Diabetes Primes Neutrophils for Neutrophil Extracellular Trap Formation through Trained Immunity.

Neutrophils are primed for neutrophil extracellular trap (NET) formation during diabetes, and excessive NET formation from primed neutrophils compromises wound healing in patients with diabetes. Here, we demonstrate that trained immunity mediates diabetes-induced NET priming in neutrophils. Under diabetic conditions, neutrophils exhibit robust metabolic reprogramming comprising enhanced glycolysis via the pentose phosphate pathway and fatty acid oxidation, which result in the accumulation of acetyl-coenzyme A. Adenosine 5'-triphosphate-citrate lyase-mediated accumulation of acetyl-coenzyme A and histone acetyltransferases further induce the acetylation of lysine residues on histone 3 (AcH3K9, AcH3K14, and AcH3K27) and histone 4 (AcH4K8). The pharmacological inhibition of adenosine 5'-triphosphate-citrate lyase and histone acetyltransferases completely inhibited high-glucose-induced NET priming. The trained immunity of neutrophils was further confirmed in neutrophils isolated from patients with diabetes. Our findings suggest that trained immunity mediates functional changes in neutrophils in diabetic environments, and targeting neutrophil-trained immunity may be a potential therapeutic target for controlling inflammatory complications of diabetes.

Timing of fractional flow reserve-guided complete revascularization in patients with ST-segment elevation myocardial infarction with multivessel disease: Rationale and design of the OPTION-STEMI trial.

BACKGROUND: Current guidelines recommend complete revascularization (CR) in hemodynamically stable patients with ST-segment elevation myocardial infarction (STEMI) and multivessel coronary artery disease (MVD). With regard to the timing of percutaneous coronary intervention (PCI) for non-infarct-related artery (non-IRA), recent randomized clinical trials have revealed that immediate CR was non-inferior to staged CR. However, the optimal timing of CR remains uncertain. The OPTION-STEMI trial compared immediate CR and in-hospital staged CR guided by fractional flow reserve (FFR) for intermediate stenosis of the non-IRA. METHODS: The OPTION-STEMI is a multicenter, investigator-initiated, prospective, open-label, non-inferiority randomized clinical trial. The study included patients with at least 1 non-IRA lesion with ≥50% stenosis by visual estimation. Patients fulfilling the inclusion criteria were randomized into 2 groups at a 1:1 ratio: immediate CR (i.e., PCI for the non-IRA performed during primary angioplasty) or in-hospital staged CR. In the in-hospital staged CR group, PCI for non-IRA lesions was performed on another day during the index hospitalization. Non-IRA lesions with 50%-69% stenosis by visual estimation were evaluated by FFR, whereas those with ≥70% stenosis was revascularized without FFR. The primary endpoint was the composite of all-cause death, non-fatal myocardial infarction, and all unplanned revascularization at 1 year after randomization. Enrolment began in December 2019 and was completed in January 2024. The follow-up for the primary endpoint will be completed in January 2025, and primary results will be available in the middle of 2025. CONCLUSIONS: The OPTION-STEMI is a multicenter, non-inferiority, randomized trial that evaluated the timing of in-hospital CR with the aid of FFR in patients with STEMI and MVD. TRIAL REGISTRATION: URL: https://www. CLINICALTRIALS: gov. Unique identifier: NCT04626882; and URL: https://cris.nih.go.kr. Unique identifier: KCT0004457.

Transradial Versus Transfemoral Access for Bifurcation Percutaneous Coronary Intervention Using Second-Generation Drug-Eluting Stent.

