Spatial accessibility and inequality analysis of rabies-exposed patients to rabies post-exposure prophylaxis clinics in Guangzhou City, China.

BACKGROUND: The incidence of rabies exposure is high and increasing in China, leading to an urgent demand of rabies post-exposure prophylaxis (PEP) clinics for the injured. However, the spatial accessibility and inequality of rabies-exposed patients to rabies PEP clinics is less known in China. METHODS: Based on rabies exposure data, PEP clinic data, and resident travel origin-destination (OD) matrix data in Guangzhou City, China, we first described the incidence of rabies exposure in Guangzhou from 2020 to 2022. Then, the Gaussian two-step floating catchment area method (2SFCA) was used to analyze the spatial accessibility of rabies-exposed patients to rabies PEP clinics in Guangzhou, and the Gini coefficient and Moran's I statistics were utilized to evaluate the inequality and clustering of accessibility scores. RESULTS: From 2020 to 2022, a total of 524,160 cases of rabies exposure were reported in Guangzhou, and the incidence showed a significant increasing trend, with an average annual incidence of 932.0/100,000. Spatial accessibility analysis revealed that the overall spatial accessibility scores for three scenarios (threshold of driving duration [d0] = 30 min, 45 min, and 60 min) were 0.30 (95% CI: 0.07, 0.87), 0.28 (95% CI: 0.11, 0.53) and 0.28 (95% CI: 0.14, 0.44), respectively. Conghua, Huangpu, Zengcheng and Nansha districts had the higher accessibility scores, while Haizhu, Liwan, and Yuexiu districts exhibited lower spatial accessibility scores. The Gini coefficient and Moran's I statistics showed that there were certain inequality and clustering in the accessibility to rabies PEP clinics in Guangzhou. CONCLUSIONS: This study clarifies the heterogeneity of spatial accessibility to rabies PEP clinics, and provide valuable insights for resource allocation to achieve the WHO target of zero human dog-mediated rabies deaths by 2030.

Macrophage-Derived GSDMD Plays an Essential Role in Atherosclerosis and Cross Talk Between Macrophages via the Mitochondria-STING-IRF3/NF-κB Axis.

BACKGROUND: Macrophages play a crucial role in atherosclerotic plaque formation, and the death of macrophages is a vital factor in determining the fate of atherosclerosis. GSDMD (gasdermin D)-mediated pyroptosis is a programmed cell death, characterized by membrane pore formation and inflammatory factor release. METHODS: ApoE-/- and Gsdmd-/- ApoE-/- mice, bone marrow transplantation, and AAV (adeno-associated virus serotype 9)-F4/80-shGSDMD (shRNA-GSDMD) were used to examine the effect of macrophage-derived GSDMD on atherosclerosis. Single-cell RNA sequencing was used to investigate the changing profile of different cellular components and the cellular localization of GSDMD during atherosclerosis. RESULTS: First, we found that GSDMD is activated in human and mouse atherosclerotic plaques and Gsdmd-/- attenuates the atherosclerotic lesion area in high-fat diet-fed ApoE-/- mice. We performed single-cell RNA sequencing of ApoE-/- and Gsdmd-/- ApoE-/- mouse aortas and showed that GSDMD is principally expressed in atherosclerotic macrophages. Using bone marrow transplantation and AAV-F4/80-shGSDMD, we identified the potential role of macrophage-derived GSDMD in aortic pyroptosis and atherosclerotic injuries in vivo. Mechanistically, GSDMD contributes to mitochondrial perforation and mitochondrial DNA leakage and subsequently activates the STING (stimulator of interferon gene)-IRF3 (interferon regulatory factor 3)/NF-κB (nuclear factor kappa B) axis. Meanwhile, GSDMD regulates the STING pathway activation and macrophage migration via cytokine secretion. Inhibition of GSDMD with GSDMD-specific inhibitor GI-Y1 (GSDMD inhibitor Y1) can effectively alleviate the progression of atherosclerosis. CONCLUSIONS: Our study has provided a novel macrophage-derived GSDMD mechanism in the promotion of atherosclerosis and demonstrated that GSDMD can be a potential therapeutic target for atherosclerosis.

