Angiotensin Receptor-Neprilysin Inhibitor Suppresses Renin-Angiotensin-Aldosterone System Activation After Cardiac Surgery Using Cardiopulmonary Bypass.

BACKGROUND: Sacubitril/valsartan, being both a neprilysin inhibitor and angiotensin receptor blocker, exhibits a renin-angiotensin-aldosterone system (RAAS) inhibitory effect. However, no study has investigated the administration of sacubitril/valsartan in patients early after surgery using cardiopulmonary bypass.Methods and Results: This was a prospective observational study of 63 patients who underwent open heart surgery and were treated with sacubitril/valsartan. No serious adverse events occurred. Among the 63 patients, sacubitril/valsartan was discontinued in 13 due to hypotension (n=10), renal dysfunction (n=2), and dizziness (n=1). Atrial natriuretic peptide concentrations increased significantly from Day 3 of treatment (P=0.0142 vs. Postoperative Day 1) and remained high thereafter. In contrast, plasma renin activity was significantly suppressed from Day 3 onwards (P=0.00206 vs. Postoperative Day 1). A decrease in creatinine concentrations and an increase in the estimated glomerular filtration rate were observed on Day 3; this improvement in renal function was not observed in the historical control group, in which patients did not receive sacubitril/valsartan. New postoperative atrial fibrillation was less frequent in the study group compared with the historical control (12.7% vs. 38.0%; P=0.0034). CONCLUSIONS: Sacubitril/valsartan administration was safe immediately after open heart surgery in patients without postoperative hypotension. It enhanced serum atrial natriuretic peptide concentrations and suppressed RAAS activation.

Clinical features and morphology of collagen fibrils in patients with vascular Ehlers-Danlos based on electron microscopy.

Background: Vascular-type Ehlers-Danlos syndrome (vEDS) is caused by collagen III deficit resulting from heterogeneous mutations in COL3A1, which occasionally causes sudden death due to arterial/visceral rupture. However, it is difficult to conduct basic research on the pathophysiology of vEDS. Moreover, the number of patients with vEDS is small, limiting the number of available samples. Furthermore, the symptoms of vEDS may vary among family members, even if they share the same mutation. Accordingly, many aspects of the pathology of vEDS remain unknown. Therefore, we investigated the structural abnormalities in collagen fibrils and endoplasmic reticulum (ER) stress in skin samples using electron microscopy as well as their relationship with clinical symptoms in 30 patients with vEDS (vEDS group) and 48 patients without vEDS (disease-negative control group). Methods: Differences between the two groups were evaluated in terms of the sizes of collagen fibrils using coefficient of variation (COV). Results: COV was found to be significantly higher in the vEDS group than in the disease-negative control group, indicating irregularity in the size of collagen fibrils. However, in the vEDS group, some patients had low COV and seldom experienced serious complications and ER stress. Conclusion: ER stress might affect collagen fibril-composing proteins. Moreover, as this stress varies among people based on environmental factors and aging, it may be the underlying cause of varying vEDS symptoms.

Risk Factors for Mortality From Aortic Aneurysm and Dissection: Results From a 26-Year Follow-Up of a Community-Based Population.

Background Aortic aneurysm rupture and acute aortic dissection are life-threatening conditions and represent an ever-growing public health challenge. Comprehensive epidemiologic investigations for their risk factors are scant. We aimed to investigate risk factors associated with mortality from aortic diseases through analysis of a community-based Japanese cohort. Methods and Results IPHS (Ibaraki Prefectural Health Study) comprises 95 723 participants who took part in municipal health checkups in 1993. Factors considered for analysis included age, sex, body mass index, blood pressure, serum lipids (high-density lipoprotein [HDL] cholesterol, non-HDL cholesterol, and triglycerides), diabetes, antihypertensive and lipid-lowering drug use, and smoking and drinking habits. Cox proportional hazards models were applied to evaluate the associations between these variables and mortality from aortic diseases. During the median 26-year follow-up, 190 participants died of aortic aneurysm rupture, and 188 died of aortic dissection. An increased multivariable hazard ratio (HR) for mortality from total aortic diseases was observed for high systolic blood pressure (1.61 [1.00-2.59]), diastolic blood pressure (2.95 [1.95-4.48]), high non-HDL cholesterol (1.63 [1.19-2.24]), low HDL cholesterol (1.86 [1.29-2.68]), and heavy (>20 cigarettes/day) smoking habit (2.46 [1.66-3.63]). A lower multivariable HR was observed for diabetes (0.50 [0.28-0.89]). Conclusions Smoking habit, higher systolic blood pressure and diastolic blood pressure levels, higher non-HDL, and lower HDL cholesterol levels were positively associated with mortality from total aortic diseases, whereas diabetes was inversely associated.

