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Objectives: We conducted an analysis of first-time tolvaptan users (≥80 years old) to determine the factors associated with the prognosis of elderly patients with heart failure. Methods: We retrospectively analyzed 66 consecutive patients with worsening heart failure (aged ≥80 years) who were admitted to Fujita Health University Bantane Hospital from 2011 to 2016 and treated with tolvaptan. Differences between the in-hospital death and survival groups were evaluated. Multivariate logistic regression analysis was also performed to identify the risk factors for mortality. Results: Sixty-six patients were included, and 26 patients died during the index hospitalization. The patients who died had a significantly higher prevalence of ischemic heart disease; a higher heart rate; higher levels of plasma C-reactive protein, blood urea nitrogen (BUN), and creatinine; a lower serum albumin level; and a lower estimated glomerular filtration rate than surviving patients. The proportion of patients requiring early initiation of tolvaptan treatment (within 3 days of admission) was significantly higher in surviving patients. On the basis of multivariate logistic regression analysis, although a high heart rate and high BUN levels were independent factors for in-hospital prognosis, they were not significantly associated with the early use of tolvaptan (≤3 days vs. ≥4 days; odds ratio=0.39; 95% confidence interval=0.07–2.21; p=0.29). Conclusions: This study revealed that a higher heart rate and higher BUN levels were independent factors for in-hospital prognosis in elderly patients who received tolvaptan and that early tolvaptan use may not always be effective in elderly patients.

We report a case of life-threatening bleeding from gastric varices in a patient with alcoholic cirrhosis, which was treated by emergency transileocolic vein obliteration (TIO). A 46-year-old male with a massive hematemesis was transported to our hospital by ambulance. Contrast-enhanced computed tomography demonstrated large gastric varices. Temporary hemostasis using balloon tamponade was attempted, however, bleeding could not be controlled, and his vital signs were unstable despite massive blood transfusions. First, endoscopic treatment was attempted, but the visual field could not be secured due to massive bleeding. Therefore, emergency TIO under general anesthesia was attempted. After laparotomy, 5 Fr. sheath was inserted into the ileocolic vein. Posterior and left gastric veins, which were the blood supply routes of gastric varices, were identified and embolized using microcoils and a 50% glucose solution. Hemostasis was achieved and vital signs recovered. Three days after TIO, transjugular retrograde obliteration was attempted successfully to embolize the residual gastric varices. After the procedures, his condition improved. We conclude that emergency TIO is a useful rescue option for life-threatening bleeding from gastric varices if endoscopic treatment or balloon tamponade is ineffective.

We used modified and dynamic intraoperative cholangiography (IOC) navigation during laparoscopic subtotal cholecystectomy for difficult gallbladders. We have defined an IOC that does not open the cystic duct as a modified IOC. Modified IOC methods include the percutaneous transhepatic gallbladder drainage (PTGBD) tube method, the infundibulum puncture method, and the infundibulum cannulation method. Case 1 was chronic cholecystitis after PTGBD for acute cholecystitis with pericholecystic abscess. In this case, modified IOC was performed via PTGBD, and biliary anatomy and incarcerated stone were confirmed. Case 2 was chronic cholecystitis after endoscopic sphincterotomy for cholecystocholedocholithiasis. In this case, modified IOC was performed via gallbladder puncture needle, and biliary anatomy and incision line were confirmed. The target point on the laparoscopic image was determined by moving the tip of the grasping forceps under modified IOC, which we call modified and dynamic IOC. We conclude that the navigation by the modified and dynamic IOC via PTGBD tube or puncture needle is useful to identify biliary anatomy, incarcerated gallbladder stone, and safe incision line during laparoscopic subtotal cholecystectomy .

Abstract Background Aging affects the incidence of diseases such as cancer and dementia, so the development of biomarkers for aging is an important research topic in medical science. While such biomarkers have been mainly identified based on the assumption of a linear relationship between phenotypic parameters, including molecular markers, and chronological age, numerous nonlinear changes between markers and aging have been identified. However, the overall landscape of the patterns in nonlinear changes that exist in aging is unknown. Result We propose a novel computational method, Data-driven Identification and Classification of Nonlinear Aging Patterns (DICNAP), that is based on functional data analysis to identify biomarkers for aging and potential patterns of change during aging in a data-driven manner. We applied the proposed method to large-scale, public DNA methylation data to explore the potential patterns of age-related changes in methylation intensity. The results showed that not only linear, but also nonlinear changes in DNA methylation patterns exist. A monotonous demethylation pattern during aging, with its rate decreasing at around age 60, was identified as the candidate stable nonlinear pattern. We also analyzed the age-related changes in methylation variability. The results showed that the variability of methylation intensity tends to increase with age at age-associated sites. The representative variability pattern is a monotonically increasing pattern that accelerates after middle age. Conclusion DICNAP was able to identify the potential patterns of the changes in the landscape of DNA methylation during aging. It contributes to an improvement in our theoretical understanding of the aging process.

