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Cardiac sarcoidosis (CS) is the scarring of heart muscles by autoimmunity, leading to heart abnormalities and patients with sarcoidosis with cardiac involvements have poor prognoses. Due to the small number of patients, it is difficult to stratify all patients of CS by human leukocyte antigen (HLA) analysis. We focused on the structure of antigen-recognizing pockets in heterodimeric HLA-class II, in addition to DNA sequences, and extracted high-affinity combinations of antigenic epitopes from candidate autoantigen proteins and HLA. Four HLA heterodimer-haplotypes (DQA1*05:03/05:05/05:06/05:08-DQB1*03:01) were identified in 10 of 68 cases. Nine of the 10 patients had low left ventricular ejection fraction (< 50%). Fourteen amino-acid sequences constituting four HLA anchor pockets encoded by the HLA haplotypes were all common, suggesting DQA1*05:0X-DQB1*03:01 exhibit one group of heterodimeric haplotypes. The heterodimeric haplotypes recognized eight epitopes from different proteins. Assuming that autoimmune mechanisms might be activated by molecular mimicry, we searched for bacterial species having peptide sequences homologous to the eight epitopes. Within the peptide epitopes form the SLC25A4 and DSG2, high-homology sequences were found in Cutibacterium acnes and Mycobacterium tuberculosis, respectively. In this study, we detected the risk heterodimeric haplotypes of ventricular dysfunction in CS by searching for high-affinity HLA-class II and antigenic epitopes from candidate cardiac proteins. [ABSTRACT FROM AUTHOR]

Evidence suggests that atrial fibrillation (AF) could increase the risk of worsening kidney function (WKF) which is linked to an increased risk of stroke, bleeding, and death in AF patients. However, limited data exist regarding the factors that could lead to WKF in these patients. Therefore, we sought to identify the potential factors associated with the development of WKF in patients with non-valvular AF (NVAF). We analyzed prospectively recruited 1122 NVAF patients [men 71.9%, median age 73.0 years (interquartile range: 66.0–79.0)] with a baseline estimated glomerular filtration rate (eGFR) ≥ 15 mL/min/1.73 m2 from the Hokuriku-Plus AF Registry. The primary outcome was incident WKF, defined as the %eGFR change from the baseline ≥ 30% during the follow-up period. We evaluated the association between baseline variables and incident WKF using univariate and multivariate Cox proportional hazard models. We also evaluated the non-linear association between the identified factors and incident WKF. During a median follow-up period of 3.0 years (interquartile range: 2.7–3.3), incident WKF was observed in 108 patients (32.6 per 1000 person-years). Compared to the patients without incident WKF, the patients with incident WKF were older and had a higher prevalence of heart failure (HF), diabetes mellitus (DM), and vascular disease at baseline. Those who experienced incident WKF also had higher diastolic blood pressure, lower hemoglobin, lower eGFR, higher B-type natriuretic peptide (BNP) and used warfarin more frequently. Upon multivariate analysis, age ≥ 75 years, HF, DM, and anemia were independently associated with incident WKF. Additionally, age and hemoglobin were linearly associated with the risk of incident WKF, whereas a J- or U-shaped association was observed for HbA1c and BNP. Age ≥ 75 years, HF, DM, and anemia were associated with the development of WKF in Japanese patients with NVAF. In patients with these risk factors, a careful monitoring of the kidney function and appropriate interventions may be important when possible. [ABSTRACT FROM AUTHOR]

Severe hyponatremia can cause life-threatening cerebral edema. Treatment comprises rapid elevation of serum sodium concentration; however, overcorrection can result in osmotic demyelination. This study investigated potential factors, including predictive correction based on the Edelman equation, associated with appropriate correction in 221 patients with a serum sodium concentration ≤ 120 mEq/L who were admitted to a hospital in Nagoya, Japan. Appropriate correction was defined as an elevation in serum sodium concentration in the range of 4–10 mEq/L in the first 24 h and within 18 mEq/L in the first 48 h after the start of the correction. Appropriate corrections were made in 132 (59.7%) of the 221 patients. Multivariate analysis revealed that predictive correction with an infusate and fluid loss formula derived from the Edelman equation was associated with appropriate correction of serum sodium concentration (adjusted odds ratio, 7.84; 95% confidence interval, 2.97–20.64). Relative without its use, the predictive equation results in a lower proportion of undercorrection (14.3% vs. 48.0%, respectively) and overcorrection (1.0% vs. 12.2%, respectively). These results suggest that predictive correction of serum sodium concentrations using the formula derived from the Edelman equation can play an essential role in the appropriate management of patients with severe hyponatremia. [ABSTRACT FROM AUTHOR]

