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Systemic sclerosis (SSc) is a chronic multisystem disorder characterized by fibrosis and autoimmunity. Interleukin (IL)-31 has been implicated in fibrosis and T helper (Th) 2 immune responses, both of which are characteristics of SSc. The exact role of IL-31 in SSc pathogenesis is unclear. Here we show the overexpression of IL-31 and IL-31 receptor A (IL-31RA) in dermal fibroblasts (DFs) from SSc patients. We elucidate the dual role of IL-31 in SSc, where IL-31 directly promotes collagen production in DFs and indirectly enhances Th2 immune responses by increasing pro-Th2 cytokine expression in DFs. Furthermore, blockade of IL-31 with anti-IL-31RA antibody significantly ameliorates fibrosis and Th2 polarization in a mouse model of SSc. Therefore, in addition to defining IL-31 as a mediator of fibrosis and Th2 immune responses in SSc, our study provides a rationale for targeting the IL-31/IL-31RA axis in the treatment of SSc., Systemic sclerosis (SSc) disease involves multisystem fibrosis and autoimmunity with limited treatment options. Here the authors demonstrate that IL-31 and IL-31RA are overexpressed in dermal fibroblasts from SSc patients and show that fibrosis and cytokine release can be reduced upon blocking of IL-31/IL-31RA.

Summary Background Systemic sclerosis is a connective tissue disease characterised by multiorgan fibrosis with an autoimmune background and poor prognosis. Although a few drugs have shown some efficacy in treating the disease, there remains a great unmet medical need. We aimed to investigate the efficacy and safety of rituximab in patients with systemic sclerosis. Methods We did a double-blind, investigator-initiated, randomised, placebo-controlled trial at four hospitals in Japan. Patients aged 20–79 years, who fulfilled the 2013 American College of Rheumatology and European League Against Rheumatism classification criteria for systemic sclerosis, with a modified Rodnan Skin Score (mRSS) of 10 or greater, and an expected survival of at least 6 months were randomly assigned (1:1) to receive intravenous rituximab (375 mg/m2) or placebo once per week for 4 weeks. Patients and investigators were masked to treatment allocation. The primary endpoint was the absolute change in mRSS 24 weeks after initiation of study treatment, measured in all patients who received at least one dose of study treatment and had one endpoint assessment. This study is registered with ClinicalTrials.gov, NCT04274257, and UMIN-CTR, UMIN000030139. Findings Between Nov 28, 2017, and Nov 6, 2018, 80 individuals were screened and 56 (70%) were enrolled and randomly assigned; 51 (91%) were women and five (9%) were men. 27 (96%) of 28 patients in the rituximab group and 22 (79%) of 28 patients in the placebo group received at least one dose of their allocated treatment and completed 24 weeks of follow-up. The absolute change in mRSS 24 weeks after initiation of study treatment was lower in the rituximab group than in the placebo group (−6·30 in the rituximab group vs 2·14 in the placebo group; difference −8·44 [95% CI −11·00 to −5·88]; p Interpretation Rituximab appears to be an effective and safe treatment for systemic sclerosis. Although this study has some limitations, this is the first clinical trial to show efficacy of rituximab with skin sclerosis as the primary endpoint. Funding Japan Agency for Medical Research and Development (AMED), Zenyaku Kogyo. Translation For the Japanese translation of the abstract see Supplementary Materials section.

The statin use in patients on hemodialysis remains controversial, and no beneficial effects of statin on the reduction of adverse cardiovascular events have been reported in these patients. This study used stratification analysis to examine the clinical factors in patients on hemodialysis who could benefit from statin for secondary prevention. This prospective multicenter study included 234 consecutive patients on hemodialysis with coronary artery disease who underwent successful reperfusion therapy with percutaneous coronary intervention. The patients were followed up for up to 3 years or until the occurrence of major adverse cardiac events (MACEs; defined as a composite of all-cause death and nonfatal myocardial infarction). Inverse probability of treatment weighting adjustment was used to remove the selection bias. During the median follow-up period of 30 months, MACEs occurred in 55 patients. Patients with MACEs had significantly lower statin therapy (P0.001). Multivariable Cox proportional hazards analysis showed that the patients on statins had a significantly reduced rate of MACE occurrence [adjusted hazard ratio 0.30 (0.11-0.81), P = 0.02]. The stratification analysis of outcomes according to the presence of clinical factors showed that beneficial effects of statin were associated with man, elderly, lower body mass index, lower abdominal circumference, hypertension, diabetes, higher C-reactive protein, symptomatic heart failure, lower left ventricular function, nonacute coronary syndrome, and shorter stent length. Statin was effective for the prevention of MACEs in patients on hemodialysis who underwent percutaneous coronary intervention. We identified specific clinical factors affecting statin effectiveness for secondary prevention.

