P3MOT-decorated metal-porphyrin-based zirconium-MOF for the efficient electrochemical detection of 4-nitrobenzaldehyde.

A novel hybrid composite integrating conductive poly-3-methoxythiophene and PCN-222(Fe) (porphyrin-metal-organic frameworks) was synthesized using an in situ polymerization strategy. Leveraging the large specific area of MOFs and the low electrical resistance of conductive polymers, the modified electrode proved to be a promising candidate for the electrochemical detection of 4-nitrobenzaldehyde. The electrocatalytic response was measured using differential pulse voltammetry techniques and cyclic voltammetry, where the linear concentration range of analyte detection was estimated to be 0-900 µM and the detection limit was 0.233 µM with high selectivity toward the analyte. The sensor demonstrated repeatability and stability, allowing the direct electroanalytical measurement of 4-nitrobenzaldehyde in real samples with reliable recovery. This methodology expands the application of porphyrin MOFs for the electroanalytical sensing of environmental contaminants.

Sequential removal of phosphate and copper(II) ions using sustainable chitosan biosorbent.

Although adsorbents are good candidates for removing phosphorus and heavy metals from wastewater, the use of biosorbents for the sequential treatment of phosphorus and copper has not yet been studied. Porous chitosan (CS)-based biosorbents (CGBs) were developed to adsorb phytic acid (PA), a major form of organic phosphate. This first adsorbate (PA) further served as an additional ligand (P-type ligand) for the CGBs (N-type ligand) to form a complex with the second adsorbate (copper). After the adsorption of PA (the first adsorbate), the spent CGBs were recycled and used as a new adsorbent to adsorb Cu(II) ions (the second adsorbate), which was expected to have a dual coordination effect through P, N-ligand complexation with copper. The interactions and complexation between CS, PA and Cu(II) ions on the PA-adsorbed CGBs (PACGBs) were investigated by performing FTIR, XPS, XRD, and SEM-EDS analyses. The PACGBs exhibited fast and enhanced adsorption of Cu(II) ions, owing to the synergistic effect of the amino groups of CS (the original ligand, N-type) and the phosphate groups of PA (an additional ligand, P-type) on the adsorption of Cu(II) ions. This is the first time that sequential removal of phosphorus and heavy metals by biosorbents has been performed using biosorbents.

Is income catch-up related to happiness catch-up? Evidence from eight European countries.

The Easterlin paradox illuminates the counter-intuitive finding that happiness is unlikely to increase with economic growth over time. This study investigates the income-happiness relationship through the concept of ß convergence (i.e., the catch-up effect). To this end, we first employed the KPSS panel unit root tests to reveal the time-varying patterns in convergences between the happiness index and real GDP per capita. Then, we conducted analyses of contingency for the linkage between the happiness catch-up and income catch-up effects via estimation using the random coefficient logit model. The data used in this study were obtained from World Database of Happiness and World Development Indicators Database. Our results indicate that both the happiness index and real GDP per capita in selected European countries exhibited signs of catch-up with their benchmark countries over the period of 1975-2020. The average income catch-up effect (generated from group mean of all individual effects) positively impacted the social harmonization of well-being (i.e., the average happiness catch-up effect). Since economic growth is the major force driving the income catch-up effect, the positive linkage between happiness and income catch-up effects provides solid proof of the beneficial effect of economic growth on the social harmonization of well-being.

On the Asymmetric Relationship Between Physician Mental Health Disorders on Quality of Healthcare Under the COVID-19 Pandemic in Taiwan: Quantile on Quantile Regression Analyses.

