Shanghai Municipal Education Commission Research Articles

Achievement of Guideline-Recommended Targets in Diabetes Care in China : A Nationwide Cross-Sectional Study.

Nationwide achievement of guideline-recommended diabetes care targets has not been comprehensively assessed in China. To estimate the proportions of adults with diabetes achieving major clinical risk factor control, body mass index (BMI), lifestyle, and dietary targets specified in the Chinese diabetes guidelines. Nationwide cross-sectional survey. China, 2015 to 2017. A national sample of 8401 adults with self-reported diabetes and a subset of 3531 with dietary data. The assessed targets included 1) ABC targets (individualized hemoglobin A1c [HbA1c] target; blood pressure [BP] <130/80 mm Hg; and low-density lipoprotein cholesterol [LDL-C] level <2.6 or <1.8 mmol/L [<100 or <70 mg/dL], depending on the presence of atherosclerotic cardiovascular disease), 2) BMI below 24 kg/m2, 3) lifestyle targets (not currently smoking or drinking, guideline-recommended leisure time activity level, and sleep duration of 7 to 8 hours), and 4) dietary targets (50% to 65% of energy from carbohydrate, 15% to 20% from protein, 20% to 30% from fat, ≥14 g of fiber per 1000 kcal, and <2000 mg of sodium per day). The proportion of adults with self-reported diabetes achieving each ABC target was 64.1% (95% CI, 61.4% to 66.8%) for HbA1c, 22.2% (CI, 20.2% to 24.1%) for BP, and 23.9% (CI, 21.9% to 25.9%) for LDL-C. The proportion achieving a BMI below 24 kg/m2 was 32.2% (CI, 30.3% to 34.2%). The proportion achieving each lifestyle target was 75.8% (CI, 73.9% to 77.7%) for smoking, 66.7% (CI, 64.4% to 69.1%) for drinking, 17.9% (CI, 15.8% to 20.1%) for leisure time activity, and 52.0% (CI, 49.6% to 54.3%) for sleep duration. The proportion achieving each dietary target was 39.1% (CI, 36.0% to 42.2%) for carbohydrate, 20.1% (CI, 16.9% to 23.3%) for protein, 20.5% (CI, 17.6% to 23.4%) for fat, 9.0% (CI, 7.0% to 10.9%) for sodium, and 2.5% (CI, 1.3% to 3.6%) for fiber. Only 4.4% (CI, 3.5% to 5.2%) of participants achieved all 3 ABC targets, 5.1% (CI, 4.3% to 6.0%) achieved all 4 lifestyle targets, and 4 participants achieved all 5 dietary targets. Self-reported data and age of the data. Achievement of guideline-recommended diabetes care targets in Chinese adults with self-reported diabetes was exceedingly low. The findings highlight the need for immediate national health actions to improve diabetes care. Shanghai Municipal Education Commission, National Key R&D Program of the People's Republic of China, and the National Health Commission of the People's Republic of China.

Educational Functions of the Chinese Communist Party Schools in Professional Development Program: A Network Governance Perspective

Governance has various structures, and involves complex decision-making. In contrast to the Western governance systems, China has the dual Party-state governance system for managing different levels of governmental agencies. Under the design of such a system, the system of Chinese Communist Party Schools (CCPS) has specific missions and agendas to train all levels of governmental leaders in the process of policy formulations and implementations. This article utilizes the school principals’ professional development program of Suzhi education in Shanghai in 2016, in which the CCPS and Shanghai Municipal Education Commission shared their power interdependence relationship, as a case. Through document analysis and semi-constructed interviews of different stakeholders, this article reports that in the implementation of Chinese education policy, the Chinese Communist Party (CCP) holds the leading power in providing policy directions for the CCPS professional development program, which aims to train educational leaders. Building a stable and interactive relationship between CCPS and the education system through professional development program is beneficial for maintaining the CCP’s leading power and strengthening the CCP’s influence in the process of education policy implementation.

42-LB: Low-Carbohydrate Diet Compared with Canagliflozin for the Treatment of Diabetes—A Randomized Noninferiority Trial