Effect of a Community-Based Program to Accelerate Referral to Physicians for Individuals at High-Risk of Lifestyle-Related Diseases: A Cluster Randomized Trial.

AIM: A cluster randomized trial was conducted within 43 Japanese municipalities (21 intervention and 22 usual care) to examine whether the standardized health counseling for individuals at high cardiovascular risk screened at community sites accelerates clinic visits to strengthen the primary health care system. METHODS: Among high-risk individuals aged 40-74 years screened by health checkups, 8,977 and 6,733 were allocated to the intervention and usual care groups, respectively, who were not under medical treatment but had high levels of blood pressure (systolic/diastolic ≥ 160/100 mmHg), hemoglobin A1c or glucose (≥ 7.0% or corresponding glucose levels), LDL-cholesterol (≥ 180 mg/dL for men), and/or proteinuria of ≥ 2+. The intervention was performed from May 2014 to March 2016 under a standardized health counseling program based on the health belief model primarily by public health nurses. The usual care group was provided with local counseling protocols. RESULTS: The cumulative proportions of clinic visits for 12 months after health checkups were 58.1% (95% confidence interval, 57.0%, 59.3%) versus 44.5% (43.2%, 45.8%), with the probability ratio of clinic visits between the groups being 1.46 (1.24, 1.72). The between-group differences between the baseline and 1-year surveys were -1.50 (-2.59, -0.41) mmHg for diastolic blood pressure in the hypertension category, -0.30% (-0.53%, -0.07%) for HbA1c in the diabetes category, -0.37 (-0.48, -0.27) mmol/L for LDL-cholesterol in the dyslipidemia category, and none for proteinuria. CONCLUSION: Standardized health counseling for high-risk individuals accelerated clinic visits, with larger reductions in blood pressure, HbA1c, and LDL-cholesterol levels. The nationwide use of counseling after health checkups for high-risk individuals could help in controlling risk factors and in preventing lifestyle-related diseases.

Current status and future prospects of the Japanese orthopaedic association national registry (JOANR), Japan's first national registry of orthopaedic surgery.

The Japanese Orthopaedic Association National Registry (JOANR) is Japan's first national registry of orthopaedic surgery, which has been developed after having been selected for the Project for Developing a Database of Clinical Outcome approved by the Health Policy Bureau of the Ministry of Health, Labour and Welfare. Its architecture has two levels of registration, one being the basic items of surgical procedure, disease, information on surgeons, surgery-related information, and outcome, and the other being detailed items in the affiliated registries of partner medical associations. It has a number of features, including the facts that, because it handles medical data, which constitute special care-required personal information, data processing is conducted entirely in a cloud environment with the imposition of high-level data security measures; registration of the implant data required to assess implant performance has been automated via a bar code reader app; and the system structure enables flexible collaboration with the registries of partner associations. JOANR registration is a requirement for accreditation as a core institution or partner institution under the board certification system, and the total number of cases registered during the first year of operation (2020) was 899,421 registered by 2,247 institutions, providing real-world evidence concerning orthopaedic surgery.

Breastfeeding in Infancy in Relation to Subsequent Physical Size: A 20-year Follow-up of the Ibaraki Children's Cohort Study (IBACHIL).

