Five percent weight loss is a significant 1-year predictor and an optimal 5-year cut-off for reducing the number of obesity-related cardiovascular disease risk components: the Japan Obesity and Metabolic Syndrome Study.

Objective: This study aimed to identify the amount of weight loss needed in patients with obesity to improve metabolic syndrome (MetS), a risk factor for cardiovascular disease (CVD), over a long period of time. Methods: A total of 576 patients with obesity were enrolled in this study. Effects of continuous physician-supervised weight loss on the cumulative MetS components excluding abdominal circumference (defined as obesity-related CVD risk score) were investigated during a 5-year follow-up period. The extent of weight loss required to reduce the obesity-related CVD risk components was assessed using receiver operating characteristic (ROC) curve analyses. Results: Of the 576 participants, 266 completed 5-year follow-up, with 39.1% and 24.1% of them achieving ≥5.0% and ≥7.5% weight loss at the 5-year follow-up, respectively. The area under the ROC curve for reducing the obesity-related CVD risk components was 0.719 [0.662-0.777] at 1 year and 0.694 [0.613-0.775] at 5 years. The optimal cut-off value for weight loss was 5.0% (0.66 sensitivity and 0.69 specificity) and the value with 0.80 specificity was 7.5% (0.45 sensitivity) at 5 years. Greater reductions in weight were associated with greater improvements in the obesity-related CVD risk score at all follow-up periods (P-trend <0.001). Obesity-related CVD risk score was significantly improved by 5.0-7.5% and ≥7.5% weight loss at 1 year (P = 0.029 and P < 0.001, respectively) and ≥7.5% weight loss at 5 years (P = 0.034). Conclusions: A weight loss of ≥5.0% at 1 year and ≥7.5% at 5 years could reduce the number of obesity-related CVD risk components in patients with obesity.

Successful Percutaneous Thoracic Duct Embolization for Chylothorax After Total Arch Replacement.

Chylothorax after cardiac surgery is a rare complication associated with severe morbidity and mortality. This report documents successful treatment with percutaneous thoracic duct embolization for chylothorax after total arch replacement. A 69-year-old man underwent replacement of the aortic arch to treat a ruptured aortic aneurysm. After surgery, the left thoracic drain discharged 2,000 to 3,000 mL serosanguineous fluid per day, even though the patient took nothing orally and was administered subcutaneous octreotide therapy. On postoperative day 9, percutaneous thoracic duct embolization was performed, and the drain could be removed. The chylothorax did not recur, and the patient was discharged on postoperative day 17.

A Surgical Case of Infected Popliteal Artery Aneurysm From Rare Bacteria, Eubacterium sp.

A 79-year-old man presented to our hospital with complaints of a sudden worsening of swelling in the right popliteal fossa and fever persisting for a week. Upon close examination, an infected popliteal artery aneurysm (PAA) was identified. Given the risk of rupture, the patient was advised to undergo surgery. The surgical procedure involved resecting the infectious PAA using a lateral approach. Additionally, a bypass was performed from the superficial femoral artery to the below-knee artery, utilizing the great saphenous vein located at the posterior aspect of the knee. Surgical findings revealed a popliteal artery pseudoaneurysm. Preoperative blood cultures identified Eubacterium spp., and cultures of the inoperative aneurysm specimens confirmed the presence of the same bacteria. After surgery, inflammation quickly subsided, and the patient was discharged on postoperative day (POD) 41 after receiving transvenous antibiotic therapy. Although PAA accounts for approximately 80% of all peripheral arterial aneurysms, mycotic aneurysms are relatively rare. Eubacterium spp. is part of the human intestinal or oral flora, and very few reports of bacteremia have been published. The present case of bacteremia caused by Eubacterium sp. is very rare; to the best of our knowledge, no literature has been published on this topic.

Asymptomatic left ventricular pseudoaneurysm.

Some cases of left ventricular pseudoaneurysms (LVPAs) are asymptomatic. While cardiac magnetic resonance imaging is important, a chest x-ray can easily be performed and is also crucial for the detection of LVPA during the first outpatient visit.

