Japanese Subjects Research Articles

Glymphatic system impairment in nonathlete older male adults who played contact sports in their youth associated with cognitive decline: A diffusion tensor image analysis along the perivascular space study.

Exposure to contact sports in youth causes brain health problems later in life. For instance, the repetitive head impacts in contact sports might contribute to glymphatic clearance impairment and cognitive decline. This study aimed to assess the effect of contact sports participation in youth on glymphatic function in old age and the relationship between glymphatic function and cognitive status using the analysis along the perivascular space (ALPS) index. A total of 52 Japanese older male subjects were included in the study, including 12 who played heavy-contact sports (mean age, 71.2 years), 15 who played semicontact sports (mean age, 73.1 years), and 25 who played noncontact sports (mean age, 71.3 years) in their youth. All brain diffusion-weighted images (DWIs) of the subjects were acquired using a 3T MRI scanner. The ALPS indices were calculated using a validated semiautomated pipeline. The ALPS indices from the left and right hemispheres were compared between groups using a general linear model, including age and years of education. Furthermore, partial Spearman's rank correlation tests were performed to assess the correlation between the ALPS indices and cognitive scores (Mini-Mental State Examination and the Japanese version of the Montreal Cognitive Assessment [MoCA-J]) after adjusting for age years of education and HbA1c. The left ALPS index was significantly lower in the heavy-contact and semicontact groups than that in the noncontact group. Although no significant differences were observed in the left ALPS index between the heavy-contact and semicontact groups and in the right ALPS index among groups, a trend toward lower was found in the right ALPS index in individuals with semicontact and heavy-contact compared to the noncontact group. Both sides' ALPS indices were significantly positively correlated with the MoCA-J scores. The findings indicated the potential adverse effect of contact sports experience in youth on the glymphatic system function in old age associated with cognitive decline.

A Soy Protein Isolate Rich in Genistein and Daidzein and Its Effects on Plasma Isoflavone Concentrations, Platelet Aggregation, Blood Lipids and Fatty Acid Composition of Plasma Phospholipid in Normal Men

The effects of consuming a soy protein isolate beverage powder (60 g/d for 28 d) vs. a casein supplement was evaluated in 20 male subjects who were randomly allocated into the two groups. A dramatic rise in plasma isoflavone concentrations was observed after supplementation in the soy protein group, the levels reaching 907 ± 245 nmol/L for genistein (a 110-fold increase) and 498 ± 102 nmol/L for daidzein (a 150-fold increase) as measured by isotope dilution gas chromatography - mass spectrometry. These concentrations are higher than previously reported for the plasma of Japanese subjects consuming a traditional diet (276 nmol/L and 107 nmol/L, respectively). No significant differences in collagen- or 9,11-dideoxy-11α, 9α-epoxymethanoprostaglandin F2α (U46619)-induced platelet aggregation were observed in platelet-rich plasma from the two groups; the increase in plasma isoflavonoids from soy protein supplementation is not sufficient to significantly inhibit platelet aggregation ex vivo. Similarly, plasma total and HDL-cholesterol were not affected by protein supplementation, possibly because the men were normo-cholesterolemic at entry. Analysis of plasma phospholipid polyunsaturated fatty acid composition showed no differences between soy protein and casein supplementation. Previous investigations reported a significant alteration in fatty acid status in animals fed soy protein relative to those fed casein. The present studies indicate that although soy protein supplementation to a typical Western diet can increase plasma concentrations of isoflavones, this may not necessarily be sufficient to counter heart disease risk factors such as high plasma cholesterol and platelet aggregation.

Metabolic dysfunction-associated fatty liver disease is associated with an increase in systolic blood pressure over time: linear mixed-effects model analyses.