BACKGROUND: Breastfeeding is said to prevent overweight and obesity in childhood but the evidence about its long-term impact on body size into adolescence and adulthood is scarce. We sought to examine the association between feeding types and subsequent physical size at the ages of 3, 6, 12, and 22 years. METHODS: The Ibaraki Children's Cohort (IBACHIL) Study, which began in 1992, involved a cohort of 4,592 Japanese children from 87 communities of a single prefecture whose parents answered health questionnaires about their child's health and life habits at the age of 3 years. Follow-up questionnaires were distributed to the same cohort when they were 6, 12, and 22 years old. Self-reported height and weight, body mass index (BMI), and overweight status at ages of 3 (n = 4,290), 6 (n = 1,999; proportion of participants analyzed = 47%), 12 (n = 2,227; 52%), and 22 (n = 1,459; 34%) years were compared according to feeding type (breastfeeding, formula feeding, and mixed feeding) during infancy. RESULTS: At the age of 3 years, multivariable adjusted-mean weight and prevalence of overweight were less for breastfed children than those formula-fed in both boys (weight: 14.6 kg vs 14.7 kg, P = 0.07, overweight: 6.3% vs 9.3%, P = 0.03) and in girls (14.0 kg vs 14.2 kg, P = 0.01 and 10.4% vs 13.6%, P = 0.06). However, there were no statistically significant differences in weight, BMI, and overweight at the ages of 6, 12, and 22 years according to feeding type. CONCLUSION: Breastfeeding may prevent overweight in childhood, but its impact is not significant in adolescence and adulthood.

Including measures of chronic kidney disease to improve cardiovascular risk prediction by SCORE2 and SCORE2-OP.

AIMS: The 2021 European Society of Cardiology (ESC) guideline on cardiovascular disease (CVD) prevention categorizes moderate and severe chronic kidney disease (CKD) as high and very-high CVD risk status regardless of other factors like age and does not include estimated glomerular filtration rate (eGFR) and albuminuria in its algorithms, systemic coronary risk estimation 2 (SCORE2) and systemic coronary risk estimation 2 in older persons (SCORE2-OP), to predict CVD risk. We developed and validated an 'Add-on' to incorporate CKD measures into these algorithms, using a validated approach. METHODS: In 3,054 840 participants from 34 datasets, we developed three Add-ons [eGFR only, eGFR + urinary albumin-to-creatinine ratio (ACR) (the primary Add-on), and eGFR + dipstick proteinuria] for SCORE2 and SCORE2-OP. We validated C-statistics and net reclassification improvement (NRI), accounting for competing risk of non-CVD death, in 5,997 719 participants from 34 different datasets. RESULTS: In the target population of SCORE2 and SCORE2-OP without diabetes, the CKD Add-on (eGFR only) and CKD Add-on (eGFR + ACR) improved C-statistic by 0.006 (95%CI 0.004-0.008) and 0.016 (0.010-0.023), respectively, for SCORE2 and 0.012 (0.009-0.015) and 0.024 (0.014-0.035), respectively, for SCORE2-OP. Similar results were seen when we included individuals with diabetes and tested the CKD Add-on (eGFR + dipstick). In 57 485 European participants with CKD, SCORE2 or SCORE2-OP with a CKD Add-on showed a significant NRI [e.g. 0.100 (0.062-0.138) for SCORE2] compared to the qualitative approach in the ESC guideline. CONCLUSION: Our Add-ons with CKD measures improved CVD risk prediction beyond SCORE2 and SCORE2-OP. This approach will help clinicians and patients with CKD refine risk prediction and further personalize preventive therapies for CVD.

Prosthetic Valve Function after Aortic Valve Replacement for Severe Aortic Stenosis by Transcatheter Procedure versus Surgery.

Background This study compared the clinical outcomes of transcatheter (TAVR) and surgical (SAVR) aortic valve replacements, focusing on postoperative valvular performance assessed by echocardiography. Method and Results A total of 425 patients who underwent TAVR (230 patients) or SAVR (195 patients) were included. Postoperative effective orifice area index (EOAI) was higher in the TAVR group (1.27 ± 0.35 cm2/m2) than in the SAVR group (1.06 ± 0.27 cm2/m2, p < 0.001), and patient−prosthesis mismatch (PPM) was more frequent in the SAVR group (22.6%) than in the TAVR group (8.7%, p < 0.001). Mild or greater paravalvular leakage (PVL) was more frequent in the TAVR group (21.3%) than in the SAVR group (0%, p < 0.001). Moreover, there was no difference in freedom from all-cause death, stroke, or rehospitalization between the groups. Patients with moderate or greater PPM (EOAI < 0.85 cm2/m2) had lower freedom from composite events than those without this PPM criterion (p = 0.008). Patients with mild or greater PVL also had lower freedom from composite events than those without this PVL criterion (p = 0.017). Conclusions Postoperative valvular performance of TAVR was superior to that of SAVR in terms of EOAI. This merit was counterbalanced by the significantly lower rates of PVL in patients who underwent SAVR. The overall clinical outcomes were similar between the study groups.

