CCL4 contributes to aging related angiogenic insufficiency through activating oxidative stress and endothelial inflammation.

Aging is a natural process associated with chronic inflammation in the development of vascular dysfunction. We hypothesized that chemokine C-C motif ligands 4 (CCL4) might play a vital role in aging-related vascular dysfunction. Circulating CCL4 was up-regulated in elderly subjects and in aged animals. CCL4 inhibition reduced generation of reactive oxygen species (ROS), attenuated inflammation, and restored cell functions in endothelial progenitor cells from elderly subjects and in aged human aortic endothelial cells. CCL4 promoted cell aging, with impaired cell functioning, by activating ROS production and inflammation. CCL4 knockout mice and therapeutic administration of anti-CCL4 neutralizing antibodies exhibited vascular and dermal anti-aging effects, with improved wound healing, via the down-regulation of inflammatory proteins and the activation of angiogenic proteins. Altogether, our findings suggested that CCL4 may contribute to aging-related vascular dysfunction via activating oxidative stress and endothelial inflammation. CCL4 may be a potential therapeutic target for vascular protections during aging.

Healthcare utilisation in people with long COVID: an OpenSAFELY cohort study.

BACKGROUND: Long COVID potentially increases healthcare utilisation and costs. However, its impact on the NHS remains to be determined. METHODS: This study aims to assess the healthcare utilisation of individuals with long COVID. With the approval of NHS England, we conducted a matched cohort study using primary and secondary care data via OpenSAFELY, a platform for analysing anonymous electronic health records. The long COVID exposure group, defined by diagnostic codes, was matched with five comparators without long COVID between Nov 2020 and Jan 2023. We compared their total healthcare utilisation from GP consultations, prescriptions, hospital admissions, A&E visits, and outpatient appointments. Healthcare utilisation and costs were evaluated using a two-part model adjusting for covariates. Using a difference-in-difference model, we also compared healthcare utilisation after long COVID with pre-pandemic records. RESULTS: We identified 52,988 individuals with a long COVID diagnosis, matched to 264,867 comparators without a diagnosis. In the 12 months post-diagnosis, there was strong evidence that those with long COVID were more likely to use healthcare resources (OR: 8.29, 95% CI: 7.74-8.87), and have 49% more healthcare utilisation (RR: 1.49, 95% CI: 1.48-1.51). Our model estimated that the long COVID group had 30 healthcare visits per year (predicted mean: 29.23, 95% CI: 28.58-29.92), compared to 16 in the comparator group (predicted mean visits: 16.04, 95% CI: 15.73-16.36). Individuals with long COVID were more likely to have non-zero healthcare expenditures (OR = 7.66, 95% CI = 7.20-8.15), with costs being 44% higher than the comparator group (cost ratio = 1.44, 95% CI: 1.39-1.50). The long COVID group costs approximately £2500 per person per year (predicted mean cost: £2562.50, 95% CI: £2335.60-£2819.22), and the comparator group costs £1500 (predicted mean cost: £1527.43, 95% CI: £1404.33-1664.45). Historically, individuals with long COVID utilised healthcare resources more frequently, but their average healthcare utilisation increased more after being diagnosed with long COVID, compared to the comparator group. CONCLUSIONS: Long COVID increases healthcare utilisation and costs. Public health policies should allocate more resources towards preventing, treating, and supporting individuals with long COVID.

Follow-up care and assessment of comorbidities and complications in patients with primary aldosteronism: The clinical practice guideline of the Taiwan Society of aldosteronism.