Metabolic dysfunction-associated fatty liver disease (MAFLD), a new feature of fatty liver (FL) disease that is defined as FL with overweight/obesity, type 2 diabetes mellitus or metabolic dysregulation, has been reported to be associated with the development of diabetes mellitus, chronic kidney disease and cardiovascular disease. However, the association between MAFLD and hypertension remains unclear. We investigated the association between MAFLD and systolic blood pressure (SBP) over a 10-year period in 28,990 Japanese subjects who received annual health examinations. After exclusion of subjects without data for SBP and abdominal ultrasonography at baseline, a total of 17,021 subjects (men/women: 10,973/6048; mean age: 49 years) were recruited. Linear mixed-effects model analyses using diagnoses of FL, nonalcoholic fatty liver disease (NAFLD) or MAFLD and age, sex, SBP, use of anti-hypertensive drugs, levels of uric acid and estimated glomerular filtration rate, family history of hypertension and habits of current smoking and alcohol drinking at baseline as well as the duration of the observation period and the interaction between each covariate and the duration of the observation period showed that the significant association of change in SBP over time with diagnosis of MAFLD (estimate: 0.223 mmHg/year, P < 0.001) was greater than that with diagnoses of FL (estimate: 0.196 mmHg/year, P < 0.001) and NAFLD (estimate: 0.203 mmHg/year, P < 0.001). Furthermore, the rate of increase in SBP over time was higher in subjects with MAFLD than in subjects without FL and subjects with FL who had no MAFLD. In conclusion, MAFLD is significantly associated with an increase in SBP over time. The presence of metabolic dysfunction-associated fatty liver disease (MAFLD) is significantly associated with an increase in systolic blood pressure over time.

Safety, Tolerability, and Pharmacokinetics of the Novel Adenosine A2A Antagonist/Inverse Agonist KW-6356 Following Single and Multiple Oral Administration in Healthy Volunteers.

KW-6356 is an adenosine A2A receptor-selective antagonist and inverse agonist. We conducted 2 studies: study 6356-001 (no NCT number), a randomized, double-blind, placebo-controlled phase 1 trial of single ascending (1, 3, 10mg) and multiple (6mg once daily) oral doses of KW-6356 in healthy Japanese subjects; and study 6356-004 (NCT03830528), including a randomized, double-blind, placebo-controlled phase 1 trial of single ascending (21, 42, 60mg) and multiple (24mg once daily) oral doses of KW-6356, and a phase 1 open-label trial of multiple oral doses (6mg once daily) of KW-6356 in healthy Japanese and White subjects, to evaluate the safety, tolerability, and pharmacokinetics of KW-6356. KW-6356 was well tolerated after administration of single doses of up to 60mg and multiple doses of up to 24mg once daily for 14days. The pharmacokinetics of KW-6356 were linear after a single dose of up to 60mg KW-6356. The mean terminal elimination half-life of KW-6356 ranged from 18.4 to 43.1hours following administration of single doses of 1-60mg. There was no clear difference in the safety or pharmacokinetics of KW-6356 between healthy Japanese and White subjects.

Association of immune-mediated necrotizing myopathy with HLA polymorphisms.

Immune-mediated necrotizing myopathy (IMNM) is a type of autoimmune myositis typically characterized clinically by proximal muscle weakness with elevated creatine kinase levels, pathologically by myofiber necrosis and regeneration with paucity of lymphocytic cell infiltration, and serologically by the presence of either of two myositis-specific autoantibodies, anti-SRP, and anti-HMGCR antibodies. However, the HLA loci and alleles associated with IMNM are still not fully understood at least partly because IMNM was a relatively recently established condition. In this study, we genotyped the six HLA loci (HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1) in 250 patients (237 patients over age 18 years and 13 juvenile patients) diagnosed with IMNM based on clinicopathological features and autoantibody information and performed a case control study with Japanese healthy subjects. In the adult patients, specific HLA alleles associated with IMNM were identified at all HLA loci, with DRB1*08:03 showing the strongest association (OR=2.5; p=0.00000017). Furthermore, subgroup analysis with various clinical information showed that C*03:04 (OR=3.7; p=0.00012) was a higher risk allele for collagen disease in adult patients, and B*13:01 (OR=23.2; p=0.021) and C*03:04 (OR=5.8; p=0.0074) were higher risk for juvenile patients with anti-HMGCR antibody-positive IMNM. These findings will help to better understand the HLA genetic background and features of IMNM in designing future studies.

Efficacy of Low-dose Dapagliflozin in Young People with Type 1 Diabetes.

