Xanthine oxidoreductase inhibition ameliorates high glucose-induced glomerular endothelial injury by activating AMPK through the purine salvage pathway.

Xanthine oxidoreductase (XOR) contributes to reactive oxygen species production. We investigated the cytoprotective mechanisms of XOR inhibition against high glucose (HG)-induced glomerular endothelial injury, which involves activation of the AMP-activated protein kinase (AMPK). Human glomerular endothelial cells (GECs) exposed to HG were subjected to febuxostat treatment for 48 h and the expressions of AMPK and its associated signaling pathways were evaluated. HG-treated GECs were increased xanthine oxidase/xanthine dehydrogenase levels and decreased intracellular AMP/ATP ratio, and these effects were reversed by febuxostat treatment. Febuxostat enhanced the phosphorylation of AMPK, the activation of peroxisome proliferator-activated receptor (PPAR)-gamma coactivator (PGC)-1α and PPAR-α and suppressed the phosphorylation of forkhead box O (FoxO)3a in HG-treated GECs. Febuxostat also decreased nicotinamide adenine dinucleotide phosphate oxidase (Nox)1, Nox2, and Nox4 expressions; enhanced superoxide dismutase activity; and decreased malondialdehyde levels in HG-treated GECs. The knockdown of AMPK inhibited PGC-1α-FoxO3a signaling and negated the antioxidant effects of febuxostat in HG-treated GECs. Despite febuxostat administration, the knockdown of hypoxanthine phosphoribosyl transferase 1 (HPRT1) also inhibited AMPK-PGC-1α-FoxO3a in HG-treated GECs. XOR inhibition alleviates oxidative stress by activating AMPK-PGC-1α-FoxO3a signaling through the HPRT1-dependent purine salvage pathway in GECs exposed to HG conditions.

Association between coenzyme Q 10-related genetic polymorphisms and statin-associated myotoxicity in Korean stroke patients.

Introduction: The purpose of this study is to identify the relationship between coenzyme Q 10 (CoQ10)-related gene polymorphisms and statin-related myotoxicity (SRM). Methods: We retrospectively analyzed prospectively collected samples from February to May 2021. To investigate the association between CoQ10-related genetic factors and SRM, we selected 37 single nucleotide polymorphisms from five genes (COQ2, COQ3, COQ5, COQ6, and COQ7). The odds ratio (OR) and adjusted OR with 95% confidence intervals (CI) were calculated for univariate and multivariable logistic regression analyses, respectively. Results: A total of 688 stroke patients were included in the analysis, including 56 SRM cases. In the multivariable analysis, two models were constructed using demographic factors only in model I, and demographic and genetic factors in model II. Compared to other statins, atorvastatin decreased the SRM risk whereas ezetimibe use increased the SRM risk in model I and model II. Patients with COQ2 rs4693075 G allele, COQ3 rs11548336 TT genotype, and COQ5 rs10849757 A allele had a 2.9-fold (95% CI: 1.6-5.3), 1.9-fold (95% CI: 1.1-3.5), and 3.3-fold (95% CI: 1.5-8.3) higher risk of SRM, respectively. Conclusion: This study could be utilized to develop a personalized medicine strategy in patients treated with statins.

Transporter Genes and statin-induced Hepatotoxicity.

PURPOSE: Hepatotoxicity has emerged as a major cause of statin treatment interruption. Although organic anion-transporting polypeptide 1B1 (SLCO1B1), multidrug resistance protein 1 (ABCB1), and breast cancer resistance protein (ABCG2) have been identified as transporters of statins, knowledge of their role in statin-associated hepatotoxicity remains limited. Therefore, we aimed to conduct a comprehensive analysis to elucidate the association between hepatotoxicity and SLCO1B1, ABCB1, and ABCG2 polymorphisms. METHODS: This study retrospectively analyzed prospectively collected samples. We selected 10 single nucleotide polymorphisms (SNPs) of SLCO1B1, 9 SNPs of ABCB1, and 12 SNPs of ABCG2. We developed two models for multivariable analyses (Model I: clinical factors only; Model II: both clinical and genetic factors), and the attributable risk (%) of variables in Model II was determined. RESULTS: Among 851 patients, 66 (7.8%) developed hepatotoxicity. In Model I, lipophilic statins, atrial fibrillation (Afib), and diabetes mellitus showed a significant association with hepatotoxicity. In Model II, lipophilic statins and Afib, SLCO1B1 rs11045818 A allele, SLCO1B1 rs4149035 T allele, and ABCG2 rs2622629 TT genotype were associated with higher hepatotoxicity risk. Among them, the SLCO1B1 rs11045818 A allele exhibited the highest attributable risk (93.2%). The area under the receiver operating characteristic curve in Model I was 0.62 (95% CI: 0.55-0.69), and it was increased to 0.71 in Model II (95% CI: 0.64-0.77). CONCLUSION: This study investigated the correlation between hepatotoxicity and polymorphisms of transporter genes in patients taking statins. The findings could help improve personalized treatments for patients receiving statin therapy.