A patient with extensive ST elevation myocardial infarction who underwent emergent Impella CP® assisted off-pump coronary artery bypass without mechanical complication.

Impella (Abiomed Inc., Danvers, MA, USA) assisted off-pump coronary artery bypass has been increasingly reported in recent years. However, there have been no reports of the procedures performed for acute myocardial infarction in which the patient is hemodynamically unstable. We report a case of a 73-year-old man with cardiogenic shock due to extensive ST elevation acute myocardial infarction that worsened despite Impella CP® support. Because of the fragile myocardium in the acute phase of myocardial infarction, Impella assisted off-pump coronary artery bypass graft causes a high risk of myocardial injury, but we were able to safely perform the procedure by ingenious techniques. Learning objective: When performing Impella-assisted off-pump coronary artery bypass for extensive acute myocardial infarction patients, the high risk of mechanical complications due to myocardial fragility must be considered. The position of Impella should be carefully monitored intraoperatively, and elevation of cardiac apex should be kept to a minimum to prevent myocardial damage caused by Impella.

Imeglimin Exhibits Novel Anti-Inflammatory Effects on High-Glucose-Stimulated Mouse Microglia through ULK1-Mediated Suppression of the TXNIP-NLRP3 Axis.

Type 2 diabetes mellitus (T2DM) is an epidemiological risk factor for dementia and has been implicated in multifactorial pathologies, including neuroinflammation. In the present study, we aimed to elucidate the potential anti-inflammatory effects of imeglimin, a novel antidiabetic agent, on high-glucose (HG)-stimulated microglia. Mouse microglial BV2 cells were stimulated with HG in the presence or absence of imeglimin. We examined the effects of imeglimin on the levels of proinflammatory cytokines, intracellular reactive oxygen species (ROS), mitochondrial integrity, and components related to the inflammasome or autophagy pathways in these cells. Our results showed that imeglimin suppressed the HG-induced production of interleukin-1beta (IL-1ß) by reducing the intracellular ROS levels, ameliorating mitochondrial dysfunction, and inhibiting the activation of the thioredoxin-interacting protein (TXNIP)-NOD-like receptor family pyrin domain containing 3 (NLRP3) axis. Moreover, the inhibitory effects of imeglimin on the TXNIP-NLRP3 axis depended on the imeglimin-induced activation of ULK1, which also exhibited novel anti-inflammatory effects without autophagy induction. These findings suggest that imeglimin exerted novel suppressive effects on HG-stimulated microglia through the ULK1-TXNIP-NLRP3 axis, and may, thereby, contribute to the development of innovative strategies to prevent T2DM-associated cognitive impairment.

Serum Growth Differentiation Factor 15 Levels Predict the Incidence of Frailty Among Patients with Cardiometabolic Diseases.

INTRODUCTION: Frailty is a crucial health issue among older adults. Growth differentiation factor 15 (GDF15) is associated with inflammation, oxidative stress, insulin resistance, and mitochondrial dysfunction, which are possible pathogeneses of frailty. However, few longitudinal studies have investigated the association between GDF15 and the incidence of frailty. Therefore, we investigated whether high serum GDF15 levels are associated with the incidence of frailty. METHODS: A total of 175 older adults (mean age : 77 ± 6 years; 63% women) with cardiometabolic diseases and no frailty out of the two criteria at baseline participated. Individuals with severe renal impairment or severe cognitive impairment were excluded. Serum GDF15 levels were measured at baseline. Patients were asked to assess frailty status at baseline and annually during follow-up using the modified version of the Cardiovascular Health Study (mCHS) and the Kihon Checklist (KCL). We examined the association between GDF15 tertiles and each frailty measure during follow-up (median 38-39 months). In the multivariate Cox regression analysis, with the GDF15 tertile groups as the explanatory variables, hazard ratios (HRs) and 95% confidence intervals (CIs) for incident frailty were calculated after adjusting for covariates and using the lowest tertile group as the reference. RESULTS: During the follow-up period, 25.6% and 34.0% of patients developed frailty, as defined by the mCHS and KCL, respectively. The highest GDF15 tertile group had a significantly higher incidence of mCHS- or KCL-defined frailty than the lowest GDF15 tertile group. Multivariate Cox regression analysis revealed that the adjusted HRs for incident mCHS- and KCL-defined frailty in the highest GDF15 tertile group were 3.9 (95% CI: 1.3-12.0) and 2.7 (95% CI: 1.1-6.9), respectively. CONCLUSION: High serum GDF15 levels predicted the incidence of frailty among older adults with cardiometabolic diseases and could be an effective marker of the risk for frailty in interventions aimed at preventing frailty, such as exercise and nutrition.