Purpose: When examining the nexus of physician mental health disorders and healthcare quality from the empirical perspective, mental health disorders are frequently associated with cyclical patterns corresponding to cyclic seasonality, mood swings, emission of air pollution and business cycles, the potential asymmetric effects of physician mental health disorders on healthcare quality have not received adequate attention from researchers. Therefore, the purpose of this study is to explore the asymmetric relationship between physician mental health disorders and healthcare quality during the pandemic outbreak in Taiwan. Methods: Daily data for care quality indicators and physician mental health disorders were collected from the National Insurance Research Database in Taiwan, and the quantile-on-quantile regression model was applied to proceed with our analyses. Results: Our results indicated that the overall aggregate effects of each quantile of physician mental health disorders on the cumulative quantiles of healthcare quality are negative (positive) for the 14-day readmission rate (preventable hospitalization rate and non-urgent ED-visit rate). Positively (negatively) cumulative effects of each quantile of physician mental health disorders were detected in the middle (low and high) quantiles of the preventable hospitalization rate. The cumulative effects of each quantile of physician mental health disorders on the high (low and middle) quantiles of the 14-day readmission rate are negative (positive), but the cumulative effects on various quantiles of the non-urgent ED-visit rate exhibit the opposite pattern. Conclusion: The observed variation in the relationship between physician mental health disorders and different quantiles of healthcare quality suggests the need for tailored strategic interventions based on distinct levels of healthcare quality when addressing the higher risk of physician mental health disorders during the pandemic outbreak conditions.

Development of FAP-Targeted Chimeric Antigen Receptor NK-92 Cells for Non-Small Cell Lung Cancer.

OBJECTIVES: Over the past two decades, great progress has been made in advancing the early detection and multimodal treatment of non-small cell lung cancer (NSCLC). However, overall cure rates and survival rates of NSCLC are still not satisfactory, and research into new therapies is needed. This study attempted to construct human Fibroblast Activation Protein-Chimeric Antigen Receptor Natural killer (NK)-92 cells (hFAP-CAR-NK-92 cells) and explore their potential therapeutic effects in NSCLC. METHODS: Immunohistochemistry analysis was carried out to examine fibroblast activation protein (FAP) and Gasdermin E (GSDME) expression in clinical specimens of lung adenocarcinoma and squamous cell carcinoma tissue. Then the engineered hFAP-CAR-NK-92 cells efficiency was determined in vitro with lactate dehydrogenase (LDH) cytotoxicity assay and the cell morphology of A549, H226, and cancer-related fibroblast (CAF) was observed by electron microscopy. After the co-culture of target cells and effect cells, flow cytometry was employed for examining the CD107a expression in the effect cells, and western blotting was conducted for the cleavage levels of Caspase 3 and GSDME proteins in the target cells. The safety and efficacy of hFAP-CAR-NK-92 cells adoptive transfer immunotherapy in a tumor-bearing mouse were evaluated. RESULTS: Clinical studies have shown FAP positivity in patients with NSCLC. Compared with A549 or H226 cells alone, FAP expression was notably raised in A549+CAF cells or H226+CAF cells in nude mice, respectively (p < 0.05). The killing efficiency of K562 cells was not significantly different between hFAP-CAR-NK-92 and NK-92 cells (p > 0.05). The hFAP-CAR-NK-92 cells presented a higher killing efficiency against the hFAP-target (A549-hFAP, H226-hFAP and CAF-hFAP) cells than the NK-92 cells (p < 0.05). The degranulation of CD107a and cleavage levels of GSDME and Caspase 3 protein in the hFAP-CAR-NK-92 group were higher than those in the NK-92 group (p < 0.05). The 300 nM Granzyme B also induced pyroptosis in hFAP- or GSDME-positive cells (p < 0.05). In vivo experiments revealed that hFAP-CAR-NK-92 cells inhibited tumor progression of hFAP-positive NSCLC (p < 0.05). CONCLUSIONS: In this study, we successfully constructed hFAP-CAR-NK-92 cells and confirmed that hFAP-CAR-NK-92 cells could target hFAP-positive NSCLC to inhibit the progression of NSCLC by activating the Caspase-3/GSDME pyroptosis pathway.

A Cu-functionalized MOF and multi-walled carbon nanotube composite modified electrode for the simultaneous determination of hydroquinone and catechol.