Aims and Introduction: A low-carbohydrate diet (LCD) is effective for glycemic control in patients with diabetes. However, most previous studies have compared LCD with a low-fat or low-calorie diet. In this study, we used canagliflozin, a sodium-glucose co-transporter-2 (SGLT2) inhibitor, as the positive control drug and aimed to establish the non-inferiority of LCD to canagliflozin in terms of blood glucose control. Methods: We conducted a 3-month, multicenter, randomized, open-label, parallel-controlled clinical trial involving patients with type 2 diabetes. Participants were randomly assigned in a 1:1 ratio to receive canagliflozin (100 mg/day) or LCD (carbohydrate intake &amp;lt; 20% of the total energy intake). The primary outcome was the change in HbA1c level, and the secondary outcomes were Continuous Glucose Monitoring (CGM)-measured time in the target glucose range of 3.9-10 mmol/L and the cost of antidiabetic agents. Results: In total, 121 participants from three hospitals were enrolled; 61 were administered canagliflozin and 60 were administered LCD. After the 3-month intervention, the mean change in HbA1c levels was -1.76% with canagliflozin and -2.23% with LCD (estimated difference, -0.47%; 95% confidence interval [CI], -0.85-0.08; P = 0.0180). Time in range (TIR) increased from 48.96% at baseline to 80.21% at 3 months in the canagliflozin group and from 52.08% to 93.75% in the LCD group. The TIR in the LCD group was significantly higher than that in the canagliflozin group (P = 0.0026). Additionally, in the LCD group, 10 of 52 patients who had been using antidiabetic drugs (19.2%) discontinued one oral antidiabetic drug or reduced their insulin doses. Conclusions: Our study showed that LCD was non-inferior to canagliflozin in glycemic control. Patients in the LCD group showed greater decline of HbA1c levels and higher TIR than those in the canagliflozin group. LCD reduced the cost of antidiabetic drugs. Disclosure Y. Gu: None. X. Xia: None. M. Xu: None. L. Li: None. J. Yin: None. Funding National Natural Science Foundation of China (82070885); Shanghai Municipal Education Commission (20172025); Xuhui Joint Research Projects on Important Diseases (XHLHGG202110)

11-LB: The Efficacy and Safety of Abelmoschus manihot for Reduction of Microalbuminuria in Patients with Type 2 Diabetes and Diabetic Nephropathy—A Multicenter, Randomized, Open-Label, Parallel-Controlled Clinical Trial

Objective: Huangkui capsule, an extract from the flowers of Abelmoschus Manihot, has been proved clinically effective in improving chronic kidney disease. This study aimed to evaluate the efficacy and safety of Huangkui capsule in patients with stage 3 diabetic nephropathy. Methods: This multicenter, randomized, open-label, parallel-controlled trial was conducted in six hospitals. The inclusion criteria were 30 mg/g ≤ albumin creatinine ratio (ACR) &amp;lt;300 mg/g, eGFR ≥ 60 mL/min/1.73 m2, and type 2 diabetes with glycosylated hemoglobin ≤ 9%. We enrolled 239 patients who were randomly assigned to the two groups in a 1:1 ratio. They were treated with Huangkui capsule 2.15 g three times a day, or losartan potassium tablets 100 mg/day for 24 weeks. The primary outcome was the change in ACR from baseline and the secondary outcome was the change in eGFR. Results: The ACR in the losartan group was 119.47±78.16 mg/g at baseline and 90.51±136.12 mg/g after 24 weeks of treatment, with a decrease of 30.46±134.16 mg/g (P=0.049). In the Huangkui group, the ACR decreased from 121.98±84.31 mg/g to 88.13±76.66 mg/g, with a drop of 31.94±91.66 mg/g (P=0.002). The change in eGFR was -3.58±10.35 mL/min/1.73 m2 and -3.82±13.05 mL/min/1.73 m2 in the losatan and Huangkui groups, respectively. In subgroup analysis of patients with baseline ACR ≥ 100 mg/g, losatan and Huangkui lowered ACR by 56.83 mg/g (P=0.044) and 78.72 mg/g (P&amp;lt;0.001), respectively. There were no significant differences between the two groups (P&amp;gt;0.05). Conclusions: Huangkui capsule significantly reduced ACR of patients with type 2 diabetes and microalbuminuria and is a promising medicine for diabetic nephropathy. Disclosure J. Yin: None. S. Chen: None. L. Wei: None. W. Jia: None. Funding National Natural Science Foundation of China (82070885); Shanghai Municipal Education Commission (20172025); Xuhui Joint Research Projects on Important Diseases (XHLHGG202110)

On Geometric Connections of Embedded and Quotient Geometries in Riemannian Fixed-Rank Matrix Optimization

In this paper, we propose a general procedure for establishing the geometric landscape connections of a Riemannian optimization problem under the embedded and quotient geometries. By applying the general procedure to the fixed-rank positive semidefinite (PSD) and general matrix optimization, we establish an exact Riemannian gradient connection under two geometries at every point on the manifold and sandwich inequalities between the spectra of Riemannian Hessians at Riemannian first-order stationary points (FOSPs). These results immediately imply an equivalence on the sets of Riemannian FOSPs, Riemannian second-order stationary points (SOSPs), and strict saddles of fixed-rank matrix optimization under the embedded and the quotient geometries. To the best of our knowledge, this is the first geometric landscape connection between the embedded and the quotient geometries for fixed-rank matrix optimization, and it provides a concrete example of how these two geometries are connected in Riemannian optimization. In addition, the effects of the Riemannian metric and quotient structure on the landscape connection are discussed. We also observe an algorithmic connection between two geometries with some specific Riemannian metrics in fixed-rank matrix optimization: there is an equivalence between gradient flows under two geometries with shared spectra of Riemannian Hessians. A number of novel ideas and technical ingredients—including a unified treatment for different Riemannian metrics, novel metrics for the Stiefel manifold, and new horizontal space representations under quotient geometries—are developed to obtain our results. The results in this paper deepen our understanding of geometric and algorithmic connections of Riemannian optimization under different Riemannian geometries and provide a few new theoretical insights to unanswered questions in the literature. Funding: X. Li was partially supported by National Key R&amp;D Program of China [Grants 2020YFA0711900, 2020YFA0711901], the National Natural Science Foundation of China [Grants 12271107, 62141407], the Young Elite Scientists Sponsorship Program by CAST [Grant 2019QNRC001], the “Chenguang Program” by the Shanghai Education Development Foundation and Shanghai Municipal Education Commission [Grant 19CG02], the Shanghai Science and Technology Program [21JC1400600]. Y. Luo and A. R. Zhang were partially supported by the National Science Foundation [CAREER-2203741].

