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Aim: To investigate the interplay of incident chronic kidney disease (CKD) and/or heart failure (HF) and their associations with prognosis in a large, population-based cohort with type 2 diabetes (T2DM).Methods: Patients aged ≥18 years with new-onset T2DM, without renal disease or HF at baseline, were identified from the territory-wide Clinical Data Analysis Reporting System between 2000 and 2015. Patients were followed up until December 31, 2020 for incident CKD and/or HF and all-cause mortality.Results: Among 102 488 patients (median age 66 years, 45.7% women, median follow-up 7.5 years), new-onset CKD occurred in 14 798 patients (14.4%), in whom 21.7% had HF. In contrast, among 9258 patients (9.0%) with new-onset HF, 34.6% had CKD. The median time from baseline to incident CKD or HF (4.4 vs. 4.1 years) did not differ. However, the median (interquartile range) time until incident HF after CKD diagnosis was 1.7 (0.5-3.6) years and was 1.2 (0.2-3.4) years for incident CKD after HF diagnosis (P < 0.001). The crude incidence of CKD was higher than that of HF: 17.6 (95% confidence interval [CI] 17.3-17.9) vs. 10.6 (95% CI 10.4-10.9)/1000 person-years, respectively, but incident HF was associated with a higher adjusted-mortality than incident CKD. The presence of either condition (vs. CKD/HF-free status) was associated with a three-fold hazard of death, whereas concomitant HF and CKD conferred a six to seven-fold adjusted hazard of mortality.Conclusion: Cardiorenal complications are common and are associated with high mortality risk among patients with new-onset T2DM. Close surveillance of these dual complications is crucial to reduce the burden of disease.

We aimed to dissect the complex relations between depressive symptoms, antidepressant use, and constituent metabolic syndrome (MetS) components in a representative U.S. population sample. A total of 15,315 eligible participants were included from 2005 to March 2020. MetS components were defined as hypertension, elevated triglycerides, reduced high-density lipoprotein cholesterol, central obesity, and elevated blood glucose. Depressive symptoms were classified as mild, moderate, or severe. Logistic regression was used to evaluate the relationship between depression severity, antidepressant use, individual MetS components and their degree of clustering. Severe depression was associated with the number of MetS components in a graded fashion. ORs for severe depression ranged from 2.08 [95%CI, 1.29–3.37] to 3.35 [95%CI, 1.57–7.14] for one to five clustered components. Moderate depression was associated with hypertension, central obesity, raised triglyceride, and elevated blood glucose (OR = 1.37 [95%CI, 1.09–1.72], 1.82 [95%CI, 1.21–2.74], 1.63 [95%CI, 1.25–2.14], and 1.37 [95%CI, 1.05–1.79], respectively). Antidepressant use was associated with hypertension (OR = 1.40, 95%CI [1.14–1.72]), raised triglyceride (OR = 1.43, 95%CI [1.17–1.74]), and the presence of five MetS components (OR = 1.74, 95%CI [1.13–2.68]) after adjusting for depressive symptoms. The depression severity and antidepressant use were associated with individual MetS components and their graded clustering. Metabolic abnormalities in patients with depression need to be recognized and treated.

Aim: The organ protective effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors may be beneficial against infectious complications. This real-world study aims to compare the risk of pneumonia and sepsis between SGLT2 inhibitors and dipeptidyl peptidase 4 (DPP-4) inhibitors in patients with type 2 diabetes.Methods: Using a territory-wide clinical registry in Hong Kong (Clinical Data Analysis and Reporting System [CDARS]), we included patients initiated on SGLT2 inhibitors or DPP-4 inhibitors between January 01, 2015 and December 31, 2019 through 1:2 propensity score matching. The primary outcomes were incident events of pneumonia, sepsis and the related mortality. Cox proportional hazards analysis was used to compare the risk of incident pneumonia and sepsis for SGLT2 inhibitors versus DPP-4 inhibitors.Results: After propensity score matching, 10,706 new users of SGLT2 inhibitors and 18,281 new users of DPP-4 inhibitors were included. The mean age of all eligible subjects were 60 years (SD 11.07) and 61.1% were male. There were 309 pneumonia events [incidence rate per 1000 person-years (IR) = 11.38] among SGLT2 inhibitors users and 961 events (IR = 20.45) among DPP-4 inhibitors users, with lower risk of pneumonia among SGLT2 inhibitors users (adjusted HR 0.63 [95%CI 0.55–0.72], pConclusion: We provide real-world evidence that irrespective of age, sex, prior-existing cardiovascular disease, or type of SGLT2 inhibitors used, patients with type 2 diabetes initiated on SGLT2 inhibitors have lower incidence of pneumonia and sepsis as well as mortality risk associated with pneumonia, sepsis, and infectious diseases, compared with those initiated on DPP-4 inhibitors.

Leadless pacing is a major breakthrough in the management of bradyarrhythmia. Results of initial clinical trials that have demonstrated a significant reduction in acute and long-term pacing-related complications have been confirmed by real-world experience in a broader spectrum of patients. Nonetheless current use of a leadless pacemaker is hampered by its limited atrial sensing and pacing capability, as well as battery life-span and retrievability. We review the current clinical outcome data, indications and contraindications, implantation and retrieval techniques, synchronous ventricular pacing, and other clinical considerations. We also provide an overview of the latest advancements in leadless pacing technology including device-to-device communication and energy harvesting technology.