Designing MOF-based materials with desired electrochemical activity and high electron conductivity may yield a novel electrochemical sensor that effectively detects various organic pollutants and conducts health monitoring. This study developed a facile and versatile electrochemical sensor for simultaneously monitoring the environmental pollutants hydroquinone (HQ) and catechol (CT). The electrodes are fabricated by modifying a GCE with a Cu-functionalized MOF (UiO-bpydc-Cu) and multi-walled carbon nanotubes (MWCNTs). The Cu-functionalized MOF effectively improved the electronic conductivity by metalating the 2,2'-bipyridyl-derived UiO-bpydc with Cu2+ ions. Moreover, due to the synergic effect, the composite electrode exhibits a significant voltammetric response to HQ's and CT's electro-redox. A rapid and sensitive method of synchronously detecting HQ and CT has been established by differential pulse voltammetry (DPV). The experiments reveal that the linear response ranges were 0.5-565 µM and 1-1350 µM for HQ and CT, respectively, with low detection limits of 0.361 µM and 0.245 µM. The proposed UiO-bpydc-Cu/MWCNTs/GCE electrochemical sensor shows high sensitivity, good anti-interference, reproducibility, and stability. It can also be applied for detecting HQ and CT in actual samples.

Effect of light-emitting diodes with different color rendering indexes on the ocular tissues of rat.

AIM: To compare the damage of light-emitting diodes (LEDs) with different color rendering indexes (CRIs) to the ocular surface and retina of rats. METHODS: Totally 20 Sprague-Dawley (SD) rats were randomly divided into four groups: the first group was normal control group without any intervention, other three groups were exposed by LEDs with low (LED-L), medium (LED-M), and high (LED-H) CRI respectively for 12h a day, continuously for 4wk. The changes in tear secretion (Schirmer I test, SIt), tear film break-up time (BUT), and corneal fluorescein sodium staining (CFS) scores were compared at different times (1d before experiment, 2 and 4wk after the experiment). The histopathological changes of rat lacrimal gland and retina were observed at 4wk, and the expressions of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in lacrimal gland were detected by immunofluorescence method. RESULTS: With the increase of light exposed time, the CFS value of each light exposed group continued to increase, and the BUT and SIt scores continued to decrease, which were different from the control group, and the differences between the light exposed groups were statistically significant. Hematoxylin-eosin (HE) results showed that the lacrimal glands of each exposed group were seen varying degrees of acinar atrophy, vacuole distribution, increasing of eosinophil granules, etc.; the retina showed obvious reduction of photoreceptor cell layer and changes in retinal thickness; LED-L group has the most significant change in all tests. Immunofluorescence suggested that the positive expressions of TNF-α and IL-6 in the lacrimal glands of each exposed group were higher than those of the control group. CONCLUSION: LED exposure for 4wk can cause the pathological changes of lacrimal gland and retina of rats, and increase the expression of TNF-α and IL-6 in lacrimal gland, the degree of damage is negatively correlated with the CRI.

The Effect of a Tele-Health Intervention Program on Home-Dwelling Persons with Dementia or MCI and on Their Primary Caregivers during the Stay-at-Home-Order Period in the COVID-19 Pandemic Outbreak: Evidence from Taiwan.

BACKGROUND: The Taiwanese government implemented a stay-at-home order that restricted all community-based health promotion activities for the elderly by shutting down all community care centers from May 2021 to August 2021 to control the spread of COVID-19. Community-based dementia care centers were barely able to provide dementia care services during that period. METHODS: The data used in this study were collected from a community-based dementia care center that was able to continue their dementia care services through a Tele-Health intervention program. The difference-in-differences methodology was applied to evaluate the effects of the Tele-Health intervention program on home-dwelling persons with dementia or mild cognitive impairment and on their primary caregivers during the COVID-19 pandemic. RESULTS: The Tele-Health intervention program significantly increased the well-being of the participants and their primary caregivers, but the negative correlations between the Tele-Health intervention program and family functioning were also found to be significant. CONCLUSIONS: The significant substitution (negative) effects between the Tele-Health intervention program and family functioning raises the concern that promotion of the Tele-Health intervention program comes at the potential cost of a loss of family functioning. Policymakers should be cautious when considering the Tele-Health intervention program in response to pandemics and demographic transitions.

Deep Phenotyping and Prediction of Long-term Cardiovascular Disease: Optimized by Machine Learning.

