A Possible Therapeutic Application of the Selective Inhibitor of Urate Transporter 1, Dotinurad, for Metabolic Syndrome, Chronic Kidney Disease, and Cardiovascular Disease.

The reabsorption of uric acid (UA) is mainly mediated by urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) in the kidneys. Dotinurad inhibits URAT1 but does not inhibit other UA transporters, such as GLUT9, ATP-binding cassette transporter G2 (ABCG2), and organic anion transporter 1/3 (OAT1/3). We found that dotinurad ameliorated the metabolic parameters and renal function in hyperuricemic patients. We consider the significance of the highly selective inhibition of URAT1 by dotinurad for metabolic syndrome, chronic kidney disease (CKD), and cardiovascular disease (CVD). The selective inhibition of URAT1 by dotinurad increases urinary UA in the proximal tubules, and this un-reabsorbed UA may compete with urinary glucose for GLUT9, reducing glucose reabsorption. The inhibition by dotinurad of UA entry via URAT1 into the liver and adipose tissues increased energy expenditure and decreased lipid synthesis and inflammation in rats. Such effects may improve metabolic parameters. CKD patients accumulate uremic toxins, including indoxyl sulfate (IS), in the body. ABCG2 regulates the renal and intestinal excretion of IS, which strongly affects CKD. OAT1/3 inhibitors suppress IS uptake into the kidneys, thereby increasing plasma IS, which produces oxidative stress and induces vascular endothelial dysfunction in CKD patients. The highly selective inhibition of URAT1 by dotinurad may be beneficial for metabolic syndrome, CKD, and CVD.

Metabolic-Dysfunction-Associated Steatotic Liver Disease-Its Pathophysiology, Association with Atherosclerosis and Cardiovascular Disease, and Treatments.

Metabolic-dysfunction-associated steatotic liver disease (MASLD) is a chronic liver disease that affects more than a quarter of the global population and whose prevalence is increasing worldwide due to the pandemic of obesity. Obesity, impaired glucose metabolism, high blood pressure and atherogenic dyslipidemia are risk factors for MASLD. Therefore, insulin resistance may be closely associated with the development and progression of MASLD. Hepatic entry of increased fatty acids released from adipose tissue, increase in fatty acid synthesis and reduced fatty acid oxidation in the liver and hepatic overproduction of triglyceride-rich lipoproteins may induce the development of MASLD. Since insulin resistance also induces atherosclerosis, the leading cause for death in MASLD patients is cardiovascular disease. Considering that the development of cardiovascular diseases determines the prognosis of MASLD patients, the therapeutic interventions for MASLD should reduce body weight and improve coronary risk factors, in addition to an improving in liver function. Lifestyle modifications, such as improved diet and increased exercise, and surgical interventions, such as bariatric surgery and intragastric balloons, have shown to improve MASLD by reducing body weight. Sodium glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been shown to improve coronary risk factors and to suppress the occurrence of cardiovascular diseases. Both SGLT2i and GLP-1 have been reported to improve liver enzymes, hepatic steatosis and fibrosis. We recently reported that the selective peroxisome proliferator-activated receptor-alpha (PPARα) modulator pemafibrate improved liver function. PPARα agonists have multiple anti-atherogenic properties. Here, we consider the pathophysiology of MASLD and the mechanisms of action of such drugs and whether such drugs and the combination therapy of such drugs could be the treatments for MASLD.

A Significant Effect of Pemafibrate on Hepatic Steatosis and Fibrosis Indexes in Patients With Hypertriglyceridemia.