BACKGROUND: The benefits of transradial access (TRA) over transfemoral access (TFA) for bifurcation percutaneous coronary intervention (PCI) are uncertain because of the limited availability of device selection. This study aimed to compare the procedural differences and the in-hospital and long-term outcomes of TRA and TFA for bifurcation PCI using second-generation drug-eluting stents (DESs). METHODS: Based on data from the Coronary Bifurcation Stenting Registry III, a retrospective registry of 2,648 patients undergoing bifurcation PCI with second-generation DES from 21 centers in South Korea, patients were categorized into the TRA group (n = 1,507) or the TFA group (n = 1,141). After propensity score matching (PSM), procedural differences, in-hospital outcomes, and device-oriented composite outcomes (DOCOs; a composite of cardiac death, target vessel-related myocardial infarction, and target lesion revascularization) were compared between the two groups (772 matched patients each group). RESULTS: Despite well-balanced baseline clinical and lesion characteristics after PSM, the use of the two-stent strategy (14.2% vs. 23.7%, P = 0.001) and the incidence of in-hospital adverse outcomes, primarily driven by access site complications (2.2% vs. 4.4%, P = 0.015), were significantly lower in the TRA group than in the TFA group. At the 5-year follow-up, the incidence of DOCOs was similar between the groups (6.3% vs. 7.1%, P = 0.639). CONCLUSION: The findings suggested that TRA may be safer than TFA for bifurcation PCI using second-generation DESs. Despite differences in treatment strategy, TRA was associated with similar long-term clinical outcomes as those of TFA. Therefore, TRA might be the preferred access for bifurcation PCI using second-generation DES. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03068494.

Transferrin-Conjugated Melittin-Loaded L-Arginine-Coated Iron Oxide Nanoparticles for Mitigating Beta-Amyloid Pathology of the 5XFAD Mouse Brain.

Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases and a major contributor to dementia. Although the cause of this condition has been identified long ago as aberrant aggregations of amyloid and tau proteins, effective therapies for it remain elusive. The complexities of drug development for AD treatment are often compounded by the impermeable blood-brain barrier and low-yield brain delivery. In addition, the use of high drug concentrations to overcome this challenge may entail side effects. To address these challenges and enhance the precision of delivery into brain regions affected by amyloid aggregation, we proposed a transferrin-conjugated nanoparticle-based drug delivery system. The transferrin-conjugated melittin-loaded L-arginine-coated iron oxide nanoparticles (Tf-MeLioNs) developed in this study successfully mitigated melittin-induced cytotoxicity and hemolysis in the cell culture system. In the 5XFAD mouse brain, Tf-MeLioNs remarkably reduced amyloid plaque accumulation, particularly in the hippocampus. This study suggested Tf-LioNs as a potential drug delivery platform and Tf-MeLioNs as a candidate for therapeutic drug targeting of amyloid plaques in AD. These findings provide a foundation for further exploration and advancement in AD therapeutics.

Effect Sizes of Cognitive and Locomotive Behavior Tests in the 5XFAD-J Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by the accumulation of amyloid ß (Aß) plaques in the brain, leading to cognitive impairment and other clinical symptoms. The 5XFAD mouse model is commonly used in AD research because it expresses five human transgenes that result in the accumulation of Aß plaques and cognitive decline at a relatively early age. Behavioral experiments are frequently conducted using this model; however, the effect size has not yet been reported. In this study, we examined basic cognition and locomotion in 5XFAD mice with a C57BL6/J background (5XFAD-J) at 6 months of age, a period in which impairments of cognitive function and locomotion are commonly observed. We analyzed the effect sizes of cognitive and locomotive experiments in the 5XFAD mice compared with those in the wild-type mice. Our results suggest that for long-term memory analysis, the novel object recognition test (p = 0.013, effect size 1.24) required a sample size of at least 12 to obtain meaningful results. Moreover, analysis of general locomotion over total distance with the Laboratory Animal Behavior Observation, Registration and Analysis System (LABORAS) test during the dark phase (p = 0.007, effect size -1.37) needed a sample size of 10 for a statistical power (1-ß) of 0.8. In conclusion, we can conduct more ethical and scientifically rigorous animal experiments using 5XFAD mice based on the effect and sample sizes suggested in this study.

De-escalation from ticagrelor to clopidogrel in patients with acute myocardial infarction: the TALOS-AMI HBR substudy.