0115 Psychometric evaluation of the Chinese version of Sleep Health Index in pregnant women

Abstract Introduction The aim of this study was to investigate the psychometric properties of the Chinese version of the Sleep Health Index (SHI-C) among pregnant women. Methods This study used a cross-sectional design. Pregnant women (N=264) from three public hospitals in China were recruited through a convenience sampling method. The Sleep Health Index (SHI-C) was used to measure sleep health. The Pittsburgh Sleep Quality Index (PSQI) and Insomnia Severity Index (ISI) were used to measure sleep quality and insomnia, respectively. Epworth Sleepiness Scale (ESS), Fatigue Assessment Scale (FAS), and Edinburgh Postnatal Depression Scale (EPDS) were used to measure daytime sleepiness, fatigue, and depression, respectively. Structural validity was assessed via confirmatory factor analysis (CFA). Concurrent and convergent validity were assessed using bivariate correlation analyses. Known-group validity was assessed by comparing the SHI-C score between different groups. Cronbach’s α was calculated for reliability. Results The sample was 30.6 years on average. CFA confirmed the three-factor structure of SHI-C. The SHI-C total and sleep quality sub-index scores had moderate to strong correlations with both PSQI (r=-0.542, p&amp;lt; 0.01; r=-0.648, p&amp;lt; 0.01) and ISI (r=-0.692, p&amp;lt; 0.01; r=-0.752, p&amp;lt; 0.01). The SHI-C total and sleep quality sub-index scores were significantly associated with ESS, FAS, and EPDS (r=-0.171 to -0.276; p&amp;lt; 0.01). The SHI-C total score also differed based on work status (p&amp;lt; 0.01), trimester (p&amp;lt; 0.01), coffee intake (p&amp;lt; 0.05), taking a nap (p&amp;lt; 0.05), subclinical insomnia (p&amp;lt; 0.01), and poor sleep quality (p&amp;lt; 0.01). The Cronbach’s α of the SHI-C total and the sleep quality sub-index were 0.723 and 0.806, respectively. The Cronbach's α of sleep duration and disordered sleep sub-indices were 0.594 and 0.545, respectively. Conclusion Overall, the SHI-C has good validity and acceptable reliability among the pregnant population in China. It can be a useful tool for the assessment of sleep health. More research is warranted to refine the sleep duration and disordered sleep sub-indices. Support (if any) This work was supported in part by the National Natural Science Foundation of China [71904119], and Innovation Research Team of High-Level Local Universities in Shanghai [SHSMU-ZDCX20212800]. Bingqian Zhu was supported by Shanghai Municipal Education Commission “Young Eastern Scholar” (China).

The Endowment Model and Modern Portfolio Theory

We develop a dynamic portfolio choice model with illiquid alternative assets to analyze the “endowment model,” widely adopted by institutional investors, such as pension funds, university endowments, and sovereign wealth funds. In the model, the alternative asset has a lockup but can be liquidated at any time by paying a proportional cost. We model how investors can engage in liquidity diversification by investing in multiple illiquid alternative assets with staggered lockup expirations and show that doing so increases alternatives allocations and investor welfare. We show how illiquidity from lockups interacts with illiquidity from secondary market transaction costs resulting in endogenous and time-varying rebalancing boundaries. We extend the model to allow crisis states and show that increased illiquidity during crises causes holdings to deviate significantly from target allocations. This paper was accepted by Bruno Biais, finance. Funding: S. G. Dimmock gratefully acknowledges financial support from the Singapore Ministry of Education [Grant R-315-000-133-133]. N. Wang gratefully acknowledges support from CKGSB Research Institute. J. Yang gratefully acknowledges the support from the National Natural Science Foundation of China [Grants 71772112, 71972122, and 72072108], Innovative Research Team of Shanghai University of Finance and Economics [Grant 2016110241], and Shuguang Program of Shanghai Education Development Foundation and Shanghai Municipal Education Commission. Supplemental Material: Data are available at https://doi.org/10.1287/mnsc.2023.4759 .