Background: We previously reported that the selective peroxisome proliferator-activated receptor alpha modulator, pemafibrate, significantly reduced serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) and significantly increased serum albumin levels at 3, 6 and 12 months after the start of pemafibrate, with an improvement of atherogenic dyslipidemia, in patients with hypertriglyceridemia. Methods: We performed a post hoc analysis of our previous data obtained from patients with hypertriglyceridemia who had been prescribed pemafibrate continuously for 1 year or longer. We compared the indexes for hepatic steatosis (hepatic steatosis index (HSI)) and fibrosis (nonalcoholic fatty liver disease (NAFLD) fibrosis score (NFS), AST to platelet ratio index (APRI) and FIB-4 index) at baseline with the data at 1 year after the start of pemafibrate. Results: Pemafibrate significantly reduced HSI at 1 year after the start of pemafibrate. NFS did not show a significant change after 1 year. However, APRI was significantly reduced by pemafibrate after 1 year. FIB-4 index significantly decreased in patients with baseline FIB-4 index ≥ 1.45 at 1 year after the start of pemafibrate. HSI at baseline tended to be negatively correlated with change in HSI after 1 year. There was no significant correlation between NFS at baseline and change in this score after 1 year. APRI and FIB-4 index at baseline were significantly and negatively correlated with changes in APRI and FIB-4 index at 1 year after the start of pemafibrate. Conclusions: The 1-year pemafibrate treatment improved hepatic steatosis and fibrosis indexes in patients with hypertriglyceridemia.

Postprandial Hyperlipidemia: Its Pathophysiology, Diagnosis, Atherogenesis, and Treatments.

Postprandial hyperlipidemia showing postprandial increases in serum triglyceride (TG) is associated with the development of atherosclerotic cardiovascular disease (ASCVD). To diagnose postprandial hyperlipidemia, the oral fat loading test (OFLT) should be performed; however, this test is very time-consuming and is difficult to perform. Elevated serum TG levels reflect an increase in TG-rich lipoproteins (TRLs), such as chylomicrons (CM), very low-density lipoproteins (VLDL), and their remnants (CM remnants [CMRs] and VLDL remnants [VLDLRs]). Understanding of elevation in CMR and/or VLDLR can lead us to understand the existence of postprandial hyperlipidemia. The measurement of apo B48, which is a constituent of CM and CMR; non-fasting TG, which includes TG content in all lipoproteins including CM and CMR; non-high-density lipoprotein cholesterol (non-HDL-C), which includes TRLs and low-density lipoprotein; and remnant cholesterol are useful to reveal the existence of postprandial hyperlipidemia. Postprandial hyperlipidemia is observed in patients with familial type III hyperlipoproteinemia, familial combined hyperlipidemia, chronic kidney disease, metabolic syndrome and type 2 diabetes. Postprandial hyperlipidemia is closely related to postprandial hyperglycemia, and insulin resistance may be an inducing and enhancing factor for both postprandial hyperlipidemia and postprandial hyperglycemia. Remnant lipoproteins and metabolic disorders associated with postprandial hyperlipidemia have various atherogenic properties such as induction of inflammation and endothelial dysfunction. A healthy diet, calorie restriction, weight loss, and exercise positively impact postprandial hyperlipidemia. Anti-hyperlipidemic drugs such pemafibrate, fenofibrate, bezafibrate, ezetimibe, and eicosapentaenoic acid have been shown to improve postprandial hyperlipidemia. Anti-diabetic drugs including metformin, alpha-glucosidase inhibitors, pioglitazone, dipeptidyl-peptidase-4 inhibitors and glucagon-like peptide 1 analogues have been shown to ameliorate postprandial hyperlipidemia. Although sodium glucose cotransporter-2 inhibitors have not been proven to reduce postprandial hyperlipidemia, they reduced fasting apo B48 and remnant lipoprotein cholesterol. In conclusion, it is important to appropriately understand the existence of postprandial hyperlipidemia and to connect it to optimal treatments. However, there are some problems with the diagnosis for postprandial hyperlipidemia. Postprandial hyperlipidemia cannot be specifically defined by measures such as TG levels 2 h after a meal. To study interventions for postprandial hyperlipidemia with the outcome of preventing the onset of ASCVD, it is necessary to define postprandial hyperlipidemia using reference values such as IGT.

Significance of Endothelial Dysfunction Amelioration for Sodium-Glucose Cotransporter 2 Inhibitor-Induced Improvements in Heart Failure and Chronic Kidney Disease in Diabetic Patients.

