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We evaluated the evolution of thyroid function and autoimmunity among COVID-19 survivors over 6 months in relation to interferon beta-1b treatment and long COVID.We included COVID-19 survivors managed in a major COVID-19 centre between July 2020 and May 2021 who were reassessed three and/or six months after acute COVID-19. Thyroid function tests (TFTs) and anti-thyroid antibody titres were measured at acute COVID-19, 3-month and 6-month.250 COVID-19 survivors were included (mean age 52.7 years, 50.4% men). Persistent thyroid function abnormalities were more likely in those with abnormal TFTs in acute COVID-19 (P 0.001). Among 51 patients with abnormal TFTs in acute COVID-19, 82.4% resolved upon follow-up. Of 199 patients with normal TFTs in acute COVID-19, only 4.5% had incident abnormal TFTs, more likely in interferon-treated patients (P = 0.044) and none clinically overt. Among 129 patients with complete 6-month follow-up for anti-thyroid antibody titres, there was no significant change overall, except for modest increase in anti-thyroid antibody titres among the 84 interferon-treated patients (P 0.05 at both 3 months and 6 months). Long COVID occurred in 19.5% and 10.4% at 3 and 6 months respectively, where TFTs and anti-thyroid antibody titres were not predictive of its occurrence.Over 6 months, most abnormal TFTs in acute COVID-19 resolved, with no significant incident thyroid dysfunction. SARS-CoV-2 infection did not lead to change in thyroid autoimmunity, while interferon treatment was associated with modest increase in anti-thyroid antibody titres. Thyroid function and anti-thyroid antibodies did not play a significant role in long COVID.

OBJECTIVE Patients with type 2 diabetes are at higher risk for fracture risk because of attenuated bone turnover and impaired bone microarchitecture. The comparative effect of warfarin over non–vitamin K antagonist oral anticoagulants (NOACs) on incident fractures among patients with type 2 diabetes comorbid with atrial fibrillation (AF) remains to be elucidated. RESEARCH DESIGN AND METHODS This was a retrospective, propensity score–weighted, population-based cohort study of adults with type 2 diabetes and AF who were started on warfarin or NOAC between 2005 and 2019 identified from an electronic database of the Hong Kong Hospital Authority. The primary outcome was a composite of major osteoporotic fractures (hip, clinical vertebral, proximal humerus, and wrist). Hazard ratios (HRs) were calculated using Cox proportional hazards regression models. RESULTS A total of 15,770 patients with type 2 diabetes comorbid with AF were included (9,288 on NOAC, 6,482 on warfarin). During a median follow-up of 20 months, 551 patients (3.5%) sustained major osteoporotic fractures (201 [2.2%] in the NOAC group, 350 [5.4%] in the warfarin group). The adjusted cumulative incidence was lower among NOAC users than warfarin users (HR 0.80; 95% CI 0.64, 0.99; P = 0.044). Subgroup analyses showed consistent protective effects against major osteoporotic fractures among NOAC users across sex, age, HbA1c, duration of diabetes, and history of severe hypoglycemia compared with warfarin users. CONCLUSIONS NOAC use was associated with a lower risk of major osteoporotic fractures than warfarin use among patients with type 2 diabetes comorbid with AF. NOAC may be the preferred anticoagulant from the perspective of bone health.

