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Introduction and Objectives: Acute liver injury (ALI) is characterized by massive hepatocyte death with high mortality and poor prognosis. Hepatocyte pyroptosis plays a key role in the physiopathological processes of ALI, which can damage mitochondria and release NLRP3 inflammasome particles, causing systemic inflammatory responses. Z-DNA Binding Protein 1 (ZBP1) is a sensor that induces cell death. Here, we investigated whether ZBP1 participates in hepatocyte pyroptosis and explored the possible pathogenesis of ALI. Materials and Methods: Hepatocyte pyrotosis was induced with lipopolysaccharide (LPS) and nigericin (Nig), and the expression of Zbp1 (ZBP1) was examined by western blot analysis and RT-qPCR. Further, we transfected AML-12 (LO2 and HepG2) cell lines with Zbp1 (ZBP1) siRNA. After ZBP1 was silenced, LDH release and flow cytometry were used to measure the cell death; Western blot analysis and RT-qPCR were used to detect the marker of NLRP3 inflammasome activation and pyroptosis. We also detected the expression of mitochondrial linear rupture marker phosphoglycerate mutase family member 5 (PGAM5) using western blot analysis and reactive oxygen species (ROS) using the DCFH-DA method. Results: The expression of ZBP1 was up-regulated in LPS/Nig-induced hepatocytes. Si-Zbp1 (Si-ZBP1) inhibited NLRP3 inflammasome activation and pyroptosis in LPS/Nig-induced hepatocytes. Moreover, ZBP1 silencing inhibited the expression of PGAM5 by reducing ROS production. Conclusions: ZBP1 promotes hepatocellular pyroptosis by modulating mitochondrial damage, which facilitates the extracellular release of ROS.

Abstract Background The majority of HBeAg-positive mothers with chronic hepatitis B have high levels of viremia and inactive disease with normal alanine aminotransferase (ALT) during pregnancy. In addition, postpartum disease activation and ALT flare have been reported in the range of 15 − 35%. However, the current International Association Guidelines have not provided clear recommendations and a risk-stratified monitoring schedule. Furthermore, data are lacking on the definition of normal ALT in the postpartum period in mothers with chronic hepatitis B. The clinical features and ALT flare patterns in HBeAg-positive mothers versus HBeAg-negative mothers are not fully explored. Thus, we design a cohort study to investigate the aforementioned area and generate data to assist healthcare providers in better managing mothers with hepatitis B. We aim to assess the frequency of postpartum ALT flares and predictors for such events. Method This study is a single-center and prospective cohort study (n = 360) that consists of two groups of patients including HBsAg-positive mothers (n = 120) and healthy mothers without HBV infection (n = 240). In HBeAg-positive mothers, antiviral therapy during late pregnancy is permitted to prevent Mother-to-child transmission (MTCT) but discontinued at delivery if there is no further indication for the treatment. Mothers are enrolled at the gestational weeks of 12–24. After delivery, both mothers and their infants will be followed up until postpartum week 24. Clinical and laboratory data are collected every 4 weeks during the study except there are no follow-up visits at the postpartum weeks 16 and 20. The primary objective is the proportion of patients with postpartum ALT flares. The secondary objectives are independent risk factors during pregnancy for predicting postpartum ALT flares and the normal range of postpartum ALT levels in healthy mothers. Discussion The current study focuses on the incidence of postpartum ALT flares in mothers with chronic hepatitis B including subgroup analysis based on HBeAg status. The data will have several clinical implications, such as providing evidence for an appropriate monitoring schedule in CHB mothers after delivery. Further analyses on predictors of such events may assist clinicians in identifying mothers who might develop severe postpartum ALT flares. The data generated from healthy mothers have the potential to identify the patterns of ALT changes during pregnancy and postpartum, so we can gain a better understanding of the normal range of ALT in this subpopulation. Trial Registration Number at the Chinese Clinical Trial Registry ChiCTR2200061130.

Abstract Background Cerebral malaria (CM) is a manifestation of malaria caused by plasmodium infection. It has a high mortality rate and severe neurological sequelae, existing a significant research gap and requiring further study at the molecular level. Methods We downloaded the GSE117613 dataset from the Gene Expression Omnibus (GEO) database to determine the differentially expressed genes (DEGs) between the CM group and the control group. Weighted gene coexpression network analysis (WGCNA) was applied to select the module and hub genes most relevant to CM. The common genes of the key module and DEGs were selected to perform further analysis. The least absolute shrinkage and selection operator (LASSO) logistic regression and support vector machine recursive feature elimination (SVM-RFE) were applied to screen and verify the diagnostic markers of CM. Eventually, the hub genes were validated in the external dataset. Gene set enrichment analysis (GSEA) was applied to investigate the possible roles of the hub genes. Results The GO and KEGG results showed that DEGs were enriched in some neutrophil-mediated pathways and associated with some lumen structures. Combining LASSO and the SVM-RFE algorithms, LEF1 and IRAK3 were identified as potential hub genes in CM. Through the GSEA enrichment results, we found that LEF1 and IRAK3 participated in maintaining the integrity of the blood–brain barrier (BBB), which contributed to improving the prognosis of CM. Conclusions This study may help illustrate the pathophysiology of CM at the molecular level. LEF1 and IRAK3 can be used as diagnostic biomarkers, providing new insight into the diagnosis and prognosis prediction in pediatric CM.

Scrub typhus (ST) is an acute focal infectious disease that is caused by Orientia tsutsugamushi . The Asia-Pacific region is an area of relatively high incidence. There is a high incidence in China, principally owing to the disease being endemic in the south of the country. The main source of ST infection is rats, which act as reservoirs of infection after being bitten by the chigger mite, and the human population is generally susceptible to the disease. ST can be controlled and treated successfully if antibiotics are administered in a timely manner. However, because it does not have a specific clinical manifestation, it is difficult to distinguish ST from other febrile diseases in clinical practice. Therefore, rapid diagnostic methods are still needed to help clinicians make a timely diagnosis. Here, we share three cases of patients with ST who experienced hemorrhage, but did not have typical skin lesions, such as eschar and ulcer, early in the course of their disease, and review the relevant literature regarding ST. We conclude that clinicians should pay attention to the risk of hemorrhage associated with this disease, and emphasize the importance of making an early diagnosis.