Beyond lowering plasma glucose levels, sodium-glucose cotransporter 2 inhibitors (SGLT2is) significantly reduce hospitalization for heart failure (HF) and retard the progression of chronic kidney disease (CKD) in patients with type 2 diabetes. Endothelial dysfunction is not only involved in the development and progression of cardiovascular disease (CVD), but is also associated with the progression of CKD. In patients with type 2 diabetes, hyperglycemia, insulin resistance, hyperinsulinemia and dyslipidemia induce the development of endothelial dysfunction. SGLT2is have been shown to improve endothelial dysfunction, as assessed by flow-mediated vasodilation, in individuals at high risk of CVD. Along with an improvement in endothelial dysfunction, SGLT2is have been shown to improve oxidative stress, inflammation, mitochondrial dysfunction, glucotoxicity, such as the advanced signaling of glycation end products, and nitric oxide bioavailability. The improvements in endothelial dysfunction and such endothelium-derived factors may play an important role in preventing the development of coronary artery disease, coronary microvascular dysfunction and diabetic cardiomyopathy, which cause HF, and play a role in retarding CKD. The suppression of the development of HF and the progression of CKD achieved by SGLT2is might have been largely induced by their capacity to improve vascular endothelial function.

Glucose-Lowering Effects of Imeglimin and Its Possible Beneficial Effects on Diabetic Complications.

Mitochondrial dysfunction is a prominent pathological feature of type 2 diabetes, which contributes to ß-cell mass reduction and insulin resistance. Imeglimin is a novel oral hypoglycemic agent with a unique mechanism of action targeting mitochondrial bioenergetics. Imeglimin reduces reactive oxygen species production, improves mitochondrial function and integrity, and also improves the structure and function of endoplasmic reticulum (ER), changes which enhance glucose-stimulated insulin secretion and inhibit the apoptosis of ß-cells, leading to ß-cell mass preservation. Further, imeglimin inhibits hepatic glucose production and ameliorates insulin sensitivity. Clinical trials into the effects of imeglimin monotherapy and combination therapy exhibited an excellent hypoglycemic efficacy and safety profile in type 2 diabetic patients. Mitochondrial impairment is closely associated with endothelial dysfunction, which is a very early event in atherosclerosis. Imeglimin improved endothelial dysfunction in patients with type 2 diabetes via both glycemic control-dependent and -independent mechanisms. In experimental animals, imeglimin improved cardiac and kidney function via an improvement in mitochondrial and ER function or/and an improvement in endothelial function. Furthermore, imeglimin reduced ischemia-induced brain damage. In addition to glucose-lowering effects, imeglimin can be a useful therapeutic option for diabetic complications in type 2 diabetic patients.

Real-World Efficacy of Glucagon-like Peptide-1 (GLP-1) Receptor Agonist, Dulaglutide, on Metabolic Parameters in Japanese Patients with Type 2 Diabetes: A Retrospective Longitudinal Study.

The glucagon-like peptide-1 receptor agonist (GLP-1RA) dulaglutide has been shown to improve body weight and glycemic control and reduce major cardiovascular (CV) events. In Japan, dulaglutide is used at a fixed dose of 0.75 mg, which is lower than that in Europe and North America. However, the reports of real-world efficacy on metabolic parameters in Japanese patients with type 2 diabetes (T2DM) are limited. This study aimed to examine the real-world efficacy of GLP-1RA dulaglutide on metabolic parameters in Japanese patients with T2DM. We retrospectively selected patients with T2DM who had been prescribed dulaglutide continuously for 12 months or longer between September 2015 and December 2020 and compared metabolic parameters at baseline with the data at 12 months after the start of dulaglutide. One hundred twenty-one patients were enrolled in this study. The 12-month dulaglutide treatment reduced body weight by 1.7 kg and hemoglobin A1c by 1.1%. Significant improvements were also observed in serum high-density lipoprotein cholesterol (HDL-C), triglyceride (TG) and non-HDL-C. The change in HbA1c during dulaglutide treatment was significantly correlated with the changes in HDL-C (R = -0.236, p = 0.013), LDL-C (R = 0.377, p = 0.005) and non-HDL-C (R = 0.415, p < 0.001). The improvements in HbA1c, HDL-C, TG and non-HDL-C were greater in patients concurrently treated with SGLT2 inhibitors (SGLT2is) at baseline. In conclusion, the treatment with dulaglutide has beneficial effects on multiple CV risk factors in Japanese patients with T2DM.

Glucagon-Like Peptide 1 Receptor Agonists Versus Sodium-Glucose Cotransporter 2 Inhibitors for Atherosclerotic Cardiovascular Disease in Patients With Type 2 Diabetes.