Patients with axial spondyloarthritis (SpA) are subjected to elevated cardiovascular risks, but assessment of early myocardial damage and clinical risk stratification remained obscure. The aim of this study was to evaluate the prognostic value of speckle-tracking strain analysis and serum high-sensitivity troponin I (hsTnI) in patients with axial SpA. Two-dimensional speckle-tracking echocardiography was performed to derive longitudinal strain (LS), circumferential strain (CS), and radial strain (RS). Serum hsTnI was measured by validated immunoassay (Architect i1000SR Abbott) as indicator of subclinical myocardial damage. The mean Bath Ankylosing Spondylitis Disease Activity Index and median modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) were 3.8 and 15.5, respectively. Over a median follow-up of 81 months, major adverse cardiovascular events (MACE) occurred in 13% of subjects (n = 116). Univariate Cox regression showed that age, disease duration, Bath Ankylosing Spondylitis Functional Index, modified Schober test, mSASSS, hsTnI, interventricular septal thickness, E/E′, LS, RS, and carotid intima-media thickness were significant predictors of MACE (all P

Type 2 diabetes is associated with an increased risk of hip fractures. We hypothesize that long-term glycemic variability predicts incident hip fractures. We demonstrated that HbA1c variability predicted incident hip fractures independent of mean HbA1c, suggesting the potential benefits of minimizing glycemic variability in addition to optimizing mean glycemia for bone health. Type 2 diabetes is associated with an increased risk of hip fractures, and a linear relationship between HbA1c levels and hip fracture incidence has been observed. We hypothesize that HbA1c variability also predicts incident hip fractures in type 2 diabetes. Chinese individuals with type 2 diabetes aged ≥ 60 years were identified from electronic health records in Hong Kong between 2008 and 2012 and observed for incident hip fractures. Hip fracture was defined by the International Classification of Diseases (Ninth Revision) code 820. HbA1c variability was determined using standard deviation, adjusted standard deviation, and coefficient of variation of HbA1c measurements in the 5 years preceding the entry date. Multivariable Cox regression analysis was used to evaluate associations between HbA1c variability and incident hip fractures. A total of 83,282 participants were included. Their mean age was 71.3 ± 7.5 years, duration of diabetes 11.7 ± 7.7 years, baseline HbA1c 56.6 ± 13.5 mmol/mol (7.33 ± 1.23%), and median follow-up 6.8 years. All indices of HbA1c variability were significant independent predictors of incident hip fractures, with an adjusted hazard ratio of up to 1.29 (all p

Background:Long-term antiplatelet agents including the potent P2Y12 antagonist ticagrelor are indicated in patients with a previous history of acute coronary syndrome. We sought to compare the effect of ticagrelor with that of aspirin monotherapy on vascular endothelial function in patients with prior acute coronary syndrome.Methods:This was a prospective, single center, parallel group, investigator-blinded randomized controlled trial. We randomized 200 patients on long-term aspirin monotherapy with prior acute coronary syndrome in a 1:1 fashion to receive ticagrelor 60 mg BD (n=100) or aspirin 100 mg OD (n=100). The primary end point was change from baseline in brachial artery flow-mediated dilation at 12 weeks. Secondary end points were changes to platelet activation marker (CD41_62p) and endothelial progenitor cell (CD34/133) count measured by flow cytometry, plasma level of adenosine, IL-6 (interleukin-6) and EGF (epidermal growth factor), and multi-omics profiling at 12 weeks.Results:After 12 weeks, brachial flow-mediated dilation was significantly increased in the ticagrelor group compared with the aspirin group (ticagrelor: 3.48±3.48% versus aspirin: −1.26±2.85%, treatment effect 4.73 [95% CI, 3.85–5.62],PP>0.05). Multi-omics pathway assessment revealed that changes in the metabolism and biosynthesis of amino acids (cysteine and methionine metabolism; phenylalanine, tyrosine, and tryptophan biosynthesis) and phospholipids (glycerophosphoethanolamines and glycerophosphoserines) were associated with improved brachial artery flow-mediated dilation in the ticagrelor group.Conclusions:In patients with prior acute coronary syndrome, ticagrelor 60 mg BD monotherapy significantly improved brachial flow-mediated dilation compared with aspirin monotherapy and was associated with significant changes in metabolomic and lipidomic signatures.Registration:URL:https://www.clinicaltrials.gov; Unique identifier: NCT03881943.

Background and Purpose: Experimental studies showed vitamin D (Vit-D) could promote vascular regeneration and repair. Prior randomized studies had focused mainly on primary prevention. Whether Vit-D protects against ischemic stroke and myocardial infarction recurrence among subjects with prior ischemic insults was unknown. Here, we dissected through Mendelian randomization any effect of Vit-D on the secondary prevention of recurrent ischemic stroke and myocardial infarction. Methods: Based on a genetic risk score for Vit-D constructed from a derivation cohort sample (n=5331, 45% Vit-D deficient, 89% genotyped) via high-throughput exome-chip screening of 12 prior genome-wide association study–identified genetic variants of Vit-D mechanistic pathways ( rs2060793 , rs4588 , and rs7041 ; F statistic, 73; P Results: In the ischemic disease subsample, 11.1% (n=49/441) had developed recurrent ischemic stroke or MI and 13.3% (n=58/441) had developed recurrent or de novo ischemic stroke/MI. Kaplan-Meier analyses showed that genetic risk score predicted improved event-free survival from recurrent ischemic stroke or MI (log-rank, 13.0; P =0.001). Cox regression revealed that genetic risk score independently predicted reduced risk of recurrent ischemic stroke or MI combined (hazards ratio, 0.62 [95% CI, 0.48–0.81]; P Conclusions: Genetically predicted lowering in Vit-D level is causal for the recurrence of ischemic vascular events in persons with prior ischemic stroke or MI.