Abstract In the field of genomic medical research, the amount of large-scale information continues to increase due to advances in measurement technologies, such as high-performance sequencing and spatial omics, as well as the progress made in genomic cohort studies involving more than one million individuals. Therefore, researchers require more computational resources to analyze this information. Here, we introduce a hybrid cloud system consisting of an on-premise supercomputer, science cloud, and public cloud at the Kyoto University Center for Genomic Medicine in Japan as a solution. This system can flexibly handle various heterogeneous computational resource-demanding bioinformatics tools while scaling the computational capacity. In the hybrid cloud system, we demonstrate the way to properly perform joint genotyping of whole-genome sequencing data for a large population of 11,238, which can be a bottleneck in sequencing data analysis. This system can be one of the reference implementations when dealing with large amounts of genomic medical data in research centers and organizations.

Gene sets are functional units for living cells. Previously, limited studies investigated the complex relations among gene sets, but documents about their altering patterns across biological conditions still need to be prepared. In this study, we adopted and modified a classical k-nearest neighbor-based association function to detect inter-gene-set similarities. Based on this method, we built multiplex networks of gene sets for the first time; these networks contain layers of gene sets corresponding to different populations of cells. The context-based multiplex networks can capture meaningful biological variation and have considerable differences from knowledge-based networks of gene sets built on Jaccard similarity, as demonstrated in this study. Furthermore, at the scale of individual gene sets, the structural coefficients of gene sets (multiplex PageRank centrality, clustering coefficient, and participation coefficient) disclose the diversity of gene sets from the perspective of structural properties and make it easier to identify unique gene sets. In gene set enrichment analysis (GSEA), each gene set is treated independently, and its contextual and relational attributes are ignored. The structural coefficients of gene sets can supplement GSEA with information about the overall picture of gene sets, promoting the constructive reorganization of the enriched terms and helping researchers better prioritize and select gene sets.

A 71-year-old woman was referred to our department for abdominal pain. She was diagnosed with acute obstructive cholangitis due to cystic duct and bile duct stones after cholecystectomy and Roux-en-Y gastrojejunostomy. Two years ago, the patient underwent endoscopic and laparoscopic treatment for cystic duct and bile duct stones, however, the stones remained. This time, she was treated with stone removal using percutaneous papillary balloon dilatation (PPBD). Large stones in the common hepatic and bile ducts were crushed by electrohydraulic lithotripsy and then pushed out into the duodenum through the dilated papilla of Vater using a balloon catheter covered with the sheath and cholangioscopy. Stone in the cystic duct was pulled to the common bile duct and pushed to the duodenum. Stone removal using PPBD is an excellent alternative for patients with cystic duct and bile duct stones unable to be treated with endoscopic or laparoscopic stone removal.

Abstract Contrast-associated acute kidney injury (CA-AKI) is a complication of percutaneous coronary intervention (PCI). Because proteinuria is a sentinel marker of renal dysfunction, we assessed its role in predicting CA-AKI in patients undergoing PCI. A total of 1,254 patients undergoing PCI were randomly assigned to a derivation (n = 840) and validation (n = 414) dataset. We identified the independent predictors of CA-AKI where CA-AKI was defined by the new criteria issued in 2020, by a multivariate logistic regression in the derivation dataset. We created a risk score from the remaining predictors. The discrimination and calibration of the risk score in the validation dataset were assessed by the area under the receiver-operating characteristic curves (AUC) and Hosmer–Lemeshow test, respectively. A total of 64 (5.1%) patients developed CA-AKI. The 3 variables of the risk score were emergency procedures, serum creatinine, and proteinuria, which were assigned 1 point each based on the correlation coefficient. The risk score demonstrated a good discriminative power (AUC 0.789, 95% CI 0.766–0.912) and significant calibration. It was strongly associated with the onset of CA-AKI (Cochran-Armitage test, p

