The innate immune system can be boosted in response to subsequent triggers by pre-exposure to microbes or microbial products, known as “trained immunity”. Compared to classical immune memory, innate trained immunity has several different features. Firstly, the molecules involved in trained immunity differ from those involved in classical immune memory. Innate trained immunity mainly involves innate immune cells (e.g., myeloid immune cells, natural killer cells, innate lymphoid cells) and their effector molecules (e.g., pattern recognition receptor (PRR), various cytokines), as well as some kinds of non-immune cells (e.g., microglial cells). Secondly, the increased responsiveness to secondary stimuli during innate trained immunity is not specific to a particular pathogen, but influences epigenetic reprogramming in the cell through signaling pathways, leading to the sustained changes in genes transcriptional process, which ultimately affects cellular physiology without permanent genetic changes (e.g., mutations or recombination). Finally, innate trained immunity relies on an altered functional state of innate immune cells that could persist for weeks to months after initial stimulus removal. An appropriate inducer could induce trained immunity in innate lymphocytes, such as exogenous stimulants (including vaccines) and endogenous stimulants, which was firstly discovered in bone marrow derived immune cells. However, mature bone marrow derived immune cells are short-lived cells, that may not be able to transmit memory phenotypes to their offspring and provide long-term protection. Therefore, trained immunity is more likely to be relied on long-lived cells, such as epithelial stem cells, mesenchymal stromal cells and non-immune cells such as fibroblasts. Epigenetic reprogramming is one of the key molecular mechanisms that induces trained immunity, including DNA modifications, non-coding RNAs, histone modifications and chromatin remodeling. In addition to epigenetic reprogramming, different cellular metabolic pathways are involved in the regulation of innate trained immunity, including aerobic glycolysis, glutamine catabolism, cholesterol metabolism and fatty acid synthesis, through a series of intracellular cascade responses triggered by the recognition of PRR specific ligands. In the view of evolutionary, trained immunity is beneficial in enhancing protection against secondary infections with an induction in the evolutionary protective process against infections. Therefore, innate trained immunity plays an important role in therapy against diseases such as tumors and infections, which has signature therapeutic effects in these diseases. In organ transplantation, trained immunity has been associated with acute rejection, which prolongs the survival of allografts. However, trained immunity is not always protective but pathological in some cases, and dysregulated trained immunity contributes to the development of inflammatory and autoimmune diseases. Trained immunity provides a novel form of immune memory, but when inappropriately activated, may lead to an attack on tissues, causing autoinflammation. In autoimmune diseases such as rheumatoid arthritis and atherosclerosis, trained immunity may lead to enhance inflammation and tissue lesion in diseased regions. In Alzheimer’s disease and Parkinson’s disease, trained immunity may lead to over-activation of microglial cells, triggering neuroinflammation even nerve injury. This paper summarizes the basis and mechanisms of innate trained immunity, including the different cell types involved, the impacts on diseases and the effects as a therapeutic strategy to provide novel ideas for different diseases.

Objective:To establish a disease risk prediction model for the newborn screening system of inherited metabolic diseases by artificial intelligence technology.Methods:This was a retrospectively study. Newborn screening data ( n=5 907 547) from February 2010 to May 2019 from 31 hospitals in China and verified data ( n=3 028) from 34 hospitals of the same period were collected to establish the artificial intelligence model for the prediction of inherited metabolic diseases in neonates. The validity of the artificial intelligence disease risk prediction model was verified by 360 814 newborns ' screening data from January 2018 to September 2018 through a single-blind experiment. The effectiveness of the artificial intelligence disease risk prediction model was verified by comparing the detection rate of clinically confirmed cases, the positive rate of initial screening and the positive predictive value between the clinicians and the artificial intelligence prediction model of inherited metabolic diseases. Results:A total of 3 665 697 newborns ' screening data were collected including 3 019 cases ' positive data to establish the 16 artificial intelligence models for 32 inherited metabolic diseases. The single-blind experiment ( n=360 814) showed that 45 clinically diagnosed infants were detected by both artificial intelligence model and clinicians. A total of 2 684 cases were positive in tandem mass spectrometry screening and 1 694 cases were with high risk in artificial intelligence prediction model of inherited metabolic diseases, with the positive rates of tandem 0.74% (2 684/360 814)and 0.46% (1 694/360 814), respectively. Compared to clinicians, the positive rate of newborns was reduced by 36.89% (990/2 684) after the application of the artificial intelligence model, and the positive predictive values of clinicians and artificial intelligence prediction model of inherited metabolic diseases were 1.68% (45/2 684) and 2.66% (45/1 694) respectively. Conclusion:An accurate, fast, and the lower false positive rate auxiliary diagnosis system for neonatal inherited metabolic diseases by artificial intelligence technology has been established, which may have an important clinical value.

