Advanced atherosclerosis is the major global cause of death, as featured by the aggregation of apoptotic cells (ACs) in necrotic cores. The defective efferocytosis and dysfunctional cholesterol efflux of macrophages are the main reasons for forming necrotic cores in advanced atherosclerosis. In this study, we constructed self-assembled procyanidins (PC) NPs for loading pitavastatin (Pita). The designed HA@PC@Pita NPs with hyaluronic acid (HA) modification combined the advantages of efferocytosis restoration of Pita and cholesterol efflux enhancement of PC. In vitro assay indicated that HA@PC@Pita NPs could induce M1/M2 repolarization and upregulate ERK5/Mertk expression to restore efferocytosis of macrophages. Simultaneously, HA@PC@Pita NPs notably promoted cholesterol efflux by promoting macrophage lipophagy, a selective autophagy of lipid droplets. In vivo study showed that HA@PC@Pita NPs cleared necrotic core and enhanced plaque stability in the ApoE ^-/- mice model with advanced atherosclerosis. Taken together, this study demonstrated the potential of HA@PC@Pita NPs for the treatment of advanced atherosclerosis.

Objective:To analyze the nonlinear correlation and inflection points between age and short-term mortality in patients with negative systemic inflammatory response syndrome (SIRS)sepsis score.Methods:A retrospective cohort study was conducted using the medical information mart for intensive care Ⅳ(MIMIC-Ⅳ)database, which included adult patients with sepsis who were admitted to the intensive care unit(ICU)within 24 hours and did not receive mechanical ventilation or vasoactive drug, with a SIRS score ≤1.Patients were divided into survivors and non-survivors based on 28-day survival.Baseline variables such as age, gender, Charlson Comorbidity Index(CCI), body mass index(BMI), Sequential Organ Failure Assessment(SOFA)score, and initial lactate levels were compared between the two groups.With case fatality rate as the dependent variable, variables with differences in univariate analysis were incorporated into the binary logistic regression model, and baseline variables with statistically significant differences except age were matched according to the 1∶3 propensity score.Restricted cubic spline (RCS) regression was used to analyze the nonlinear relationship between patient age and mortality after matching and to determine the inflection point.Results:A total of 53 150 hospital records in the MIMIC-Ⅳ database were retrospectively screened, and 1 691 adult patients[aged(69.82±14.87)years]diagnosed with sepsis and negative SIRS score within 24 hours of ICU admission were included, with 101(5.97%)deaths within 28 days.Patients in the non-survivor group were older [(73.63±14.55)years vs.(69.58±14.86)years, t=-2.663, P=0.008], had higher CCI(4.38±2.64 vs.2.99±2.34, t=-5.732, P<0.001), and higher SOFA score (8.18±3.58 vs.5.04±2.67, t=-8.664, P<0.001)compared to the survivor group.There were no significant differences in gender, BMI, initial lactate levels, and the suspected infection sites (all P>0.05).Multivariable logistic regression analysis showed that increased age ( OR=1.03, 95% CI: 1.02-1.05, P<0.001), increased CCI ( OR=1.16, 95% CI: 1.06-1.26, P<0.001), and increased SOFA score ( OR=1.34, 95% CI: 1.26-1.43, P<0.001)were significantly associated with increased mortality in patients with negative SIRS score.After including SOFA score and CCI in the propensity score matching, there were 271 survivors and 93 non-survivors.RCS results showed a non-linear association between age and mortality( Poverall=0.001, Pnon-linear=0.001), with a significant increase in the OR for mortality when age exceeded 73 years. Conclusions:In sepsis patients with comparable organ function, the short-term mortality rate of patients with negative SIRS score increases non-linearly with age.These patients have mild symptoms but poor clinical outcomes, necessitating early and enhanced monitoring when age exceeds 73 years.

