Serum potassium level, variability and in-hospital mortality in acute myocardial infarction.

OBJECTIVE: Clinical guidelines recommend an optimal serum potassium concentration between 4.0 and 5.0 mmol/L in patients with acute myocardial infarction (AMI), which was based on lower-quality evidence from more than 20 years ago. Therefore, it is essential to re-evaluate the range of optimal potassium levels in patients with AMI in intensive care unit (ICU). METHODS: This was a retrospective study based on Philips eICU Collaborative Research Database, which covered 9776 patients with AMI between 2014 and 2015. All patients had more than or equal to 2 serum potassium measurements and were categorized by the mean serum potassium level (<3.5, 3.5-4.5, 4.5-5.5, ≥5.5 mmol/L) and potassium variability (1st, 2nd, and ≥3rd standard deviation (SD)). Binary logistic regression was used to determine the association between mean potassium levels, variability and in-hospital mortality in AMI. RESULTS: Of all 9776 AMI patients in ICU, 8731 (89.3%) patients were included. A total of 69847 potassium measurements were performed in these patients. There was a J-shaped relationship between mean serum potassium level and in-hospital mortality. The lowest mortality (mortality rate, 7.2%; 95% CI, 6.57%-7.76%) was observed in patients with mean potassium level between 3.5 and 4.5 mmol/L and a low potassium variability within the 1st SD. Logistic regression showed that the risk of in-hospital mortality is highest when the mean potassium level ≥5.5 mmol/L (57.6%; 95% Cl, 45.02%-70.24%; multivariable adjusted OR, 14.8; 95% CI, 8.4-26.2) compared to the reference group of 3.5-4.5 mmol/L and potassium variability within the 3rd SD (16.5%; 95% Cl, 15.19%-17.88%; multivariable adjusted OR, 3.3; 95% CI, 2.7-4.1) compared to 1st SD. Several sensitivity analyses confirmed these results. CONCLUSION: Among AMI patients in ICU, the minimum risk of in-hospital mortality was observed in those with mean potassium levels between 3.5 and 4.5 mmol/L or a minimal potassium variability compared to those who had higher or lower values.

Comparison of New Glucose-Lowering Drugs on the Risk of Pancreatitis in Type 2 Diabetes: A Network Meta-Analysis.

OBJECTIVE: To explore whether new glucose-lowering drugs increase the risk of pancreatitis in individuals with type 2 diabetes. This present network meta-analysis aimed to investigate the risk of pancreatitis associated with the use of glucagon-like peptide-1 (GLP-1) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors in the treatment of type 2 diabetes mellitus. METHODS: PubMed, Web of Science, Embase, and the Cochrane Library were searched. The literature was published from the date of their inception to July 21, 2021, including placebo-controlled or head-to-head trials of 2 new glucose-lowering drugs. The relative ratio (RR) and 95% confidence interval (CI) were used to assess the risk of GLP-1 agonists and DPP-4 inhibitors for pancreatitis or pancreatic cancer among patients with type 2 diabetes. RESULTS: Seventeen studies were identified, covered 102 257 participants. The pooled results showed a neutral relationship between GLP-1 agonists and pancreatitis (overall RR, 0.96; 95% CI, 0.31-3.00) or pancreatic cancer (overall RR, 1.10; 95% CI, 0.31-4.10) compared with placebo. Meanwhile, DPP-4 inhibitors were not associated with the increased risk of pancreatitis (overall RR, 1.60; 95% CI, 0.25-11.00) or pancreatic cancer (overall RR, 0.79; 95% CI, 0.26-2.40). Among them, lixisenatide and saxagliptin may be the safest drugs compared with other drugs according to the ranking of probability. Sensitivity and subgroup analysis confirmed the stability of the core results. CONCLUSION: The most obvious finding of this study is that GLP-1 agonists and DPP-4 inhibitors are safe with respect to the risk of pancreatitis and pancreatic cancer compared with placebo. This conclusion may provide useful evidence for correlated clinical researches.

The global burden of periodontal diseases in 204 countries and territories from 1990 to 2019.

AIMS: The aim of this study was to report the incidence, prevalence, and disability-adjusted life-years (DALYs) of periodontal diseases during the period 1990-2019. METHODS: Data on periodontal diseases were retrieved from the Global Burden of Diseases, Injuries, and Risk Factors study (GBD) 2019. The estimated annual percentage changes were calculated to evaluate the changing trend of age-standardized incidence, prevalence, and DALY rates related to periodontal diseases. RESULTS: Globally, there were 1,087,367,744.0 cases with 91,518,820.6 new incidence and 7,090,390.3 DALYs of periodontal diseases in 2019, almost twice as many as in 1990. Moreover, the pace of increase in age-standardized incidence, age-standardized prevalence, and age-standardized DALY rates had accelerated during the 1990-2019 time period, with EAPC of 0.29 (95% CI, 0.22 to 0.35), 0.34 (95% CI, 0.26 to 0.43), and 0.35 (95% CI, 0.27 to 0.44) separately. The corresponding age-standardized percentage changes were more pronounced in females, Southeast Asia, and low-middle SDI regions. Western Sub-Saharan Africa was the high-risk area of standardized periodontal diseases burden in 2019, among which Gambia was the country with the heaviest burden. CONCLUSION: The globally incidence, prevalence, and DALYs of periodontal diseases are substantially increased from 1990 to 2019, which highlights the importance and urgency of periodontal care.

