Real-World Effectiveness of Primary Series and Booster Doses of Inactivated Coronavirus Disease 2019 Vaccine Against Omicron BA.2 Variant Infection in China: A Retrospective Cohort Study.

BACKGROUND: China has been using inactivated coronavirus disease 2019 (COVID-19) vaccines as primary series and booster doses to protect the population from severe to fatal COVID-19. We evaluated primary and booster vaccine effectiveness (VE) against Omicron BA.2 infection outcomes. METHODS: This was a 13-province retrospective cohort study of quarantined close contacts of BA.2-infected individuals. Outcomes were BA.2 infection, COVID-19 pneumonia or worse, and severe/critical COVID-19. Absolute VE was estimated by comparison with an unvaccinated group. RESULTS: There were 289 427 close contacts ≥3 years old exposed to Omicron BA.2 cases; 31 831 turned nucleic acid amplification test-positive during quarantine, 97.2% with mild or asymptomatic infection, 2.6% with COVID-19 pneumonia, and 0.15% with severe/critical COVID-19. None died. Adjusted VE (aVE) against any infection was 17% for primary series and 22% when boosted. Primary series aVE in adults >18 years was 66% against COVID-19 pneumonia or worse and 91% against severe/critical COVID-19. Booster dose aVE was 74% against pneumonia or worse, and 93% against severe/critical COVID-19. CONCLUSIONS: Inactivated COVID-19 vaccines provided modest protection from infection, very good protection against pneumonia, and excellent protection against severe/critical COVID-19. Booster doses are necessary to provide strongest protection.

Clinical variable-based cluster analysis identifies novel subgroups with a distinct genetic signature, lipidomic pattern and cardio-renal risks in Asian patients with recent-onset type 2 diabetes.

AIMS/HYPOTHESIS: We sought to subtype South East Asian patients with type 2 diabetes by de novo cluster analysis on clinical variables, and to determine whether the novel subgroups carry distinct genetic and lipidomic features as well as differential cardio-renal risks. METHODS: Analysis by k-means algorithm was performed in 687 participants with recent-onset diabetes in Singapore. Genetic risk for beta cell dysfunction was assessed by polygenic risk score. We used a discovery-validation approach for the lipidomics study. Risks for cardio-renal complications were studied by survival analysis. RESULTS: Cluster analysis identified three novel diabetic subgroups, i.e. mild obesity-related diabetes (MOD, 45%), mild age-related diabetes with insulin insufficiency (MARD-II, 36%) and severe insulin-resistant diabetes with relative insulin insufficiency (SIRD-RII, 19%). Compared with the MOD subgroup, MARD-II had a higher polygenic risk score for beta cell dysfunction. The SIRD-RII subgroup had higher levels of sphingolipids (ceramides and sphingomyelins) and glycerophospholipids (phosphatidylethanolamine and phosphatidylcholine), whereas the MARD-II subgroup had lower levels of sphingolipids and glycerophospholipids but higher levels of lysophosphatidylcholines. Over a median of 7.3 years follow-up, the SIRD-RII subgroup had the highest risks for incident heart failure and progressive kidney disease, while the MARD-II subgroup had moderately elevated risk for kidney disease progression. CONCLUSIONS/INTERPRETATION: Cluster analysis on clinical variables identified novel subgroups with distinct genetic, lipidomic signatures and varying cardio-renal risks in South East Asian participants with type 2 diabetes. Our study suggests that this easily actionable approach may be adapted in other ethnic populations to stratify the heterogeneous type 2 diabetes population for precision medicine.

Association of Plasma Leucine-Rich Alpha-2 Glycoprotein 1 (LRG1) with All-Cause and Cause-Specific Mortality in Individuals with Type 2 Diabetes.