Context Metabolic associated fatty liver disease (MAFLD) is the hepatic manifestation of obesity-related metabolic syndrome (MetS). Noninvasive biomarkers for monitoring the progression and severity of these metabolic comorbidities are needed. Objectives To investigate the associations of serum thrombospondin-2 (TSP2) with MetS and MAFLD severity, and the potential diagnostic value of serum TSP2 for identifying at-risk metabolic associated steatohepatitis (MASH). Methods Blood samples, clinical data, and liver biopsies were collected from consecutively recruited 252 individuals with morbid obesity receiving bariatric surgery. Histopathology samples of liver biopsies were examined in a blinded fashion by 3 independent pathologists. Serum TSP2 levels were measured by enzyme-linked immunosorbent assay. Results Serum TSP2 levels were significantly elevated in MetS (1.58 [1.07-2.20] ng/mL) compared with non-MetS (1.28 [0.84-1.73] ng/mL; P = .006) in obese patients and positively correlated with increasing number of the MetS components, fasting glucose, glycated hemoglobin, fasting insulin, C-peptide, and homeostatic model assessment of insulin resistance after adjustment of conventional confounders. Serum TSP2 levels differentiated MASH (1.74 [1.32-3.09] ng/mL) from the other non-MASH less severe groups: normal liver (1.41 [1.04-1.63] ng/mL), simple steatosis (1.45 [0.89-1.92] ng/mL), and borderline MASH (1.30 [0.99-2.17] ng/mL) (P Conclusion Serum TSP2 is closely associated with severity and progression of MetS and MAFLD, and is a promising noninvasive biomarker for differentiating MASH from benign steatosis and identifying at-risk MASH patients among individuals with obesity.

Background Thrombospondin-2 (TSP2) is a matricellular protein with tissue expression induced by hyperglycaemia. TSP2 has been implicated in non-diabetic renal injury in preclinical studies and high circulating levels were associated with worse kidney function in cross-sectional clinical studies. Therefore, we investigated the prospective associations of circulating TSP2 level with kidney function decline and the trajectories of estimated glomerular filtration rate (eGFR) in type 2 diabetes. Methods Baseline serum TSP2 level was measured in 5471 patients with type 2 diabetes to evaluate its association with incident eGFR decline, defined as ≥40% sustained eGFR decline, using multivariable Cox regression analysis. Among participants with relatively preserved kidney function (baseline eGFR ≥60 mL/min/1.73 m2), joint latent class modelling was employed to identify three different eGFR trajectories. Their associations with baseline serum TSP2 were evaluated using multinomial logistic regression analysis. The predictive performance of serum TSP2 level was examined using time-dependent c-statistics and calibration statistics. Results Over a median follow-up of 8.8 years, 1083 patients (19.8%) developed eGFR decline. Baseline serum TSP2 level was independently associated with incident eGFR decline [hazard ratio (HR) 1.21, 95% confidence interval (CI) 1.07–1.37, P = .002]. With internal validation, incorporating serum TSP2 to a model of clinical risk factors including albuminuria led to significant improvement in c-statistics from 83.9 to 84.4 (P Conclusion Serum TSP2 level was independently associated with incident eGFR decline, particularly a rapidly declining trajectory, in type 2 diabetes.

ContextAdipocyte fatty acid-binding protein (AFABP), fibroblast growth factor 21 (FGF21), and pigment epithelium–derived factor (PEDF) are 3 diabetes-related biomarkers whose circulating levels had been shown to associate with nephropathy progression in Chinese patients with type 2 diabetes.ObjectiveHere, we evaluated and compared their prospective associations with the development of sight-threatening DR (STDR), another important diabetic microvascular complication.MethodsBaseline serum AFABP, PEDF, and FGF21 levels were measured in 4760 Chinese individuals with type 2 diabetes and without STDR at baseline. The associations of these biomarkers with incident STDR were analyzed using Cox regression analysis.ResultsAmong these 4760 participants (mean diabetes duration of 11 years and ≥ 50% with nonproliferative DR at baseline), 172 participants developed STDR over a median follow-up of 8.8 years. Participants with incident STDR had comparable baseline serum FGF21 levels but significantly higher baseline serum AFABP and PEDF levels (both P < .001) than those without. However, in multivariable Cox regression analysis, only serum AFABP remained independently associated with incident STDR (hazard ratio 1.28; 95% CI, 1.05-1.55; P = .013). The addition of serum AFABP to a clinical model of conventional STDR risk factors including diabetes duration, glycemic control, albuminuria, and baseline DR status significantly improved the c statistics (P < .001), net reclassification index (P = .0027), and integrated discrimination index (P = .033) in predicting incident STDR among participants without DR or with mild DR at baseline.ConclusionAmong the 3 diabetes-related biomarkers, serum AFABP level appeared to be a more clinically useful biomarker for predicting incident STDR in type 2 diabetes.