Functional Outcomes Associated With Blood Pressure Decrease After Endovascular Thrombectomy.

Importance: The associations between blood pressure (BP) decreases induced by medication and functional outcomes in patients with successful endovascular thrombectomy remain uncertain. Objective: To evaluate whether BP reductions induced by intravenous BP medications are associated with poor functional outcomes at 3 months. Design, Setting, and Participants: This cohort study was a post hoc analysis of the Outcome in Patients Treated With Intra-Arterial Thrombectomy-Optimal Blood Pressure Control trial, a comparison of intensive and conventional BP management during the 24 hours after successful recanalization from June 18, 2020, to November 28, 2022. This study included 302 patients who underwent endovascular thrombectomy, achieved successful recanalization, and exhibited elevated BP within 2 hours of successful recanalization at 19 stroke centers in South Korea. Exposure: A BP decrease was defined as at least 1 event of systolic BP less than 100 mm Hg. Patients were divided into medication-induced BP decrease (MIBD), spontaneous BP decrease (SpBD), and no BP decrease (NoBD) groups. Main Outcomes and Measures: The primary outcome was a modified Rankin scale score of 0 to 2 at 3 months, indicating functional independence. Primary safety outcomes were symptomatic intracerebral hemorrhage within 36 hours and mortality due to index stroke within 3 months. Results: Of the 302 patients (median [IQR] age, 75 [66-82] years; 180 [59.6%] men), 47 (15.6%)were in the MIBD group, 39 (12.9%) were in the SpBD group, and 216 (71.5%) were in the NoBD group. After adjustment for confounders, the MIBD group exhibited a significantly smaller proportion of patients with functional independence at 3 months compared with the NoBD group (adjusted odds ratio [AOR], 0.45; 95% CI, 0.20-0.98). There was no significant difference in functional independence between the SpBD and NoBD groups (AOR, 1.41; 95% CI, 0.58-3.49). Compared with the NoBD group, the MIBD group demonstrated higher odds of mortality within 3 months (AOR, 5.15; 95% CI, 1.42-19.4). The incidence of symptomatic intracerebral hemorrhage was not significantly different among the groups (MIBD vs NoBD: AOR, 1.89; 95% CI, 0.54-5.88; SpBD vs NoBD: AOR, 2.75; 95% CI, 0.76-9.46). Conclusions and Relevance: In this cohort study of patients with successful endovascular thrombectomy after stroke, MIBD within 24 hours after successful recanalization was associated with poor outcomes at 3 months. These findings suggested lowering systolic BP to below 100 mm Hg using BP medication might be harmful.

Improved Oral Health Is Associated with a Lower Risk of Late Onset Ankylosing Spondylitis: A Nationwide Cohort Study.

Background: The aim of this study was to evaluate the association of oral health status and habits with the occurrence of ankylosing spondylitis (AS) in a nationwide population-based cohort in a longitudinal setting. Methods: A total of 2,415,963 individuals aged 40-79 years who underwent oral health examinations were included from the National Health Insurance Service-National Health Screening (NHIS-HEALS) cohort of Korea between 2003 and 2004. The occurrence of AS was analyzed according to the oral health status and oral hygiene habits. Results: Among 2,271,221 of the participants, AS occurred in 6366 (0.3%) participants over 16.7 years. The likelihood of AS was higher in participants who had periodontitis (hazard ratio [HR]: 1.33, 95% confidence interval [CI]: 1.20-1.46, p < 0.0001) and more missing teeth (HR: 1.68, 95% CI: 1.42-1.99, p < 0.0001). However, better oral hygiene habits such as frequent tooth brushing (HR: 0.77, 95% CI: 0.71-0.83, p < 0.0001) and a history of dental scaling within the last year (HR 0.88, 95% CI 0.82-0.95, p = 0.001) were associated with a lower occurrence of AS. Conclusions: Periodontitis and an increased number of missing teeth could be related to the occurrence of late-onset AS. Improved oral hygiene care may attenuate the likelihood of late-onset AS.