BACKGROUND: Leucine-rich alpha-2 glycoprotein 1 (LRG1) is a circulating protein in the transforming growth factor-beta superfamily. We sought to study whether LRG1 might predict risk for all-cause and cause-specific mortality in individuals with type 2 diabetes. METHODS: 2012 outpatients with type 2 diabetes were followed for a median of 7.2 years and 188 death events were identified. Association of LRG1 with risk for mortality was assessed by multivariable Cox regression models. RESULTS: Participants with a higher concentration of LRG1 had an increased risk for all-cause mortality [HR (95% CI), 1.76 (1.03-3.01), 1.75 (1.03-2.98), and 4.37 (2.72-7.02) for quartiles 2, 3, and 4, respectively, compared to quartile 1]. The association remained significant after adjustment for known cardio-renal risk factors including estimated glomerular filtration rate and albuminuria [adjusted HR 2.76 (1.66-4.59), quartile 4 versus 1]. As a continuous variable, a 1-SD increment in LRG1 was associated with 1.34 (1.14-1.57)-fold adjusted risk for all-cause mortality. High plasma LRG1 was independently associated with mortality attributable to cardiovascular disease, infection, and renal diseases. Adding LRG1 into a clinical variable-based model improved discrimination (c statistics from 0.828 to 0.842, P = 0.006) and reclassification (net reclassification improvement 0.47, 95% CI 0.28-0.67) for prediction of 5-year all-cause mortality. CONCLUSION: Plasma LRG1 predicts risk for all-cause mortality and mortality attributable to cardiovascular disease, infection, and renal disease independent of known cardio-renal risk factors. It may be a potential novel biomarker to improve risk stratification in individuals with type 2 diabetes.

Aortic pulse wave velocity, central pulse pressure, augmentation index and chronic kidney disease progression in individuals with type 2 diabetes: a 3- year prospective study.

BACKGROUND: Pulse wave velocity (PWV), central pulse pressure and augmentation index are arterial stiffness- related hemodynamic parameters but their associations with renal outcome are still controversial. We hereby aim to study, 1) which hemodynamic parameter is independently associated with progressive chronic kidney disease (CKD), 2) the association of 3-year change in PWV with CKD progression and, 3) the additive predictive value of PWV for progressive CKD. METHODS: Carotid- femoral PWV, central pulse pressure and augmentation index were measured in 1444 participants with type 2 diabetes at baseline and 3 years apart. Progressive CKD was defined as confirmed eGFR decline 40% or greater. RESULTS: In the follow-up, 102 participants experienced progressive CKD. All 3 hemodynamic parameters were significantly associated with progressive CKD In univariable analysis. However, only PWV remained statistically significant after adjustment for known clinical risk factors and the other 2 hemodynamic parameters (OR 1.14 [95% CI 1.01-1.29] per m/s increment). One m/s regression (decrement) in PWV in the 3-year follow-up was associated with 26% lower adjusted- risk of progressive CKD (OR 0.74, 95% CI 0.56-0.97). Adding PWV onto traditional risk factor- based model significantly improved classification (net reclassification improvement 0.25, 95% CI 0.05-0.45, P = 0.01) and positive prediction rate (24.5 to 32.3%). CONCLUSIONS: Of 3 arterial stiffness- related hemodynamic parameters, only PWV is independently associated with progressive CKD. PWV may be a potential intervention target to mitigate risk of CKD progression and also a biomarker to improve risk-stratification of adverse renal outcome in individuals with type 2 diabetes.

Involvement of PML-I in reformation of PML nuclear bodies in acute promyelocytic leukemia cells by leptomycin B.

Acute promyelocytic leukemia (APL) is characterized by a reciprocal translocation between chromosomes 15 and 17, t(15;17), resulting in the expression of PML-RARα fusion protein, which disrupts the normal PML nuclear bodies (PML-NBs) to micro-speckled pattern, leading to loss of their original functions. Moreover, reformation of PML-NBs in APL by arsenic is considered as one of the important step for APL treatment. Leptomycin B (LMB), a nuclear export inhibitor, is commonly used to inhibit the proteins exporting from the nucleus to the cytoplasm. In the present study, we found that LMB could induce the reformation of PML-NBs in leukemia NB4 cells as well as in APL blast cells from the patients, implying that nuclear shuttle proteins might be involved in the reformation of PML-NBs. Herein, we further found that LMB totally lost the ability to induce PML-NBs reformation when the endogenous PML gene was knocked out, indicating that endogenous PML protein is probably involved in the reformation of PML-NBs. More interestingly, among all PML isoforms (i.e., seven isoforms), reformation of PML-NBs was only observed when co-transfection of PML-RARα with PML-I after LMB treatment. Similarly, deletion of nuclear export signal (NES) of PML-I could also reform PML-NBs, suggesting that the protein level of endogenous PML-I in nucleus is important for the reformation of PML-NBs that interfered by PML-RARα fusion protein. Additionally, LMB has synergistic effect with iAsIII on enhancing PML-RARα fusion protein degradation, and it might provide new insight into APL treatment at clinical level in the near future.