Purpose Of Review: Artificial intelligence (AI) can make advanced inferences based on a large amount of data. The mainstream technologies of the AI boom in 2021 are machine learning (ML) and deep learning, which have made significant progress due to the increase in computational resources accompanied by the dramatic improvement in computer performance. In this review, we introduce AI/ML-based medical devices and prediction models regarding diabetes.Recent Findings: In the field of diabetes, several AI-/ML-based medical devices and regarding automatic retinal screening, clinical diagnosis support, and patient self-management tool have already been approved by the US Food and Drug Administration. As for new-onset diabetes prediction using ML methods, its performance is not superior to conventional risk stratification models that use statistical approaches so far. Despite the current situation, it is expected that the predictive performance of AI will soon be maximized by a large amount of organized data and abundant computational resources, which will contribute to a dramatic improvement in the accuracy of disease prediction models for diabetes. [ABSTRACT FROM AUTHOR]

Subclinical peripheral artery disease (PAD) might be associated with pathophysiology of contrast-induced acute kidney injury (CI-AKI). We hypothesized that concomitant PAD in patients with the acute coronary syndrome (ACS) would represent a high-risk subgroup with a greater incidence of CI-AKI, both of which lead to higher mortality after percutaneous coronary intervention (PCI). Six hundred and seventy-five consecutive patients with ACS who underwent PCI and examination of ankle-brachial index (ABI) were analyzed retrospectively. The presence of PAD was defined as an ABI < 0.9. We investigated whether (1) PAD was an independent predictor of CI-AKI (≥ 0.3 mg/dL or ≥ 50% relative increase in serum creatinine within 48 h after PCI) and (2) PAD and CI-AKI were independently associated with long-term mortality. Of the 675 patients with ACS, 114 (17%) exhibited PAD. The incidence of CI-AKI was significantly higher in PAD patients, compared with the remaining patients (12% vs. 4%, p < 0.001). Multivariate logistic regression analysis revealed that the presence of PAD was an independent predictor for the development of CI-AKI [odds ratio 2.50, 95% confidence interval (CI) 1.07–5.73, p < 0.05]. During the median 4-year follow-up, there were 65 incidents of all-cause death. In the multivariate Cox proportional hazard regression analysis, the presence of PAD [hazard ratio (HR) 2.08, 95% CI 1.17–3.65, p < 0.05] and CI-AKI (HR 2.23, 95% CI 1.08–4.26, p < 0.05) were associated with an increased risk of all-cause mortality. Assessment of ABI provides useful information for predicting CI-AKI and long-term mortality in patients with ACS after PCI. [ABSTRACT FROM AUTHOR]

Evidence of the long-term efficacy of digital therapies for smoking cessation that include a smartphone application (app) is limited. In this multi-center randomized controlled trial, we tested the efficacy of a novel digital therapy for smoking cessation: the "CureApp Smoking Cessation (CASC)" system, including a CASC smartphone app, a web-based patient management PC software for primary physicians, and a mobile exhaled carbon monoxide (CO) checker. A total of 584 participants with nicotine dependence were recruited from October 2017 to January 2018, and allocated 1:1 to the CASC intervention group or the control group. Both groups received a standard smoking cessation treatment with pharmacotherapy and counseling for 12 weeks. Meanwhile, the intervention group used the CASC system, and the control group used a control-app without a mobile CO checker, each for 24 weeks. The primary outcome was the biochemically validated continuous abstinence rate (CAR) from weeks 9 to 24. The main secondary outcome was an extended CAR from weeks 9 to 52. Except for 12 participants who did not download or use the apps, 285 participants were assigned to the intervention group, and 287, to the control. CAR from weeks 9 to 24 in the intervention group was significantly higher than that in the control group (63.9% vs. 50.5%; odds ratio [OR], 1.73; 95% confidence interval [CI], 1.24 to 2.42; P = 0.001). The CAR from weeks 9 to 52 was also higher in the intervention group than that in the control group (52.3% vs. 41.5%; OR, 1.55; 95% CI, 1.11 to 2.16; P = 0.010). No specific adverse events caused by the CASC system were reported. Augmenting standard face-to-face counseling and pharmacotherapy with a novel smartphone app, the CASC system significantly improved long-term CARs compared to standard treatment and a minimally supportive control app. [ABSTRACT FROM AUTHOR]