BACKGROUND: The benefits of de-escalation of P2Y12 inhibition after percutaneous coronary intervention (PCI) may differ by high bleeding risk (HBR) status. AIMS: We investigated the efficacy and safety of de-escalation from ticagrelor to clopidogrel after PCI by HBR status. METHODS: This is a non-prespecified post hoc analysis of the TicAgrelor Versus CLOpidogrel in Stabilized Patients with Acute Myocardial Infarction (TALOS-AMI) trial. Net adverse clinical events (a composite of cardiovascular death, myocardial infarction, stroke, or Bleeding Academic Research Consortium [BARC] bleeding type 2, 3, or 5) at 1 year post-PCI were compared between the de-escalation (clopidogrel plus aspirin) and the active control (ticagrelor plus aspirin) groups by HBR status, as defined by the modification of the Academic Research Consortium (ARC) criteria. RESULTS: A total of 2,625 patients in the TALOS-AMI trial were analysed. Of these, 589 (22.4%) met the modified ARC-HBR criteria. The de-escalation group had lower primary endpoint rates than the control group in both HBR (hazard ratio [HR] 0.47, 95% confidence interval [CI]: 0.26-0.84) and non-HBR (HR 0.59, 95% CI: 0.41-0.84) patients. There were no differences in treatment effect for the primary endpoint regardless of HBR status (p for interaction=0.904). BARC bleeding type 3 or 5 was less common in the de-escalation than the control group among HBR patients only (HR 0.24, 95% CI: 0.07-0.84). CONCLUSIONS: In stabilised acute myocardial infarction patients, unguided de-escalation from ticagrelor to clopidogrel was associated with a lower rate of net adverse clinical outcomes irrespective of HBR status. The effect of de-escalation of P2Y12 inhibition on reducing haemorrhagic events was greater in patients with HBR.

High Platelet Reactivity Combined with CYP2C19 Genotype in Predicting Outcomes in East Asian Patients Undergoing Percutaneous Coronary Intervention.

Loss-of-function (LoF) alleles of cytochrome P450 2C19 (CYP2C19), which are prevalent in East Asians, are linked to high platelet reactivity (HPR) phenotype and poor prognosis. We aimed to investigate the incremental predictive value of HPR combined with CYP2C19 genotype in predicting outcomes after drug-eluting stent (DES) implantation. The patients treated with platelet function and genotype-related long-term prognosis in drug-eluting stent (PTRG-DES) consortium enrolled a total of 13,160 Korean patients treated with DES who had platelet function test (PFT) or CYP2C19 genotype, of which, 6,717 patients with PFT and genotype together were categorized. HPR was defined as VerifyNow ≥ 252 P2Y12 reaction unit. The primary outcome was the incidence of major adverse cardiac and cerebrovascular event (MACCE) 5 years after treatment. The patients with both HPR and CYP2C19 LoF/LoF had the highest MACCE rates (6.2%) and increased MACCE risk (adjusted hazard ratio: 1.89, 95% confidence interval: 1.20-2.91, P = 0.006) compared with those without both HPR and CYP2C19 LoF/LoF. There was no effect of interaction between HPR and CYP2C19 genotype on the primary outcome (P = 0.424). Adding combined HPR and CYP2C19 genotype to the conventional model had an incremental influence in predicting MACCE and stent thrombosis. Compared to the model including HPR or CYP2C19 genotype alone, a combination model significantly improved the risk stratification for stent thrombosis but not MACCE. In DES-treated East Asian patients, the combined evaluation of PFT results and CYP2C19 genotyping might improve risk prediction of ischemic events during clopidogrel treatment.

Impact of guideline-directed medical therapy on 5-year mortality in patients with newly diagnosed peripheral artery disease.