Relationship between periodontitis and microangiopathy in type 2 diabetes mellitus: a meta-analysis.

OBJECTIVE: Whether periodontitis increases the risk of diabetic microangiopathy remains controversial. The present meta-analysis aims to investigate the relationship between periodontitis and diabetic microangiopathy in patients with type 2 diabetes mellitus. METHODS: PubMed, EMBASE, Web of Science, the Cochrane Library, CNKI, and WanFang data were searched without language restrictions. The methodological quality of the studies included was assessed using Newcastle-Ottawa Scale method, and meta-analysis was performed by Review Manager 5.3. Odds ratio (OR) and 95% confidence interval (CI) were used to assess the risk of periodontitis for diabetic microangiopathy among patients with type 2 diabetes. RESULTS: Thirteen cross-sectional studies, covering 10 570 participants, were included in the present meta-analysis. The results demonstrated that periodontitis was associated with increased risk of type 2 diabetic microangiopathy (OR: 2.43, 95% CI: 1.65-3.56), diabetic retinopathy (OR: 4.33, 95% CI: 2.19-8.55), and diabetic nephropathy (OR: 1.75, 95% CI: 1.07-2.85), while periodontitis was not associated with diabetic neuropathy (OR: 0.99, 95% CI: 0.19-5.12). Subgroup analysis among the studies in Asian (OR: 3.06, 95% CI: 1.94-4.84) and North American (OR: 1.42, 95% CI: 1.08-1.86) populations confirmed the existed association between periodontitis and type 2 diabetic microangiopathy. The relationship still existed in groups with sample size larger than 500 (OR: 1.77, 95% CI: 1.34-2.34) and smaller than 500 (OR: 3.33, 95% CI: 1.38-8.03). A sensitivity analysis confirmed the stability of the results by excluding moderate quality studies or removing articles one after the other. CONCLUSION: Current evidences have proved that periodontitis is associated with increased risk of diabetic microangiopathy in patients with type 2 diabetes mellitus. This conclusion may provide useful evidence for correlated clinical researches. PROSPERO registration number CRD42021247773.

Ampelopsin Inhibits Breast Cancer Cell Growth through Mitochondrial Apoptosis Pathway.

Ampelopsin, a flavonoid with a wide variety of biological activities, has been proposed to be a potent antitumor agent. However, the mechanism by which Ampelopsin shows anti-breast cancer activity remains unclear. Therefore, this study will explore the mechanism of Ampelopsin's anti-breast cancer activity by culturing MDA-MB-231 and MCF-7 breast cancer cells. Cell Counting Kit-8 (CCK-8) method and plate cloning method were used to detect the proliferation inhibition of breast cancer cells. Fluorescence microscopy was used to detect mitochondrial membrane potential (MMP). 2',7'-Dichlorodihydrofluorescein diacetate (DCFH-DA) method was used to determine the content of intracellular reactive oxygen species (ROS). Hoechst 33258 staining was used to detect the apoptotic morphological changes. Transmission electron microscope was used to observe the mitochondrial structure. Western blot was used to detect the protein expression of Bax and Bcl-2. The results showed that Ampelopsin could significantly inhibit the proliferation of breast cancer cells, and promote cells apoptosis. In addition, the occurrence of apoptosis in breast cancer cells was associated with mitochondrial dysfunction, including the loss of mitochondrial membrane potential, the production of large amounts of reactive oxygen species, and the up-regulation of Bax/Bcl-2 expression. In conclusion, Ampelopsin-induced mitochondria damage leads to loss of mitochondria membrane potential, overproduction of ROS and activation of Bax, increasing mitochondria membrane permeability and ultimately inducing breast cell apoptosis. These findings provided a new perspective on the role of Ampelopsin in breast cancer prevention and treatment.

Mediation effect of stroke recurrence in the association between post-stroke lactate dehydrogenase and functional disability.

