Causal Association of Golgi Protein 73 With Coronary Artery Disease: Evidence from Proteomics and Mendelian Randomization.

Background: Identification of the unknown pathogenic factor driving atherosclerosis not only enhances the development of disease biomarkers but also facilitates the discovery of new therapeutic targets, thus contributing to the improved management of coronary artery disease (CAD). We aimed to identify causative protein biomarkers in CAD etiology based on proteomics and 2-sample Mendelian randomization (MR) design. Methods: Serum samples from 33 first-onset CAD patients and 31 non-CAD controls were collected and detected using protein array. Differentially expressed analyses were used to identify candidate proteins for causal inference. We used 2-sample MR to detect the causal associations between the candidate proteins and CAD. Network MR was performed to explore whether metabolic risk factors for CAD mediated the risk of identified protein. Vascular expression of candidate protein in situ was also detected. Results: Among the differentially expressed proteins identified utilizing proteomics, we found that circulating Golgi protein 73 (GP73) was causally associated with incident CAD and other atherosclerotic events sharing similar etiology. Network MR approach showed low-density lipoprotein cholesterol and glycated hemoglobin serve as mediators in the causal pathway, transmitting 42.1% and 8.7% effects from GP73 to CAD, respectively. Apart from the circulating form of GP73, both mouse model and human specimens imply that vascular GP73 expression was also upregulated in atherosclerotic lesions and concomitant with markers of macrophage and phenotypic switching of vascular smooth muscle cells (VSMCs). Conclusions: Our study supported GP73 as a biomarker and causative for CAD. GP73 may involve in CAD pathogenesis mainly via dyslipidemia and hyperglycemia, which may enrich the etiological information and suggest future research direction on CAD.

High triglyceride-glucose index in young adulthood is associated with incident cardiovascular disease and mortality in later life: insight from the CARDIA study.

BACKGROUND: This study aimed to investigate the associations between the triglyceride-glucose (TyG) index in young adulthood with incident cardiovascular disease (CVD) and mortality. METHODS: We included 4,754 participants from the Coronary Artery Risk Development in Young Adults study at baseline. The TyG index was calculated as ln (fasting TG [mg/dl] × fasting glucose [mg/dl]/2), and the TyG index trajectories were identified by using the latent class growth mixture model. We evaluated the association between the baseline and trajectories of the TyG index with incident CVD events and all-cause mortality using Cox proportional hazards regression analysis. The added value of the TyG index included in pooled cohort equations for CVD prediction was also analyzed. RESULTS: Among 4754 participants (mean age 24.72 years, 45.8% male, 51.2% black), there were 158 incident CVD events and 246 all-cause mortality during a median 25 years follow-up. After adjusting for multiple confounding variables, each one-unit increase in the TyG index was associated with a 96% higher CVD risk (hazard ratio [HR] 1.96, 95% confidence interval [CI] 1.44-2.66) and a 85% higher all-cause mortality risk (HR 1.85, 95% CI 1.45-2.36). Three distinct trajectories of the TyG index along the follow-up duration were identified: low (44.0%), moderate (45.5%), and high (10.5%). Compared with those participants in the low TyG index trajectory group, those in the high TyG index trajectory group had a greater risk of CVD events (HR 2.35, 95% CI 1.34-4.12) and all-cause mortality (HR 3.04, 95% CI 1.83-5.07). The addition of baseline TyG index to pooled cohort equations for CVD improved the C-statistics (P < 0.001), integrated discrimination improvement value (P < 0.001), and category-free net reclassification improvement value (P = 0.003). CONCLUSIONS: Higher baseline TyG index levels and higher long-term trajectory of TyG index during young adulthood were significantly associated with an increased risk of incident CVD events and all-cause mortality in later life.

Risk Stratification and Efficacy of Spironolactone in Patients with Heart Failure with Preserved Ejection Fraction: Secondary Analysis of the TOPCAT Randomized Clinical Trial.