Primary aldosteronism (PA) is the most common form of endocrine hypertension, characterized by excess aldosterone production that leads to an increased risk of cardiovascular events and target organ damage. Both adrenalectomy and medical treatment have shown efficacy in improving clinical outcomes and comorbidities associated with PA, including a specific subtype of PA with autonomous cortisol secretion (ACS). Understanding the comorbidities of PA and establishing appropriate follow-up protocols after treatment are crucial for physicians to enhance morbidity and mortality outcomes in patients with PA. Additionally, the screening for hypercortisolism prior to surgery is essential, as the prognosis of patients with coexisting PA and ACS differs from those with PA alone. In this review, we comprehensively summarize the comorbidities of PA, encompassing cardiovascular, renal, and metabolic complications. We also discuss various post-treatment outcomes and provide insights into the strategy for glucocorticoid replacement in patients with overt or subclinical hypercortisolism. This clinical practice guideline aims to equip medical professionals with up-to-date information on managing concurrent hypercortisolism, assessing treatment outcomes, and addressing comorbidities in patients with PA, thereby improving follow-up care.

The predictors of long-term outcomes after targeted therapy for primary Aldosteronism.

Unilateral primary aldosteronism is thought to be a surgically curable disease, and unilateral adrenalectomy is the mainstay treatment. The Primary Aldosteronism Surgical Outcome (PASO) consensus was developed to assess clinical and biochemical outcomes to standardize the classification of surgical outcomes. However, fewer than half of patients are cured of hypertension after adrenalectomy; therefore, preoperative patient counseling and evaluation might be necessary. Moreover, current studies show that genetic mutations and histopathology classification are associated with the treatment outcome. The Task Force of Taiwan PA recommends using a specific scoring system, including the PASO score and nomogram-based preoperative score, to predict the clinical outcome before adrenalectomy. Herein, we discuss the associations of current histopathological classification and specific somatic gene mutations with clinical outcomes after surgery.

CXCL5 suppression recovers neovascularization and accelerates wound healing in diabetes mellitus.

BACKGROUND: Higher chemokine C-X-C motif ligand 5 (CXCL5) level was observed in type 2 diabetes mellitus (DM) patients; however, its role in diabetic vasculopathy was not clarified. This study aimed to explore the impacts and mechanistic insights of CXCL5 in neovasculogenesis and wound healing in DM. METHODS: Endothelial progenitor cells (EPCs) and human aortic endothelial cells (HAECs) were used in vitro. Streptozotocin-induced diabetic mice and Leprdb/JNarl mice were used as type 1 and type 2 DM models. Moreover, CXCL5 knockout mice were used to generate diabetic mice. Hindlimb ischemia surgery, aortic ring assays, matrigel plug assay, and wound healing assay were conducted. RESULTS: CXCL5 concentrations were increased in plasma and EPCs culture medium from type 2 DM patients. CXCL5 neutralizing antibody upregulated vascular endothelial growth factor (VEGF)/stromal cell-derived factor-1 (SDF-1) and promoted cell function in EPCs from type 2 DM patients and high glucose-treated EPCs from non-DM subjects as well as HAECs. CXCL5 directly up-regulated interleukin (IL)-1ß/IL-6/tumor necrosis factor-α and down-regulated VEGF/SDF-1 via ERK/p65 activation through chemokine C-X-C motif receptor 2 (CXCR2). CXCL5 neutralizing antibody recovered the blood flow after hindlimb ischemia, increased circulating EPC number, and enhanced VEGF and SDF-1 expression in ischemic muscle. CXCL5 suppression promoted neovascularization and wound healing in different diabetic animal models. The above observation could also be seen in streptozotocin-induced CXCL5 knockout diabetic mice. CONCLUSIONS: CXCL5 suppression could improve neovascularization and wound healing through CXCR2 in DM. CXCL5 may be regarded as a potential therapeutic target for vascular complications of DM.

Holothurian triterpene glycoside cucumarioside A2-2 induces macrophages activation and polarization in cancer immunotherapy.

