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Contradiction between ultrafast nucleation and deposition rates of lithium (Li) crystals at high rate and heterogeneity of Li+ flux resulting from concentration polarization has compromised the performance of Li metal anodes especially at high areal capacity and current density. Here, multifunctional protective layer consisting of MoO3 nanobelt films (MoO3-NF) is introduced on the surface of Li by a simple rolling method. The strong binding energy between Li and MoO3 guides the homogeneous nucleation and deposition of Li, while the nanobelt networks provide effective ion channels for uniform distribution of the Li+ flux. Because of the novel multifunctional protective layer, the MoO3-NF@Li anodes demonstrate a remarkable stability for 800 h with ultralow overpotential of 159 mV at extreme harsh conditions of 60 mA·h/cm2 and 60 mA/cm2. MoO3-NF@Li||LiNi0.6Co0.2Mn0.2O2 full-cells can run 100 cycles with a superior capacity retention of 84.2% under practical test conditions, demonstrating great potential for high output and energy-density metal batteries.

Epidemiological studies have suggested a positive association between environmental cadmium (Cd) exposure and type 2 diabetes mellitus (T2DM). Skeletal muscle insulin resistance (IR) plays a critical role in the pathogenesis of T2DM. This study aimed to investigate the effects of chronic low-level Cd exposure on skeletal muscle IR and its potential mechanism. Rats were exposed to drinking water containing 2 or 10 mg/L Cd for 24 weeks. Differentiated L6 myotubes were treated with Cd for 72 h. Immunofluorescence, flow cytometry assay, RNA-sequencing, and Seahorse analysis were conducted to determine the effects of Cd and its underlying mechanism on relevant parameters, including insulin sensitivity, glucose uptake, oxidative stress, mitophagy, and mitochondrial function in skeletal muscle and L6 myotubes. N-acetyl-cysteine (NAC), a scavenger of reactive oxygen species (ROS), and mitophagy inhibitor Cyclosporin A (CsA) were used to confirm the role of oxidative stress in mitophagy and mitochondrial dysfunction caused by Cd. We found that rats exposed to 10 mg/L Cd exhibited hyperglycemia and skeletal muscle IR. Cd markedly increased IRS-1 phosphorylation at Ser612, while decreased levels of phosphorylated PI3K, Akt, AS160, inhibited GLUT4 translocation and glucose uptake. Mechanistically, Cd increased the intracellular ROS, hydrogen peroxide, and malondialdehyde levels and decreased antioxidase activity in L6 myotubes. Furthermore, Cd upregulated the mRNA and protein levels of LC3II/I, PINK1, and Parkin. In addition, Cd induced the formation of mitophagosomes, reduced the mitochondrial membrane potential, decreased the adenosine triphosphate content, and impaired the mitochondrial respiratory capacity. Strikingly, NAC ameliorated oxidative stress, excessive mitophagy, and the associated reduction in myotube insulin sensitivity, while inhibition of mitophagy by CsA alleviated skeletal muscle IR. In conclusion, this study reveals a previously unrecognized mechanism that chronic low-level Cd exposure may induce mitophagy by activating the PINK1/Parkin signal pathway by increasing ROS, thus causing skeletal muscle IR and elevated blood glucose.

The automatic extraction of inspection points for pylons is essential for intelligent Unmanned Aerial Vehicle (UAV) power inspections, especially in generating inspection route. However, current researches primarily focus on power scene perception and power component fault detection, with little attention paid to the inspection point detection. The primary reason are the lack of public pylon datasets for keypoint detection and the neglect of distinguish the inspection points from the keypoints used in feature extraction. Regarding that, this paper proposes a two-stage unsupervised pylon keypoint detection (UPKD) method to improve the efficiency of power inspections. In the first stage, the UPKD Network processes the point cloud to generate candidate keypoints, which comprises two main components: a data normalization module and an unsupervised keypoint detection network (UKD-Net). The data normalization module compresses information based on the symmetric structure of pylons, thereby reducing instability in inspection point detection. The UKD-Net incorporates a Point Transformer layer that uses self-attention mechanisms to extract features from the point cloud. In the second stage, a convex optimization strategy is applied to filter and acquire inspection points. These inspection points are then interconnected using a shortest-path strategy to generate the UAV inspection route. Our dataset is obtained using the Riegl VUX-1 laser measurement system and comprises 3,296 pylons of 10 types. Each pylon’s point cloud contains up to 25,000 points, with a high point density of 100 pts/m2. Extensive experiments show that the UPKD Network achieved state-of-the-art performance on our dataset, with repeatability achieving 90.39%, effectiveness (the ratio of effective keypoints to annotation points) achieving 69.95%, and completeness (the ratio of detected annotation points to keypoints) achieving 79.55%.

Chemotherapy has been the standard treatment for liver cancer. However, intrinsic or acquired drug resistance remains a major barrier to successful treatment. At present, the underlying molecular mechanisms of chemoresistance in liver cancer have not been elucidated. Dipeptidyl peptidase 9 (DPP9) is a member of the dipeptidyl peptidase IV family that has been found to be highly expressed in a variety of tumors, including liver cancer. It is unclear whether DPP9 affects chemoresistance in liver cancer. In this study, we find that DPP9 weakens the responses of liver cancer cells to chemotherapy drugs by up-regulating NQO1 and inhibiting intracellular ROS levels. In terms of mechanism, DPP9 inhibits ubiquitin-mediated degradation of NRF2 protein by binding to KEAP1, up-regulates NRF2 protein levels, promotes mRNA transcription of NQO1, and inhibits intracellular ROS levels. In addition, the NQO1 inhibitor dicoumarol can enhance the efficacy of chemotherapy drugs in liver cancer cells. Collectively, our findings suggest that inhibiting DPP9/NQO1 signaling can serve as a potential therapeutic strategy for liver cancer.

Background: Medicare Part D plans are required to provide Medication therapy management (MTM) services to eligible beneficiaries to optimize medication utilization. Comprehensive medication review (CMR) is a core element of the MTM program. Despite the availability of advanced medical treatment for patients with chronic obstructive pulmonary disease (COPD), medication adherence to maintenance medications poses a continued challenge for patients with COPD. Objective: To examine the effects of CMR on medication adherence among patients with COPD. Methods: Medicare data for 2016–2017 linked to Area Health Resource Files were analyzed. The study population was Medicare beneficiaries with COPD. The intervention group consisted of beneficiaries who received CMR in 2017 but not in 2016. Patients who were eligible for MTM services but did not receive these services in 2016 or 2017 made up the control group. Propensity score matching was used to select an intervention and control group with balanced characteristics. The study outcome was adherence to COPD medications with the proportion of days covered at or above 80%. A difference-in-differences approach was adopted in the logistic regression analyses with an interaction term between the status of CMR receipt and the year 2017. Results: The study sample included 25,564 patients with COPD. The proportions of adherent patients were similar in the control group in both years but increased significantly from 60.08% in 2016 to 69.38% in 2017 in the intervention group (P

Endometriosis is a common chronic gynecological disease with endometrial cell implantation outside the uterus. Angiogenesis is a major pathophysiology in endometriosis. Our previous studies have demonstrated that the prodrug of epigallocatechin gallate (ProEGCG) exhibits superior anti-endometriotic and anti-angiogenic effects compared to epigallocatechin gallate (EGCG). However, their direct binding targets and underlying mechanisms for the differential effects remain unknown. In this study, we demonstrated that oral ProEGCG can be effective in preventing and treating endometriosis. Additionally, 1D and 2D Proteome Integral Solubility Alteration assay-based chemical proteomics identified metadherin (MTDH) and PX domain containing serine/threonine kinase-like (PXK) as novel binding targets of EGCG and ProEGCG, respectively. Computational simulation and BioLayer interferometry were used to confirm their binding affinity. Our results showed that MTDH-EGCG inhibited protein kinase B (Akt)-mediated angiogenesis, while PXK-ProEGCG inhibited epidermal growth factor (EGF)-mediated angiogenesis via the EGF/hypoxia-inducible factor (HIF-1a)/vascular endothelial growth factor (VEGF) pathway. In vitro and in vivo knockdown assays and microvascular network imaging further confirmed the involvement of these signaling pathways. Moreover, our study demonstrated that ProEGCG has superior therapeutic effects than EGCG by targeting distinct signal transduction pathways and may act as a novel antiangiogenic therapy for endometriosis.