OBJECTIVE: Current guidelines recommend that patients with peripheral artery disease (PAD) should be treated with antithrombotic agents, renin-angiotensin-system blockers, and statins. However, the clinical impact of guideline-directed medical therapy (GDMT) on long-term mortality in patients with newly diagnosed PAD remains unclear. We aimed to investigate the prevalence of GDMT and evaluate 5-year mortality according to GDMT after PAD diagnosis. METHODS: This retrospective cohort study, using nationwide health insurance claims data in Korea, included patients newly diagnosed with PAD between 2006 and 2015. GDMT was defined as the use of all drugs, including antithrombotic agents, renin-angiotensin-system blockers, and statins, within 3 months of PAD diagnosis. The primary endpoint was all-cause mortality. RESULTS: We investigated 19,561 newly diagnosed patients with PAD without proven cardiovascular disease. Among the study population, 4378 patients (22.4%) were categorized in the GDMT and 15,183 (77.6%) in the non-GDMT groups. During the 5-year follow-up, GDMT showed a lower incidence of all-cause mortality than that of non-GDMT (2.8% vs 4.8%; adjusted hazard ratio, 0.329; 95% confidence interval, 0.257-0.421; P < .001). Even in the propensity-matched population, GDMT showed a lower mortality rate than non-GDMT (hazard ratio, 0.283; 95% confidence interval, 0.217-0.370; P < .001). As the number of guideline-recommended drugs increased, the mortality rate decreased proportionately. CONCLUSIONS: After PAD diagnosis, GDMT was associated with a lower incidence of mortality regardless of proven cardiovascular disease. This retrospective analysis showed an insufficient prevalence of GDMT among patients with PAD in real-world practice.

Device Effectiveness for Femoropopliteal Artery Disease Treatment: An Analysis of K-VIS ELLA Registry.

BACKGROUND: Although drug-coated balloons (DCBs) and drug-eluting stents (DES) are frequently used for the treatment of femoropopliteal artery (FPA) disease, their mid- or long-term clinical efficacy in real-world practice is still limited. OBJECTIVES: From the K-VIS ELLA (Korean Vascular Intervention Society Endovascular Therapy in Lower Limb Artery Diseases) multicenter registry cohort, clinical outcomes of drug-eluting devices for FPA lesions in comparison with bare-metal stents (BMS) were evaluated. METHODS: Limbs that underwent percutaneous transluminal angioplasty for FPA lesions with plain old balloon angioplasty (POBA, n = 826), BMS (n = 943), DCBs (n = 778), or DES (n = 227) between 2012 and 2020 were included. The primary outcome was target lesion revascularization (TLR) at 2 years. Inverse probability of treatment weighting was used to account for confounding. RESULTS: After inverse probability of treatment weighting, baseline characteristics were well-balanced among groups. Compared with the 2-year cumulative incidence of TLR with BMS (26.5%), the incidence of TLR was significantly lower in limbs treated with DCBs (15.9%; HR: 0.44; 95% CI: 0.30-0.64; P < 0.001) or DES (15.9%; HR: 0.51; 95% CI: 0.29-0.87; P = 0.014). No significant differences were observed in the risk of TLR between DCBs vs DES (HR: 0.87; 95% CI: 0.51-1.49; P = 0.613) and POBA vs BMS (HR: 0.94; 95% CI: 0.73-1.21; P = 0.626). All-cause mortality was comparable in the 4 groups. Treatment with DCBs showed a more pronounced favorable outcome in limbs with Trans-Atlantic Inter-Society Consensus II type C/D lesions or long lesions (≥150 mm) compared with POBA, BMS, or DES (Pinteraction< 0.05). CONCLUSIONS: In real-world practice, DCBs and DES demonstrated comparably superior midterm outcomes over POBA or BMS in the treatment of FPA lesions.

Clinical safety and effectiveness of the Genoss drug-eluting stent in real-world clinical practice.