Antiviral Activity of Dual-acting Hydrocarbon-stapled Peptides against HIV-1 Predominantly Circulating in China.

OBJECTIVE: New rationally designed i,i+7-hydrocarbon-stapled peptides that target both HIV-1 assembly and entry have been shown to have antiviral activity against HIV-1 subtypes circulating in Europe and North America. Here, we aimed to evaluate the antiviral activity of these peptides against HIV-1 subtypes predominantly circulating in China. METHODS: The antiviral activity of three i,i+7-hydrocarbon-stapled peptides, NYAD-36, NYAD-67, and NYAD-66, against primary HIV-1 CRF07_BC and CRF01_AE isolates was evaluated in peripheral blood mononuclear cells (PBMCs). The activity against the CRF07_BC and CRF01_AE Env-pseudotyped viruses was analyzed in TZM-bl cells. RESULTS: We found that all the stapled peptides were effective in inhibiting infection by all the primary HIV-1 isolates tested, with 50% inhibitory concentration toward viral replication (IC50) in the low micromolar range. NYAD-36 and NYAD-67 showed better antiviral activity than NYAD-66 did. We further evaluated the sensitivity of CRF01_AE and CRF07_BC Env-pseudotyped viruses to these stapled peptides in a single-cycle virus infectivity assay. As observed with the primary isolates, the IC50s were in the low micromolar range, and NYAD-66 was less effective than NYAD-36 and NYAD-67. CONCLUSION: Hydrocarbon-stapled peptides appear to have broad antiviral activity against the predominant HIV-1 viruses in China. This finding may provide the impetus to the rational design of peptides for future antiviral therapy.

Distinctive Drug-resistant Mutation Profiles and Interpretations of HIV-1 Proviral DNA Revealed by Deep Sequencing in Reverse Transcriptase.

OBJECTIVE: To investigate distinctive features in drug-resistant mutations (DRMs) and interpretations for reverse transcriptase inhibitors (RTIs) between proviral DNA and paired viral RNA in HIV-1-infected patients. METHODS: Forty-three HIV-1-infected individuals receiving first-line antiretroviral therapy were recruited to participate in a multicenter AIDS Cohort Study in Anhui and Henan Provinces in China in 2004. Drug resistance genotyping was performed by bulk sequencing and deep sequencing on the plasma and whole blood of 77 samples, respectively. Drug-resistance interpretation was compared between viral RNA and paired proviral DNA. RESULTS: Compared with bulk sequencing, deep sequencing could detect more DRMs and samples with DRMs in both viral RNA and proviral DNA. The mutations M184I and M230I were more prevalent in proviral DNA than in viral RNA (Fisher's exact test, P<0.05). Considering 'majority resistant variants', 15 samples (19.48%) showed differences in drug resistance interpretation between viral RNA and proviral DNA, and 5 of these samples with different DRMs between proviral DNA and paired viral RNA showed a higher level of drug resistance to the first-line drugs. Considering 'minority resistant variants', 22 samples (28.57%) were associated with a higher level of drug resistance to the tested RTIs for proviral DNA when compared with paired viral RNA. CONCLUSION: Compared with viral RNA, the distinctive information of DRMs and drug resistance interpretations for proviral DNA could be obtained by deep sequencing, which could provide more detailed and precise information for drug resistance monitoring and the rational design of optimal antiretroviral therapy regimens.

Recrystallization-induced self-assembly for the growth of Cu2O superstructures.