PURPOSE: We aimed to develop a simple risk score for patients with HFpEF and assessed the efficacy of spironolactone across baseline risk. METHODS: We developed risk stratification scheme for cardiovascular death in placebo arm of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial (TOPCAT). We screened candidate risk indicators and determined strong risk predictors using COX regression. The absolute risk reduction (ARR) in cardiovascular death with spironolactone was evaluated across baseline risk groups. COX regressions were performed to assess the hazard ratios (HRs) of spironolactone therapy for cardiovascular death and drug discontinuation in each risk category. RESULTS: A simple risk score scheme was constructed based on five risk indicators weighted by estimates from the model, including age, diastolic blood pressure, renal dysfunction, white blood cell, and left ventricular ejection fraction. The risk score scheme showed good discrimination in placebo cohort (C index=0.70). ARR with spironolactone therapy was observed only in patients at very high risk (7.9%). Spironolactone therapy significantly reduced the risk of cardiovascular death in the very high-risk group (HR: 0.57; 95%CI, 0.39-0.84; P =0.005 and P for interaction 0.03) but showed similar risk of drug discontinuation across risk categories (P for interaction=0.928). CONCLUSION: This simple risk score stratifies patients with HFpEF by their baseline risk of cardiovascular death. Patients at very high risk derive great benefits from spironolactone therapy. This easy-to-use risk score provides a practical tool that can facilitate risk stratification and tailoring therapy for those who benefit most from spironolactone. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00094302.

Identification of Novel Phenotypes Correlated with CKD: A Phenotype-Wide Association Study.

Background: A comprehensive understanding of phenotypes related to CKD will facilitate the identification and management of CKD. We aimed to panoramically test and validate associations between multiple phenotypes and CKD using a phenotype-wide association study (PheWAS). Methods: 15,815 subjects from cross-sectional cohorts of the National Health and Nutrition Examination Survey (1999-2006) were randomly 50:50 split into training and testing sets. CKD was defined as eGFR < 60 mL/min/1.73m2. We performed logistic regression analyses between each of 985 phenotypes with CKD in the training set (false discovery rate < 1%) and validated in the testing set (false discovery rate < 1% ). Random forest (RF) model, Nagelkerke's Pseudo-R2, and the area under the receiver operating characteristic (AUROC) were used to validate the identified phenotypes. Results: We identified 18 phenotypes significantly related to CKD, among which retinol, red cell distribution width (RDW), and C-peptide were less researched. The top 5 identified phenotypes were blood urea nitrogen (BUN), homocysteine (HCY), retinol, parathyroid hormone (PTH), and osmolality in RF importance ranking. Besides, BUN, HCY, PTH, retinol, and uric acid were the most important phenotypes based on Pseudo-R2. AUROC of the RF model was 0.951 (full model) and 0.914 (top 5 phenotypes). Conclusion: Our study demonstrated associations between multiple phenotypes with CKD from a holistic view, including 3 novel phenotypes: retinol, RDW, and C-peptide. Our findings provided valid evidence for the identification of novel biomarkers for CKD.

The efficacy of Lactobacillus acidophilus and rhamnosus in the reduction of bacterial load of Helicobacter pylori and modification of gut microbiota-a double-blind, placebo-controlled, randomized trial.