Objective:To investigate the protective effect and its mechanism of proscillaridin A (PSD-A) on podocyte injury in lupus nephritis (LN).Methods:Molecular docking and surface plasmon resonance techniques were used to analyze the binding status of PSD-A to signal transducer and activator of transcription 1 (STAT1). The immortalized human podocyte injury model in the lupus group was induced by the serum of systemic lupus erythematosus patients, and the control and PSD-A intervention (2 nmol/L, 4 nmol/L) groups were also set up. Six female 12-week-old C57BL/6 mice were designated as the control group, and 12 female 12-week-old MRL/lpr lupus mice were randomly divided into lupus group and PSD-A intervention group by random number table method. The PSD-A intervention group was intraperitoneally injected with 5 mg/kg PSD-A, once per week for 6 consecutive weeks. While the control group and the lupus group were intraperitoneally injected with the same volume of the solvent without PSD-A. Western blotting and real-time quantitative PCR were employed to detect the relative protein and mRNA expression levels of podocin, STAT1, and interferon-induced protein with tetratricopeptide repeat 1 (IFIT1) in podocytes of each group. Enzyme-linked immunosorbent assay was used to detect the levels of serum anti-double strand DNA antibody and interferon-α in mice. Coomassie brilliant blue was used to detect the urinary protein level. HE, PAS, Masson and PASM staining and transmission electron microscopy were used to observe the pathological changes of renal tissues. Immunohistochemistry was used to examine the protein expression of podocin, STAT1 and IFIT1 in renal tissues.Results:Molecular docking and surface plasmon resonance techniques proved that PSD-A could bind to STAT1 protein and they exhibited a robust binding affinity. The podocyte experiments showed that, compared with the lupus group, the relative expression levels of podocin protein and mRNA in the PSD-A intervention group were upregulated, while the relative expression levels of STAT1 and IFIT1 protein and mRNA were downregulated (all P<0.05). The animal experiments showed that, compared with the lupus group, the serum levels of anti-double strand DNA antibody, interferon-α, and urinary protein in PSD-A intervention group were decreased, the pathological damage of renal tissues was alleviated, and the injury of renal podocytes was reduced. Immunohistochemical staining showed that the relative protein expression levels of STAT1 and IFIT1 of renal tissues in the PSD-A intervention group were lower than those in the lupus group (all P<0.05). Conclusion:PSD-A can play a protective role in podocyte injury in LN, and its mechanism may be related to the inhibition of the STAT1 signaling pathway.

Objective To explore the mechanism of methyltransferase METTL3 in premature ovarian failure(POF)using a POF mouse model,providing a theoretical basis for the pathological research and clinical treatment of POF.Methods C57BL/6 female mice aged 6 to 8 weeks were selected for the study.The experimental group consisted of mice with a premature ovarian failure(POF)model established using the D-galactose metabolic method,while the control group comprised normal mice subjected to the same intervention with an equal volume of physiological saline.The levels of sex hormones were measured using ELISA,and histopathological changes in ovarian tissue were observed through HE staining to verify the successful establishment of the POF mouse model and to explore the correlation between METTL3 and POF at the tissue level.Additionally,stable transgenic mouse granulosa cell lines with METTL3 overexpression and knockdown were constructed at the cellular level.Cell proliferation and apoptosis were assessed using CCK-8 and FITC/PI dual staining methods to clarify the regulatory role of METTL3 in granulosa cell apoptosis and its impact on the occurrence of POF.Results The POF mouse model was successfully established.TUNEL staining revealed a significant increase in apoptotic granulosa cells in the ovarian tissue of the POF group(P＜0.05),which also exhibited high expression of METTL3.In cellular experiments,stable transcriptional cell lines of mouse granulosa cells with METTL3 overexpression and knockdown were successfully constructed.Upregulation of METTL3 expression promoted granulosa cell apoptosis and inhibited their proliferation(P＜0.05).Conclusion METTL3 participates in the development of POF by promoting granulosa cell apoptosis.

Objective:To describe the prevalence of perinatal death in Tongzhou District of Beijing,and to estimate the association between maternal periconceptional supplementation of folic acid or multiple micronutrients containing folic acid and perinatal mortality rate.Methods:A retrospective cohort study was conducted based on the maternal and child care system in Tongzhou District of Beijing.The subjects were 94 490 perinatal who were born during January 2013 to December 2018.The information on perina-tal outcomes and maternal periconceptional supplementation of folic acid or multiple micronutrients contai-ning folic acid were collected.The Poisson log-linear model was used to estimate the association between maternal periconceptional folic acid or multiple micronutrients supplementation and perinatal mortality rate.Results:The overall perinatal mortality rate was 2.71‰.The perinatal mortality rates for maternal nutrients supplementation containing folic acid and no supplementation during periconceptional period were 2.63‰ and 3.43‰,respectively,and the difference in rates was not statistically significant[crude risk ratio(cRR)=0.77,95％CI:0.54-1.14].After adjusting for potential confounding factors in-cluding ethnicity,age,education level,occupation,household registration,parity,numbers of fetuses,gestational age,pregnant with assisted reproductive technology,delivery year and pre-pregnancy body mass index,the rates remained not statistically significant[adjusted risk ratio(aRR)=0.93,95％CI:0.77-1.13].The perinatal mortality rates were 2.23‰ and 2.99‰ for pure folic acid and multi-nutrients supplements containing folic acid,respectively,and the difference in rates was statistically sig-nificant(cRR=1.34,95％CI:1.02-1.76).The rates difference remained statistically significant after adjusting for potential confounders(aRR=1.31,95％CI:1.06-1.62).Additionally,the peri-natal mortality rates differences among the non-supplementation group and the supplementation group with variate timing of initiation(pre-conception or post-conception)or frequency of supplementation(low-frequency or high-frequency)were not statistically significant,regardless of adjusting for confounders.Conclusion:The overall perinatal mortality rate was lower than the national average level in Tongzhou District of Beijing.Maternal periconceptional supplementation of pure folic acid or micronutrients contai-ning folic acid had no impact on perinatal mortality.The association between maternal periconceptional supplementation of multiple micronutrients containing folic acid and perinatal mortality rate need further research.