Resolved Proteinuria May Attenuate the Risk of Heart Failure: A Nationwide Population-Based Cohort Study.

Although proteinuria is a risk factor for heart failure (HF), proteinuria can be reversible or persistent. Our objective was to explore the link between changes in the proteinuria status and the risk of HF. We included participants from a Korean national health screening cohort who underwent health examinations in 2003-2004 and 2005-2006 and had no history of HF. Participants were categorized into four groups: proteinuria-free, proteinuria-resolved, proteinuria-developed, and proteinuria-persistent. The outcome of interest was the occurrence of HF. The study included 1,703,651 participants, among whom 17,543 (1.03%) were in the proteinuria-resolved group and 4585 (0.27%) were in the proteinuria-persistent group. After a median follow-up period of 14.04 years (interquartile range 14.19-15.07), HF occurred in 75,064 (4.41%) participants. A multivariable Cox proportional hazards regression analysis indicated that the proteinuria-persistent group had a higher risk of HF compared with the proteinuria-free group (hazard ratio (HR): 2.19, 95% confidence interval (CI): 2.03-2.36, p < 0.001). In a further pairwise comparison analysis, participants in the proteinuria-resolved group had a relatively low risk of HF compared with those in the proteinuria-persistent group (HR: 0.64, 95% CI: 0.58-0.70, p < 0.001). In conclusion, the risk of HF can change with alterations in the proteinuria status.

Omega-3 Fatty Acids Attenuate Renal Fibrosis via AMPK-Mediated Autophagy Flux Activation.

The unilateral ureteral obstruction (UUO) injury model is well-known to mimic human chronic kidney disease, promoting the rapid onset and development of kidney injury. ω3-poly unsaturated fatty acids (PUFAs) have been observed to protect against tissue injury in many disease models. In this study, we assessed the efficacy of ω3-PUFAs in attenuating UUO injury and investigated their mechanism of action. The immortalized human proximal tubular cells human kidney-2 (HK2) were incubated for 72 h with docosahexaenoic acid (DHA) or eicosapentaenoic acid (EPA) in various concentrations, in the presence or absence of transforming growth factor (TGF)-ß. DHA/EPA reduced the epithelial-mesenchymal transition in the TGF-ß-treated HK2 cells by enhancing autophagy flux and adenosine monophosphate-activated protein kinase (AMPK) phosphorylation. C57BL/6 mice were divided into four groups and treated as follows: sham (no treatment, n = 5), sham + ω3-PUFAs (n = 5), UUO (n = 10), and UUO + ω3-PUFAs (n = 10). Their kidneys and blood were harvested on the seventh day following UUO injury. The kidneys of the ω3-PUFAs-treated UUO mice showed less oxidative stress, inflammation, and fibrosis compared to those of the untreated UUO mice. Greater autophagic flux, higher amounts of microtubule-associated protein 1A/1B-light chain 3 (LC3)-II, Beclin-1, and Atg7, lower amounts of p62, and higher levels of cathepsin D and ATP6E were observed in the kidneys of the omega-3-treated UUO mice compared to those of the control UUO mice. In conclusion, ω3-PUFAs enhanced autophagic activation, leading to a renoprotective response against chronic kidney injury.

Intensive vs Conventional Blood Pressure Lowering After Endovascular Thrombectomy in Acute Ischemic Stroke: The OPTIMAL-BP Randomized Clinical Trial.