Macrophage-derived GSDMD promotes abdominal aortic aneurysm and aortic smooth muscle cells pyroptosis.

Macrophage is a vital factor in determining the fate of abdominal aortic aneurysm (AAA). The crosstalk between macrophage and other cells plays a crucial role in the development of aneurysm. Gasdermin D (GSDMD) is a vital executive protein of pyroptosis, which is a novel programmed cell death associated with inflammation. In this study, we identified aortic macrophage as the main expressing cell of GSDMD in AAA. Using Gsdmd-/-ApoE-/- mouse and AAV-F4/80-shGSDMD, we demonstrated the potential role of macrophage-derived GSDMD in AAA and aortic pyroptosis induced by Ang II in vivo. In vitro experiments showed that GSDMD promotes the pyroptosis of mouse primary peritoneal macrophages (MPMs), murine aortic vascular smooth muscle cells (MOVAS) and primary smooth muscle cells. Mechanistically, a mouse cytokine antibody array showed that Gsdmd-/- inhibited LPS + nigericin (LN)- induced secretion of multiple cytokines from MPMs. Furthermore, GSDMD is involved in the crosstalk between MPMs and MOVAS via cytokine secretion. This study provides a novel fundamental insight into macrophage-derived GSDMD in AAA and showed that GSDMD could be a promising therapeutic target for AAA.

Onset of ADL and IADL limitation among Chinese middle-aged and older adults.

It is important to measure the prevalence and onset of limitations for older adults to take critical day-to-day activities in the population. However, too often, only very older people are covered, and too few activities are included in the studies. Using a nationally representative sample from 2011 to 2018 (N = 16, 381), this study characterizes the limitation pattern covering ADL and IADL activities among middle-aged and older adults in China. We use survival models to characterize the limitation transition. We find that half of the population become limited in activities including housekeeping, toileting, managing money, and cooking in their early 70s, followed by shopping, bathing, transferring and dressing in their late 70s, continence, and taking medications in their early 80s, and feeding in their early 90s. In addition, women show significantly younger age of limitation onsets for all activities except continence.

Assessing the impact of COVID-19 interventions on the hand, foot and mouth disease in Guangdong Province, China: a Bayesian modeling study.

Background: The non-pharmaceutical interventions (NPIs) against COVID-19 may have affected the transmission of hand, foot and mouth disease (HFMD). We aimed to assess the impact of the NPIs on HFMD in the high epidemic area of HFMD, Guangdong Province. Methods: The data of HFMD cases, etiological information, and meteorological factors in Guangdong from January 1, 2012, to December 31, 2021, were collected. Using a Bayesian structural time series (BSTS) model integrated counterfactual framework, we assessed the effect of NPIs on HFMD by different intervention periods, populations (gender, age, occupation), and cities. We further explored the correlation between the reduction of HFMD and socioeconomic factors in 21 cities. Results: A total of 351,217 HFMD cases were reported and 455,327 cases were averted in Guangdong Province during 2020-2021 with a reduction of 84.94% (95%CI: 81.63-87.22%) in 2020 and 29.49% (95%CI: 15.26-39.54%) in 2021. The impact of NPIs on HFMD differed by age and gender. The effects of NPIs were more remarkable for children aged 0-2 years and scattered children. We found that the relative reductions in 21 cities were related to the composition ratio of children and COVID-19 incidence. Conclusion: The reduction of HFMD incidence was significantly associated with COVID-19 NPIs, and school closure was an effective intervention to prevent HFMD outbreaks. Our findings will contribute to the development of HFMD prevention and control measures.