BACKGROUND/AIMS: The Genoss DES™ is a novel, biodegradable, polymer-coated, sirolimus-eluting stent with a cobalt- chromium stent platform and thin strut. Although the safety and effectiveness of this stent have been previously investigated, real-world clinical outcomes data are lacking. Therefore, the aim of this prospective, multicenter trial was to evaluate the clinical safety and effectiveness of the Genoss DES™ in all-comer patients undergoing percutaneous coronary intervention. METHODS: The Genoss DES registry is a prospective, single-arm, observational trial for evaluation of clinical outcomes after Genoss DES™ implantation in all-comer patients undergoing percutaneous coronary intervention from 17 sites in South Korea. The primary endpoint was a device-oriented composite outcome of cardiac death, target vessel-related myocardial infarction (MI), and clinically driven target lesion revascularization (TLR) at 12 months. RESULTS: A total of 1,999 patients (66.4 ± 11.1 years of age; 72.8% male) were analyzed. At baseline, 62.8% and 36.7% of patients had hypertension and diabetes, respectively. The implanted stent number, diameter, and length per patient were 1.5 ± 0.8, 3.1 ± 0.5 mm, and 37.0 ± 25.0 mm, respectively. The primary endpoint occurred in 1.8% patients, with a cardiac death rate of 1.1%, target vessel-related MI rate of 0.2%, and clinically driven TLR rate of 0.8%. CONCLUSION: In this real-world registry, the Genoss DES™ demonstrated excellent safety and effectiveness at 12 months among all-comer patients undergoing percutaneous coronary intervention. These findings suggest that the Genoss DES™ may be a viable treatment option for patients with coronary artery disease.

Occult Pneumothorax in Blunt Thoracic Trauma: Clinical Characteristics and Results of Delayed Tube Thoracostomy in a Level 1 Trauma Center.

Occult pneumothorax in blunt trauma patients is often diagnosed only after computed tomography because supine chest X-ray (CXR) is preferred as an initial evaluation. However, improperly managed preexisting occult pneumothorax could threaten the vitality of patients. Therefore, this study aimed to evaluate the incidence, characteristics, risk factors, and outcomes of occult pneumothorax in a single trauma center. From 2020 to 2022, patients who were admitted to the level 1 trauma center were retrospectively investigated. Inclusion criteria focused on blunt chest trauma. Variables including demographic factors, image findings, injury-related factors, tube thoracostomy timing, and treatment results were evaluated. Of the 1621 patients, 187 who met the criteria were enrolled in the study: 32 with overt pneumothorax and 81 with occult pneumothorax. Among all of the pneumothorax cases, the proportion of occult pneumothorax was 71.7% (81/113), and its incidence in all admitted trauma victims was 5.0% (81/1621). Subcutaneous emphysema and rib fractures on supine CXR were risk factors for occult pneumothorax. Six patients underwent delayed tube thoracostomy; however, none had serious complications. Given that occult pneumothorax is common in patients with blunt chest trauma, treatment plans should be established that consider the possibility of pneumothorax. However, the prognosis is generally good, and follow-up is an alternative.

Remnant cholesterol, low-density lipoprotein cholesterol, and incident cardiovascular disease among Koreans: a national population-based study.

AIMS: The synergistic association of remnant cholesterol (remnant-C) and low-density lipoprotein cholesterol (LDL-C) levels with incident cardiovascular disease (CVD) in various subgroups of Koreans was investigated. METHODS AND RESULTS: Using the national health insurance data, we included subjects aged between 40 and 70 years without a history of CVD and at least two health screenings between 2009 and 2011. The subjects were divided into four groups by LDL-C and remnant-C levels. The primary outcome was CVD, which occurred between 2014 and 2017. Among 3 686 034 (45.6% women) subjects, 144 004 cardiovascular events occurred. Individuals in both high LDL-C and high remnant-C [hazard ratio (HR) 1.266, 95% confidence interval (CI) 1.243-1.289; 7.9%], high LDL-C only (HR 1.098, 95% CI 1.083-1.113; 21.2%), and high remnant-C only groups (HR 1.102, 95% CI 1.087-1.118; 19.1%) had higher risks of CVD than those in the reference group (LDL-C < 3.4 mmol/L and remnant-C < 0.8 mmol/L; 51.8%). A continuous and linear increase in CVD risk was found in those with higher remnant-C levels after adjustment for several confounders, including LDL-C levels. The association of remnant-C ≥ 0.8 mmol/L with an increased CVD risk was consistent across various strata. CONCLUSIONS: Combined high remnant-C and LDL-C levels confer a higher CVD risk than that individually. Elevated remnant-C values independent of LDL-C levels were associated with a risk of incident CVD. Remnant cholesterol levels in addition to LDL-C levels are important considerations in risk stratification for the primary prevention of CVD.