BACKGROUND: Probiotics may alter the gut microbiota and may reduce antibiotic-related dysbiosis after H. pylori eradication. However, whether probiotics are effective in reducing the bacterial load of H. pylori and modifying the gut microbiota remains unknown. We aimed to assess the efficacy of Lactobacillus acidophilus and Lactobacillus rhamnosus in reducing the bacterial load of H. pylori and modifying the gut microbiota. MATERIALS AND METHODS: In this double-blind, randomized, placebo-controlled trial, we recruited 40 adult subjects with moderate to high bacterial loads of H. pylori, defined as a mean delta over baseline (DOB) value of the 13 C-urea breath test (13 C-UBT) of 10 or greater every 4 days 6 times. Eligible subjects were randomized in a 1:1 ratio to receive either probiotics containing Lactobacillus acidophilus and Lactobacillus rhamnosus or placebo twice daily for 4 weeks. 13 C-UBT was measured weekly from the beginning of treatment to 2 weeks after treatment. Amplification of the V3 and V4 hypervariable regions of the 16S rRNA was performed for fecal microbiota. RESULTS: A total of 40 subjects were randomized to receive probiotics or placebo. The DOB value was significantly lower in the probiotic group than in the placebo group after 4 weeks of treatment (26.0 vs. 18.5, p = .045). The DOB value was significantly reduced compared to that at baseline in the probiotic group (18.5 vs. 26.7, p = .001) but not in the placebo group (26.0 vs. 25.0, p = .648). However, the eradication rate for H. pylori was 0% in both groups. There was no significant difference in the DOB values between the two groups 1 and 2 weeks after discontinuation of the probiotics. There were also no significant changes observed in the α-diversity and ß-diversity at week 4 compared to baseline in the probiotic group (p = .77 and 0.91) and the placebo group (p = .26 and 0.67). CONCLUSIONS: Although the use of Lactobacillus acidophilus and Lactobacillus rhamnosus may reduce the bacterial load of H. pylori, there were no significant changes in the composition of gut microbiota. This trial is registered with ClinicalTrials.gov, NCT02725138.

Behavioral Factors Mediating the Impact of Educational Attainment on Incident Heart Failure　- A Mediation Analysis.

BACKGROUND: To examine the association of low educational attainment with incident heart failure (HF) and explore potential behavioral mediators of the causal pathway.Methods and Results:A total of 12,109 participants in the Atherosclerosis Risk in Communities Study (ARIC) were included. Educational attainment was measured at baseline, and the risk of HF across educational attainment groups was assessed by Cox proportional hazards models. Using mediation analysis, we evaluated the mediating role of behavioral factors in the causal pathway between educational attainment and HF. During a median follow-up of 25.1 years, 2,407 cases (19.9%) of HF occurred. Educational attainment showed an inverse association with HF risk (hazard ratio (HR), 1.41; 95% confidence interval (CI), 1,26-1.57 for low educational attainment; HR, 1.13; 95% CI, 1.02-1.25 for medium educational attainment). In the mediation analysis, the association between educational attainment and HF was partially mediated by income, waist-to-hip ratio, current smoking, body mass index, current drinking, sports and physical activity, which explained 24.3%, 20.2%, 13.8%, 10.1%, 7.7%, 7.3% and 4.5%, respectively, of the relationship. In total, all mediators contributed 56.3% of the total effect. CONCLUSIONS: Low educational attainment was associated with increased risk for HF. Income, obesity and current smoking mediated a great proportion of the total effect of educational attainment on HF. Our results provide underlying insights for the development of targeted public health interventions to reduce educational disparities on HF incidence.

Impact of RAAS Blockers on Contrast-Induced Nephropathy in Patients With Renal Insufficiency: A Meta-Analysis.

The effect of renin-angiotensin-aldosterone system (RAAS) blockers [angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers] on Contrast-induced nephropathy (CIN) is unclear in patients with renal insufficiency. Thus, we conduct a meta-analysis to evaluate the association between the administration of RAAS blockers and CIN in patients with renal insufficiency. We searched PubMed, EMBASE, and Cochrane Library for relevant studies published before September 2019. The primary outcome was the incidence of CIN, and the secondary outcome was the changes in serum creatinine (SCr) from baseline to postprocedure (ΔSCr). Pooled odds ratio (OR) or weighted mean difference (WMD) with their 95% confidence interval (CIs) for the CIN incidence, ΔSCr were used to calculate original data. A total of 8 studies were included in the meta-analysis. Compared with controls, ACEI/angiotensin receptor blocker increased the risk of CIN (OR = 1.61, 95% CI 1.14-2.28, I = 30%; P = 0.007), whereas this association was not significant in Chinese patients (OR = 1.07, 95% CI 0.65-1.77, I = 19%, P = 0.79). The total weighted mean differences of the ΔSCr were 0.06 mg/dL (95% CI: 0.01-0.11, I = 82%; P = 0.03). Administration of RAAS blockers in patients with renal insufficiency was associated with a significantly higher incidence of CIN, whereas it did not show a significant effect on Chinese patients.