BACKGROUND: Despite intensive developments of adoptive T cell and NK cell therapies, the efficacy against solid tumors remains elusive. Our study demonstrates that macrophage-based cell therapy could be a potent therapeutic option against solid tumors. METHODS: To this end, we determine the effect of a natural triterpene glycoside, cucumarioside A2-2 (CA2-2), on the polarization of mouse macrophages into the M1 phenotype, and explore the antitumor activity of the polarized macrophage. The polarization of CA2-2-pretreated macrophages was analyzed by flow cytometry and confocal imaging. The anti-cancer activity of CA2-2 macrophages was evaluated against 4T1 breast cancer cells and EAC cells in vitro and syngeneic mouse model in vivo. RESULTS: Incubation of murine macrophages with CA2-2 led to polarization into the M1 phenotype, and the CA2-2-pretreated macrophages could selectively target and kill various types of cancer in vitro. Notably, loading near-infrared (NIR) fluorochrome-labeled nanoparticles, MnMEIO-mPEG-CyTE777, into macrophages substantiated that M1 macrophages can target and penetrate tumor tissues in vivo efficiently. CONCLUSION: In this study, CA2-2-polarized M1 macrophages significantly attenuated tumor growth and prolonged mice survival in the syngeneic mouse models. Therefore, ex vivo CA2-2 activation of mouse macrophages can serve as a useful model for subsequent antitumor cellular immunotherapy developments.

Transient Postictal Hyperglycemia as a Diagnostic Clue of Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes.

PURPOSE: To propose that transient postictal hyperglycemia as a diagnostic clue of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). CASE REPORT: We reported two non-diabetic patients presenting with generalized seizure and transient postictal hyperglycemia. At the acute stage, both patients had hyperglycemia with serum glucose levels more than 400 mg/dl, normal glycated hemoglobin (HbA1C) levels, normal ketone body levels, and absence of infection signs. Within three days of the seizure event, both patients were euglycemic and did not require any diabetes treatment. Brain MRI examination revealed gyriform restricted diffusion at bilateral superior temporal gyrus in one patient, and diffuse cerebral and cerebellar atrophy without restricted diffusion lesions in another patient. Polymerase chain reaction and restriction fragment length polymorphism (RFLP) analysis confirmed that both patients harbored the m.3243A more than G mutation. CONCLUSION: Seizure-induced stress hyperglycemia is uncommon in normal individuals, but such kind of energy crisis may be pronounced in patients with mitochondrial dysfunction. Early diagnosis of mitochondrial diseases-related epilepsy and hyperglycemia is crucial since certain antiepileptic drugs (ex. Valproic acid) and antihyperglycemic agents (ex. Metformin) are contraindicated in patients with mitochondrial diseases. Our findings support that transient postictal hyperglycemia may be a red flag to consider the diagnosis of MELAS.

Soluble Tumor Necrosis Factor Receptor Type 1 Levels Exhibit A Stronger Association With Renal Outcomes Than Traditional Risk Factors in Chinese Subjects With Type 2 Diabetes Mellitus.

OBJECTIVE: Associations between albuminuria and renal outcomes are inconsistent in patients with type 2 diabetes (T2D). Soluble tumor necrosis factor receptor type 1 (sTNFR1) is involved in declined kidney function and poor renal outcomes but this has not been confirmed among Chinese T2D patients. This study aimed to examine the association of sTNFR1 and renal outcomes in a cohort of these patients. METHODS: Two hundred and eighty-three Chinese T2D patients were enrolled in a prospective observational study which excluded individuals with estimated glomerular filtration rates (eGFR) <30 mL/min/1.73m2. Composite renal outcomes included either or both a >30% decline in eGFR and worsening albuminuria from consecutive tests of blood/urine during a 3.5-year follow-up. RESULTS: Higher sTNFR1 levels were associated with impaired renal outcomes. sTNFR1 levels of ≥979 pg/mL yielded the most sensitivity and specific predictions of renal outcomes according to the receiver operating curve (area under the curve 0.68, P<.001; sensitivity 78.3%, specificity 48.9%). Renal events occurred more frequently in subjects with sTNFR1 ≥979 pg/mL than in others (sTNFR1 <979 pg/mL; 29% versus 10%; P<.001 by log-rank test). The association between sTNFR1 ≥979 pg/mL and renal outcomes remained significant after adjustment for relevant covariates (adjusted hazard ratio 2.43, 95% confidence interval 1.18 to 5.02; P = .01) and consistent across subgroups stratified by age, sex, blood pressure, eGFR, albuminuria, and the use of renin-angiotensin system inhibitors. CONCLUSION: Increased sTNFR1 levels were associated with renal outcomes in Chinese T2D subjects, making sTNFR1 a potential biomarker in diabetic kidney disease.

