Abstract The issue of multimorbidity in children and adolescents is becoming increasingly prominent, but there is no consensus on the definition of multimorbidity. As research deepens, issues related to the comparability and standardization of relevant findings are gradually emerging. As a solution, a systematic review of both domestic and international research on multimorbidity is conducted, and a classification system for defining the concept of multimorbidity is proposed, offering more convenient conditions for the advancement of future research and cross study exchange.

BACKGROUND: The epidemiological pattern and disease burden of type 2 diabetes have been shifting in China over the past decades. This analysis described the epidemiological transition of type 2 diabetes in the past three decades and projected the trend in the future three decades in China. METHODS: Age-, sex-, and year-specific incidence, prevalence, death, and disability-adjusted life years (DALYs) for people with 15 years or older and diabetes or high fasting glucose in China and related countries from 1990 to 2021 were obtained from the Global Burden of Disease. We obtained the trends of age-, sex-, and year-specific rates and absolute numbers of incidence, prevalence, deaths, and DALYs attributable to type 2 diabetes in China from 1990 to 2021. Using the Lee-Carter model, we projected the incidence, prevalence, death, and DALYs attributable to type 2 diabetes to 2050 stratified by age and sex. RESULTS: The age-standardized incidence of type 2 diabetes was 341.5 per 100,000 persons (1.6 times in 1990) and the age-standardized prevalence was 9.96% (9960.0 per 100,000 persons, 2.5 times in 1990) in China 2021. In 2021, there were 0.9 million deaths and 26.8 million DALYs due to type 2 diabetes or hyperglycemia, as 2.9 and 2.7 times the data in 1990, respectively. The age-standardized rates of type 2 diabetes and hyperglycemia were projected to raise to 449.5 per 100,000 persons for incidence, 18.17% for prevalence, 244.6 per 100,000 persons for death, and 4720.2 per 100,000 persons for DALYs by 2050. The incidence of type 2 diabetes kept growing among individuals under the age of 20 years in the past three decades (128.7 per 100,000 persons in 1990 and 439.9 per 100,000 persons in 2021) and estimating 1870.8 per 100,000 in 2050. CONCLUSIONS The incidence, prevalence, and disease burden of type 2 diabetes grew rapidly in China in the past three decades. The prevention of type 2 diabetes in young people and the care for elder adults will be the greatest challenge for the country.
Humans ; Diabetes Mellitus, Type 2/mortality* ; China/epidemiology* ; Prevalence ; Female ; Male ; Incidence ; Middle Aged ; Adult ; Aged ; Adolescent ; Young Adult ; Disability-Adjusted Life Years ; Aged, 80 and over

OBJECTIVES: To investigate the inhibitory effect of multimerin-2 (MMRN2) overexpression on growth and metastasis of cutaneous melanoma cells. METHODS: Clinical data of patients with cutaneous melanoma were obtained from the GEO database to compare MMRN2 expressions between normal and tumor tissues. A protein-protein interaction network was constructed using the STRING database, and the intersecting genes from GEPIA2.0 were subjected to GO and KEGG enrichment analysis. The prognostic relevance of MMRN2 expression level was assessed using Cox regression and "timeROC". The correlations of MMRN2 expression level with immune infiltration and angiogenesis-related genes were analyzed using GSCA database and the ssGSEA algorithm. Colony-forming assay, Transwell assay, and wound healing assay were used to examine the changes in proliferation and migration of cultured cutaneous melanoma cells following MMRN2 knockdown. In a mouse model bearing cutaneous melanoma xenograft, the effect of MMRN2 knockdown on vital organ pathologies, survival of the mice and GM-CSF, CXCL9, and TGF‑β1 protein expressions were analyzed. RESULTS: MMRN2 was significantly upregulated in metastatic cutaneous melanoma (P<0.001). Protein interaction network analysis identified 15 intersecting genes, which were enriched in endothelium development and cell-cell junctions. In patients with cutaneous melanoma, a high MMRN2 expression was correlated with a poor prognosis, an advanced T stage, a greater Breslow depth, and ulceration (P<0.05). MMRN2 expression level was strongly correlated with 24 immune cell types (P<0.001), fibroblasts, endothelial cells, and expressions of the pro-angiogenic genes (KCNJ8, SLCO2A1, NRP1, and COL3A1; P<0.001). In cultured B16F10 cells, MMRN2 knockdown significantly suppressed cell proliferation, migration and invasion and caused remo-deling of the immunosuppressive microenvironment. CONCLUSIONS MMRN2 overexpression drives progression of cutaneous melanoma by enhancing tumor metastasis, angiogenesis and immune evasion, highlighting its potential as a therapeutic target for melanomas.
Humans ; Melanoma/metabolism* ; Animals ; Cell Movement ; Prognosis ; Skin Neoplasms/metabolism* ; Mice ; Cell Proliferation ; Neoplasm Invasiveness ; Cell Line, Tumor ; Protein Interaction Maps