Objective: Patients with type 2 diabetes are at higher fracture risk owing to the attenuated bone turnover and impaired bone microarchitecture. The comparative effect of warfarin over non-vitamin K antagonist oral anticoagulants (NOACs) on incident fractures among patients with type 2 diabetes comorbid with atrial fibrillation (AF) remains to be elucidated. Research Design and Methods: This was a retrospective propensity-score weighted population-based cohort study of adults with type 2 diabetes and AF who were started on warfarin or NOAC between 2005 and 2019, identified from the electronic database of the Hong Kong Hospital Authority. The primary outcome was a composite of major osteoporotic fractures (hip, clinical vertebral, proximal humerus and wrist). Hazard ratios (HR) were calculated using Cox proportional hazard regression models. Results: 15,770 type 2 diabetes patients comorbid with AF were included (9,288 on NOAC and 6,482 on warfarin). During a median follow-up of 20 months, 551 patients (3.5%) sustained major osteoporotic fractures (201 in NOAC group [2.2%]; 350 in warfarin group [5.4%]). The adjusted cumulative incidence was lower among NOAC users than warfarin users (HR 0.80, 95% CI 0.64-0.99, p=0.044). Subgroup analyses showed consistent protective effects against major osteoporotic fractures among NOAC users across sex, age, HbA1c, duration of diabetes and history of severe hypoglycemia, compared with warfarin users. Conclusions: NOAC use was associated with a lower risk of major osteoporotic fractures than warfarin use, among type 2 diabetes patients comorbid with AF. NOAC may be the preferred anticoagulant from the perspective of bone health.

Context There are concerns for COVID-19 vaccination in triggering thyroid autoimmunity and causing thyroid dysfunction. Also, data on the effect of preexisting thyroid autoimmunity on the efficacy of COVID-19 vaccination are limited. Objectives We evaluated the effect of COVID-19 vaccination on thyroid function and antibodies, and the influence of preexisting thyroid autoimmunity on neutralizing antibody (NAb) responses. Methods Adults without a history of COVID-19/thyroid disorders who received the COVID-19 vaccination during June to August 2021 were recruited. All received 2 doses of vaccines. Thyrotropin (TSH), free thyroxine (fT4), free 3,5,3′-triiodothyronine (fT3), antithyroid peroxidase (anti-TPO), and antithyroglobulin (anti-Tg) antibodies were measured at baseline and 8 weeks post vaccination. NAb against SARS-CoV-2 receptor-binding domain was measured. Results A total of 215 individuals were included (129 [60%] BNT162b2; 86 [40%] CoronaVac recipients): mean age 49.6 years, 37.2% men, and 12.1% anti-TPO/Tg positive at baseline. After vaccination, TSH did not change (P = .225), but fT4 slightly increased (from 12.0 ± 1.1 to 12.2 ± 1.2 pmol/L [from 0.93 ± 0.09 to 0.95 ± 0.09 ng/dL], P Conclusion COVID-19 vaccination was associated with a modest increase in antithyroid antibody titers. Anti-TPO increase was greater among BNT162b2 recipients. However, there was no clinically significant thyroid dysfunction post vaccination. NAb responses were not influenced by preexisting thyroid autoimmunity. Our results provide important reassurance for people to receive the COVID-19 vaccination.