The assembly of inorganic nanoparticles (NPs) into 3D superstructures with defined morphologies is of particular interest. A novel strategy that is based on recrystallization-induced self-assembly (RISA) for the construction of 3D Cu2O superstructures and employs Cu2O mesoporous spheres with diameters of approximately 300 nm as the building blocks has now been developed. Balancing the hydrolysis and recrystallization rates of the CuCl precursors through precisely adjusting the experimental parameters was key to success. Furthermore, the geometry of the superstructures can be tuned to obtain either cubes or tetrahedra and was shown to be dependent on the growth behavior of bulk CuCl. The overall strategy extends the applicability of recrystallization-based processes for the guided construction of assemblies and offers unique insights for assembling larger particles into complicated 3D superstructures.

The A3 adenosine receptor as multifaceted therapeutic target: pharmacology, medicinal chemistry, and in silico approaches.

Adenosine is an ubiquitous local modulator that regulates various physiological and pathological functions by stimulating four membrane receptors, namely A(1), A(2A), A(2B), and A(3). Among these G protein-coupled receptors, the A(3) subtype is found mainly in the lung, liver, heart, eyes, and brain in our body. It has been associated with cerebroprotection and cardioprotection, as well as modulation of cellular growth upon its selective activation. On the other hand, its inhibition by selective antagonists has been reported to be potentially useful in the treatment of pathological conditions including glaucoma, inflammatory diseases, and cancer. In this review, we focused on the pharmacology and the therapeutic implications of the human (h)A(3) adenosine receptor (AR), together with an overview on the progress of hA(3) AR agonists, antagonists, allosteric modulators, and radioligands, as well as on the recent advances pertaining to the computational approaches (e.g., quantitative structure-activity relationships, homology modeling, molecular docking, and molecular dynamics simulations) applied to the modeling of hA(3) AR and drug design.

Association between neutrophil/lymphocyte ratio and kidney impairment in type 2 diabetes mellitus: A role of extracellular water/total body water ratio.

AIMS: We explored the predictive utility of baseline neutrophil/lymphocyte ratio (NLR), which reflects a systemic inflammatory tone, in kidney impairment in type 2 diabetes mellitus (T2DM); and investigated the effect of extracellular water/total body water (ECW/TBW) ratio on the relationship. METHODS: This longitudinal study included 1,224 T2DM adults recruited from a single centre. Cox regression analyses examined the association between NLR and progressive kidney function decline or albuminuria progression. Improvements in risk discrimination were assessed using Harrell's concordance-statistics. The mediatory role of ECW/TBW ratio estimated by bioelectrical impedance was evaluated. RESULTS: Higher baseline NLR levels were observed in cases with kidney function decline or albuminuria progression over a median 2-year follow-up. NLR independently predicted progressive kidney function decline (hazard ratio:1.39, 95% CI:1.21-1.60, P < 0.001) or albuminuria progression (hazard ratio:1.34, 95% CI:1.08-1.68, P = 0.009). Addition of NLR to a base model comprising demographics, T2DM duration, metabolic and renal parameters, and medications significantly improved the risk discrimination of kidney function decline (P = 0.022) but not albuminuria progression. ECW/TBW ratio accounted for 19.7% of the total effect between NLR and kidney function loss. CONCLUSIONS: Increased NLR reflecting systemic inflammation is associated with progressive kidney function decline in T2DM, partially explained by dysregulated body fluid balance.

A population-based nomogram to individualize treatment modality for pancreatic cancer patients underlying surgery.

As the most aggressive tumor, TNM staging does not accurately identify patients with pancreatic cancer who are sensitive to therapy. This study aimed to identify associated risk factors and develop a nomogram to predict survival in pancreatic cancer surgery patients and to select the most appropriate comprehensive treatment regimen. First, the survival difference between radiotherapy and no radiotherapy was calculated based on propensity score matching (PSM). Cox regression was conducted to select the predictors of overall survival (OS). The model was constructed using seven variables: histologic type, grade, T stage, N stage, stage, chemotherapy and radiotherapy. All patients were classified into high- or low-risk groups based on the nomogram. The nomogram model for OS was established and showed good calibration and acceptable discrimination (C-index 0.721). Receiver operating characteristic curve (ROC) and DCA curves showed that nomograms had better predictive performance than TNM stage. Patients were divided into low-risk and high-risk groups according to nomogram scores. Radiotherapy is recommended for high-risk patients but not for low-risk patients. We have established a well-performing nomogram to effectively predict the prognosis of pancreatic cancer patients underlying surgery. The web version of the nomogram https://rockeric.shinyapps.io/DynNomapp/ may contribute to treatment optimization in clinical practice.