Prevalence, co-occurring difficulties, and risk factors of developmental language disorder: first evidence for Mandarin-speaking children in a population-based study

Developmental language disorder (DLD) is a condition that significantly affects children's achievement but has been understudied. We aim to estimate the prevalence of DLD in Shanghai, compare the co-occurrence of difficulties between children with DLD and those with typical development (TD), and investigate the early risk factors for DLD. We estimated DLD prevalence using data from a population-based survey with a cluster random sampling design in Shanghai, China. A subsample of children (aged 5-6 years) received an onsite evaluation, and each child was categorized as TD or DLD. The proportions of children with socio-emotional behavior (SEB) difficulties, low non-verbal IQ (NVIQ), and poor school readiness were calculated among children with TD and DLD. We used multiple imputation to address the missing values of risk factors. Univariate and multivariate regression models adjusted with sampling weights were used to estimate the correlation of each risk factor with DLD. Of 1082 children who were approached for the onsite evaluation, 974 (90.0%) completed the language ability assessments, of whom 74 met the criteria for DLD, resulting in a prevalence of 8.5% (95% CI 6.3-11.5) when adjusted with sampling weights. Compared with TD children, children with DLD had higher rates of concurrent difficulties, including SEB (total difficulties score at-risk: 156 [17.3%] of 900 TD vs. 28 [37.8%] of 74 DLD, p<0.0001), low NVIQ (3 [0.3%] of 900 TD vs. 8 [10.8%] of 74 DLD, p<0.0001), and poor school readiness (71 [7.9%] of 900 TD vs. 13 [17.6%] of 74 DLD, p=0.0040). After accounting for all other risk factors, a higher risk of DLD was associated with a lack of parent-child interaction diversity (adjusted odds ratio [aOR]=3.08, 95% CI=1.29-7.37; p=0.012) and lower kindergarten levels (compared to demonstration and first level: third level (aOR=6.15, 95% CI=1.92-19.63; p=0.0020)). The prevalence of DLD and its co-occurrence with other difficulties suggest the need for further attention. Family and kindergarten factors were found to contribute to DLD, suggesting that multi-sector coordinated efforts are needed to better identify and serve DLD populations at home, in schools, and in clinical settings. The study was supported by Shanghai Municipal Education Commission (No. 2022you1-2, D1502), the Innovative Research Team of High-level Local Universities in Shanghai (No. SHSMU-ZDCX20211900), Shanghai Municipal Health Commission (No.GWV-10.1-XK07), and the National Key Research and Development Program of China (No. 2022YFC2705201).

Tunable Multicolor Circularly Polarized Luminescence via Co-assembly of One Chiral Electron Acceptor with Various Donors

Tunable Multicolor Circularly Polarized Luminescence via Co-assembly of One Chiral Electron Acceptor with Various Donors

Prophet Inequality for Bipartite Matching: Merits of Being Simple and Nonadaptive

We consider the Bayesian online selection problem of a matching in bipartite graphs, that is, the weighted online matching problem where the edges arrive online and edge weights are generated from a known distribution. This setting corresponds to the intersection of two matroids in the work of Kleinberg and Weinberg [ 40 ] and Feldman et al. [ 27 ]. We study a simple class of nonadaptive policies that we call vertex-additive policies. A vertex-additive policy assigns static prices to every vertex in the graph and accepts only those edges whose weight exceeds the sum of the prices on the edge endpoints. We show that there exists a vertex-additive policy with the expected payoff of at least one-third of the prophet’s payoff and present a gradient descent algorithm that quickly converges to the desired vector of vertex prices. Our results improve on the adaptive online policies of Kleinberg and Weinberg and Feldman et al. for the intersection of two matroids in two ways: our policy is nonadaptive and has a better approximation guarantee of 3 instead of the previous guarantees of 5.82 in Kleinberg and Weinberg and 5.43 in Feldman et al. We give a complementary lower bound of 2.25 for any online algorithm in the bipartite matching setting. Funding: This work was supported by Fundamental Research Funds of the Central Universities in China, a Science and Technology Innovation 2030 major project [“New Generation of Artificial Intelligence,” Project 2018AAA0100903], the Shanghai Municipal Education Commission Innovation Program, and the Program for Innovative Research Team of the Shanghai University of Finance and Economics (IRTSHUFE).

Ibrutinib, rituximab, and lenalidomide in unfit or frail patients aged 75 years or older with de novo diffuse large B-cell lymphoma: a phase 2, single-arm study

The optimal treatment for older adults with diffuse large B-cell lymphoma (DLBCL) needs to be further explored due to patient comorbidities, standard immunochemotherapy intolerance, and unfavourable genetic features. We did a phase 2 trial of ibrutinib, rituximab, and lenalidomide (iR2) to evaluate the efficacy and safety in older adult patients with de novo DLBCL. In this phase 2, single-arm study, unfit or frail patients with de novo DLBCL aged 75 years or older were enrolled at Shanghai Ruijin Hospital, Shanghai, China. During the induction phase from cycle 1 to 6, 560 mg ibrutinib was given orally daily throughout each 21-day treatment cycle, 375 mg/m2 rituximab was given intravenously on day 1, and 25 mg lenalidomide was given orally daily from day 1 to 10 in each cycle. Patients who had a complete response after induction were given another 6 cycles of lenalidomide maintenance (25 mg orally daily from day 1 to 10 every 21 days from cycle 7 to 12). The primary endpoint was complete response rate after 6 cycles or at the end of the induction treatment. This trial is registered with ClinicalTrials.gov, NCT03949062. Between May 15, 2019, and May 8, 2020, a total of 30 patients were enrolled. The end of induction complete response rate was 56·7% (95% CI 37·4-74·5), and overall response rate was 66·7% (95% CI 47·2-82·7). With a median follow-up of 27·6 months (IQR 23·9-29·6), the 2-year progression-free survival rate was 53·3% (95% CI 34·3-69·1) and the 2-year overall survival rate was 66·7% (95% CI 46·9-80·5). The main grade 3-4 haematological adverse events were neutropenia (seven patients [23%]), thrombocytopenia (three patients [10%]), and anaemia (two patients [7%]). The most common grade 3-4 non-haematological adverse event was pulmonary infection (seven patients [23%]). Atrial fibrillation was observed in three (10%) patients, including one grade 2 and two grade 3. A chemotherapy-free iR2 regimen is clinically effective and safe and warrants further investigation in phase 3 trials as first-line treatment in older adult patients with DLBCL. National Natural Science Foundation of China, Shanghai Municipal Education Commission Gaofeng Clinical Medicine Grant Support, Clinical Research Plan of Shanghai Hospital Development Center, and Multicenter Clinical Research Project by Shanghai Jiao Tong University School of Medicine.