Cardiovascular disease (CVD) is a major contributor to the global burden of disease. Berberine, a long-standing, widely used, traditional Chinese medicine, is thought to have beneficial effects on CVD risk factors and in women with polycystic ovary syndrome. The mechanisms and effects, specifically in men, possibly via testosterone, have not been examined previously. To assess the effect of berberine on CVD risk factors and any potential pathway via testosterone in men, we conducted a randomized, double-blind, placebo-controlled, parallel trial in Hong Kong. In total, 84 eligible Chinese men with hyperlipidemia were randomized to berberine (500 mg orally, twice a day) or placebo for 12 weeks. CVD risk factors (lipids, thromboxane A2, blood pressure, body mass index and waist–hip ratio) and testosterone were assessed at baseline, and 8 and 12 weeks after intervention. We compared changes in CVD risk factors and testosterone after 12 weeks of intervention using analysis of variance, and after 8 and 12 weeks using generalized estimating equations (GEE). Of the 84 men randomized, 80 men completed the trial. Men randomized to berberine had larger reductions in total cholesterol (−0.39 mmol/L, 95% confidence interval (CI) −0.70 to −0.08) and high-density lipoprotein cholesterol (−0.07 mmol/L, 95% CI −0.13 to −0.01) after 12 weeks. Considering changes after 8 and 12 weeks together, berberine lowered total cholesterol and possibly low-density lipoprotein-cholesterol (LDL-c), and possibly increased testosterone. Changes in triglycerides, thromboxane A2, blood pressure, body mass index and waist–hip ratio after the intervention did not differ between the berberine and placebo groups. No serious adverse event was reported. Berberine is a promising treatment for lowering cholesterol. Berberine did not lower testosterone but instead may increase testosterone in men, suggesting sex-specific effects of berberine. Exploring other pathways and assessing sex differences would be worthwhile, with relevance to drug repositioning and healthcare.

Summary Background & aims Little is known about the risk of nasopharyngeal carcinoma (NPC) in relation to vitamin D exposure. The aim of this study was to examine the associations of NPC risk with serum level of 25-hydroxyvitamin D (25OHD) and genetic predicted 25OHD, and potential effect modification by several putative risk factors of NPC. Methods Our multicenter case–control study in Hong Kong recruited 815 NPC cases and 1502 frequency-matched (by sex and age) hospital controls from five major regional hospitals, and recruited 299 healthy subjects from blood donation centers (2014–2017). Circulating level of 25-hydroxyvitamin D (25OHD) and genetic predicted 25OHD (rs12785878, rs11234027, rs12794714, rs4588 and rs6013897) were measured by validated enzyme immunoassay and the iPLEX assay on the MassARRAY System, respectively. Data were also collected on demographics, lifestyle factors, ultraviolet radiation exposure, and potential confounders using a computer-assisted, self-administered questionnaire with satisfactory test-retest reliability. Unconditional logistic regression models were used to estimate ORs and 95% CIs. Results Despite no significant association of NPC risk with circulating 25OHD and genetic predicted 25OHD, there was evidence for an inverse association in participants with normal body mass index (between 18.5 and 27.5) across categories of 25OHD (Ptrend = 0.003), and a positive association in those with low socioeconomic status across categories based on the genetic score (Ptrend = 0.005). In addition, risk of NPC diagnosed at an early stage was higher for genetically lower 25OHD level (adjusted OR = 3.09, 95% CI = 1.04–9.21, Ptrend = 0.022). Conclusions Findings of this first comprehensive study to investigate the positive association of NPC risk with vitamin D deficiency need to be confirmed and be best interpreted with results of further similar studies. Our findings may inform possible etiological mechanisms of the associations with several putative risk/protective factors of NPC.

Background High blood pressure is a major risk factor for cardiovascular disease. Visit-to-visit blood pressure variability (BPV) has recently been shown to predict cardiovascular outcomes. We investigated the predictive value of BPV for major adverse cardiovascular events (MACE) among patients with coronary artery disease (CAD), with and without type 2 diabetes mellitus (T2DM). Methods Patients with stable CAD were enrolled and monitored for new MACE. Visit-to-visit BPV was defined as the coefficient of variation (CV) of systolic and diastolic BP across clinic visits. Multivariable logistic regression analysis was performed to evaluate the association of BPV with MACE. Area under the receiver operating characteristic curve (AUC) was used to assess its predictive ability. Results Among 1140 Chinese patients with stable CAD, 192 (17%) experienced a new MACE. In multivariable analyses, the risk of MACE was significantly associated with CV of systolic BP (odds ratio [OR] for highest versus lowest quartile, 3.30; 95% CI 1.97–5.54), and diastolic BP (OR for highest versus lowest quartile, 2.39; 95% CI 1.39–4.11), after adjustment for variables of the risk factor model (age, gender, T2DM, hypertension, antihypertensive agents, number of BP measurements) and mean BP. The risk factor model had an AUC of 0.70 for prediction of MACE. Adding systolic/diastolic CV into the risk factor model with mean BP significantly increased the AUC to 0.73/0.72 (P = 0.002/0.007). In subgroup analyses, higher CV of systolic BP remained significantly associated with an increased risk for MACE in patients with and without T2DM, whereas the association of CV of diastolic BP with MACE was observed only in those without T2DM. Conclusions Visit-to-visit variability of systolic BP and of diastolic BP was an independent predictor of new MACE and provided incremental prognostic value beyond mean BP and conventional risk factors in patients with stable CAD. The association of BPV in CAD patients without T2DM with subsequent risk for MACE was stronger than in those with T2DM.

