Diagnostic Performance of an Automated Blood Pressure Monitor With an Irregular Heartbeat Algorithm Designed to Detect Atrial Fibrillation.

Background: Early detection of atrial fibrillation (AF) remains an unsolved challenge and because the greatest risk factor for AF is hypertension, blood pressure (BP) monitors with AF detectors have been developed. We evaluated the clinical performance of an irregular heartbeat (IHB) algorithm built into an A&D automated BP monitor for AF diagnosis. Methods and Results: Each of the 239 enrolled patients underwent BP measurement 3 times using the A&D UM-212 with the IHB algorithm. Real-time 3-lead ECG was recorded using automated ECG analysis software. Independent of the ECG analysis software results, 2 cardiologists interpreted the ECG and made the final diagnosis. Of the 239 patients, 135 were in sinus rhythm, 31 had AF, and 73 had non-AF arrhythmias. The respective sensitivity, specificity, and accuracy of the IHB algorithm for AF diagnosis were 98.9%, 91.2%, and 92.2% for the per-measurement evaluation, and 96.8%, 95.7%, and 95.8% for the per-patient evaluation (3/3 positive measurements). The respective sensitivity, specificity, and accuracy of the ECG analysis software for AF diagnosis were 91.4%, 97.9%, and 97.1% for the per-measurement evaluation, and 77.4%, 99.5%, and 96.7% for the per-patient evaluation (3/3 positive measurements). Conclusions: The IHB algorithm built into an A&D automated BP monitor had high diagnostic performance for AF in general cardiology patients, especially when multiple measurements were obtained.

Transitional Medicine of Intractable Primary Dyslipidemias in Japan.

Transitional medicine refers to the seamless continuity of medical care for patients with childhood-onset diseases as they grow into adulthood. The transition of care must be seamless in medical treatment as the patients grow and in other medical aids such as subsidies for medical expenses in the health care system. Inappropriate transitional care, either medical or social, directly causes poorer prognosis for many early-onset diseases, including primary dyslipidemia caused by genetic abnormalities. Many primary dyslipidemias are designated as intractable diseases in the Japanese health care system for specific medical aids, as having no curative treatment and requiring enormous treatment costs for lipid management and prevention of complications. However, there are problems in transitional medicine for primary dyslipidemia in Japan. As for the medical treatment system, the diagnosis rate remains low due to the shortage of specialists, their insufficient link with generalists and other field specialists, and poor linkage between pediatricians and physicians for adults. In the medical care system, there is a mismatch of diagnostic criteria of primary dyslipidemias between children and adults for medical care expense subsidization, as between The Program for the Specific Pediatric Chronic Diseases and the Program for Designated Adult Intractable Diseases. This could lead some patients subsidized in their childhood to no longer be under the coverage of the aids after transition. This review intends to describe these issues in transitional medicine of primary dyslipidemia in Japan as a part of the efforts to resolve the problems by the Committee on Primary Dyslipidemia under the Research Program on Rare and Intractable Disease of the Ministry of Health, Labour and Welfare of Japan.

A case of a peritoneal dialysis patient with left pleuroperitoneal communication caused by a pericardial defect after coronary artery bypass surgery.

A 74-year-old woman with reduced kidney and cardiac function and a history of coronary artery bypass surgery involving the gastroepiploic artery to the right coronary artery and posterior descending artery #4 presented with dyspnea on exertion. Shortly after the induction of peritoneal dialysis (PD), an increase in the left pleural effusion was observed, and a diagnosis of left pleuroperitoneal communication was made by puncture drainage. The pleuroperitoneal communication hole was not detected under thoracoscopic observation; however, a 10 mm-sized hole in the pericardium was found, confirming leakage of ICG-loaded peritoneal dialysate fluid (PDF). CT peritoneography using PDF mixed with iodine contrast medium revealed that the gastroepiploic artery-to-right coronary artery pathway was defective on the abdominal side. We concluded that the left pleuroperitoneal communication was caused by a two-stage fistulous pathway between the abdominal and pleural cavities through the pericardial cavity after coronary artery bypass graft surgery. Although closure of the diaphragmatic hole around the gastroepiploic artery graft should have been performed to restart PD, the patient did not wish to undergo further invasive procedures. Identification of the fistulous pathway is extremely important for prompt diagnosis and treatment of pleuroperitoneal communication.