Acute liver failure (ALF) is a severe liver disease caused by disruptions in the body’s immune microenvironment. In the early stages of ALF, Kupffer cells (KCs) become depleted and recruit monocytes derived from the bone marrow or abdomen to replace the depleted macrophages entering the liver. These monocytes differentiate into mature macrophages, which are activated in the immune microenvironment of the liver and polarized to perform various functions. Macrophage polarization can occur in two directions: pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages. Controlling the ratio and direction of M1 and M2 in ALF can help reduce liver injury. However, the liver damage caused by pyroptosis should not be underestimated, as it is a caspase-dependent form of cell death. Inhibiting pyroptosis has been shown to effectively reduce liver damage induced by ALF. Furthermore, macrophage polarization and pyroptosis share common binding sites, signaling pathways, and outcomes. In the review, we describe the role of macrophage polarization and pyroptosis in the pathogenesis of ALF. Additionally, we preliminarily explore the relationship between macrophage polarization and pyroptosis, as well as their effects on ALF.

Abstract Glioblastomas (GBM) is the most common primary malignant brain tumor, and radiotherapy plays a critical role in its therapeutic management. Unfortunately, the development of radioresistance is universal. Here, we identified calcium-regulated heat-stable protein 1 (CARHSP1) as a critical driver for radioresistance utilizing genome-wide CRISPR activation screening. This is a protein with a cold-shock domain (CSD)-containing that is highly similar to cold-shock proteins. CARHSP1 mRNA level was upregulated in irradiation-resistant GBM cells and knockdown of CARHSP1 sensitized GBM cells to radiotherapy. The high expression of CARHSP1 upon radiation might mediate radioresistance by activating the inflammatory signaling pathway. More importantly, patients with high levels of CARHSP1 had poorer survival when treated with radiotherapy. Collectively, our findings suggested that targeting the CARHSP1/TNF-α inflammatory signaling activation induced by radiotherapy might directly affect radioresistance and present an attractive therapeutic target for GBM, particularly for patients with high levels of CARHSP1.

Abstract Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has spread to many countries around the world. In addition to lung disease, severe cases also displayed varying degrees of liver injury. This article will describe the latest developments regarding coronavirus and the pathogenesis of liver injury, the prone population and clinical characteristics of these patients, as well as providing some suggestions for clinical treatment.

ObjectiveThis article aims to study the influencing factors of pgRNA and its change magnitude based on the real world.MethodsA total of 421 patients who were tested for pgRNA were selected. According to the baseline data, the subjects were divided into negative and positive groups. The Chi-square test and logistic regression were used to analyze the influencing factors of pgRNA status. Based on the follow-up data, the rank-sum test and linear regression were used to analyze the influencing factors of pgRNA change magnitude.ResultsA total of 153 (36.3%) of the 421 subjects were pgRNA-negative and 268 (63.7%) were pgRNA-positive. Logistic regression analysis showed that positive HBV DNA (OR: 40.51), positive HBeAg (OR: 66.24), tenofovir treatment (OR: 23.47), and entecavir treatment (OR: 14.90) were the independent risk factors for positive pgRNA. Univariate linear regression showed that the pgRNA change magnitude of patients treated with entecavir was higher than that of patients treated with tenofovir. Multivariate linear regression showed that age was an independent factor influencing pgRNA change magnitude.ConclusionsThe pgRNA of patients who were young, female, HBV DNA-positive, high-HBsAg, HBeAg-positive is higher than the detection line. HBV DNA and HBeAg are the independent risk factors of positive pgRNA. Different antiviral regimens and disease stages have significantly different effects on pgRNA status. There was a significant correlation between pgRNA and FIB-4, suggesting that pgRNA is related to liver fibrosis. The decrease in pgRNA was greater in young patients than in non-young patients. The decrease in pgRNA was greater in patients treated with tenofovir than in patients treated with entecavir.

BackgroundDrug exposure during gestation or in prematurely born children represents a significant risk to congenital heart disease (CHD). Amantadine is an antiviral agent also effective in the treatment of Parkinson’s disease. However, while its potential side effects associated with tetralogy of fallot (ToF) and birth defects were implicated, its underlying etiologic mechanisms of action remain unknown. Here, we report teratogenic effects of amantadine drug during early cardiogenesis through developing a novel zebrafish (Danio rerio) knock-in (KI) animal model and explore the underlying mechanisms.MethodsHomologous recombination (HR) pathway triggered by CRISPR/Cas9 system was utilized to generate an enhanced green fluorescent protein (EGFP) KI zebrafish animal model. Dynamic fluorescence imaging coupled with a whole-mount in-situ hybridization (WISH) assay was employed to compare the spatial and temporal expression patterns of the EGFP reporter in the KI animal model with the KI-targeted endogenous gene. Heart morphology and EGFP expression dynamics in the KI animal models were monitored to assess cardiac side effects of different doses of amantadine hydrochloride. Expression of key genes required for myocardium differentiation and left–right (LR) asymmetry was analyzed using WISH and quantitative reverse transcription-PCR (RT-PCR).ResultsA novel EGFP KI line targeted at the ventricular myosin heavy chain (vmhc) gene locus was successfully generated, in which EGFP reporter could faithfully recapitulate the endogenous expression dynamics of the ventricle chamber-specific expression of the vmhc gene. Amantadine drug treatment-induced ectopic expression of vmhc gene in the atrium and caused cardiac-looping or LR asymmetry defects to dose-dependently during early cardiogenesis, concomitant with dramatically reduced expression levels of key genes required for myocardium differentiation and LR asymmetry.ConclusionWe generated a novel zebrafish KI animal model in which EGFP reports the ventricle chamber-specific expression of vmhc gene dynamics that is useful to effectively assess drug safety on the cardiac morphology in vivo. Specifically, this study identified teratogenic effects of amantadine drug during early cardiogenesis dose dependent, which could be likely conveyed by inhibiting expression of key genes required for cardiac myocardium differentiation and LR asymmetry.

Abstract Background Streptococcus agalactiae (GBS) is the causative pathogen of puerperal sepsis in pregnant women and pneumonia, sepsis and meningitis in infants. Infection of GBS is responsible for the increased morbidity in pregnant women and the elderly, and bring challenges to clinical diagnosis and treatment. However, culture-based approaches to detect S.agalactiae is time-consuming with limited sensitivity. Besides, real-time quantitative PCR demands expensive instruments with tedious steps. Thus, we aim to establish a new detection method for more accurate and rapid detection of S.agalactiae. Results The ddPCR primer targeted the CpsE gene showed better amplified efficiency in the reaction. The limit of detection for GBS DNA with ddPCR was able to reach 5 pg/μL. Moreover, no positive amplified signals could be detected in the reactions which served 11 non-GBS strains DNA as templates. Furthermore, the coefficient of variation of this method was 4.5%, indicating excellent repeatability of ddPCR assay. Conclusions In our study, ddPCR was performed as a rapid detection of S.agalactiae with high sensitivity and specificity. This technique can promote the accuracy of the diagnosis of GBS infection and provide a scientific basis for clinical treatment.

