Status of adult outpatients with congenital heart disease in Japan: The Japanese Network of Cardiovascular Departments for Adult Congenital Heart Disease Registry.

BACKGROUND: The Japanese Network of Cardiovascular Departments for Adult Congenital Heart Disease (JNCVD-ACHD) was founded in 2011 for the lifelong care of adult patients with congenital heart disease (ACHD patients). This network maintains the first Japanese ACHD registry. METHODS AND RESULTS: From 2011 to 2019, the JNCVD-ACHD registered 54 institutions providing specialized care for ACHD patients in 32 of the 47 prefectures in Japan. The registry collected data on the disease profile for 24,048 patients from 50 institutions and the patient characteristics for 9743 patients from 24 institutions. The most common ACHDs were atrial septal defect (20.5 %), ventricular septal defect (20.5 %), tetralogy of Fallot (12.9 %), and univentricular heart (UVH)/single ventricle (SV; 6.6 %). ACHD patients without biventricular repair accounted for 37.0 % of the population. Also examined were the serious anatomical and/or pathophysiological disorders such as pulmonary arterial hypertension (3.0 %) including Eisenmenger syndrome (1.2 %), systemic right ventricle under biventricular circulation (sRV-2VC; 2.8 %), and Fontan physiology (6.0 %). The sRV-2VC cases comprised congenitally corrected transposition of the great arteries without anatomical repair (61.9 %) and transposition of the great arteries with atrial switching surgery (38.1 %). The primary etiology (86.4 %) for Fontan physiology was UVH/SV. In addition, developmental/chromosomal/genetic disorders were heterotaxy syndromes (asplenia, 0.9 %; polysplenia, 0.7 %), trisomy 21 (4.0 %), 22q11.2 deletion (0.9 %), Turner syndrome (0.2 %), and Marfan syndrome (1.1 %). CONCLUSIONS: Although the specific management of ACHD has systematically progressed in Japan, this approach is still evolving. For ideal ACHD care, the prospective goals for the JNCVD-ACHD are to create local networks and provide a resource for multicenter clinical trials to support evidence-based practice.

Oral Health in Japan: State-of-the-Art and Perspectives.

In the near future, Japan is entering a super-aging society that will be called the age of 100 years of life [...].

Systemic Disorders Closely Associated with Malocclusion in Late Adolescence: A Review and Perspective.

Oral diseases such as dental caries and periodontal disease are reported to be associated with various systemic diseases such as heart disease, respiratory disease, diabetes, rheumatism, and metabolic syndrome, thus increasing the importance of prevention and early treatment [...].

Efficacy of treat-and-repair strategy for atrial septal defect with pulmonary arterial hypertension.

OBJECTIVE: Therapeutic strategies for atrial septal defect (ASD) with severe pulmonary arterial hypertension (PAH) are controversial. This study aimed to evaluate the efficacy of PAH-specific medications and subsequent transcatheter closure (ie, treat-and-repair strategy) on clinical outcomes. METHODS: We enrolled 42 patients who were referred to 13 institutions for consideration of ASD closure with concomitant PAH and underwent the treat-and-repair strategy. The endpoint was cardiovascular death or hospitalisation due to heart failure or exacerbated PAH. RESULTS: At baseline prior to PAH-specific medications, pulmonary to systemic blood flow ratio (Qp:Qs), pulmonary vascular resistance (PVR), and mean pulmonary artery pressure (PAP) were 1.9±0.8, 6.9±3.2 Wood units and 45±15 mm Hg. Qp:Qs was increased to 2.4±1.2, and PVR and mean PAP were decreased to 4.0±1.5 Wood units and 35±9 mm Hg at the time of transcatheter ASD closure after PAH-specific medications. Transcatheter ASD closure was performed without any complications. During a median follow-up period of 33 months (1-126 months) after transcatheter ASD closure, one older patient died and one patient was hospitalised due to heart failure, but the other patients survived with an improvement in WHO functional class. PAP was further decreased after transcatheter ASD closure. CONCLUSIONS: The treat-and-repair strategy results in low complication and mortality rates with a reduction in PAP in selected patients with ASD complicated with PAH who have a favourable response of medical therapy.