Objective Young people with type 1 diabetes are likely to gain body weight and not achieve optimal glycemic control with only high doses of insulin. This study examined the efficacy of the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin as an adjunct-to-insulin therapy in young Japanese subjects with type 1 diabetes who had been diagnosed before 15 years old, were overweight, and had inadequate control despitereceiving intensive insulin therapy. Methods Twenty-two patients with type 1 diabetes (12 boys and 10 girls 16.0-33.9 years old) were involved in the study. All patients had a body mass index (BMI) >25 kg/m2, glycated hemoglobin (HbA1c) level >7.0%, and daily insulin dose >0.5 units/kg. They were treated with a low dose of dapagliflozin (5.0 mg/day) as an adjunctive therapy to insulin. Fourteen patients were treated with multiple daily injections of insulin, while eight used an insulin pump. Results The body weights and BMIs were significantly reduced during the 12-month study period (change of -4.4 kg and -1.7 kg/m2, p<0.001, respectively). Their insulin dose was significantly decreased (-0.17 units/kg, P <0.001), and glycemic control was significantly improved (fasting plasma glucose: -18.7 mg/dL, HbA1c: -0.62%, p<0.001) during the study period. There was one episode of diabetic ketoacidosis, with no other problematic adverse events, including severe hypoglycemia, observed. Conclusion The use of low-dose dapagliflozin as an adjunct therapy may be beneficial in overweight young people with poorly controlled type 1 diabetes.

A family study of compound variants of flavin-containing monooxygenase 3 (FMO3) in Japanese subjects found by urinary phenotyping for trimethylaminuria

Phenotype–gene analyses and the increasing availability of mega-databases have revealed the impaired human flavin-containing monooxygenase 3 (FMO3) variants associated with the metabolic disorder trimethylaminuria. In this study, a novel compound variant of FMO3, p.[(Val58Ile; Tyr229His)], was identified in a 1-year-old Japanese girl who had impaired FMO3 metabolic capacity (70%) in terms of urinary trimethylamine N-oxide excretion levels divided by total levels of trimethylamine and its N-oxide. One cousin in the family had the same p.[(Val58Ile); (Tyr229His)]; [(Glu158Lys; Glu308Gly)] FMO3 haplotype and had a similar FMO3 metabolic capacity (69%). In a family study, the novel p.[(Val58Ile); (Tyr229His)] compound FMO3 variant was also detected in the proband 1's mother and aunt. Another novel compound FMO3 variant p.[(Glu158Lys; Met260Lys; Glu308Gly; Ile426Thr)] was identified in a 7-year-old girl, proband 2. This novel compound FMO3 variant was inherited from her mother. Recombinant FMO3 Val58Ile; Tyr229His variant and Glu158Lys; Met260Lys; Glu308Gly; Ile426Thr variant showed moderately decreased capacities for trimethylamine N-oxygenation compared to wild-type FMO3. Analysis of trimethylaminuria phenotypes in family studies has revealed compound missense FMO3 variants that impair FMO3-mediated N-oxygenation in Japanese subjects; moreover, these variants could result in modified drug clearances.

PS-BPP03-4: METABOLIC DYSFUNCTION-ASSOCIATED FATTY LIVER DISEASE (MAFLD) PREDICTS NEW ONSET OF CHRONIC KIDNEY DISEASE BETTER THAN DOES FATTY LIVER OR NAFLD

Background: Possible associations of chronic kidney disease (CKD) with fatty liver (FL) and nonalcoholic fatty liver disease (NAFLD) have recently been focused on. Metabolic dysfunction-associated fatty liver disease (MAFLD), defined as FL with overweight/obesity, type 2 diabetes mellitus or metabolic abnormalities, has been proposed as a new feature of chronic liver disease. However, the relationship between MAFLD and new onset of CKD has not been fully addressed. Methods: We investigated the associations of FL, NAFLD and MAFLD with the development of CKD, defined as estimated glomerular filtration rate (eGFR) &lt; 60 mL/min/1.73m2 or positive for urinary protein, over a 10-year period in 28,890 Japanese subjects who received annual health examinations. After exclusion of subjects with no data for abdominal ultrasonography and subjects with CKD at baseline, a total of 13,159 subjects (men/women: 8,581/4,578, mean age: 48 years) were recruited. Results: The prevalences of FL, NAFLD and MAFLD were 34.6% (men/women: 45.1%/15.1%), 32.8% (men/women: 42.7%/14.5%) and 32.3% (men/women: 42.4%/13.4%), respectively. During the 10-year follow-up period, 2,163 subjects (men/women: 1,475/688) had new onset of CKD. Multivariable Cox proportional hazard model analyses showed that MAFLD (hazard ratio [95% confidence interval]: 1.12 [1.02–1.26], p = 0.027), but not FL or NAFLD, was an independent risk factor for new onset of CKD after adjustment of age, sex, eGFR, current smoking habit, ischemic heart disease, diabetes mellitus, overweight/obesity, hypertension and dyslipidemia. The addition of MAFLD (continuous net reclassification improvement [NRI]: 0.154, integrated discrimination improvement [IDI]: 0.0024) to traditional risk factors without metabolic abnormalities significantly improved the discriminatory capacity better than did the addition of FL (NRI: 0.138, IDI: 0.0018) or NAFLD (NRI: 0.132, IDI: 0.0017). Conclusions: MAFLD is independently associated with new onset of CKD and predicts the risk for development of CKD better than does FL or NAFLD.