Successfully, theoretical equations were established to study the effect of solvent polarities on the electron current density, fill factor and efficiencies of Tris (8-hydroxy) quinoline aluminum (Alq3)/ ZnO solar cells. Three different solvents studied in this theoretical works, namely 1-propanol, ethanol and acetonitrile. The quantum model of transition energy in donor–acceptor system was used to derive a current formula. After that, it has been used to calculate the fill factor and the efficiency of the solar cell. The calculations indicated that the efficiency of the solar cell is influenced by the polarity of solvents. The best performance was for the solar cell based on acetonitrile as a solvent with electron current density of (5.078-12.331) mA/cm2between (1-6) V. In addition, the highest efficiency calculated for the (Alq3)/ ZnO solar cell was 2.593% which corresponds to the highest current density. However, the calculated fill-factor values were significantly unchanged with the changing of the current density. Interestingly, the measured values are in a good agreement with previously reported experimental values.

Background: Evidence is sparse on the effects of Medicare medication therapy management (MTM) on racial/ethnic disparities in medication adherence among patients with Alzheimer's disease and related dementias. Objectives: This study examined the Medicare MTM program's effects on racial/ethnic disparities in the adherence to antidementia medications among patients with Alzheimer's disease and related dementias. Methods: This is a retrospective analysis of 100% of 2010–2017 Medicare Parts A, B, and D data linked to Area Health Resources Files. The study outcome was nonadherence to antidementia medications, and intervention was defined as new MTM enrollment in 2017. Propensity score matching was conducted to create intervention and comparison groups with comparable characteristics. A difference-in-differences model was employed with logistic regression, including interaction terms of dummy variables for the intervention group and racial/ethnic minorities. Results: Unadjusted comparisons revealed that Black, Hispanic, and Asian/Pacific Islander patients were more likely to be nonadherent than non-Hispanic White (White) patients in 2016. Differences in odds of nonadherence between Black and White patients among the intervention group were lower in 2017 than in 2016 by 27% (odds ratios [OR]: 0.73, 95% confidence interval [CI]: 0.65–0.82). A similar lowering was seen between Hispanic and White patients by 26% (OR: 0.74, 95% CI: 0.63–0.87). MTM enrollment was associated with reduced disparities in nonadherence for Black-White patients of 33% (OR: 0.67, 95% CI: 0.57–0.78) and Hispanic-White patients of 19% (OR: 0.81, 95% CI: 0.67–0.99). Discussion: The Medicare MTM program was associated with lower disparities in adherence to antidementia medications between Black and White patients, and between Hispanic and White patients in the population with Alzheimer's disease and related dementias. Conclusions: Expanding the MTM program may particularly benefit racial/ethnic minorities in Alzheimer's disease and related dementia care.

Background: Serum prostate-specific antigen (PSA) is a primary metric for diagnosis and prognosis of prostate cancer (PCa). Exposure to heavy metals, such as lead, cadmium, mercury, and zinc can impact PSA levels in PCa patients. However, it is unclear whether this effect also occurs in men without PCa, which may lead to the overdiagnosis of PCa. Method: Data on a total of 5089 American men who had never been diagnosed with PCa were obtained from the National Health and Nutrition Examination Survey performed from 2003–2010. The relationship between serum PSA levels (dependent variable) and concentrations of lead (μmol/L), cadmium (nmol/L), and mercury (μmol/L) were investigated with dietary zinc intake being used as a potential modifier or covariate in a weighted linear regression model and a generalized additive model. A series of bootstrapping analyses were performed to evaluate sensitivity and specificity using these models. Results: Regression analyses suggested that, in general, lead, cadmium, or mercury did not show an association with PSA levels, which was consistent with the results of the bootstrapping analyses. However, in a subgroup of participants with a high level of dietary zinc intake (≥14.12 mg/day), a significant positive association between cadmium and serum PSA was identified (1.06, 95% CI, P = 0.0268, P for interaction=0.0249). Conclusions: With high-level zinc intake, serum PSA levels may rise in PCa-free men as the exposure to cadmium increases, leading to a potential risk of an overdiagnosis of PCa and unnecessary treatment. Therefore, environmental variables should be factored in the current diagnostic model for PCa that is solely based on PSA measurements. Different criteria for PSA screening are necessary based on geographical variables. Further investigations are needed to uncover the biological and biochemical relationship between zinc, cadmium, and serum PSA levels to more precisely diagnose PCa.

Due to the lack of scientific and systematic thinking in the early stages of high-quality urbanisation, the interaction and stress between the social-human-ecological (SHE)11 SHE social-human-ecological. system intensified, resulting in a series of problems related to the low level of ecological environment and the imbalanced socio-economic development. It is crucial to enhance the safety, health, and well-being of city dwellers, as well as to promote the sustainable development of the region. Based on complex systems science, using the Three Gorges Reservoir Area (TGRA)22 TGRA Three Gorges Reservoir Area. as an instance, this study develops a multidimensional coupling conceptual model of the SHE system, employs the system dynamics (SD)33 SD system dynamics. method to clarify the SHE system’s causal feedback mechanism, and simulates the coupling coordination degree (CCD)44 CCD coupling coordination degree. from 2010 to 2030. Simultaneously, eight scenarios are created to improve the system’s CCD by modifying factors. According to historical and sensitivity test findings, the SD model used in this work can effectively represent the SHE system’s dynamic coupling and interaction connection. Furthermore, under the comprehensive development scenario that takes into account the protection of the ecological environment, human intelligent regulation, and socio-economic development, the TGRA has the biggest growth in CCD. As a result, raising the policy intensity of a single subsystem is insufficient. Balancing policy implementation for each subsystem is advantageous to improving the coupling coordination of the SHE system in the TGRA. The study is of significant importance for achieving high-quality socio-economic development and sustainable ecological management in the TGRA region.

Background: Whether or not there is targeted pharmacotherapy for dementia, an active and healthy lifestyle that includes physical activity (PA) may be a better option than medication for preventing dementia. We examined the association between leisure-time sedentary behavior (SB) and the risk of dementia incidence and mortality. We further quantified the effect on dementia risk of replacing sedentary time with an equal amount of time spent on different physical activities. Methods: In the UK Biobank, 484,169 participants (mean age = 56.5 years; 45.2% men) free of dementia were followed from baseline (2006–2010) through July 30, 2021. A standard questionnaire measured individual leisure-time SB (watching TV, computer use, and driving) and PA (walking for pleasure, light and heavy do-it-yourself activity, strenuous sports, and other exercise) frequency and duration in the 4 weeks prior to evaluation. Apolipoprotein E (APOE) genotype data were available for a subset of 397,519 (82.1%) individuals. A Cox proportional hazard model and an isotemporal substitution model were used in this study. Results: During a median 12.4 years of follow-up, 6904 all-cause dementia cases and 2115 deaths from dementia were recorded. In comparison to participants with leisure-time SB 8 h/day, and the HR of dementia mortality was 1.35 (1.12–1.61) for >8 h/day. A 1 standard deviation increment of sedentary time (2.33 h/day) was strongly associated with a higher incidence of dementia and mortality (HR = 1.06, 95%CI: 1.03–1.08 and HR = 1.07, 95%CI: 1.03–1.12, respectively). The association between sedentary time and the risk of developing dementia was more profound in subjects 8 h/day, p for interaction = 0.013). Replacing 30 min/day of leisure sedentary time with an equal time spent in total PA was associated with a 6% decreased risk and 9% decreased mortality from dementia, with exercise (e.g., swimming, cycling, aerobics, bowling) showing the strongest benefit (HR = 0.82, 95%CI: 0.78–0.86 and HR = 0.79, 95%CI: 0.72–0.86). Compared with APOE ε4 noncarriers, APOE ε4 carriers are more likely to see a decrease in Alzheimer's disease incidence and mortality when PA is substituted for SB. Conclusion: Leisure-time SB was positively associated with the risk of dementia incidence and mortality. Replacing sedentary time with equal time spent doing PA may be associated with a significant reduction in dementia incidence and mortality risk.