The impact of dietary fat type on lipid profiles in lean mass hyper-responder phenotype.

Key Clinical Message: Although the lean mass hyper-responder (LMHR) phenotype is well known, its diagnosis is impeded by the influence of fat type and intake on the lipid profile. Accordingly, a detailed assessment is warranted if LMHR is suspected. Abstract: A 47-year-old man with suspected familial hypercholesterolemia presented with elevated triglyceride and low-density lipoprotein cholesterol levels. He had adhered to a ketogenic diet and was suspected of a lean mass hyper-responder phenotype; however, his lipid profile did not meet the definition. His lipid profile improved through dietary management without medication.

Improved Efficiency of the Clinical Diagnostic Criteria for Familial Hypercholesterolemia in Children: A Comparison of the Japan Atherosclerosis Society Guidelines of 2017 and 2022.

AIMS: Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C) levels, which increases the risk of premature coronary artery disease. Early detection and treatment are vital, especially in children. To improve FH diagnosis in children, the Japan Atherosclerosis Society (JAS) released new guidelines in July 2022. This study assessed and compared the sensitivity and specificity of the clinical diagnostic criteria from the JAS pediatric FH guidelines of 2017 and 2022. METHODS: From September 2020 to March 2023, 69 children with elevated plasma LDL-C levels (≥ 140 mg/dL) were included in a pediatric FH screening project in Kagawa. The children were evaluated using genetic testing alongside the clinical diagnostic criteria from the JAS pediatric FH guidelines of 2017 and 2022. RESULTS: Using the JAS pediatric FH 2017 criteria, eight children were diagnosed as FH-positive and 61 children as FH-negative. The JAS pediatric FH 2022 criteria identified 15 children with definite FH, 31 with probable FH, and 23 with possible FH. Genetic testing detected FH pathogenic variants in 24 children. The sensitivity and specificity for the JAS pediatric FH 2017 criteria were 0.292 and 0.978, respectively. For the JAS pediatric FH 2022 criteria, the sensitivity was 0.542 for definite FH with a specificity of 0.956, and 0.917 for probable FH with a specificity of 0.467. CONCLUSION: The clinical diagnostic criteria of the JAS pediatric FH 2022 guidelines demonstrated improved diagnostic efficiency compared with those of 2017, as evidenced by the increased sensitivity while preserving specificity.

Phenotypic homozygous familial hypercholesterolemia successfully treated with proprotein convertase subtilisin/kexin type 9 inhibitors.

Recent data reveal phenotypic HoFH patients may be responsive to PCSK9 inhibitors, challenging prior assumptions. Genetic testing advancements now more accurately forecast patient responses to these therapies, improving treatment strategies.

Partial replacement of d-glucose with d-allose ameliorates peritoneal injury and hyperglycaemia induced by peritoneal dialysis fluid in rats.