Urine Leucine-Rich α-2 Glycoprotein 1 (LRG1) Predicts the Risk of Progression to End-Stage Kidney Disease in Patients With Type 2 Diabetes.

OBJECTIVE: Leucine-rich α-2 glycoprotein 1 (LRG1) was recently identified as an amplifier of transforming growth factor-ß (TGF-ß)-induced kidney fibrosis in animal models. We aimed to study whether urine LRG1 is associated with risk of progression to end-stage kidney disease (ESKD) in individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 1,837 participants with type 2 diabetes and estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m2 were recruited from a regional hospital and a primary care facility. Association of urine LRG1 with risk of ESKD (progression to sustained eGFR <15 mL/min/1.73 m2, dialysis, or death resulting from renal causes) was assessed by survival analyses. RESULTS: During a median follow-up of 8.6 (interquartile range 5.8-9.6) years, 134 incident ESKD events were identified. Compared with those in the lowest tertile, participants with baseline urine LRG1 in the highest tertile had a 1.91-fold (95% CI 1.04-3.50) increased risk of progression to ESKD, after adjustment for cardiorenal risk factors, including eGFR and albuminuria. As a continuous variable, 1 SD increment in urine LRG1 was associated with a 1.53-fold (95% CI 1.19-1.98) adjusted risk of ESKD. Of note, the association of urine LRG1 with ESKD was independent of plasma LRG1. Moreover, urine LRG1 was associated with rapid kidney function decline and progression to macroalbuminuria, two common pathways leading to ESKD. CONCLUSIONS: Urine LRG1, a TGF-ß signaling modulator, predicts risk of progression to ESKD independently of clinical risk factors in patients with type 2 diabetes, suggesting that it may be a novel factor involved in the pathophysiological pathway leading to kidney disease progression.

Plasma Tryptophan-Kynurenine Pathway Metabolites and Risk for Progression to End-Stage Kidney Disease in Patients With Type 2 Diabetes.

OBJECTIVE: We sought to study the associations between plasma metabolites in the tryptophan-kynurenine pathway and the risk of progression to end-stage kidney disease (ESKD) in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Plasma tryptophan, kynurenine, 3-hydroxykynurenine, kynurenic acid, and xanthurenic acid concentrations were measured in discovery (n = 1,915) and replication (n = 346) cohorts. External validation was performed in Chronic Renal Insufficiency Cohort (CRIC) participants with diabetes (n = 1,312). The primary outcome was a composite of incident ESKD (progression to estimated glomerular filtration rate [eGFR] <15 mL/min/1.73 m2, sustained dialysis, or renal death). The secondary outcome was annual eGFR decline. RESULTS: In the discovery cohort, tryptophan was inversely associated with risk for ESKD, and kynurenine-to-tryptophan ratio (KTR) was positively associated with risk for ESKD after adjustment for clinical risk factors, including baseline eGFR and albuminuria (adjusted hazard ratios [HRs] 0.62 [95% CI 0.51, 0.75] and 1.48 [1.20, 1.84] per 1 SD). High levels of kynurenic acid and xanthurenic acid were associated with low risks of ESKD (0.74 [0.60, 0.91] and 0.74 [0.60, 0.91]). Consistently, high levels of tryptophan, kynurenic acid, and xanthurenic acid were independently associated with a slower eGFR decline, while a high KTR was predictive of a faster eGFR decline. Similar outcomes were obtained in the replication cohort. Furthermore, the inverse association between kynurenic acid and risk of ESKD was externally validated in CRIC participants with diabetes (adjusted HR 0.78 [0.65, 0.93]). CONCLUSIONS: Accelerated catabolism of tryptophan in the kynurenine pathway may be involved in progressive loss of kidney function. However, shunting the kynurenine pathway toward the kynurenic acid branch may potentially slow renal progression.

Dipeptidyl peptidase IV inhibitor attenuates kidney injury in streptozotocin-induced diabetic rats.