Importance: Optimal blood pressure (BP) control after successful reperfusion with endovascular thrombectomy (EVT) for patients with acute ischemic stroke is unclear. Objective: To determine whether intensive BP management during the first 24 hours after successful reperfusion leads to better clinical outcomes than conventional BP management in patients who underwent EVT. Design, Setting, and Participants: Multicenter, randomized, open-label trial with a blinded end-point evaluation, conducted across 19 stroke centers in South Korea from June 2020 to November 2022 (final follow-up, March 8, 2023). It included 306 patients with large vessel occlusion acute ischemic stroke treated with EVT and with a modified Thrombolysis in Cerebral Infarction score of 2b or greater (partial or complete reperfusion). Interventions: Participants were randomly assigned to receive intensive BP management (systolic BP target <140 mm Hg; n = 155) or conventional management (systolic BP target 140-180 mm Hg; n = 150) for 24 hours after enrollment. Main Outcomes and Measures: The primary outcome was functional independence at 3 months (modified Rankin Scale score of 0-2). The primary safety outcomes were symptomatic intracerebral hemorrhage within 36 hours and death related to the index stroke within 3 months. Results: The trial was terminated early based on the recommendation of the data and safety monitoring board, which noted safety concerns. Among 306 randomized patients, 305 were confirmed eligible and 302 (99.0%) completed the trial (mean age, 73.0 years; 122 women [40.4%]). The intensive management group had a lower proportion achieving functional independence (39.4%) than the conventional management group (54.4%), with a significant risk difference (-15.1% [95% CI, -26.2% to -3.9%]) and adjusted odds ratio (0.56 [95% CI, 0.33-0.96]; P = .03). Rates of symptomatic intracerebral hemorrhage were 9.0% in the intensive group and 8.1% in the conventional group (risk difference, 1.0% [95% CI, -5.3% to 7.3%]; adjusted odds ratio, 1.10 [95% CI, 0.48-2.53]; P = .82). Death related to the index stroke within 3 months occurred in 7.7% of the intensive group and 5.4% of the conventional group (risk difference, 2.3% [95% CI, -3.3% to 7.9%]; adjusted odds ratio, 1.73 [95% CI, 0.61-4.92]; P = .31). Conclusions and Relevance: Among patients who achieved successful reperfusion with EVT for acute ischemic stroke with large vessel occlusion, intensive BP management for 24 hours led to a lower likelihood of functional independence at 3 months compared with conventional BP management. These results suggest that intensive BP management should be avoided after successful EVT in acute ischemic stroke. Trial Registration: ClinicalTrials.gov Identifier: NCT04205305.

Association of total cholesterol variability with risk of venous thromboembolism: A nationwide cohort study.

BACKGROUND: The effects of total cholesterol (TC) on coagulation and hemostatic systems could contribute to the development of venous thromboembolism (VTE). We investigated this possible association using TC variability. METHODS: From the Korean NHIS-HEALS database, 1,236,589 participants with health screenings between 2003 and 2008 were included. TC variability was assessed using various parameters, including the coefficient of variation (CV), standard deviation (SD), and variability independent of mean (VIM). Occurrence of VTE was established by identifying at least two medical claims with a diagnostic code including various types of VTE: deep vein thrombosis (DVT) (I80.2-80.3), pulmonary embolism (PE) (I26, I26.0, I26.9), intraabdominal VTE (I81, I82, I82.2-82.3), and other VTE (I82.8-82.9). RESULTS: Throughout the study's median follow-up period of 12.4 years (interquartile range 12.2-12.6) years, TC levels were assessed a total of 5,702,800 times. VTE occurred in 11,769 (1.08%) patients (DVT (4,708 (0.43%)), PE (3,109 (0.29%)), intraabdominal VTE (5,215 (0.48%)), and other VTE (4,794, (0.44%)). As a result, there was gradual association was observed between higher TC variability and occurrence of VTE. Multivariable analysis showed that quartile of TC variability using CV showed a positive correlation with the occurrence of VTE (adjusted hazard ratio (the highest versus lowest quartile), 1.14, 95% confidence interval, 1.08-1.20, p < 0.001). This result remained consistent applying to SD and VIM. In addition, higher quartile of TC variability was consistently associated with the development of various types of VTE in subgroup analysis. CONCLUSIONS: Increased TC variability may be associated with increased VTE risk. This analysis highlights the importance of maintaining stable TC levels to prevent the development of VTE.

ω-3 Polyunsaturated Fatty Acids Improve the Blood-Brain-Barrier Integrity in Contrast-Induced Blood-Brain-Barrier Injury in Uremic Mice.