Novel antibacterial agents are urgently needed to address the infections caused by multi-drug resistant bacteria. Urinary tract infections are common infectious diseases in clinical. Most of these infections are caused by drug-resistant uropathogenic Escherichia coli. PPK1 is an essential kinase for bacterial motility, biofilm formation, quorum sensing, and virulence factors in the expression of uropathogenic E. coli. In the present study, two small molecules potentially targeting PPK1 were discovered through virtual screening and biological assays. The in vitro and in vivo results suggested that the interaction of these compounds with PPK1 can disrupt biofilm formation of uropathogenic E. coli and reduce invasive ability and resistance to oxidative stress of this strain. Moreover, the compounds exhibit good antibacterial bacterial activity in the mice with urinary tract infection. Taken together, our findings could provide a new chemotype for the development of antibacterials targeting PPK1.

Backgroud: The metabolism of epicardial adipose tissue (EAT) is closely related to coronary atherosclerotic heart disease (CAHD), but the specific mechanism is not fully understood. In this study, we investigated the effects of EAT microenvironment on adipose metabolism from the viewpoint of EAT-derived exosomes and epicardial adipose stem cells (EASCs).Methods: EAT samples from CAHD patients and non-CAHD patients were collected to obtain exosomes via tissue culture. MiRNA sequencing was performed to analyze differences in miRNA expression in exosomes between groups. Luciferase reporter assay was then performed to verify the miRNA target gene. EAT was digested by collagenase to obtain EASCs, which were induced to mature adipocytes in vitro. Immunochemical staining and western blotting were performed to detect protein expression levels.Results: The results showed that CAHD patients had higher levels of EASCs in EAT, and no significant difference in the adipogenic differentiation ability of EASCs was observed between CAHD and non-CAHD patients in vitro. This indicates that the EAT microenvironment is a key factor affecting the adipogenic differentiation of EASCs. The EAT-derived exosomes from CAHD patients inhibited adipogenic differentiation of EASCs in vitro. Sequencing analysis showed that miR-3064-5p was highly expressed in EAT-derived exosomes in CAHD patients, and its inhibitor could improve the adipogenic differentiation of EASCs. Luciferase reporter assay results showed that the target gene of miR-3064-5p is neuronatin (Nnat). Nnat remained silent in EASCs and was less expressed in EAT of CAHD patients.Conclusion: Abovementioned results suggest that Nnat is the key to regulating the adipogenic differentiation of EASCs, and miR-3064-5p in EAT-derived exosomes can inhibit the expression of Nnat by targeting its mRNA, thereby affecting the adipogenic differentiation of EASCs.

This study investigated the effects of reynoutrin on the improvement of ischemic heart failure (IHF) and its possible mechanism in rats. The rat heart failure model was established by permanently ligating the left anterior descending coronary artery (LAD) and administering different doses of reynoutrin. Cardiac function, inflammatory factors releasing, oxidative stress, cardiomyocytes apoptosis, and myocardial fibrosis were evaluated. Western blotting was used to determine protein expression levels of S100 calcium-binding protein A1 (S100A1), matrix metallopeptidase 2(MMP2), MMP9, phosphorylated (p-) p65, and transforming growth factor -β1 (TGF-β1) in myocardial tissue of the left ventricle. Results showed that reynoutrin significantly improved cardiac function, suppressed the release of inflammatory factors, reduced oxidative stress, inhibited cardiomyocytes apoptosis, and attenuated myocardial fibrosis in rats with IHF. In rat myocardial tissue, permanent LAD-ligation resulted in a significant down-regulation in S100A1 expression, whereas reynoutrin significantly up-regulated S100A1 protein expression while down-regulating MMP2, MMP9, p-p65, and TGF-β1 expressions. However, when S100A1 was knocked down in myocardial tissue, the above-mentioned positive effects of reynoutrin were significantly reversed. Reynoutrin is a potential natural drug for the treatment of IHF, and its mechanism of action involves the up-regulation of S100A1 expression, thereby inhibiting expressions of MMPs and the transcriptional activity of nuclear factor kappa-B.

ABSTRACT The consequences of COVID-19 infecting pregnant women and the potential risks of vertical transmission have become a major issue. Since little is currently known about COVID-19 in pregnancy, the understanding of COVID-19 in this particular group will be updated in time, and a comprehensive review will be useful to evaluate the impact of COVID-19 in pregnancy. Based on recently published literature and official documents, this review provides an introduction to the pathogenesis, pathology, and clinical features of COVID-19 and has focused on the current researches on clinical features, pregnancy outcomes and placental histopathological analysis from pregnant women infected with SARS-CoV-2 in comparison with SARS-CoV and MERS-CoV. These viruses trigger a cytokine storm in the body, produce a series of immune responses, and cause changes in peripheral leukocytes and immune system cells leading to pregnancy complications that may be associated with viral infections. The expression of ACE2 receptors in the vascular endothelium may explain the histological changes of placentas from pregnant women infected by SARS-CoV-2. Pregnant women with COVID-19 pneumonia show similar clinical characteristics compared with non-pregnant counterparts. Although there is no unequivocal evidence to support the fetal infection by intrauterine vertical transmission of SARS, MERS and SARS-CoV-2 so far, more and more articles began to report maternal deaths due to COVID-19. In particular, from February 26, 2020 (date of the first COVID-19 case reported in Brazil) until June 18, 2020, Brazil reported 124 maternal deaths. Therefore, pregnant women and neonates require special attention regarding the prevention, diagnosis and management of COVID-19.