Background::Pancreatic ductal adenocarcinoma (PDAC) is one of the main types of malignant tumor of the digestive system, and patient prognosis is affected by difficulties in early diagnosis, poor treatment response, and a high postoperative recurrence rate. Carbohydrate antigen 19-9 (CA19-9) has been widely used as a biomarker for the diagnosis and postoperative follow-up of PDAC patients. Nevertheless, the production mechanism and potential role of CA19-9 in PDAC progression have not yet been elucidated.Methods::We performed single-cell RNA sequencing on six samples pathologically diagnosed as PDAC (three CA19-9-positive and three CA19-9-negative PDAC samples) and two paracarcinoma samples. We also downloaded and integrated PDAC samples (each from three CA19-9-positive and CA19-9-negative patients) from an online database. The dynamics of the proportion and potential function of each cell type were verified through immunofluorescence. Moreover, we built an in vitro coculture cellular model to confirm the potential function of CA19-9. Results::Three subtypes of cancer cells with a high ability to produce CA19-9 were identified by the markers TOP2A, AQP5, and MUC5AC. CA19-9 production bypass was discovered on antigen-presenting cancer-associated fibroblasts (apCAFs). Importantly, the proportion of immature ficolin-1 positive (FCN1+) macrophages was high in the CA19-9-negative group, and the proportion of mature M2-like macrophages was high in the CA19-9-positive group. High proportions of these two macrophage subtypes were associated with an unfavourable clinical prognosis. Further experiments indicated that CA19-9 could facilitate the transformation of M0 macrophages into M2 macrophages in the tumor microenvironment. Conclusions::Our study described CA19-9 production at single-cell resolution and the dynamics of the immune atlas in CA19-9-positive and CA19-9-negative PDAC. CA19-9 could promote M2 polarization of macrophage in the pancreatic tumor microenvironment.