Background: We aimed to use lactate dehydrogenase (LDH) as a marker of inflammation burden and quantify post-stroke inflammation's direct and indirect effect on functional disability. Methods: We analyzed 5,129 patients with acute ischemic stroke (AIS) admitted to Shenyang First People's Hospital. Stroke recurrence and functional outcome measured by the modified Rankin Scale (mRS) were assessed at 90 days. Functional disability was defined as mRS score > 2. Receiver operating characteristic curve and restricted cubic spline (RCS) analysis were conducted to illustrate the associations between LDH levels and 90-day functional outcomes in patients with AIS. Mediation analyses were performed to examine the potential causal chain in which stroke recurrence may mediate the relationship between LDH and functional outcome. Positive correlation between LDH and hs-CRP was found and mediation effects of stroke recurrence in the association between LDH or hs-CRP and functional disability were both less than 20%. Sensitivity analyses in different subgroups showed comparable results. Results: Among 5,129 included AIS patients, the median (IQR) level of LDH was 186 (161-204.4) U/L. Functional disability was seen in 1200 (23.4%) patients and recurrence was observed in 371(7.2%) patients at 90-day follow-up. Each standard deviation increase in the concentration of LDH was linked to an increased risk of functional disability (adjusted odds ratio[aOR], 1.07; 95%CI,1.04-1.09) and stroke recurrence (aOR,1.02; 95%CI, 1.01-1.04) within 90 days. The highest quartile of LDH (>204.2 U/L) had an elevated risk of suffering functional disability (aOR, 1.21; 95%CI, 1.00-1.47) and recurrence (aOR, 1.21; 95%CI,1.00-1.47) compared with the lowest quartile of LDH (<161 U/L). Stroke recurrence during follow-up explained 12.90% (95%CI, 6.22-21.16%) of the relationship between LDH and functional disability. Positive correlation between LDH and hs-CRP was found and mediation effects of recurrence in the association between LDH or hs-CRP and functional disability were both less than 20%. Sensitivity analyses in different subgroups showed comparable results. Conclusion: The relationship between LDH and functional disability at 90 days among AIS patients is partially mediated by stroke recurrence, accounting for less than 20%. LDH deserves equal attention as hs-CRP in predicting recurrence and functional outcome. In addition to traditional secondary prevention measures, innovative anti-inflammatory strategies warrant further investigation.

Effectiveness of the acute stroke care map program in reducing in-hospital delay for acute ischemic stroke in a Chinese urban area: an interrupted time series analysis.

Background: Timely intravenous thrombolysis (IVT) is crucial for improving outcomes in acute ischemic stroke (AIS) patients. This study evaluates the effectiveness of the Acute Stroke Care Map (ASCaM) initiative in Shenyang, aimed at reducing door-to-needle times (DNT) and thus improving the timeliness of care for AIS patients. Methods: An retrospective cohort study was conducted from April 2019 to December 2021 in 30 hospitals participating in the ASCaM initiative in Shenyang. The ASCaM bundle included strategies such as EMS prenotification, rapid stroke triage, on-call stroke neurologists, immediate neuroimaging interpretation, and the innovative Pre-hospital Emergency Call and Location Identification feature. An interrupted time series analysis (ITSA) was used to assess the impact of ASCaM on DNT, comparing 9 months pre-intervention with 24 months post-intervention. Results: Data from 9,680 IVT-treated ischemic stroke patients were analyzed, including 2,401 in the pre-intervention phase and 7,279 post-intervention. The ITSA revealed a significant reduction in monthly DNT by -1.12 min and a level change of -5.727 min post-ASCaM implementation. Conclusion: The ASCaM initiative significantly reduced in-hospital delays for AIS patients, demonstrating its effectiveness as a comprehensive stroke care improvement strategy in urban settings. These findings highlight the potential of coordinated care interventions to enhance timely access to reperfusion therapies and overall stroke prognosis.

Machine learning-based prediction of early neurological deterioration after intravenous thrombolysis for stroke: insights from a large multicenter study.

Background: This investigation seeks to ascertain the efficacy of various machine learning models in forecasting early neurological deterioration (END) following thrombolysis in patients with acute ischemic stroke (AIS). Methods: Employing data from the Shenyang Stroke Emergency Map database, this multicenter study compiled information on 7,570 AIS patients from 29 comprehensive hospitals who received thrombolytic therapy between January 2019 and December 2021. An independent testing cohort was constituted from 2,046 patients at the First People's Hospital of Shenyang. The dataset incorporated 15 pertinent clinical and therapeutic variables. The principal outcome assessed was the occurrence of END post-thrombolysis. Model development was executed using an 80/20 split for training and internal validation, employing classifiers like logistic regression with lasso regularization (lasso regression), support vector machine (SVM), random forest (RF), gradient-boosted decision tree (GBDT), and multi-layer perceptron (MLP). The model with the highest area under the curve (AUC) was utilized to delineate feature significance. Results: Baseline characteristics showed variability in END incidence between the training (n = 7,570; END incidence 22%) and external validation cohorts (n = 2,046; END incidence 10%; p < 0.001). Notably, all machine learning models demonstrated superior AUC values compared to the reference model, indicating their enhanced predictive capacity. The lasso regression model achieved the highest AUC at 0.829 (95% CI: 0.799-0.86; p < 0.001), closely followed by the MLP model with an AUC of 0.828 (95% CI: 0.799-0.858; p < 0.001). The SVM, RF, and GBDT models also showed commendable AUCs of 0.753, 0.797, and 0.774, respectively. Decision curve analysis revealed that the SVM and MLP models demonstrated a high net benefit. Feature importance analysis emphasized "Onset To Needle Time" and "Admission NIHSS Score" as significant predictors. Conclusion: Our research establishes the MLP and lasso regression as robust tools for predicting early neurological deterioration in acute ischemic stroke patients following thrombolysis. Their superior predictive accuracy, compared to traditional models, highlights the significant potential of machine learning approaches in refining prognosis and enhancing clinical decisions in stroke care management. This advancement paves the way for more tailored therapeutic strategies, ultimately aiming to improve patient outcomes in clinical practice.