Lei Bai,1,* Zhenqiu Liu,2,3,* Qiwen Fang,2,3 Qiong Yan,4 Oumin Shi,5 Pingping Bao,6 Lina Mu,7 Xingdong Chen,8,9 Tiejun Zhang2,3 1Institut Pasteur of Shanghai, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China; 2Department of Epidemiology, School of Public Health, Fudan University, Shanghai, China; 3Key Laboratory of Public Health Safety, Fudan University, Ministry of Education, Shanghai, China; 4Department of Child and Maternal Health, School of Public Health, Fudan University, Shanghai, China; 5Department of Neurology, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China; 6Department of Chronic Non-Communicable Disease Surveillance, Shanghai Municipal Center for Disease Control and Prevention, Shanghai, China; 7Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, State University of New York (SUNY) at Buffalo, Buffalo, NY, USA; 8State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China; 9Fudan University Taizhou Institute of Health Sciences, Taizhou, China *These authors contributed equally to this work Background: In 2012, liver cancer ranked as the fifth and eighth most common cancer in men and women, respectively, in urban Shanghai. This study aims to present the trend and projection of age-specific incidence and mortality of liver cancer in Shanghai.Methods: We extracted data of liver cancer incident cases and deaths between 1973 and 2012. An age–period–cohort model was used to analyze the data.Results: A total of 47,344 men and 18,692 women were diagnosed with liver cancer from 1973 to 2012. The overall age-standardized incidence was 26.89 and 8.89 per 100,000 for men and women, respectively. Correspondingly, a total of 44,355 and 18,084 men and women died from liver cancer during this period. The overall age-standardized death rate was 25.34 per 100,000 in men and 9.39 per 100,000 in women. Between 1973 and 2012, liver cancer incidence and mortality in all age groups, except people aged 0–19 years, experienced a significant decline. Similar temporal patterns were detected in liver cancer mortality in both sexes when compared with incidence. Liver cancer incidence and mortality are expected to further decline among all age groups in 2013–2020 in both sexes, though the numbers of incident cases will remain stable.Conclusion: Incidence and mortality of liver cancer in urban Shanghai have decreased by about 40% and 50%, respectively, over the past four decades. This decline is expected to continue in the near future. However, the population is aging, which is reflected in the increasing crude rates and decreasing age-adjusted rates. Keywords: liver cancer, incidence, mortality, Shanghai

An amendment to this paper has been published and can be accessed via the original article.

In this experiment, a series of poly(propylene 2,5-furan dicarboxylate)-b-poly(ethylene glycol) (PPFEG) copolymers with different ratios were synthesized using melt polycondensation of dimethylfuran-2,5-dicarboxylate (DMFD), 1,3-propanediol (PDO) and poly(ethylene glycol) (PEG). The effect of PEG content on the crystallization behavior of the poly(propylene 2,5-furan dicarboxylate) (PPF) copolymers was investigated. For PPF, the nucleation density of the β -crystals was higher than that of α -crystals. As T c increases, the β crystals are suppressed more, but at T c = 140 °C, the bulk of PPF has already been converted to α crystals, which crystallize faster at higher nucleation densities, resulting in a difference in polymer properties. For this case, we chose to add a soft segment material, PEG, which led to an early multi-melt crystallization behavior of the PPF. The addition of PEG led to a decrease in the crystallization temperature of PPF, as well as a decrease in the cold crystallization peak of PPF. From the crystalline morphology, it can be seen that the addition of PEG caused the transformation of the PPF crystalline form to occur earlier. From the crystalline morphology of PPF at 155 °C, it can be observed that the ring-banded spherical crystals of the PPF appear slowly with increasing time. With the addition of PEG, spherical crystals of the ring band appeared earlier, and even appeared first, and then disappeared slowly.

Objectives: This study aimed to estimate the burden of colorectal cancer (CRC) attributable to high plasma glucose from 1990 to 2019., Study Design and Methods: Data on the disease burden were retrieved from the Global Burden of Disease online database. Estimated average percentage change (EAPC) was used to quantify the age-standardized mortality rate (ASMR) and age-standardized disability-adjusted life years (DALYs) rate (ASDR) of high plasma glucose-related CRC trends by sex and location between 1990 and 2019., Results: Globally, the death number and DALYs of CRC attributable to high plasma glucose remained a steady increase at global level from 1990 to 2019, and similar trends have been reported in age-standardized rate. The country with the largest number of death cases and DALYs of high plasma glucose-related CRC in 2019 was China, followed by the United States of America and India. Nearly three-quarters of total countries experienced an increase in the ASMR and ASDR, and the greatest increase of ASMR and ASDR was found in Uzbekistan (EAPC = 5.32) and Equatorial Guinea (EAPC = 4.65), respectively. A negative correlation was found between sociodemographic indices and the EAPC of ASMR and ASDR (r ASMR  = -0.259, p < 0.001; r ASDR  = -0.282, p < 0.001)., Conclusions: A significant increase in mortality and DALYs of CRC attributable to high plasma glucose was observed in global and most countries, especially in the developing countries. Public health policies and targeted programs are needed to reduce the burden of disease., (Copyright © 2023 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.)

Advances in immune-based therapies have revolutionized cancer treatment and research. This has triggered growing demand for the characterization of the tumor immune landscape. Although standard immunohistochemistry is suitable for studying tissue architecture, it is limited to the analysis of a small number of markers. Conversely, techniques such as flow cytometry can evaluate multiple markers simultaneously, although information about tissue morphology is lost. In recent years, multiplexed strategies that integrate phenotypic and spatial analysis have emerged as comprehensive approaches to the characterization of the tumor immune landscape. Herein, we discuss an innovative technology combining metal-labeled antibodies and secondary ion mass spectrometry focusing on the technical steps in assay development and optimization, tissue preparation, and image acquisition and processing. Before staining, a metal-labeled antibody panel must be developed and optimized. This hi-plex image system supports up to 40 metal-tagged antibodies in a single tissue section. Of note, the risk of signal interference increases with the number of markers included in the panel. After panel design, particular attention should be given to the metal isotope assignment to the antibody to minimize this interference. Preliminary panel testing is performed using a small subset of antibodies and subsequent testing of the entire panel in control tissues. Formalin-fixed, paraffin-embedded tissue sections are obtained and mounted on gold-coated slides and further stained. The staining takes 2 days and closely resembles standard immunohistochemical staining. Once samples are stained, they are placed in the image acquisition instrument. Fields of view are selected, and images are acquired, uploaded, and stored. The final stage is image preparation for the filtering and removal of interference using the system's image processing software. A disadvantage of this platform is the lack of analytical software. However, the images generated are supported by different computational pathology software.