PS-BPP02-3: FACTORS FOR NEW-ONSET ISOLATED DIASTOLIC HYPERTENSION AND PROGRESSION TO SYSTOLIC HYPERTENSION IN JAPAN

Objective: Factors for New-Onset of isolated diastolic hypertension (IDH: systolic blood pressure ≧ 140 mmHg and diastolic blood pressure ≧ 90 mmHg) have been identified as increasing body mass index (BMI), young age at baseline, male, and BMI by analysis of the Framingham Study in middle-class Caucasians. However, in Japanese, there are few reports of predictors of IDH or the progression from IDH to systolic and diastolic hypertension (SDH: systolic blood pressure ≧ 140 mmHg and diastolic blood pressure ≧ 90 mmHg). Method: The present study analyzed 42,591 subjects aged 35 to 65 years who underwent a health checkup between 2007 and 2013 and re-examined 5 years later. A logistic regression analysis was performed for three patterns of blood pressure change (normal to IDH, normal to SDH, and IDH to SDH) after 5 years from the time of the first health checkup. Systolic and diastolic blood pressure, age, gender, smoking habit, exercise habit, fasting blood glucose level, total cholesterol level, heart rate, and BMI were used as factors for adjustment. Results: At the time of the first checkup, 29,965 subjects were normotensive, 1,169 had IDH, and 11,457 had SDH. Of the 29,965 normotensive subjects, 566 developed IDH after 5 years. Multivariate logistic regression analysis adjusted for blood pressure showed a 1-unit increase in age (OR 0.96, CI[0.95–0.97], p &lt; 0.0001), men (OR 1.44, CI[1.14–1.82], p = 0.002), BMI (OR 1.03, CI[1.00–1.06], p = 0.002), and a 1-unit increase in heart rate (OR 1.02, CI[1.01–1.03], p &lt; 0.0001) were independently significant predictors of developing IDH. Of the 29,965 normotensive subjects, 4,631 developed SDH after 5 years, and all factors except heart rate were independently significant predictors. On the other hand, 612 (52%) of the 1,169 subjects with IDH at the initial visit developed SDH 5 years later. The first checkup systolic blood pressure was significantly (p &lt; 0.0001, 132.3 ± 5.5 mmHg vs. 129.5 ± 6.5 mmHg) higher, but no factors were found to be associated with the development of SDH. Conclusions: In Japanese subjects, IDH predominantly occurs in young, male, obese, and high heart rate individuals. However, the progression from IDH to SDH is difficult to predict, and it is important to prevent obesity from developing IDH.

PS-C04-10: THE ASSOCIATION OF ORAL HYPOFUNCTION AND ARTERIAL STIFFNESS

Objective: Frailty is associated with higher risk of cardiovascular disease (CVD) and mortality. Recently, oral hypofunction, a disease in which the oral function is complexly reduced not only by ageing but also by a variety of factors, is regarded as a major risk factor for frailty, as it develops malnutrition and sarcopenia. However, no studies have evaluated the association of oral hypofunction and arterial stiffness, a marker for CVD. The objective of this study is to evaluate the association of oral hypofunction and arterial stiffness. Design and method: Japanese subjects above 50 years old who underwent annual health checkup were enrolled in this cross-sectional study. Subjects with history of CVD and dementia were excluded. Arterial stiffness was evaluated by brachial-ancle pulse wave velocity (baPWV). Oral hypofunction was evaluated based on the guidance by the Japanese Association for Dental Science. Seven oral functional factors, oral hygiene, oral moisture, occlusal force, tongue-lip motor function, tongue pressure, masticatory function, and swallowing function were assessed. Oral hypofunction was diagnosed if more than 3 factors showed deterioration. The association of oral hypofunction and baPWV was evaluated by multivariate linear regression analysis adjusted for conventional CVD risk factors. We also performed secondary analysis to evaluate the association of each oral functional factors and arterial stiffness. Results: Among 138 subjects (mean age: 59 ± 6 years), 29 subjects (21%) had oral hypofunction. After adjustment for CVD risk factors, oral hypofunction was not significantly associated with baPWV (β; = 24 ± 52, p = 0.65). In secondary analysis, higher oral bacterial count, a marker of oral hygiene, was significantly associated with increased baPWV even after adjustment for conventional CVD risk factors (1SD increase of oral bacterial count; β; = 51 ± 23, P = 0.03). But, this association was not observed with other oral functional factors and arterial stiffness. Conclusions: Oral hypofunction was not associated with increase of arterial stiffness. However, higher oral bacterial count was associated with increased arterial stiffness. Further research on oral hypofunction and CVD is warranted.