In patients with chronic kidney disease, the need for examinations using contrast media (CM) increases because of underlying diseases. Although contrast agents can affect brain cells, the blood-brain barrier (BBB) protects against brain-cell damage in vivo. However, uremia can disrupt the BBB, increasing the possibility of contrast-agent-induced brain-cell damage in patients with chronic kidney disease (CKD). ω-3 polyunsaturated fatty acids (PUFAs) have shown protective effects on various neurological disorders, including uremic brain injury. This study examined whether ω-3 PUFAs attenuate damage to the BBB caused by uremia and contrast agents in a uremic mouse model and evaluated its associated mechanisms. C57BL/6 mice (eight weeks old, male) and fat-1 mice (b6 background/eight weeks old, male) were divided into groups according to uremic induction, CM, and ω-3 PUFA administration. Uremia was induced via 24 h ischemia-reperfusion (IR) renal injury. One day after CM treatment, the brain tissue, kidney tissue, and blood were collected. The expression levels of glial fibrillary acidic protein (GFAP), claudin 5, CD31, laminin α4, and laminin α5 increased in ω-3 PUFA + CM-treated uremic mice and the brain of fat-1 + CM-treated uremic mice compared with those in the brains of CM-treated uremic mice. The pro-apoptotic protein expression decreased, whereas the anti-apoptotic proteins increased in ω-3 PUFA + CM-treated uremic mice and fat-1 + CM-treated uremic mice compared with CM-treated uremic mice. In addition, the brain-expression levels of p-JNK, p-P53, and p-P38 decreased in the ω-3 PUFA + CM-treated uremic mice and fat-1 + CM-treated uremic mice compared with those in wild-type uremic mice. Our results confirm that uremic toxin and CM damage the BBB and cause brain-cell death. ω-3 PUFAs play a role in BBB protection caused by CM in uremic mice.

Cancer Prediction With Machine Learning of Thrombi From Thrombectomy in Stroke: Multicenter Development and Validation.

BACKGROUND: We aimed to develop and validate machine learning models to diagnose patients with ischemic stroke with cancer through the analysis of histopathologic images of thrombi obtained during endovascular thrombectomy. METHODS: This was a retrospective study using a prospective multicenter registry which enrolled consecutive patients with acute ischemic stroke from South Korea who underwent endovascular thrombectomy. This study included patients admitted between July 1, 2017 and December 31, 2021 from 6 academic university hospitals. Whole-slide scanning was performed for immunohistochemically stained thrombi. Machine learning models were developed using transfer learning with image slices as input to classify patients into 2 groups: cancer group or other determined cause group. The models were developed and internally validated using thrombi from patients of the primary center, and external validation was conducted in 5 centers. The model was also applied to patients with hidden cancer who were diagnosed with cancer within 1 month of their index stroke. RESULTS: The study included 70 561 images from 182 patients in both internal and external datasets (119 patients in internal and 63 in external). Machine learning models were developed for each immunohistochemical staining using antibodies against platelets, fibrin, and erythrocytes. The platelet model demonstrated consistently high accuracy in classifying patients with cancer, with area under the receiver operating characteristic curve of 0.986 (95% CI, 0.983-0.989) during training, 0.954 (95% CI, 0.937-0.972) during internal validation, and 0.949 (95% CI, 0.891-1.000) during external validation. When applied to patients with occult cancer, the model accurately predicted the presence of cancer with high probabilities ranging from 88.5% to 99.2%. CONCLUSIONS: Machine learning models may be used for prediction of cancer as the underlying cause or detection of occult cancer, using platelet-stained immunohistochemical slide images of thrombi obtained during endovascular thrombectomy.

Association of gamma-glutamyl transferase variability with risk of osteoporotic fractures: A nationwide cohort study.

OBJECTIVES: Gamma-glutamyl transferase (GGT) is related to inflammation, osteoporosis, and vascular diseases. Recently, changes in metabolic parameters have been proposed as osteoporosis biomarkers. We aimed to assess longitudinally the association of GGT variability with osteoporotic fractures. METHODS: From the National Health Insurance Service-Health Screening Cohort database, participants who underwent three or more health examinations between 2003 and 2008 were included (n = 1,072,432). Variability indexes were as follows: (1) coefficient of variation (CV), (2) standard deviation (SD), and (3) variability independent of the mean (VIM). The primary outcome was occurrence of osteoporotic fracture, defined as identification of one of the following international classification of diseases-10 codes: vertebral fractures (S22.0, S22.1, S32.0, S32.7, T08, M48.4, M48.5, M49.5), hip fractures (S72.0, S72.1), distal radius fractures (S52.5, S52.6), or humerus fractures (S42.2, S42.3). RESULTS: During a median of 12.3 years (interquartile range 12.1-12.6), osteoporotic fractures occurred in 49,677 (4.6%) participants. In multivariable analysis, GGT variability based on CV positively correlated with the occurrence of osteoporotic fracture (adjusted hazard ratio [HR] of the highest quartile compared with the lowest quartile 1.15, 95% confidence interval [CI] 1.12-1.18, P < 0.001). These results were consistent even when GGT variability was defined by SD (adjusted HR 1.22, 95% CI 1.19-1.25, P < 0.001) and VIM (adjusted HR 1.12, 95% CI 1.09-1.15, P < 0.001). CONCLUSIONS: Increased GGT variability is associated with an increased risk of osteoporotic fractures in the Korean population. Maintaining constant and stable GGT level may help reduce the risk of osteoporotic fractures.