Abstract The spread through air spaces (STAS) is recognized as a negative prognostic factor in patients with early-stage lung adenocarcinoma. The present study aimed to develop a machine learning model for the prediction of STAS using peritumoral radiomics features extracted from preoperative CT imaging. A total of 339 patients who underwent lobectomy or limited resection for lung adenocarcinoma were included. The patients were randomly divided (3:2) into training and test cohorts. Two prediction models were created using the training cohort: a conventional model based on the tumor consolidation/tumor (C/T) ratio and a machine learning model based on peritumoral radiomics features. The areas under the curve for the two models in the testing cohort were 0.70 and 0.76, respectively (P = 0.045). The cumulative incidence of recurrence (CIR) was significantly higher in the STAS high-risk group when using the radiomics model than that in the low-risk group (44% vs. 4% at 5 years; P = 0.002) in patients who underwent limited resection in the testing cohort. In contrast, the 5-year CIR was not significantly different among patients who underwent lobectomy (17% vs. 11%; P = 0.469). In conclusion, the machine learning model for STAS prediction based on peritumoral radiomics features performed better than the C/T ratio model.

Physical reservoir computing (PRC) with visible-light signals was demonstrated using dye-sensitized solar cells. The short-term memory required for PRC was confirmed using light pulse inputs. Waveform learning was demonstrated for nonlinear autoregressive moving-average time series level 2 (NARMA2) signals with normalized mean square error of 0.027. The relatively slow (milliseconds to seconds) and complex charge transfer dynamics in the TiO _2 porous layer with redox reactions in the solution phase provided the characteristics required for PRC.

Objectives: There are benefits of exercise-based cardiac rehabilitation (CR) in patients with heart failure (HF), but their underlying molecular mechanisms remain elusive. The effect of CR on the expression profile of circulating microRNAs (miRNAs), which are short noncoding RNAs that regulate posttranscriptional expression of target genes, is unknown. If miRNAs respond to changes following CR for HF, then serum profiling of miRNAs may reveal cardioprotective mechanisms of CR. Methods: This study enrolled three hospitalized patients with progressed systolic HF and three normal volunteer controls. In patients, CR was initiated after improvement of HF, which included 2 weeks of bicycle ergometer and resistance exercises. Genome-wide expression profiling of circulating miRNAs was performed using microarrays for the patients (mean±SD age, 60.0±12.2 years) and controls (58.7±0.58 years). Circulating miRNA expression profiles were compared between patients with HF before and after CR and the controls. Results: Expression levels of two miRNAs were significantly different in patients before CR compared with controls and patients after CR. The expression of hsa-miR-125b-1-3p was significantly downregulated and that of hsa-miR-1290 was significantly upregulated in patients before CR. Conclusions: When performing CR, expression of certain circulating miRNAs in patients with HF is restored to nonpathological levels. The benefits of CR for HF may result from regulation of miRNAs through multiple effects of gene expression.

Background: Anaerobic threshold (AT) during cardiopulmonary exercise testing (CPET) is not always determinable in patients with heart failure (HF). However, little is known about the clinical features of patients with HF who have indeterminable AT. Therefore, the present study aimed to clarify the clinical features of such patients. Methods: A total of 70 patients with HF (58 males; age: 68±12 years) who underwent CPET during hospitalization were divided into two groups: determinable AT (n=50) and indeterminable AT (n=20). Physical function, echocardiographic results, and laboratory findings were subsequently determined. Results: Univariate analyses showed that the indeterminable AT group had significantly higher age and left ventricular ejection fraction, and significantly lower body mass index, calf circumference, handgrip strength, walking speed, serum hemoglobin, and serum albumin than the determinable AT group. Multiple logistic regression analysis identified handgrip strength and walking speed as independent predictive factors for indeterminable AT. Receiver-operating characteristic analyses revealed that handgrip strength of 21.2 kg and walking speed of 0.97 m/s were optimal cutoff values for differentiating patients who were likely to experience indeterminable AT. Conclusions: The present study identified handgrip strength and walking speed as powerful predictors for indeterminable AT with HF.