Delayed Giant Pseudoaneurysm With Left-to-Right Shunt Following Postinfarct Ventricular Septal Perforation Repair.

Left ventricular pseudoaneurysm with a left-to-right shunt is extremely rare, requiring surgery if symptomatic; however, surgery has a high risk. Here, the case of a 77-year-old man with heart failure symptoms is reported, in which he develops a giant left ventricular pseudoaneurysm 16 months after ventricular septal perforation repair as a result of acute myocardial infarction, with mild shunt blood flow from the pseudoaneurysm to the right ventricle. Intraoperative findings showed a free wall rupture along the area where the patch was secured during the initial surgery. The patient was discharged on postoperative day 13, and postoperative examination revealed no abnormalities.

Novel pathological implications of serum uric acid with cardiovascular disease risk in obesity.

AIMS: This cohort study intended to elucidate the association between serum uric acid (SUA) levels and cardiovascular disease events in Japanese patients with obesity. METHODS: Altogether, 450 obese Japanese outpatients were enrolled in a multicenter prospective cohort Japan, the Japan Obesity and Metabolic Syndrome Study. Primary analysis regarding the measurements of cardiovascular risk factors, including SUA levels, and the occurrence of macrovascular complications was based on following the participants over a 5-year period. RESULTS: Of the eligible patients, 335 (74.4%) were followed into the fifth year. During the study period, 15 coronary heart disease, 7 stroke, and 6 arteriosclerosis obliterans events occurred in 39 patients. The CVD incidence rate was 15.8 per 1000 person-years. In the analysis of adjusted models for traditional risk factors, hyperuricemia was a significant factor for the incidence of CVD events, especially in female obese patients. Additionally, we estimated the association between SUA levels and CVD events using cubic spline models, which showed a U-shaped association in both male and female patients. CONCLUSIONS: SUA is an effective predictor of CVD events in female obese patients and a risk factor for CVD incident in obese patients.

Taxifolin Suppresses Inflammatory Responses of High-Glucose-Stimulated Mouse Microglia by Attenuating the TXNIP-NLRP3 Axis.

Type 2 diabetes mellitus is associated with an increased risk of dementia, potentially through multifactorial pathologies, including neuroinflammation. Therefore, there is a need to identify novel agents that can suppress neuroinflammation and prevent cognitive impairment in diabetes. In the present study, we demonstrated that a high-glucose (HG) environment elevates the intracellular reactive oxygen species (ROS) levels and triggers inflammatory responses in the mouse microglial cell line BV-2. We further found that thioredoxin-interacting protein (TXNIP), a ROS-responsive positive regulator of the nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, was also upregulated, followed by NLRP3 inflammasome activation and subsequent interleukin-1beta (IL-1ß) production in these cells. Conversely, caspase-1 was not significantly activated, suggesting the involvement of noncanonical pathways in these inflammatory responses. Moreover, our results demonstrated that taxifolin, a natural flavonoid with antioxidant and radical scavenging activities, suppressed IL-1ß production by reducing the intracellular ROS levels and inhibiting the activation of the TXNIP-NLRP3 axis. These findings suggest the novel anti-inflammatory effects of taxifolin on microglia in an HG environment, which could help develop novel strategies for suppressing neuroinflammation in diabetes.

Secondary structure of the human mitochondrial genome affects formation of deletions.