Since remnant-C has recently emerged as a potential risk factor for CVD, the synergistic association of LDL-C and remnant-C with CVD has been investigated among 3 686 034 Koreans (45.6% women) without preceding CVD using nationwide population-based big data. Remnant cholesterol remained proportional to the risk of incident CVD after adjusting for multiple variables, including LDL-C levels.Low-density lipoprotein cholesterol and remnant-C synergistically contributed to incident CVD.

Impact of the ultra-long 48 mm drug-eluting stent on procedural and clinical outcomes in patients with diffuse long coronary artery disease.

BACKGROUND: Diffuse coronary artery disease (CAD) is a prognostic factor after percutaneous coronary intervention (PCI) and requires multiple overlapping stent implantations. HYPOTHESIS: We investigated the impact of ultra-long 48 mm drug-eluting stent (DES) on procedural and clinical outcomes in real-world practice. METHODS: Patients who underwent DES implantation for a lesion length of >40 mm were selected from a prospective registry between 2019 and 2021. Patients treated with one or more ultra-long 48 mm DES were in the ultra-long DES group (n = 221). The others comprised the conventional DES group (n = 428). Procedural and clinical outcomes were compared after propensity score matching (PSM). The primary endpoint was a device-oriented composite outcome (DOCO) consisting of cardiac death, target vessel-related myocardial infarction, and target lesion revascularization at 1-year follow-up. RESULTS: After PSM, 158 matched pairs of patients showed no differences in the baseline clinical and angiographic characteristics. The stent delivery failure rate, the use of guide-extension catheter or anchor balloon technique, and the procedural success rate were similar for both groups. Approximately two-thirds of lesions could be treated with one DES in the ultra-long DES group. At 1-year follow-up, the DOCO was similar for both groups (2.5% vs. 0.6%, p = .168). CONCLUSIONS: In daily clinical practice, ultra-long DES implantation is as safe and effective as multiple overlapping conventional DES implants in treating diffuse long CAD. However, ultra-long DES can reduce the number of stents. (Trial Registration: ClinicalTrials.gov Identifier: NCT02038127).

Effect of Obesity and High-Density Lipoprotein Concentration on the Pathological Characteristics of Alzheimer's Disease in High-Fat Diet-Fed Mice.

The typical pathological features of Alzheimer's disease (AD) are the accumulation of amyloid plaques in the brain and reactivity of glial cells such as astrocytes and microglia. Clinically, the development of AD and obesity are known to be correlated. In this study, we analyzed the changes in AD pathological characteristics in 5XFAD mice after obesity induction through a high-fat diet (HFD). Surprisingly, high-density lipoprotein and apolipoprotein AI (APOA-I) serum levels were increased without low-density lipoprotein alteration in both HFD groups. The reactivity of astrocytes and microglia in the dentate gyrus of the hippocampus and fornix of the hypothalamus in 5XFAD mice was decreased in the transgenic (TG)-HFD high group. Finally, the accumulation of amyloid plaques in the dentate gyrus region of the hippocampus was also significantly decreased in the TG-HFD high group. These results suggest that increased high-density lipoprotein level, especially with increased APOA-I serum level, alleviates the pathological features of AD and could be a new potential therapeutic strategy for AD treatment.

Reference diameter and characteristics of the distal radial artery based on ultrasonographic assessment.