Objectives: MicroRNAs (miRNA) are functional RNAs that have emerged as pivotal gene expression regulators in cardiac disease. Although several cardiomyocyte miRNAs have been reported to play roles in heart failure progression among patients with idiopathic dilated cardiomyopathy (DCM), the role of circulating miRNAs has not yet been well-examined. Methods: After total RNA extraction from the peripheral blood samples of three control participants and six patients with DCM, miRNA profiling was performed using miRNA arrays. Based on the results of this initial screening, real-time polymerase chain reaction (RT-PCR) was used to perform a quantitative analysis of blood samples from a larger number of matched patients (DCM, n=20; controls, n=5). Finally, the correlations between specific miRNA expression levels and hemodynamic parameters were analyzed. Results: A primary screening of 2,565 miRNAs resulted in the identification of nine miRNA candidates. Quantitative RT-PCR results revealed significantly increased miR-489 expression levels in the DCM group. Moreover, there was a significant positive correlation between miR-489 expression level and left ventricular ejection fraction. Conclusions: Our results suggest that circulating miR-489 could be a potential noninvasive diagnostic biomarker for DCM. Additionally, the quantification of circulating miR-489 may have value as a potential prognostic marker for patients with DCM.

Abstract Background A model that can predict treatment response for a patient with specific baseline characteristics would help decision-making in personalized medicine. The aim of the study is to develop such a model in the treatment of rheumatoid arthritis (RA) patients who receive certolizumab (CTZ) plus methotrexate (MTX) therapy, using individual participant data meta-analysis (IPD-MA). Methods We will search Cochrane CENTRAL, PubMed, and Scopus as well as clinical trial registries, drug regulatory agency reports, and the pharmaceutical company websites from their inception onwards to obtain randomized controlled trials (RCTs) investigating CTZ plus MTX compared with MTX alone in treating RA. We will request the individual-level data of these trials from an independent platform ( http://vivli.org ). The primary outcome is efficacy defined as achieving either remission (based on ACR-EULAR Boolean or index-based remission definition) or low disease activity (based on either of the validated composite disease activity measures). The secondary outcomes include ACR50 (50% improvement based on ACR core set variables) and adverse events. We will use a two-stage approach to develop the prediction model. First, we will construct a risk model for the outcomes via logistic regression to estimate the baseline risk scores. We will include baseline demographic, clinical, and biochemical features as covariates for this model. Next, we will develop a meta-regression model for treatment effects, in which the stage 1 risk score will be used both as a prognostic factor and as an effect modifier. We will calculate the probability of having the outcome for a new patient based on the model, which will allow estimation of the absolute and relative treatment effect. We will use R for our analyses, except for the second stage which will be performed in a Bayesian setting using R2Jags. Discussion This is a study protocol for developing a model to predict treatment response for RA patients receiving CTZ plus MTX in comparison with MTX alone, using a two-stage approach based on IPD-MA. The study will use a new modeling approach, which aims at retaining the statistical power. The model may help clinicians individualize treatment for particular patients. Systematic review registration PROSPERO registration number pending (ID#157595).

The cell's movement and morphological change are two interrelated cellular processes. An integrated analysis is needed to explore the relationship between them. However, it has been challenging to investigate them as a whole. The cell's trajectory can be described by its speed, curvature, and torsion. On the other hand, the three-dimensional (3D) cell shape can be studied by using a shape descriptor such as spherical harmonic (SH) descriptor, which is an extension of a Fourier transform in 3D space. We propose a novel method using parallel-transport (PT) to integrate these shape-movement data by using moving frames as the 3D-shape coordinate system. This moving frame is purely determined by the velocity vector. On this moving frame, the movement change will influence the coordinate system for shape analysis. By analyzing the change of the SH coefficients over time in the moving frame, we can observe the relationship between shape and movement. We illustrate the application of our approach using simulated and real datasets in this paper.

The heart is a significant organ in mammalian life, and the heartbeat mechanism has been an essential focus of science. However, few studies have focused on species differences. Accordingly, challenges remain in studying genes that have universal functions across species and genes that determine species differences. Here, we analyzed transcriptome data in mouse, rat, and human atria, ventricles, and sinoatrial nodes (SA) obtained from different platforms and compared them by calculating specificity measure (SPM) values in consideration of species differences. Among the three heart regions, the species differences in SA were the greatest, and we searched for genes that determined the essential characteristics of SA, which was SHOX2 in our criteria. The SPM value of SHOX2 was prominently high across species. Similarly, by calculating SPM values, we identified 3 atrial-specific, 11 ventricular-specific, and 17 SA-specific markers. Ontology analysis identified 70 cardiac region- and species-specific ontologies. These results suggest that reanalyzing existing data by calculating SPM values may identify novel tissue-specific genes and species-dependent gene expression. This study identified the importance of SHOX2 as an SA-specific transcription factor, a novel cardiac regional marker, and species-dependent ontologies.