Additional file 2: Figure S1. Flow chart of study recruitment. BP, blood pressure; BPV, blood pressure variability; CAD, coronary artery disease.

Additional file 3: Table S1. Comparison of baseline characteristics in patients with and without T2DM. Table S2. Baseline characteristics according to quartiles of coefficient of variation of SBP. Table S3. Baseline characteristics according to quartiles of coefficient of variation of DBP. Table S4. Multivariable linear regression models for coefficient of variation of SBP/DBP. Table S5. Pearson correlation coefficient analysis based on number of BP measurements. Table S6. Logistic regression analysis for predicting MACE in stable CAD patients. Table S7. Odds ratios for MACE associated with quartiles of SD and ARV of SBP/DBP. Table S8. Odds ratios for MACE associated with CV of SBP/DBP, based on six BP measurements. Table S9. Intraclass correlation coefficient for CV of SBP/DBP.

Additional file 1. Supplemental Methods

Background Liver stiffness (LS) assessed by transient elastography is associated with adverse events in patients with heart failure. However, the predictive value of LS for adverse outcome is uncertain in patients undergoing tricuspid annuloplasty (TA). This study sought to evaluate the prognostic value and reversibility of LS in patients undergoing TA during left-sided valve surgery. Methods and results A total of 158 patients who underwent TA were prospectively evaluated. Patients were divided into three groups according to tertile of LS. Adverse outcome was defined as heart failure that required hospital admission or all-cause mortality following TA. The median LS was 13.9 (inter-quartile range 8.1–22.3) kPa and independently correlated positively with tricuspid regurgitation (TR) severity, inferior vena cava diameter and negatively with tricuspid annular plane systolic excursion. During a median follow-up of 31 months, 49 adverse events occurred. Multivariable Cox regression analysis revealed that LS was an independent predictor of adverse events. Significant improvement in LS at 1-year post-TA (13.1–7.8 kPa, P Conclusions This study demonstrated that LS is predictive of adverse outcome and is reversible in patients undergoing TA without TR recurrence at 1 year. These findings suggest that assessing LS, an integrative correlate of right heart condition, may aid the pre-operative risk assessment of candidate for heart surgery including TA.

Background Hepatic dysfunction was previously suggested to be related to poor outcome in patients undergoing tricuspid annuloplasty (TA), the predictive value of liver stiffness (LS) for adverse events is nonetheless uncertain. Purpose The aim of this study was to evaluate the prognostic value and reversibility of LS in patients undergoing TA. Methods A total of 158 patients (age 63, male 35%) who underwent TA during left-sided valve surgery were prospectively evaluated. Transient elastography was used to assess LS. Patients were divided into three groups according to tertiles of LS. Adverse outcome was defined as heart failure requiring hospital admission or mortality. Results The median LS was 13.9 (8.1–22.3) kPa which independently correlates with tricuspid regurgitation severity (assessed by effective regurgitant orifice area), inferior vena cava diameter and tricuspid annular plane systolic excursion. During a median follow-up of 31 months, 49 adverse events occurred. Multivariable Cox regression analysis demonstrated that LS was an independent predictor of adverse events. Furthermore, a higher LS tertile was predictive for adverse events (Hazard Ratio 4.19, P Conclusions The present study demonstrates that LS is predictive of adverse outcome in patients undergoing TA. These findings suggested that assessing LS, an integrative assessment of right heart condition, may aid the management of patients undergoing TA. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): The Health and Medical Research Fund from the Food and Health Bureau, the Government of Hong Kong Special Administrative Region.

Background We investigated the relationship of Epstein-Barr virus viral capsid antigen (EBV VCA-IgA) serostatus with ambient and personal ultraviolet radiation (UVR) and vitamin D exposure. Methods Using data from a multicenter case-control study, we included 1026 controls subjects in 2014–2017 in Hong Kong, China. Odds ratios (ORs) and 95% confidence intervals (CIs) of the association between UVR exposure and EBV VCA-IgA (seropositivity vs seronegativity) were calculated using unconditional logistic regression models adjusted for potential confounders. Results We observed a large increase in seropositivity of EBV VCA-IgA in association with duration of sunlight exposures at both 10 years before recruitment and age 19–30 years (adjusted OR = 3.59, 95% CI = 1.46–8.77; and adjusted OR = 2.44, 95% CI = 1.04–5.73 for ≥8 vs Conclusions Our results suggest that personal UVR exposure may be associated with higher risk of EBV reactivation, but we did not find clear evidence of vitamin D exposure (observational or genetic), a molecular mediator of UVR exposure. Further prospective studies in other populations are needed to confirm this finding and to explore the underlying biological mechanisms. Information on photosensitizing agents, and serological markers of EBV, and biomarkers related to systemic immunity and inflammation should be collected and are also highly relevant in future studies.