BACKGROUND: Aging in postmitotic tissues is associated with clonal expansion of somatic mitochondrial deletions, the origin of which is not well understood. Such deletions are often flanked by direct nucleotide repeats, but this alone does not fully explain their distribution. Here, we hypothesized that the close proximity of direct repeats on single-stranded mitochondrial DNA (mtDNA) might play a role in the formation of deletions. RESULTS: By analyzing human mtDNA deletions in the major arc of mtDNA, which is single-stranded during replication and is characterized by a high number of deletions, we found a non-uniform distribution with a "hot spot" where one deletion breakpoint occurred within the region of 6-9 kb and another within 13-16 kb of the mtDNA. This distribution was not explained by the presence of direct repeats, suggesting that other factors, such as the spatial proximity of these two regions, can be the cause. In silico analyses revealed that the single-stranded major arc may be organized as a large-scale hairpin-like loop with a center close to 11 kb and contacting regions between 6-9 kb and 13-16 kb, which would explain the high deletion activity in this contact zone. The direct repeats located within the contact zone, such as the well-known common repeat with a first arm at 8470-8482 bp (base pair) and a second arm at 13,447-13,459 bp, are three times more likely to cause deletions compared to direct repeats located outside of the contact zone. A comparison of age- and disease-associated deletions demonstrated that the contact zone plays a crucial role in explaining the age-associated deletions, emphasizing its importance in the rate of healthy aging. CONCLUSIONS: Overall, we provide topological insights into the mechanism of age-associated deletion formation in human mtDNA, which could be used to predict somatic deletion burden and maximum lifespan in different human haplogroups and mammalian species.

Roles and Competencies of Doctors in Artificial Intelligence Implementation: Qualitative Analysis Through Physician Interviews.

BACKGROUND: Artificial intelligence (AI) is a term used to describe the use of computers and technology to emulate human intelligence mechanisms. Although AI is known to affect health services, the impact of information provided by AI on the patient-physician relationship in actual practice is unclear. OBJECTIVE: The purpose of this study is to investigate the effect of introducing AI functions into the medical field on the role of the physician or physician-patient relationship, as well as potential concerns in the AI era. METHODS: We conducted focus group interviews in Tokyo's suburbs with physicians recruited through snowball sampling. The interviews were conducted in accordance with the questions listed in the interview guide. A verbatim transcript recording of all interviews was qualitatively analyzed using content analysis by all authors. Similarly, extracted code was grouped into subcategories, categories, and then core categories. We continued interviewing, analyzing, and discussing until we reached data saturation. In addition, we shared the results with all interviewees and confirmed the content to ensure the credibility of the analysis results. RESULTS: A total of 9 participants who belonged to various clinical departments in the 3 groups were interviewed. The same interviewers conducted the interview as the moderator each time. The average group interview time for the 3 groups was 102 minutes. Content saturation and theme development were achieved with the 3 groups. We identified three core categories: (1) functions expected to be replaced by AI, (2) functions still expected of human physicians, and (3) concerns about the medical field in the AI era. We also summarized the roles of physicians and patients, as well as the changes in the clinical environment in the age of AI. Some of the current functions of the physician were primarily replaced by AI functions, while others were inherited as the functions of the physician. In addition, "functions extended by AI" obtained by processing massive amounts of data will emerge, and a new role for physicians will be created to deal with them. Accordingly, the importance of physician functions, such as responsibility and commitment based on values, will increase, which will simultaneously increase the expectations of the patients that physicians will perform these functions. CONCLUSIONS: We presented our findings on how the medical processes of physicians and patients will change as AI technology is fully implemented. Promoting interdisciplinary discussions on how to overcome the challenges is essential, referring to the discussions being conducted in other fields.

Association Between Serum GDF15 Concentration and Total Mortality in Community-Dwelling Japanese Older Populations: The Involvement of Renal Dysfunction.