Prevalence, awareness, and treatment of isolated diastolic hypertension in the United States.

BACKGROUND: Isolated diastolic hypertension (IDH) is recognized as a risk factor for cardiovascular disease, yet its clinical epidemiology remains poorly understood due to insufficient recognition. This study aims to describe the trend in the prevalence, awareness, and treatment of IDH in the United States from 2001 to 2018. METHODS: This cross-sectional study utilized data from the National Health and Nutrition Examination Survey (NHANES) conducted in nine consecutive two-year cycles from 2001-2002 to 2017-2018, comprising a sample of 48,742 adults aged over 18 years. IDH was defined as a diastolic blood pressure ≥ 80 mm Hg with a systolic BP < 130 mm Hg by the 2017 American College of Cardiology (ACC)/American Heart Association (AHA) guidelines. RESULTS: In the nationally representative dataset, 8.9% of participants had IDH in 2017-2018, a decreased of 3.6% (95% confidence interval [CI], -2.6% to -5.0%, P<0.0002) since 2001-2002. IDH prevalence was highest among Mexican American (10.5%), individuals aged 40-59 (12.3%), increased with body mass index (BMI) (11.2% among those BMI ≥30.0 kg/m2), and tended to be higher in men (12.3%). A multiple regression analysis showed that men, white race/ethnicity, young and middle-aged people (aged 18-59), and increasing BMI were independently associated with increased risks of IDH. Among IDH patients, there was a modest increase in awareness (P<0.0002), from 22.4% (95%CI, 18.4% to 27.1%) in 2001-2002 to 35.0% (95%CI, 28.2% to 42.5%) in 2017-2018, with the largest percentage increases among non-Hispanic white and men. IDH treatment increased by 7.6% (95%CI, 3.1% to 12.1%) between 2001-2002 and 2017-2018, with the greatest increases occurring in Mexican American and men. CONCLUSION: IDH prevalence is decreasing from 2001-2002 to 2017-2018 in the United States. Despite the significantly increased in both awareness and treatment, they remain below 50%.

Effect of comorbidity assessed by the Charlson Comorbidity Index on the length of stay, costs, and mortality among colorectal cancer patients undergoing colorectal surgery.

OBJECTIVE: Charlson Comorbidity Index (CCI) is a good predictor for hospitalization cost and mortality among patients with chronic disease. However, the impact of CCI on patients after colorectal cancer surgery is unclear. This study aims to investigate the influence of comorbidity assessed by CCI on length of stay, hospitalization costs, and in-hospital mortality in patients with colorectal cancer (CRC) who underwent surgical resection. METHODS: This historical cohort study collected 10,271 adult inpatients for CRC undergoing resection surgery in 33 tertiary hospitals between January 2018 and December 2019. All patients were categorized by the CCI score into four classes: 0, 1,2, and ≥3. Linear regression was used for outcome indicators as continuous variables and logical regression for categorical variables. EmpowerStats software and R were used for data analysis. RESULTS: Of all 10,271 CRC patients, 51.72% had at least one comorbidity. Prevalence of metastatic solid tumor (19.68%, except colorectal cancer) and diabetes without complication (15.01%) were the major comorbidities. The highest average cost of hospitalization (86,761.88 CNY), length of stay (18.13 days), and in-hospital mortality (0.89%) were observed in patients with CCI score ≥3 compared to lower CCI scores (p < .001). Multivariate regression analysis showed that the CCI score was associated with hospitalization costs (ß, 7340.46 [95% confidence interval (CI) (5710.06-8970.86)], p < .001), length of stay (ß, 1.91[95%CI (1.52-2.30)], p < .001), and in-hospital mortality(odds ratio (OR),16.83[95%CI (2.23-126.88)], p = .0062) after adjusted basic clinical characteristics, especially when CCI score ≥3. Notably, the most specific complication associated with hospitalization costs and length of stay was metastatic solid tumor, while the most notable mortality-specific comorbidity was moderate or severe renal disease. CONCLUSION: The research work has discovered a strong link between CCI and clinical plus economic outcomes in patients with CRC who underwent surgical resection.