How moles destroy your lawn: the forelimb kinematics of eastern moles in loose and compact substrates.

The interplay between morphological specialization and kinematic flexibility is important for organisms that move between habitats within different substrates. Burrowing is energetically expensive and requires substantial interaction with soil to dislodge and transport it. True moles (Talpidae) have extraordinary forelimb morphologies and a unique ability to dig in loose as well as compact soils, yet we know little of how moles coordinate their forelimb joint kinematics when digging in soils of different compactness. Using marker-based X-ray Reconstruction of Moving Morphology (XROMM), we tested the hypothesis that moles burrow using different forelimb kinematics in loose and compact substrates. We predicted that moles raise mounds of loose soil by performing powerful compacting strokes mainly with long-axis rotation of the humerus (i.e. pronation/supination), but shear compact soil away by performing scratching strokes involving amplified elbow extension, similar to most scratching diggers. We also predicted that in both types of substrate, moles displace soil rearward like other mammalian diggers. Our results support our hypothesis but not the predictions. Eastern moles (Scalopus aquaticus) move substrates upward using compacting strokes in loose substrates and outward from the body midline using scratching strokes in compact substrates; unlike the digging strokes of most mammalian forelimb diggers, the power-stroke of moles itself does not displace substrates directly rearward. Compacting and scratching strokes involve similar ranges of humeral pronation and retraction at the scapulohumeral (shoulder) joint, yet the movements at the elbow and carpal joints differ. Our results demonstrate that the combination of stereotypic movements of the shoulder joint, where the largest digging muscles are located, and flexibility in the elbow and carpal joints makes moles extremely effective diggers in both loose and compact substrates.

How moles walk; it's all thumbs.

A recurring theme in the evolution of tetrapods is the shift from sprawling posture with laterally orientated limbs to erect posture with the limbs extending below the body. However, in order to invade particular locomotor niches, some tetrapods secondarily evolved a sprawled posture. This includes moles, some of the most specialized digging tetrapods. Although their forelimb anatomy and posture facilitates burrowing, moles also walk long distances to forage for and transport food. Here, we use X-ray Reconstruction Of Moving Morphology (XROMM) to determine if the mole humerus rotates around its long axis during walking, as it does when moles burrow and echidnas walk, or alternatively protracts and retracts at the shoulder in the horizontal plane as seen in sprawling reptiles. Our results reject both hypotheses and demonstrate that forelimb kinematics during mole walking are unusual among those described for tetrapods. The humerus is retracted and protracted in the parasagittal plane above, rather than below the shoulder joint and the 'false thumb', a sesamoid bone (os falciforme), supports body weight during the stance phase, which is relatively short. Our findings broaden our understanding of the diversity of tetrapod limb posture and locomotor evolution, demonstrate the importance of X-ray-based techniques for revealing hidden kinematics and highlight the importance of examining locomotor function at the level of individual joint mobility.

Paper-based 1-MCP treatment suppresses cell wall metabolism and delays softening of Huanghua pears during storage.

BACKGROUND: Huanghua pear will lose its firmness quickly during postharvest storage at ambient temperature, and hence has limited storage and marketing potential. In this study, Huanghua pears treated with paper containing 0 (control) or 0.9 µL L-1 1-methylcyclopropene (1-MCP) for 12 h, and then stored at (25 ± 1) °C for 30 days, were investigated for the effect on fruit firmness, cell wall composition and activities of cell wall-degrading enzymes. RESULTS: Huanghua pears without 1-MCP treatment softened rapidly during room-temperature storage and cell wall composition analyses showed an increase in water-soluble pectin (WSP) and decreases in cell wall materials (CWM) and cell wall components such as Na2 CO3 -soluble pectin (NSP), cellulose and hemicellulose. In contrast, the 1-MCP-treated fruits maintained higher firmness than the control; also, the treatment prevented the formation of WSP and reduced the degradation of CWM and cell wall components including NSP, cellulose and hemicellulose. 1-MCP treatment also significantly lowered the activities of cell wall-degrading enzymes such as pectinesterase, polygalacturonase, ß-galactosidase and cellulase during storage. CONCLUSION: 1-MCP treatment can slow down the softening of Huanghua pears through reducing cell wall-degrading enzyme activities and hence maintain the integrity of the cell wall structure. © 2016 Society of Chemical Industry.