Beyond improving hemoglobin A1c (HbA1c) in adults with type 2 diabetes, glucagon-like peptide 1 receptor agonists (GLP-1RA) have been approved for reducing risk of major adverse cardiovascular events (MACE) with established cardiovascular disease (CVD) or multiple CV risk factors. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) also reduced the risk for the primary composite CV outcome in patients with type 2 diabetes at high risk for CV events. In the American Diabetes Association (ADA) and European Association of Study in Diabetes (EASD) consensus report 2022, there is the description "In people with established atherosclerotic CVD (ASCVD) or with a high risk for ASCVD, GLP-1RA were prioritized over SGLT2i"; however, the evidence supporting such statement is limited. Therefore, we studied the superiority of GLP-1RA over SGLT2i for prevention of ASCVD from various viewpoints. We could not find a meaningful difference in the risk reduction in three-point MACE (3P-MACE), mortality due to any cause, mortality due to CV cause and nonfatal myocardial infarction between GLP-1RA and SGLT2i trials. The risk of nonfatal stroke decreased in all five GLP-1RA trials; however, two of three SGLT2i trials showed an increase in risk of nonfatal stroke. The risk of hospitalization for heart failure (HHF) decreased in all three SGLT2i trials, and one GLP-1RA trial showed an increase in risk of HHF. The risk reduction of HHF in SGLT2i trials was greater than that in GLP-1RA trials. These findings were consistent with current systematic reviews and meta-analyses. The risk reduction of 3P-MACE was significantly and negatively correlated with changes in HbA1c (R = -0.861, P = 0.006) and body weight (R = -0.895, P = 0.003) in GLP-1RA and SGLT2i trials. The studies using SGLT2i failed to reduce carotid intima media thickness (cIMT), the surrogate marker for atherosclerosis; however, several studies using GLP-1RA successfully reduced cIMT in patients with type 2 diabetes. Compared with SGLT2i, GLP-1RA had a higher probability of decreasing serum triglyceride. GLP-1RA have multiple vascular biological anti-atherogenic properties.

Urate Transporter 1 Can Be a Therapeutic Target Molecule for Chronic Kidney Disease and Diabetic Kidney Disease: A Retrospective Longitudinal Study.

Chronic kidney disease (CKD) is a major global health problem for which there are no curative drug treatments. Hyperuricemia is one of risk factors for CKD. The evidence on effects of uric acid (UA)-lowering treatments on the progression of CKD was very limited and previous meta-analyses used only trials which primarily used xanthin oxidase (XO) inhibitors because the reports on fulminant hepatitis due to benzbromarone kept us from using uricosuric agents for hyperuricemia patients. Dotinurad, a novel selective urate reabsorption inhibitor for the treatment of hyperuricemia, reduces serum UA levels by selectively inhibiting urate transporter 1 (URAT1). We retrospectively picked up patients who had taken dotinurad from June 2018 to August 2021 and compared metabolic parameters at baseline with the data at 3 and 6 months after the start of dotinurad. We found 84 patients, and approximately 74% of patients were complicated with CKD. After the start of dotinurad, improvements in serum lipids, systolic blood pressure, body weight, and albuminuria, in addition to reduction in serum UA, were observed. Dotinurad increased urinary UA excretion, and was effective to reduce serum UA in patients with both UA underexcretion type and renal UA overload type. Furthermore, urinary UA excretion was significantly and negatively correlated with serum creatine levels at baseline and at 6 months after the start of dotinurad, and the change in urinary UA excretion after 3 months was significantly and negatively correlated with change in serum creatine levels. The property of dotinurad, which selectively inhibits URAT1, but not other UA transporters, such as ATP-binding cassette, subfamily G, and 2 (ABCG2), which ABCG2 is a UA and uremic toxin exporter, may be beneficially associated with pathology of CKD. URAT1 can be a therapeutic target molecule for CKD and DKD.

Clinical, Hematological, Biochemical and Radiological Characteristics for Patients With Splenic Infarction: Case Series With Literature Review.