Dipeptidyl peptidase (DPP) IV inhibitors are probably beneficial for preventing diabetic complication and modulating glucagon-like peptide-1 receptor (GLP-1R) expression. The aim of this study was to determine whether the DPP IV inhibitor LAF237 (vildagliptin) has renoprotective qualities in streptozotocin-induced diabetic rats. Diabetic and nondiabetic rats were treated with an oral dose of 4 or 8 mg/kg/day LAF237 or placebo for 24 weeks, and renal injury was observed by light and electron microscopy. We also assessed DPP IV activity, active GLP-1 level, cAMP and 8-hydroxy-deoxyguanosine excretion, and GLP-1R, cleaved caspase 3, and transforming growth factor-ß1 (TGF-ß1) expression. LAF237 significantly decreased proteinuria, albuminuria, and urinary albumin/creatinine ratio, improved creatinine clearance, and dose-dependently inhibited interstitial expansion, glomerulosclerosis, and the thickening of the glomerular basement membrane in diabetic rats. It is noteworthy that LAF237 markedly down-regulated DPP IV activity and increased active GLP-1 levels, which probably prevented oxidative DNA damage and renal cell apoptosis by activating the GLP-1R and modulating cAMP. Renoprotection was also associated with a reduction in TGF-ß1 overexpression. Our study suggests that DPP IV inhibitors may ameliorate diabetic nephropathy as well as reduce the overproduction of TGF-ß1. The observed renoprotection is probably attributable to inhibition of DPP IV activity, mimicking of incretin action, and activation of the GLP-1R.

Beckmann rearrangement of ketoximes induced by phenyl dichlorophosphate at ambient temperature.

Upon treatment with phenyl dichlorophosphate (PhOP=OCl(2)) in acetonitrile at ambient temperature, a variety of ketoximes underwent a Beckmann rearrangement in an effective manner to afford the corresponding amides in moderate to high yields.

Paraquat mediates BV-2 microglia activation by raising intracellular ROS and inhibiting Akt1 phosphorylation.

Microglia is the innate immune cell in central nervous system (CNS) and plays an important role in neuroinflammation. Microglia mediated neuroinflammation is the key factor affecting the development of neurodegenerative diseases. Although there was evidence that paraquat (PQ) could induce inflammatory response, its mechanism was not clear. The present study investigated the mechanisms of PQ-induced inflammatory responses in BV-2 microglia cells, and tried to reveal the role of ROS/Akt1 pathway. The results showed that the cell activation markers (iNOS and CD206) of BV-2 cells were increased after PQ treatment, suggesting that BV-2 microglia were activated. PQ induced the reactive oxygen species (ROS) and inhibited the AKT1 phosphorylation in BV-2 cells. Besides, the M1 markers expression (IL-6, TNF-α and IL-1ß) were significantly increased after PQ treatment, which suggested that PQ induced the increase of M1 phenotype of BV-2 microglia. Pre-treated with NAC (ROS scavenger), the M1 phenotype was decreased while the p-Akt1 was restored compared to PQ stimulation. Furthermore, we built an Akt1(S473E)-overexpression BV-2 cell line. The Akt1 (S473E) partially attenuated the PQ induced increase in M1 phenotype, while ROS did not significantly change. These results indicated that PQ induced BV-2 microglia activation by increased ROS mediated Akt1 activation inhibition, leading to neuroinflammation.

Risk of Incident Heart Failure in Individuals With Early-Onset Type 2 Diabetes.

CONTEXT: Early-onset diabetes has been associated with unfavorable cardiovascular risk but data on heart failure (HF) in this subpopulation are scarce. OBJECTIVE: We aimed to study the risk of, and risk factors for, incident HF in individuals with early-onset type 2 diabetes. METHODS: We studied 606 individuals with type 2 diabetes diagnosed before 40 years of age (early-onset) and 1258 counterparts with diabetes diagnosed from 41 to 65 years of age (usual-onset) with no HF history, at a regional hospital, over a median follow-up period of 7.1 years. Incident HF by European Cardiology Society criteria was determined. RESULTS: A total of 62 and 108 HF events were identified in the early- and usual-onset groups (1.55 and 1.29 per 100 patient-years), respectively. Compared with usual-onset counterparts, individuals with early-onset diabetes had a 1.20-fold unadjusted (95% CI, 0.88-1.63; P = 0.26) and 1.91-fold age-adjusted (95% CI, 1.37-2.66; P < 0.001) hazard ratio (HR) for incident HF. Adjustment for traditional cardiometabolic risk factors only moderately mitigated the hazards (adjusted HR 1.69; 95% CI, 1.19-2.40; P = 0.003). However, additional adjustment for estimated glomerular filtration rate and albuminuria markedly attenuated the association of early-onset age with incident HF (adjusted HR 1.24; 95% CI, 0.87-1.77; P = 0.24). Notably, a long diabetes duration was not significantly associated with HF risk after accounting for kidney measures. CONCLUSION: Individuals with early-onset diabetes have at least the same absolute risk and a 2-fold age-adjusted relative risk for incident HF. Excess cardiorenal risk factors but not a long diabetes duration are main drivers for HF development in this diabetic population.