Background & Aims: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a newly proposed disease category that derived from non-alcoholic fatty liver disease. The impact of MAFLD on health events has not been investigated., Methods: UK Biobank participants were diagnosed for whether MAFLD presented at baseline. Five genetic variants (PNPLA3 rs738409 C/G, TM6SF2 rs58542926 C/T, GCKR rs1260326 T/C, MBOAT7 rs641738 C/T, and HSD17B13 rs72613567 T/TA) were integrated into a genetic risk score (GRS). Cox proportional hazard model was used to examine the association of MAFLD with incident diseases., Results: A total of 160 979 (38.0%, 95% confidence interval [CI] 37.9%, 38.2%) participants out of 423 252 were diagnosed as MAFLD. Compared with participants without MAFLD, MAFLD cases had multivariate adjusted hazard ratio (HR) for liver cancer of 1.59 (95% CI, 1.28, 1.98), cirrhosis of 2.77 (2.29, 3.36), other liver diseases of 2.09 (1.95, 2.24), cardiovascular diseases of 1.39 (1.34, 1.44), renal diseases of 1.56 (1.48, 1.65), and cancers of 1.07 (1.05, 1.10). The impact of MAFLD, especially on hepatic events, was amplified by high GRS, of which the genetic variations in PNPLA3, TM6SF2, and MBOAT7 play the principal roles. MAFLD case with normal body weight is also associated with an increased risk of hepatic outcomes, but the genetic factor seems do not influence the risk in this subpopulation., Conclusions: MAFLD is independently associated with an increased risk of both intrahepatic and extrahepatic events. Fatty liver disease related genetic variants amplify the effect of MAFLD on disease outcomes., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Norovirus (NoV) is the leading cause of acute gastroenteritis (AGE) worldwide. Globally, the GII.4 Sydney 2012 strain has predominated since 2012, although GII.4 variant strains have caused AGE outbreaks in China. Recent patterns of NoV genotype distributions in 6011 children with AGE in Tianjin, China were investigated. NoV was detected using real-time reverse-transcriptase polymerase chain reaction and sequencing of partial sequences of the viral capsid gene. NoV genotypes were determined, and phylogenetic analysis was conducted. Epidemiological and clinical data were compared between children infected with different NoV genotypes. NoV was detected in 27.6% of the specimens tested. GII.4 strains comprised 49.4% infections, followed by GII.3 at 39.9%. Genotypes GII.2, GII.13, GII.17, GII.1, GII.6, and GII.14 were also detected. NoV was detected during most of the year, with a peak season of cases in the winter. Diarrhea, vomiting, fever, abdominal pain, and dehydration were present in patients with NoV infection. The main genotypes were GII.4 and GII.3, with a slight increase in GII.2, beginning in March 2017. Among the GII.4 strains, GII.4 Sydney 2012 was the only epidemic strain in Tianjin. Patients with GII.4 genotypes were more likely to present with diarrhea and vomiting than those with GII.3. Children with GII. Others were prone to suffered from dehydration and abdominal pain than those with GII.3. NoV GII has become the main cause of viral AGE in Tianjin, China. The predominant genotypes of NoV were GII.4 and GII.3. Identification of emerging genotypes is crucial for the prevention and control of NoV-caused AGE., (© 2021 The Authors. Journal of Medical Virology Published by Wiley Periodicals LLC.)

The molecular basis of the mechanism and the potential biomarkers of endometrial cancer (EC) remain to be studied. In the present study, we hypothesized that the comprehensive characterization of transcriptional changes in EC could help achieve this aim. By taking advantage of RNA-seq data from The Cancer Genome Atlas, we determined the profile of differently expressed genes (DEGs) between EC tumor tissues and normal samples. On this basis, we performed Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways enrichment analyses. The interacting partners for each of the DEGs were explored and a protein-protein interaction network was constructed. Consequently, 10 hub genes were identified and their association with mortality in EC patients was investigated. The genes, AURKA, CENPA, and KIF2C, were found to be potential biomarkers for EC with a significant prognostic effect. Our work provided a basis for EC studies in both biological and clinical settings., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: We aimed to synthesize available cohorts about the relationship between various types of noise and hypertension, and to explore the potential dose-response relationship between them in an updated meta-analysis., Methods: PubMed and Embase were searched through October 2019 to identify cohort studies that met predetermined inclusion criteria. A random-effects model was used to combine the results of included studies. Dose-response meta-analysis was conducted to examine the potential dose-response relationship., Results: Eleven cohort studies involving 224,829 participants were included in this systematic review. Pooled result showed that living or working in environment with noise exposure was significantly associated with increased risk of hypertension (RR: 1.18; 95% CI: 1.06 to 1.32), with low heterogeneity (P = 0.098, I 2  = 42.1%). We found no evidence of a nonlinear association of elevated noise with hypertension risk (P = 0.443). The summary risk ratio of hypertension for an increment of per 10 dB(A) of noise was 1.13 (95% CI: 0.99 to 1.28), with moderate heterogeneity (P = 0.003, I 2  = 72.1%)., Conclusions: Integrated evidence from cohort studies supports the hypothesis that exposure to noise may be a risk factor of hypertension., (Copyright © 2021. Published by Elsevier Inc.)

Background: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 infection, has been spreading globally. We aimed to develop a clinical model to predict the outcome of patients with severe COVID-19 infection early., Methods: Demographic, clinical and first laboratory findings after admission of 183 patients with severe COVID-19 infection (115 survivors and 68 non-survivors from the Sino-French New City Branch of Tongji Hospital, Wuhan) were used to develop the predictive models. Machine learning approaches were used to select the features and predict the patients' outcomes. The area under the receiver operating characteristic curve (AUROC) was applied to compare the models' performance. A total of 64 with severe COVID-19 infection from the Optical Valley Branch of Tongji Hospital, Wuhan, were used to externally validate the final predictive model., Results: The baseline characteristics and laboratory tests were significantly different between the survivors and non-survivors. Four variables (age, high-sensitivity C-reactive protein level, lymphocyte count and d-dimer level) were selected by all five models. Given the similar performance among the models, the logistic regression model was selected as the final predictive model because of its simplicity and interpretability. The AUROCs of the external validation sets were 0.881. The sensitivity and specificity were 0.839 and 0.794 for the validation set, when using a probability of death of 50% as the cutoff. Risk score based on the selected variables can be used to assess the mortality risk. The predictive model is available at [https://phenomics.fudan.edu.cn/risk&#95;scores/]., Conclusions: Age, high-sensitivity C-reactive protein level, lymphocyte count and d-dimer level of COVID-19 patients at admission are informative for the patients' outcomes., (© The Author(s) 2020; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Aim: We assessed the correlations between non-invasive fibrosis scores and mortality in both the general population and non-alcoholic fatty liver disease (NAFLD) patients., Methods: We used data from the US National Health and Nutrition Examination Survey 1988-2014. The NAFLD fibrosis score (NFS), Fibrosis-4 index (FIB-4) score, aspartate aminotransferase to platelet ratio index (APRI) score, and Forns index score were calculated at baseline. The associations of these scores with the risk of mortality were determined using additive Cox proportional hazard models. The area under the receiver operating characteristic curve (AUROC) was used to study the predictive capacity of each scoring system., Results: A total of 44 508 participants were included; among them, 9721 deaths occurred during a mean follow-up of 12.5 years. A "J"-shaped correlation pattern was observed for both the FIB-4 and APRI scores. A "U"-shaped correlation pattern was observed for both the Forns index and NFS. Similar correlation patterns were observed in 1955 NAFLD patients. For overall mortality, the AUROC values of the selected fibrosis scores were comparable between general population and NAFLD patients. The superior predictive capacity was found for FIB-4, with AUROC of 75.03% (95% confidence interval, 70.91% to 79.82%) in general population and 75.32% (95% confidence interval, 69.43% to 80.11%) in NAFLD patients, respectively., Conclusions: Non-linear associations were shown between the fibrosis scoring systems and mortality risk. These scores could serve as indicators for mortality in people with or without NAFLD., (© 2020 The Japan Society of Hepatology.)