Ovulation induction is a first-line medical treatment for infertility in polycystic ovary syndrome (PCOS). Poor ovulation responses are assumed to be due to insulin resistance and hyperandrogenism. In a prospective cohort (PCOSAct) of 1000 infertile patients with PCOS, whole-exome plus targeted single-nucleotide polymorphism (SNP) sequencing and comprehensive metabolomic profiling were conducted. Significant genome-wide common variants and rare mutations associated with anovulation were identified, and a prediction model was built using machine learning. Common variants in zinc-finger protein 438 gene (ZNF438) indexed by rs2994652 (p = 2.47 × 10–8) and a rare functional mutation in REC114 (rs182542888, p = 5.79 × 10–6) were significantly associated with failure of ovulation induction. Women carrying the A allele of rs2994652 and REC114 p.Val101Leu (rs182542888) had lower ovulation (odds ratio (OR) = 1.96, 95% confidence interval (95%CI) = 1.55–2.49; OR = 11.52, 95%CI = 3.08–43.05, respectively) and prolonged time to ovulation (mean = 56.7 versus (vs) 49.0 days, p

Background & Aims: Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with dreadful clinical outcome. Tyrosine kinase inhibitors and immune checkpoint inhibitors are the only United States Food and Drug Administration-approved therapeutic options for patients with advanced HCC with limited therapeutic success. Ferroptosis is a form of immunogenic and regulated cell death caused by chain reaction of iron-dependent lipid peroxidation. Coenzyme Q10 (CoQ10)/ferroptosis suppressor protein 1 (FSP1) axis was recently identified as a novel protective mechanism against ferroptosis. We would like to explore whether FSP1 could be a potential therapeutic target for HCC. Methods: FSP1 expression in human HCC and paired non-tumorous tissue samples were determined by reverse transcription-quantitative polymerase chain reaction, followed by clinicopathologic correlation and survival studies. Regulatory mechanism for FSP1 was determined using chromatin immunoprecipitation. The hydrodynamic tail vein injection model was used for HCC induction to evaluate the efficacy of FSP1 inhibitor (iFSP1) in vivo. Single-cell RNA sequencing revealed the immunomodulatory effects of iFSP1 treatment. Results: We showed that HCC cells greatly rely on the CoQ10/FSP1 system to overcome ferroptosis. We found that FSP1 was significantly overexpressed in human HCC and is regulated by kelch-like ECH-associated protein 1/nuclear factor erythroid 2-related factor 2 pathway. FSP1 inhibitor iFSP1 effectively reduced HCC burden and profoundly increased immune infiltrates including dendritic cells, macrophages, and T cells. We also demonstrated that iFSP1 worked synergistically with immunotherapies to suppress HCC progression. Conclusions: We identified FSP1 as a novel, vulnerable therapeutic target in HCC. The inhibition of FSP1 potently induced ferroptosis, which promoted innate and adaptive anti-tumor immune responses and effectively suppressed HCC tumor growth. FSP1 inhibition therefore represents a new therapeutic strategy for HCC.

Introduction: Predicting pathological complete response (pCR) for patients receiving neoadjuvant chemotherapy (NAC) is crucial in establishing individualized treatment. Whole-slide images (WSIs) of tumor tissues reflect the histopathologic information of the tumor, which is important for therapeutic response effectiveness. In this study, we aimed to investigate whether predictive information for pCR could be detected from WSIs. Materials and methods: We retrospectively collected data from four cohorts of 874 patients diagnosed with biopsy-proven breast cancer. A deep learning pathological model (DLPM) was constructed to predict pCR using biopsy WSIs in the primary cohort, and it was then validated in three external cohorts. The DLPM could generate a deep learning pathological score (DLPs) for each patient; stromal tumor-infiltrating lymphocytes (TILs) were selected for comparison with DLPs. Results: The WSI feature-based DLPM showed good predictive performance with the highest area under the curve (AUC) of 0.72 among the cohorts. Alternatively, the combination of the DLPM and clinical characteristics offered a better prediction performance (AUC >0.70) in all cohorts. We also evaluated the performance of DLPM in three different breast subtypes with the best prediction for the triple-negative breast cancer (TNBC) subtype (AUC: 0.73). Moreover, DLPM combined with clinical characteristics and stromal TILs achieved the highest AUC in the primary cohort (AUC: 0.82) and validation cohort 1 (AUC: 0.80). Conclusion: Our study suggested that WSIs integrated with deep learning could potentially predict pCR to NAC in breast cancer. The predictive performance will be improved by combining clinical characteristics. DLPs from DLPM can provide more information compared to stromal TILs for pCR prediction.

Background: Previous literature suggested that the consequences of inappropriate medication use may be borne disproportionately by racial/ethnic minorities. It is, therefore, essential to examine if quality improvement initiatives, such as Medicare Part D Star Ratings (Star Ratings), can improve these disparities. Objective: To assess the impact of Star Ratings bonus payments to Medicare Advantage prescription drug plans (MAPDs) implemented in 2012 on racial/ethnic disparities in medication utilization issues (MUIs). Methods: This study mainly used secondary data from Medicare administrative data linked to Area Health Resources Files for years before (2010–2011) and after MAPD bonus payment implementation (2016–2017). Patients in MAPDs were treated as the intervention group, and those in independent prescription drug plans (PDPs) were used as the comparison group because PDPs were ineligible for bonuses. MUIs targeted and not targeted in Star Ratings were both examined to determine spillover effects. A difference-in-differences approach was applied by including in a logistic regression a 3-way interaction term for dummy variables for racial/ethnic minorities, later period of 2016–2017, and MAPD plan. Results: Racial/ethnic minorities experienced more MUIs: e.g., the odds of MUIs targeted in Star Ratings among MAPD enrollees were 83% higher (odds ratio [OR] = 1.83; 95% confidence interval [CI] = 1.71–1.96) for Black than White patients. Black-White disparities in MUIs targeted in Star Ratings decreased 16% more (OR = 0.84; 95% = CI 0.78–0.91) over time among MAPD enrollees than those in PDPs. This pattern was not found for non-Star Ratings measures. Changes in Hispanic-White disparities were similar between MAPD and PDP enrollees for MUIs targeted and not-targeted by Star Ratings. Asian-White and Other-White disparities in MUIs did not experience a higher reduction among MAPD enrollees than PDP enrollees. Conclusions: Part D bonus payments are associated with lower Black-White disparities in MUIs targeted by Star Ratings. However, Part D bonus payments may not have reduced Hispanic-White or Asian-White disparities. Future research should explore the causes of the bonus payments' heterogeneous effects across racial/ethnic groups.