BACKGROUND: Prediction of cardiovascular disease (CVD) is important in clinical practice. Machine learning (ML) may offer an improved alternative to current CVD risk stratification in individual patients. We aim to identify important predictors and compare ML models with traditional models according to their prediction performance in a large long-term follow-up cohort. METHODS: The Atherosclerosis Risk in Communities (ARIC) study was designed to study the progression of subclinical disease to cardiovascular events over a 25-year follow-up period. All phenotypic variables at visit 1 were obtained. All-cause death, CVD, and coronary heart disease were the outcomes for analysis. The ML framework involved variable selection using the random survival forest (RSF) method, model building, and 5-fold cross-validation. Model performance was evaluated by discrimination using the Harrell concordance index (C-index), accuracy using the Brier score (BS), and interpretability using the number of variables in the model. RESULTS: Of the 14,842 participants in ARIC, the average age was 54.2 years, with 45.2% male and 26.2% Black participants. Thirty-eight unique variables were selected in the RSF top 20 importance ranking of all 6 outcomes. Aging, hypertension, glucose metabolism, renal function, coagulation, adiposity, and sodium retention dominated the predictions of all outcomes. The ML models outperformed the regression models and established risk scores with a higher C-index, lower BS, and varied interpretability. CONCLUSIONS: The ML framework is useful for identifying important predictors of CVD and for developing models with robust performance compared with existing risk models.

Thermoelectric Coolers: Progress, Challenges, and Opportunities.

Owing to the free of noise, mechanical component, working fluid, and chemical reaction, thermoelectric cooling is regarded as a suitable solution to address the greenhouse emission for the broad cooling scenarios. Here, the significant progress of state-of-the-art thermoelectric coolers is comprehensively summarized and the related aspects of materials, fundamental design, heat sinks, and structures, are overviewed. Particularly, the usage of thermoelectric coolers in smart city, greenhouse, and personal and chip thermal management is highlighted. In the end, current challenges and future opportunities for further improvement of designs, performance, and applications of thermoelectric coolers are pointed out.

The Effect of Interdependences of Referral Behaviors on the Quality of Ambulatory Care: Evidence from Taiwan.

PURPOSE: The purpose of this study is to investigate the effect of interdependences of healthcare providers' referral behaviors on the quality of ambulatory care. The significance of this study is to address the concern regarding the low quality of ambulatory care due to the lack of a compulsory referral system under Taiwan's National Health Insurance system. METHODS: We applied the dynamic connectedness network analysis to estimate the total connectedness index of the referral behavior network, which was separated into the horizontal and vertical referral behavior components in order to measure the interdependences of horizontal and vertical referral behaviors across hospitals and local clinics, respectively. RESULTS: Our results suggest that the interdependences of referral behaviors increase the quality of ambulatory care. The harmful effect on the quality of ambulatory care from the interdependences of horizontal referral behaviors within the local clinics sector is more significant than that from the interdependences of horizontal referral behaviors within the hospital sector, and the negative effect on the overall and chronic composite measures of avoidable hospital admissions from the interdependences of vertical behaviors associated with local clinics is more substantial than that from the interdependences of vertical behaviors within the hospital sector. CONCLUSION: These results not only highlight the significance of care collaboration between local clinics and hospitals to restrain avoidable hospital admissions of chronic diseases for a better overall quality of ambulatory care, but they also suggest that the surveillance system established for the quality of ambulatory care under the global budget payment scheme for the local clinics sector should target ambulatory care for patients with acute conditions.

[Research Progress of CD4+T Cells-mediated Regulation of Neuroinflammation Involved in Neurodegenerative Diseases].

Neurodegenerative diseases are associated with neuroinflammation,oxidative stress,and aging,which can lead to cognitive and motor dysfunctions.Recent studies suggest that the development of neurodegenerative diseases is related to adaptive immunity,in which CD4+T cells are involved as adaptive immune cells.Through different pathways,CD4+T cells differentiate into effector and regulatory subsets,which may have different effects on the progression of neurodegenerative diseases such as Alzheimer's disease,Parkinson's disease,multiple sclerosis,and amyotrophic lateral sclerosis.Here,we review the role and research progress of CD4+T cells in neurodegenerative diseases.

On the Network Transmission Mechanisms of Disease-Specific Healthcare Expenditure Spillovers: Evidence from the Connectedness Network Analyses.