Inhibition of macrophage inflammatory protein-1ß improves endothelial progenitor cell function and ischemia-induced angiogenesis in diabetes.

Systemic inflammation might contribute to the impairment of neovasculogenesis and endothelial progenitor cell (EPC) function in clinical diabetes mellitus (DM). Macrophage inflammatory protein-1ß (MIP-1ß) is an inflammatory chemokine that may be up-regulated in clinical DM. Its role in diabetic vasculopathy was not clarified. This study aimed to investigate the role of MIP-1ß in human EPCs and in neovasculogenesis in different diabetic animal models with hindlimb ischemia. EPCs chamber assay and in vitro tube formation assay were used to estimate the degree of EPC migration and tube formation abilities. Leprdb/JNarl mice, C57BL/6 mice fed a high-fat diet, and streptozotocin-induced diabetic mice were used as different diabetic animal models. Laser Doppler imaging and flow cytometry were used to evaluate the degree of neovasculogenesis and the circulating levels of EPCs, respectively. MIP-1ß impaired human EPC function for angiogenesis in vitro. Plasma MIP-1ß levels were up-regulated in type 2 DM patients. MIP-1ß inhibition enhanced the function and the C-X-C chemokine receptor type 4 expression of EPCs from type 2 diabetic patients, and improved EPC homing for ischemia-induced neovasculogenesis in different types of diabetic animals. MIP-1ß directly impaired human EPC function. Inhibition of MIP-1ß improved in vitro EPC function, and enhanced in vivo EPC homing and ischemia-induced neovasculogenesis, suggesting the critical role of MIP-1ß for vasculopathy in the presence of DM.

UPSTROKE TIME PER CARDIAC CYCLE IS ASSOCIATED WITH CARDIOVASCULAR PROGNOSIS IN TYPE 2 DIABETES.

Objective: Upstroke time per cardiac cycle (UTCC) in the lower extremities has been found to be predictive of cardiovascular mortality in the general population. Therefore, the purpose of the study was to test the associations between increasing UTCC and outcomes in patients with type 2 diabetes. Methods: A total of 452 patients with type 2 diabetes (age, 67.5 ± 8.6 years; male, 54%) registered in a share-care program participated in the study at an outpatient clinic in Taipei Veterans General Hospital across a mean of 5.8 years. Primary outcomes were all-cause mortality hospitalization for coronary artery disease, stroke, revascularization, amputation, and diabetic foot syndrome. Secondary end-point outcome was all-cause mortality. Results: Increment of UTCC associations with primary and secondary outcomes were undertaken prior to baseline characteristic adjustments. A UTCC of 20.1% exhibited the greatest area under curve (AUC), sensitivity, and specificity balance to predict composite events in receiver operating curves (AUC, 0.63 [P = .001]; sensitivity, 67.7%; specificity, 54.9%). Sixty-four composite events and 17 deaths were identified from medical records. UTCC ≥20.1% was associated with the occurrence of composite events and an increased risk of mortality. For composite events, an adjusted hazard ratio (HR) of 2.45 and 95% confidence interval (CI) of 1.38 to 4.35 (P = .002) were calculated. For all-cause mortality, an adjusted HR of 1.91 and 95% CI of 0.33 to 10.99 (P = .467) were calculated. Conclusion: Increasing UTCC was associated with cardiovascular outcomes in patients with type 2 diabetes. Therefore, UTCC is advocated as a noninvasive screening tool for ambulatory patients with type 2 diabetes. Abbreviations: CAD = coronary artery disease; CI = confidence interval; eGFR = estimated glomerular filtration rate; HR = hazard ratio; PAD = peripheral artery disease; UTCC = upstroke time per cardiac cycle.