Patients with axial spondyloarthritis (SpA) are subjected to elevated cardiovascular risks, but assessment of early myocardial damage and clinical risk stratification remained obscure. The aim of this study was to evaluate the prognostic value of speckle-tracking strain analysis and serum high-sensitivity troponin I (hsTnI) in patients with axial SpA.Two-dimensional speckle-tracking echocardiography was performed to derive longitudinal strain (LS), circumferential strain (CS), and radial strain (RS). Serum hsTnI was measured by validated immunoassay (Architect i1000SR Abbott) as indicator of subclinical myocardial damage.The mean Bath Ankylosing Spondylitis Disease Activity Index and median modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) were 3.8 and 15.5, respectively. Over a median follow-up of 81 months, major adverse cardiovascular events (MACE) occurred in 13% of subjects (n = 116). Univariate Cox regression showed that age, disease duration, Bath Ankylosing Spondylitis Functional Index, modified Schober test, mSASSS, hsTnI, interventricular septal thickness, E/E', LS, RS, and carotid intima-media thickness were significant predictors of MACE (all P 0.05). After adjustment for age, sex, and statistically significant disease-related parameters, only subclinically raised hsTnI and impaired LS remained independent predictors for MACE. Kaplan-Meier analysis showed that combined impaired LS ≥ - 17.5% and hsTnI ≥ 3.0 pg/ml significantly predicted MACE (log-rank test P 0.01; sensitivity 50%; specificity 90%; positive predictive value 43%; negative predictive value 92%).Depressed LS indicating subclinical left ventricular systolic dysfunction and elevated serum hsTnI both independently predicted MACE among young patients with axial SpA. Combined analysis of speckle-tracking-derived strain analysis and serum hsTnI improves risk stratification in these patients. Key Points • Both depressed longitudinal strain (LS) and elevated serum high-sensitivity troponin I (hsTnI) are promising independent predictors for cardiovascular (CV) events in axial SpA. • Importantly, patients with LS ≥ - 17.5% and hsTnI ≥ 3.0 pg/ml had the highest risk of incident MACE. • Axial SpA patients with concomitant impaired LS and raised hsTnI are at a high risk of CV events.

Background Rheumatoid arthritis is associated with both abnormal bone metabolism and atherogenesis but mechanistic links were missing. Aim This study aimed to investigate the role of osteocalcin (OCN)-expressing circulating endothelial progenitor cells (EPC)s in the severity and dissemination of systemic arterial calcifications in rheumatoid arthritis. Methods We performed flow cytometry studies in 145 consecutive patients with rheumatoid arthritis to determine osteogenic circulating levels of OCN-positive (OCN+) CD34+KDR+ and OCN+CD34+, versus conventional early EPC CD34+CD133+KDR+. Total calcium load of the thoracic aorta (ascending plus descending) and the carotid arteries were assessed by non-contrast computed tomography (CT) and contrast CT angiography. Results Osteogenic EPCs OCN+CD34+KDR+ (P=0.002) and OCN+CD34+ were strikingly associated with the clustered presence of aortic and carotid calcification (P=0.002 and 0.001 respectively, Figure). Multivariable analyses revealed that circulating OCN+CD34+KDR+ (B=14.4 [95% CI 4.0 to 24.8], P=0.007) and OCN+CD34+ (B=9.6 [95% CI 4.9 to 14.3], P Conclusions Circulating level of osteogenic EPC is associated with promulgated aortic and carotid calcification in patients with rheumatoid arthritis, suggesting a potential mechanistic role of the bone-vascular axis in pro-atherogenicity of rheumatic diseases. Acknowledgement/Funding General Research Fund, Hong Kong Research Grants Council

Background Rheumatic diseases are related to both abnormal bone turnover and atherogenesis, but a mechanistic link was missing. Methods and Results We investigated the effect of cumulative rheumatic inflammation ( CRI ) on risk of coronary calcification in a retrospective cohort of 145 rheumatoid arthritis patients. A time‐adjusted aggregate CRI score was derived by conglomerating all quarterly biomarker encounters of serum C‐reactive protein over 60 months immediately preceding computed tomography coronary angiography. Flow cytometry was performed to measure the osteocalcin‐positive ( OCN + ) CD 34 + KDR + and OCN + CD 34 + circulating endothelial progenitor cells ( EPCs ). Conventional early circulating EPCs CD 34 + CD 133 + KDR + was determined. Coronary calcification was defined as any Agatston score >0. 50% of patients (n=72/145) had coronary calcification. CRI score was associated with presence of coronary calcification ( P =0.004) (multivariable‐adjusted: highest versus lowest quartile: odds ratio=5.6 [95% CI 1.1–28.9], P =0.041). Receiver operating characteristics curve revealed divergent behavior of OCN ‐expressing circulating EPCs ( OCN + CD 34 + EPCs : area under the curve=0.60, P =0.034; OCN + CD 34 + KDR + EPCs : area under the curve=0.59, P =0.053, positive predictors) versus conventional early EPCs ( CD 34 + CD 133 + KDR + : area under the curve=0.60, P =0.034, negative predictor) for coronary calcification, which persisted after multivariable adjustments ( OCN + CD 34 + KDR + [>75th percentile]: odds ratio=7.2 [95% CI 1.8–27.9], P =0.005; OCN + CD 34 + EPCs [>75th percentile]: odds ratio=6.0 [95% CI 1.5–23.3], P =0.010; CD 34 + CD 133 + KDR + [>75th percentile: odds ratio=0.3 [95% CI 0.1–1.0], P =0.053). Intriguingly, the CRI score was associated with increased OCN + CD 34 + EPCs (highest versus lowest quartile: B=+25.6 [95% CI 0.8–50.5] [×10 3 /mL peripheral blood], P =0.043), but reduced CD 34 + CD 133 + KDR + EPCs (highest versus lowest quartile: B=−16.2 [95% CI −31.5 to −0.9], P =0.038). Conclusions Preceding 60 months of CRI is associated with increased risk of coronary calcification and altered OCN expression in circulating EPCs .