Integrative genome‐wide chromatin accessibility and transcriptome profiling of diffuse large B‐cell lymphoma

Integrative genome‐wide chromatin accessibility and transcriptome profiling of diffuse large B‐cell lymphoma

1360-P: Calorie Restriction Enhanced Glycogen Metabolism to Compensate for Lipid Insufficiency

Backgrounds: It's well known that calorie restriction (CR) brings striking benefits in metabolic improvement with complex and unclear mechanism. In this study, we aimed to investigate the specific manifestation and possible mechanisms of metabolism in CR mice. Methods: B6 mice were randomly assigned to three groups: (1) chow diet (control) , (2) chow diet with 40% calorie restriction (CR) , (3) high-fat diet (HFD) . The metabolism status and related examination were performed after 12 weeks of feeding. Results: In this study, we found that CR increased fasting blood glucose and plasma insulin, as well as reduced insulin sensitivity reflected by insulin tolerance test. Comparing to the control mice, the decrease of phosphorylation levels of IRS-1 including serine307 and tyrosine632 residues, and AKT (threonine308) after insulin rejection further confirmed that CR induced insulin resistance. Different from insulin resistance induced by HFD, CR improved glucose tolerance and reduced gluconeogenesis. Meanwhile, CR led to absolute lipid reduction, manifested in decreased plasma lipid, liver lipid deposition and fat mass. In contrast, liver glycogen increased dramatically. Fasting glycogen was twice as much as that of HFD group and 20 times as that of control group. Furthermore, the CR increased p-PYGL, p-GSK3β and decreased p-GS notably indicating active glycogen synthesis and decomposition. Subsequently, we found that CR increased plasma corticosterone and decreased plasma c-reactive protein (CRP) compared with control and HFD groups, while plasma corticosterone and CRP in HFD were higher than those in control group. Additionally, CR lowered levels of orexigenic neuropeptides and elevated levels of anorexigenic neuropeptides. Conclusions: Our study suggested that CR induced lipid insufficiency and stress from starvation, resulting in physiological insulin resistance and enhanced glycogen metabolism, including increased glycogen synthesis, glycogenolysis and glycogen content. Disclosure L.Hu: None. X.Xia: None. Y.Gu: None. J.Yin: None. Funding National Natural Science Foundation of China (No. 82070885) ,Shanghai Municipal Education Commission—Gaofeng Clinical Medicine Grant Support (No. 20172025)

91-OR: Association between Complexity of Glucose Time Series and All-Cause Mortality in Patients with Type 2 Diabetes Mellitus: A Prospective Cohort study

Background: Continuous glucose monitoring (CGM) can comprehensively reflect the dynamic changes of blood glucose varying with time. CGM data with more patterns of change represents glucose time series with higher complexity. However, the relationship between complexity of glucose dynamics and clinical outcomes of diabetes remains unknown. Objective: To investigate the association between complexity of glucose time series, quantified by multiscale entropy (MSE) analysis, and all-cause mortality in patients with type 2 diabetes mellitus (T2DM) in a prospective cohort study. Methods: Data of 6,001 adult inpatients with T2DM included from January 2005 to December 2015 in a single center was analyzed. Complexity of glucose index (CGI) of glucose time series from CGM was measured by MSE analysis at baseline. Participants were stratified by the tertiles of CGI: &amp;lt; 2.15,2.15∼2.99, and ≥ 3.00. Cox proportional hazards regression models were used to estimate the association between different levels of CGI and the risks of all-cause mortality. Results: During a median follow-up of 6.8 years, 799 deaths were identified. Multivariate Cox regression analysis revealed that the increase of CGI was associated with a lower risk of all-cause mortality (P for trend = 0.021) . The multivariable-adjusted HRs for all-cause mortality at different CGI levels [&amp;lt; 2.15 (reference group) , 2.15∼2.99, and ≥ 3.00] were 1.00, 0.49 (95%CI 0.30-0.79) , and 0.56 (95%CI 0.36-0.87) in patients with HbA1c &amp;lt; 7.0% (P for trend = 0.015) , while the association was nonsignificant in those with HbA1c ≥ 7.0%. And a significant interaction between HbA1c and CGI (P for interaction = 0.032) was noted in the study. Conclusion: Lower CGI is associated with an increased risk of all-cause mortality in T2DM achieving HbA1c target, which suggests that the improvement of CGI may further reduce the risk of long-term adverse outcomes in T2DM at an early stage or with good glycemic control. Disclosure J.Cai: None. J.Lu: None. Y.Shen: None. W.Lu: None. W.Zhu: None. J.Zhou: None. Funding The Shanghai Municipal Education Commission—Gaofeng Clinical Medicine Grant Support (20161430)