Viral hepatitis has been recognized as a leading cause of deaths worldwide. We aimed to analyse the disease burden of viral hepatitis at the global, regional and national levels. We collected the data of death number, mortality rate, and disability-adjusted life years (DALYs) of viral hepatitis by sex, age, geography and type of disease from the Global Health Data Exchange platform. Estimated average percentage change (EAPC) was used to quantify the age-standardized mortality rate (ASMR) of viral hepatitis between 1990 and 2017. Globally, the number of deaths from viral hepatitis increased from 980.9 thousand in 1990 to 1412.3 thousand in 2017, accompanying by the DALYs increased from 35.2 million to 43.1 million in the same period. Hepatitis B and C accounted for 97.6% of total viral hepatitis-related deaths worldwide in 2017. While the death number and DALYs were decreased in acute hepatitis A, B, C and E, a significant increase was found in liver cancer and cirrhosis due to hepatitis B and C. The ASMRs of liver cancer and cirrhosis caused by hepatitis B and C were decreased at the global level and in most regions. However, a significant increase was observed in several developed countries, such as the USA and the UK. The disease burden of viral hepatitis continues to increase worldwide, which was driven by the increase in burden of chronic hepatitis B and C., (© 2020 John Wiley & Sons Ltd.)

Background: Ovarian cancer (OC) is a commonly diagnosed gynecologic cancer. Knowing the incidence and mortality rates of OC is critical to understanding the disease burden and updating prevention strategies., Methods: We retrieved the age-standardized incidence and mortality rates (ASIR and ASMR, respectively) of OC from the Global Burden of Disease study online database. Estimated average percentage change (EAPC) was used to quantify the trends of OC incidence and mortality from 1990 to 2017., Results: Worldwide, the number of incident cases and deaths from OC increased from 152.1 and 95.5 thousand in 1990 to 286.1 and 176.0 thousand in 2017, respectively. Both the ASIR and ASMR decreased slightly during the study period (EAPC = -0.10, 95% CI, -0.16, -0.03; EAPC = -0.32, 95% CI, -0.38, -0.27). The greatest decreases of ASIR and ASMR were observed in Western Europe (EAPC = -1.22, 95% CI, -1.31, -1.14; EAPC = -1.31, 95% CI, -1.37, -1.25). A total of 137, 10, and 48 countries or territories experienced an increase, remained stable, and experienced a decrease in OC ASIR, respectively, between 1990 and 2017. For ASMR, a total of 129, 9, and 57 countries or territories experienced an increase, remained stable, and experienced a decrease, respectively, during the same period. The greatest increases in the ASIR and the ASMR were found in countries located in the Caribbean and Latin America., Conclusions: The incidence and mortality of OC significantly decreased in developed countries. However, remarkable increases were observed in more than two-thirds of all countries, suggesting that OC will be more frequently diagnosed in developing countries., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Cardiovascular disease is the leading cause of death in China. The aim of this study was to evaluate the levels of cardiovascular health among Chinese adults and to understand the geographic pattern of cardiovascular health., Methods: In 2015, a total of 74,726 respondents aged ≥ 20 years with no history of cardiovascular disease were randomly sampled from 298 counties/districts of 31 provinces in mainland China and were interviewed. Seven metrics, including smoking, body mass index, physical activity, diet, total cholesterol, blood pressure, and fasting glucose, were determined. Ideal cardiovascular health was defined as the simultaneous presence of all metrics at the ideal level. A score ranging from 0 to 14 was calculated as the sum of all seven metrics for each province. Scores for cardiovascular health behaviors (smoking, body mass index, physical activity and diet) and those for cardiovascular health factors (smoking, total cholesterol, blood pressure, and fasting glucose) were also calculated., Findings: The mean age was 44.4 ± 15.9 years, and 49.3% were women. The age-sex-standardized prevalence of ideal cardiovascular health was universally poor, ranging from 0.02% [95% confidence interval (CI): 0%, 0.05%] in Tibet to 2.76% (95% CI: 0.45%, 5.07%) in Heilongjiang. Ideal diet (7.1%) was the least common factor of the seven metrics in each province and varied considerably across provinces. Other component metrics of ideal cardiovascular health were also spatially patterned. In all provinces, women had higher scores than men for cardiovascular health, health behaviors and health factors. Differences in cardiovascular health and health behavior scores between urban and rural areas were associated with levels of socio-economic development., Interpretation: Strategies for addressing poor cardiovascular health require geographic targeting and localized consideration., Funding: This research was supported by National Key R&D Program, the Shenzhen Strategic Emerging Industry Development Special Fund, and the Fund of "Sanming" Project of Medicine in Shenzhen., Competing Interests: There are no conflicts of interest to declare., (© 2020 Published by Elsevier Ltd.)

Background: Leukemias are a group of life-threatening malignant disorders of the blood and bone marrow. The incidence of leukemia varies by pathological types and among different populations., Methods: We retrieved the incidence data for leukemia by sex, age, location, calendar year, and type from the Global Burden of Disease online database. The estimated average percentage change (EAPC) was used to quantify the trends of the age-standardized incidence rate (ASIR) of leukemia from 1990 to 2017., Results: Globally, while the number of newly diagnosed leukemia cases increased from 354.5 thousand in 1990 to 518.5 thousand in 2017, the ASIR decreased by 0.43% per year. The number of acute lymphoblastic leukemia (ALL) cases worldwide increased from 49.1 thousand in 1990 to 64.2 thousand in 2017, whereas the ASIR experienced a decrease (EAPC = - 0.08, 95% CI - 0.15, - 0.02). Between 1990 and 2017, there were 55, 29, and 111 countries or territories that experienced a significant increase, remained stable, and experienced a significant decrease in ASIR of ALL, respectively. The case of chronic lymphocytic leukemia (CLL) has increased more than twice between 1990 and 2017. The ASIR of CLL increased by 0.46% per year from 1990 to 2017. More than 85% of all countries saw an increase in ASIR of CLL. In 1990, acute myeloid leukemia (AML) accounted for 18.0% of the total leukemia cases worldwide. This proportion increased to 23.1% in 2017. The ASIR of AML increased from 1.35/100,000 to 1.54/100,000, with an EAPC of 0.56 (95% CI 0.49, 0.62). A total of 127 countries or territories experienced a significant increase in the ASIR of AML. The number of chronic myeloid leukemia (CML) cases increased from 31.8 thousand in 1990 to 34.2 thousand in 2017. The ASIR of CML decreased from 0.75/100,000 to 0.43/100,000. A total of 141 countries or territories saw a decrease in ASIR of CML., Conclusions: A significant decrease in leukemia incidence was observed between 1990 and 2017. However, in the same period, the incidence rates of AML and CLL significantly increased in most countries, suggesting that both types of leukemia might become a major global public health concern., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)