BACKGROUND: Peritoneal dialysis (PD) is a crucial dialysis method for treating end-stage kidney disease. However, its use is restricted due to high glucose-induced peritoneal injury and hyperglycaemia, particularly in patients with diabetes mellitus. In this study, we investigated whether partially replacing d-glucose with the rare sugar d-allose could ameliorate peritoneal injury and hyperglycaemia induced by peritoneal dialysis fluid (PDF). METHODS: Rat peritoneal mesothelial cells (RPMCs) were exposed to a medium containing d-glucose or d-glucose partially replaced with different concentrations of d-allose. Cell viability, oxidative stress and cytokine production were evaluated. Sprague-Dawley (SD) rats were administrated saline, a PDF containing 4% d-glucose (PDF-G4.0%) or a PDF containing 3.6% d-glucose and 0.4% d-allose (PDF-G3.6%/A0.4%) once a day for 4 weeks. Peritoneal injury and PD efficiency were assessed using immuno-histological staining and peritoneal equilibration test, respectively. Blood glucose levels were measured over 120 min following a single injection of saline or PDFs to 24-h fasted SD rats. RESULTS: In RPMCs, the partial replacement of d-glucose with d-allose increased cell viability and decreased oxidative stress and cytokine production compared to d-glucose alone. Despite the PDF-G3.6%/A0.4% having a lower d-glucose concentration compared to PDF-G4.0%, there were no significant changes in osmolality. When administered to SD rats, the PDF-G3.6%/A0.4% suppressed the elevation of peritoneal thickness and blood d-glucose levels induced by PDF-G4.0%, without impacting PD efficiency. CONCLUSIONS: Partial replacement of d-glucose with d-allose ameliorated peritoneal injury and hyperglycaemia induced by high concentration of d-glucose in PDF, indicating that d-allose could be a potential treatment option in PD.

A Comparison of Sleep Duration Accuracy Between Questionnaire and Accelerometer in Middle Childhood.

Purpose Healthy sleep is vital to children's well-being, and assessing sleep efficiently and accurately can help understand children's lifestyles. Due to the difficulty in objectively measuring sleep duration using wearable sensors in large-scale surveys of children, self-administered questionnaires are often used in Japan; however, their accuracy is uncertain. We evaluated and compared the accuracy of questionnaire-based sleep times to those of wearable sensors. Methods This observational study was conducted between November 2019 and January 2020. A self-administered questionnaire on lifestyle habits and ActiGraph GT3X+ (ActiGraph, Inc., Pensacola, USA) accelerometer data were collected from 40 fourth-grade elementary school students in Kagawa Prefecture, Japan. We analyzed measurements for 256 days out of 280 days (40 persons × 7 days) after excluding days when the rate of wearing the accelerometer was < 90%. Results The median sleep duration per accelerometry was 453 minutes, and the median time in bed was 519 minutes. Questionnaire-based time in bed was 11 minutes longer, with relatively high inter-individual variability. The difference in bedtime was 26 minutes earlier, and wake-up time was 12 minutes earlier for the questionnaire. The average sleep efficiency was 87.4%, and one-third of the children had sleep efficiency < 85%. Conclusion The difference in sleep duration by questionnaire compared to accelerometry was approximately 10 minutes, suggesting the questionnaire may determine sleep duration with accuracy.

A false decrease in the automatically measured atrial pacing threshold when using the automatic pacing threshold adjustment algorithm.

Automatic pacing threshold adjustment algorithms and remote monitoring are widely used to improve the utility of pacemakers and ensure patient safety. However, healthcare providers involved in the management of permanent pacemakers should know the potential pitfalls of these functions. In this report, we present a case of atrial pacing failure induced by the automatic pacing threshold adjustment algorithm that went unnoticed even under remote monitoring.

Successful treatment with ivabradine in a ß-blocker-refractory patient with acute decompensated heart failure with reduced ejection fraction.

Ivabradine is an established treatment for chronic heart failure with reduced ejection fraction (HFrEF); however, it is not used for acute heart failure treatment. Negative inotropic effects (NIE) often limit the up-titration of ß-blockers. Contrarily, ivabradine has no NIE, and enables ß-blockers usage for treating patients with acute decompensated HFrEF.

Guidelines for the Diagnosis and Treatment of Pediatric Familial Hypercholesterolemia 2022.

As atherosclerosis begins in childhood, early diagnosis and treatment of familial hypercholesterolemia (FH) is considered necessary. The basic diagnosis of pediatric FH (under 15 years of age) is based on hyper-low-density lipoprotein (LDL) cholesterolemia and a family history of FH; however, in this guideline, to reduce overlooked cases, "probable FH" was established. Once diagnosed with FH or probable FH, efforts should be made to promptly provide lifestyle guidance, including diet. It is also important to conduct an intrafamilial survey, to identify family members with the same condition. If the level of LDL-C remains above 180 mg/dL, drug therapy should be considered at the age of 10. The first-line drug should be statin. Evaluation of atherosclerosis should be started using non-invasive techniques, such as ultrasound. The management target level is an LDL-C level of less than 140 mg/dL. If a homozygous FH is suspected, consult a specialist and determine the response to pharmacotherapy with evaluating atherosclerosis. If the response is inadequate, initiate lipoprotein apheresis as soon as possible.