Background: This study assessed the potential cost-effectiveness of high (80–100%) vs low (21–35%) fraction of inspired oxygen (FiO2) at preventing surgical site infections (SSIs) after abdominal surgery in Nigeria, India, and South Africa. Methods: Decision-analytic models were constructed using best available evidence sourced from unbundled data of an ongoing pilot trial assessing the effectiveness of high FiO2, published literature, and a cost survey in Nigeria, India, and South Africa. Effectiveness was measured as percentage of SSIs at 30 days after surgery, a healthcare perspective was adopted, and costs were reported in US dollars ($). Results: High FiO2 may be cost-effective (cheaper and effective). In Nigeria, the average cost for high FiO2 was $216 compared with $222 for low FiO2 leading to a −$6 (95% confidence interval [CI]: −$13 to −$1) difference in costs. In India, the average cost for high FiO2 was $184 compared with $195 for low FiO2 leading to a −$11 (95% CI: −$15 to −$6) difference in costs. In South Africa, the average cost for high FiO2 was $1164 compared with $1257 for low FiO2 leading to a −$93 (95% CI: −$132 to −$65) difference in costs. The high FiO2 arm had few SSIs, 7.33% compared with 8.38% for low FiO2, leading to a −1.05 (95% CI: −1.14 to −0.90) percentage point reduction in SSIs. Conclusion: High FiO2 could be cost-effective at preventing SSIs in the three countries but further data from large clinical trials are required to confirm this.

Summary: As we interact with our surroundings, we encounter the same or similar objects from different perspectives and are compelled to generalize. For example, despite their variety we recognize dog barks as a distinct sound class. While we have some understanding of generalization along a single stimulus dimension (frequency, color), natural stimuli are identifiable by a combination of dimensions. Measuring their interaction is essential to understand perception. Using a 2-dimension discrimination task for mice and frequency or amplitude modulated sounds, we tested untrained generalization across pairs of auditory dimensions in an automatized behavioral paradigm. We uncovered a perceptual hierarchy over the tested dimensions that was dominated by the sound’s spectral composition. Stimuli are thus not perceived as a whole, but as a combination of their features, each of which weights differently on the identification of the stimulus according to an established hierarchy, possibly paralleling their differential shaping of neuronal tuning.

Background & Aims: Hepatic immune microenvironment plays a pivotal role in the development of nonalcoholic steatohepatitis (NASH). However, the role of natural killer (NK) cells, accounting for 10%–20% of liver lymphocytes, in NASH is still unclear. In this study, we aim to investigate the functional significance of NK cells in NASH evolution. Methods: NASH was induced in mice fed methionine- and choline-deficient diet (MCD), choline-deficient high-fat diet (CD-HFD), or high-fat diet with streptozotocin injection (STAM model). NK cell deficient mice (Nfil3-/-) and neutralization antibody (PK136) were used in this study. Results: Activated liver NK cells were identified with increased expression of NKG2D, CD107a, and interferon-γ but decreased inhibitory NKG2A. With NK cell deficiency Nfil3-/- mice, the absence of NK cells ameliorated both MCD- and CDHF- induced NASH development with significantly decreased hepatic triglycerides, peroxides, alanine aminotransferase, and aspartate aminotransferase compared with Nfil3+/+ mice. Further molecular analysis unveiled suppressed pro-inflammatory cytokines and associated signaling. Mechanistically, NK cells isolated from NASH liver secreted higher levels of pro-inflammatory cytokines (interferon-γ, interleukin 1β, interleukin 12, CCL4, CCL5, and granulocyte-macrophage colony-stimulating factor), which could activate hepatic JAK-STAT1/3 and nuclear factor kappa B signaling and induce hepatocyte damage evidenced by elevated reactive oxygen species and apoptosis rate. Moreover, neutralization antibody PK136-dependent NK cell depletion can significantly alleviate MCD-induced steatohepatitis with suppressed cytokine levels and JAK-STAT1/3 activity. Conclusions: NK cells in NASH liver are activated with a more pro-inflammatory cytokine milieu and promote NASH development via cytokine-JAK-STAT1/3 axis. Modulation of NK cells provides a potential therapeutic strategy for NASH.

At present, lactic acid bacteria (LAB) fermentation is commonly considered as an effective strategy to remarkably drive the improvement of flavor and nutritional value, and extend shelf-life of fermented foods. In this study, the by-product of tea manufacture, including broken tea segments and tea stalk, was used to produce fermented tea beverages. In addition, the residual components of matrices and bacterial metabolites were measured, as well as the sensory quality of the beverage was evaluated. Subsequently, the determination of monosaccharides, volatile aroma profile, free amino acids, biogenic amines and organic acids, and several functional substances involving γ-aminobutyric acid (GABA), polyphenols, caffeine and L-theanine were carried out. The results revealed that glucose, fructose, mannose and xylose are principal carbon source of Lactobacillus plantarum RLL68 during the fermentation; moreover, the abundance of aromatic substances is varied dramatically and the characteristic flavors of the beverages, particularly fermentation for 48 h and 72 h, are imparted with sweet and fruity odor on the basis of initial nutty and floral odor; Meanwhile, the organoleptic qualities of fermented beverages is also enhanced. Furthermore, the levels of organic acids and GABA are elevated, while the bitter amino acids, as well as some bioactive substances including tea polyphenols and L-theanine are declined; Besides, the caffeine level almost remains constant, and quite low levels of various biogenic amines are also observed. The results of this study will provide the theoretical basis to steer and control the flavor and quality of the fermented tea beverages in the future.

Background: Racial/ethnic minorities are less likely than non-Hispanic White (White) patients to be included in the Medicare Part D Star Ratings measure assessment due to the restrictive inclusion criteria for the measures. Objective: This paper examined the effects of racial/ethnic disparities in the measure assessment in Part D Star Ratings on disparities in healthcare costs among patients with Alzheimer's disease and related dementias (ADRD). Methods: This cross-sectional study analyzed 2017 Medicare data. Proportions of Beneficiaries with ADRD were categorized into the included and excluded groups based on the inclusion criteria for the calculation of medication adherence measures in Star Ratings. Outcomes included costs for medications, physician visits, emergency room (ER) visits, and total costs. A generalized linear model was employed to compare costs across racial/ethnic groups. To explore the differential disparities in healthcare costs between the 2 groups, interaction terms between dummy variables for being excluded from the measure calculation and racial/ethnic minorities were included in the models. Results: The patterns of racial/ethnic disparities in healthcare costs found in this study were generally consistent with expectations, with some exceptions. For example, compared with White patients, in the hyperlipidemia cohort, the physician visit cost for Black patients among the included group was 31% lower (cost ratio or CR = 0.69, 95% CI = 0.67–0.72); in the hypertension cohort, the hospitalization cost for Blacks among the excluded group was 15% higher (CR = 1.15, 95% CI = 1.12–1.19). More importantly, exclusion from measurement assessments was associated with differential cost disparities. For example, compared with individuals included in the measure assessment for hypertension, the Black-White disparities in costs for hospitalization and total healthcare were 30% higher (CR = 1.30, 95% CI = 1.26–1.34), and 10% higher (CR = 1.10; 95% CI = 1.08–1.12), respectively, among the excluded group. Conclusions: Medicare Part D Star Ratings may be associated with aggravated racial/ethnic disparities in healthcare costs in the Medicare Part D population.

Summary: Different from traditional procedures of using solid stabilizers like polymers and surfactants, here we demonstrate that water, as a very “soft” matter, could function as a “spacer” to prevent the aggregation of metal-organic frameworks (MOFs) in aqueous dispersions. Our theoretical calculations reveal in case of an excess of positively charged metal nodes of MOFs, where water molecules are ligated to metal nodes that greatly enhance MOFs’ solution dispersibility through electrostatic stabilization. This discovery has motivated us to develop a facile experimental approach for producing a category of “clean” MOF dispersions without foreign additives. Potential application has been demonstrated for the size fractionation of MOFs, which results in small-size MOFs (50–80 nm) characteristic of superior electrocatalytic oxygen evolution activities (256 mV at 10 mA cm−2, Tafel slope of 49 mV dec−1 and durability >30 h). This work would provide new clues for aqueous processing of MOFs for many emerging applications.