Introduction: Nutritional intervention is effective in improving glycemic control in patients with type 2 diabetes but requires large inputs of manpower. Recent improvements in photo analysis technology facilitated by artificial intelligence (AI) and remote communication technologies have enabled automated evaluations of nutrient intakes. AI- and mobile-supported nutritional intervention is expected to be an alternative approach to conventional in-person nutritional intervention, but with less human resources, although supporting evidence is not yet complete. The aim of this study is to test the hypothesis that AI-supported nutritional intervention is as efficacious as the in-person, face-to-face method in terms of improving glycemic control in patients with type 2 diabetes. Methods: This is a multicenter, unblinded, parallel, randomized controlled study comparing the efficacy of AI-supported automated nutrition therapy with that of conventional human nutrition therapy in patients with type 2 diabetes. Patients with type 2 diabetes mainly controlled with diet are to be recruited and randomly assigned to AI-supported nutrition therapy (n = 50) and to human nutrition therapy (n = 50). Asken, a mobile application whose nutritional evaluation has been already validated to that by the classical method of weighted dietary records, has been specially modified for this study so that it follows the recommendations of Japan Diabetes Society (total energy restriction with proportion of carbohydrates to fat to protein of 50–60, 20, and 20–30%, respectively). Planned Outcomes: The primary outcome is the change in glycated hemoglobin levels from baseline to 12 months, and this outcome is to be compared between the two groups. The secondary outcomes are changes in fasting plasma glucose, plasma lipid profile, body weight, body mass index, waist circumference, blood pressures, and urinary albumin excretion. The results of this randomized controlled trial will fill the gap between the demand for support of AI in nutritional interventions and the scientific evidence on its efficacy. Trial Registration: UMIN000032231. [ABSTRACT FROM AUTHOR]

Heterologous expression systems play a vital role in the characterization of potassium voltage-gated channel subfamily H member 2 (KCNH2) gene mutations, such as E637K which is associated with long QT syndrome type 2 (LQT2). In vivo assays using zebrafish provide a means for testing genetic variants of cardiac disease; however, limited information on the role of the E637K mutation is available from in vivo systems and their utility has yet to be fully exploited in the context of LQT2. We sought to evaluate the ability of the E637K mutant channel to restore normal repolarization in larval zebrafish with a human KCNH2 orthologue, kcnh2a-knockdown. A morpholino (MO) targeting kcnh2a was injected alone or with wild type (WT) or E637K KCNH2 cRNA into zebrafish embryos at the 1-2 cell stage. Cardiac repolarization phenotypes were screened using light microscopy and the QT interval was measured by single lead electrocardiograph (ECG) analysis at 72-h post-fertilization. In the MO alone group, 17% of zebrafish had a normal phenotype; this rate increased to 60% in the WT KCNH2 cRNA injected zebrafish and to 35% in the E637K injected zebrafish. The ECG of larval zebrafish revealed that QTc was significantly prolonged in the MO alone group compared to the control group. Co-injection of WT KCNH2 cRNA shortened the QTc interval, however, that of the E637K did not. We suggest that this in vivo cardiac assay using microscopy and ECG in larval zebrafish offers a reliable approach for risk discrimination of KCNH2 mutations. [ABSTRACT FROM AUTHOR]

Although statin therapy is beneficial in the setting of acute coronary syndrome (ACS), a substantial proportion of patients with ACS still do not receive the guideline-recommended lipid management in contemporary practice. We hypothesize that the low-density lipoprotein cholesterol (LDL-C) level at the time of admission might affect patient management and the subsequent outcome. Nine-hundred and forty-two consecutive patients with ACS who underwent percutaneous coronary intervention were analyzed retrospectively. The study patients were first divided into two groups based on the LDL-C level on admission: group A (n = 267), with LDL-C < 100 mg/dL; and group B (n = 675), with LDL-C ≥ 100 mg/dL. Each group was then further divided into those who were prescribed statins or not at the time of discharge from the hospital. The primary endpoint was all-cause death. In addition, we analyzed the serial changes of LDL-C within 1 year. Patients in group A were significantly older and more likely to have multiple comorbidities compared with group B. The proportion of patients who were prescribed statin at discharge was significantly smaller in group A compared with group B (57.7 vs. 77.3%, p < 0.001). During the median 4-year follow-up, there were 122 incidents of all-cause death. Multivariate Cox proportional hazard analysis revealed that LDL-C < 100 mg/dL on admission [hazard ratio (HR), 1.61; 95% confidence interval (CI), 1.09-2.39; p < 0.05] and prescription of statins at discharge (HR, 0.52; 95% CI, 0.36-0.76; p < 0.001) were associated significantly with all-cause death. Under these conditions, increasing LDL-C levels were documented during follow-up in those patients in group A when no statins were prescribed at discharge (79 ± 15-96 ± 29 mg/dL, p < 0.001), whereas these remained unchanged when statins were prescribed at discharge (79 ± 15-77 ± 22 mg/dL, p = 0.30). These results demonstrate that decreased LDL-C on admission in ACS led to less prescription for statins, which could result in increased death, probably due to underestimation of the baseline LDL-C. [ABSTRACT FROM AUTHOR]