Objective:To summarize and analyze the clinical data of Chinese patients with colony-stimulating factor 1 receptor (CSF1R)-related leukoencephalopathy, and clarify the phenotypic and genetic characteristics of Chinese patients.Methods:Medical history of patients with CSF1R-related leukoencephalopathy diagnosed from April 1, 2018 to January 31, 2021 in the department of neurology of 22 hospitals in China was collected, and scores of Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment Scale (MoCA), magnetic resonance severity scale were evaluated. Group comparison was performed between male and female patients.Results:A total of 62 patients were included, and the male-female ratio was 1∶1.95. The age of onset was (40.35±8.42) years. Cognitive impairment (82.3%, 51/62) and motor symptoms (77.4%,48/62) were the most common symptoms. The MMSE and MoCA scores were 18.79±7.16 and 13.96±7.23, respectively, and the scores of two scales in male patients (22.06±5.31 and 18.08±5.60) were significantly higher than those in females (15.53±7.41 , t=2.954, P=0.006; 10.15±6.26, t=3.328 , P=0.003). The most common radiographic feature was bilateral asymmetric white matter changes (100.0%), and the magnetic resonance imaging severity scale score was 27.42±11.40, while the white matter lesion score of females (22.94±8.39) was significantly higher than that of males (17.62±8.74 , t=-2.221, P<0.05). A total of 36 CSF1R gene mutations were found in this study, among which c.2381T>C/p.I794T was the hotspot mutation that carried by 17.9% (10/56) of the probands. Conclusions:The core phenotypic characteristics of CSF1R-related leukoencephalopathy in China are progressive motor and cognitive impairment, with bilateral asymmetrical white matter changes. In addition, there exist gender differences clinically, with severer cognitive impairment and imaging changes in female patients. Thirty-six CSF1R gene mutations were found in this study, and c.2381T>C/p. I794T was the hotspot mutation.

Background: Few data are available regarding the progression of liver disease and therapeutic efficacy in chronic hepatitis B virus (HBV) carriers infected by mother-to-child transmission (MTCT). This study aimed to investigate these two aspects by comparing the adult chronic HBV carriers in MTCT group with those in horizontal transmission group. Methods: The 683 adult chronic HBV patients qualified for liver biopsy including 191 with MTCT and 492 with horizontal transmission entered the multi-center prospective study from October 2013 to May 2016. Biopsy results from 217 patients at baseline and 78 weeks post antiviral therapy were collected. Results: Patients infected by MTCT were more likely to have e antigen positive (68.6% vs. 58.2%, χ² = -2.491, P = 0.012) than those with horizontal transmission. However, in patients with MTCT, levels of alkaline phosphatase (ALP) (P = 0.031), Fibroscan (P = 0.013), N-terminal propeptide of Type III procollagen (PIIINP) (P = 0.014), and Laminin (LN) (P = 0.006) were high, in contrast to the patients with horizontal transmission for whom the levels of albumin (ALB) (P = 0.041), matrix metalloproteinase-3 (MMP-3) (P = 0.001) were high. The 47.2% of patients with MTCT and 36.8% of those with horizontal transmission had significant liver fibrosis (P = 0.013). Following antiviral therapy for 78 weeks, 21.2% and 38.0% patients with MTCT and horizontal transmission acquired hepatitis B e antigen (HBeAg) clearance, respectively (P = 0.043), and the virological response rates were 54.7% and 74.1% in the MTCT and horizontal groups, respectively (P = 0.005). MTCT was a risk factor for HBeAg clearance and virological response. Conclusion: Adult patients with MTCT were more prone to severe liver diseases, and the therapeutic efficacy was relatively poor, which underlined the importance of earlier, long-term treatment and interrupting perinatal transmission. Trial Registration NCT01962155; https://clinicaltrials.gov.