Epicatechin gallate promotes vascularization in co-culture of human osteoblasts and outgrowth endothelial cells.

Prevascularization is crucial for the survival of tissue-engineered bone and further bone repair/regeneration. Since epicatechin gallate (ECG), the most abundant flavanol in green tea, shows potential beneficial effects on endothelial cells and bone cells, we decided to investigate whether it promotes vascularization/angiogenesis and osteogenesis using a co-culture system containing human primary osteoblasts (POBs) and outgrowth endothelial cells (OECs). We found that treatment with ECG (1) significantly enhanced microvessel formation in co-culture of POB and OECs, (2) improved cell viability/proliferation and the angiogenic/osteogenic capacities of OEC/POBs, (3) significantly increased the levels of E-selectin, IL-6, TNF-α, IFN-γ, VEGF, and PDGF-BB in co-cultures of POB and OEC, and (4) upregulated HIF-1α, HIF-2α, NF-κB, iNOS, GLUT1, VEGF, and Ang1/2 but downregulated PHD1 in monocultures of OEC or POB. Our findings demonstrate that ECG promotes angiogenesis and osteogenesis (probably via HIF signaling) in co-cultures of OECs and POBs. ECG thus has potential applications in the promotion of angiogenesis/vascularization in many tissue constructs including those of bone.

Machine learning-based prediction of symptomatic intracerebral hemorrhage after intravenous thrombolysis for stroke: a large multicenter study.

Background: This study aimed to compare the performance of different machine learning models in predicting symptomatic intracranial hemorrhage (sICH) after thrombolysis treatment for ischemic stroke. Methods: This multicenter study utilized the Shenyang Stroke Emergency Map database, comprising 8,924 acute ischemic stroke patients from 29 comprehensive hospitals who underwent thrombolysis between January 2019 and December 2021. An independent testing cohort was further established, including 1,921 patients from the First People's Hospital of Shenyang. The structured dataset encompassed 15 variables, including clinical and therapeutic metrics. The primary outcome was the sICH occurrence post-thrombolysis. Models were developed using an 80/20 split for training and internal validation. Performance was assessed using machine learning classifiers, including logistic regression with lasso regularization, support vector machine (SVM), random forest, gradient-boosted decision tree (GBDT), and multilayer perceptron (MLP). The model boasting the highest area under the curve (AUC) was specifically employed to highlight feature importance. Results: Baseline characteristics were compared between the training cohort (n = 6,369) and the external validation cohort (n = 1,921), with the sICH incidence being slightly higher in the training cohort (1.6%) compared to the validation cohort (1.1%). Among the evaluated models, the logistic regression with lasso regularization achieved the highest AUC of 0.87 (95% confidence interval [CI]: 0.79-0.95; p < 0.001), followed by the MLP model with an AUC of 0.766 (95% CI: 0.637-0.894; p = 0.04). The reference model and SVM showed AUCs of 0.575 and 0.582, respectively, while the random forest and GBDT models performed less optimally with AUCs of 0.536 and 0.436, respectively. Decision curve analysis revealed net benefits primarily for the SVM and MLP models. Feature importance from the logistic regression model emphasized anticoagulation therapy as the most significant negative predictor (coefficient: -2.0833) and recombinant tissue plasminogen activator as the principal positive predictor (coefficient: 0.5082). Conclusion: After a comprehensive evaluation, the MLP model is recommended due to its superior ability to predict the risk of symptomatic hemorrhage post-thrombolysis in ischemic stroke patients. Based on decision curve analysis, the MLP-based model was chosen and demonstrated enhanced discriminative ability compared to the reference. This model serves as a valuable tool for clinicians, aiding in treatment planning and ensuring more precise forecasting of patient outcomes.

Nomogram to predict 6-month mortality in acute ischemic stroke patients treated with endovascular treatment.