Background: Splenic infarction is a frequently missed diagnosis in acute clinical conditions and is often under-diagnosed due to the lack of high-quality evidence on pathophysiology of splenic infarction. Due to the scarcity of such evidence, no consensus guidelines regarding the diagnostic approach and management of patients with splenic infarction exist. Most of published articles on splenic infarction are case reports and there was no systematic review on splenic infarction. Methods: We conducted a retrospective analysis of all radiologically confirmed cases of splenic infarction patients with any history of admission at National Center for Global Health and Medicine Kohnodai Hospital, from 2014 to 2020. Further, to understand the pathophysiology that causes splenic infarction, we searched the literatures on splenic infarction. Results: We found 18 patients with splenic infarction. The average age was 78 years, and about half of patients had abdominal pain; however, the other half did not have abdominal pain. One-third of patients with splenic infarction died. Leukocytosis with neutrophilia, a decrease of lymphocytes, anemia, hypoalbuminemia, and liver dysfunction were observed. Fibrinogen was decreased and D-dimer was remarkably elevated. Lactate dehydrogenase (LDH) and C-reactive protein (CRP) were remarkably increased. Six patients (33.3%) had cancer, four patients (22.2%) had atrial fibrillation, and four patients (22.2%) had infection. We found 466 case reports on splenic infarction published from 1975 to 2021. Recently, the number of case reports on splenic infarction due to infection, especially, coronavirus disease 2019 (COVID-19), has been remarkably increasing. Furthermore, we found that leukocytosis, a decrease of lymphocytes, elongated activated partial thromboplastin time, decrease of fibrinogen, liver dysfunction, elevation of LDH and blood urea nitrogen can be the prognosis predicting factors for patients with splenic infarction. Conclusion: Our study elucidated clinical, hematological, biochemical and radiological characteristics for patients with splenic infarction. We newly found significant differences in blood cell counts, coagulation markers, transaminases, LDH and blood urea nitrogen between patients who died and those who survived, suggesting that these parameters can be the prognosis predicting factors for splenic infarction. Further, our systematic review on case reports about splenic infarction showed the etiology of splenic infarction and the trend of the causative diseases.

Use of biologics for systemic sclerosis and systemic sclerosis-associated interstitial lung disease: Information from a Japanese hospital claims database.

OBJECTIVES: Limited information is available on the use of biologics in patients with systemic sclerosis (SSc) or SSc-associated interstitial lung disease (SSc-ILD) in Japan. The types of biologics, treatment duration, treatment prior to biologics, concomitant treatment, and characteristics of patients receiving biologics were investigated. METHODS: We used a Japanese hospital claims database provided by Medical Data Vision Co. (2008-2021). RESULTS: In the database, 1186 of 34,207 SSc patients (3.5%) and 620 of 12,303 SSc-ILD patients (5.0%) received anti-interleukin-6 (anti-IL-6) drugs, anti-tumour necrosis factor (anti-TNF) drugs, abatacept, or rituximab. The most common were anti-IL-6 drugs [used in 35.5% of SSc patients and 38.5% of SSc-ILD patients (tocilizumab, 34.5% and 36.6%)], followed by anti-TNF drugs [31.3% and 26.5% (etanercept, 10.5% and 9.0%; others, <8%)], abatacept (17.5% and 20.6%), and rituximab (15.7% and 14.4%). Among SSc and SSc-ILD patients treated with anti-IL-6 drugs, anti-TNF drugs, or abatacept, the most common immunosuppressive drugs prior to initiation of biologics were methotrexate and tacrolimus. Approximately half of patients receiving anti-IL-6 drugs, anti-TNF drugs, or abatacept continued treatment beyond 1 year. CONCLUSIONS: Our study indicates that off-label biologics have been used in a certain number of SSc or SSc-ILD patients in Japan, with tocilizumab the most common.

A Significant Effect of Oral Semaglutide on Cardiovascular Risk Factors in Patients With Type 2 Diabetes.