Relationship between Health Counselor Characteristics and Counseling Impact on Individuals at High-Risk for Lifestyle-Related Disease: Sub-Analysis of the J-HARP Cluster-Randomized Controlled Trial.

Early diagnosis and treatment are necessary to prevent lifestyle-related diseases among high-risk individuals. This study aimed to examine the impact of counselor characteristics on clinic visits among individuals at high risk for lifestyle-related diseases. A total of 8975 patients aged 40 to 74 years with lifestyle-related comorbidities, who underwent an annual health checkup and received health counseling, were included in this study. Data intervention timing, mode of counseling, number of counseling sessions, and explanation methods were collected. We assessed the impact of counselor characteristics, including profession (public health nurse, clinical nurse, and nutritionist), age, and years of counseling experience, on counseling outcomes. The probability ratios (95% confidence intervals) of clinic visits were 1.22 (1.11-1.35) for public health nurses and 1.04 (0.90-1.20) for nurses compared with nutritionists. After adjustment for participant and counselor characteristics and initial timing, mode, and number of counseling sessions, the corresponding probability ratios (95% confidence intervals) were 1.16 (1.05-1.29) and 1.12 (0.95-1.31), respectively. Counselor age and years of experience did not influence clinic visits of the target population. Public health nurses were more effective in increasing clinic visits among the target population owing to their profession-specific knowledge, skills, and experience.

Striatal dopamine transporter degeneration in right-handed REM sleep behavior disorder patients progresses faster in the left hemisphere.

OBJECTIVE: In right-handed patients with idiopathic rapid eye movement sleep behavior disorder (IRBD) or Parkinson's disease (PD), dopamine transporter (DAT) single-photon emission computed tomography (SPECT) shows a predominant nigrostriatal deficit in the left striatum. To confirm this hypothesis, we longitudinally investigated whether the nigrostriatal function is asymmetric in Japanese patients with IRBD. METHODS: In 91 polysomnography-confirmed IRBD patients, which included 87 right-handed IRBD patients who underwent 33 repeat DAT-SPECT scans, we retrospectively examined the striatal dopaminergic terminals in each hemisphere using DAT-SPECT. We calculated the values of interhemispheric laterality index for the right and left sides. RESULTS: The proportion of IRBD patients with lower SBR in the striatum was different between the left (n = 60, 69.0%) and right (n = 27, 31.0%) hemispheres. In the repeat DAT-SPECT scan (n = 33), the rate of decline in the striatum was greater on the left than on the right side, and the proportion of patients with lower decline rates in the left striatum (n = 25, 73.5%) was greater than the that in the right striatum (n = 3, 8.8%). The proportion of lower SBR side at baseline did not predict the development of PD or DLB. CONCLUSION: Right-handed IRBD patients have asymmetric nigrostriatal dopaminergic function, as evidenced by the faster estimated rate of decline for the left striatum than the right striatum. The left-right hemispheric striatal predominance of the nigrostriatal deficit in the right-handed prodromal PD or DLB patients represents a difference in the early pathological process of the disease.

Right bundle branch block and risk of cardiovascular mortality: the Ibaraki Prefectural Health Study.