Background: Acute Ischemic Stroke (AIS) presents significant challenges in evaluating the effectiveness of Endovascular Treatment (EVT). This study develops a novel prognostic model to predict 6-month mortality post-EVT, aiding in identifying patients likely to benefit less from this intervention, thus enhancing therapeutic decision-making. Methods: We employed a cohort of AIS patients from Shenyang First People's Hospital, serving as the Validation set, to develop our model. LASSO regression was used for feature selection, followed by logistic regression to create a prognostic nomogram for predicting 6-month mortality post-EVT. The model's performance was validated using a dataset from PLA Northern Theater Command General Hospital, assessing discriminative ability (C-index), calibration (calibration plot), and clinical utility (decision curve analysis). Statistical significance was set at p < 0.05. Results: The development cohort consisted of 219 patients. Six key predictors of 6-month mortality were identified: "Lack of Exercise" (OR, 4.792; 95% CI, 1.731-13.269), "Initial TICI Score 1" (OR, 1.334; 95% CI, 0.628-2.836), "MRS Score 5" (OR, 1.688; 95% CI, 0.754-3.78), "Neutrophil Percentage" (OR, 1.08; 95% CI, 1.042-1.121), "Onset Blood Sugar" (OR, 1.119; 95% CI, 1.007-1.245), and "Onset NIHSS Score" (OR, 1.074; 95% CI, 1.029-1.121). The nomogram demonstrated a high predictive capability with a C-index of 0.872 (95% CI, 0.830-0.911) in the development set and 0.830 (95% CI, 0.726-0.920) in the validation set. Conclusion: Our nomogram, incorporating factors such as Lack of Exercise, Initial TICI Score 1, MRS Score 5, Neutrophil Percentage, Onset Blood Sugar, and Onset NIHSS Score, provides a valuable tool for predicting 6-month mortality in AIS patients post-EVT. It offers potential to refine early clinical decision-making and optimize patient outcomes, reflecting a shift toward more individualized patient care.

Gut microbiota-bile acids-glucagon like peptide-1 axis contributes the resistance to high fat diet-induced obesity in mice.

In human and rodents, some individuals may remain lean even when they are challenged with high calorie intake. Here, we used C57BL/6J mice to establish animal models of high-fat diet (HFD) induced obesity sensitive (DIO) mice and obesity resistant (DIR) mice. In DIR mice, improved metabolic profile through brown adipose tissue (BAT) activation was observed, while plasma unconjugated bile acids (BAs) were decreased together with increased intestine tauro-conjugated BAs (e.g., T-ß-MCA). The composition of the gut flora also differs greatly between DIR and DOR. Using fecal microbiota transplants from DIR mice, HFD fed recipient mice exhibited a trend toward reduced adiposity and improved glucose tolerance, showing increased serum tauro-conjugated BAs levels. STC-1 cell experiments confirmed T-ß-MCA could activate FXR/TGR5 pathway and induce the production of GLP-1, inhibiting genes that regulate the ceramide synthesis. Our results indicated that the DIR mice exhibited higher energy expenditure by activating BAT thermogenesis, which may be related to altered gut microbiota-bile acids-glucagon like peptide-1 axis.

Promotion of angiogenesis in vitro by Astragalus polysaccharide via activation of TLR4 signaling pathway.

During the implantation of functional tissue-engineered constructs for treating bone defects, a functional vascular network is critical for the survival of the construct. One strategy to achieve rapid angiogenesis for this application is the co-culture of outgrowth endothelial cells (OECs) and primary human osteoblasts (POBs) within a scaffold prior to implantation. In the present study, we aim to investigate whether Astragalus polysaccharide (APS) promotes angiogenesis or vascularization via the TLR4 signaling pathway in a co-culture of OECs and POBs. The co-cultures were treated with various concentrations of APS for 24 h and, subsequently, another 7 days, followed by CD31 staining and analysis of micro-vessel-formation areas using software. Additionally, APS (0.4 mg/ml for 24 h) was added to monocultures of OECs or POBs for evaluating proliferation, apoptosis, angiogenesis, osteogenesis, TLR4 signaling pathway, and inflammatory cytokine release. We found that APS promoted angiogenesis in the co-culture at the optimal concentration of 0.4 mg/ml. TLR4 activation by APS up-regulated the expression level of TLR4/MyD88 and enhanced angiogenesis and osteogenesis in monocultures of OECs and POBs. The levels of E-selectin adhesion molecules, three cytokines (IL-6, TNF-α, and IFN-γ), and VEGF and PDGF-BB, which can induce angiogenesis, increased significantly (p < .05) following APS treatment. Therefore, APS appears to promote angiogenesis and ossification in the co-culture system via the TLR4 signaling pathway. PRACTICAL APPLICATIONS: This study demonstrates that APS may promote angiogenesis and osteocyte proliferation in OEC and POB co-culture systems through the MyD88-dependent TLR4 signaling pathway. APS might represent a potential therapeutic strategy in tissue-engineered bone implantation for the treatment of large bone defects; additionally, it has the advantage of safety, as it exhibits low or no side effects. In the future, it is expected to be used in vitro for the construction of tissue-engineered bone and in vivo after implantation in patients with bone defects for promoting rapid vascularization and ossification of tissue-engineered bone and early fusion with the recipient's bone. In addition, as a food additive, Astragalus membranaceus can be used as a tonic material in patients recovering from a fracture for promoting blood-vessel formation at the fracture site and fracture recovery. Combining traditional Chinese medicine with tissue engineering can provide further strategies for promoting the development of regenerative medicine.