Objective :To explore therapeutic effect of single Chinese medicine Bidens pilosa grain on hyperlipidemia and its influence on serum levels of matrix metalloproteinase‐9 (MMP‐9) and tissue inhibitor of metalloproteinases‐1 (TIMP‐1).Methods :A total of 186 hyperlipidemia patients treated in our hospital from Jan 2014 to Jun 2017 were randomly divid‐ed into Bidens pilosa group (n＝94 ,received Bidens pilosa grain based on routine treatment ) and Xuezhikang group (n＝92 ,received Xuezhikang based on routine treatment ).Both groups were treated for two months .Serum levels of total cho‐lesterol (TC) , triglyceride (TG ) ,low density lipoprptein cholesterol (LDL‐ C) , high density lipoprptein cholesterol (HDL‐C) ,MMP‐9 and TIMP‐1 before and after treatment ,and total effective rate were observed and compared between two groups.Results :Compared with before treatment ,after treatment ,there were significant reductions in serum levels of TC ,TG ,LDL‐C and MMP‐9 [ Bidens pilosa group : (24.46 ± 4.92) μg／L vs.(20.53 ± 2.69) μg／L ,Xuezhikang group :(23.40 ± 2.57) μg／L vs.(19.98 ± 2.02) μg／L] ,and significant rise in serum levels of HDL‐C [ Bidens pilosa group :(1.28 ± 0.45) mmol／L vs.(1.54 ± 0.52) mmol／L , Xuezhikang group : (1.28 ± 0.45) mmol／L vs.(1.55 ± 0.52) mmol／L] and TIMP‐1 [ Bidens pilosa group : (4.67 ± 1.26) μg／L vs.(6.02 ± 2.24) μg／L ,Xuezhikang group :(4.63 ± 1.30) μg／L vs.(6.01 ± 2.31) μg／L] in two groups , P＝0.001 all.After treatment ,there were no significant difference in serum levels of TC ,TG ,LDL‐C ,HDL‐C ,MMP‐9 and TIMP‐1 and total effective rate between two groups , P＞0.05 all.Conclusion :Bidens pilosa can significantly improve serum lipid level ,reduce serum level of MMP‐9 and increase serum level of TIMP‐1 in hyperlipidemia patients .It＇s no significant difference compared with Xuezhikang .

OBJECTIVE： To prepare Magnolol nano-crystal suspension （MAG-NS）， and to conduct quality evaluation. METHODS： The preparation technology of MAG-NS was optimized by central composite design-response surface methodology with OD value of particle size and polydispersity coefficient as evaluation indexes， using volume ratio of organic phase to water phase， ratio of excipient to drug， concentration of magnolol as factors and conduct validation tests. The quality of MAG-NS prepared optimal technology was evaluated. RESULTS： Optimized technology included that the volume ratio of organic phase to water phase was 1 ∶ 5， mass ratio of excipient to drug was 4 ∶ 1， concentration of magnolol was 2 mg/mL. In 3 times of validation tests， average OD value was 0.940 0 （RSD＝0.08％）， relative error of which to predicted value 0.977 7 was 3.86％. magnolol nano-crystals of MAG-NS prepared by the optimal technology were spherical， uniform in size， smooth in surface， with particle size of （34.88±0.33） nm， polydispersity coefficient of 0.032±0.001 and drug loading amount of （17.83±0.92）％. CONCLUSIONS： Established preparation method is simple and feasible. Prepared MAG-NS is in line with quality requirements. It can provide reference for further development and utilization of MAG-NS.

ObjectiveTo investigate the role of reducing the door-to-needle time for patients with acute ischemic stroke based on the quality improvement program of PDCA cycle.MethodsConsecutive patients with acute ischemic stroke admitted to hospital were registered prospectively from January 1, 2016 to September 30, 2016.Questionnaires and time tracking method were used to investigate the door-to-needle (DNT) and its influencing factors.PDCA cycle method was used to improve the stroke channel workflow and the changing trend of DNT was analyzed.ResultsA total of 71 patients with acute ischemic stroke were enrolled.After 3 PDCA cycles, DNT (median, interquartile range) from 100.0 min (65.5-127.0 min) reduced to58.0 min (45.5-80.0 min) (Z=11.689, P<0.001), the proportion of the patients with DNT ≤60 min increased from 19.05% to 60.00% (χ2=7.893, P=0.019).Conclusions The quality improvement program of PDCA cycle may effectively reduce the time of DNT in patients with acute ischemic stroke.

OBJECTIVETo study subtype classification of gastric neuroendocrine neoplasm (NEN) and their clinicopathological characteristics in order to provide reference for clinical practice.