[Three-dimensional finite element analysis of Swanson prosthesis-arthroplasty of the first metatarsophalangeal joint combined with osteotomy and bone grafting of the first metatarsal bone for hallux valgus].

Objective: To analyze the biomechanical changes of hallux valus after Swanson prosthesis-arthroplasty of the 1st metatarsophalangeal joint combined with osteotomy and bone grafting of the 1st metatarsal bone by three-dimensional finite element analysis, so as to provide data basis for studying the changes of foot morphology and physiological function after hallux valus correction surgery. Methods: A 65-year-old female patient with severe hallux valus admitted in January 2013 was selected as the research object. The CT data of the right foot was obtained, and the three-dimensional finite element models before and after Swanson prosthesis-arthroplasty of the 1st metatarsophalangeal joint combined with osteotomy and bone grafting of the 1st metatarsal bone were established by Mimics10.01, Geomagic Studio, and ANSYS12.0 software. ANSYS 12.0 software was used for nonlinear static stress analysis, and the hallux valgus angle (HVA), the intermetatarsal angle (IMA), and the von Mises stress distributions of the forefoot plantar surface and the 1st to 5th metatarsal bones were observed before and after operation. Results: The HVA and IMA were 56.3° and 16.3° before operation and 9.2° and 9.8° after operation, respectively. Before operation, the stress on the forefoot was the largest in the 4th metatarsal head zone and the smallest in the 1st metatarsal head zone; the stress on the medial side of the forefoot was significantly smaller than that on the lateral side, and the center of forefoot pressure was located on the lateral side. After operation, the stress on the forefoot was the largest in the 1st metatarsal head zone and the smallest in the 5th metatarsal head zone; the stress on the lateral side of the forefoot was significantly smaller than that on the medial side, and the center of forefoot pressure was located on the medial side. Before operation, the stress of the 5th metatarsal bone was the largest, and the 1st metatarsal bone was the smallest. After operation, the stress of the 1st metatarsal bone was the largest, and the 4th metatarsal bone was the smallest. Conclusion: Swanson prosthesis-arthroplasty of the 1st metatarsophalangeal joint combined with osteotomy and bone grafting of the 1st metatarsal bone can effectively correct hallux valgus and make HVA, IMA, and plantar pressure distribution close to normal. However, postoperative stresses of the 1st to 5th metatarsal bones elevate, which may lead to associated complications.

Why Was There More Household Stock Market Participation During the COVID-19 Pandemic?

Although the nation was experiencing an economic downturn due to the COVID-19 pandemic outbreak, we nonetheless observed an increase in household equity share value relative to both domestic market capitalization and retail investors' trading volume. In this paper, we aim to interpret the reasons underlying this seemingly unexpected phenomenon. We investigate portfolio choices with stocks, bonds, and life annuities under an inverse S-shaped probability distortion function. The results indicate that people invest more heavily in risky assets and buy more annuities when reducing their savings in risk-free accounts, which is indeed consistent with the reality.

Health-seeking and diagnosis delay and its associated factors: a case study on COVID-19 infections in Shaanxi Province, China.

This time-to-event study examines social factors associated with health-seeking and diagnosis of 165 COVID-19 cases in response to the pandemic spread in Shaanxi Province, China. In particular, we investigate the differential access to healthcare in terms of delayed time from symptom onset to first medical visit and subsequently to diagnosis by factors such as sex, age, travel history, and type of healthcare utilization. We show that it takes more time for patients older than 60 (against those under 30) to seek healthcare after developing symptoms (+ 2.5 days, [Formula: see text]), surveillance on people with living or travel history to Wuhan helps shorten the time to the first doctor visit (- 0.8 days) and diagnosis (- 2.2 days, [Formula: see text]). A delay cut is associated with the adoption of intermediary and large hospitals rather than community-based care as primary care choices (- 1.6 days, [Formula: see text] and - 2.2 days, [Formula: see text]). One unit increase of healthcare workers per 1000 people saves patients 0.5 days ([Formula: see text]) for diagnosis from the first doctor visit and 0.6 days ([Formula: see text]) in total. Our analysis of factors associated with the time delay for diagnosis may provide a better understanding of the health-seeking behaviors of patients and the diagnosis capacity of healthcare providers during the COVID-19 pandemic.