Abstract Background It is well known that vascular endothelial growth factor (VEGF) inhibitors can cause proteinuria. The incidence of proteinuria is high for bevacizumab, a humanized monoclonal antibody directed against VEGF, but the range of proteinuria rarely becomes nephrotic (2.2% occurrence according to a meta-analysis). In such cases, renal pathology shows thrombotic microangiopathy (TMA). Ramucirumab, anti-VEGF receptor 2 (VEGFR2) monoclonal antibody, can also cause proteinuria, but it is not yet reported whether the drug may induce TMA. Case presentation Here, we report a case who immediately developed TMA by ramucirumab after multiple courses of bevacizumab treatment. This is the first case of pathologically-proved TMA by ramucirumab. After cessation of the drug, symptoms of TMA improved gradually. Conclusions This case demonstrates that not only blockade of VEGF but also VEGFR2 antagonism may result in TMA, which is a rare but life-threatening complication of cancer treatment drug.

Objectives: There are well-established risk prediction models of in-hospital mortality due to heart failure (HF). However, the predictors of mortality during acute hospitalization in individuals with HF receiving tolvaptan, a vasopressin type 2 receptor antagonist, are poorly understood. Methods: Sixty-one hospitalized patients prescribed tolvaptan to treat worsening HF were consecutively enrolled in this study. The study endpoint was death during hospitalization. Results: Compared with survivors, patients who died in hospital had higher Get With The Guidelines-Heart Failure (GWTG-HF) risk scores, decreased albumin levels, increased serum creatinine levels, smaller inferior vena cava (IVC) diameters on echocardiography, and were more likely to have received catecholamine infusion. A multivariate logistic regression analysis revealed that in addition to GWTG-HF risk score >47, albumin level ≤2.4 g/dL, creatinine level >1.5 mg/dL, IVC diameter ≤15 mm, and catecholamine infusion were all novel and significant predictors of in-hospital death. Moreover, combining these novel predictors to the GWTG-HF risk score significantly improved prediction of in-hospital death, as shown by the greater area under the receiver operating characteristic (ROC) curve. Conclusions: In patients with worsening HF receiving oral tolvaptan, we identified novel predictors of in-hospital death. Our findings may be helpful in developing novel treatment strategies for patients receiving tolvaptan for HF in clinical settings.

Myopic maculopathy is a complication of myopia that often progresses to blindness. Here, in a genome-wide association study, Hosoda et al. find that rs11873439 intronic to CCDC102B is associated with myopic maculopathy, but not with myopia, thus representing a risk factor independent of myopia.

Abstract We conducted a genome-wide association study (GWAS) on the outcome of anti-VEGF treatment for exudative age-related macular degeneration (AMD) in a prospective cohort. Four hundred and sixty-one treatment-naïve AMD patients were recruited at 13 clinical centers and all patients were treated with 3 monthly injections of ranibizumab followed by pro re nata regimen treatment for one year. Genomic DNA was collected from all patients for a 2-stage GWAS on achieving dry macula after the initial treatment, the requirement for an additional treatment, and visual acuity changes during the 12-month observation period. In addition, we evaluated 9 single-nucleotide polymorphisms (SNPs) in 8 previously reported AMD-related genes for their associations with treatment outcome. The discovery stage with 256 patients evaluated 8,480,849 SNPs, but no SNPs showed genome-wide level significance in association with treatment outcomes. Although SNPs with P-values of

Abstract Background Pulmonary arterial hypertension (PAH) is a severe lung disease with only few effective treatments available. Familial cases of PAH are usually recognized as an autosomal dominant disease, but incomplete penetrance of the disease makes it difficult to identify pathogenic variants in accordance with a Mendelian pattern of inheritance. Methods To elucidate the complex genetic basis of PAH, we obtained whole exome- or genome-sequencing data of 17 subjects from 9 families with heritable PAH and applied gene-based association analysis with 9 index patients and 300 PAH-free controls. Results A burden of rare variants in BMPR2 significantly contributed to the risk of the disease (p = 6.0 × 10−8). Eight of nine families carried four previously reported single nucleotide variants and four novel insertion/deletion variants in the gene. One of the novel variants was a large 6.5 kilobase-deletion. In the remaining one family, the patient carried a pathogenic variant in a member of potassium channels, KCNK3, which was the first replicative finding of channelopathy in an Asian population. Conclusions The variety of rare pathogenic variants suggests that gene-based association analysis using genome-wide sequencing data from increased number of samples is essential to tracing the genetic heterogeneity and developing an appropriate panel for genetic testing.