Objective:To investigate the role of an inflammatory microenvironment induced by Porphyromonasgingivalis ( P. gingivalis) in the occurrence of esophageal squamous cell carcinoma (ESCC) in mice. Methods:A total of 180 C57BL/6 mice were randomly divided into 6 groups, i.e. control group, P. gingivalis group, 4NQO group, 4NQO + P. gingivalis group, 4NQO + P. gingivalis + celecoxib group, and 4NQO + P. gingivalis + antibiotic cocktail (ABC, including metronidazole, neomycin, ampicillin, and vancomycin) group, with 30 mice in each group, using the random number table. All mice were normalized by treatment with ABC in drinking water for 2 weeks. In the following 2 weeks, the mice in the control group and the P. gingivalis group were given drinking water, while the other 4 groups were treated with 30 μg/ml 4NQO in the drinking water. In weeks 11-12, the mice in the P. gingivalis group, the 4NQO + P. gingivalis group, the 4NQO + P. gingivalis + celecoxib group, and the 4NQO + P. gingivalis + ABC group were subjected to ligation of the second molar in oral cavity followed by oral P. gingivalis infection thrice weekly for 24 weeks in weeks 11-34. In weeks 13-34, the mice in 4NQO + P. gingivalis+celecoxib group and 4NQO + P. gingivalis + ABC group were administered with celecoxib and ABC for 22 weeks, respectively. At the end of 34 weeks, gross and microscopic alterations were examined followed by RT-qPCR and immunohistochemistry to examine the expression profiles of inflammatory- and tumor-molecules in esophagi of mice. Results:At 34 weeks, 4NQO treatment alone did not affect the foci of papillary hyperproliferation, diseased area, and the thickness of the esophageal wall, but significantly enhanced the foci of hyperproliferation (median 1.00, P＜0.05) and mild/moderate dysplasia (median 2.00, P＜0.01). In addition, the expression levels of IL-6 [8.35(3.45,8.99)], IL-1β [6.90(2.01,9.72)], TNF-α [12.04(3.31,14.08)], c-myc [2.21(1.80,3.04)], pSTAT3, Ki-67, and pH2AX were higher than those in the control group. The pathological changes of the esophageal mucosa were significantly more overt in the 4NQO + P. gingivalis group in terms of the foci of papillary hyperproliferation (median 2.00), diseased area (median 2.51 mm 2), the thickness of the esophageal wall (median 172.52 μm), the foci of hyperproliferation (median 1.00, P＜0.05), and mild/moderate dysplasia (median 1.00, P＜0.01). In mice of the 4NQO + P. gingivalis group, the expression levels of IL-6 [12.27(5.35,22.08)], IL-1β [13.89(10.04,15.96)], TNF-α [19.56(6.07,20.36)], IFN-γ [11.37(8.23,20.07)], c-myc [2.62(1.51,4.25)], cyclin D1 [4.52(2.68,7.83)], nuclear pSTAT3, COX-2, Ki-67, and pH2AX were significantly increased compared with the mice in the control group. In mice of the 4NQO + P. gingivalis group, the diseased area, invasive malignant foci as well as pSTAT3 and pH2AX expression were significantly blunted by celecoxib. Treatment with ABC markedly reduced the papillary hyperproliferative foci, invasive malignant foci, and pSTAT3 expression but not pH2AX. Conclusions:P. gingivalis promotes the occurrence of esophageal squamous cell carcinoma in mice by inducing an inflammatory microenvironment primed with 4NQO induced DNA damage. Clearance of P. gingivalis with ABC or anti-inflammatory intervention holds promise for prevention of esophageal squamous cell malignant pathogenesis via blockage of IL-6/STAT3 signaling and amelioration of inflammation.

Objective:To clarify the clinicopathological features, prognosis, and recurrence pattern of early-onset gastric cancer (EOGC).Methods:Using data from the gastric cancer database of Zhongshan Hospital, Fudan University, we performed a retrospective, large-scale, real-world study of 5046 patients with gastric cancer who had undergone redical or palliative gastrectomy from January 2013 to December 2018, including 425 patients with EOGC (age ≤45 years) and 4621 controls. All those patients were pathologically confirmed adenocarcinoma with complete follow-up of five years. Residue gastric cancer and patients without complete clinical or follow-up data were excluded. We used a combination of outpatient and telephone follow-up, ending in October 2022 (median duration of follow-up 60 months), and compared the clinicopathological features and prognosis of the two groups.Results:The clinicopathological features of EOGC included female predominance (61.1% [262/425 vs. 26.3% [1217/4621], χ 2=234.215, P<0.001), fewer comorbidities (31.3% [133/425] vs. 58.5% [2703/4621], χ 2=34.378, P<0.001), poorer differentiation (90.6% [385/425] vs. 78.2% [3614/4621], χ 2=30.642, P<0.001), higher proportion of diffuse type (53.9% [229/425] vs. 18.3% [846/4621], χ 2=274.474, P<0.001), higher proportion of T4 stage (44.7% [190/425] vs. 37.5% [1733/4621], χ 2=17.535, P=0.001), more lymph node metastases (60.5% [257/425] vs. 53.9% [2491/4621], χ 2=6.764, P=0.009), and higher proportion of pathological stage III/IV (47.5% [202/425] vs. 42.4% [1959/4621], χ 2=4.093, P=0.043). The 5-year overall survival rates of the EOGC and control groups were 55.1% and 49.1%, respectively. Overall survival was significantly better in the EOGC than in the control group ( P<0.001). According to subgroup analysis, the prognosis of pathological stage I/II/III EOGC was better than that of the control group. Recurrence rates were similar in the two groups, whereas patients with EOGC had a higher proportion of peritoneal recurrence (7.8% [33/425] vs. 3.2% [146/4621], χ 2=23.741, P<0.001) and a lower proportion of distant metastasis (4.9% [21/425] vs. 8.3% [385/4621], χ 2=6.247, P=0.012). Conclusion:EOGC has unique clinicopathological features and recurrence patterns and resectable EOGC has a better prognosis, suggesting that patients with EOGC should be actively treated with the focus on preventing peritoneal recurrence.