Highly sensitive fluorescent sensor for mercury based on hyperbranched rolling circle amplification.

A label-free hyperbranched rolling circle amplification (HRCA) based fluorescent sensor has been developed for Hg(2+) detection. The fluorescence intensity has a linear relationship with the concentration of the target in the range of 0.425 pmol L(-1) to 42.5 nmol L(-1), and the detection limit is as low as 0.14 pmol L(-1) (S/N = 3). The proposed sensor had been applied to detect Hg(2+) in water samples with satisfying results.

Development of the Low-Temperature Inducible System for Recombinant Protein Production in Escherichia coli Nissle 1917.

The pET system is commonly used for producing foreign proteins in Escherichia coli, but its reliance on the costly and metabolically demanding inducer IPTG limits its industrial use. This study engineered a low-temperature inducible system (LTIS) in E. coli Nissle 1917 (EcN) by combining the T7 expression system with the thermal inducible mechanism CI857-λPRPL to generate the new LTIS strain, ENL7P. The strain ENL7P-sfGFP-Km underwent overnight culture at 37 °C for 14-16 h, followed by subculturing at 30 °C for 24 h. This resulted in a notable 5.53-fold increase in the sfGFP induction rate when the strain was cultivated under 37-30 °C conditions. Moreover, gene expression was induced using a two-stage strategy. Initially, the strain was cultured overnight at 39 °C for 14-16 h, followed by a subculture at 30 °C for 6 h, and finally, another subculture at 30 °C for 24 h. This cultivation strategy led to an impressive 158.37-fold induction rate for sfGFP. Similar effects could be achieved through utilization of the LTIS system for inducing the production of thermophilic trehalose synthase from Thermus antranikianii (TaTS). The results of this study proved that the LTIS system has the potential for industrial applications.

Fabricating active Egg Albumin/Sodium Alginate/Sodium Lignosulfonate Nanoparticles film with significantly improved multifunctional characteristics for food packing.

In food packaging, sodium lignosulfonate nanoparticles (SLS NPs) showed significant antibacterial properties, antioxidant and UV barrier activities. Herein, the SLS NPs were synthesized via a sustainable green method and were added into egg albumin/sodium alginate mixture (EA/SA) to fabricate a safe, edible EA/SA/SNPs food packaging. A composite film EA/SA/SNP was examined microstructurally and physicochemically. The mechanical characteristics, UV protection, water resistance, and the composite film's thermal stability were all enhanced by the inclusion of SLS NPs, and water vapor permeability reduced by 44 %. This composite film exhibited robust antioxidative properties with DPPH and ABTS free radical scavenging rates reaching 76.84 % and 92.56 %, and effective antimicrobial activity against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) with antibacterial rates reaching 98.25 % and 97.13 % for the positively charged nanoparticles interacting with the cell membrane. Freshness tests showed that the EA/SA/SNPs packaging film could delay the quality deterioration of fresh tomatoes. This composite film can slow down spoilage bacteria proliferation and prolongs food's preservation period by eight days at ambient temperature.

Dicyclohexylcarbodiimide and disodium succinate induce the change of energy metabolism in relation to longan pulp breakdown.

Compared to control longan, DCC-treated longan had higher pulp breakdown index, lower ATP, ADP and EC levels, and lower H+, Ca2+ and Mg2+-ATPase activities. On day 6, DCC-treated longan presented 18% higher pulp breakdown index, with 44%, 9% and 31% lower levels of ATP, ADP and EC, respectively. Additionally, DCC-treated longan showed 29%, 53%, 37% lower activity of H+-ATPase, 34%, 54%, 4% lower activity of Ca2+-ATPase, and 13%, 21%, 6% lower activity of Mg2+-ATPase in the membranes of plasma, vacuole, and mitochondria, respectively. Whereas, DS-treated longan manifested the opposite trends of DCC treatment. These results suggest that the accelerated pulp breakdown in DCC-treated longan was linked to energy deficiency and reduced energy production. However, DS treatment restrained pulp breakdown occurrence in fresh longan by maintaining a higher energy level through the elevated energy production and ATPase activity.