Background: The Medicare Part D medication therapy management (MTM) program has positive effects on medication and health service utilization. However, little is known about its utilization, much less so about the use among racial and ethnic minorities. Objective: To examine MTM service utilization among older Medicare beneficiaries and to identify any racial and ethnic disparity patterns. Methods: A retrospective cross-sectional analysis of 2017 Medicare administrative data, linked to the Area Health Resources Files. Fourteen outcomes related to MTM service nature, initiation, quantity, and delivery were examined using logistic, negative binomial, and Cox proportional hazards regression models. Results: Racial and ethnic disparities were found with varying patterns across outcomes. For example, compared with White patients, the odds of opting out of MTM were 8% higher for Black patients (odds ratio [OR] = 1.08, 95% confidence interval [CI] = 1.03–1.14), 57% higher for Hispanic patients (OR = 1.57, 95% CI = 1.42–1.72), and 57% higher for Asian patients (OR = 1.57, 95% CI = 1.33–1.85). The odds of continuing MTM from the previous years were 12% lower for Black patients (OR = 0.88, 95% CI = 0.86–0.90) and 3% lower for other patients (OR = 0.97, 95% CI = 0.95–0.99). In addition, the probability of being offered a comprehensive medication review (CMR) after MTM enrollment was 9% lower for Hispanic patients (hazard ratio [HR] = 0.91, 95% CI = 0.85–0.97), 9% lower for Asian patients (HR = 0.91, 95% CI = 0.87–0.94), and 3% lower for other patients (HR = 0.97, 95% CI = 0.95–0.99). Hispanic and Asian patients were more likely to have someone other than themselves receive a CMR. Conclusions: Racial and ethnic disparities in MTM service utilization were identified. Although the disparities in specific utilization outcomes vary across racial/ethnic groups, it is evident that these disparities exist and may result in vulnerable communities not fully benefiting from the MTM services. Causes of the disparities should be explored to inform future reform of the Medicare Part D MTM program.

Background & Aims: Tenofovir is recommended as part of the first-line antiretroviral therapy (ART) to treat people living with HIV (PLWH) with HBV coinfection. However, the effects of tenofovir-containing ART on hepatocellular carcinoma (HCC) risk among PLWH with/without chronic hepatitis virus infections remain unclear. Methods: This study included 23,838 PLWH. All of them were males aged ≥20 years and followed prospectively during 2000–2017. Four major nationwide registries – the Human Immunodeficiency Virus surveillance database, Taiwan Cancer Registry, Death Certification System, and National Health Insurance Database – were applied to define ART and comorbidities and ascertain newly diagnosed HCC. Tenofovir-containing ART was identified through prescription records. Cox proportional hazards models were used to determine the association of tenofovir use with HCC incidence. Results: HCC incidence was lower among ever users of tenofovir than among never users (24.2 and 85.7 per 100,000 person-years, respectively). Ever users had significantly reduced HCC risk (adjusted hazard ratio 0.20, 95% CI 0.13–0.31). The effect of tenofovir use on reduced risk for HCC consistently favored never users across many prespecified subgroups, including HBV or HCV coinfection (p

The increasing demand for enhanced osteointegration calls for next-generation polyetheretherketone (PEEK) that can offer fast bone integration. Whether polydopamine (PDA) and epigallocatechin-3-gallate (EGCG) cross-linked coatings could improve osteointegration of PEEK remains unclear. Here, we fabricated a series of PDA and EGCG cross-linked coatings (PE coatings: P2E0.1, P2E0.5, P2E1, and P2E2 coatings) to enhance osteointegration of PEEK. The material characteristics of coatings were studied using scanning electron microscopy, X-ray photoelectron spectroscopy, micro-BCA tests, and static water contact angle tests. We evaluated the cytotoxicity, cell adhesion, and osteogenic effects of the coatings in vitro. Furthermore, the P2E0.5 coating was selected to coat porous PEEK scaffold to observe osteointegration using micro-computed tomography and histology in a rabbit. The results show that the PE coatings provide phenolic hydroxyl and amino groups and enhanced hydrophilicity of PEEK, especially in the P2E0.5 coating. Several lines of cellular evidence suggest that P2E0.5 coatings exhibit a noncytotoxic and excellent osteogenic effect. Compared with PEEK, the P2E0.5-coated PEEK shows higher values of bone volume, trabecular number, and trabecular thickness. This study suggests that the PE coating is a promising candidate for surface modification of PEEK and may lay the foundation for further application of PE coatings in clinical practice.

Our environment is made of a myriad of stimuli present in combinations often patterned in predictable ways. For example, there is a strong association between where we are and the sounds we hear. Like many environmental patterns, sound-context associations are learned implicitly, in an unsupervised manner, and are highly informative and predictive of normality. Yet, we know little about where and how unsupervised sound-context associations are coded in the brain. Here we measured plasticity in the auditory midbrain of mice living over days in an enriched task-less environment in which entering a context triggered sound with different degrees of predictability. Plasticity in the auditory midbrain, a hub of auditory input and multimodal feedback, developed over days and reflected learning of contextual information in a manner that depended on the predictability of the sound-context association and not on reinforcement. Plasticity manifested as an increase in response gain and tuning shift that correlated with a general increase in neuronal frequency discrimination. Thus, the auditory midbrain is sensitive to unsupervised predictable sound-context associations, revealing a subcortical engagement in the detection of contextual sounds. By increasing frequency resolution, this detection might facilitate the processing of behaviorally relevant foreground information described to occur in cortical auditory structures.

Surface modification and wetting state transformation of ZnO based nanomaterials have been extensively investigated due to their substantial roles in current industrial applications. In this work, we demonstrated the formation of highly crystalline and ordered Bi/ZnO nanorods arrays (Bi/ZNRs) grown on FTO substrate via a feasible hydrothermal method, as a function of reaction time (t). The lateral diameter of the nanostructures were found increased from 23 nm to 43 nm when the reaction time increased from 30 min to 90 min. An in-depth analysis and incisive mechanism of crystal growth under the function of reaction time were proposed. The crystal defect which originated from different Bi incorporation pathways has been declared as the main factor altering the optical energy, electrical properties and band structure of Bi/ZNRs. The Bi/ZNRs showed a higher localize current of 14.5 pA as compared to pristine ZNRs under an 6V applied bias condition, revealing the nature of Bi as a pentavalent dopant that contributed to a density of free electron. Additionally, the Bi/ZNRs also revealed a red shifted in optical energy band gap and exhibit a wetting transition from hydrophobic to hydrophilic textured surface. The novel nanostructures reported herein exhibit interesting physical and optical properties for the fabrication of high performance optoelectronic devices.

Objectives: Meningitis in neonates and young infants leads to significant morbidity and mortality worldwide. This study aimed to investigate pathogens, antibiotic resistance and secular change of incidence in Hong Kong. Methods: A retrospective search was performed on meningitis in neonates and infants aged

Benefiting from the development of deep learning, researchers have made significant progress and achieved superior performance in the semantic segmentation of remote sensing (RS) data. However, when encountering an unseen scenario, the performance of a trained model deteriorates dramatically because of the domain shift. Unsupervised domain adaptation (UDA) provides an alternative to address the issue. Aligning the high-level representations via adversarial learning is a popular way, but it is difficult when there is a large gap in input space. With this consideration, we design a framework to jointly align the distribution in input and feature space. For input space alignment, we unify the resolution for the consistency of content and propose a lightweight module named Digital Number Transformer (DNT) to reduce the visual differences. For feature space alignment, we design a Multi-Scale Feature aggregation (MSF) module and introduce the Fine-Grained Discriminator (FGD) to conduct a category-level alignment at multiple layers so that features can be fully aligned and negative transfer can be reduced. We carried out experiments in diverse cross-domain scenarios, including the discrepancy in geographic position and the discrepancy in both geographic position and imaging mode. Comprehensive experiments demonstrate that our method outperforms other state-of-the-art methods in all scenarios.