BACKGROUND: Osteogenic circulating endothelial progenitor cells (EPC) play a pathogenic role in cardiovascular system degeneration through promulgating vasculature calcification, but its role in conduction disorders as part of the cardiovascular degenerative continuum remained unknown. AIM: To investigate the role of osteocalcin (OCN)‐expressing circulating EPCs in cardiac conduction disorders in the unique clinical sample of rheumatoid arthritis (RA) susceptible to both abnormal bone metabolism and cardiac conduction disorders. METHODS: We performed flow cytometry studies in 134 consecutive asymptomatic patients with rheumatoid arthritis to derive osteogenic circulating OCN‐positive (OCN+) CD34+KDR+ vs. CD34+CD133+KDR+ conventional EPC. Study endpoint was the prespecified combined endpoint of electrocardiographic conduction abnormalities. RESULTS: Total prevalence of cardiac conduction abnormality was 9% (n = 12). All patients except one had normal sinus rhythm. One patient had atrial fibrillation. No patient had advanced atrioventricular (AV) block. Prevalence of first‐degree heart block (>200 ms), widened QRS duration (>120 ms) and right bundle branch block were 6.7%, 2.1%, and 2.2% respectively. Circulating osteogenic OCN(+)CD34(+)KDR(+) EPCs were significantly higher among patients with cardiac conduction abnormalities (p = 0.039). Elevated OCN(+)CD34(+)KDR(+) EPCs> 75th percentile was associated with higher prevalence of cardiac conduction abnormalities (58.3% vs. 20.02%, p = 0.003). Adjusted for potential confounders, elevated OCN(+)CD34(+)KDR(+ )EPCs> 75th percentile remained independently associated with increased risk of cardiac conduction abnormalities (OR = 4.4 [95%CI 1.2–16.4], p = 0.028). No significant relation was found between conventional EPCs CD34+CD133+KDR+ and conduction abnormalities (p = 0.36). CONCLUSIONS: Elevated osteogenic OCN(+)CD34(+)KDR(+ )EPCs are independently associated with the presence of electrocardiographic conduction abnormalities in patients with rheumatoid arthritis, unveiling a potential novel pathophysiological mechanism.

BACKGROUND Some studies have hypothesized that vitamin D may have a role to play in protection against influenza virus infections and illnesses, and that seasonal fluctuation in serum 25-hydroxyvitamin D [25(OH)D] may affect seasonal patterns of influenza virus infections. OBJECTIVE We aimed to investigate whether serum 25(OH)D concentrations were associated with the incidence of influenza virus infections and illnesses in children and adults in Hong Kong. METHODS In 2009-2010, 3030 children and adults of all ages from 796 households in Hong Kong were followed up to identify acute respiratory illnesses. Sera from 2694 participants were collected at baseline and after ∼1 mo, 6 mo, and 12 mo. Influenza virus infections were confirmed by reverse transcriptase-polymerase chain reaction performed on nasal and throat swab samples collected during illness episodes. Serologic evidence of influenza virus infection was measured by hemagglutination inhibition assays in unvaccinated participants. The serum 25(OH)D concentrations were measured after collection of all specimens. Each individual's baseline serum 25(OH)D concentration on 1 January 2010 was predicted by a random-effects linear regression model. RESULTS We found that, in children and adults who had not received a seasonal influenza vaccine, baseline serum 25(OH)D concentrations (

Nasopharyngeal carcinoma (NPC) is uncommon with a unique geographical distribution. The age-standardized incidence ranges from below 1 in nonendemic areas to 25+/100,000 person-years in endemic regions, and has decreased without specific primary prevention in the past four decades. We have found that smoking is likely a causal factor, family history of NPC a strong risk factor, while vitamin D and milk consumption, and better socioeconomic status, could be protective. The interaction between genetic factors, Epstein–Barr virus (EBV) infection, and environmental and lifestyle risk factors (classical and novel) warrants further investigation using more vigorous methods. Screening by EBV serological markers and circulating EBV DNA in asymptomatic Chinese men has identified NPC cases at earlier stages and with better survival than a historical cohort in Southern China. Further trials and assessment are needed. International or multicenter collaborations on individual data meta-analysis of case-control and cohort studies are warranted.

Background Whether PR prolongation independently predicts new-onset ischemic events of myocardial infarction and stroke was unclear. Underlying pathophysiological mechanisms of PR prolongation leading to adverse cardiovascular events were poorly understood. We investigated the role of PR prolongation in pathophysiologically-related adverse cardiovascular events and underlying mechanisms. Methods We prospectively investigated 597 high-risk cardiovascular outpatients (mean age 66 ± 11 yrs.; male 67%; coronary disease 55%, stroke 22%, diabetes 52%) for new-onset ischemic stroke, myocardial infarction (MI), congestive heart failure (CHF), and cardiovascular death. Vascular phenotype was determined by carotid intima-media thickness (IMT). Results PR prolongation >200 ms was present in 79 patients (13%) at baseline. PR prolongation >200 ms was associated with significantly higher mean carotid IMT (1.05 ± 0.37 mm vs 0.94 ± 0.28 mm, P = 0.010). After mean study period of 63 ± 11 months, increased PR interval significantly predicted new-onset ischemic stroke (P = 0.006), CHF (P = 0.040), cardiovascular death (P 200 ms. Using multivariable Cox regression, PR prolongation >200 ms independently predicted new-onset ischemic stroke (HR 8.6, 95% CI: 1.9–37.8, P = 0.005), cardiovascular death (HR 14.1, 95% CI: 3.8–51.4, P 162 ms (C-statistic 0.70, P = 0.001; HR: 8.0, 95% CI: 1.65–38.85, P = 0.010). Conclusions PR prolongation strongly predicts new-onset ischemic stroke, MI, cardiovascular death, and combined cardiovascular endpoint including CHF in coronary patients or risk equivalent. Adverse vascular function may implicate an intermediate pathophysiological phenotype or mediating mechanism. Electronic supplementary material The online version of this article (doi:10.1186/s12872-017-0667-2) contains supplementary material, which is available to authorized users.