The Efficacy of Concurrent or Sequential Intravenous and Intratympanic Steroid for Idiopathic Sudden Sensorineural Hearing Loss.

OBJECTIVE: The purpose of this retrospective study was to investigate the difference in treatment outcomes for patients with idiopathic sudden sensorineural hearing loss (SSNHL) undergoing concurrent or sequential intravenous (IV) and intratympanic (IT) steroid therapies. METHODS: Patients with idiopathic SSNHL admitted to Taipei Veterans Hospital from August 2011 to August 2012 were enrolled. Patients were treated with both IV dexamethasone 5 mg b.i.d. for 5 days, then tapered over 6 days, and IT injections of dexamethasone 5 mg daily. The administration of IV and IT steroids was given either concurrently or sequentially (IV steroid was administered from days 1-5 followed by IT steroid treatment starting on day 4 or day 5). The hearing outcomes of the concurrent and sequential groups were analyzed. RESULTS: Overall, after ≥2 months following treatment, across frequencies ranging from 250 to 8,000 Hz and pure-tone average (PTA) assessments, hearing improvements were similar between treatment groups, except at the frequencies of 4,000 and 8,000 Hz where the concurrent treatment group had greater hearing gain than the sequential group (4,000 Hz: 30.68 ± 28.96 vs. 14.52 ± 24.06 dB, respectively, p = 0.042; 8,000 Hz: 22.62 ± 23.59 vs. 7.67 ± 21 dB, p = 0.030). Across frequencies and PTA assessments, a similar percentage of patients had ≥20-dB gains in hearing compared with patients treated sequentially, except at 8,000 Hz where a greater percentage of patients in the concurrent group (57.1%) than the sequential group (23.3%) (p = 0.014) had ≥20-dB hearing gains. CONCLUSION: The findings suggest that both concurrent and sequential treatment improve hearing in patients with idiopathic SSNHL, and that concurrent treatment may show greater benefit than sequential therapy, particularly at high frequencies.

Aliskiren directly improves endothelial progenitor cell function from Type II diabetic patients.

BACKGROUND: Endothelial progenitor cell (EPC) functions are impaired in the presence of diabetes mellitus. Aliskiren is a direct renin inhibitor, which is expected to modify proangiogenic cells. This study aimed to investigate whether and how aliskiren could improve the function of EPCs from patients with type II diabetes (T2DM). MATERIALS AND METHODS: Endothelial progenitor cells fibronectin adhesion assay, chamber assay and in vitro tube formation assay were used to estimate the degree of EPC adhesion, migration and tube formation abilities. EPC protein and mRNA expressions were evaluated by Western blot and quantitative RT-PCR, respectively. EPC vascular endothelial growth factor (VEGF) and (pro)renin receptor ((P)RR) expression was knocked down by VEGF and (P)RR siRNA. RESULTS: Aliskiren (0·1 or 10 µM) dose-dependently improved functions and increased both VEGF and stromal cell-derived factor-1α (SDF-1α) expression of EPCs from patients with T2DM or EPCs from healthy volunteers and treated with high glucose. Transfection with VEGF siRNA significantly reduced the aliskiren-induced SDF-1α expression. Furthermore, (P)RR siRNA transfection impaired the aliskiren-induced VEGF and SDF-1 expression. CONCLUSIONS: The results show that aliskiren improved EPC function from patients with T2DM in a dose-dependent manner probably via the (P)RR and VEGF/SDF-1α-related mechanisms.

Hypertension subtypes modify metabolic response to thiazide diuretics.