Background: Identifying the temporal trends of kidney cancer (KC) incidence in both the past and the future at the global and national levels is critical for KC prevention., Methods: We retrieved annual KC case data between 1990 and 2017 from the Global Burden of Disease (GBD) online database. The average annual percentage change (AAPC) was used to quantify the temporal trends of KC age-standardized incidence rates (ASRs) from 1990 to 2017. Bayesian age-period-cohort models were used to predict KC incidence through 2030., Results: Worldwide, the number of newly diagnosed KC cases increased from 207.3 thousand in 1990 to 393.0 thousand in 2017. The KC ASR increased from 4.72 per 100,000 to 4.94 per 100,000 during the same period. Between 2018 and 2030, the number of KC cases is projected to increase further to 475.4 thousand (95% highest density interval [HDI] 423.9, 526.9). The KC ASR is predicted to decrease slightly to 4.46 per 100,000 (95% HDI 4.06, 4.86). A total of 90, 2, and 80 countries or territories are projected to experience increases, remain stable, and experience decreases in KC ASR between 2018 and 2030, respectively. In most developed countries, the KC incidence is forecasted to decrease irrespective of past trends. In most developing countries, the KC incidence is predicted to increase persistently through 2030., Conclusions: KC incidence is predicted to decrease in the next decade, and this predicted decrease is mainly driven by the decreases in developed countries. More attention should be placed on developing countries., Competing Interests: Competing interestsNone., (© The Author(s) 2020.)

Background: Bystander CPR (B-CPR) is crucial to increase survival of out-of-hospital cardiac arrest (OHCA), and this study is performed to assess the willingness and obstacles of Chinese healthcare professionals (HCPs) to perform B-CPR on strangers, as well as the factors associated with the willingness., Methods: An internet-based questionnaire surveying demographic information, CPR training, CPR knowledge, willingness, and obstacles to perform B-CPR among 10,393 HCPs. A multivariate logistic regression analysis was used to evaluate the factors associated with the willingness., Results: Here, 73.9% of HCPs were willing to perform B-CPR on strangers in China. The factors associated with the willingness were as follows: female, senior, working in Third-class hospitals, working in Pre-hospital emergency and Cardiology or Cardiac surgery, receiving current training, having adequate CPR knowledge. The main obstacles were fear of infection via mouth-to-mouth ventilations (MMV), fear of being blackmailed and fear of legal liability., Conclusion: About three quarters of HCPs are willing to perform B-CPR. Female HCPs, those who have more CPR experience, adequate knowledge, and recent training are more likely to perform B-CPR. Reform of the legal and credit system are needed, and recommendation of hands-only CPR is a possibility to encourage HCPs to perform B-CPR on strangers., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Loss to follow-up (LFU) of ≥2 consecutive months contributes to the poor levels of treatment success in multidrug-resistant tuberculosis (MDR-TB) reported by TB programmes. We explored the timing of when LFU occurs by month of MDR-TB treatment and identified patient-level risk factors associated with LFU.We analysed a dataset of individual MDR-TB patient data (4099 patients from 22 countries). We used Kaplan-Meier survival curves to plot time to LFU and a Cox proportional hazards model to explore the association of potential risk factors with LFU.Around one-sixth (n=702) of patients were recorded as LFU. Median (interquartile range) time to LFU was 7 (3-11) months. The majority of LFU occurred in the initial phase of treatment (75% in the first 11 months). Major risk factors associated with LFU were: age 36-50 years (HR 1.3, 95% CI 1.0-1.6; p=0.04) compared with age 0-25 years, being HIV positive (HR 1.8, 95% CI 1.2-2.7; p<0.01) compared with HIV negative, on an individualised treatment regimen (HR 0.7, 95% CI 0.6-1.0; p=0.03) compared with a standardised regimen and a recorded serious adverse event (HR 0.5, 95% CI 0.4-0.6; p<0.01) compared with no serious adverse event.Both patient- and regimen-related factors were associated with LFU, which may guide interventions to improve treatment adherence, particularly in the first 11 months., Competing Interests: Conflict of interest: I.F. Walker reports grants from DFID, UK Government, during the conduct of the study. Conflict of interest: O. Shi has nothing to disclose. Conflict of interest: J.P. Hicks has nothing to disclose. Conflict of interest: H. Elsey has nothing to disclose. Conflict of interest: X. Wei has nothing to disclose. Conflict of interest: D. Menzies has nothing to disclose. Conflict of interest: Z. Lan has nothing to disclose. Conflict of interest: D. Falzon has nothing to disclose. Conflict of interest: G.B. Migliori has nothing to disclose. Conflict of interest: C. Pérez-Guzmán has nothing to disclose. Conflict of interest: M.H. Vargas has nothing to disclose. Conflict of interest: L. García-García has nothing to disclose. Conflict of interest: J. Sifuentes Osornio has nothing to disclose. Conflict of interest: A. Ponce-De-León has nothing to disclose. Conflict of interest: M. van der Walt has nothing to disclose. Conflict of interest: J.M. Newell has nothing to disclose., (Copyright ©ERS 2019.)

Background: The incidence of cancer was determined by genetic and environmental factors and varied across the world. The discrepancies in cancer profile among Chinese people living in different regions remained obscure., Methods: Chinese people living in urban Shanghai, Hong Kong, Taiwan, Macau, Singapore, and Los Angeles were included in this study. The cancer case data and population data were collected from either the Cancer Incidence in Five Continents Plus database or the regional cancer registry. A rate model was applied to examine the regional differences in cancer risk with Shanghai set as the reference., Results: From 1983 to 2013, the cancer profiles in most regions were changed. Significant differences in cancer incidence, by sex, period, and age, were detected across regions. The most pronounced disparities were found between Shanghai people and American Chinese in Los Angeles. For cancer site, the most significant differences were detected in prostate, gastrointestinal, gynecologic, oral cavity and pharynx, and brain and central nervous system (CNS) cancers. Specifically, Shanghai was significantly higher in stomach, liver, esophageal, pancreatic, and brain and CNS cancers, while lower in colon, prostate, breast, cervical, and oral cavity and pharynx cancers compared with the other five populations., Conclusions: Cancer profile was distinct across Chinese populations, which shared a similar genetic background but lived in different regions. The disparities indicate that cancer development was majorly determined by environmental factors, and suggests that region-tailored cancer prevention strategies were warranted., Impact: The cancer patterns in populations sharing the same genetic background were significantly influenced by different living conditions., (©2019 American Association for Cancer Research.)