Single-cell expression analysis is an effective tool for studying the dynamics of cell population profiles. However, the majority of statistical methods are applied to individual profiles and the methods for comparing multiple profiles simultaneously are limited. In this study, we propose a nonparametric statistical method, called Decomposition into Extended Exponential Family (DEEF), that embeds a set of single-cell expression profiles of several markers into a low-dimensional space and identifies the principal distributions that describe their heterogeneity. We demonstrate that DEEF can appropriately decompose and embed sets of theoretical probability distributions. We then apply DEEF to a cytometry dataset to examine the effects of epidermal growth factor stimulation on an adult human mammary gland. It is shown that DEEF can describe the complex dynamics of cell population profiles using two parameters and visualize them as a trajectory. The two parameters identified the principal patterns of the cell population profile without prior biological assumptions. As a further application, we perform a dimensionality reduction and a time series reconstruction. DEEF can reconstruct the distributions based on the top coordinates, which enables the creation of an artificial dataset based on an actual single-cell expression dataset. Using the coordinate system assigned by DEEF, it is possible to analyze the relationship between the attributes of the distribution sample and the features or shape of the distribution using conventional data mining methods.

Background Medical decision-making is difficult when information is limited due to its rareness. For example, there are two treatment options for patients affected by a rare disease with high lethality. The information about both treatment effects is unavailable or very limited. Patients are inclined to accept one of the interventions rather than waiting for death, but they are reluctant to be assigned the inferior one. While a single patient selects one treatment that seems better based on the limited information, he or she loses the chance to select the other treatment, which may be the better option. This is the so-called dilemma between exploitation (enjoying the benefits of using current knowledge) and exploration (taking the risk to obtain new knowledge). In clinical settings, the statistical advice for individual patients seems to be the maximum expected success rate or something equivalent and patients’ selections tend to be homogeneous, which does not solve the dilemma. In this study, our aim is to investigate the effects of the heterogeneity of decision-makers in the decision process. Methods Here, we proposed a decision strategy that introduced the heterogeneity of decision-makers by considering patients’ self-decisions where the patients’ heterogeneous attitudes towards the treatment are integrated into the probabilistic utility function based on the Beta Bayesian posterior. Based on the context of two-armed bandit treatment options with limited information, we compared the overall success rate of treatment between our heterogeneous decision strategy and a homogeneous decision strategy that is defined to select the treatment with the largest posterior mean. Results The heterogeneity of decision-makers in a population improved the overall benefit of treatment under some conditions. Discussion In clinical settings, there exists heterogeneity of decision-making among patients. Our study investigated a targeting strategy by respecting the self-decision of all individuals and found that the heterogeneity of decision-making can improve the overall benefit under some conditions. In addition, this outperformance may suggest that heterogeneity of decision-making is of importance to human beings. Besides the ethical merit, our findings provide meaningful ideas for better strategies towards decision-making dilemmas in clinical settings for rare diseases or cases where only limited information is available. Furthermore, it is suggested to investigate the effects of heterogeneity of decision-making in other fashions, such as genetic heterogeneity and phenotypic heterogeneity.