TDP43 Exacerbates Atherosclerosis Progression by Promoting Inflammation and Lipid Uptake of Macrophages.

OBJECTIVE: Atherosclerosis (AS), characterized by cholesterol overloaded-macrophages accumulation and plaque formation in blood vessels, is the major cause of cardiovascular disease. Transactive response DNA-binding protein∼43 kDa (TDP43) has recently been identified as an independent driver of neurodegenerative diseases through triggering inflammatory response. This study investigated whether TDP43 is involved in AS development, especially in macrophages-mediated-foam cell formation and inflammatory responses. METHODS: Transactive response DNA-binding protein∼43 kDa expressions in oxidized low-density lipoprotein (oxLDL)-treated macrophages and peripheral blood mononuclear cells (PBMCs) from patients with coronary artery disease (CAD) were detected by real time-polymerase chain reaction (RT-PCR), Western blot, and immunofluorescence. Gene gain or loss of function was used to investigate the effects of TDP43 on macrophages-mediated lipid untake and inflammation with ELISA, protein immunoprecipitation, RT-PCR, Western blot, and immunofluorescence. Macrophage TDP43 specific knockout mice with ApoE-/- background were fed with western diet for 12 weeks to establish AS model, and used to explore the role of TDP43 on AS progression. RESULTS: Transactive response DNA-binding protein∼43 kDa expression increases in oxLDL-treated macrophages and PBMCs from patients with CAD. Furthermore, we find that TDP43 promotes activation of NF-κB to increase inflammatory factor expression in macrophages through triggering mitochondrial DNA release to activate cGAS-STING signaling. Moreover, TDP43 strengthens lipid uptake of macrophages through regulating ß-catenin and PPAR-γ complex to promote scavenger receptor gene CD36 transcription. Finally, using macrophage TDP43 specific knockout mice with ApoE-/- background fed with western diet for 12 weeks to establish AS model, we find that specific knockout of TDP43 in macrophages obviously alleviates western diet-induced AS progression in mice. CONCLUSIONS: Transactive response DNA-binding protein∼43 kDa exacerbates atherosclerosis progression by promoting inflammation and lipid uptake of macrophages, suggesting TDP43 as a potential target for developing atherosclerotic drug.

Characterization of fragment sizes, copy number aberrations and 4-mer end motifs in cell-free DNA of hepatocellular carcinoma for enhanced liquid biopsy-based cancer detection.

Circulating cell-free DNA (cfDNA) fragmentomics, which encompasses the measurement of cfDNA length and short nucleotide motifs at the ends of cfDNA molecules, is an emerging field for cancer diagnosis. The utilization of cfDNA fragmentomics for the diagnosis of patients with hepatocellular carcinoma (HCC) caused by hepatitis B virus (HBV) is currently limited. In this study, we utilized whole-genome sequencing data of cfDNA in samples from patients with HCC (n = 197) and HBV (n = 187) to analyze the association of fragment size selection (< 150 bp) with tumor fraction (TF), copy number variation (CNV) alterations and the change in the proportion of 4-mer end motifs in HCC and HBV samples. Our analyses identified five typical CNV markers (i.e. loss in chr1p, chr4q and chr8p, and gain in chr1q and chr8q) in cfDNA with a cumulatively positive rate of ˜ 95% in HCC samples. Size selection (< 150 bp) significantly enhanced TF and CNV signals in HCC samples. Additionally, three 4-mer end motifs (CCCA, CCTG and CCAG) were identified as preferred end motifs in HCC samples. We identified 139 end motifs significantly associated with fragment size that showed similar patterns of associations between patients with HCC and HBV, suggesting that end motifs might be inherently coupled with fragment size by a ubiquitous mechanism. Here we conclude that CNV markers, fragment size selection and end-motif pattern in cfDNA have potential for effective detection of patients with HCC.