BACKGROUND/AIMS: While distal radial artery (DRA) access is increasingly being used for diagnostic coronary angiography, limited information is available regarding DRA size. We aimed to determine the DRA reference diameters of Korean patients and identify the predictors of DRA diameter < 2.3 mm. METHODS: The outer bilateral DRA diameters were assessed using a linear ultrasound probe in 1,162 consecutive patients who underwent transthoracic echocardiography. The DRA diameter was measured by the perpendicular angle in the dorsum of the hand, and the average values were compared by sex. DRA diameter < 2.3 mm was defined as unsuitable for routine diagnostic coronary angiography using a 5 Fr introducer sheath. RESULTS: The mean DRA diameters were 2.31 ± 0.43 mm (right) and 2.35 ± 0.45 mm (left). The DRA was smaller in women than men (right: 2.15 ± 0.38 mm vs. 2.43 ± 0.44 mm, p < 0.001; left: 2.18 ± 0.39 mm vs. 2.47 ± 0.45 mm, p < 0.001). The DRA diameter was approximately 20% smaller than the radial artery diameter. A total of 630 (54.2%) and 574 (49.4%) patients had DRA diameter < 2.3 mm in the right and left hands, respectively. Female sex, low body mass index (BMI), and low body surface area (BSA) were significant predictors of DRA diameter < 2.3 mm. CONCLUSION: We provided reference DRA diameters for Korean patients. Approximately 50% of the studied patients had DRA diameter < 2.3 mm. Female sex, low BMI, and low BSA remained significant predictors of DRA diameter < 2.3 mm.

Differential association of metabolic syndrome and low-density lipoprotein cholesterol with incident cardiovascular disease according to sex among Koreans: a national population-based study.

AIMS: To investigate sex differences in the association of metabolic syndrome (MetS) and/or low-density lipoprotein cholesterol (LDL-C) with the incidence of cardiovascular and cerebrovascular disease (CCVD). METHODS AND RESULTS: A total of 4 702 458 individuals, aged between 40 and 70, without a previous diagnosis of CCVD, underwent at least two health screenings between 2009 and 2011. Of them, 4 193 878 individuals (48.6% women) fulfilled the study requirements. The main outcome measured was the incidence of CCVD. By the end of 2017, 68 921 CCVD events occurred. Men in high LDL-C only, MetS only, and both MetS and high LDL-C groups had higher risks of CCVD. Women in MetS only and both MetS and high LDL-C groups, but not those in high LDL-C only group, had higher risks of CCVD than those in the reference group. The effect of the interaction between the presence of MetS and high LDL-C levels on the primary outcome was found among women (P for interaction 0.016) but not among men (P for interaction 0.897). A combination of MetS and LDL-C > 3.4 mmol/L increased the risk of CCVD as compared to MetS or LDL-C > 3.4 mmol/L alone in both men and women. CONCLUSIONS: Metabolic syndrome confers an increased risk of CCVD irrespective of sexes; LDL-C > 3.4 mmol/L alone has a greater influence on CCVD occurrence in men than in women. Metabolic syndrome and high LDL-C beget a synergistically detrimental impact on the incidence of CCVD in both men and women. Treatment of dyslipidaemia and metabolic syndrome should be tailored according to patient characteristics.

Myeloid-Specific PTP1B Deficiency Attenuates Inflammation-Induced and Ovariectomy-Induced Bone Loss in Mice by Inhibiting Osteoclastogenesis.

The differentiation and activity of bone-resorbing osteoclasts are tightly regulated to maintain the homeostasis of healthy bones. In this study, the role of protein tyrosine phosphatase 1B (PTP1B) during osteoclastogenesis was studied in myeloid-specific Ptpn1-deficient (conditional knockout [cKO]) mice. The mRNA and protein expression of PTP1B increased during the formation of mature osteoclasts from mouse bone macrophages on stimulation with macrophage-colony stimulating factor (M-CSF) and receptor activator of nuclear factor κB ligand (RANKL). The Ptpn1 cKO mice exhibited increased femoral trabecular bone volume with a decreased number and activity of osteoclasts compared with control mice. The in vitro culture of osteoclast precursors corroborated the inhibition of osteoclastogenesis in cKO cells compared with control, with concomitantly decreased RANKL-dependent proliferation, lower osteoclast marker gene expression, reduced nuclear expression of nuclear factor of activated T cells cytoplasmic 1 (NFATc1), diminished intracellular Ca2+ oscillations, and increased phosphorylation of proto-oncogene tyrosine-protein kinase Src on inhibitory tyrosine residue. In a ligature-induced periodontitis model, Ptpn1 cKO mice exhibited attenuated osteoclastogenesis and alveolar bone loss following the induction of inflammation. The Ptpn1-deficient mice were similarly protected from ovariectomy-induced bone loss compared with control mice. These results provide a novel regulatory role of PTP1B in osteoclastogenesis and suggest a potential as a therapeutic target for bone-lytic diseases. © 2021 American Society for Bone and Mineral Research (ASBMR).