BACKGROUND: Serum growth differentiation factor 15 (GDF15) is associated with age-related adverse outcomes. However, renal function has not been thoroughly evaluated in studies addressing the association between GDF15 and mortality. We aimed to clarify whether GDF15 is associated with total mortality after carefully controlling renal function markers. METHODS: We divided 1 801 community-dwelling Japanese older adults into quartiles according to their serum GDF15 concentrations. The correlation of GDF15 with renal function and inflammation markers was assessed by calculating Spearman correlation coefficients. Cumulative survival rates of the quartiles were estimated. In a Cox regression analysis adjusted for confounders, the association between GDF15 and mortality was evaluated. The discriminative capacity of GDF15 for the prediction of mortality was assessed with receiver-operating characteristic analysis. RESULTS: GDF15 was correlated with cystatin C (r = 0.394), ß2-microglobulin (r = 0.382), C-reactive protein (r = 0.124), and interleukin-6 (r = 0.166). The highest GDF15 quartile showed poor survival compared to the others. Older adults with higher GDF15 were associated with an increased mortality risk, independent of demographics and clinically relevant variables (hazard ratio [95% confidence interval]: 1.98 [1.09-3.59]). This significant association disappeared when additionally adjusted for cystatin C (1.65 [0.89-3.05]) or ß2-microglobulin (1.69 [0.91-3.12]). The ability to predict mortality was approximately comparable between GDF15 (area under the curve: 0.667), cystatin C (0.691), and ß2-microglobulin (0.715). CONCLUSIONS: Serum GDF15 is associated with total mortality in older Japanese after adjustment for major confounders. The increased mortality risk in older adults with higher GDF15 may be partly attributed to decreased renal function.

A Comparative Study to Investigate the Effects of Bisoprolol in Patients with Chronic Heart Failure and Hypertension When Switched from Tablets to Transdermal Patches.

BACKGROUND: Oral beta-blockers are effective for heart failure and hypertension. Here, we conducted a prospective study to investigate the efficacy of the beta-blocker bisoprolol in patients switching from the oral tablet to the transdermal patch. METHODS: We studied 50 outpatients receiving oral bisoprolol for chronic heart failure and hypertension. After patients switched treatments, we measured heart rate (HR) over 24 h by Holter echocardiography as the primary endpoint. Secondary endpoints were (1) HR at 00:00, 06:00, 12:00, and 18:00, (2) the total number of premature atrial contractions (PACs) over 24 h and the incidence rate per time segment, and the total number of premature ventricular contractions (PVCs) over 24 h and the incidence rate per time segment, (3) blood pressure, (4) atrial natriuretic peptide and B-type natriuretic peptide, and (5) echocardiography. RESULTS: Minimum, maximum, mean, and total HR over 24 h was not significantly different between the two groups. Mean and maximum HR at 06:00, total PACs, total PVCs, and PVCs at 00:00 to 05:59 and 06:00 to 11:59 were significantly lower in the patch group. CONCLUSION: Compared with oral bisoprolol, the bisoprolol transdermal patch lowers HR at 06:00 and inhibits the onset of PVCs during sleep and in the morning.

Management of acute pulmonary embolism with sequential hybrid therapy of surgical thrombectomy and rivaroxaban intensive therapy: a case report.

Acute pulmonary embolism (PE) is often associated with rapid hemodynamic deterioration or death. Therefore, early therapeutic intervention is important. A 45-year-old man was diagnosed with intermediate-high risk PE, and sequential hybrid therapy consisting of surgical thrombectomy and rivaroxaban intensive therapy was administered. During the course of treatment, echocardiography revealed improvement in pulmonary artery systolic pressure, and thrombus volume analysis by computed tomography revealed a drastic reduction in the size of the thrombus. Sequential hybrid therapy for acute PE not only stabilizes hemodynamics, but may also prevent conversion to chronic thromboembolic pulmonary hypertension by sufficiently reducing the volume of the thrombus.

A Single Arm Clinical Study on the Effects of Continuous Erythropoietin Receptor Activator Treatment in Non-Dialysis Patients with Chronic Heart Failure and Renal Anemia.