Objective:To clarify the clinicopathological features, prognosis, and recurrence pattern of early-onset gastric cancer (EOGC).Methods:Using data from the gastric cancer database of Zhongshan Hospital, Fudan University, we performed a retrospective, large-scale, real-world study of 5046 patients with gastric cancer who had undergone redical or palliative gastrectomy from January 2013 to December 2018, including 425 patients with EOGC (age ≤45 years) and 4621 controls. All those patients were pathologically confirmed adenocarcinoma with complete follow-up of five years. Residue gastric cancer and patients without complete clinical or follow-up data were excluded. We used a combination of outpatient and telephone follow-up, ending in October 2022 (median duration of follow-up 60 months), and compared the clinicopathological features and prognosis of the two groups.Results:The clinicopathological features of EOGC included female predominance (61.1% [262/425 vs. 26.3% [1217/4621], χ 2=234.215, P<0.001), fewer comorbidities (31.3% [133/425] vs. 58.5% [2703/4621], χ 2=34.378, P<0.001), poorer differentiation (90.6% [385/425] vs. 78.2% [3614/4621], χ 2=30.642, P<0.001), higher proportion of diffuse type (53.9% [229/425] vs. 18.3% [846/4621], χ 2=274.474, P<0.001), higher proportion of T4 stage (44.7% [190/425] vs. 37.5% [1733/4621], χ 2=17.535, P=0.001), more lymph node metastases (60.5% [257/425] vs. 53.9% [2491/4621], χ 2=6.764, P=0.009), and higher proportion of pathological stage III/IV (47.5% [202/425] vs. 42.4% [1959/4621], χ 2=4.093, P=0.043). The 5-year overall survival rates of the EOGC and control groups were 55.1% and 49.1%, respectively. Overall survival was significantly better in the EOGC than in the control group ( P<0.001). According to subgroup analysis, the prognosis of pathological stage I/II/III EOGC was better than that of the control group. Recurrence rates were similar in the two groups, whereas patients with EOGC had a higher proportion of peritoneal recurrence (7.8% [33/425] vs. 3.2% [146/4621], χ 2=23.741, P<0.001) and a lower proportion of distant metastasis (4.9% [21/425] vs. 8.3% [385/4621], χ 2=6.247, P=0.012). Conclusion:EOGC has unique clinicopathological features and recurrence patterns and resectable EOGC has a better prognosis, suggesting that patients with EOGC should be actively treated with the focus on preventing peritoneal recurrence.

Objective To investigate the effect of the aqueous extract of Chuan Xiong Rhizoma(CR)on brain metastasis of melanoma B16F10 cells in mice.Methods C57BL/6J mouse models of brain metastasis of melanoma were established by ultrasound-guided intraventricular injection of Luc-labeled B16F10 cells,and brain tumor growth was monitored by in vivo imaging.The mouse models were then randomized for daily gavage of saline or aqueous extract of CR(equivalent crude drug concentration of 1 mg/g).Behavioral tests were used to evaluate the neuroprotective effects of CR in the tumor-bearing mice,and the changes in proteins associated with blood-brain barrier integrity,neuronal cell proliferation and apoptosis,and microglial cell apoptosis and activation were observed using immunofluorescence assay.The efficacy of CR combined with temozolomide(25 mg/kg)against brain metastases of B16F10 cells was observed by in vivo imaging.Results CR-treated mouse models did not show obvious progression of brain metastases and had a reduced rate of body weight loss and lowered protein expressions of ZO-1,claudin-5,occludin,P-gp,TNF-α,AQP4 and PDGFRβ.In the behavioral tests,the CR-treated mice showed prolonged stay on the wooden stick with a shortened time of sticky stick removal.Immunofluorescence assay showed increased proliferation and decreased apoptosis of neuronal cells and microglia in CR-treated mice.CR treatment significantly increased the levels of CD86,CD206,IL-4 and IL-10 and decreased the levels of CD163 and IL-1β in the microenvironment of brain metastases.The mice receiving combined treatments with CR and temozolomide showed significantly lower intensity of fluorescent signals in the brain than those treated with temozolomide alone.Conclusion CR does not promote brain metastasis of melanoma while inducing opening of the blood-brain barrier,and its combined use with TMZ results in enhanced inhibition against brain metastasis of melanoma B16F10 cells in mice.