Five-year clinical outcomes of the first Korean-made sirolimus-eluting coronary stent with abluminal biodegradable polymer.

ABSTRACT: This study evaluated the 5-year clinical outcomes of the Genoss DES, the first Korean-made sirolimus-eluting coronary stent with abluminal biodegradable polymer.We previously conducted the first-in-patient prospective, multicenter, randomized trial with a 1:1 ratio of patients using the Genoss DES and Promus Element stents; the angiographic and clinical outcomes of the Genoss DES stent were comparable to those of the Promus Element stent. The primary endpoint was major adverse cardiac events (MACE), which was a composite of death, myocardial infarction (MI), and target lesion revascularization (TLR) at 5 years.We enrolled 38 patients in the Genoss DES group and 39 in the Promus Element group. Thirty-eight patients (100%) from the Genoss DES group and 38 (97.4%) from the Promus Element group were followed up at 5 years. The rates of MACE (5.3% vs 12.8%, P = .431), death (5.3% vs 10.3%, P = .675), TLR (2.6% vs 2.6%, P = 1.000), and target vessel revascularization (TVR) (7.9% vs 2.6%, P = .358) at 5 years did not differ significantly between the groups. No TLR or target vessel revascularization was reported from years 1 to 5 after the index procedure, and no MI or stent thrombosis occurred in either group during 5 years.The biodegradable polymer Genoss DES and durable polymer Promus Element stents showed comparable low rates of MACE at the 5-year clinical follow-up.

Nucleocapsid and Spike Proteins of SARS-CoV-2 Drive Neutrophil Extracellular Trap Formation.

Patients with severe coronavirus disease 2019 (COVID-19) demonstrate dysregulated immune responses including exacerbated neutrophil functions. Massive neutrophil infiltrations accompanying neutrophil extracellular trap (NET) formations are also observed in patients with severe COVID-19. However, the mechanism underlying severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced NET formation has not yet been elucidated. Here we show that 2 viral proteins encoded by SARS-CoV-2, the nucleocapsid protein and the whole spike protein, induce NET formation from neutrophils. NET formation was ROS-independent and was completely inhibited by the spleen tyrosine kinase inhibition. The inhibition of p38 MAPK, protein kinase C, and JNK signaling pathways also inhibited viral protein-induced NET formation. Our findings demonstrate one method by which SARS-CoV-2 evades innate immunity and provide a potential target for therapeutics to treat patients with severe COVID-19.

Extracellular vesicles from dHL-60 cells as delivery vehicles for diverse therapeutics.

Extracellular vesicles (EVs) are membrane-derived heterogeneous vesicles that mediate intercellular communications. They have recently been considered as ideal vehicles for drug-delivery systems, and immune cells are suggested as a potential source for drug-loaded EVs. In this study, we investigated the possibility of neutrophils as a source for drug-loaded EVs. Neutrophil-like differentiated human promyelocytic leukemia cells (dHL-60) produced massive amounts of EVs within 1 h. The dHL-60 cells are also easily loaded with various cargoes such as antibiotics (penicillin), anticancer drug (paclitaxel), chemoattractant (MCP-1), miRNA, and Cas9. The EVs derived from the dHL-60 cells showed efficient incorporation of these cargoes and significant effector functions, such as bactericidal activity, monocyte chemotaxis, and macrophage polarization. Our results suggest that neutrophils or neutrophil-like promyelocytic cells could be an attractive source for drug-delivery EVs.