Association of triglyceride/high-density lipoprotein cholesterol ratio with severe complications of COVID-19.

Background: The coronavirus disease 2019 (COVID-19) caused by the SARS-CoV-2 virus can lead to serious complications such as respiratory failure, requiring mechanical ventilation or ICU care, and can even result in death, especially in older patients with comorbidities. The ratio of triglyceride to high-density lipoprotein cholesterol (TG/HDL), a biomarker of atherosclerotic dyslipidemia and insulin resistance, is related to cardiovascular mortality and morbidity. We aimed to evaluate the link between serious complications of COVID-19 and TG/HDL in the general population. Methods: We conducted a comprehensive analysis of 3,933 COVID-19 patients from a nationwide cohort in Korea spanning from January 1 to June 4, 2020. TG/HDL ratio was calculated from the national health screening examination data underwent before the COVID-19 infection. Serious complications of COVID-19 were defined as a composite of high-flow oxygen therapy, mechanical ventilation, admission to the intensive care unit (ICU), and mortality. We employed logistic regression analysis to investigate the relationship between the TG/HDL ratio and the likelihood of developing severe complications within 2 months of the diagnosis. To visualize this association, we used a smoothing spline plot based on the generalized additive regression model. Multivariate analysis was performed with adjustment for age, gender, body mass index, lifestyle measures, and comorbidities. Results: Among the 3,933 COVID-19 patients, the proportion of serious complications was 7.53%. Regarding individual outcomes, the number of patients who received high-flow oxygen therapy, mechanical ventilation, ICU care, and died was 84 (2.14%), 122 (3.10%), 173 (4.40%), and 118 (3.00%), respectively. In the multivariable logistic regression, a positive association was found between TG/HDL ratio and serious complications of COVID-19 (adjusted OR, 1.09; 95% CI [1.03-1.15], p = 0.004). Conclusion: Our study revealed a significant positive association between TG/HDL ratio and the risk of developing severe complications in COVID-19-infected patients. While this finding provides valuable insight into the potential prognostic role of TG/HDL ratio in COVID-19, further studies are needed to fully elucidate the underlying mechanisms behind this relationship.

Corrigendum: Clinical implications of atrial fibrillatioN detection using wearabLE devices in patients with cryptogenic stroke (CANDLE-AF) trial: Design and rationale.

[This corrects the article DOI: 10.3389/fcvm.2022.837958.].

Association of gamma-glutamyl transferase variability with risk of venous thrombosis.

Gamma-glutamyl transferase (GGT) is a biomarker of inflammation, and is known to be associated with stroke and atrial fibrillation. Venous thromboembolism (VT), a not uncommon thrombotic disorder, shares similar mechanisms with other thrombotic disorders including these stroke and atrial fibrillation. Given these associations, we intended to investigate the potential association between variability in GGT and VT. The study included data from the National Health Insurance Service-Health Screening Cohort, comprising 1,085,105 participants with health examinations 3 or more times from 2003 to 2008. Variability indexes were the coefficient of variation, standard deviation, and variability independent of the mean. The occurrence of venous thromboembolism (VT) was defined with more than one claim of the following ICD-10 codes: deep VT (I80.2-80.3), pulmonary thromboembolism (I26), intraabdominal venous thrombosis (I81, I82.2, I82.3), or other VT (I82.8, I82.9). To determine the relationship of quartiles of GGT with incident VT risk, Kaplan-Meier survival curve and logrank test were used. Cox's proportional hazard regression was used to investigate the risk of VT occurrence by GGT quartile (Q1-Q4). A total of 1,085,105 subjects were incorporated in the analysis, and the average follow-up was 12.4 years (interquartile range 12.2-12.6). VT occurred in 11,769 (1.08%) patients. The GGT level was measured 5,707,768 times in this stud. Multivariable analysis showed that GGT variability were positively associated with the occurrence of VT. Compared to the Q1, the Q4 showed an adjusted HR of 1.15 (95% CI 1.09-1.21, p < 0.001) when using coefficient of variation, 1.24 (95% CI 1.17-1.31, p < 0.001) when using standard deviation, and 1.10 (95% CI 1.05-1.16, p < 0.001) when using variability independent of the mean. Increased variability of GGT may be related to an increased risk of VT. Maintaining a stable GGT level would be beneficial in reducing the risk of VT.