Clinical Outcome of Closure of a Small Atrial Septal Defect in a Patient with Pulmonary Arterial Hypertension.

The closure of small/coincidental atrial septal defects (ASDs) in patients with pulmonary arterial hypertension (PAH) has been described in recent major guidelines as useless or even contraindicated. We confirm the effectiveness of "Treat and Repair" for ASD closure through one patient diagnosed with idiopathic PAH with small ASD, under careful observation with right heart catheterization and cardiac magnetic resonance imaging. The clinical decision concerning the closure of ASD with PAH should be made not only by referring to the guidelines but also by evaluating the benefits and risks specific to that case.

Interpretations of SARS-CoV-2 IgM and IgG antibody titers in the seroepidemiological study of asymptomatic healthy volunteers.

INTRODUCTION: The usefulness of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody tests in asymptomatic individuals has not been well validated, although they have satisfied sensitivity and specificity in symptomatic patients. In this study, we investigated the significance of IgM and IgG antibody titers against SARS-CoV-2 in the serum of asymptomatic healthy subjects. METHODS: From June 2020, we recruited 10,039 participants to the project named the University of Tokyo COVID-19 Antibody Titer Survey (UT-CATS), and measured iFlash-SARS-CoV-2 IgM and IgG (YHLO IgM and IgG) titers in the collected serum. For the samples with increased IgM or IgG titers, we performed additional measurements using Elecsys Anti-SARS-CoV-2 Ig (Roche total Ig) and Architect SARS-CoV-2 IgG (Abbott IgG) and investigated the reactivity to N, S1, and receptor binding domain (RBD) proteins. RESULTS: After setting the cutoff value at 5 AU/mL, 61 (0.61%) were positive for YHLO IgM and 104 (1.04%) for YHLO IgG. Few samples with elevated YHLO IgM showed reactivity to S1 or RBD proteins, and IgG titers did not increase during the follow-up in any samples. The samples with elevated YHLO IgG consisted of two groups: one reacted to S1 or RBD proteins and the other did not, which was reflected in the results of Roche total Ig. CONCLUSIONS: In SARS-CoV-2 seroepidemiological studies of asymptomatic participants, sufficient attention should be given to the interpretation of the results of YHLO IgM and IgG, and the combined use of YHLO IgG and Roche total Ig might be more reliable.

A case of a middle-aged patient with a ventricular septal defect complicated by severe pulmonary hypertension-stepwise surgical repair with pulmonary vasodilators.

We report a case of ventricular septal defect (VSD) in which we attempted to treat pulmonary arterial hypertension (PAH) with the goal of VSD closure in an adult with suspected Eisenmenger syndrome in childhood. Four years previously (age 41 years), she was referred to our department due to repeated hemoptysis requiring further treatment of PAH. We started combination therapy with several pulmonary vasodilators. Two years later, her pulmonary vascular resistance (PVR) was improved but still not at the level where VSD closure was possible. To control the increased PA flow resulting from intensive PAH treatment and to reduce the risk of hemoptysis, we performed pulmonary artery banding (PAB). As the risk of hemoptysis decreased, a prostacyclin analog was introduced, and the dose was increased. More than 1 year after PAB, active vasoactivity testing became positive, suggesting that the pulmonary vascular lesion was now "reversible". We performed VSD closure and atrial septal defect creation even though her PVR was still high. After the operation, her exercise capacity was remarkably improved. We suggest that stepwise surgical repair with pulmonary vasodilators is an important treatment option for select patients with VSD with severe PAH. .

Epidemiological study using IgM and IgG antibody titers against SARS-CoV-2 in The University of Tokyo, Japan (UT-CATS).