Study on the association between the polymorphism of MCP-1 rs1024611 and the genetic susceptibility of type 2 diabetes with sepsis.

Monocyte chemoattractant protein-1 (MCP-1) rs1024611 (-2518 A > G) polymorphism are associated with inflammatory diseases. In this study, we investigate the relationship between MCP-1 rs1024611 polymorphism and genetic susceptibility of type 2 diabetes mellitus (T2DM) with sepsis. Two hundred eighty-five patients with T2DM are divided into the diabetes with sepsis group (combined group, 113 cases) and the diabetes group (172 cases). Blood samples and corresponding clinical data were collected. MCP-1 rs1024611 polymorphism in blood samples was detected by pyrosequencing. Meanwhile, the expressions of MCP-1, tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1ß, and IL-6 in blood samples were detected by real-time quantitative polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. The relationship between different genotypes of MCP-1 rs1024611 polymorphic locus and T2DM with sepsis was analyzed by combining with the clinical data of the patients. The frequencies of rs1024611 AG/GG genotypes and G allele in T2DM with sepsis group were significantly higher than those in T2DM patients without sepsis (P = .004 for AG/GG vs AA genotypes; P = .037 for G allele vs A allele). Subgroup analysis showed that the rs1024611 G allele frequency in the septic shock group was significantly higher than the general sepsis group (P = .02). The expressions of MCP-1 and TNF-α in GG genotypes in T2DM with sepsis group were significantly higher than AA or GA genotypes (P < .05). This study preliminarily showed that the rs1024611 A > G polymorphism within the promoter region of MCP-1 gene can upregulate the expression of MCP-1 gene and proinflammatory cytokine TNF-α, which ultimately contributed to the predisposition and progression of T2DM with sepsis.

Triglyceride-glucose index is prospectively associated with chronic kidney disease progression in Type 2 diabetes - mediation by pigment epithelium-derived factor.

BACKGROUND: Triglyceride-glucose (TyG) index is a surrogate marker of insulin resistance. Its role in chronic kidney disease (CKD) progression in Type 2 Diabetes Mellitus (T2DM) is unclear. We investigated the association between TyG index and CKD progression, and possible mediation of the association by pigment epithelium-derived factor (PEDF). METHODS: This was a prospective study on 1571 patients with T2DM. CKD progression was defined as worsening across KDIGO estimated glomerular filtration rate (eGFR) categories with ≥25% reduction from baseline. PEDF was quantitated using enzyme-linked immunosorbent assay method. Cox proportional hazards regression model was used to assess the relationship between TyG index and CKD progression. RESULTS: Over a follow-up period of up to 8.6 years (median 4.6 years, IQR 3.0-3.6), 42.7% of subjects had CKD progression. Every unit increase in TyG was associated with hazards of 1.44 (95%CI 1.29-1.61; p < 0.001) in unadjusted analysis and 1.21 (1.06-1.37; p = 0.004) in fully adjusted model. Compared to tertile 1, tertiles 2 and 3 TyG index were positively associated with CKD progression with corresponding hazard ratios HRs 1.24 (1.01-1.52; p = 0.037) and 1.37 (1.11-1.68; p = 0.003) in fully adjusted models. PEDF accounted for 36.0% of relationship between TyG index and CKD progression. CONCLUSIONS: Higher TyG index independently predicted CKD progression in T2DM. PEDF mediated the association between TyG index and CKD progression.