Background: The once-daily glucagon-like peptide 1 (GLP-1) analogue, liraglutide has been shown to reduce major adverse cardiovascular events (MACE) and progression of chronic kidney disease (CKD). The once-weekly GLP-1 analogue, semaglutide also reduced MACE and renal events. Based on the evidence for GLP-1 analogues on MACE and renal events, the guideline recommended to treat high-risk diabetic individuals with GLP-1 analogues to reduce MACE and CKD progression. Recently, a once-daily oral semaglutide was developed and shown to reduce MACE. However, its effects on renal outcome and cardiovascular metabolic risk factors remain unknown. Methods: We retrospectively picked up patients who had taken oral semaglutide from March 2021 to June 2022 and compared metabolic parameters at baseline with the data at 3, 6 months after the start of oral semaglutide. Results: We found 47 patients who had taken oral semaglutide. Body weight significantly decreased at 3 and 6 months after the start of oral semaglutide, and systolic blood pressure significantly decreased after 6 months. Hemoglobin A1c (HbA1c) tended to decrease after 3 months and significantly deceased after 6 months. Serum low-density lipoprotein cholesterol (LDL-C) levels significantly decreased after 6 months and non-high-density lipoprotein-cholesterol (non-HDL-C) levels tended to decrease after 6 months. Urinary albumin to creatinine ratio (UACR) tended to decrease after 3 and 6 months. Such favorable metabolic changes by oral semaglutide were observed more prominently in patients who had not ever used GLP-1 analogues than in patients who switched from subcutaneous GLP-1 analogues. Conclusions: Our study showed that oral semaglutide improved body weight, blood pressure, HbA1c, LDL-C, non-HDL-C and UACR, in type 2 diabetic obese patients, especially, in patients who had not ever used GLP-1 analogues.

Chronic Kidney Disease Stage G4 in a Diabetic Patient Improved by Multi-Disciplinary Treatments Based Upon Literature Search for Therapeutic Evidence.

In the EMPA-REG OUTCOME trial, sodium-glucose cotransporter 2 (SGLT2) inhibitor, empagliflozin, reduced incident or worsening nephropathy. In the LEADER trial, a glucagon-like peptide 1 (GLP-1) receptor agonist, liraglutide, resulted in lower rates of the development and progression of diabetic kidney disease than placebo. Therefore, the American Diabetes Association and the European Association for the Study of Diabetes recommend the decision to treat high-risk individuals with a GLP-1 receptor agonist or SGLT2 inhibitor to reduce chronic kidney disease (CKD) progression should be considered. A 72-year-old male obese diabetic patient developed CKD stage G4 despite of use of both SGLT2 inhibitor and GLP-1 receptor agonist. We started using sodium bicarbonate because he showed metabolic acidosis due to uremia. We also started to use spherical carbonaceous adsorbent which adsorbs indole, the precursor of indoxyl sulfate, uremic toxin. We started the treatment with finerenone, a nonsteroidal, selective mineralocorticoid receptor antagonist, which has been recently shown to lower risks of CKD progression. Considering unfavorable effects of hyperuricemia on CKD, to treat his hyperuricemia, we started to use dotinurad, a novel selective urate reabsorption inhibitor, which reduces serum urate levels by selective inhibition of urate transporter 1. The improvement of CKD stage G4 in a diabetic patient was obtained by such multi-disciplinary treatments in addition to SGLT2 inhibitor and GLP-1 receptor agonist.

Atherogenic Lipoproteins for the Statin Residual Cardiovascular Disease Risk.

Randomized controlled trials (RCTs) show that decreases in low-density lipoprotein cholesterol (LDL-C) by the use of statins cause a significant reduction in the development of cardiovascular disease (CVD). However, one of our previous studies showed that, among eight RCTs that investigated the effect of statins vs. a placebo on CVD development, 56-79% of patients had residual CVD risk after the trials. In three RCTs that investigated the effect of a high dose vs. a usual dose of statins on CVD development, 78-87% of patients in the high-dose statin arms still had residual CVD risk. The risk of CVD development remains even when statins are used to strongly reduce LDL-C, and this type of risk is now regarded as statin residual CVD risk. Our study shows that elevated triglyceride (TG) levels, reduced high-density lipoprotein cholesterol (HDL-C), and the existence of obesity/insulin resistance and diabetes may be important metabolic factors that determine statin residual CVD risk. Here, we discuss atherogenic lipoproteins that were not investigated in such RCTs, such as lipoprotein (a) (Lp(a)), remnant lipoproteins, malondialdehyde-modified LDL (MDA-LDL), and small-dense LDL (Sd-LDL). Lp(a) is under strong genetic control by apolipoprotein (a), which is an LPA gene locus. Variations in the LPA gene account for 91% of the variability in the plasma concentration of Lp(a). A meta-analysis showed that genetic variations at the LPA locus are associated with CVD events during statin therapy, independent of the extent of LDL lowering, providing support for exploring strategies targeting circulating concentrations of Lp(a) to reduce CVD events in patients receiving statins. Remnant lipoproteins and small-dense LDL are highly associated with high TG levels, low HDL-C, and obesity/insulin resistance. MDA-LDL is a representative form of oxidized LDL and plays important roles in the formation and development of the primary lesions of atherosclerosis. MDA-LDL levels were higher in CVD patients and diabetic patients than in the control subjects. Furthermore, we demonstrated the atherogenic properties of such lipoproteins and their association with CVD as well as therapeutic approaches.