Supplementary Information The online version contains supplementary material available at https://doi.org/10.1007/s00380-022-02218-5. B Correction: b Heart and Vessels https://doi.org/10.1007/s00380-022-02178-w In the original publication of the article, electronic supplementary material was published incorrectly. [Extracted from the article]

We have developed a culture system for guinea pig alveolar type II cells using an epithelium-denuded human amnion membrane as a substratum. The differentiated morphology was maintained for 3 wk by both air-interface feeding and immersion feeding when type II cells were cultured on the basement membrane side of the amnion with fibroblasts on the opposite side (coculture). Functionally, high levels of surfactant protein, B (SP-B) and C (SP-C) messenger ribonucleic acids (mRNAs) were expressed even after the 3-wk cultivation and surfactant protein A mRNA was detected on day 10 of the culture. The differentiation was also maintained when fibroblasts were cultured on lower chambers of the culture plates (separate culture). In contrast, culture of type II cells without fibroblasts (monoculture) could not preserve the mature morphology. When the monoculture was supplemented with keratinocyte growth factor or hepatocyte growth factor, a monolayer of rather cuboidal type II cells with apical microvilli was maintained. However, the percent area of lamellar bodies in these cells was significantly less than that in freshly isolated type II cells, and mRNA expressions of SP-B and SP-C were also considerably suppressed. These findings suggest that other growth factors or combinations of these factors are necessary for the maintenance of the differentiated phenotype. As substratum, a permeable collagen membrane or a thin gel layer of Engelbreth-Holm-Swarm mouse sarcoma extracts did not preserve the mature characteristics. This culture system using an acellular human amnion membrane may provide novel models for research in type II cells. [ABSTRACT FROM AUTHOR]

Retinoic acid-related orphan receptor gamma (RORγ) plays pivotal roles in autoimmune diseases by controlling the lineage of interleukin 17 (IL-17)-producing CD4+ T cells (Th17 cells). Structure-based drug design has proven fruitful in the development of inhibitors targeting the ligand binding domain (LBD) of RORγ. Here, we present the crystal structure of a novel RORγ inhibitor co-complex, in the presence of a corepressor (CoR) peptide. This ternary complex with compound T reveals the structural basis for an inhibitory mechanism different from the previously reported inverse agonist. Compared to the inverse agonist, compound T induces about 2 Å shift of helix 5 (H5) backbone and side-chain conformational changes of Met365 on H5. These conformational changes correlate to reduced CoR peptide binding to RORγ-LBD in the presence of compound T, which suggests that the shift of H5 is responsible. This crystal structure analysis will provide useful information for the development of novel and efficacious drugs for autoimmune disorders. [ABSTRACT FROM AUTHOR]

Lithium-air batteries (LABs) are expected to provide a cell with a much higher capacity than ever attained before, but their prototype cells present a limited areal cell capacity of no more than 10 mAh cm−2, mainly due to the limitation of their air electrodes. Here, we demonstrate the use of flexible carbon nanotube (CNT) sheets as a promising air electrode for developing ultra-high capacity in LAB cells, achieving areal cell capacities of up to 30 mAh cm−2, which is approximately 15 times higher than the capacity of cells with lithium-ion battery (LiB) technology (~2 mAh cm−2). During discharge, the CNT sheet electrode experienced enormous swelling to a thickness of a few millimeters because of the discharge product deposition of lithium peroxide (Li2O2), but the sheet was fully recovered after being fully charged. This behavior results from the CNT sheet characteristics of the flexible and fibrous conductive network and suggests that the CNT sheet is an effective air electrode material for developing a commercially available LAB cell with an ultra-high cell capacity. [ABSTRACT FROM AUTHOR]