DNP and ATP modulate the pulp softening and breakdown in fresh longan by acting on the antioxidant system and the metabolisms of membrane lipids and cell wall polysaccharides.

Compared to the control longan, DNP treatment elevated pulp breakdown index, reduced the values of pulp firmness, CSP, ISP, cellulose, and hemicellulose by enhancing the activities of PE, PG, Cx, XET, and ß-Gal. Additionally, DNP treatment increased the levels of PLD, lipase, LOX, PA, and SFA, and decreased the values of PC, PI, USFA, U/S, and IUFA, displaying higher cell membrane permeability and more severe cell membrane damage in longan pulp. Furthermore, DNP treatment weakened the levels of SOD, CAT, APX, AsA, GSH, TP, and TF, thereby exacerbating ROS outbreak and MDA production. These results indicate that DNP treatment destroyed the antioxidant system to cause ROS eruption. This disruption further disturbed the metabolisms of membrane lipids and cell wall polysaccharides, leading to the breakdown of cell membrane and cell wall, and eventually aggravated longan pulp softening and breakdown. However, ATP treatment exhibited the opposite effects of DNP treatment.

Comparative transcriptome and metabolome reveal the role of acidic electrolyzed oxidizing water in improving postharvest disease resistance of longan fruit.

Acidic electrolyzed oxidizing water (AEOW) was applied to suppress disease development and maintain good quality of fresh fruit. However, the involvement of AEOW in improving disease resistance of fresh longan remains unknown. Here, transcriptomic and metabolic analyses were performed to compare non-treated and AEOW-treated longan during storage. The transcriptome analysis showed AEOW-induced genes associated with phenylpropanoid and flavonoid biosynthesis. The metabolome analysis found the contents of coumarin, phenolic acid, and tannin maintained higher levels in AEOW-treated longan than non-treated longan. Moreover, the weighted correlation network analysis (WGCNA) was performed to identify hub genes, and a gene-metabolite correlation network associated with AEOW-improved disease resistance in longan was constructed by the co-analysis of transcriptomics and metabolomics. These findings identified a series of important genes and metabolites involving in AEOW-induced disease resistance of longan fruit, expanding our knowledges on fruit disease resistance and quality maintenance at the transcript and metabolic levels.

Acidic electrolyzed-oxidizing water treatment mitigated the disease progression in Phomopsis longanae Chi-infected longans by modulating ROS and membrane lipid metabolism.

Postharvest harmful pathogenic infestation leads to rapid decay in longan fruit. Compared with P. longanae-infected longans, AEOW alleviated fruit disease severity and diminished the O2-. production rate and MDA content. It also increased APX, CAT, and SOD activities, delayed the decrease in the levels of GSH and AsA, as well as the reducing power and DPPH radical scavenging ability, which resulted in a decline in membrane lipid peroxidation in P. longanae-infected longans. Additionally, AEOW reduced LOX, lipase, PI-PLC, PC-PLC, and PLD activities, maintained higher levels of PC, PI, IUFA, USFAs, and U/S, while reducing levels of PA, DAG, SFAs, and CMP. These effects alleviated membrane lipid degradation and peroxidation in P. longanae-infected longans. Consequently, AEOW effectively maintained membrane integrity via improving antioxidant capacity and suppressing membrane lipid peroxidation. This comprehensive coordination of ROS and membrane lipid metabolisms improved fruit resistance and delayed disease development in longans.

Inflammatory myofibroblastic tumor of the heart in an older woman with paroxysmal atrial fibrillation: a case report and review of the literature.

Inflammatory myofibroblastic tumors (IMTs) of the heart are rarely observed in the eldly. We report a case involving an elderly woman with an IMT situated on the right atrial wall. The tumor was fully excised. The patient had a smooth recovery post-surgery and remained free of recurrence for three years.