1515-PUB: Opposite Effects of Low-Carbohydrate High-Fat Diet on Metabolism in Humans and Mice

Aims: Low-carbohydrate diet (LCD) , characterized by low consumption of carbohydrate and high intake of fat, is well known to decrease body weight and blood glucose in humans. However, in animal experiments, high-fat diet (HFD) is widely used to induce dietary obese model with metabolic disorders. The study aims to explore why LCD/HFD has the opposite effects on humans and animals. Methods: Twenty-two adults with overweight or obesity were enrolled to receive LCD for three weeks. The subjects were divided into two groups according to whether carbohydrate intake is below 10% by calories, and their weight loss and glucose homeostasis were compared. C57 mice were randomly assigned to five groups: chow diet (CD) , HFD with respectively 60%, 70% and 75% fat (cocoa butter) by calories and 60% fat (lard) by calories (60%HFD-L) , and metabolism of mice was evaluated. Results: In this trial, subjects who consumed less carbohydrate had greater weight loss and better glycemic control compared with the others. The questionnaires revealed that most of the subjects favored high-carbohydrate (HC) food rather than low-carbohydrate food. However, in mice, HFD groups showed more weight gain and higher blood glucose compared with CD group. When provided with CD and HFD at the same time, mice ate little CD. Besides, we found HFD group had lower mRNA level of Npy and Agrp and higher mRNA level of Pomc and Cartpt in hypothalamus in comparison with CD group. Among HFD with coco butter groups, mice took in more calories and gained more weight as the fat content in diet increases. Compared with HFD with coco butter groups, mice in 60%HFD-L group consumed even more calories, and had heavier body weight and poorer glucose metabolism. Conclusion: LCD has opposite effects on metabolism in humans and mice because of different food preferences. People prefer HC food while mice favor HFD. Mice consume more and feel less hungry when the diet contains higher proportion of fat, which leads to poorer metabolic status. Besides, mice prefer lard to coco butter. Disclosure X.Xia: None. L.Cai: None. Y.Gu: None. J.Yin: None. Funding National Natural Science Foundation of China (No. 82070885) ,Shanghai Municipal Education Commission—Gaofeng Clinical Medicine Grant Support (No. 20172025)

Patient-derived microphysiological model identifies the therapeutic potential of metformin for thoracic aortic aneurysm.

SummaryBackgroundThoracic aortic aneurysm (TAA) is the permanent dilation of the thoracic aortic wall that predisposes patients to lethal events such as aortic dissection or rupture, for which effective medical therapy remains scarce. Human-relevant microphysiological models serve as a promising tool in drug screening and discovery.MethodsWe developed a dynamic, rhythmically stretching, three-dimensional microphysiological model. Using patient-derived human aortic smooth muscle cells (HAoSMCs), we tested the biological features of the model and compared them with native aortic tissues. Drug testing was performed on the individualized TAA models, and the potentially effective drug was further tested using β-aminopropionitrile-treated mice and retrospective clinical data.FindingsThe HAoSMCs on the model recapitulated the expressions of many TAA-related genes in tissue. Phenotypic switching and mitochondrial dysfunction, two disease hallmarks of TAA, were highlighted on the microphysiological model: the TAA-derived HAoSMCs exhibited lower alpha-smooth muscle actin expression, lower mitochondrial membrane potential, lower oxygen consumption rate and higher superoxide accumulation than control cells, while these differences were not evidently reflected in two-dimensional culture flasks. Model-based drug testing demonstrated that metformin partially recovered contractile phenotype and mitochondrial function in TAA patients’ cells. Mouse experiment and clinical investigations also demonstrated better preserved aortic microstructure, higher nicotinamide adenine dinucleotide level and lower aortic diameter with metformin treatment.InterpretationThese findings support the application of this human-relevant microphysiological model in studying personalized disease characteristics and facilitating drug discovery for TAA. Metformin may regulate contractile phenotypes and metabolic dysfunctions in diseased HAoSMCs and limit aortic dilation.FundingThis work was supported by grants from National Key R&D Program of China (2018YFC1005002), National Natural Science Foundation of China (82070482, 81771971, 81772007, 51927805, and 21734003), the Science and Technology Commission of Shanghai Municipality (20ZR1411700, 18ZR1407000, 17JC1400200, and 20YF1406900), Shanghai Municipal Science and Technology Major Project (2017SHZDZX01), and Shanghai Municipal Education Commission (Innovation Program 2017-01-07-00-07-E00027). Y.S.Z. was not supported by any of these funds; instead, the Brigham Research Institute is acknowledged.