Findings on trabecular bone score (TBS), an index of bone quality, have been reported in prediabetes defined by impaired fasting glucose or HbA1c. Here, we assessed the bone mineral density (BMD) and TBS in prediabetes individuals with impaired glucose tolerance (IGT), and investigated the association of these bone parameters with serum levels of fibroblast growth factor 21 (FGF21), a hormone implicated in bone metabolism and with higher levels in IGT. Chinese postmenopausal women aged 55–80 years, without diabetes, were recruited from the Hong Kong Cardiovascular Risk Factor Prevalence Study in 2016–2018. Normal glucose tolerance (NGT) was defined by fasting glucose

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

Aims We carried out this prospective study of predominantly non-severe COVID-19 patients, to evaluate the influence of glycaemic status on clinical outcomes and neutralising antibody (Nab) responses, potentially relevant to the COVID-19 vaccination programme. Methods We included consecutive adults admitted to Queen Mary Hospital for COVID-19 from July 2020–May 2021. Glycaemic status was defined by admission HbA1c. Clinical deterioration was defined by radiological progression/new oxygen requirement/intensive care requirement/death. COVID-19 survivors had Nab measurements at 1-month, 2-month, 3-month and 6-month post-discharge. Results Among 605 patients (96.9% non-severe COVID-19; 325 normoglycaemia, 185 prediabetes, 95 diabetes), 74(12.2%) had clinical deterioration, more likely with worse glycaemic status and higher HbA1c (p

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.

It is unknown how concomitant hepatic steatosis affects disease progression in chronic hepatitis B (CHB). Adipokines such as fibroblast growth factor 21 (FGF21) and adipocyte fatty acid-binding protein (AFABP) have been associated with non-alcoholic fatty liver disease. We determined the significance of these metabolic markers in CHB-related liver injury.We recruited CHB patients on antiviral treatment for transient elastography assessment to determine liver stiffness (advanced fibrosis/cirrhosis, F3/F4, defined by EASL-ALEH criteria) and controlled attenuation parameter (hepatic steatosis, defined as ≥ 248 dB/m). Plasma FGF-21, AFABP and adiponectin levels were measured.A total of 415 patients [mean age 59.6 years, 71.6% male, median treatment duration 6.2 years] were recruited. Patients with F3/F4 (N = 151) had lower FGF-21 (11.7 vs 13.6 pg/mL, P = 0.055), higher AFABP (126.8 vs 84.1 pg/mL, P 0.001) and HOMA-IR (7.1 vs 5.1, P = 0.004) levels compared to those without F3/F4 (N = 264). Multivariate analysis showed that FGF-21 level was associated with hepatic steatosis (OR 1.005, 95% CI 1.001-1.009) and F3/F4 (OR 0.993, 95% CI 0.989-0.998), while AFABP level (OR 1.001, 95% CI 1-1.002), body mass index (BMI) (OR 1.107, 95% CI 1.037-1.182) and presence of diabetes mellitus (OR 2.059, 95% CI 1.206-3.516) were associated with F3/F4. With the combined presence of BMI ≥ 25 kg/mLow FGF-21 and high AFABP levels were associated with advanced fibrosis/cirrhosis in CHB patients on antiviral treatment. Plasma AFABP, together with other metabolic risk factors, may aid identification of patients lacking fibrosis improvement during antiviral treatment.

Persistent, unresolved inflammation in adipose tissue is a major contributor to obesity-associated metabolic complications. However, the molecular links between lipid-overloaded adipocytes and inflammatory immune cells in obese adipose tissues remain elusive. Here we identified adipocyte-secreted microRNA-34a (miR-34a) as a key mediator through its paracrine actions on adipose-resident macrophages. The expression of miR-34a in adipose tissues was progressively increased with the development of dietary obesity. Adipose-selective or adipocyte-specific miR-34a-KO mice were resistant to obesity-induced glucose intolerance, insulin resistance, and systemic inflammation, and this was accompanied by a significant shift in polarization of adipose-resident macrophages from proinflammatory M1 to antiinflammatory M2 phenotype. Mechanistically, mature adipocyte-secreted exosomes transported miR-34a into macrophages, thereby suppressing M2 polarization by repressing the expression of Krüppel-like factor 4 (Klf4). The suppressive effects of miR-34a on M2 polarization and its stimulation of inflammatory responses were reversed by ectopic expression of Klf4 in both bone marrow-derived macrophages and adipose depots of obese mice. Furthermore, increased miR-34a expression in visceral fat of overweight/obese subjects correlated negatively with reduced Klf4 expression, but positively with the parameters of insulin resistance and metabolic inflammation. In summary, miR-34a was a key component of adipocyte-secreted exosomal vesicles that transmitted the signal of nutrient overload to the adipose-resident macrophages for exacerbation of obesity-induced systemic inflammation and metabolic dysregulation.