Medical Management of Dyslipidemia for Secondary Stroke Prevention: Narrative Review.

Dyslipidemia is a major risk factor for stroke, following hypertension, diabetes, and smoking, and is an important risk factor for the prevention and treatment of coronary artery disease and peripheral vascular disease, including stroke. Recent guidelines recommend considering low-density lipoprotein cholesterol (LDL-C)-lowering therapies, such as statins (preferably), ezetimibe, or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors to prevent the occurrence or recurrence of stroke, adhering to the "lower is better" approach. In this review, we examined the evidence supporting lipid-lowering medications like statins, ezetimibe, and PCSK9 inhibitors for secondary stroke prevention and dyslipidemia management in different stroke subtypes. Stroke guidelines advocate for administering the maximum tolerable dose of statins as the primary treatment and as soon as possible despite the potential for new-onset diabetes mellitus and possible muscle and liver toxicity due to their demonstrated benefits in secondary prevention of cardiovascular diseases and mortality reduction. When statin use is insufficient for LDL lowering, ezetimibe and PCSK9 inhibitors are recommended as complementary therapies. It is essential to establish lipid-lowering therapy goals based on the stroke subtype and the presence of comorbidities.

Association of Oral Health with Risk of Rheumatoid Arthritis: A Nationwide Cohort Study.

Periodontitis and rheumatoid arthritis (RA) are inflammatory diseases that share many similarities. We aimed to investigate the associations of periodontitis and oral hygiene status and behaviors with RA in a nationwide general population cohort. Participants from the National Health Screening cohort database of Korea who underwent oral health screening by dentists between 2003 and 2004 were included. The occurrence of RA was analyzed according to the presence of periodontitis, oral health examination findings, and behaviors. Overall, 2,239,586 participants were included. During a median of 16.7 years, RA occurred in 27,029 (1.2%) participants. The risk for incident RA was higher when participants had periodontitis (hazard ratio (HR) 1.2, 95% confidence interval (CI), 1.08-1.24) and an increased number of missing teeth (HR 1.5, 95% CI, 1.38-1.69). In contrast, better oral hygiene behaviors, such as a higher frequency of daily tooth brushing (HR 0.76, 95% CI 0.73-0.79, p for trend <0.001) and a recent history of dental scaling (HR 0.96, 95% CI 0.94-0.99), were associated with a lower occurrence of RA. Periodontitis and increased missing teeth were associated with an increased risk of RA. Maintaining good oral hygiene through frequent tooth brushing and regular dental scaling may reduce the risk of RA occurrence.

First-Pass Recanalization with EmboTrap II in Acute Ischemic Stroke (FREE-AIS): A Multicenter Prospective Study.