INTRODUCTION: The worldwide pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has continued to date. Given that some of the patients with coronavirus disease 2019 (COVID-19) are asymptomatic, antibody tests are useful to determine whether there is a previous infection with SARS-CoV-2. In this study, we measured IgM and IgG antibody titers against SARS-CoV-2 in the serum of asymptomatic healthy subjects in The University of Tokyo, Japan. METHODS: From June 2020, we recruited participants, who were students, staff, and faculty members of The University of Tokyo in the project named The University of Tokyo COVID-19 Antibody Titer Survey (UT-CATS). Following blood sample collection, participants were required to answer an online questionnaire about their social and health information. We measured IgG and IgM titers against SARS-CoV-2 using iFlash-SARS-CoV-2 IgM and IgG detection kit which applies a chemiluminescent immunoassay (CLIA) for the qualitative detection. RESULTS: There were 6609 volunteers in this study. After setting the cutoff value at 10 AU/mL, 32 (0.48%) were positive for IgG and 16 (0.24%) for IgM. Of six participants with a history of COVID-19, five were positive for IgG, whereas all were negative for IgM. The median titer of IgG was 0.40 AU/mL and 0.39 AU/mL for IgM. Both IgG and IgM titers were affected by gender, age, smoking status, and comorbidities. CONCLUSIONS: Positive rates of IgG and IgM titers were relatively low in our university. Serum levels of these antibodies were affected by several factors, which might affect the clinical course of COVID-19.

Close Association between Awareness of Teeth-Alignment Disorder and Systemic Disorders in Late Adolescence.

BACKGROUND: Oral diseases are associated with various systemic disorders. Our previous research revealed new insights into the close relationship between occlusal disorder (functional disorder) and systemic disorders (allergic rhinitis, asthma, and arrhythmia) in late adolescence. Here, we investigated whether there was an association between the awareness of teeth-alignment disorder (morphological disorder) and common systemic disorders. SUBJECTS AND METHODS: We retrospectively reviewed the data of the mandatory medical questionnaire that is required for the freshman medical checkup in Japan. We collected the data of all students who completed the questionnaire between April 2017 and April 2019. The data were analyzed using the χ2 test, and a multivariate analysis was performed with a binomial logistic regression model. RESULTS: The subjects were 8903 students aged 17-19 who had no awareness of occlusal disorder. The rate of awareness of teeth-alignment disorder was 20.43% (1819 of 8903 eligible subjects), and the aware students had significantly greater rates of gum bleeding (p < 0.001), pollinosis (n = 0.007), and atopic dermatitis (n = 0.042). The multivariate analysis revealed significant rates of gum bleeding (odds ratio (OR) 1.540, 95% confidence interval (CI): 1.386-1.711, p < 0.001), pollinosis (OR 1.197, 95% CI: 1.040-1.378, p = 0.012), and female gender (OR 1.141, 95% CI: 1.002-1.299, p = 0.046) among the students with awareness of teeth-alignment disorder. CONCLUSION: We identified close associations between the awareness of teeth-alignment disorder and both gum bleeding and pollinosis in a late-adolescent population. The systemic disorders that are targeted by teeth-alignment disorder were found to be different from those targeted by occlusal disorder.

Improvements in French risk stratification score were correlated with reductions in mean pulmonary artery pressure in pulmonary arterial hypertension: a subanalysis of the Japan Pulmonary Hypertension Registry (JAPHR).

BACKGROUND: Since there was no previous report, we analyzed the relationship between French Risk Stratification parameters in pulmonary arterial hypertension (PAH) and mean pulmonary arterial pressures (mPAP) using Japan PH Registry (JAPHR) national-wide cohort. METHODS: We enrolled 108 patients with PAH from JAPHR from previous reported cohort and analyzed the relations between French Risk Stratification scores and hemodynamic improvements. RESULTS: The ratio meeting 0 to 4 French Risk Stratification score was 21.3%, 31.5%, 32.4%, 13.0%, and 1.9% at baseline, and 6.5%, 23.2%, 33.3%, 23.2%, 13.9% at follow-up, respectively. The improvements in the number of criteria met were associated both with mPAP at follow-up (p = 0.03) and with the improvements in mPAP (p < 0.001). CONCLUSION: The improvements in French Risk Stratification may become a marker of improved hemodynamics including mPAP.

Selexipag for Chronic Thromboembolic Pulmonary Hypertension in Japanese Patients　- A Double-Blind, Randomized, Placebo-Controlled, Multicenter Phase II Study.