OBJECTIVE Preclinical studies have suggested that thrombospondin-2 (TSP2) is implicated in liver fibrosis. However, the clinical relevance of TSP2 in nonalcoholic fatty liver disease (NAFLD) remains undefined. Here, we investigated the cross-sectional and longitudinal associations of circulating TSP2 levels with advanced fibrosis (F3 or greater [≥FE] fibrosis) in NAFLD. RESEARCH DESIGN AND METHODS Serum TSP2 levels were measured in 820 patients with type 2 diabetes and NAFLD. All participants received vibration-controlled transient elastography (VCTE) at baseline to evaluate their hepatic steatosis and fibrosis using controlled attenuation parameter (CAP) and liver stiffness (LS) measurements, respectively. Among those without advanced fibrosis at baseline, reassessment VCTE was performed to determine whether ≥F3 fibrosis had developed over time. Multivariable logistic regression analysis was used to evaluate the cross-sectional and longitudinal associations of serum TSP2 level with ≥F3 fibrosis. RESULTS Baseline serum TSP2 level was independently associated with the presence of ≥F3 fibrosis (odds ratio [OR] 5.13, P < 0.001). The inclusion of serum TSP2 level significantly improved the identification of ≥F3 fibrosis by clinical risk factors. Over a median follow-up of 1.5 years, 8.8% developed ≥F3 fibrosis. Baseline serum TSP2 level was significantly associated with incident ≥F3 fibrosis (OR 2.82, P = 0.005), independent of other significant clinical risk factors of fibrosis progression, including BMI, platelet count, and CAP at baseline. CONCLUSIONS Circulating TSP2 level was associated with both the presence and the development of advanced fibrosis and might be a potentially useful prognostic biomarker for the development and progression of liver fibrosis in patients with type 2 diabetes and NAFLD.

In Chinese, ethnicity-based and/or diabetes specific modifications of the Modification of Diet in Renal Disease (MDRD) and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations have been developed for determining estimated glomerular filtrate rate (eGFR). This study aimed to compare the performance of five different creatinine-based eGFR equations in predicting all-cause mortality among Chinese subjects with type 2 diabetes (T2DM).A total of 6739 Chinese subjects with T2DM were included. Their eGFR was calculated using the MDRD, CKD-EPI, their respective modified equations for Chinese, and the diabetes specific CKD-EPI Chinese T2DM equations. Multiple Cox regression analysis was used to evaluate the associations of eGFR with all-cause mortality. C-statistics, net reclassification index (NRI) and integrated discrimination index (IDI) were applied to assess the discrimination and reclassification of each eGFR equation in predicting mortality outcome.Over a follow-up of 5.7years, the incidence of all-cause mortality was 12.9% (N=867). The CKD-EPI equation discriminated all-cause mortality better than the MDRD equation (C-statistics: 0.714 vs. 0.689, p0.0001), and Chinese modification of their respective equations did not improve discrimination. Among the five eGFR equations evaluated, the CKD-EPI Chinese T2DM equation provided the best discrimination in predicting all-cause mortality among Chinese subjects with T2DM, and was the only equation providing a significantly positive NRI and IDI relative to the CKD-EPI equation.Among Chinese subjects with T2DM, our findings suggested that the CKD-EPI Chinese T2DM equation best predicted all-cause mortality, and relative to the CKD-EPI equation, conferred improved discrimination and reclassification.