Objective To investigate the effect of the aqueous extract of Chuan Xiong Rhizoma(CR)on brain metastasis of melanoma B16F10 cells in mice.Methods C57BL/6J mouse models of brain metastasis of melanoma were established by ultrasound-guided intraventricular injection of Luc-labeled B16F10 cells,and brain tumor growth was monitored by in vivo imaging.The mouse models were then randomized for daily gavage of saline or aqueous extract of CR(equivalent crude drug concentration of 1 mg/g).Behavioral tests were used to evaluate the neuroprotective effects of CR in the tumor-bearing mice,and the changes in proteins associated with blood-brain barrier integrity,neuronal cell proliferation and apoptosis,and microglial cell apoptosis and activation were observed using immunofluorescence assay.The efficacy of CR combined with temozolomide(25 mg/kg)against brain metastases of B16F10 cells was observed by in vivo imaging.Results CR-treated mouse models did not show obvious progression of brain metastases and had a reduced rate of body weight loss and lowered protein expressions of ZO-1,claudin-5,occludin,P-gp,TNF-α,AQP4 and PDGFRβ.In the behavioral tests,the CR-treated mice showed prolonged stay on the wooden stick with a shortened time of sticky stick removal.Immunofluorescence assay showed increased proliferation and decreased apoptosis of neuronal cells and microglia in CR-treated mice.CR treatment significantly increased the levels of CD86,CD206,IL-4 and IL-10 and decreased the levels of CD163 and IL-1β in the microenvironment of brain metastases.The mice receiving combined treatments with CR and temozolomide showed significantly lower intensity of fluorescent signals in the brain than those treated with temozolomide alone.Conclusion CR does not promote brain metastasis of melanoma while inducing opening of the blood-brain barrier,and its combined use with TMZ results in enhanced inhibition against brain metastasis of melanoma B16F10 cells in mice.

ObjectTo explore the risk factors related to the intensity of post-stroke depression in patients with cerebral infarction during hospitalization in the rehabilitation department. MethodsThe hospital consultation records of cerebral infarction patients in Beijing Bo'ai Hospital from December, 2019 to February, 2023 were reviewed from the hospital information system, and those who were diagnosed as depression visited the department of psychology were selected. It was collected including general information of sexes, ages, education levels, matrimony; medical features of course, location, affected side, sensory disorders, aphasia, agrypnia, dysphagia, hand-shoulder syndrome, constipation; functioning of muscle strength and Brunnstrom stages; and scores of Mini-Mental State Examination (MMSE), National Institutes of Health Stroke Scale (NIHSS), Fugl-Meyer Assessment (FMA), Fugl-Meyer Assessment-Balance (FMA-B), modified Barthel Index (MBI) and Hamilton Depression Scale (HAMD). Patients with HAMD scores ≤ 20 were as the low group, and those > 20 were as the high group. ResultA total of 2 403 hospitalized stroke patients were included, out of which 269 patients with cerebral infarction were diagnosed as depression and visited the department of psychology; while 103 cases were in the low group and 166 cases were in the high group. The incidence of constipation was less, and the incidence of dysphagia and shoulder-hand syndrome was higher in the high group (χ² > 5.379, P < 0.05), with weaker strength of iliopsoas muscle and quadriceps muscle, earlier of Brunnstrom stage of lower extremities and hands, and worse scores of NIHSS, MMSE, FMA, FMA-B and MBI (|Z| > 2.020, t > 2.171, P < 0.05). Logistic regression showed that constipation (OR = 0.435), quadriceps muscle strength (OR = 0.782) and dysphagia (OR = 2.602) related to the intensity of post-stroke depression in convalescent patients (P < 0.05). ConclusionPost-stroke dysphagia and poor quadriceps muscle strength may exacerbate post-stroke depression; however, constipation may not.