Low vitamin D level is associated with atrial fibrillation (AF) and may be implicated in its pathogenesis.We studied single nucleotide polymorphisms (SNPs) of vitamin D mechanistic pathways and serum 25-hydroxyvitamin D [25(OH)D] levels in an age- and gender-matched case-control study (controls without AF: mean age 68.6 ± 8.7 years, female 25%; n = 1019; with AF: mean age 69.7 ± 9.5 years, female 30%; n = 156) recruited from a Chinese clinical cohort of patients with stable coronary artery disease. Twelve SNPs involved in the vitamin D mechanistic pathways were studied [biosynthetic: rs4646536, rs10877012, rs3829251, rs1790349; activation: rs2060793, rs1993116; vitamin D-binding protein (VBP)/group-specific component (GC): rs4588, rs7041, rs2282679, rs1155563; and vitamin D receptor: rs1544410, rs10735810]. A genetic risk score (GRS) (0-8) was constructed from SNPs associated with serum 25(OH)D as a proxy to lifelong vitamin D-deficient state. All 4 SNPs involved in the VBP/GC were significantly associated with serum 25(OH)D (rs4588, P 0.001; rs2282679, P 0.001; rs7041, P = 0.011; rs1155563, P 0.001; all other SNPs, P 0.05). Vitamin D GRS (points 0-8) generated from these 4 SNPs was independently predictive of serum 25(OH)D [B = 0.54, 95% confidence interval (CI) 0.30-0.79; P 0.001]. Genetically deprived vitamin D status as denoted by a low GRS (0-3) independently predicted an increased risk of AF, compared to a high GRS (4-8) (odds ratio = 1.848, 95% CI 1.217-2.805; P = 0.004).Genetically deprived vitamin D exposure predisposes to increased AF among patients with coronary artery disease. Whether VBP/GC may alter the risk of AF via alternative mechanisms warrants further studies.

To investigate whether the CHADS2 and CHA2DS2-VASc scores have clinical utility for prediction of adverse vascular function and vascular dysfunction-mediated incident cardiovascular (CV) events among high-risk patients without atrial fibrillation (AF), and the additional value of incorporating PR prolongation to the scores.We analyzed 579 high-risk CV outpatients without clinical AF in a prospective cohort for new-onset ischemic stroke, myocardial infarction (MI), congestive heart failure (CHF), and CV death. Brachial flow-mediated dilation (FMD) and nitroglycerin-mediated dilatation (NMD), carotid intima-media thickness (IMT) and pulse wave velocity (PWV) were determined.Baseline CHADS2 score was associated with lower FMD (Pearson r = -0.16, P0.001) and NMD (r = -0.17, P0.001), higher carotid IMT (r = 0.30, P0.001) and PWV (r = 0.35, P0.001; similar for CHA2DS2-VASc score: All P0.05). After follow-up of 63 ± 11 months, 82 patients (14.2%) developed combined CV endpoint. ROC curve analysis showed that both CHADS2 and CHA2DS2-VASc scores were predictors for ischemic stroke (C-Statistic: CHADS2 0.70, P = 0.004; CHA2DS2-VASc 0.68, P = 0.010), MI (CHADS2 0.63, P = 0.030; CHA2DS2-VASc 0.70, P = 0.001), and CV death (CHADS2 0.63, P = 0.022; CHA2DS2-VASc 0.65, P = 0.011). Higher CHADS2 score was associated with reduced event-free survival from combined CV endpoints (log-rank = 16.7, P0.001) with differences potentiated if stratified by CHA2DS2-VASc score (log-rank = 29.2, P0.001). Incorporating PR prolongation, the CHA2DS2-VASc-PR score achieved the highest C-Statistic for CV death prediction (0.70, P0.001) superior to the CHADS2 score (chi-square: 12.1, P = 0.0005).The CHADS2 and CHA2DS2-VASc predict vascular dysfunction and cardiovascular events in high-risk CV patients without clinical AF, with further improved performance incorporating PR prolongation.

Background: Patients with myocardial infarction (MI) are at risk of the development of atrial fibrillation (AF) and ischemic stroke. We sought to evaluate the prognostic performance of the CHADS 2 and CHA 2 DS 2 -VASc scores in predicting new AF and/or ischemic stroke in post-ST segment elevation MI (STEMI) patients. Six hundred and seven consecutive post-STEMI patients with no previously documented AF were studied. Methods and Results: After a follow-up of 63 months (3,184 patient-years), 83 (13.7%) patients developed new AF (2.8% per year). Patients with a high CHADS 2 and/or CHA 2 DS 2 -VASc score were more likely to develop new AF. The annual incidence of new AF was 1.18%, 2.10%, 4.52%, and 7.03% in patients with CHADS 2 of 0, 1, 2, and ≥ 3; and 0.39%, 1.72%, 1.83%, and 5.83% in patients with a CHA 2 DS 2 -VASc score of 1, 2, 3 and ≥ 4. The CHA 2 DS 2 -VASc score (C-statistic = 0.676) was superior to the CHADS 2 (C-statistic = 0.632) for discriminating new AF. Ischemic stroke occurred in 29 patients (0.9% per year), the incidence increasing in line with the CHADS 2 (0.41%, 1.02%, 1.11%, and 1.95% with score of 0, 1, 2, and ≥ 3) and CHA 2 DS 2 -VASc scores (0.39%, 0.49%, 1.02%, and 1.48% with score of 1, 2, 3 and ≥ 4). The C-statistic of the CHA 2 DS 2 -VASc score as a predictor of ischemic stroke was 0.601, superior to that of CHADS 2 score (0.573). CHADS 2 and CHA 2 DS 2 -VASc scores can identify post-STEMI patients at high risk of AF and stroke. Conclusions: The CHADS 2 and CHA 2 DS 2 -VASc scores can identify post-STEMI patients at high risk of AF and ischemic stroke. This enables close surveillance and prompt anticoagulation for stroke prevention.