Historically, a right bundle branch block has been considered a benign finding in asymptomatic individuals. However, this conclusion is based on a few old studies with small sample sizes. We examined the association between a complete right bundle branch block (CRBBB) and subsequent cardiovascular mortality in the general population in Japan. In this large community-based cohort study, data of 90,022 individuals (mean age, 58.5 ± 10.2 years; 66.2% women) who participated in annual community-based health check-ups were assessed. Subjects were followed up from 1993 to the end of 2016. Cox proportional hazards' models and log-rank tests were used for the data analysis. CRBBB was documented in 1,344 participants (1.5%). Among all included participants, CRBBB was associated with an increased risk of cardiovascular mortality after adjustment for all potential confounders (hazard ratio [HR] 1.21; 95% confidence interval [CI] 1.06-1.38). The increased risk of cardiovascular mortality was particularly evident in women aged < 65 years (HR 2.00; 95% CI 1.34-2.98) and men aged ≥ 65 years (HR 1.28; 95% CI 1.06-1.55). CRBBB is associated with an increased risk of cardiovascular mortality in women aged < 65 years and men aged ≥ 65 years. Clinicians should be aware of the presence of CRBBB in young women and elderly men, even if they exhibit no symptoms.

Contemporary short-term outcomes of surgery for aortic stenosis: transcatheter vs. surgical aortic valve replacement.

OBJECTIVES: This study aimed to compare the short-term outcomes of transcatheter and surgical aortic valve replacements (TAVR and SAVR) in high-, intermediate-, and low-preoperative risk patients. METHODS: A total of 454 patients who underwent TAVR or SAVR were included. Patients were categorized into high-, intermediate-, and low-risk according to the Society of Thoracic Surgery-Predicted Risk of Mortality score and clinical outcomes were compared between TAVR and SAVR groups. RESULTS: TAVR was less invasive, with less bleeding and transfusion (p < 0.001), less frequent new-onset atrial fibrillation (p < 0.001), and shorter intensive care unit stay (p < 0.001). Furthermore, transcatheter valves performed better than surgical valves, with lower peak velocity (p = 0.003) and pressure gradient (p < 0.001) and higher effective orifice area index (p < 0.001). The clinical outcomes of TAVR were comparable to or even superior to those of SAVR in high- and intermediate-risk patients. In low-risk patients, the 1- and 2-year mortality rates were 6.3% and 12.1%, respectively, in the TAVR group and 0% and 0.9%, respectively, in the SAVR group (p < 0.001). Mild or greater paravalvular leakage was a risk factor for mortality (hazard ratio 35.78; p < 0.001). CONCLUSIONS: TAVR was superior to SAVR in the sense of less invasiveness and valvular function. However, the indication of TAVR in low-risk patients should be carefully discussed, because paravalvular leakage was a risk factor for short-term mortality.

Expression of SATB2 in Neuroendocrine Carcinomas of the Lung: Frequent Immunopositivity of Large Cell Neuroendocrine Carcinoma with a Diagnostic Pitfall.

Small cell lung carcinoma (SCLC) and pulmonary large cell neuroendocrine carcinoma (LCNEC) are both classified as lung neuroendocrine carcinoma (NEC). It has recently been reported that the special AT-rich sequence-binding protein 2 (STAB2), known as a colorectal cancer marker, is also expressed in NECs occurring in various organs including the lung. However, few studies have examined any differences of SATB2 immunopositivity between SCLC and LCNEC. We investigated SATB2 expression in 45 SCLC and 14 LCNEC cases using immunohistochemistry as well as the expression of caudal-type homeobox 2 (CDX2) and keratin (KRT) 20. The LCNEC cases were more frequently positive for SATB2 (ten out of 14, 71%) than the SCLC ones (seventeen out of 45, 38%) with a statistically significance (P = 0.035). Furthermore, two LCNEC cases were positive for CDX2 while no positive findings were observed for any SCLC cases, the difference of which, however, was not statistically significant (P = 0.053). KRT20 was negative in all LCNEC and SCLC cases. These results require our attention when we use SATB2 and CDX2 as colorectal cancer markers because their expression in pulmonary NECs can lead to a misdiagnosis that the tumor is of metastatic colorectal adenocarcinoma, especially when the patient has a past history of colorectal cancer. Analyzing the relationship between the demographic/clinical variables and the SATB2 expression in the SCLC cases, just high Brinkman index (≥ 600) was significantly related to the positivity of SATB2 (P = 0.017), which is interesting considering the strong relationship between SCLC and smoking.

Adiposity rebound in very-low-birth-weight infants.