BACKGROUND: Blood pressure (BP) and metabolic response to thiazide diuretics might be varied in patients with different hypertension subtypes and ethnicities. This study aimed to investigate the response of BP and metabolic profiles to short-term thiazide treatment in an Asian cohort with different hypertension subtypes. DESIGN: Serial ethnic Chinese nondiabetic subjects with hypertension were evaluated. After diet instruction and lifestyle modification for 2 weeks, patients who still had elevated systolic BP (SBP≥140 mmHg) and/or diastolic BP (DBP≥90 mmHg) were given 50 mg of hydrochlorothiazide daily for 2 weeks. The responses of BP and metabolic profiles were evaluated before and after treatment according to the patient's baseline BP subtype - isolated systolic hypertension (ISH), systo-diastolic hypertension (SDH) and isolated diastolic hypertension (IDH). RESULTS: Hydrochlorothiazide treatment significantly reduced the BP in all 92 patients (62 males, aged 45·7 ± 9·6 years), irrespective of their baseline BP subtypes. In patients with SDH (n = 39) or IDH (n = 40), hydrochlorothiazide treatment significantly increased serum adiponectin (P = 0·001 and 0·007, respectively) and reduced asymmetric dimethylarginine levels (P < 0·001, in both groups). Serum cholesterol (P = 0·027) and fasting blood sugar levels (P = 0·044) were significantly improved only in the IDH patients. Furthermore, IDH was independently associated with changes in fasting blood sugar (ß = -11·178, P = 0·022) and cholesterol (ß = -22·654, P = 0·027). CONCLUSIONS: The characteristics of the Asian hypertensive patients with diastolic hypertension can present a favourable metabolic response to the short-term hydrochlorothiazide treatment. The potential positive effect on cardiovascular risk should be validated in long-term studies in this diastolic type of hypertension.

Migraine is associated with an increased risk for benign paroxysmal positional vertigo: a nationwide population-based study.

BACKGROUND: There is evidence suggesting that migraine may be associated with vertigo. The aim of this study was to assess the risk of benign paroxysmal positional vertigo (BPPV), the most common form of vertigo, in patients with migraine using a population-based dataset. METHODS: The National Health Insurance Research Database in Taiwan was searched for migraine patients and was also used to select an age- and sex-matched cohort of subjects without migraine. The analyses included 8266 migraine patients and 8266 controls. The incidence rates of BPPV in the two cohorts were compared. Cox proportional hazard models were used to identify risk factors for BPPV in migraine patients. RESULTS: In the migraine cohort, 1.11% of the patients developed BPPV compared to 0.5% of the controls. The incidence rate ratio was 2.03 (95% CI 1.41-2.97; p <0.001). Cox proportional hazards analysis showed that age ≥40 years (HR 2.20; 95% CI 1.40-3.45; p = 0.001), coronary artery disease (HR 4.62; 95% CI 1.12-19.01; p = 0.034), and the number of outpatient department visits to neurologists because of migraine (HR 2.93; 95% CI 2.50-3.44; p >0.001) were associated with an increased risk for BPPV. CONCLUSION: The results showed that patients with migraine had a 2.03-fold increased risk of developing BPPV compared with age- and sex-matched controls. Although BPPV may not be a common condition in migraine patients, migraine sufferers with vestibular symptoms should alert physicians to the possibility of BPPV, particularly if patients are aged ≥40 years, have a history of coronary artery disease, or have frequent visits to neurologists clinics because of migraine.

Effects of pitavastatin versus atorvastatin on the peripheral endothelial progenitor cells and vascular endothelial growth factor in high-risk patients: a pilot prospective, double-blind, randomized study.