The global burden of type 2 diabetes attributable to high body mass index in 204 countries and territories, 1990-2019: An analysis of the Global Burden of Disease Study.

Background: High body mass index (BMI) plays a critical role in the initiation and development of type 2 diabetes (T2D). Up to now, far too little attention has been paid to the global burden of T2D attributable to high BMI. This study aims to report the deaths and disability-adjusted life years (DALYs) of T2D related to high BMI in 204 countries and territories from 1990 to 2019. Methods: Data on T2D burden attributable to high BMI were retrieved from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019. The global cases, age-standardized rates of mortality (ASMR), and disability-adjusted life years (ASDR) attributable to high BMI were estimated by age, sex, geographical location, and socio-demographic index (SDI). The estimated annual percentage change (EAPC) was calculated to quantify the trends of ASMR and ASDR during the period 1990-2019. Results: Globally, there were 619,494.8 deaths and 34,422,224.8 DALYs of T2D attributed to high BMI in 2019, more than triple in 1990. Moreover, the pace of increase in ASMR and ASDR accelerated during 1990-2019, with EAPC of 1.36 (95% CI: 1.27 to 1.45) and 2.13 (95% CI: 2.10 to 2.17) separately, especially in men, South Asia, and low-middle SDI regions. Oceania was the high-risk area of standardized T2D deaths and DALYs attributable to high BMI in 2019, among which Fiji was the country with the heaviest burden. In terms of SDI, middle SDI regions had the biggest T2D-related ASMR and ASDR in 2019. Conclusion: The global deaths and DALYs of T2D attributable to high BMI substantially increased from 1990 to 2019. High BMI as a major public health problem needs to be tackled properly and timely in patients with T2D.

The clinical efficacy of urate-lowering therapy in acute gout: a meta-analysis of randomized controlled trials.

BACKGROUND: Gout is a common chronic disease with a high recurrence rate. To date, the debate continues about the best time for using urate lowering therapy (ULT) during an acute gout attack. OBJECTIVE: This updated meta-analysis is designed to assess the clinical efficacy of ULT in the management of acute exacerbations of gout. Through the results, we hope to determine whether uric acid lowering agents should be used to manage acute exacerbations of gout. METHODS: A comprehensive search of six databases without language restrictions includes PubMed, Cochrane Library, Web of Science, EMBASE, CNKI, and WanFang data. The literature used was published before October 2019. Six randomized controlled trials (RCTs) with 557 patients met the inclusion criteria. Standardized mean difference (SMD), weighted mean difference (WMD), risk ratio (RR), and 95% confidence interval (CI) were used for estimating the clinical efficacy of ULT in acute gout. RESULTS: Data results showed no statistical difference in the pain visual analogue score (VAS) by day 3 (weighted mean difference (WMD), 0.06; 95% CI, - 0.13 to 0.25; I2 0%; P = 0.55), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) between the group using uric acid lowering agents and the group that was not using such agents. Moreover, the patients using ULT agents had lower serum uric acid level (standardized mean difference (SMD), - 0.73; 95% CI, -0.92 to -0.54; I2 23%; P < 0.00001) and showed better adherence to medication (risk ratio (RR), 1.40; 95% CI, 1.18 to 1.65; I2 0%; P < 0.0001) as compared with the patients not that were not using such agents. However, there was no substantial difference in the recurrence rate of acute gout attacks (RR, 0.84; 95% CI, 0.59 to 1.19; I2 0%; P = 0.33).The evidence for this is, however, very moderate. CONCLUSION: Our finding shows that it is beneficial in many aspects to use uric-acid-lowering drugs at the initial stage of an acute gout attack. However, larger sample size studies are still needed to prove our results. TRIAL REGISTRATION: Registration number: PROSPERO (CRD42020153924). Key Points • This is a first meta-analysis about the clinical efficacy of urate-lowering therapy (ULT) in acute gout without language restrictions. • ULT in acute gout may not aggravate the pain (WMD, 0.06; 95% CI, - 0.13 to 0.25). • ULT at the initial stage of an acute gout attack can reduce serum uric acid level (SMD, -0.73; 95% CI, - 0.92 to - 0.54) and improve medication compliance in patients (RR, 1.40; 95% CI, 1.18 to 1.65). • ULT in acute gout is not associated with the risk of gout flares (RR, 0.84; 95% CI, 0.59 to 1.19).

Maternal obesity interrupts the coordination of the unfolded protein response and heat shock response in the postnatal developing hypothalamus of male offspring in mice.