Chiral Bicyclic Imidazole-Catalyzed Direct Enantioselective C -Acetylation of Indolones

Chiral Bicyclic Imidazole-Catalyzed Direct Enantioselective <i>C</i> -Acetylation of Indolones

The extracellular vesicular pseudogene LGMNP1 induces M2-like macrophage polarization by upregulating LGMN and serves as a novel promising predictive biomarker for ovarian endometriosis recurrence.

How does ectopic endometrial stromal cell (Ecto-ESC)-derived extracellular vesicular Legumain pseudogene 1 (EV-LGMNP1), a newly identified pseudogene of Legumain (LGMN), contribute to M2-phenotype macrophage polarization, and does it predict recurrence in patients with ovarian endometriosis (EMs)? EV-LGMNP1, which is abundant in Ecto-ESCs and serum from ovarian EMs, can direct macrophages towards an M2 phenotype by upregulating LGMN expression and is a promising biomarker for predicting ovarian EMs recurrence. Extracellular vesicles (EVs) can mediate cell-to-cell crosstalk to promote disease progression via cargo molecule transport. Recently, LGMNP1, a newly identified pseudogene of LGMN, has been reported to promote cancer progression by upregulating LGMN. LGMN is a well-studied protein that can induce M2-like polarization. An in vitro study was conducted with Ecto-ESCs isolated from ectopic endometrial samples, collected from two patients with ovarian EMs (diagnosed by laparoscopy and histological analysis). A clinical retrospective cohort study of 52 ovarian EMs patients and 21 controls with available preoperative serum samples was carried out (2013-2017). The follow-up period ended either at the time of recurrence or on 31 December 2018. Ecto-ESC-derived EVs (EV/Ecto-ESCs) were characterized by nanoparticle tracking analysis, transmission electron microscopy and western blotting. EV internalization by THP-1 cells, which are the most widely used primary human macrophages model, was detected by fluorescence labelling. After EV treatment, THP-1 cell polarization was detected by quantitative real-time PCR (qRT-PCR) and western blot analyses of CD86 (M1-related marker) and CD206 (M2-related marker). LGMNP1 mRNA expression level in EVs from both primary ectopic endometrioc stromal cells and serum was examined using qRT-PCR. Additionally, the expression of LGMN, the downstream target gene of LGMNP1, in THP-1 cells was evaluated using qRT-PCR and western blotting. Kaplan-Meier and multivariate Cox regression analyses were applied to evaluate the independent predictive factors of EMs recurrence-free survival. A novel nomogram model based on serum EV-LGMNP1 was then formulated to predict EMs recurrence. In vitro assays demonstrated that EV/Ecto-ESCs drove macrophages towards an M2-like phenotype. Moreover, LGMNP1 contributed to EV/Ecto-ESC-induced M2 macrophage polarization by upregulating LGMN mRNA expression levels. Clinically, serum EV-LGMNP1 was more highly expressed in recurrent EMs patients than in controls and EMs patients without recurrence. Survival analysis and our novel nomogram reconfirmed that serum EV-LGMNP1 was a novel promising and meaningful non-invasive biomarker for predicting EMs recurrence. N/A. In vitro experiments were only performed on samples from two patients with ovarian endometriosis, and a larger sample size is needed. ESCs isolated from the eutopic endometrium of EMs and non-EMs patients should be studied in the future. Additionally, in vitro experiments should be performed using endometrial epithelium cells and further in vivo experiments, such as using mice endometriotic models to investigate whether EV/Ecto could induce M2 macrophage polarization, should be conducted. Moreover, multicentre, large-sample data are needed to validate our predictive nomogram model. Our study provides novel insights into the mechanism of M2 polarization involved in ovarian EMs progression mediated by an 'EV-shuttled pseudogene LGMNP1' mode. In addition, serum EV-LGMNP1 may serve as a novel non-invasive biomarker for predicting recurrence, providing a new therapeutic target for ovarian EMs. This project was supported by funding from the National Natural Science Foundation of China (81971361), the Natural Science Foundation of Shanghai Science and Technology (19ZR1406900), the Shanghai 'Rising Stars of Medical Talent' Youth Development Program (AB83030002019004), the Clinical Research Plan of SHDC (SHDC2020CR4087), the Shanghai Municipal Health Commission (202040498), the Research and Innovation Project of the Shanghai Municipal Education Commission (2019-01-07-00-07-E00050) and the Clinical Research Plan of SHDC (SHDC2020CR1045B). There are no competing interests to declare.

Exercise downregulates HIPK2 and HIPK2 inhibition protects against myocardial infarction.