BACKGROUND: Circulating endothelial progenitor cells (EPCs) reflect endothelial repair capacity and may be a significant marker for the clinical outcomes of cardiovascular disease. While some high-dose statin treatments may improve endothelial function, it is not known whether different statins may have similar effects on EPCs.This study aimed to investigate the potential class effects of different statin treatment including pitavastatin and atorvastatin on circulating EPCs in clinical setting. METHODS: A pilot prospective, double-blind, randomized study was conducted to evaluate the ordinary dose of pitavastatin (2 mg daily) or atorvastatin (10 mg daily) treatment for 12 weeks on circulating EPCs in patients with cardiovascular risk such as hypercholesterolemia and type 2 diabetes mellitus (T2DM). Additional in vitro study was conducted to clarify the direct effects of both statins on EPCs from the patients. RESULTS: A total of 26 patients (19 with T2DM) completed the study. While the lipid-lowering effects were similar in both treatments, the counts of circulating CD34+KDR+EPCs were significantly increased (from 0.021 ± 0.015 to 0.054 ± 0.044% of gated mononuclear cells, P < 0.05) only by pitavastatin treatment. Besides, plasma asymmetric dimethylarginine level was reduced (from 0.68 ± 0.10 to 0.53 ± 0.12 µmol/L, P < 0.05) by atorvastatin, and plasma vascular endothelial growth factor (VEGF) level was increased (from 74.33 ± 32.26 to 98.65 ± 46.64 pg/mL, P < 0.05) by pitavastatin. In the in vitro study, while both statins increased endothelial nitric oxide synthase (eNOS) expression, only pitavastatin increased the phosphorylation of eNOS in EPCs. Pitavastatin but not atorvastatin ameliorated the adhesion ability of early EPCs and the migration and tube formation capacities of late EPCs. CONCLUSIONS: While both statins similarly reduced plasma lipids, only pitavastatin increased plasma VEGF level and circulating EPCs in high-risk patients, which is probably related to the differential pleiotropic effects of different statins. TRIAL REGISTRATION: This trial is registered at ClinicalTrials.gov, NCT01386853.

Soluble tumor necrosis factor receptor type 1 is an alternative marker of urinary albumin-creatinine ratio and estimated glomerular filtration rate for predicting the decline of renal function in subjects with type 2 diabetes mellitus.

BACKGROUND: Urinary albumin-creatinine ratio (UACR) and estimated glomerular filtration rates (eGFR) help predict worsening diabetic kidney disease (DKD) but have their limitations. Soluble tumor necrosis factor receptor type 1 (sTNFR1) is a biomarker of DKD. The predictive abilities of sTNFR1 and UACR plus eGFR have not been compared. METHODS: This prospective cohort study included patients with type 2 diabetes (T2D) to identify the risk factors of worsening DKD. Renal events were defined as > 30 % loss in eGFR based on consecutive tests after 6 months. The associations of sTNFR1, UACR, and eGFR levels and the risks of renal events were tested using a Cox regression model and the area under the curve (AUC) was compared between sTNFR1 levels and UACR plus eGFR using receiver-operating characteristic (ROC) analysis. The accuracy of stratification was evaluated using Kaplan-Meier analysis. RESULTS: Levels of sTNFR1 and UACR were associated with risks of > 30 % decline in eGFR after adjusting for relevant factors. The association between sTNFR1 levels and renal outcomes was independent of UACR and eGFR at baseline. The AUC of sTNFR1 level was comparable with that of combined UACR and eGFR (0.73 vs. 0.71, respectively, p = 0.72) and the results persisted for quartile groups of sTNFR1 and risk categories of Kidney Disease: Improving Global Outcomes (KDIGO) (0.70 vs. 0.71, respectively, p = 0.84). Both stratifications by sTNFR1 levels and KDIGO were accurate. CONCLUSION: sTNFR1 could be an alternative marker for identifying patients with diabetes at risk of declining renal function.

Novel prognostic impact and cell specific role of endocan in patients with coronary artery disease.

BACKGROUND: Both the clinical and mechanistic impacts of endocan were not well elucidated especially in coronary artery disease (CAD). OBJECTIVE: This study aimed to investigate the prognostic and potential pathological role of endocan for cardiovascular (CV) events in stable CAD patients. METHODS: A total of 1,071 stable CAD patients with previous percutaneous coronary intervention (PCI) were enrolled prospectively in a nationwide Biosignature study. Another cohort of 76 CAD patients with or without PCI were enrolled for validation. Baseline biomarkers including endocan level was measured and total CV events especially hard CV events (including CV mortality, non-fatal myocardial infection and stroke) during follow-up were identified. Circulating endothelial progenitor cells (EPCs) as an in vivo biological contributor to vascular repairment from CAD patients were used for the in vitro functional study. RESULTS: After 24 months, there were 42 patients (3.92%) with hard CV events and 207 (19.3%) with total CV events in the study group. The incidence of both events was increased with the tertiles of baseline endocan level (hard events: 1.7%,3.4%, and 6.7% in 1st,2nd, and 3rd tertile respectively, p = 0.002; total events: 13.8%vs.16.2%vs.28.0%, p < 0.0001). Multivariate regression analysis revealed the independent association of endocan level with total and hard CV events. These findings were validated in another cohort with a 5-year follow-up. Furthermore, in vitro inhibition of endocan improved cell migration and tube formation capacities, and reduced cell adhesiveness of EPCs from CAD patients. CONCLUSIONS: Endocan might be a novel prognostic indicator, mechanistic mediator, and potential therapeutic target for clinical CAD.