Maternal obesity malprograms offspring obesity and associated metabolic disorder. As a common phenomenon in obesity, endoplasmic reticulum (ER) stress also presents early prior to the development. Here, we investigate metabolic effect of early activated hypothalamic ER stress in offspring exposed to maternal obesogenic environment and the underlying mechanism in ICR mice model. We found higher body weight, hyperphagia and defective hypothalamic feeding-circuit in the offspring born to obese dams, with hypothalamic ER stress, and even more comprehensive cell proteotoxic stress were induced during the early postnatal period. However, neonatal inhibition of hypothalamic ER stress worsened the metabolic end. We believe that the uncoordinated interaction between the unfolded protein response and the heat shock response, regulated by heat shock protein 70, might be responsible for the malformed hypothalamic feeding circuit of the offspring exposure to maternal obesogenic conditions and were linked with deleterious metabolism in adulthood, especially when exposure to high-energy conditions.

Efficacy of Antiangiogenic Drugs in the Treatment of Diabetic Macular Edema: A Bayesian Network Analysis.

Aims: To compare the efficacy of five kinds of antiangiogenic drugs in the treatment of diabetic macular edema Methods: A comprehensive search of seven databases without language restrictions includes PubMed, EMBASE, Web of Science, CBM, the Cochrane Library, CNKI, and WanFang date. All literature used was published before October 2020. Eligible randomized trials were screened for inclusion in this study, and Bayesian framework was used to perform a network meta-analysis (NMA). Data on the mean change of best-corrected visual acuity (BCVA), central macular thickness (CMT) and intraocular pressure (IOP) at 6 months were extracted. Results: 25 randomized controlled trials (RCTs) that covered 2214 eyes, which received treatment of more than 3 months durations were included. In the pooled pair-wise meta-analysis, there was no statistically significant difference between all treatments. The same result was observed in the network meta-analysis with 0-37.82% Global I-squared. For BCVA at 6 months, conbercept and ranibizumab may be favorable than bevacizumab, aflibercept, triamcinolone acetonide and sham injections according to the ranking probabilities. As for CMT at 6 months, ranibizumab may be the most effective compared to bevacizumab, aflibercept and triamcinolone acetonide. In terms of IOP at 6 months, ranibizumab have better effect than bevacizumab, triamcinolone acetonide and sham injections. The results of sensitivity analysis also confirm it. Conclusion: The analysis confirms that ranibizumab may be the most favorable for BCVA improvement and have a stronger efficacy in decreasing CMT and IOP than other drugs when taking all the indicators into consideration. This conclusion may provide clinical evidence to guide treatment decisions. However, more high-quality randomized controlled trials will be necessary to further confirm this.

Comparison of New Oral Hypoglycemic Agents on Risk of Urinary Tract and Genital Infections in Type 2 Diabetes: A Network Meta-analysis.

INTRODUCTION: Dipeptidyl peptidase 4 (DPP4) inhibitors and sodium-glucose co-transporter 2 (SGLT2) inhibitors have often been used for patients with T2DM because of the reduced risk of hypoglycemia. However, DPP4 inhibitors and SGLT2 inhibitors may increase the risk of infectious diseases. This network meta-analysis (NMA) was performed to investigate the risk of urinary tract and genital infections associated with the use of two new glucose-lowering drug classes in patients with type 2 diabetes. METHODS: PubMed, Web of Science, Embase, and the Cochrane Library were comprehensively searched for articles from the date of database inception until September 8, 2020. Placebo-controlled or head-to-head trials of the two new drug classes used for treatment of adults with type 2 diabetes were included. The primary outcome was the incidence of any confirmed urinary tract infection; genital infection was also used as an important outcome indicator. RESULTS: Fifty-five studies were identified, covering 29,574 participants. Regarding urinary tract infections, SGLT2 inhibitors were not associated with increased risk, and among all drugs, sitagliptin, ipragliflozin, and linagliptin were the safest according to probability ranking. Regarding genital infections, saxagliptin was associated with significantly reduced risk in pairwise comparisons with placebo (RR 0.12, 95% CI 0.00-0.78), linagliptin (RR 0.09, 95% CI 0.00-0.78), canagliflozin (RR 0.04, 95% CI 0.00-0.31), dapagliflozin (RR 0.04, 95% CI 0.00-0.26), empagliflozin (RR 0.03, 95% CI 0.00-0.25), and ertugliflozin (RR 0.03, 95% CI 0.00-0.24). Among all drugs, saxagliptin, sitagliptin, and ipragliflozin were the safest according to probability ranking. Considering both urinary tract and genital infection risks, DPP4 inhibitors showed greater reductions than SGLT2 inhibitors and placebo. Saxagliptin was the safest drug according to probability ranking for both infection risks. CONCLUSIONS: This NMA showed that, to reduce genital infection risk, current evidence favors DPP4 inhibitors over SGLT2 inhibitors. Most SGLT2 inhibitors may not be associated with the risk of urinary tract infections. Considering both infection risks, saxagliptin may be the safest drug. Finally, mechanistic studies are needed to better understand the physiological basis for these effects.