Prevalence and factors related to hypouricemia and hyperuricemia in schoolchildren: results of a large-scale cross-sectional population-based study conducted in Japan.

Hypouricemia in children including renal hypouricemia, which is a major cause of exercise-induced acute renal injury (EIAKI), is an important clinical problem, in addition to hyperuricemia. However, no large-scale studies of serum uric acid (UA) concentrations in the general pre-adolescent population have been carried out. We conducted a population-based cross-sectional study to measure the prevalences of hypouricemia and hyperuricemia and identify the associated factors. We analyzed 31,822 (16,205 boys and 15,617 girls) 9-10-year-old children who underwent pediatric health check-ups in Kagawa prefecture between 2014 and 2018. Hypouricemia and hyperuricemia were defined using serum UA concentrations of ≤ 2.0 mg/dL and ≥ 6.0 mg/dL, respectively. The prevalence of hypouricemia was 0.38% in both 9- and 10-year-old boys and girls, and was not significantly associated with age, sex, or environmental factors, including overweight. The prevalence of hyperuricemia was significantly higher in boys (2.7%) than in girls (1.9%), and was significantly associated with age, overweight, future diabetes risk, hypertriglyceridemia, low high-density lipoprotein-cholesterol, and liver damage, but not with high low-density lipoprotein cholesterol. Therefore, some pre-adolescent children in the general population in Japan showed hypouricemia. A means of identifying children with hypouricemia and lifestyle guidance measures for the prevention of EIAKI should be established.

d-allulose protects against diabetic nephropathy progression in Otsuka Long-Evans Tokushima Fatty rats with type 2 diabetes.

d-allulose is a rare sugar that has been reported to possess anti-hyperglycemic effects. In the present study, we hypothesized that d-allulose is effective in attenuating the progression of diabetic nephropathy in the Otsuka Long-Evans Tokushima Fatty (OLETF) rat model of type 2 diabetes mellitus. Drinking water with or without 3% d-allulose was administered to OLETF rats for 13 weeks. Long-Evans Tokushima Otsuka rats that received drinking water without d-allulose were used as non-diabetic control rats. d-allulose significantly attenuated the increase in blood glucose levels and progressive mesangial expansion in the glomerulus, which is regarded as a characteristic of diabetic nephropathy, in OLETF rats. d-allulose also attenuated the significant increases in renal IL-6 and tumor necrosis factor-α mRNA levels in OLETF rats, which is a proinflammatory parameter. Additionally, we showed that d-allulose suppresses mesangial matrix expansion, but its correlation with suppressing renal inflammation in OLETF rats should be investigated further. Collectively, our results support the hypothesis that d-allulose can prevent diabetic nephropathy in rats.

Galectin-9 deficiency exacerbates lipopolysaccharide-induced hypothermia and kidney injury.

BACKGROUND: Galectin-9 (Gal-9) is a multifunctional lectin that moderates inflammation and organ damage. In this study, we tested whether Gal-9 has a protective role in the pathogenesis of endotoxemic acute kidney injury. METHODS: We examined the levels of Gal-9 in control mice after lipopolysaccharide (LPS) administration. We developed Gal-9 knockout (KO) mice that lack Gal-9 systemically and evaluated the role of Gal-9 in LPS-induced proinflammatory cytokines, vascular permeability, and renal injury. RESULTS: Gal-9 levels were increased in the plasma, kidney, and spleen within 4 h after LPS administration to wild-type mice. Gal-9 deficiency did not affect the LPS-induced increase in plasma tumor necrosis factor-α levels at 1 h or vascular permeability at 6 h. Lower urine volume and reduced creatinine clearance were observed in Gal-9-KO mice compared with wild-type mice after LPS administration. Gal-9-KO mice had limited improvement in urine volume after fluid resuscitation compared with wild-type mice. LPS reduced the body temperature 12 h after its administration. Hypothermia had disappeared in wild-type mice by 24 h, whereas it was sustained until 24 h in Gal-9-KO mice. Importantly, maintaining body temperature in Gal-9-KO mice improved the response of urine flow to fluid resuscitation. CONCLUSION: Deficiency in Gal-9 worsened LPS-induced hypothermia and kidney injury in mice. The accelerated hypothermia induced by Gal-9 deficiency contributed to the blunted response to fluid resuscitation.