Recent progress in unraveling cardiovascular complications associated with primary aldosteronism: a succinct review.

This comprehensive review offers a thorough exploration of recent advancements in our understanding of the intricate cardiovascular complications associated with Primary Aldosteronism (PA). PA encompasses a spectrum of conditions characterized by hypertension and excessive production of aldosterone operating independently of the renin-angiotensin system. Given its association with an elevated risk of cardiovascular and cerebrovascular complications, as well as a higher incidence of metabolic syndrome in comparison to individuals with essential hypertension (EH), an accurate diagnosis of PA is of paramount importance. This review delves into the intricate interplay between PA and cardiovascular health and focuses on the key pathophysiological mechanisms contributing to adverse cardiac outcomes. The impact of different treatment modalities on cardiovascular health is also examined, offering insights into potential therapeutic approaches. By highlighting the significance of recognizing PA as a significant contributor to cardiovascular morbidity, this review emphasizes the need for improved screening, early diagnosis, and tailored management strategies to both enhance patient care and mitigate the burden of cardiovascular diseases. The findings presented herein underscore the growing importance of PA in the context of cardiovascular medicine and emphasize the potential for translating these insights into targeted interventions to improve patient outcomes.

Impact of long COVID on health-related quality-of-life: an OpenSAFELY population cohort study using patient-reported outcome measures (OpenPROMPT).

Background: Long COVID is a major problem affecting patient health, the health service, and the workforce. To optimise the design of future interventions against COVID-19, and to better plan and allocate health resources, it is critical to quantify the health and economic burden of this novel condition. We aimed to evaluate and estimate the differences in health impacts of long COVID across sociodemographic categories and quantify this in Quality-Adjusted Life-Years (QALYs), widely used measures across health systems. Methods: With the approval of NHS England, we utilised OpenPROMPT, a UK cohort study measuring the impact of long COVID on health-related quality-of-life (HRQoL). OpenPROMPT invited responses to Patient Reported Outcome Measures (PROMs) using a smartphone application and recruited between November 2022 and October 2023. We used the validated EuroQol EQ-5D questionnaire with the UK Value Set to develop disutility scores (1-utility) for respondents with and without Long COVID using linear mixed models, and we calculated subsequent Quality-Adjusted Life-Months (QALMs) for long COVID. Findings: The total OpenPROMPT cohort consisted of 7575 individuals who consented to data collection, with which we used data from 6070 participants who completed a baseline research questionnaire where 24.6% self-reported long COVID. In multivariable regressions, long COVID had a consistent impact on HRQoL, showing a higher likelihood or odds of reporting loss in quality-of-life (Odds Ratio (OR): 4.7, 95% CI: 3.72-5.93) compared with people who did not report long COVID. Reporting a disability was the largest predictor of losses of HRQoL (OR: 17.7, 95% CI: 10.37-30.33) across survey responses. Self-reported long COVID was associated with an 0.37 QALM loss. Interpretation: We found substantial impacts on quality-of-life due to long COVID, representing a major burden on patients and the health service. We highlight the need for continued support and research for long COVID, as HRQoL scores compared unfavourably to patients with conditions such as multiple sclerosis, heart failure, and renal disease. Funding: This research was supported by the National Institute for Health and Care Research (NIHR) (OpenPROMPT: COV-LT2-0073).