An extended hierarchical ordered probit model robust to heteroskedastic vignette perceptions with an application to functional limitation assessment.

To improve interpersonal comparability of self-reported measures, anchoring vignettes are increasingly collected in surveys and modeled as the hierarchical ordered probit (HOPIT) model. This paper-based on the idea of psychological distance-relaxes the assumption of vignette equivalence in the HOPIT by allowing for heteroscedasticity in respondents' perceptions of vignettes. Particularly, we assume that respondents who are more similar to a vignette are more familiar with the condition described and therefore are capable of forming a more precise perception of the vignette. We show evidence in favor of this extended HOPIT through Monte Carlo simulations and an application concerning self-reported vision difficulty from the WHO Study on Global Aging and Adult Health (SAGE).

RBM4 regulates M1 macrophages polarization through targeting STAT1-mediated glycolysis.

M1/M2 macrophages polarization play important roles in regulating tissue homeostasis. Recently, RNA-binding motif 4 (RBM4) has been reported to modulate the proliferation and expression of inflammatory factors in HeLa cells. However, whether RBM4 is involved in regulating macrophage polarization and inflammatory factor expression are still unknown. In this study, RAW264.7, a mouse macrophage cell line, were stimulated with interferon γ (IFN-γ) or interleukin-4 (IL-4) to induce M1/M2 macrophages polarization. We found that IFN-γ, but not IL-4, stimulation decreased RBM4 expression in macrophages, and RBM4 overexpression inhibits IFN-γ-induced M1 macrophage polarization. Furthermore, RNA-Sequencing, protein immunoprecipitation accompanied with mass spectrometry, and extracellular acidification rate analysis showed that RBM4 suppresses IFN-γ-induced M1 macrophage polarization though inhibiting glycolysis. Moreover, RBM4 knockdown promoted IFN-γ-induced signal transducer and activator of transcription 1 (STAT1) activation via increasing STAT1 mRNA stability, leading to the increase of glycolysis-related gene transcripts regulated by STAT1. Finally, we find that RBM4 interacts with YTH N6-methyladenosine RNA binding protein 2 (YTHDF2) to degrade m6A modified STAT1 mRNA, thereby regulating glycolysis and M1 macrophage polarization. Collectively, the current study firstly reports that RBM4 regulates M1 macrophages polarization through targeting STAT1-mediated glycolysis and shows that RBM4 is a possible candidate for regulating macrophage M1 polarization and inflammatory responses.

Effect of Heat Treatment Temperature on the Spinning Structure and Properties of a Cu-Sn Alloy.

A thin-walled copper (Cu)-tin (Sn) alloy cylinder was treated after spinning at 200-400°C for 0.5 h. The characteristics of the alloy microstructure under different temperatures were analyzed through electron back-scattered diffraction. The results were as follows. The grain size at 200-300°C decreases as the heat treatment temperature rises, but the grain size at 400°C increases. At 200-300°C, the microstructure primarily consists of deformed grains. It is found that the main reason for the formation of high-angle grain boundaries (HAGBs) is static recrystallization. For the grain boundary orientation differential, the low-angle sub-grain boundary gradually grows into the HAGB, and multiple annealing twin Σ9 boundaries appear. Grain orientation is generally random at any temperature range. The mechanical property test indicated that, at the upper critical recrystallization temperature of 300°C, the elongation of the Cu-Sn alloy gradually increases, and its yield strength and ultimate tensile strength rapidly decrease.

Hyperuricemia and Cardiovascular Disease.