Aims/Introduction To develop a new non‐invasive risk score for undiagnosed diabetes in Chinese people, and to evaluate the incident diabetes risk in those with high‐risk scores, but no diabetes on initial testing. Materials and Methods A total of 2,609 participants with no known diabetes (aged 25–74 years) who underwent oral glucose tolerance tests in Hong Kong (HK) were investigated for independent risk factors of diabetes to develop a categorization point scoring system, the Non‐invasive Diabetes Score (NDS). This NDS was validated in a cross‐sectional study of 2,746 participants in Shaanxi, China. HK participants tested to not have diabetes at baseline were assessed for subsequent incident diabetes rates. Results In the HK cohort, hypertension, age and body mass index were the key independent risk factors selected to develop the NDS, with ≥28 out of 50 NDS points considered as high risk. The area under the receiver operating characteristic curve for undiagnosed diabetes was 0.818 and 0.720 for the HK and Shaanxi cohort, respectively. The negative predictive value was 97.4% (HK) and 95.8% (Shaanxi); the number needed to screen to identify one case of diabetes was five (HK) and 11 (Shaanxi), respectively. Among those that tested non‐diabetes at baseline, individuals with NDS ≥28 had a threefold risk of incident diabetes during the subsequent 20.9 years, compared with those with NDS, We described the development, validation and longitudinal evaluation of a simple diabetes risk score with the fewest number of variables for undiagnosed diabetes in Chinese people. This risk score might help in opportunistic screening of diabetes, and inform subsequent testing interval for high‐risk individuals after initial testing.

Aims Few prospective studies have evaluated sex-specific pattern, natural progression of left ventricular (LV) remodelling, and diastolic dysfunction in patients with type 2 diabetes (T2DM). The aim of this study was to study the sex-specific prevalence, longitudinal changes of LV remodelling, and diastolic dysfunction in patients with T2DM. Further, the prognostic value of diastolic function in women and men was also evaluated. Methods and results A total of 350 patients with T2DM (mean age 61 ± 11 years; women, 48.3%) was recruited. Detailed echocardiography was performed at baseline and after 25 months. A major adverse cardiovascular event (MACE) was defined as cardiovascular death, heart failure hospitalization, or myocardial infarction. Despite a similar age, prevalence of hypertension and body mass index, women had a higher prevalence of LV hypertrophy and diastolic dysfunction at baseline and follow-up compared with men. A total of 21 patients developed MACE (5 cardiovascular death, 9 hospitalization for heart failure, and 7 myocardial infarction) during a median follow-up of 56 months. Women with diastolic dysfunction had a higher incidence of MACE than those with normal diastolic function but this association was neutral in men. Multivariable Cox-regression analysis indicated that diastolic dysfunction was associated with MACE in women [hazard ratio = 6.30; 95% confidence interval (CI) = 1.06–37.54; P < 0.05] but not men (hazard ratio = 2.29, 95% CI = 0.67–7.89; P = 0.19). Conclusion LV hypertrophy and diastolic dysfunction, both at baseline and follow-up, were more common in women than men. Pre-clinical diastolic dysfunction was independently associated with MACE only in women with T2DM but was neutral in men.

Circulating adiponectin (APN) levels decrease with age and obesity. On the other hand, a reduction in APN levels is associated with neurodegeneration and neuroinflammation. We previously showed that aged adiponectin knockout (APN-/-) mice developed Alzheimer's like pathologies, cerebral insulin resistance, and cognitive impairments. More recently, we also demonstrated that APN deficiency increased Aβ-induced microglia activation and neuroinflammatory responses in 5xFAD mice. There is compelling evidence that deregulated insulin activities or cerebral insulin resistance contributes to neuroinflammation and Alzheimer's disease (AD) pathogenesis. Here, we demonstrated that APN levels were reduced in the brain of AD patients and 5xFAD mice. We crossbred 5xFAD mice with APN-/- mice to generate APN-deficient 5xFAD (5xFAD;APN-/-). APN deficiency in 5xFAD mice accelerated amyloid loading, increased cerebral amyloid angiopathy, and reduced insulin-signaling activities. Pharmacokinetics study demonstrated adipoRon (APN receptor agonist) was a blood-brain barrier penetrant. AdipoRon improved neuronal insulin-signaling activities and insulin sensitivity in vitro and in vivo. Chronic adipoRon treatment improved spatial memory functions and significantly rescued neuronal and synaptic loss in 5xFAD and 5xFAD;APN-/- mice. AdipoRon lowered plaque and Aβ levels in AD mice. AdipoRon also exerted anti-inflammatory effects by reducing microglial and astrocytes activation as well as suppressing cerebral cytokines levels. The microglial phagocytic activity toward Aβ was restored after adipoRon treatment. Our results indicated that adipoRon exerts multiple beneficial effects providing important therapeutic implications. We propose chronic adipoRon administration as a potential treatment for AD.