METHODSClinicopathological data of 241 gastric NEN patients (174 cases from China-Japan Friendship Hospital and 67 cases from The First Affiliated Hospital of Sun Yat-Sen University) between January 2011 and June 2016 were retrospectively summarized. According to serum gastrin, 24-hour intragastric pH monitoring and pathological grade, patients with gastric NEN were divided into 4 types: type I( (hypergastrinemia and achlorhydria, related to autoimmune chronic atrophic gastritis), type II( [hypergastrinemia and Zollinger-Ellison syndrome, related to gastrinoma or multiple endocrine neoplasia type I( (MEN-I()], type III( (sporadic disease with normal serum gastrin level), and type IIII( [poorly differentiated gastric neuroendocrine carcinoma (NEC) and mixed adenoneuroendocrine carcinoma (MANEC)]. Clinicopathological features, treatment and prognosis of 4 types were analyzed.

RESULTSOf 241 gastric NEN cases, there were 86 cases (35.7%) in type I(, 7 cases (2.9%) in type II(, 61 cases (25.3%) in type III( and 87 cases(36.1%) in type IIII(. Among 86 cases of type I( gastric NEN, 73 cases (84.9%) were multiple lesions,tumor size of 66 cases (76.7%) was less than 1 cm, all the 86 cases were polypoid or granular lesions. 2 cases(2.3%)presented distant metastasis, 69 cases (80.2%) had pathological grading as NET G1; most of them received endoscopic surgery treatment and follow-up; somatostatin analogs(SSA) was used in patients with multiple lesions and repeated recurrence after endoscopic treatment. Among 7 cases of type II(, 4 cases were gastrinoma, 3 cases MEN-I(; 5 cases presented distant metastasis; treatment included surgery, SSA and proton pump inhibitor (PPI) therapy. Among 61 cases of type III( gastric NEN, 49 cases(80.3%) were single lesion,tumor size of 25 cases(41.0%) was more than 2 cm, 29 cases(47.5%) had lymph node metastasis or distant metastasis; treatment included endoscopic resection, surgery or SSA therapy according to the tumor staging. Among 87 patients of type IIII( gastric NEN, 74 cases(85.0%) had single lesion,tumor size of 51 cases (58.6%) was more than 2 cm; lesions were found in gastric cardia in 35 cases (40.2%); 65 cases (74.7%) had lymph node metastasis or distant metastasis; treatment included chemotherapy, or surgery plus chemotherapy. At the end of follow-up(June 30, 2016), 58 patients were dead, including 1 case of type I(, 12 cases of type III( and 45 cases of type IIII(. The overall survival rate of all the patients was 74.2%, and was 98.8%, 100%, 79.3%, 39.2% of types I(, II(, III(, IIII( respectively. The overall survival rate between type III( and type IIII( gastric NEN was significantly different(P = 0.000).

CONCLUSIONSSubtype classification of gastric NEN is very significant for making therapeutic decisions and prognostic evaluation. Patients of type I( or type II( gastric NEN have good prognosis,while those of type III( and type IIII( have poor prognosis, and those of type IIII( have the worst prognosis.

Adult ; China ; Female ; Humans ; Lymphatic Metastasis ; Male ; Neoplasm Recurrence, Local ; Neoplasm Staging ; Neuroendocrine Tumors ; pathology ; therapy ; Prognosis ; Retrospective Studies ; Stomach Neoplasms ; pathology ; therapy ; Survival Rate

Objective To investigate elastic modulus of double-stranded DNA (dsDNA) biofilm adsorbed on microcantilever substrate. Methods Parsegian’s empirical potentials based on mesoscopic continuum liquid crystal theory was employed to describe the interaction energy among coarse-grained DNA cylinders; Monte Carlo method was used to simulate the distribution pattern of DNA chains before and after loading. The thought experiment method combined with the compression bar model in the sense of macroscopic continuum mechanics was adopted to predict the elastic modulus of DNA biofilm. Results The elastic modulus of dsDNA biofilm ranged from 0.1 MPa to 80 MPa. Conclusions It was found out that the classic hypothesis with uniform hexagonal pattern may underestimate the elastic modulus of DNA biofilm when compared with that in random pattern. Moreover, either the increase of packing density or the decrease of buffer salt concentration will help to enhance elastic modulus of DNA biofilm. These results have great significances in further understanding the mechanical properties and regulation rules of DNA biofilm related with clinical work.