Universal Screening for Familial Hypercholesterolemia in Children in Kagawa, Japan.

AIM: Familial hypercholesterolemia (FH) is an underdiagnosed autosomal dominant genetic disorder characterized by high levels of plasma low-density lipoprotein cholesterol (LDL-C) from birth. This study aimed to assess the genetic identification of FH in children with high LDL-C levels who are identified in a universal pediatric FH screening in Kagawa, Japan. METHOD: In 2018 and 2019, 15,665 children aged 9 or 10 years underwent the universal lipid screening as part of the annual health checkups for the prevention of lifestyle-related diseases in the Kagawa prefecture. After excluding secondary hyper-LDL cholesterolemia at the local medical institutions, 67 children with LDL-C levels of ≥ 140 mg/dL underwent genetic testing to detect FH causative mutations at four designated hospitals. RESULTS: The LDL-C levels of 140 and 180 mg/dL in 15,665 children corresponded to the 96.3 and 99.7 percentile values, respectively. Among 67 children who underwent genetic testing, 41 had FH causative mutations (36 in the LDL-receptor, 4 in proprotein convertase subtilisin/kexin type 9, and 1 in apolipoprotein B). The area under the curve of receiver operating characteristic curve predicting the presence of FH causative mutation by LDL-C level was 0.705, and FH causative mutations were found in all children with LDL-C levels of ≥ 250 mg/dL. CONCLUSION: FH causative mutations were confirmed in almost 60% of the referred children, who were identified through the combination of the lipid universal screening as a part of the health checkup system and the exclusion of secondary hyper-LDL cholesterolemia at the local medical institutions.

Heartbeat tracking task performance, an indicator of interoceptive accuracy, is associated with improvement of exercise tolerance in patients undergoing home-based cardiac rehabilitation.

Aims: Interoception is the sensing function of physiological conditions and is crucial in self-regulation and decision-making. We examined the association of heartbeat tracking task performance, an indicator of interoceptive accuracy, with the degree of improvement in exercise tolerance in patients undergoing home-based cardiac rehabilitation. Methods and results: Participants underwent baseline peak oxygen uptake (VO2) measurements and a heartbeat tracking task. The heartbeat tracking task score varies between 0 and 1, with higher scores indicating a better heartbeat perception. After 6 months of home-based exercise training, peak VO2 was measured again, and the percentage change (%Δ peak VO2) relative to the peak VO2 at baseline was calculated. Univariate regression analysis was performed to examine the association between %Δ peak VO2 and the heartbeat tracking task score. Multiple regression analysis was performed to determine the predictors of %Δ peak VO2. Of 120 participants, 100 patients (age 65.9 ± 11.9 years; 86% male) were included. There was a significant positive association between %Δ peak VO2 and the heartbeat tracking task score at baseline (R 2 = 0.236, P < 0.001). In multiple regression analysis, the percentage of measured peak VO2 to the predicted value (%predicted peak VO2) (ß = -0.248, P = 0.002), exercise adherence (ß = 0.364, P < 0.001), and heartbeat tracking task score at baseline (ß = 0.372, P < 0.001) were significantly associated with %Δ peak VO2. Conclusions: Heartbeat tracking task performance, an indicator of interoceptive accuracy, at baseline is associated with the degree of improvement in exercise tolerance.