Destruction of mesoscopic chemically modulated domains in single phase high entropy alloy via plastic deformation.

Chemically modulated mesoscopic domains in a fcc single phase CrMnFeCoNi equi-atomic high entropy alloy (HEA) are detected by small angle diffraction performed at a synchrotron radiation facility, whereas the mesoscopic domains cannot be detected by conventional X-ray diffraction and 2D mappings of energy dispersive X-ray spectroscopy by scanning electron microscopy and scanning transmission electron microscopy. The mesoscopic domains are deformed and shrieked, and finally destructed by plastic deformation, which is supported by the comprehensive observations/measurements, such as electrical resistivity, Vickers hardness, electron backscattering diffraction, and hard X-ray photoemission spectroscopy. The destruction of the mesoscopic domains causes the decrease in electrical resistivity via plastic deformation, so called K-effect, which is completely opposite to the normal trend of metals. We confirmed that the presence and the size of local chemical ordering or short-range order domains in the single phased HEA, and furthermore, Cr and Mn are related to form the domains.

Early, Noninvasive Clinical Indicators of Kidney Prognosis in Primary Nephrotic Syndrome: A Retrospective Exploratory Study.

This retrospective exploratory study aimed to identify early clinical indicators of kidney prognosis in primary nephrotic syndrome (NS). Univariate Cox proportional hazards regression analysis identified clinical parameters in the 2-month period after initiating immunosuppressive therapy (IST); it predicted 40% reduction in the estimated glomerular filtration rate (eGFR) in 36 patients with primary NS. Time-dependent receiver operating characteristic curve analysis was used to evaluate the performance of the predictors for the cumulative incidence of 40% reduction in the eGFR up to 8 years after initiating IST. The mean follow-up period was 71.9 months. The eGFR was reduced by 40% in four patients. Significant predictors for time to 40% reduction in the eGFR were as follows: an increase in the serum soluble urokinase plasminogen activator receptor (s-suPAR) 2 months after initiating IST (Δs-suPAR (2M); hazard ratio (HR) for every 500 pg/mL increase: 1.36, P=0.006), s-suPAR at 2 months after initiating IST (s-suPAR (2M); HR for every 500 pg/mL increase: 1.13, P=0.015), urinary protein-to-creatinine ratio (u-PCR) (u-PCR (2M); HR for every 1.0 g/gCr increase: 2.94, P=0.003), and urinary liver-type fatty acid-binding protein (u-L-FABP) (u-L-FABP (2M); HR for every 1.0 µg/gCr increase: 1.14, P=0.006). All four factors exhibited high predictive accuracy for cumulative incidence of 40% reduction in the eGFR up to 8 years after initiating IST, with areas under the receiver operating characteristic curve of 0.92 for Δs-suPAR (2M), 0.87 for s-suPAR (2M), 0.93 for u-PCR (2M), and 0.93 for u-L-FABP (2M). These findings suggest that Δs-suPAR (2M), s-suPAR (2M), u-PCR (2M), and u-L-FABP (2M) could be useful indicators of initial therapeutic response for predicting kidney prognosis in primary NS.

Habitual Hot-Tub Bathing and Cardiovascular Risk Factors in Patients With Type 2 Diabetes Mellitus: A Cross-Sectional Study.