Objective:To describe the prevalence of perinatal death in Tongzhou District of Beijing,and to estimate the association between maternal periconceptional supplementation of folic acid or multiple micronutrients containing folic acid and perinatal mortality rate.Methods:A retrospective cohort study was conducted based on the maternal and child care system in Tongzhou District of Beijing.The subjects were 94 490 perinatal who were born during January 2013 to December 2018.The information on perina-tal outcomes and maternal periconceptional supplementation of folic acid or multiple micronutrients contai-ning folic acid were collected.The Poisson log-linear model was used to estimate the association between maternal periconceptional folic acid or multiple micronutrients supplementation and perinatal mortality rate.Results:The overall perinatal mortality rate was 2.71‰.The perinatal mortality rates for maternal nutrients supplementation containing folic acid and no supplementation during periconceptional period were 2.63‰ and 3.43‰,respectively,and the difference in rates was not statistically significant[crude risk ratio(cRR)=0.77,95％CI:0.54-1.14].After adjusting for potential confounding factors in-cluding ethnicity,age,education level,occupation,household registration,parity,numbers of fetuses,gestational age,pregnant with assisted reproductive technology,delivery year and pre-pregnancy body mass index,the rates remained not statistically significant[adjusted risk ratio(aRR)=0.93,95％CI:0.77-1.13].The perinatal mortality rates were 2.23‰ and 2.99‰ for pure folic acid and multi-nutrients supplements containing folic acid,respectively,and the difference in rates was statistically sig-nificant(cRR=1.34,95％CI:1.02-1.76).The rates difference remained statistically significant after adjusting for potential confounders(aRR=1.31,95％CI:1.06-1.62).Additionally,the peri-natal mortality rates differences among the non-supplementation group and the supplementation group with variate timing of initiation(pre-conception or post-conception)or frequency of supplementation(low-frequency or high-frequency)were not statistically significant,regardless of adjusting for confounders.Conclusion:The overall perinatal mortality rate was lower than the national average level in Tongzhou District of Beijing.Maternal periconceptional supplementation of pure folic acid or micronutrients contai-ning folic acid had no impact on perinatal mortality.The association between maternal periconceptional supplementation of multiple micronutrients containing folic acid and perinatal mortality rate need further research.

Objective:To analyze the nonlinear correlation and inflection points between age and short-term mortality in patients with negative systemic inflammatory response syndrome (SIRS)sepsis score.Methods:A retrospective cohort study was conducted using the medical information mart for intensive care Ⅳ(MIMIC-Ⅳ)database, which included adult patients with sepsis who were admitted to the intensive care unit(ICU)within 24 hours and did not receive mechanical ventilation or vasoactive drug, with a SIRS score ≤1.Patients were divided into survivors and non-survivors based on 28-day survival.Baseline variables such as age, gender, Charlson Comorbidity Index(CCI), body mass index(BMI), Sequential Organ Failure Assessment(SOFA)score, and initial lactate levels were compared between the two groups.With case fatality rate as the dependent variable, variables with differences in univariate analysis were incorporated into the binary logistic regression model, and baseline variables with statistically significant differences except age were matched according to the 1∶3 propensity score.Restricted cubic spline (RCS) regression was used to analyze the nonlinear relationship between patient age and mortality after matching and to determine the inflection point.Results:A total of 53 150 hospital records in the MIMIC-Ⅳ database were retrospectively screened, and 1 691 adult patients[aged(69.82±14.87)years]diagnosed with sepsis and negative SIRS score within 24 hours of ICU admission were included, with 101(5.97%)deaths within 28 days.Patients in the non-survivor group were older [(73.63±14.55)years vs.(69.58±14.86)years, t=-2.663, P=0.008], had higher CCI(4.38±2.64 vs.2.99±2.34, t=-5.732, P<0.001), and higher SOFA score (8.18±3.58 vs.5.04±2.67, t=-8.664, P<0.001)compared to the survivor group.There were no significant differences in gender, BMI, initial lactate levels, and the suspected infection sites (all P>0.05).Multivariable logistic regression analysis showed that increased age ( OR=1.03, 95% CI: 1.02-1.05, P<0.001), increased CCI ( OR=1.16, 95% CI: 1.06-1.26, P<0.001), and increased SOFA score ( OR=1.34, 95% CI: 1.26-1.43, P<0.001)were significantly associated with increased mortality in patients with negative SIRS score.After including SOFA score and CCI in the propensity score matching, there were 271 survivors and 93 non-survivors.RCS results showed a non-linear association between age and mortality( Poverall=0.001, Pnon-linear=0.001), with a significant increase in the OR for mortality when age exceeded 73 years. Conclusions:In sepsis patients with comparable organ function, the short-term mortality rate of patients with negative SIRS score increases non-linearly with age.These patients have mild symptoms but poor clinical outcomes, necessitating early and enhanced monitoring when age exceeds 73 years.