AIMS Few prospective studies have evaluated the natural progression of left ventricular (LV) remodelling in patients with Type 2 diabetes mellitus (T2DM). The aim of this study was to evaluate the impact of obesity on longitudinal cardiac structural and functional changes in patients with T2DM. METHODS AND RESULTS This study comprised of 274 patients with T2DM (mean age, 62.2 ± 11.4 years; male, 51.5%). Echocardiographic parameters including LV geometry, systolic, and diastolic functions were measured at baseline and follow-up. The median follow-up was 24 months (from 12 months to 48 months). The entire cohort showed a significant increase in LV wall thickness, LV mass (LVM), and prevalence of concentric hypertrophy (19.6-27.3%). Further, systolic function and diastolic function had deteriorated at follow-up assessment. Multivariable adjusted linear regression demonstrated that baseline body mass index (BMI) predicted longitudinal change to LVM (β = 0.29, P

Background Existing data on the risk of ischemic stroke in hyperthyroidism-related atrial fibrillation (AF) and the impact of long-term anticoagulation in these patients, particularly those with self-limiting AF, remain inconclusive. Hypothesis Risk of stroke in hyperthyroidism-related AF is the same as nonhyperthyroid counterparts. Methods This was a single-center observational study of 9727 Chinese patients with nonvalvular AF from July 1997 to December 2011. Patients with AF diagnosed concomitantly with hyperthyroidism were identified. Primary and secondary endpoints were defined as hospitalization with ischemic stroke and intracranial hemorrhage in the first 2 years. Patient characteristics, duration of AF, and choice of antithrombotic therapy were recorded. Self-limiting AF was defined as

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.

OBJECTIVE: Androgen deprivation therapy (ADT) increases fracture risk in men with carcinoma of the prostate, but little is known about the fracture risk for different types of ADT. We studied the fracture risk amongst Chinese patients with carcinoma of the prostate prescribed different ADT regimens. SUBJECTS AND METHODS: This was a single-centered observational study that involved 741 patients with carcinoma of the prostate from January 2001 to December 2011. RESULTS: After a median follow-up of 5 years, 71.7% of the study cohort received ADT and the incidence rate of fracture was 8.1%. Multivariable Cox regression analysis revealed that use of ADT was significantly associated with risk of incident fracture (Hazard Ratio [HR] 3.60; 95% Confidence Interval [95% CI] 1.41-9.23; p = 0.008), together with aged >75 years and type 2 diabetes. Compared with no ADT, all three types of ADT were independently associated with the risk of incident fracture: anti-androgen monotherapy (HR 4.47; 95% CI 1.47-13.7; p = 0.009), bilateral orchiectomy ± anti-androgens (HR 4.01; 95% CI 1.46-11.1; p = 0.007) and luteinizing hormone-releasing hormone agonists ± anti-androgens (HR 3.16; 95% CI 1.18-8.43; p = 0.022). However, there was no significant difference in the relative risks among the three types of ADT. CONCLUSIONS: Fracture risk increases among all types of ADT. Clinicians should take into account the risk-benefit ratio when prescribing ADT, especially in elderly patients with type 2 diabetes., published_or_final_version