The Mediterranean-style diet is widely advocated for the prevention of cardiovascular diseases (CVD). Meanwhile, blood pressure variability (BPV) is a novel risk factor for CVD. It is unknown whether dietary pattern plays a role in modulating BPV.We prospectively followed-up 274 consecutive patients with stable coronary artery disease (CAD). The Mediterranean diet score (MDS) was derived for all individuals upon recruitment, blood pressure (BP) was measured during each subsequent clinic visit and the visit-to-visit BPV was calculated. The occurrence of major adverse cardiovascular events (MACEs) and all-cause mortality was monitored.After a mean follow-up of 77±12 months, 16.1% of the study population developed MACEs. About 11.3% died from all causes. Patients who developed MACEs or all-cause mortality had a greater systolic BPV compared to those who did not develop an adverse event. Patients who developed a MACE had a lower MDS and further analysis revealed those who developed a stroke had a lower MDS compared with those who did not develop a stroke, but there were no significant differences in MDS between CAD patients with or without subsequent acute coronary syndrome, cardiovascular, or all-cause mortality. After adjusting for confounding variables, a high MDS was an independent predictor for low systolic BPV (B -0.74, 95% confidence interval -1.27 to -0.21, P0.01) and was noted to be protective against subsequent development of stroke (hazards ratio 0.48, 95% confidence interval 0.24 to 0.94, P = 0.03).Among patients with CAD, a higher MDS is associated with a lower visit-to-visit BPV and with lower stroke risk.

Summary Objectives Despite identification of important risk factors, aetiology of nasopharyngeal cancer (NPC) remained enigmatic. Oncogenic Human Papillomavirus (HPV), a cause of cervical and genital tract epithelial cancers, has recently been isolated from NPC tumour tissues, raising the question of whether HPV may play a role in NPC. Accumulating evidence showed that perinatal HPV transmission to newborns can occur through exposures to genital tract secretions, amniotic fluid, or blood during vaginal delivery in mothers with cervical HPV infection, with viral DNA fingerprint showing maternal–foetal concordance. Persistence of perinatally acquired oncogenic HPV infection presents clear biological plausibility as an aetiological agent. Co-infection of HPV and EBV may also co-operatively impact on neoplastic transformation. Our findings also suggest that regional disease burdens of oncogenic HPV strains have strong type-specific associations with regional risk of NPC. If true, this hypothesis presents immense potentials for preventive interventions through community control of HPV infection and newborn vaccination.

Early identification of individuals who are at risk of developing atrial fibrillation (AF) and ischemic stroke may enable a closer surveillance and thus prompt initiation of oral anticoagulation for stroke prevention.This study sought to investigate whether congestive heart failure, hypertension, age ≥ 75 years, diabetes, previous stroke (CHADS2) and CHA2DS2-vascular disease, age 65-74 years, sex category (CHA2DS2-VASc) scores can predict new-onset AF and/or ischemic stroke in patients presenting with arrhythmic symptoms.We prospectively followed up 528 patients (68.5 ± 10.6 years, male 46.2 %) presented for assessment of arrhythmic symptoms but without any documented arrhythmia, including AF for development of new-onset AF and/or ischemic stroke. Their mean CHADS2 and CHA2DS2-VASc scores on presentation were 1.3 ± 1.3 and 2.3 ± 1.5, respectively. After 6.1 years, 89 patients (16.8 %, 2.77 per 100 patient-years) had documented AF, and 65 patients (12.3 %, 2.0 per 100 patient-years) suffered stroke. Both the CHADS2 (C statistic 0.63, 95 % confidence interval (CI) 0.58-0.67, P 0.0001, optimal cutoff at 1) and CHA2DS2-VASc (C statistic 0.63, 95 % CI 0.59-0.67, P 0.0001, optimal cutoff at 2) scores provided similar prediction for the new-onset AF. Similarly, CHADS2 (C statistic 0.69, 95 % CI 0.65-0.73, P 0.0001, optimal cutoff at 2) and CHA2DS2-VASc (C statistic 0.69, 95 % CI 0.65-0.73, P 0.0001, optimal cutoff at 2) have compatible efficacy for stroke prediction in this Chinese population.The CHADS2 and CHA2DS2-VASc scores can be used in patients who presented with arrhythmic symptoms to identify those who are at risk with developing new-onset clinical AF and ischemic stroke for close clinical surveillance and early intervention.

Table S1. Univariable and Multivariable Predictors for Carotid IMT. Table S2. Univariable and Multivariable Predictors for Cardiovascular Death. Table S3. Univariable and Multivariable Predictors for New-Onset Ischemic Stroke. Table S4. Univariable and Multivariable Predictors for New-Onset Myocardial Infarction. Table S5. Univariable and Multivariable Predictors for Combined Cardiovascular Endpoints of New-Onset Myocardial Infarction, Ischemic Stroke, Congestive Heart Failure and Cardiovascular Death. Table S6. Estimates of Sensitivity (Se), Specificity (Sp), Positive Predictive Value (PPV) and Negative Predictive Value (NPV) of PR Interval in the Prediction for Cardiovascular Events. (DOC 444 kb)