Serum Klotho Modifies the Associations of 25-Hydroxy Vitamin D With All-Cause and Cardiovascular Mortality.

BACKGROUND: The association between 25-hydroxyvitamin D and mortality remains controversial. Klotho, a biomarker of vitamin D activation and metabolism, may play a key role in this association. However, it is unclear whether the association between vitamin D deficiency and mortality risk is modified by klotho levels. Therefore, this study investigated the joint association of serum 25-hydroxyvitamin D [25(OH)D] and klotho with mortality risk in American community-dwelling adults. METHODS: A total of 9870 adults from the National Health and Nutrition Examination Survey (2007-2016) were included in our study. Mortality data were ascertained by linking participants to National Death Index records. Cox proportional hazards models were used to assess the association among serum 25(OH)D, serum klotho, and all-cause and cardiovascular disease (CVD) mortality. RESULTS: We found a significant interaction between klotho and serum 25(OH)D in all-cause mortality (P = .028). With klotho > 848.4 pg/mL (risk threshold on mortality), no significant all-cause and CVD mortality risk was observed at any level of serum 25(OH)D. However, with klotho < 848.4 pg/mL, a significant all-cause and CVD mortality risk was observed with serum 25(OH)D < 50 nmol/L [hazards ratio (HR), 1.36; 95% confidence interval (CI), 1.10-1.69; HR, 1.78; 95% CI, 1.16-3.45) and serum 25(OH)D of continuous variable (HR, 0.98; 95% CI, .97-.99; HR, 0.98; 95% CI, .98-.99). In addition, vitamin D metabolism disruption accessed by the combination of decreasing serum 25(OH)D (<50 nmol/L) and klotho (<848.4 pg/mL) was associated with significant all-cause mortality (HR, 1.48; 95% CI, 1.11-1.96) and CVD mortality (HR, 2.36; 95% CI, 1.48-3.75). CONCLUSIONS: Vitamin D-associated mortality risk is observed only with concurrently decreasing klotho, indicating that vitamin D metabolism dysfunction increases the risk of mortality. Klotho levels could help predict long-term mortality outcomes and thus may be useful concurrently for guiding vitamin D supplementation therapy decision-making in populations with vitamin D deficiency.

Intensive Glycemic Therapy in Type 2 Diabetes Patients With Cardiac Autonomic Dysfunction: The ACCORD Trial.

OBJECTIVE: To assess whether the presence of cardiac autonomic dysfunction denoted by low heart rate variability (HRV) modifies the effect of intensive glycemic therapy on outcomes in patients with type 2 diabetes. PATIENTS AND METHODS: This study included 7946 participants in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial from January 2001 through June 2009. Heart rate variability measures included standard deviation of all normal-to-normal intervals (SDNN) and root mean square of successive differences between normal-to-normal intervals (rMSSD). Abnormal values were defined based on less than the 10th percentile for SDNN and rMSSD. RESULTS: Compared with standard therapy, intensive therapy was associated with improved primary outcome (composite of cardiovascular events) in the low-HRV group (SDNN: HR, 0.57; 95% CI, 0.39 to 0.84; rMSSD: HR, 0.57; 95% CI, 0.38 to 0.84), but not in the normal-HRV group (SDNN: HR, 0.90; 95% CI, 0.77 to 1.05; rMSSD: HR, 0.90; 95% CI, 0.77 to 1.05). A similar pattern was found for coronary heart disease. Conversely, intensive therapy had a neutral effect on all cause death in the low-HRV group (SDNN: HR, 0.88; 95% CI, 0.54 to 1.41; rMSSD: HR, 0.71; 95% CI, 0.43 to 1.17;), but increase risk of all-cause death in the normal-HRV group (SDNN: HR, 1.21; 95% CI, 1.00 to 1.46; rMSSD: HR, 1.25; 95% CI, 1.03 to 1.51). Intensive therapy induced a greater risk of hypoglycemia in the normal-HRV group than that in the low-HRV group. CONCLUSION: Cardiac autonomic dysfunction expressed as low HRV identified subpopulations in ACCORD with more benefits and less harms from intensive therapy.