Factors Associated with Relapse of Type 2 Diabetes Mellitus after Laparoscopic Sleeve Gastrectomy in Japanese Subjects: A Subgroup Analysis of J-SMART Study

Introduction: Laparoscopic sleeve gastrectomy (LSG) for morbidly obese patients often results in remission of type 2 diabetes (T2DM), but diabetes relapses in some of those patients. The frequency of T2DM relapse in Asians and the factors involved have not been adequately investigated. Methods: The J-SMART study was conducted on 322 Japanese subjects with body mass index (BMI) ≥32 kg/m² who underwent LSG at 10 accredited centers in Japan between 2011 and 2014. Of these, 82 T2DM subjects with diabetes in complete or partial remission at 1 year after LSG and followed postoperatively for 5 years were included in the subgroup analysis and classified into two groups: diabetes remission-maintained and diabetes relapse. Results: The mean age of all included subjects was 49.2 years, median BMI was 41.5 kg/m², and median HbA1c was 6.7%. Compared with the diabetes remission-maintained group, the diabetes relapse group at 5 years after LSG had significantly higher preoperative HbA1c, number of antidiabetic medications, and high-density lipoprotein cholesterol level; and lower BMI and homeostasis model assessment-beta cell function (HOMA-β). As many as 83.0% of the subjects were able to achieve HbA1c <7% at 5 years after LSG, but 26.8% of the subjects had diabetes relapse. Preoperative HbA1c significantly contributed to diabetes relapse (odds ratio 1.54, p = 0.049). In addition, the diabetes relapse group tended to have lower percentage total weight loss (%TWL) at 1 year after LSG and higher percentage weight regain (%WR) from postoperative nadir weight, compared with the diabetes remission-maintained group. The hazard ratio for diabetes relapse was 3.14-fold higher in subjects with %TWL ≥20% and %WR ≥25%, and 5.46-fold higher in those with %TWL <20% and %WR ≥25%, compared with %TWL ≥20% and %WR <25%. Conclusion: While LSG provides a high remission rate for T2DM, relapse is not uncommon. Preoperative HbA1c, poor weight loss, and excess weight regain after LSG contribute to diabetes relapse, suggesting the importance of treatment strategies focusing on these factors.

Application of Machine Learning Technology for Automatic Motion Recognition for Japanese Tea-Making Procedure of CHA-NO-YU

CHA-NO-YU, the Japanese traditional tea-making ceremony, has been a research subject in many academic fields including anthropology, psychology, and engineering. To effectively study the CHA-NO-YU, automatic recognition of motions of the tea-making procedure is desirable. Hence, herein, a method is proposed to recognize 12 motion classes of the tea-making procedure with acceleration, angular velocity, and right-hand tilt angle data. In the experiment, one Japanese subject with 18 years of experience in CHA-NO-YU performed the 12 motion classes repeatedly, and a 99-sensor dataset was obtained for every motion class. In the recognition step, random forest classifier was adopted. Finally, the recognition of the 12 motion classes of the tea-making procedure could be realized with greater than 0.98 accuracy, precision, recall, and F1-score

Pharmacokinetics of low doses of colchicine in the leukocytes of Japanese healthy individuals.