Purine metabolism in the circulatory system yields uric acid as its final oxidation product, which is believed to be linked to the development of gout and kidney stones. Hyperuricemia is closely correlated with cardiovascular disease, metabolic syndrome, and chronic kidney disease, as attested by the epidemiological and empirical research. In this review, we summarize the recent knowledge about hyperuricemia, with a special focus on its physiology, epidemiology, and correlation with cardiovascular disease. This review also discusses the possible positive effects of treatment to reduce urate levels in patients with cardiovascular disease and hyperuricemia, which may lead to an improved clinical treatment plan.

LncRNA MALAT1 regulates oxLDL-induced CD36 expression via activating ß-catenin.

The expression of scavenger receptors in macrophages regulating lipid uptake plays an important role in foam cell formation and the subsequent atherosclerotic plaque formation. Long non-coding RNA MALAT1 is abundantly expressed in THP-1-derived macrophages, and oxidized low-density lipoprotein promotes its transcription by qRT-PCR and RNA FISH detection. Through chemical inhibitor treatments and by performing a dual luciferase reporter analysis, we found that oxLDL induces MALAT1 transcription through the NF-κB pathway. The knockdown of MALAT1 using siRNA transfection affects lipid uptake in macrophages. To understand the details, we checked the scavenger receptors, which mainly control lipid uptake, and found that MALAT1 knockdown decreased CD36 expression. Additionally, we also incubated macrophages with actinomycin D, combined with a dual luciferase reporter analysis, and we found that MALAT1 influenced CD36 expression at the transcription level. We aim to investigate the detailed mechanism by which MALAT1 promotes CD36 transcription, and thus, we designed and synthesized biotin-TEG labeled oligonucleotides to precipitate the MALAT1 RNA-DNA-protein complex in vivo. Combined with SDS-PAGE electrophoresis and a subsequent mass spectra analysis, ß-catenin, a transcription factor that promotes CD36 transcription, was found in the complex. By performing R-IPs, we validated that ß-catenin was bound to MALAT1 under the oxLDL treatment. In addition, using VAX939, a chemical inhibitor of ß-catenin, MALAT1 was demonstrated to promote CD36 transcription partly via ß-catenin. We also performed chips to detect whether MALAT1 affects ß-catenin accumulation in the binding sites of the CD36 promoter and found that MALAT1 knockdown decreases ß-catenin binding to the CD36 promoter and vice versa. In conclusion, oxLDL induced MALAT1 transcription and MALAT1 recruits ß-catenin to binding sites on the CD36 promoter to induce CD36 expression, which enhances lipid uptake in macrophages.

Association of P2Y12 gene promoter DNA methylation with the risk of clopidogrel resistance in coronary artery disease patients.

BACKGROUND: Clopidogrel inhibits the ADP receptor P2Y12 to keep down the platelet aggregation. The goal of our study is to investigate the contribution of P2Y12 promoter DNA methylation to the risk of clopidogrel resistance (CR). METHODS: The platelet functions were measured by the VerifyNow P2Y12 assay. Applying the bisulfite pyrosequencing technology, DNA methylation levels of two CpG dinucleotides on P2Y12 promoter were tested among 49 CR cases and 57 non-CR controls. We also investigated the association among P2Y12 DNA methylation, various biochemical characteristics, and CR. RESULT: Lower methylation of two CpGs indicated the poorer clopidogrel response (CpG1, P=0.009; CpG2, P=0.022) in alcohol abusing status. Meanwhile CpG1 methylation was inversely correlated with CR in smoking patients (P=0.026) and in subgroup of Albumin<35 (P=0.002). We observed that the level of DNA methylation might be affected by some clinical markers, such as TBIL, LEVF, Albumin, AST. The results also showed that the quantity of stent, fasting blood-glucose, and lower HbAC1 were the predictors of CR. CONCLUSIONS: The evidence from our study indicates that P2Y12 methylation may bring new hints to elaborate the pathogenesis of CR.