Given the initial calibration of multiple sensors, the fine registration between Mobile Laser Scanning (MLS) point clouds and panoramic images is still challenging due to the unforeseen movement and temporal misalignment while collecting. To tackle this issue, we proposed a novel automatic method to register the panoramic images and MLS point clouds based on the matching of pole objects. Firstly, 2D pole instances in the panoramic images are extracted by a semantic segmentation network and then optimized. Secondly, every corresponding frustum point cloud of each pole instance is obtained by a shape-adaptive buffer region in the panoramic image, and the 3D pole object is extracted via a combination of slicing, clustering, and connected domain analysis, then all 3D pole objects are fused. Finally, 2D and 3D pole objects are re-projected onto virtual images respectively, and then fine 2D-3D correspondences are collected through maximizing pole overlapping area by Particle Swarm Optimization (PSO). The accurate extrinsic orientation parameters are acquired by the Efficient Perspective-N-Point (EPnP). The experiments indicate that the proposed method performs effectively on two challenging urban scenes with an average registration error of 2.01 pixels (with RMSE 0.88) and 2.35 pixels (with RMSE 1.03), respectively.

Significance: Few studies have analyzed how loneliness-related factors differ across generations for older adults in non-Western societies. Building upon the stress process model, this study aimed to explore the relationships between work-family conflict before retirement, social engagement after retirement and changes in loneliness after retirement among retirees across two birth cohorts (Baby Boomers and pre-Boomers) in Taiwan. Methods: Data from the Taiwan Health and Retirement Study, a nationwide retired cohort sample collected from two waves between 2015/2016 and 2018/2019, was analyzed. A total of 2370 retirees aged 50–74 years were included in the analysis after excluding those who died or were lost to follow-up. Multivariate multinomial logistic models were used to estimate four types of changes in loneliness: (1) remaining not lonely, (2) becoming not lonely, (3) becoming lonely, and (4) remaining lonely. Results: About two-thirds of the retirees remained not lonely, and less than 10% maintained their feelings of loneliness across two waves. Multinomial logit models showed that both cohorts who experienced work-family conflict before retirement and stressful life events after retirement had higher odds of remaining lonely than those who remained not lonely. However, an increase in social engagement, especially social contact, appeared to be a protective factor against becoming and remaining lonely for both cohorts. Yet, work-related characteristics before retirement were significantly related to the changes in loneliness among pre-Boomers rather than Baby Boomers. Conclusions: The results suggest that work-family conflict before retirement produces an exacerbating effect; in contrast, social engagement after retirement is beneficial to not feeling lonely across two birth cohorts in Taiwan. This investigation highlights the importance of social stressors occurring before retirement because these have an effect on retirees’ feelings of loneliness beyond individual socioeconomic status.

Experimental studies suggest the diabetogenic effects of lead, but relevant data in humans are limited and have been primarily based on cross-sectional study design. We aimed to prospectively examine the association between lead exposure and glucose homeostasis in general population using repeated measurements. This cohort study included 5505 Chinese adults free of glucose-lowering medication use at baseline in 2014 and followed up 5 years later. Blood lead and glucose metabolic traits including fasting plasma glucose (FPG), fasting serum insulin, the homeostasis model assessment of insulin resistance (HOMA-IR), and HOMA of beta-cell function (HOMA-B) were measured at baseline and follow-up. Linear mixed models and linear regression models were performed to evaluate the associations between blood lead and markers of glucose homeostasis. After full adjustment for confounders including BMI, an interquartile range (IQR) increase in blood lead levels was associated with a 2.26 % increase in FPG (95 % CI: 0.16 %, 4.39 %) and an 11.3 % decrease in HOMA-B (95 % CI: − 19.1 %, − 2.71 %) in women. The odds ratios of hyperglycemia and beta-cell dysfunction corresponding to an IQR increase in blood lead levels were 1.39 (95 % CI: 0.99, 1.95) and 1.74 (95 % CI: 1.00, 3.03), respectively. Similar results were found for 5-year changes of glucose metabolic markers. Compared with the first quartile of baseline lead levels, the highest lead quartile was associated with an additional 3.03 % increase in FPG (95 % CI: 0.84 %, 5.26 %) and an additional 13.3 % decrease in HOMA-B (95 % CI: − 20.4 %, − 5.53 %) in women during follow-up. We observed no overall associations between blood lead levels and glucose metabolic markers in men. Our findings provide suggestive evidence that environmental exposure to lead might contribute to sex-dependent disruption of glucose homeostasis in general adult population.

As the most common primitives, line segments play an essential role in the vectorized reconstruction of artificial scenes. In this paper, a geometric feature enhanced line extraction method with Hierarchical Topological Optimization is proposed to extract line segments from large-scale point clouds. Firstly, 3D projection plane regions are extracted from point clouds using region growing and merging; Secondly, the point clouds in the detected planar region are projected onto 2D grids for efficiently geometry features enhanced line detection. Specifically, the edge feature index of each point inside each projection grid is calculated and fused to represent the edge-geometry enhanced feature. The likelihood of edge presenting on the projection grids is produced using a pre-trained convolutional neural network that combines multi-scale edge locating outputs. Then, line segments on the projected edge maps are extracted by the MCMLSD algorithm and further back-projected into 3D space to form the 3D line segment candidates. Thirdly, the hierarchical topological relationships between the contour and line segments are used to optimize the candidate 3D line segments. The optimization process consists of merging perceptually accurate 3D line segments, closing the contour line based on the contour and merging plane intersection lines based on line segments. The point clouds of seven large-scale outdoor scenes from the Semantic 3D and WHU-TLS public datasets are selected for qualitative and quantitative evaluations. Experiments show that the proposed approach can efficiently extract line segments that represent the geometric characteristics of the scenes comprehensively and accurately. Compared with the SOTA line segments extraction algorithms (i.e., Lu et al. (2019), Zhang et al. (2020a)), the proposed method filters out major miscellaneous/broken lines and extract more complete line segments. The Completeness and Correctness of the line segments extraction results reach 86% on average compared with manual labeled ground truth (dl, ds: 0.5,0.5), at an average processing speed of 25,000 points per second.

The stable and reliable supply of electric power is strongly related to the normal social production. In recent years, power transmission lines inspection based on remote sensing methods has made great progress, especially using the UAV-borne LiDAR system. The extraction and identification of power transmission lines (i.e., conductors) from 3D point clouds are the basis of LiDAR data-based power grid risk management. However, existing rule-based/traditional machine learning extraction approaches have exposed some limitations, such as the lack of timeliness and generalization. Moreover, the potential of deep learning is seriously overlooked in RoW (Right of Way) LiDAR inspection tasks. Thus, we proposed DCPLD-Net: a diffusion coupled convolution neural network for real-time power transmission lines detection from UAV-borne LiDAR data. To implement efficient 2D convolution on 3D point clouds, we proposed a novel point cloud representation, named Cross Section View (CSV), which transforms the discrete point clouds into 3D tensors constructed by voxels with a deformed geometric shape along the flight trajectory. After the CSV feature generation, the encoded features of each voxel are treated as energy (i.e., heat) signals and diffused in space to generate diffusion feature maps. The feature of the power line points are thus enhanced through this simulated physical process (diffusion). Finally, a single-stage detector named PLDNet is proposed for the multiscale detection of conductors on the diffused CSV representations. The experimental results show that the DCPLD-Net achieves an average F1 score of 97.14 % at 8 Hz detection frequency on RoWs inspection LiDAR datasets collected by both mini-UAV LiDAR and large-scale fully autonomous UAV power lines inspection robots, and surpasses compared methods (i.e. PointNet ++, RandLA-Net) in terms of F1 scores and IoU.