Previous studies investigating factors influencing healthcare expenditure growth ignored the network transmission mechanisms of disease-specific healthcare expenditure spillovers and regarded the processes culminating in healthcare expenditure growth as a black box. In this study, we investigated factors influencing the network transmission mechanisms underlying the determinants of healthcare expenditure growth through the dynamic connectedness network and the robust least square regression analyses. Our results indicate that demographic transition and business cycles are key factors increasing interconnectedness of different disease-specific healthcare expenditures, and that promotion of primary care utilization would reduce total healthcare expenditure spillovers. In order to reduce diffusion of disease-specific healthcare expenditures, health promotion activities should focus on those clinical diagnosis-related groups of diseases classified as pure net transmitters of spillover, and preventive interventions targeting different diseases should be activated in different phrases of the business cycle.

The welfare effect of co-payment adjustments on emergency department visits in medical centers: Evidence from Taiwan.

This study investigates the welfare effect of copayment adjustments on emergency department (ED) visits in medical centers under the National Health Insurance (NHI) program in Taiwan. To this end, we first applied the smooth time-varying co-integration model to estimate the time-varying price and income elasticities of ED care demand in medical centers, and then welfare effects of various copayment adjustments were simulated. Our empirical results suggested that an upward adjustment in copayment neither cause a potential pricing-out effect nor generate a significant amount of welfare gain, despite there exists a negatively long-run relationship between copayment and ED care utilization in medical centers. Nevertheless, the share of non-urgent ED visits is positively correlated with both the negative time-varying price elasticities and welfare gain. These findings serve as important evidence to validate the application of the copayment as a strategic policy instrument to moderate both non-urgent ED care utilization and welfare loss due to moral hazard behavior under Taiwan's NHI program.

Age Structural Transitions and Copayment Policy Effectiveness: Evidence from Taiwan's National Health Insurance System.

BACKGROUND: Population ageing is a worldwide phenomenon that could influence health policy effectiveness. This research explores the impact of age structural transitions on copayment policy responses under Taiwan's National Health Insurance (NHI) system. METHODS: The time-varying parameter vector autoregressive model was applied to create two measures of the copayment policy effectiveness, and multiple linear regression models were used to verify the nonlinear effect of age structural transitions on copayment policy responses. RESULTS: Our results show that copayment policy effectiveness (in terms of the negative response of medical center outpatient visits to upward adjustments in copayment) is positively correlated with the proportions of the population in two older age groups (aged 55-64 and ≥ 65) and children (age < 15), but negatively correlated with the proportion of the population that makes up most of the workforce (aged 15‒54). These tendencies of age distribution, which influence the responses of medical center outpatient visits to copayment policy changes, predict that copayment policy may have a greater influence on medical center outpatient utilization in an ageing society. CONCLUSIONS: Policymakers should be concerned about the adverse effects of copayment adjustments on the elderly, such as an increasing financial burden and the effect of pricing some elderly patients out of Taiwan's NHI system.

Defining human cardiac transcription factor hierarchies using integrated single-cell heterogeneity analysis.

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have become a powerful tool for human disease modeling and therapeutic testing. However, their use remains limited by their immaturity and heterogeneity. To characterize the source of this heterogeneity, we applied complementary single-cell RNA-seq and bulk RNA-seq technologies over time during hiPSC cardiac differentiation and in the adult heart. Using integrated transcriptomic and splicing analysis, more than half a dozen distinct single-cell populations were observed, several of which were coincident at a single time-point, day 30 of differentiation. To dissect the role of distinct cardiac transcriptional regulators associated with each cell population, we systematically tested the effect of a gain or loss of three transcription factors (NR2F2, TBX5, and HEY2), using CRISPR genome editing and ChIP-seq, in conjunction with patch clamp, calcium imaging, and CyTOF analysis. These targets, data, and integrative genomics analysis methods provide a powerful platform for understanding in vitro cellular heterogeneity.

Evolution of drug-resistant mutations in HBV genomes in patients with treatment failure during the past seven years (2010-2016).