BackgroundExercise can protect myocardial infarction (MI) and downregulate cardiac Homeodomain-Interacting Protein Kinase 2 (HIPK2). However, the role of HIPK2 in MI is unclear.MethodsHIPK2–/– mice and miR-222–/– rats, HIPK2 inhibitor (PKI1H) and adeno-associated virus serotype 9 (AAV9) carrying miR-222 were applied in the study. Animals were subjected to running, swimming, acute MI or post-MI remodeling. HIPK2 inhibition and P53 activator were used in neonatal rat cardiomyocytes (NRCMs) and human embryonic stem cell-derived cardiomyocytes (hESC-CMs) subjected to oxygen glucose deprivation/reperfusion (OGD/R). Serum miR-222 levels were analyzed in healthy people and MI patients that were survival or readmitted to the hospital and/or died.FindingsCardiac HIPK2 protein levels were reduced by exercise while increased in MI. In vitro, HIPK2 suppression by lentiviral vectors or inhibitor prevented apoptosis induced by OGD/R in NRCMs and hESC-CMs. HIPK2 inhibitor-treated mice and HIPK2–/– mice reduced infarct size after acute MI, and preserved cardiac function in MI remodeling. Mechanistically, protective effect against apoptosis by HIPK2 suppression was reversed by P53 activators. Furthermore, increasing levels of miR-222, targeting HIPK2, protected post-MI cardiac dysfunction, whereas cardiac dysfunction post-MI was aggravated in miR-222–/– rats. Moreover, serum miR-222 levels were significantly reduced in MI patients, as well as in MI patients that were readmitted to the hospital and/or died compared to those not.InterpretationExercise-induced HIPK2 suppression attenuates cardiomyocytes apoptosis and protects MI by decreasing P-P53. Inhibition of HIPK2 represents a potential novel therapeutic intervention for MI.FundingThis work was supported by the grants from National Key Research and Development Project (2018YFE0113500 to JJ Xiao), National Natural Science Foundation of China (82020108002, 81722008, and 81911540486 to JJ Xiao, 81400647 to MJ Xu, 81800265 to YJ Liang), Innovation Program of Shanghai Municipal Education Commission (2017-01-07-00-09-E00042 to JJ Xiao), the grant from Science and Technology Commission of Shanghai Municipality (18410722200 and 17010500100 to JJ Xiao), the “Dawn” Program of Shanghai Education Commission (19SG34 to JJ Xiao), Shanghai Sailing Program (21YF1413200 to QL Zhou). JS is supported by Horizon2020 ERC-2016-COG EVICARE (725229).

SLC1A1 mediated glutamine addiction and contributed to natural killer T-cell lymphoma progression with immunotherapeutic potential.

BackgroundMetabolic reprogramming plays an essential role on lymphoma progression. Dysregulation of glutamine metabolism is implicated in natural-killer T-cell lymphoma (NKTCL) and tumor cell response to asparaginase-based anti-metabolic treatment.MethodsTo understand the metabolomic alterations and determine the potential therapeutic target of asparaginase, we assessed metabolomic profile using liquid chromatography-mass spectrometry in serum samples of 36 NKTCL patients, and integrated targeted metabolic analysis and RNA sequencing in tumor samples of 102 NKTCL patients. The biological function of solute carrier family 1 member 1 (SLC1A1) on metabolic flux, lymphoma cell growth, and drug sensitivity was further examined in vitro in NK-lymphoma cell line NK-92 and SNK-6, and in vivo in zebrafish xenograft models.FindingsIn NKTCL patients, serum metabolomic profile was characterized by aberrant glutamine metabolism and SLC1A1 was identified as a central regulator of altered glutaminolysis. Both in vitro and in vivo, ectopic expression of SLC1A1 increased cellular glutamine uptake, enhanced glutathione metabolic flux, and induced glutamine addiction, leading to acceleration of cell proliferation and tumor growth. Of note, SLC1A1 overexpression was significantly associated with PD-L1 downregulation and reduced cytotoxic CD3+/CD8+ T cell activity when co-cultured with peripheral blood mononuclear cells. Asparaginase treatment counteracted SLC1A1-mediated glutamine addiction, restored SLC1A1-induced impaired T-cell immunity. Clinically, high EAAT3 (SLC1A1-encoded protein) expression independently predicted superior progression-free and overall survival in 90 NKTCL patients treated with asparaginase-based regimens.InterpretationSLC1A1 functioned as an extracellular glutamine transporter, promoted tumor growth through reprogramming glutamine metabolism of NKTCL, while rendered tumor cells sensitive to asparaginase treatment. Moreover, SLC1A1-mediated modulation of PD-L1 expression might provide clinical rationale of co-targeting metabolic vulnerability and immunosuppressive microenvironment in NKTCL.FundingThis study was supported, in part, by research funding from the National Natural Science Foundation of China (82130004, 81830007 and 81900192), Chang Jiang Scholars Program, Shanghai Municipal Education Commission Gaofeng Clinical Medicine Grant Support (20152206 and 20152208), Clinical Research Plan of SHDC (2020CR1032B), Multicenter Clinical Research Project by Shanghai Jiao Tong University School of Medicine (DLY201601), Shanghai Chenguang Program (19CG15), Shanghai Sailing Program (19YF1430800), Medical-Engineering Cross Foundation of Shanghai Jiao Tong University (ZH2018QNA46), and Shanghai Yi Yuan Xin Xing Program.