More than 120 genes have been reported to be associated with deafness, and deletion of the TBL1X gene may cause deafness in humans. In this study, we generated an induced pluripotent stem cell (iPSC) line from dermal fibroblasts of a 34-year-old deaf person with a novel variant c.342_343insGCGGCG in the TBL1X gene. The induced patient-specific iPSC line with a normal karyotype and expressed pluripotent markers, it also shows differentiation totipotency and tridermogenesis in vivo. It may be a good model for studying hearing loss in vitro and it will benefit to the development of new therapies for deafness.

The effect of hydrothermal process on the morphology and piezoelectric performance of zinc oxide/polyvinylidene fluoride (ZnO@PVDF) composite nanofibers is rarely studied. In this work, highly aligned ZnO nanorods were epitaxially grown on the electrospun PVDF nanofibers to form ZnO@PVDF composite nanofibers with a pine-needle-like bionic structure. Nanofibers before and after hydrothermal reaction were characterized by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD) and piezoelectric analysis. Results demonstrated that hydrothermal reaction conditions, including mass ratio of ZnCl2 to HMTA, ammonium hydroxide volume, hydrothermal reaction time and temperature should be carefully controlled and cooperated with each other to produce ZnO nanorods with ideal microstructure and piezoelectric performance. FTIR and XRD results confirmed the transformation of β phase in PVDF nanofibers from α phase in PVDF powder due to the elongation under strong electric field during electrospinning. Results of SEM and XRD certified the successful growth of ZnO nanorods with hexagonal wurtzite structure, which plays an important role in facilitating the percentage of β phase and the resulted piezoelectric capacity of ZnO@PVDF composite nanofibers. All of these characterizations suggest that the proposed pine-needle-like ZnO@PVDF composite nanofibers demonstrate promising potential in the wide application of electromechanical energy conversion.

Irreversible blindness from glaucoma and optic neuropathies is attributed to retinal ganglion cells (RGCs) losing the ability to regenerate axons. While several transcription factors and proteins have demonstrated enhancement of axon regeneration after optic nerve injury, mechanisms contributing to the age-related decline in axon regenerative capacity remain elusive. In this study, we show that microRNAs are differentially expressed during RGC development and identify microRNA-19a (miR-19a) as a heterochronic marker; developmental decline of miR-19a relieves suppression of phosphatase and tensin homolog (PTEN), a key regulator of axon regeneration, and serves as a temporal indicator of decreasing axon regenerative capacity. Intravitreal injection of miR-19a promotes axon regeneration after optic nerve crush in adult mice, and it increases axon extension in RGCs isolated from aged human donors. This study uncovers a previously unrecognized involvement of the miR-19a-PTEN axis in RGC axon regeneration, and it demonstrates therapeutic potential of microRNA-mediated restoration of axon regenerative capacity in optic neuropathies.

Current antiviral therapy fails to cure chronic hepatitis B virus (HBV) infection because of persistent covalently closed circular DNA (cccDNA). CRISPR/Cas9-mediated specific cleavage of cccDNA is a potentially curative strategy for chronic hepatitis B (CHB). However, the CRISPR/Cas system inevitably targets integrated HBV DNA and induces double-strand breaks (DSBs) of host genome, bearing the risk of genomic rearrangement and damage. Herein, we examined the utility of recently developed CRISPR/Cas-mediated “base editors” (BEs) in inactivating HBV gene expression without cleavage of DNA. Candidate target sites of the SpCas9-derived BE and its variants in HBV genomes were screened for generating nonsense mutations of viral genes with individual guide RNAs (gRNAs). SpCas9-BE with certain gRNAs effectively base-edited polymerase and surface genes and reduced HBV gene expression in cells harboring integrated HBV genomes, but induced very few insertions or deletions (indels). Interestingly, some point mutations introduced by base editing resulted in simultaneous suppression of both polymerase and surface genes. Finally, the episomal cccDNA was successfully edited by SpCas9-BE for suppression of viral gene expression in an in vitro HBV infection system. In conclusion, Cas9-mediated base editing is a potential strategy to cure CHB by permanent inactivation of integrated HBV DNA and cccDNA without DSBs of the host genome.

The vertebral column is the most common site of osteoporotic fractures in long-term users of glucocorticoids. Vertebral fracture leads to significant morbidities such as unrelenting pain, spinal deformities and reduced mobility, leading to diminished quality of life. Epidemiological data on the prevalence of glucocorticoid-induced vertebral fractures are limited. As vertebral fracture is a strong risk factor for further fragility fractures and mortality, it should be treated appropriately. This article reviews recent data on the prevalence of vertebral fractures in glucocorticoid users, fracture risk stratification, and evidence-based treatment options. The risk of osteoporotic fractures estimated by FRAX should be adjusted for glucocorticoid users. The first-line treatment of glucocorticoid-induced osteoporosis remains the bisphosphonates. Teriparatide and denosumab are alternative options. Percutaneous vertebroplasty and kyphoplasty may be considered for symptomatic control of acute vertebral fracture-related pain when conservative measures fail. Keywords: Glucocorticoids, Vertebral fracture, Fragility, Osteoporosis

Background: Lead (Pb) has been suggested as an endocrine-disrupting chemical. However, few studies have investigated the association between chronic Pb exposure and fatty liver disease. Objectives: We aimed to investigate the association of chronic Pb exposure with fatty liver disease and whether the variations of the gut microbiota involve in the mechanism of the fatty liver disease induced by chronic Pb exposure. Methods: We conducted a cross-sectional study of 3066 rural participants in East China. Blood lead level (BLL) was detected, and abdominal ultrasonography was used to diagnose hepatic steatosis. Both the definition of non-alcoholic fatty liver disease (NAFLD) and metabolic dysfunction-associated fatty liver disease (MAFLD) were used. Wistar rats were randomly divided into two groups and each group was exposed to 0 or 0.05% w/v Pb through drinking water for 28 weeks. The relevant parameters of hepatic lipid metabolism and gut microbiota were analyzed. Results: In humans, after adjusting for potential confounders, the odds of having NAFLD and MAFLD were significantly increased by 54% and 52% in the participants in the fourth BLL quartile (OR 1.54, 95% CI 1.24, 1.91 and OR 1.52, 95% CI 1.22, 1.89). In the rats, chronic Pb exposure induced the increased visceral fat, hepatic steatosis, and dysbiosis of the gut microbiota, including the decrease of richness, diversity, evenness and phylogenetic diversity of the gut microbiota and the significant alternations of the gut microbiota composition, particularly, the decrease of the relative abundance of Coprococcus and Oscillospira at the genus level. Conclusions: Chronic Pb exposure could induce fatty liver disease, which may be associated with the variations of the gut microbiota.

Background: Hypoxic-Ischemic Encephalopathy (HIE) occurs when an infant's brain does not receive adequate blood and oxygen supply, resulting in ischemic and hypoxic brain damage during delivery. Currently, supportive care and hypothermia have been the standard treatment for HIE. However, there are still a 20% mortality and most of the survivors are associated with significant neurodevelopmental disability. HIE animal model was first established by Vannucci et al., in 1981, and has been used extensively to explore the mechanisms of brain damage and its potential treatment. The Vannucci model involves the unilateral common carotid artery occlusion followed by 90 min hypoxia (8% oxygen). The purpose of this study is to define and validate a modified HIE model which mimics closely that of the human neonatal HIE. Method: The classic Vannucci HIE model occludes one common carotid artery followed by 90 min hypoxia. In the new model, common carotid arteries were occluded bilaterally followed by breathing 8% oxygen in a hypoxic chamber for 90, 60 and 30 min, followed by the release of the common carotid artery ligatures, mimicking a reperfusion. Result: We studied 110 neonatal rats in detail, following the modified in comparison with the classical Vannucci models. The classical Vannucci model has a consistent surgical mortality of 18% and the new modified models have a 20%–46%. While mortality depended on the duration of hypoxia, fifty-two animals survived for behavioral assessments and standard histology. The modified HIE model with 60 min of transient carotid occlusion is associated with a moderate brain damage, and has a 30% surgical mortality. This modified experimental model is regarded closer to the human situation than the classical Vannucci model.