The venerable drug colchicine has garnered significant recent attention due to its endorsement by the United States Food and Drug Administration as an anti-inflammatory medication for cardiovascular diseases. However, the administration of this drug at its minimal available dose of 0.5 mg has been associated with certain adverse reactions. Once colchicine is administered, the drug disappears from blood in a short time and distributes in the leukocytes for a certain period of time that elicits anti-inflammatory effect. Consequently, an in-depth comprehension of the pharmacokinetics of lower dosages within leukocytes assumes important for its broader application in routine clinical contexts. In this study, we present a comprehensive analysis of the pharmacological disposition of colchicine in the plasma, polymorphonuclear leukocytes, and mononuclear leukocytes among healthy Japanese male subjects, following both single and multiple oral administrations of 0.5 mg and 0.25 mg doses of colchicine. Our investigation reveals that colchicine persists within leukocyte populations even when administered at reduced dosages. The findings herein hold promise for mitigating the adverse effects associated with its use in the treatment of inflammatory cardiovascular disorders.

PS-P07-5: PHARMACEUTICAL INFLUENCES ON IN-HOSPITAL DEATH IN PATIENTS WITH AND THOSE WITHOUT DIABETES AT A JAPANESE COMMUNITY GENERAL HOSPITAL

Background: Diabetes mellitus (DM) is associated with increased risks of cancers, cardiovascular disease (CVD), liver disease and death. In recent years, cardiovascular and metabolic medications have been developed for reducing cardiovascular events and mortality. We examined mortality statistics by cause of in-hospital death in patients with DM and patients without DM and we analyzed the effects of cardiovascular and metabolic medications on the lifespans of patients in a Japanese community general hospital during the past decade. Methods: We performed a retrospective analysis of cause of death in hospitalized patients at Anan Medical Center, a community general hospital in Tokushima, Japan, during the period from 2011 to 2020. Information on clinical characteristics of the patients including age at death, cause of death, complications and medications used was obtained from medical records. Statistical comparisons were performed in patients with DM and those without DM. Multivariate analysis was also carried out to determine the effects of medications on age at death. Results: A total of 2336 deaths were recorded during the 10-year period. The mean age at death was not significantly different between diabetic and nondiabetic patients for both sexes (78.9 (DM) vs. 79.6 (non DM) years in males and 82.5 (DM) vs. 83.6 (non DM) years in females). The rates of hepato-pancreatic cancer and cardio-renal failure as a cause of death were significantly higher in patients with DM than in patients without DM (p &lt; 0.01 and p &lt; 0.05, respectively). The incidences of hepato-renal failure, CVD, hypertension and dyslipidemia as comorbidities were significantly higher in diabetic patients than in nondiabetic patients (all p &lt; 0.01). The percentages of patients taking antihypertensive, antiplatelet, diuretic and statin medications were higher in diabetic patients than in nondiabetic patients (all p &lt; 0.01). Multivariate analysis of medications for determinants of age at death showed that insulin was a negative contributor in diabetic patients. On the other hand, the use of an angiotensin receptor blocker (ARB)/angiotensin-converting enzyme inhibitor (ACEi) or Ca antagonists was a positive correlator for longevity in all of the subjects including diabetic and nondiabetic patients. Conclusions: In our community general hospital, DM had no influence on age at death. It is possible that comprehensive treatment for DM and its complications eliminates the difference between lifespans of individuals with DM and those without DM. In addition, treatment of hypertension with ARB/ACEi or Ca antagonists was positively associated with the longevity of Japanese community subjects.

PS-C06-12: HETEROGENEITY AND OVERLAP OF THE LONGITUDINAL ASSOCIATIONS AMONG INCREASED ARTERIAL STIFFNESS, HYPERTENSION AND DIABETES MELLITUS: A 16-YEAR PROSPECTIVE OBSERVATIONAL STUDY

Background: Hypertension and diabetes mellitus frequently coexist; however, differences in the bi-directional longitudinal relationships of arterial stiffness with hypertension and diabetes mellitus have not yet been clarified. Methods: In this 16-year prospective observational study, 3981 middle-aged Japanese subjects without hypertension/diabetes mellitus at the study baseline underwent annual measurements of the blood pressure, serum glycosylated hemoglobin A1c (HbA1c), and brachial-ankle pulse wave velocity (baPWV). Results: By the end of the study period, 664, 779, 154 and 406 subjects developed hypertension, prehypertension, diabetes mellitus and prediabetes, respectively. Increased baPWV at the baseline was associated with a significant odds ratio for new onset of prehypertension/hypertension without (beta = 5.0 x 10–3, P &lt; 0.01) or with (beta = 4.0 x 10–3, P &lt; 0.01) coexisting prediabetes/diabetes mellitus; no such association was found with new onset of prediabetes/diabetes mellitus alone. Furthermore, baPWV showed significant longitudinal associations with the development of all of the above conditions. Conversely, elevated mean blood pressure, even in the pre-hypertensive range, showed a significant longitudinal association with increase of the baPWV. Conclusions: In middle-aged Japanese subjects, a vicious cycle may be triggered between elevated blood pressure, even from the prehypertensive stage, and arterial stiffening and development of diabetes mellitus may be observed as a cross phenomenon of this vicious cycle with a collateral event. Arterial stiffness may be a key element in the development of hypertension, so that its contribution to cardiovascular risk may be greater in patients with hypertension than in those with diabetes mellitus.