Erythropoiesis-stimulating agents improve the NYHA functional class and decrease the hospital readmission rates for heart failure; however, little is known about the influence of continuous erythropoietin receptor activator (CERA) on the heart. Therefore, a prospective study was conducted to investigate the effects of CERA on cardiac and renal function and oxidative stress in chronic heart failure with renal anemia. Sixty patients with chronic heart failure and renal anemia were enrolled and received CERA for 12 months. The primary endpoints were hemoglobin (Hb) and hematocrit, and the secondary endpoints were: (1) atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP); (2) NYHA class; (3) echocardiography; (4) blood urea nitrogen, creatinine, cystatin C, and urinary albumin; (5) high-sensitivity C-reactive protein; (6) oxidized low-density lipoprotein (Ox-LDL); and (7) renin, angiotensin-II, and aldosterone. There was a significant difference in the Hb levels measured before and after CERA administration. The BNP, ANP, NYHA, left ventricular mass index, renal function, and Ox-LDL decreased significantly after CERA administration. This study shows that CERA improves anemia and reduces renal impairment, as well as cardiac and oxidative stress. The result of this study is useful for a study in which switching from CERA to a new renal anemia drug, hypoxia-inducible factor prolyl-hydroxylase inhibitor, is investigated.

Intraoperative Type B Aortic Dissection during Total Arch Replacement.

BACKGROUND: Intraoperative aortic dissection is an extremely serious complication that should be prevented whenever possible. When it does occur, it requires urgent clinical management. CASE PRESENTATION: We report the case of a 78-year-old man with Marfan syndrome who developed an intraoperative complicated type B aortic dissection with a distal anastomosis entry site during total arch replacement for a chronic dissection. CONCLUSION: Performing immediate thoracic endovascular aortic repair, we were able to improve malperfusion to the lower extremities occurred during total arch replacement.

Japan should initiate the discussion on voluntary assisted dying legislation now.

BACKGROUND: No laws or official guidelines govern voluntary assisted dying (VAD) in Japan. A legislative bill on the termination of life-sustaining measures has yet to be sent to deliberations for legislation, due to strong opposition that has prevented it from being submitted to the Diet. However, Japan has recently witnessed several cases involving VAD. MAIN TEXT: Against this backdrop, we argue that Japan should begin discussion on VAD legislation, referring to the Voluntary Assisted Dying Act 2017 (VADA2017), which was established in 2017 in Victoria, Australia. VADA2017 puts in place a wide range of stringent safeguards and is considered worldwide to be the safest and most conservative policy on a physician offering assisted dying based on the patient's premeditated request. We consider what opposing opinions from society would arise in response to the VADA2017. Among these will include arguments against VAD itself, those against the validation of this act, and opinions that oppose even the initiation of the dialogue on VAD. CONCLUSIONS: We conclude that to protect the right to life among those placed in vulnerable positions and, at the same time, to respect decision-making of those who wish for immediate death due to unbearable suffering, the dialogue must immediately begin with that on introducing a policy more conservative than that of the VADA2017, which solidly considers arguments against VAD.

Novel Therapeutic Potentials of Taxifolin for Obesity-Induced Hepatic Steatosis, Fibrogenesis, and Tumorigenesis.

The molecular pathogenesis of nonalcoholic steatohepatitis (NASH) includes a complex interaction of metabolic stress and inflammatory stimuli. Considering the therapeutic goals of NASH, it is important to determine whether the treatment can prevent the progression from NASH to hepatocellular carcinoma. Taxifolin, also known as dihydroquercetin, is a natural bioactive flavonoid with antioxidant and anti-inflammatory properties commonly found in various foods and health supplement products. In this study, we demonstrated that Taxifolin treatment markedly prevented the development of hepatic steatosis, chronic inflammation, and liver fibrosis in a murine model of NASH. Its mechanisms include a direct action on hepatocytes to inhibit lipid accumulation. Taxifolin also increased brown adipose tissue activity and suppressed body weight gain through at least two distinct pathways: direct action on brown adipocytes and indirect action via fibroblast growth factor 21 production in the liver. Notably, the Taxifolin treatment after NASH development could effectively prevent the development of liver tumors. Collectively, this study provides evidence that Taxifolin shows pleiotropic effects for the treatment of the NASH continuum. Our data also provide insight into the novel mechanisms of action of Taxifolin, which has been widely used as a health supplement with high safety.