Aims/hypothesis: Hypoadiponectinaemia and raised C-reactive protein (CRP) level are obesity-related biomarkers associated with glucose dysregulation. We evaluated the combined use of these two biomarkers in predicting the deterioration of glycaemia in a prospective study after a median of 5.4 years. Methods: In total 1,288 non-diabetic participants from the Hong Kong Cardiovascular Risk Factor Prevalence Study-2, with high-sensitivity CRP (hsCRP) and total adiponectin levels measured were included. OGTT was performed in all participants. Two hundred and six participants had deterioration of glycaemia at follow-up, whereas 1,082 participants did not. Results: Baseline age, hsCRP and adiponectin levels were significant independent predictors of the deterioration of glycaemia in a Cox regression analysis after adjusting for baseline age, sex, BMI, hypertension, triacylglycerols, 2 h post-OGTT glucose and homeostasis model assessment of insulin resistance index (all p < 0.01). The introduction of hsCRP or adiponectin level to a regression model including the other biomarker improved the prediction of glycaemic progression significantly in all participants, especially in women (all p < 0.01). The combined inclusion of the two biomarkers resulted in a modest improvement in model discrimination, compared with the inclusion of either one alone. Among participants with impaired fasting glucose/impaired glucose tolerance (IFG/IGT) at baseline, hsCRP and adiponectin levels were not predictive of progression or improvement of glycaemic status. Conclusions/interpretation: Adiponectin and hsCRP levels are independent factors in predicting the deterioration of glycaemia, supporting the role of adiposity-related inflammation in the development of type 2 diabetes. Their combined use as predictive biomarkers is especially useful in women, but not in participants with IFG/IGT. © 2011 The Author(s)., published_or_final_version, Springer Open Choice, 21 Feb 2012

Adipose tissue is a highly dynamic endocrine organ, secreting a number of bioactive substances (adipokines) regulating insulin sensitivity, energy metabolism and vascular homeostasis. Dysfunctional adipose tissue is a key mediator that links obesity with insulin resistance, hypertension and cardiovascular disease. Obese adipose tissue is characterized by adipocyte hypertrophy and infiltration of inflammatory macrophages and lymphocytes, leading to the augmented production of pro-inflammatory adipokines and vasoconstrictors that induce endothelial dysfunction and vascular inflammation through their paracrine and endocrine actions. By contrast, the secretion of adiponectin, an adipokine with insulin sensitizing and anti-inflammatory activities, is decreased in obesity and its related pathologies. Emerging evidence suggests that adiponectin is protective against vascular dysfunction induced by obesity and diabetes, through its multiple favourable effects on glucose and lipid metabolism as well as on vascular function. Adiponectin improves insulin sensitivity and metabolic profiles, thus reducing the classical risk factors for cardiovascular disease. Furthermore, adiponectin protects the vasculature through its pleiotropic actions on endothelial cells, endothelial progenitor cells, smooth muscle cells and macrophages. Data from both animal and human investigations demonstrate that adiponectin is an important component of the adipo-vascular axis that mediates the cross-talk between adipose tissue and vasculature. This review highlights recent work on the vascular protective activities of adiponectin and discusses the molecular pathways underlying the vascular actions of this adipokine.

Summary Objective The metabolic syndrome has been associated with increased mortality in some Caucasian populations, but data in Asian populations are not available. We present data describing the association of the metabolic syndrome with mortality. Methods The impact of the US National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) metabolic syndrome guidelines definition (using Asian central obesity criteria) on mortality was examined using Cox regression analyses in a population-based cohort (n = 2863) of Chinese subjects. Results The cohort was followed up for a mean duration of 8·45 years, a total of 24 101 person-years, with 89 deaths (33·7% of vascular origin). Compared to those without any component of the metabolic syndrome, following adjustment for age, socioeconomic status and a range of lifestyle habits, those with the metabolic syndrome had increased risk of both all-cause [hazard ratio (HR) 2·02, 95% confidence interval (CI) 1·02–4·00, P for trend = 0·037] and vascular disease (HR 6·39, 95% CI 1·40–29·2, P