Objective:To investigate the protective effect and its mechanism of proscillaridin A (PSD-A) on podocyte injury in lupus nephritis (LN).Methods:Molecular docking and surface plasmon resonance techniques were used to analyze the binding status of PSD-A to signal transducer and activator of transcription 1 (STAT1). The immortalized human podocyte injury model in the lupus group was induced by the serum of systemic lupus erythematosus patients, and the control and PSD-A intervention (2 nmol/L, 4 nmol/L) groups were also set up. Six female 12-week-old C57BL/6 mice were designated as the control group, and 12 female 12-week-old MRL/lpr lupus mice were randomly divided into lupus group and PSD-A intervention group by random number table method. The PSD-A intervention group was intraperitoneally injected with 5 mg/kg PSD-A, once per week for 6 consecutive weeks. While the control group and the lupus group were intraperitoneally injected with the same volume of the solvent without PSD-A. Western blotting and real-time quantitative PCR were employed to detect the relative protein and mRNA expression levels of podocin, STAT1, and interferon-induced protein with tetratricopeptide repeat 1 (IFIT1) in podocytes of each group. Enzyme-linked immunosorbent assay was used to detect the levels of serum anti-double strand DNA antibody and interferon-α in mice. Coomassie brilliant blue was used to detect the urinary protein level. HE, PAS, Masson and PASM staining and transmission electron microscopy were used to observe the pathological changes of renal tissues. Immunohistochemistry was used to examine the protein expression of podocin, STAT1 and IFIT1 in renal tissues.Results:Molecular docking and surface plasmon resonance techniques proved that PSD-A could bind to STAT1 protein and they exhibited a robust binding affinity. The podocyte experiments showed that, compared with the lupus group, the relative expression levels of podocin protein and mRNA in the PSD-A intervention group were upregulated, while the relative expression levels of STAT1 and IFIT1 protein and mRNA were downregulated (all P<0.05). The animal experiments showed that, compared with the lupus group, the serum levels of anti-double strand DNA antibody, interferon-α, and urinary protein in PSD-A intervention group were decreased, the pathological damage of renal tissues was alleviated, and the injury of renal podocytes was reduced. Immunohistochemical staining showed that the relative protein expression levels of STAT1 and IFIT1 of renal tissues in the PSD-A intervention group were lower than those in the lupus group (all P<0.05). Conclusion:PSD-A can play a protective role in podocyte injury in LN, and its mechanism may be related to the inhibition of the STAT1 signaling pathway.

Surgical operation is the main treatment of oral and maxillofacial tumors.Dysphagia is a common postoperative complication.Swal-lowing disorder can not only lead to mis-aspiration,malnutrition,aspiration pneumonia and other serious consequences,but also may cause psychological problems and social communication barriers,affecting the quality of life of the patients.At present,there is no systematic evalua-tion and rehabilitation management plan for the problem of swallowing disorder after oral and maxillofacial tumor surgery in China.Combining the characteristics of postoperative swallowing disorder in patients with oral and maxillofacial tumors,summarizing the clinical experience of ex-perts in the field of tumor and rehabilitation,reviewing and summarizing relevant literature at home and abroad,and through joint discussion and modification,a group of national experts reached this consensus including the core contents of the screening of swallowing disorders,the phased assessment of prognosis and complications,and the implementation plan of comprehensive management such as nutrition management,respiratory management,swallowing function recovery,psychology and nursing during rehabilitation treatment,in order to improve the evalua-tion and rehabilitation of swallowing disorder after oral and maxillofacial tumor surgery in clinic.