Andexanet alfa (ONDEXXYA&lt;sup&gt;®&lt;/sup&gt; for Intravenous Injection 200 mg), a reversal agent for direct factor Xa inhibitors: pharmacological characteristics and clinical evidence

Andexanet alfa is a modified recombinant human factor Xa (FXa) that was designed to serve as a binding target for FXa inhibitors as decoy protein. It sequesters FXa inhibitors from binding to endogenous FXa, thereby reversing anticoagulant effect of FXa inhibitors. Andexanet alfa has been approved in March 2022 in Japan for patients with life-threatening or uncontrolled bleeding while on treatment with a FXa inhibitor, apixaban, rivaroxaban, or edoxaban tosilate hydrate. It is administered via two dosing regimens, based on the type of FXa inhibitor, dose, and time since the last dose. In nonclinical studies, andexanet alfa significantly inhibited bleeding induced by FXa inhibitors in animal bleeding models. In the development for Japanese patients, the following two clinical studies have been conducted to confirm the efficacy and safety. First, safety and the reversal effect of andexanet alfa on the FXa inhibitor-mediated anticoagulant activity in healthy adults were confirmed in the overseas phase 2 study including Japanese subjects. Next, the reversal effect of andexanet alfa on the anticoagulation activity and the hemostasis were demonstrated in patients with acute major bleeding while on FXa inhibitor treatment in the global phase 3b/4 study (ANNEXA-4 study). The subgroup analysis of Japanese population showed that the efficacy and safety results were consistent with those of overall population. Andexanet alfa is the first approved reversal agent for FXa inhibitors in Japan and is expected to contribute to the improvement of prognosis in patients with fatal and/or uncontrolled bleeding by timely reversing anticoagulant effect of FXa inhibitors.

The morphology of the femoral posterior condyle affects the external rotation of the femur

PurposeThe purpose of this study was to identify factors related to the external rotation of the femur during knee flexion.MethodsThree-dimensional (3D) digital models of the femur and tibia were reconstructed from computed tomography images of 41 healthy Japanese subjects. Thirteen parameters related to femoral and tibial morphology and alignment of the lower extremities were evaluated, including the inclination angle of the posterior lateral and medial femoral condyles, the ratio of the medial and lateral posterior condyle radii approximated as spheres, the spherical condylar angle, the posterior condylar angle, the medial and lateral posterior tibial slope, the difference of medial and lateral posterior tibial slope, the tibiofemoral rotation angle, the 3D femorotibial angle, the 3D hip-knee-ankle angle, and the passing point of the weight-bearing line (medial–lateral and anterior–posterior). The rotation angle of the femur relative to the tibia during squatting was investigated using a 3D to 2D image matching technique and the relationships with the13 parameters were determined.ResultsThe femur externally rotated substantially up to 20° of knee flexion (9.2° ± 3.7°) and gently rotated after 20° of knee flexion (12.8° ± 6.2°). The external rotation angle at 20°–120° of knee flexion correlated with the spherical condylar angle, the tibiofemoral rotation angle and the inclination angle of the posterior medial condyles (correlation coefficient; 0.506, 0.364, 0.337, respectively).ConclusionThe parameter that was most related to the external rotation of the femur during knee flexion was the spherical condylar angle.Level of EvidenceIV

Validation of Estimated Small Dense Low-Density Lipoprotein Cholesterol Concentration in a Japanese General Population.