Background: Several studies suggested that heat therapy, including sauna or hot-tub bathing, was associated with improved glycemia and other risk factors for cardiovascular diseases. This study aimed to assess the influences of the habit of hot-tub bathing on cardiovascular risk factors in patients with type 2 diabetes in a real-world setting. Methods: In this cross-sectional study, we enrolled the patients with type 2 diabetes who regularly visited the outpatient clinic between October 2018 and March 2019. We obtained the information on the habit of hot-tub bathing by using a self-reported questionnaire. The results of anthropometric measurements, blood tests and medications were obtained from the medical charts. We divided the patients into three groups according to the frequency of hot-tub bathing as follows; group 1: ≥ 4 times a week, group 2: < 4 times a week, ≥ 1 time a week, group 3: < 1 time a week. The biomarkers were compared among the groups by one-way analysis of variance. Multiple linear regression analyses were performed to adjust for confounding variables. Results: We enrolled 1,297 patients. There were significant differences in body mass index (group1: 25.5 ± 5.0, group 2: 26.0 ± 5.4, group 3: 26.7 ± 6.0, P = 0.025), diastolic blood pressure (73 ± 12, 75 ± 12, 77 ± 13, P = 0.001) and hemoglobin A1c (7.10 ± 0.97, 7.20 ± 1.11, 7.36 ± 1.67, P = 0.012). Multiple regression analysis revealed that the frequency of hot-tub bathing was a significant determinant of hemoglobin A1c, body mass index and diastolic blood pressure. Conclusions: In this real-world study, habitual hot-tub bathing was associated with slight improvements in glycemia, obesity and diastolic blood pressure, and thus, can be a possible lifestyle intervention in patients with type 2 diabetes.

Automated Design of Li+ -Conducting Polymer by Quantum-Inspired Annealing.

Automated molecule design by computers is an essential topic in materials informatics. Still, generating practical structures is not easy because of the difficulty in treating material stability, synthetic difficulty, mechanical properties, and other miscellaneous parameters, often leading to the generation of junk molecules. The problem is tackled by introducing supervised/unsupervised machine learning and quantum-inspired annealing. This autonomous molecular design system can help experimental researchers discover practical materials more efficiently. Like the human design process, new molecules are explored based on knowledge of existing compounds. A new solid-state polymer electrolyte for lithium-ion batteries is designed and synthesized, giving a promising room temperature conductivity of 10-5 S cm-1 with reasonable thermal, chemical, and mechanical properties.

Molecular Biological and Clinical Understanding of the Statin Residual Cardiovascular Disease Risk and Peroxisome Proliferator-Activated Receptor Alpha Agonists and Ezetimibe for Its Treatment.

Several randomized, double blind, placebo-controlled trials (RCTs) have demonstrated that low-density lipoprotein cholesterol (LDL-C) lowering by using statins, including high-doses of strong statins, reduced the development of cardiovascular disease (CVD). However, among the eight RCTs which investigated the effect of statins vs. placebos on the development of CVD, 56-79% of patients had the residual CVD risk after the trials. In three RCTs which investigated the effect of a high dose vs. a usual dose of statins on the development of CVD, 78-87% of patients in the high-dose statin arms still had the CVD residual risk after the trials. An analysis of the characteristics of patients in the RCTs suggests that elevated triglyceride (TG) and reduced high-density lipoprotein cholesterol (HDL-C), the existence of obesity/insulin resistance, and diabetes may be important metabolic factors which determine the statin residual CVD risk. To understand the association between lipid abnormalities and the development of atherosclerosis, we show the profile of lipoproteins and their normal metabolism, and the molecular and biological mechanisms for the development of atherosclerosis by high TG and/or low HDL-C in insulin resistance. The molecular biological mechanisms for the statin residual CVD risk include an increase of atherogenic lipoproteins such as small dense LDL and remnants, vascular injury and remodeling by inflammatory cytokines, and disturbed reverse cholesterol transport. Peroxisome proliferator-activated receptor alpha (PPARα) agonists improve atherogenic lipoproteins, reverse the cholesterol transport system, and also have vascular protective effects, such as an anti-inflammatory effect and the reduction of the oxidative state. Ezetimibe, an inhibitor of intestinal cholesterol absorption, also improves TG and HDL-C, and reduces intestinal cholesterol absorption and serum plant sterols, which are increased by statins and are atherogenic, possibly contributing to reduce the statin residual CVD risk.