building a green transportation system. This can reserve more preparation time for achieving carbon neutrality and provide decision-making reference for the low-carbon development of industrial parks in China.

Differential Bioactivation Profiles of Different GS-441524 Prodrugs in Cell and Mouse Models: ProTide Prodrugs with High Cell Permeability and Susceptibility to Cathepsin A Are More Efficient in Delivering Antiviral Active Metabolites to the Lung.

We assessed factors that determine the tissue-specific bioactivation of ProTide prodrugs by comparing the disposition and activation of remdesivir (RDV), its methylpropyl and isopropyl ester analogues (MeRDV and IsoRDV, respectively), the oral prodrug GS-621763, and the parent nucleotide GS-441524 (Nuc). RDV and MeRDV yielded more active metabolite remdesivir-triphosphate (RDV-TP) than IsoRDV, GS-621763, and Nuc in human lung cell models due to superior cell permeability and higher susceptivity to cathepsin A. Intravenous administration to mice showed that RDV and MeRDV delivered significantly more RDV-TP to the lung than other compounds. Nevertheless, all four ester prodrugs exhibited very low oral bioavailability (<2%), with Nuc being the predominant metabolite in blood. In conclusion, ProTides prodrugs, such as RDV and MeRDV, are more efficient in delivering active metabolites to the lung than Nuc, driven by high cell permeability and susceptivity to cathepsin A. Optimizing ProTides' ester structures is an effective strategy for enhancing prodrug activation in the lung.

Assessing heterogeneity of patient and health system delay among TB in a population with internal migrants in China.

Backgrounds: The diagnostic delay of tuberculosis (TB) contributes to further transmission and impedes the implementation of the End TB Strategy. Therefore, we aimed to describe the characteristics of patient delay, health system delay, and total delay among TB patients in Shanghai, identify areas at high risk for delay, and explore the potential factors of long delay at individual and spatial levels. Method: The study included TB patients among migrants and residents in Shanghai between January 2010 and December 2018. Patient and health system delays exceeding 14 days and total delays exceeding 28 days were defined as long delays. Time trends of long delays were evaluated by Joinpoint regression. Multivariable logistic regression analysis was employed to analyze influencing factors of long delays. Spatial analysis of delays was conducted using ArcGIS, and the hierarchical Bayesian spatial model was utilized to explore associated spatial factors. Results: Overall, 61,050 TB patients were notified during the study period. Median patient, health system, and total delays were 12 days (IQR: 3-26), 9 days (IQR: 4-18), and 27 days (IQR: 15-43), respectively. Migrants, females, older adults, symptomatic visits to TB-designated facilities, and pathogen-positive were associated with longer patient delays, while pathogen-negative, active case findings and symptomatic visits to non-TB-designated facilities were associated with long health system delays (LHD). Spatial analysis revealed Chongming Island was a hotspot for patient delay, while western areas of Shanghai, with a high proportion of internal migrants and industrial parks, were at high risk for LHD. The application of rapid molecular diagnostic methods was associated with reduced health system delays. Conclusion: Despite a relatively shorter diagnostic delay of TB than in the other regions in China, there was vital social-demographic and spatial heterogeneity in the occurrence of long delays in Shanghai. While the active case finding and rapid molecular diagnosis reduced the delay, novel targeted interventions are still required to address the challenges of TB diagnosis among both migrants and residents in this urban setting.

Corrigendum: Assessing heterogeneity of patient and health system delay among TB in a population with internal migrants in China.

[This corrects the article DOI: 10.3389/fpubh.2024.1354515.].

Spatial pattern of isoniazid-resistant tuberculosis and its associated factors among a population with migrants in China: a retrospective population-based study.

Background: Isoniazid-resistant, rifampicin-susceptible tuberculosis (Hr-TB) globally exhibits a high prevalence and serves as a potential precursor to multidrug-resistant tuberculosis (MDR-TB). Recognizing the spatial distribution of Hr-TB and identifying associated factors can provide strategic entry points for interventions aimed at early detection of Hr-TB and prevention of its progression to MDR-TB. This study aims to analyze spatial patterns and identify socioeconomic, demographic, and healthcare factors associated with Hr-TB in Shanghai at the county level. Method: We conducted a retrospective study utilizing data from TB patients with available Drug Susceptible Test (DST) results in Shanghai from 2010 to 2016. Spatial autocorrelation was explored using Global Moran's I and Getis-Ord Gi∗ statistics. A Bayesian hierarchical model with spatial effects was developed using the INLA package in R software to identify potential factors associated with Hr-TB at the county level. Results: A total of 8,865 TB patients with DST were included in this analysis. Among 758 Hr-TB patients, 622 (82.06%) were new cases without any previous treatment history. The drug-resistant rate of Hr-TB among new TB cases in Shanghai stood at 7.20% (622/8014), while for previously treated cases, the rate was 15.98% (136/851). Hotspot areas of Hr-TB were predominantly situated in southwestern Shanghai. Factors positively associated with Hr-TB included the percentage of older adult individuals (RR = 3.93, 95% Crl:1.93-8.03), the percentage of internal migrants (RR = 1.35, 95% Crl:1.15-1.35), and the number of healthcare institutions per 100 population (RR = 1.17, 95% Crl:1.02-1.34). Conclusion: We observed a spatial heterogeneity of Hr-TB in Shanghai, with hotspots in the Songjiang and Minhang districts. Based on the results of the models, the internal migrant population and older adult individuals in Shanghai may be contributing factors to the emergence of areas with high Hr-TB notification rates. Given these insights, we advocate for targeted interventions, especially in identified high-risk hotspots and high-risk areas.

Stepwise chemical reaction strategy for highly sensitive electrochemiluminescent detection of dopamine.

A stepwise chemical reaction strategy based on the specific recognition of boronic acid to diol, and N-hydroxysuccinimide (NHS) ester to amine group, was designed to construct a "signal on" electrochemiluminescence (ECL) platform for highly sensitive detection of dopamine. A boronic acid-functionalized pyrene probe was synthesized and was self-assembled on the sidewalls of carbon nanotubes via π-π stacking interactions as capture probes on a glassy carbon electrode. Meanwhile, 3,3'-dithiodipropionic acid di(N-hydroxysuccinimide ester) (DSP)-functionalized CdTe quantum dots (QDs) were designed as signal probes and characterized with transmission electron microscopy and spectroscopic techniques. Upon stepwise chemical reaction of dopamine with boronic acid and then DSP-QDs, the QDs were captured on the electrode as ECL emitters for signal readout, leading to an ultralow background signal. By using O2 as an endogenous coreactant, the "signal on" ECL method was employed to quantify the concentration of dopamine from 50 pM to 10 nM with a detection limit of 26 pM. Moreover, the stepwise chemical reaction-based biosensor showed high specificity against cerebral interference and was successfully applied in the detection of dopamine in cerebrospinal fluid samples. The stepwise chemical reaction strategy should be a new concept for the design of highly selective analytical methods for the detection of small biomolecules.