Changes in Prevalence and Health Checkup Coverage Rate of Chronic Kidney Disease (CKD) after Introduction of Prefecture-Wide CKD Initiative: Results of the Kagawa Association of CKD Initiatives.

The National Health Insurance (NHI) special health checkup system in Japan targets the NHI population aged 40-74 years. Since 2015, the Kagawa NHI special health checkup was initiated in a prefecture-wide chronic kidney disease (CKD) initiative, including renal examination as an essential item in NHI health checkups. Here, we aimed to investigate the effects of the prefecture-wide CKD initiative. We conducted a retrospective cohort survey using the Kagawa National Health Insurance database created by the Kagawa National Health Insurance Organization. Results of the NHI health checkup (2015-2019) and prefecture-wide outcomes (2013-2019) were analyzed. The prevalence of CKD among examinees who underwent the NHI health checkup increased from 17.7% in 2015 to 23.2% in 2019. The percentage of examinees who completed a medical visit was 29.4% in 2015. After initiation of the initiative, the NHI health checkup coverage rate increased significantly, from a mean (standard deviation) of 40.8% (0.4%) to 43.2% (1.1%) (p = 0.04). After the start of the CKD initiative, we found an increase in the prevalence of CKD and the NHI health checkup coverage rate.

Transplant Prognosis in Kidney Transplant Recipients with Diabetes under Mycophenolic Acid-Focused Therapeutic Drug Monitoring.

Mycophenolate mofetil is a key immunosuppressant that is metabolized into mycophenolic acid (MPA). The prognostic impact of MPA-focused therapeutic drug monitoring on allograft prognosis has not been determined in kidney transplant recipients with diabetes. In this study, we assessed the pharmacokinetics of MPA and allograft prognosis in recipients with diabetes. This study retrospectively analyzed 64 adult kidney transplant recipients. MPA blood concentration data (e.g., the time to the maximum concentration (Tmax), and the area under the concentration-time curve from 0 to 12 h (AUC0-12)) were collected at 3 weeks and 3 months after kidney transplantation. Of the 64 recipients, 15 had pre-existing diabetes. At 3 months after kidney transplantation, the Tmax of MPA was significantly longer in recipients with diabetes (mean (standard deviation): 2.8 (2.1) h) than in recipients without diabetes (1.9 (1.1) h, p = 0.02). However, the allograft estimated glomerular filtration rate and acute rejection rate, including borderline change, did not differ according to the diabetes status in patients with adjusted AUC0-12 of MPA within the target range. In conclusion, a longer Tmax of MPA was observed in recipients with diabetes; however, acceptable allograft prognosis was observed in kidney transplant recipients with diabetes and a sufficient AUC0-12 of MPA.

ASB2 is a novel E3 ligase of SMAD9 required for cardiogenesis.

Cardiogenesis requires the orchestrated spatiotemporal tuning of BMP signalling upon the balance between induction and counter-acting suppression of the differentiation of the cardiac tissue. SMADs are key intracellular transducers and the selective degradation of SMADs by the ubiquitin-proteasome system is pivotal in the spatiotemporal tuning of BMP signalling. However, among three SMADs for BMP signalling, SMAD1/5/9, only the specific E3 ligase of SMAD9 remains poorly investigated. Here, we report for the first time that SMAD9, but not the other SMADs, is ubiquitylated by the E3 ligase ASB2 and targeted for proteasomal degradation. ASB2, as well as Smad9, is conserved among vertebrates. ASB2 expression was specific to the cardiac region from the very early stage of cardiac differentiation in embryogenesis of mouse. Knockdown of Asb2 in zebrafish resulted in a thinned ventricular wall and dilated ventricle, which were rescued by simultaneous knockdown of Smad9. Abundant Smad9 protein leads to dysregulated cardiac differentiation through a mechanism involving Tbx2, and the BMP signal conducted by Smad9 was downregulated under quantitative suppression of Smad9 by Asb2. Our findings demonstrate that ASB2 is the E3 ligase of SMAD9 and plays a pivotal role in cardiogenesis through regulating BMP signalling.