Background: There has been a lack of evidence on whether there are racial and ethnic disparities in medication nonadherence among individuals receiving comprehensive medication review (CMR), a required component of the Medicare Part D medication therapy management (MTM) services. Objectives: To explore racial/ethnic disparities in medication nonadherence among older MTM enrollees who received a CMR and to determine how much the identified disparities can be explained by observed characteristics. Methods: The retrospective study used 100% of the 2017 Medicare claims, including MTM data. Linked Area Health Resources Files provided community characteristics. Nonadherence was defined as proportion of days covered

Background: Type 2 diabetes (T2D) increases the risk of many types of cancer. Dysregulation of proteasome-related protein degradation leads to tumorigenesis, while Exendin-4, a glucagon-like peptide 1 receptor (GLP-1R) agonist, possesses anti-cancer effects. Methods: We explored the co-expression of proteasome alpha 2 subunit (PSMA2) and GLP-1R in the Cancer Genome Atlas (TCGA) database and human cervical cancer specimens, supplemented by in vivo and in vitro studies using multiple cervical cancer cell lines. Findings: PSMA2 expression was increased in 12 cancer types in TCGA database and cervical cancer specimens from patients with T2D (T2D vs non-T2D: 3.22 (95% confidence interval CI: 1.38, 5.05) vs 1.00 (0.66, 1.34) fold change, P = 0.01). psma2-shRNA decreased cell proliferation in vitro, and tumour volume and Ki67 expression in vivo. Exendin-4 decreased psma2 expression, tumour volume and Ki67 expression in vivo. There was no change in GLP-1R expression in 12 cancer types in TCGA database. However, GLP-1R expression (T2D vs non-T2D: 5.49 (3.0, 8.1) vs 1.00 (0.5, 1.5) fold change, P

Objectives: Breast cancers show different regression patterns after neoadjuvant chemotherapy. Certain regression patterns are associated with more reliable margins in breast-conserving surgery. Our study aims to establish a nomogram based on radiomic features and clinicopathological factors to predict regression patterns in breast cancer patients. Methods: We retrospectively reviewed 144 breast cancer patients who received neoadjuvant chemotherapy and underwent definitive surgery in our center from January 2016 to December 2019. Tumor regression patterns were categorized as type 1 (concentric regression + pCR) and type 2 (multifocal residues + SD + PD) based on pathological results. We extracted 1158 multidimensional features from 2 sequences of MRI images. After feature selection, machine learning was applied to construct a radiomic signature. Clinical characteristics were selected by backward stepwise selection. The combined prediction model was built based on both the radiomic signature and clinical factors. The predictive performance of the combined prediction model was evaluated. Results: Two radiomic features were selected for constructing the radiomic signature. Combined with two significant clinical characteristics, the combined prediction model showed excellent prediction performance, with an area under the receiver operating characteristic curve of 0.902 (95% confidence interval 0.8343–0.9701) in the primary cohort and 0.826 (95% confidence interval 0.6774–0.9753) in the validation cohort. Conclusions: Our study established a unique model combining a radiomic signature and clinicopathological factors to predict tumor regression patterns prior to the initiation of NAC. The early prediction of type 2 regression offers the opportunity to modify preoperative treatments or aids in determining surgical options.

Personal care and consumer products are extensively used and contain various chemicals that are recognized as endocrine disrupting chemicals. Few epidemiological studies measured the associations of these chemicals and metabolites, especially phenols, with bone health. We measured the associations between nine urinary phenol biomarkers and BMD and the subsequent prevalence of osteopenia/osteoporosis. National representative data from US adults aged over 20 years who participated in the National Health and Nutrition Examination Survey from 2005 to 2010 were used. 2,267 men, 1,145 premenopausal women and 1,033 postmenopausal women were included in the final analyses. Bisphenol A, benzophenone-3, triclosan, butylparaben, ethylparaben, methylparaben, propylparaben, 2,5-dichlorophenol and 2,4-dichlorophenol were measured by high-performance liquid chromatography-isotope dilution tandem mass spectrometry. Paraben concentrations, especially ethyl-, methyl- and propylparabens, were related to greater BMD in the femoral neck and intertrochanter and lumbar spine in men and premenopausal women. 2,4-dichlorophenol concentrations was associated with lower BMD and a higher prevalence of osteopenia + osteoporosis in men. Bisphenol A was associated with a higher prevalence of osteopenia + osteoporosis in the lumbar spine in postmenopausal women. Benzophenone-3 tended to be associated with a higher BMD of femur in men and premenopausal women. In conclusion, certain urinary personal care and consumer product chemicals and metabolites were significantly associated with BMD or osteopenia + osteoporosis. These results further indicate that, in future research, determination of the causal relationships and detection of undelying mechanism could be next important directions.

Haematological and immunological data of children with COVID-19 infection is lacking. Between 21st January and 20th March 2020, 244 children who were confirmed to have COVID-19 infection and admitted to the Wuhan Children's Hospital, China were retrospectively reviewed. 193 children were considered as symptomatic, which was defined as having either the presence of clinical symptoms or the presence of CT thorax abnormalities. Their haematological and immunological profiles, including complete blood counts, lymphocyte subsets (T, B and NK cell counts), immunoglobulin (Ig) profiles (IgG, IgA and IgM) and cytokine profiles were analysed and compared between the symptomatic and asymptomatic groups. The median values and the interquartile ranges were calculated. Comparison was made using the Mann–Whitney U test. Children with symptomatic COVID-19 infection had significantly lower haemoglobin levels, but higher absolute lymphocyte and monocyte counts, IgG and IgA levels, as well as interleukin 6 (IL-6), IL-10, tumour necrosis factor alpha and interferon gamma levels. The obtained data will be utilized for further studies in comparing children and adults with COVID-19 infections in other parts of the world and with different severity .

L-DOPA-induced dyskinesia (LID) is a major complication of long-term dopamine replacement therapy in Parkinson's disease. Characteristic neural oscillation and abnormal activity of striatal projection neurons (SPNs) are typical pathological events of LID, which would be reliable biomarkers for assessment of novel anti-dyskinetic approach if fully profiled. Glutamate dysregulation plays a critical role in the development of LID, and the group II metabotropic glutamate receptors (mGluR2/3) is believed to regulate the release of glutamate on the presynaptic terminals and inhibits postsynaptic excitation. However, the anti-dyskinetic effect of modulating mGluR2/3 is still unclear. In this study, rats with unilateral dopaminergic lesion were injected with L-DOPA (12 mg/kg, i.p.) for seven days, while motor behavior was correlated with in vivo electrophysiology analyzing LFP and single-cell activity in both primary motor cortex and dorsolateral striatum. Our study showed that as LID established, high γ oscillation (hγ) predominated during LID, the number of unstable responses of SPN to dopamine increased, and the coherence between these patterns of oscillation and spiking activity also increased. We found that pretreatment of NMDA receptor antagonist, amantadine 60 mg/kg, i.p. (AMAN) significantly reduced abnormal involuntary movements (AIMs), in parallel with the reduction of hγ oscillation, and more markedly with a decrease in unstable responses of SPNs. In contrast, a mGluR2/3 agonist, LY354740 12 mg/kg, i.p. (LY) significantly shortened the duration of LID but merely exhibited a weak effect in diminishing the intensity of LID or reversing SPN responses. Together results indicate that AIMs in the rat model of PD are associated with abnormal corticostriatal signaling, which could be reversed by NMDAR antagonism more efficiently than mGluR2/3 agonism.