A high level of directly measured small dense low-density lipoprotein cholesterol (sdLDL-C) is a strong risk factor for atherosclerotic cardiovascular disease. A method for estimating sdLDL-C by using Sampson's equation that includes levels of total cholesterol, high-density lipoprotein cholesterol (HDL-C), non-HDL-C and triglycerides (TG) has recently been proposed. We investigated the validation and exploration of estimated sdLDL-C level. The associations between measured and estimated sdLDL-C levels were investigated in 605 Japanese subjects (men/women: 280/325; mean age: 65±15 years) who received annual health check-ups in the Tanno-Sobetsu Study, a population-based cohort. Estimated sdLDL-C level was highly correlated with measured sdLDL-C level in all subjects (R2=0.701), nondiabetic subjects without any medication (n=254, R2=0.686) and subjects with diabetes mellitus (n=128, R2=0.721). Multivariable regression analysis showed that levels of non-HDL-C, TG and γ-glutamyl transpeptidase (γGTP) were independent predictors of measured sdLDL-C level. In a stratification of the LDL window, all of the subjects with a combination of high non-HDL-C (≥ 170 mg/dL) and high TG (≥ 150 mg/dL) had high levels of measured and estimated sdLDL-C (≥ 35 mg/dL). Furthermore, machine learning-based estimation of sdLDL-C level by artificial intelligence software, Prediction One, was substantially improved by using components of Sampson's equation (R2=0.803) and by using those components with the addition of γGTP and deletion of TC (R2=0.929). sdLDL-C level estimated by Sampson's equation can be used instead of measured sdLDL-C level in general practice. By building multiple machine learning models of artificial intelligence, a more accurate and practical estimation of sdLDL-C level might be possible.

Linear association between aging and decreased blood thiol antioxidant activity in patients with cataract.

We comprehensively assessed the roles of systemic redox markers by including both prooxidant and antioxidant markers in 121 Japanese subjects (mean ± SD age, 70 ± 11 years; 38 men) with no ocular pathology except age-related cataract. Serum levels of lipid peroxides, ferric-reducing activity, and thiol antioxidant activity were measured using the diacron reactive oxygen metabolite (dROM), biologic antioxidant potential (BAP), and sulfhydryl (SH) tests, respectively, using a free-radical analyzer. Univariate analyses suggested that older age, higher pulse rate, worse best-corrected visual acuity (BCVA), higher intraocular pressure, and higher cataract grade were associated with a lower SH level. Scatterplots revealed virtually linear associations between age and the SH level (estimate, -4.4 μM/year). Multivariate analyses suggested that older age, higher systolic blood pressure, and worse BCVA were associated with a lower SH level. Neither the univariate nor multivariate analyses, except between female sex and higher dROM level, were associated with the dROM or BAP level. A lower serum SH level was the driver of aging itself and age-related decline in VA due to cataract. The serum SH level may be an excellent predictor of aging status in each subject.

PS-C04-2: LONGITUDINAL CONSTANCY OF VASCULAR AGEING PHENOTYPES AND FACTORS ASSOCIATED WITH THE PHENOTYPE CONSTANCY OVER TIME

Background: The concept of two phenotypes of vascular aging, healthy vascular aging (HVA) and early vascular aging (EVA) has been proposed. Objectives: To examine the: (1) constancy of these phenotypes over time; (2) validity of assuming that a constantly maintained phenotype reflects the rate of structural arterial stiffening; and (3) longitudinal associations between the vascular phenotypes and cardiovascular risk factors/heart rate (HR). Methods: The brachial-ankle pulse wave velocity (baPWV) was measured annually over a 16-year period in 4682 middle-aged Japanese subjects. The vascular phenotypes of 4682 middle-aged Japanese subjects were measured at the start and end of a 16-year study period, by measuring the arterial stiffness as a function of the age and blood pressure. Results: Of 4682 subjects, 158 (3.4%) showed constancy of the HVA phenotype, and 192 (4.1%) subjects showed constancy of the EVA phenotype throughout the study periods. The baPWV adjusted for the mean blood pressure differed significantly between the two groups. Elevated mean blood pressure, serum HbA1c levels and HR were significantly associated with constancy of the EVA phenotype, whereas only a low HR was significantly associated with constancy of the HVA phenotype. Conclusions: In middle-aged Japanese subjects with the HVA/EVA phenotype at the study baseline, while the phenotype changed during the study period in many subjects, phenotype constancy appeared to reflect the rate of structural arterial stiffening. Elevated blood pressure and abnormal glucose metabolism were associated with constancy of the EVA phenotype. On the other hand, HR was a robust marker of the presence/constancy of the HVA/EVA phenotype.