BACKGROUND: Selexipag is an oral prostacyclin receptor (IP receptor) agonist with a non-prostanoid structure. This study examined its efficacy and safety in Japanese patients with non-operated or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH).Methods and Results:This Phase II study was a randomized, double-blind, placebo-controlled parallel-group comparison. The primary endpoint was a change in pulmonary vascular resistance (PVR) from baseline to week 17. The main analysis involved a per-protocol set group of 28 subjects. The change in PVR (mean±SD) after 17 weeks of treatment in the selexipag group was -104±191 dyn·s/cm5, whereas that in the placebo group was 26±180 dyn·s/cm5. Thus, the treatment effect after 17 weeks of selexipag treatment was calculated as -130±189 dyn·s/cm5(P=0.1553). Although the primary endpoint was not met, for the group not concomitantly using a pulmonary vasodilator the PVR in the selexipag group was significantly decreased compared with placebo group (P=0.0364). The selexipag group also showed improvement in total pulmonary resistance and cardiac index. CONCLUSIONS: Selexipag treatment improved pulmonary hemodynamics in Japanese patients with CTEPH, but PVR did not show a significant difference between the selexipag and placebo groups. (Trial registration: JAPIC Clinical Trials Information [JapicCTI-111667]).

The Clinical Efficacy of Endothelin Receptor Antagonists in Patients with Pulmonary Arterial Hypertension.

Therapeutic strategies for pulmonary arterial hypertension (PAH) have made remarkable progress over the last two decades. Currently, 3 types of drugs can be used to treat PAH; prostacyclins, phosphodiesterase 5 inhibitors, and endothelin receptor antagonists (ERA). In Japan, the first generation ERA bosentan was reimbursed in 2005, following which the 2nd generation ERAs ambrisentan and macitentan were reimbursed in 2009 and 2015, respectively. The efficacy of each ERA on hemodynamics in PAH patients remains to be elucidated. The aims of this study were to evaluate the hemodynamic effects of ERAs and compare these effects among each generation of ERAs.We retrospectively examined the clinical parameters of 42 PAH patients who were prescribed an ERA (15 bosentan, 12 ambrisentan, and 15 macitentan) and who underwent a hemodynamic examination before and after ERA introduction at our institution from January 2007 to July 2019.In a total of 42 patients, mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR) were significantly decreased and cardiac index was significantly increased after ERA introduction (P < 0.001) and the World Health Organization-Functional class (WHO-Fc) was significantly improved after ERA introduction (P = 0.005). Next, in a comparison between 1st and 2nd generation ERAs, 2nd generation ERAs were found to have brought about greater improvements in hemodynamic parameters (mPAP and PVR. P < 0.01), heart rate, brain natriuretic peptide, arterial oxygen saturation, and mixed venous oxygen saturation than the 1st generation ERA bosentan.We conclude that all ERAs could successfully improve the hemodynamics of PAH patients and that the newer generation ERAs, ambrisentan and macitentan, seemed to be preferable to bosentan.

Awareness of Malocclusion Is Closely Associated with Allergic Rhinitis, Asthma, and Arrhythmia in Late Adolescents.

BACKGROUND: Oral infectious diseases are typified by dental caries and periodontal diseases and are known to be associated with various systemic diseases. However, clear associations between occlusal disorders and systemic diseases have not yet been established. We investigated the association between an awareness of malocclusion and common diseases in late adolescence. METHODS: We retrospectively reviewed the data of mandatory medical questionnaires that are a legal requirement of the freshman medical checkup. We collected the data of all the students who completed the questionnaires between April 2017 and 2019. The data were analyzed using the χ2 test and multivariate analysis was performed with a binomial logistic regression model. RESULTS: The subjects were 9098 students aged 17-19 (mean age 18.3 years). The rate of awareness of malocclusion was 2.14% (195 out of 9098 eligible subjects; 160 males and 35 females). These students had significantly greater rates of allergic rhinitis, asthma, and arrhythmia (p < 0.001). Multivariate analysis revealed significant rates of allergic rhinitis (odds ratio [OR] 2.184, 95% confidence interval [CI]: 1.468-3.250, p < 0.001), asthma (OR 1.843, 95%CI: 1.153-2.945, p = 0.011), and arrhythmia (OR 2.809, 95%CI: 1.083-7.288, p = 0.034) among students with an awareness of malocclusion. CONCLUSION: We identified close associations between an awareness of malocclusion and systemic diseases including allergic rhinitis, asthma, and arrhythmia in the late adolescent population. These results reinforce the associations between malocclusion and allergic rhinitis and asthma, as well as providing novel insight into the association of malocclusion and arrhythmia. However, further research is necessary to confirm the associations and explore the mechanisms underlying these associations.