Background: China has made substantial progress in tackling its HIV and AIDS epidemic. But the changing patterns of HIV and AIDS incidence based on the longitudinal observation data were rarely studied., Methods: The reporting incidence (RI) and mortality data on HIV and AIDS in China covering 31 provinces from 2004 to 2014 were collected from the Chinese Public Health Science Data Center. To decompose the time-series data, Empirical Mode Decomposition (EMD) was applied to properly describe the trends of HIV and AIDS incidence. A mathematical model was used to estimate the relative change of incidence among provinces and age groups., Results: A total of 483,010 newly HIV infections and 214,205 AIDS cases were reported between 2004 and 2014 nationwide. HIV infection increased from 13,258 in 2004 (RI 1.02 per 100,000 person years) to 74,048 in 2014 (RI 5.46 per 100,000). The number of AIDS cases increased from 3054 in 2004 (RI 0.23 per 100,000) to 45,145 in 2014 (RI 3.33 per 100,000). The overall relative changes for HIV infection and AIDS incidence were 1.11 (95% confidence interval [CI] 1.10-1.13) and 1.28 (95% CI 1.23-1.33), respectively. The relative increase for HIV and AIDS RI was higher in northwest provinces while lower in Henan, Xinjiang, Guangxi and Yunnan. The overall relative changes for HIV infection were 1.12 (95% CI 1.11-1.14) in males and 1.10 (95% CI 1.06-1.13) in females. For AIDS RI, the relative increases were 1.31 (95% CI 1.26-1.36) in males and 1.22 (95% CI 1.17-1.28) in females. The lowest relative increase was detected among young adults, while the largest relative increase (odds ratio [OR] > 1.30) was detected in people aged 55 years or above., Conclusions: HIV and AIDS showed an increasing trend in China from 2004 to 2014, respectively, but the epidemic tended to be under control among provinces and young people that used to have a high HIV and AIDS incidence. Northwest China and older people could be new "hop-spots" for HIV and AIDS risk.

Background: Compared to ST-segment elevation myocardial infarction (STEMI) patients who present at centres with catheterization facilities, those transferred for primary percutaneous coronary intervention (PCI) have substantially longer door-in to door-out (DIDO) times, where DIDO is defined as the time interval from arrival at a non-PCI hospital, to transfer to a PCI hospital. We aimed to identify potentially modifiable factors to improve DIDO times in Ontario, Canada and to assess the impact of DIDO times on 30-day mortality., Methods: A population-based, retrospective cohort study of 966 STEMI patients transferred for primary PCI in Ontario in 2012 was conducted. Baseline factors were examined across timely DIDO status. Multivariate logistic regression was used to examine independent predictors of timely DIDO as well as the association between DIDO times and 30-day mortality., Results: The median DIDO time was 55 min, with 20.1% of patients achieving the recommended DIDO benchmark of ≤30 min. Age (OR > 75 vs 18-55 0.30, 95% CI: 0.16-0.56), symptom-to-first medical contact (FMC) time (OR 61-120mins vs < 60mins 0.60, 95% CI: 0.39-0.90; OR >120mins vs < 60mins 0.53, 95% CI:0.35-0.81) and emergency medical services transport with a pre-hospital electrocardiogram (ECG) (OR EMS transport + ECG vs self-transport 2.63, 95% CI:1.59-4.35) were the strongest predictors of timely DIDO. Patients with timely ECG were more likely to have recommended DIDO times (33.0% vs 12.3%; P < 0.001). A significantly higher proportion of those who met the DIDO benchmark had timely FMC-to-balloon times (78.7% vs 27.4%; P < 0.001). Compared to patients with DIDO time ≤ 30 min, those with DIDO times > 90 min had significantly higher adjusted 30-day mortality rates (OR 2.82, 95% CI:1.10-7.19)., Conclusions: While benchmark DIDO times were still rarely achieved in the province, we identified several potentially modifiable factors in the STEMI system that might be targeted to improve DIDO times. Our findings that patients who received a pre-hospital ECG were still being transferred to non-PCI capable centres suggest strategies addressing this gap may improve patient outcomes.

Purpose: Neural tube defects (NTDs) are common congenital malformations. In this study, we aimed to explore the association between single nucleotide polymorphisms (SNPs) related to one-carbon metabolism (OCM) and NTDs in Han population of Northern China., Methods: A case-control study was conducted in 152 children with NTDs and 169 controls. Twenty-nine SNPs in five genes were genotyped by Sequenom MassARRAY technology, and haplotype analysis was done by Haploview4.2 software., Results: The allele frequency of rs3733890 in betaine-homocysteine methyltransferase (BHMT) gene was statistically different between NTDs and control groups (P = 0.041), and the children with A allele had higher risk for NTDs than G allele (OR = 1.408, 95%CI 1.013-1.956). In addition, there was a statistical difference in the allele and genotype frequencies of rs1051266 in reduced folate carrier1 (RFC1) gene between cases and controls (P = 0.013, 0.034), and the risk for NTDs was also higher in children with G allele and GG genotype, compared with A allele and AA genotype, respectively (OR = 1.492, 95%CI 1.089-2.044; OR = 2.020, 95%CI 1.081-3.780). The statistical significant difference was also found in allele frequency of rs1805087 in methionine synthetase (MTR) gene between cases and controls (P = 0.031), and the children with G allele were associated with an increased NTDs risk, compared with A allele (OR = 1.664, 95%CI 1.045-2.647). Meanwhile, haplotype analysis showed C-A-A-A haplotype of BHMT, and G-G-G-T haplotype of RFC1 was correlated with an increased risk of NTDs, but C-G-A-A haplotype of BHMT and G-G-C-A haplotype of MTR might decrease the risk of NTDs., Conclusions: The BHMT gene rs3733890, RFC1 gene rs1051266 and MTR gene rs1805087 were associated with the occurrence of NTDs in Han population of Northern China. It was confirmed that the gene variation related to OCM was one of the susceptibility factors for NTDs.