The objective of this study was to analyze the prevalence of drug-resistant HBV mutants in patients with treatment failure during the past seven years (2010-2016). 4055 HBV-infected patients who underwent HBV polymerase gene mutation test from 2010 to 2016 were enrolled. The nucleos(t)ide analogues (NAs) resistance mutation positions, including rtL180, rtA181, rtT184, rtS202, rtM204, rtI233, rtN236, rtI169, rtV173, and rtM250 were analyzed. Genotypic resistance mutations were detected in 30.8% (1248/4055) of the patients with treatment failure. Rates of drug-resistant mutations associated with LAM, ADV, ETV, and multidrug were 27.23% (1104/4055), 9.67% (392/4055), 3.69% (150/4055), and 0.79% (32/4055). Among the primary NA-resistant mutations, rtM204I (13.44%, 545/4055) occurred more frequently, followed by rtM204V, rtN236T, rtA181T, and rtA181V. For single-base mutations, rtL180M and rtA181V increased gradually during the past seven years, while rtM204I/V and rtN236T decreased after 2015. The development of drug-resistant mutations positively correlated with the consumption of ETV (r = 0.964, P = 0.002), and weakly correlated with that of LAM (r = 0.679, P = 0.109) and ADV (r = 0.429, P = 0.354). Moreover, single-base mutation rtA181V and multi-base mutations (rtL180M + M204I and rtL180M + M204V + M204I) were more common in HBV genotype C than those in genotype B (1.94% vs. 0.66%, 1.84% vs. 0.16%, 1.02% vs. 0.16%, respectively). NA-related mutations in HBV RT region increased in the past seven years, especially for LAM. Frequencies of rtL180M and rtA181T/V increased gradually in the past seven years, to which we should pay more attention.

Comparison of Non-Coding RNAs in Exosomes and Functional Efficacy of Human Embryonic Stem Cell- versus Induced Pluripotent Stem Cell-Derived Cardiomyocytes.

Both human embryonic stem cell-derived cardiomyocytes (ESC-CMs) and human induced pluripotent stem cell-derived CMs (iPSC-CMs) can serve as unlimited cell sources for cardiac regenerative therapy. However, the functional equivalency between human ESC-CMs and iPSC-CMs for cardiac regenerative therapy has not been demonstrated. Here, we performed a head-to-head comparison of ESC-CMs and iPSC-CMs in their ability to restore cardiac function in a rat myocardial infarction (MI) model as well as their exosomal secretome. Human ESCs and iPSCs were differentiated into CMs using small molecule inhibitors. Fluorescence-activated cell sorting analysis confirmed ∼85% and ∼83% of CMs differentiated from ESCs and iPSCs, respectively, were positive for cardiac troponin T. At a single-cell level, both cell types displayed similar calcium handling and electrophysiological properties, with gene expression comparable with the human fetal heart marked by striated sarcomeres. Sub-acute transplantation of ESC-CMs and iPSC-CMs into nude rats post-MI improved cardiac function, which was associated with increased expression of angiogenic genes in vitro following hypoxia. Profiling of exosomal microRNAs (miRs) and long non-coding RNAs (lncRNAs) revealed that both groups contain an identical repertoire of miRs and lncRNAs, including some that are known to be cardioprotective. We demonstrate that both ESC-CMs and iPSC-CMs can facilitate comparable cardiac repair. This is advantageous because, unlike allogeneic ESC-CMs used in therapy, autologous iPSC-CMs could potentially avoid immune rejection when used for cardiac cell transplantation in the future. Stem Cells 2017;35:2138-2149.

A novel double kink-turn module in euryarchaeal RNase P RNAs.

RNase P is primarily responsible for the 5΄ maturation of transfer RNAs (tRNAs) in all domains of life. Archaeal RNase P is a ribonucleoprotein made up of one catalytic RNA and five protein cofactors including L7Ae, which is known to bind the kink-turn (K-turn), an RNA structural element that causes axial bending. However, the number and location of K-turns in archaeal RNase P RNAs (RPRs) are unclear. As part of an integrated approach, we used native mass spectrometry to assess the number of L7Ae copies that bound the RPR and site-specific hydroxyl radical-mediated footprinting to localize the K-turns. Mutagenesis of each of the putative K-turns singly or in combination decreased the number of bound L7Ae copies, and either eliminated or changed the L7Ae footprint on the mutant RPRs. In addition, our results support an unprecedented 'double K-turn' module in type A and type M archaeal RPR variants.