The genetic factors affecting the natural history of nonalcoholic fatty liver disease (NAFLD), including the development of nonalcoholic steatohepatitis (NASH) and NASH-derived hepatocellular carcinoma (NASH-HCC), are still unknown. In the current study, we sought to identify genetic factors related to the development of NAFLD, NASH, and NASH-HCC, and to establish risk-estimation models for them. For these purposes, 936 histologically proven NAFLD patients were recruited, and genome-wide association (GWA) studies were conducted for 902, including 476 NASH and 58 NASH-HCC patients, against 7,672 general-population controls. Risk estimations for NAFLD and NASH were then performed using the SNPs identified as having significant associations in the GWA studies. We found that rs2896019 in PNPLA3 [p = 2.3x10-31, OR (95%CI) = 1.85 (1.67-2.05)], rs1260326 in GCKR [p = 9.6x10-10, OR (95%CI) = 1.38(1.25-1.53)], and rs4808199 in GATAD2A [p = 2.3x10-8, OR (95%CI) = 1.37 (1.23-1.53)] were significantly associated with NAFLD. Notably, the number of risk alleles in PNPLA3 and GATAD2A was much higher in Matteoni type 4 (NASH) patients than in type 1, type 2, and type 3 NAFLD patients. In addition, we newly identified rs17007417 in DYSF [p = 5.2x10-7, OR (95%CI) = 2.74 (1.84-4.06)] as a SNP associated with NASH-HCC. Rs641738 in TMC4, which showed association with NAFLD in patients of European descent, was not replicated in our study (p = 0.73), although the complicated LD pattern in the region suggests the necessity for further investigation. The genetic variants of PNPLA3, GCKR, and GATAD2A were then used to estimate the risk for NAFLD. The obtained Polygenic Risk Scores showed that the risk for NAFLD increased with the accumulation of risk alleles [AUC (95%CI) = 0.65 (0.63-0.67)].We demonstrated that NASH is genetically and clinically different from the other NAFLD subgroups. We also established risk-estimation models for NAFLD and NASH using multiple genetic markers. These models can be used to improve the accuracy of NAFLD diagnosis and to guide treatment decisions for patients.

Group 2 innate lymphoid cells (ILC2s) are critical for the immune response against parasite infection and tissue homeostasis and involved in the pathogenesis of allergy and inflammatory diseases. Although multiple molecules positively regulating ILC2 development and activation have been extensively investigated, the factors limiting their population size and response remain poorly studied. Here, we found that CD45, a membrane-bound tyrosine phosphatase essential for T cell development, negatively regulated ILC2s in a cell-intrinsic manner. ILC2s in CD45-deficient mice exhibited enhanced proliferation and maturation in the bone marrow and hyperactivated phenotypes in the lung with high glycolytic capacity. Furthermore, CD45 signaling suppressed the type 2 inflammatory response by lung ILC2s and alleviated airway inflammation and pulmonary fibrosis. Finally, the interaction with galectin-9 influenced CD45 signaling in ILC2s. These results demonstrate that CD45 is a cell-intrinsic negative regulator of ILC2s and prevents lung inflammation and fibrosis via ILC2s. [ABSTRACT FROM AUTHOR]

The cart-type friction measurement device developed by the authors facilitates measurement of both the static coefficient of friction (SCOF) and the dynamic coefficient of friction (DCOF) between the shoe and the floor simultaneously, as well as measurement with variation in sliding velocity. However, whether slip–resistance evaluation using this cart-type friction measurement device corresponds to the actual slip and fall risks is unclear. To investigate the validity of evaluation of slip resistance between the shoe and the floor by using the SCOF and DCOF values measured with a cart-type friction measurement device, we aimed to investigate the relationship between the slip angle in a ramp test and the coefficient of friction (COF) values between the test safety shoe and the 10 test floor sheets contaminated with a glycerol solution. The results indicate that the SCOF values and the DCOF values corresponding to sliding velocity lower than 0.3 m/s are highly correlated with the slip angle in the ramp test, which suggests that the cart-type friction measurement device can simulate the slip between the shoe and the floor in the ramp test under such sliding velocity conditions. Because the ramp test has been used widely to assess the slip resistance of floors and because the slip angle is highly correlated to the risk of slip-induced falls during level walking, the results suggest that the cart-type friction measurement device is valid and effective for assessing the slip resistance between the shoe and the floor. This study provides new information about the evaluation of slip resistance and indicates that the cart-type friction measurement device will contribute toward the prevention of slip-induced fall accidents.

Non-restorative sleep (NRS) was suggested to be associated with cardiovascular outcomes. However, causative factors for NRS have not been fully elucidated. This study aimed to clarify factors and their relationships with NRS to better understand the clinical and epidemiological implications of NRS and to develop a score that can objectively evaluate NRS status.Study subjects consisted of 9,788 community residents (age 53.6 ± 13.4 y). Subjective NRS as well as possible clinical and lifestyle factors for NRS were investigated by questionnaires. Other clinical parameters were obtained from personal records of information obtained at the baseline examination.A total of 3,261 participants complained of NRS. Factors independently associated with subjective NRS were younger age (odds ratio = 1.43), use of a hypnotic drug (2.04), irregular sleep schedule (2.02), short sleep duration (