OBJECTIVE: We aimed to evaluate the efficacy of EmboTrap II in terms of first-pass recanalization and to determine whether it could yield favorable outcomes. MATERIALS AND METHODS: In this multicenter, prospective study, we consecutively enrolled patients who underwent mechanical thrombectomy using EmboTrap II as a front-line device. The primary outcome was the first pass effect (FPE) rate defined by modified Thrombolysis In Cerebral Infarction (mTICI) grade 2c or 3 by the first pass of EmboTrap II. In addition, modified FPE (mFPE; mTICI grade 2b-3 by the first pass of EmboTrap II), successful recanalization (final mTICI grade 2b-3), and clinical outcomes were assessed. We also analyzed the effect of FPE on a modified Rankin Scale (mRS) score of 0-2 at 3 months. RESULTS: Two hundred-ten patients (mean age ± standard deviation, 73.3 ± 11.4 years; male, 55.7%) were included. Ninety-nine patients (47.1%) had FPE, and mFPE was achieved in 150 (71.4%) patients. Successful recanalization was achieved in 191 (91.0%) patients. Among them, 164 (85.9%) patients underwent successful recanalization by exclusively using EmboTrap II. The time from groin puncture to FPE was 25.0 minutes (interquartile range, 17.0-35.0 minutes). Procedure-related complications were observed in seven (3.3%) patients. Symptomatic intracranial hemorrhage developed in 14 (6.7%) patients. One hundred twenty-three (58.9% of 209 completely followed) patients had an mRS score of 0-2. Sixteen (7.7% of 209) patients died during the follow-up period. Patients who had successful recanalization with FPE were four times more likely to have an mRS score of 0-2 than those who had successful recanalization without FPE (adjusted odds ratio, 4.13; 95% confidence interval, 1.59-10.8; p = 0.004). CONCLUSION: Mechanical thrombectomy using the front-line EmboTrap II is effective and safe. In particular, FPE rates were high. Achieving FPE was important for an mRS score of 0-2, even in patients with successful recanalization.

Inhibition of Xanthine Oxidase Protects against Diabetic Kidney Disease through the Amelioration of Oxidative Stress via VEGF/VEGFR Axis and NOX-FoxO3a-eNOS Signaling Pathway.

Xanthine oxidase (XO) is an important source of reactive oxygen species. This study investigated whether XO inhibition exerts renoprotective effects by inhibiting vascular endothelial growth factor (VEGF) and NADPH oxidase (NOX) in diabetic kidney disease (DKD). Febuxostat (5 mg/kg) was administered to streptozotocin (STZ)-treated 8-week-old male C57BL/6 mice via intraperitoneal injection for 8 weeks. The cytoprotective effects, its mechanism of XO inhibition, and usage of high-glucose (HG)-treated cultured human glomerular endothelial cells (GECs) were also investigated. Serum cystatin C, urine albumin/creatinine ratio, and mesangial area expansion were significantly improved in febuxostat-treated DKD mice. Febuxostat reduced serum uric acid, kidney XO levels, and xanthine dehydrogenase levels. Febuxostat suppressed the expression of VEGF mRNA, VEGF receptor (VEGFR)1 and VEGFR3, NOX1, NOX2, and NOX4, and mRNA levels of their catalytic subunits. Febuxostat caused downregulation of Akt phosphorylation, followed by the enhancement of dephosphorylation of transcription factor forkhead box O3a (FoxO3a) and the activation of endothelial nitric oxide synthase (eNOS). In an in vitro study, the antioxidant effects of febuxostat were abolished by a blockade of VEGFR1 or VEGFR3 via NOX-FoxO3a-eNOS signaling in HG-treated cultured human GECs. XO inhibition attenuated DKD by ameliorating oxidative stress through the inhibition of the VEGF/VEGFR axis. This was associated with NOX-FoxO3a-eNOS signaling.

Oral Health and Risk of Retinal Vascular Occlusions: A Nationwide Cohort Study.

Retinal vascular occlusions are a common cause of visual loss. The association between oral health and the risk of retinal vascular occlusions remains unknown. We investigated whether oral health was associated with the risk of retinal vascular occlusions. We conducted a retrospective cohort study including 138,484 participants who completed a national health screening program with an oral health examination from the National Health Insurance Service-National Health Screening Cohort (NHIS-HEALS) 2002-2015. Oral health markers, such as the presence of periodontitis, tooth loss, and dental caries, and the frequency of daily tooth brushing, were evaluated. The primary outcome was the occurrence of retinal vascular occlusions up to December 2015. In total, 2533 participants developed retinal vascular occlusions (215 with retinal artery occlusion, 1686 with retinal vein occlusion, 632 with unspecified retinal vascular occlusion). In the multivariable Cox regression analysis, periodontitis was an independent risk factor for retinal vascular occlusions (adjusted hazard ratio: 1.18; 95% confidence interval: 1.02-1.36; p = 0.024). Frequent tooth brushing was negatively associated with the risk of retinal vascular occlusions (adjusted hazard ratio: 0.89; 95% confidence interval: 0.80-0.98; p = 0.022). Improving oral hygiene may contribute to the attenuation of the risk of retinal vascular occlusions.