OBJECTIVES: Adiposity rebound (AR) refers to an increase in body mass index (BMI) after a nadir. Early AR, in which AR occurs earlier than five years old, is a risk factor for future obesity and metabolic syndrome, but has not been widely studied in very-low-birth-weight infants (VLBWIs). METHODS: The subjects were VLBWIs born in Dokkyo Medical University NICU from January 2008 to December 2010. Height and weight measured at birth and at intervals until seven years old were obtained from medical records. The lowest BMI after one year of age was used for the age of AR. The subjects were divided into those with early and normal AR (<5 and ≥5 years old). BMI percentile at age seven years was compared using the interquartile range (IQR). Changes in BMI were evaluated by repeated measures analysis of variance (ANOVA). RESULTS: There were 38 early AR cases and 62 normal AR cases, giving a prevalence of early AR similar to that in infants with normal birth weight. BMI percentile at age seven years was significantly higher in early AR cases than in normal AR cases (44.6 [IQR: 21.0-79.2] vs. 14.4 [IQR: 3.8-40.8] kg/m2). Changes in BMI were also significantly higher in early AR cases (p=0.024 by ANOVA). CONCLUSIONS: Early AR in VLBWIs is a predictor of future obesity.

Diabetes Mellitus Modifies the Association of Serum Triglycerides with Ischemic Cardiovascular Disease Mortality: The Ibaraki Prefectural Health Study (IPHS).

AIM: Diabetes mellitus and hypertriglyceridemia may adversely interact with the development of ischemic cardiovascular disease, but epidemiological evidence on this issue is scarce. We hypothesized that the impact of hypertriglyceridemia on ischemic cardiovascular disease (ischemic heart disease and ischemic stroke) would differ according to the presence or absence of diabetes mellitus and tested our a priori hypothesis under a large population-based prospective study. METHODS: A total of 90,468 men and women aged 40-79 years in 1993 were enrolled in the Ibaraki Prefectural Health Study (IPHS), a community-based cohort study of Japanese. The participants' serum triglyceride levels (mostly nonfasting) were measured every 5 years, and the participants were followed up for mortality from ischemic cardiovascular disease through 2016. Hazard ratios (95% confidence intervals) were calculated according to 5-year updated triglyceride levels (＜100, 100-149, 150-199, 200-299, and ≥ 300 mg/dl). RESULTS: During 1,795,877 person-years, there were 3,323 deaths from ischemic cardiovascular diseases (1,968 ischemic heart diseases and 1,355 ischemic strokes). We found no association between triglyceride levels and the risk of mortality from ischemic cardiovascular disease after adjustment for known cardiovascular risk factors. However, when stratified by the presence or absence of diabetes mellitus, excess mortality from ischemic cardiovascular disease appeared among participants with diabetes mellitus with triglyceride levels of ≥ 300 mg/dl. Further adjustment for high-density lipoprotein-cholesterol attenuated the association toward being statistically nonsignificant. CONCLUSION: The impact of high serum triglyceride levels on the risk of ischemic cardiovascular disease mortality was confined to participants with diabetes mellitus.

A large-scale population-based epidemiological study on the prevalence of central sensitization syndromes in Japan.

A cross-sectional study of 21,665 Japanese residents was performed to investigate the prevalence of central sensitization syndromes (CSS). CSS were assessed using the Central Sensitization Inventory (CSI-A). CSS were defined as a CSI-A score of 40 or higher. Age, sex, district, 10 CSS-related diseases (CSI-B), lifestyle, and mental factors were rated in a self-reported survey. The prevalence of CSS and its relationship with potential factors were examined by sex using descriptive and logistic regression models. The prevalence of CSS was 4.2% in all participants and was significantly higher in women (4.9%) than in men (2.7%). Adjusted odds ratios correlated with CSS for an age of 80-97 years versus 60-79 years (2.07 and 2.89), one or more CSI-B diseases (3.58 and 3.51), few sleeping hours (2.18 and 1.98), high perceived stress (5.00 and 4.91), low (2.94 and 2.71) and high (0.45 and 0.66) resilience versus moderate resilience, and exercise habits (0.68 and 0.55) in men and women (all P < 0.05). The relationship between CSS and age 20 and 59 years, ex-smokers, coffee intake, and alcohol intake differed by sex. The prevalence of CSS was estimated to be low in the healthy population. CSS correlated with CSS-related diseases and some positive and negative factors.