Close Associations of Gum Bleeding with Systemic Diseases in Late Adolescence.

BACKGROUND: Though it is well known that periodontal diseases are associated with various systemic diseases in adults, the associations in late adolescents have not been adequately elucidated. We investigated the association between gum bleeding (a major symptom of periodontal diseases) and common systemic diseases in late adolescents: allergic, respiratory, and otorhinolaryngologic diseases. METHODS: We conducted a retrospective review of the mandatory medical questionnaires administered as a part of legally required freshman medical checkup between April 2017 and April 2019 at the University of Tokyo. Among the total of 9376 sets of responses, 9098 sets from students aged less than 20 were analyzed. An χ2 test and univariate and multivariate binomial logistic regression analyses were performed using SAS ver. 9.4. A value of p < 0.05 was accepted as significant. RESULTS: According to the questionnaire data, 3321 students (36.5%; 2780 males and 541 females) responded that they experienced gum bleeding whenever they brushed their teeth. These students had significantly higher incidence rates of otitis media/externa and asthma/cough-variant asthma (p = 0.001 and p = 0.006, respectively). The results of the multivariate analysis showed significant rates of the following complications among these students: (1) otitis media/externa (odds ratio (OR) 1.691; 95% confidence interval (CI): 1.193-2.396; p = 0.003), (2) asthma/cough-variant asthma (OR 1.303; 95% CI: 1.091-1.556; p = 0.003), and (3) male gender (OR 1.536; 95% CI: 1.337-1.765; p < 0.001). CONCLUSIONS: Gum bleeding was closely associated with otitis media/externa and asthma in late adolescents. Our study reinforces new evidence about the association between periodontal diseases and asthma, and it reveals a novel and close association between gum bleeding and otitis media/externa.

Fractional exhaled nitric oxide in adult congenital heart disease.

BACKGROUND: Fractional exhaled nitric oxide levels are related to various clinical diseases. This study investigated the associations between the clinical characteristics and the level of fractional exhaled nitric oxide in patients with adult congenital heart disease. METHODS AND RESULTS: Fractional exhaled nitric oxide values were measured in 30 adult patients with stable congenital heart disease who had undergone right heart catheterization and 17 healthy individuals (controls). There was no significant difference in fractional exhaled nitric oxide values between patients with congenital heart disease and healthy controls. Depending on whether their fractional exhaled nitric oxide values were above or below the median value, patients with congenital heart disease were divided into two groups (low vs. high fractional exhaled nitric oxide groups). The relationship between fractional exhaled nitric oxide values and clinical characteristics was investigated. There was a higher percentage of patients with cyanosis in the low fractional exhaled nitric oxide group (50%) than in the high fractional exhaled nitric oxide group (7.1%). There was no significant difference in right heart catheterization data between the low and high fractional exhaled nitric oxide groups. The fractional exhaled nitric oxide value was correlated to the number of neutrophils in patients with cyanosis (r = 0.84 (N = 8), p = 0.005). CONCLUSIONS: In this cohort of patients with adult congenital heart disease, lower levels of fractional exhaled nitric oxide corresponded to the presence of cyanosis.

Time-resolved pair distribution function analysis of disordered materials on beamlines BL04B2 and BL08W at SPring-8.

A dedicated apparatus has been developed for studying structural changes in amorphous and disordered crystalline materials substantially in real time. The apparatus, which can be set up on beamlines BL04B2 and BL08W at SPring-8, mainly consists of a large two-dimensional flat-panel detector and high-energy X-rays, enabling total scattering measurements to be carried out for time-resolved pair distribution function (PDF) analysis in the temperature range from room temperature to 873 K at pressures of up to 20 bar. For successful time-resolved analysis, a newly developed program was used that can monitor and process two-dimensional image data simultaneously with the data collection. The use of time-resolved hardware and software is of great importance for obtaining a detailed understanding of the structural changes in disordered materials, as exemplified by the results of commissioned measurements carried out on both beamlines. Benchmark results obtained using amorphous silica and demonstration results for the observation of sulfide glass crystallization upon annealing are introduced.