Cutaneous arteritis (CA) is necrotizing vasculitis invading the small- to medium-sized arteries of the skin. The majority of patients can be favorably managed by low- to medium-dose systemic corticosteroids (prednisolone

The May-Hegglin anomaly is characterized by inherited thrombocytopenia, giant platelets, and leukocyte cytoplasmic inclusion bodies. The Fechtner, Sebastian, and Epstein syndromes are associated with mutations of the MYH9-coding nonmuscle myosin heavy chain ⅡA, similar to the May-Hegglin anomaly, and are together classified as MYH9 disorders. MYH9 disorders may include symptoms of Alport syndrome, including nephritis and auditory and ocular disorders. A 6-year-old boy was diagnosed with an MYH9 disorder after incidental discovery of hematuria and proteinuria. Focal segmental glomerulosclerosis was detected on renal biopsy. However, despite no prior bleeding diatheses, he developed a large post-biopsy hematoma despite a preprocedural platelet transfusion calculated to increase the platelet count from 54,000/μL to >150,000/μL. Idiopathic thrombocytopenic purpura is a major cause of pediatric thrombocytopenia following acute infection or vaccination, and patients with MYH9 disorders may be misdiagnosed with idiopathic thrombocytopenic purpura and inappropriately treated with corticosteroids. Careful differential diagnosis is important in thrombocytopenic patients with hematuria and proteinuria for the early detection of thrombocytopenia. Patients with MYH9 disorders require close follow-up and treatment with angiotensin Ⅱ receptor blockers to prevent the onset of progressive nephritis, which may necessitate hemodialysis or renal transplantation. The need for renal biopsy in patients with MYH9 disorders should be carefully considered because there could be adverse outcomes even after platelet transfusion.

Aim To examine whether improvement in flow-mediated endothelium-dependent dilatation (FMD) of the brachial artery and brachial-ankle pulse wave velocity (baPWV) has an additive effect on achieving optimal goals of traditional risk factors to reduce cardiovascular risk in patients with coronary artery disease (CAD). Methods We assessed 323 patients with CAD and impaired vascular function, defined as an impaired FMD of the brachial artery (＜5.5%) and increased baPWV (＞1,440 cm/sec). After FMD and baPWV measurements at 24 weeks of optimal medical treatment (OMT), the study patients were followed up for ＜60 months or until a composite of cardiac death, nonfatal myocardial infarction (MI), unstable angina, or ischemic stroke occurs. Results During the median follow-up period of 35 months, cardiovascular events occurred in 72 patients. Multivariate Cox hazards analysis showed that patients with an improvement in FMD and baPWV had the lowest probability of future cardiovascular events. In addition, the improvement in FMD and baPWV had a significant incremental effect on the predictive value of the achievement of optimal goals for blood pressure (BP), low-density lipoprotein cholesterol (LDL-C), and hemoglobin A1c (HbA1c) using net reclassification improvement (NRI) and integrated discrimination improvement (IDI). Conclusions The improvement in FMD and baPWV had additive effects on risk reduction of the achievement of the optimal goals of traditional risk factors in patients with CAD. Thus, serial measurements of FMD and baPWV may be useful for identifying CAD patients at residual risk for adverse cardiovascular events following OMT.

Introdução: A ninfoplastia é uma cirurgia que envolve a redução dos lábios genitais e correção de assimetrias. A hipertrofia de pequenos lábios corrobora com o desconforto na função sexual. Logo, esse procedimento visa melhorar a qualidade de vida em relação a parte álgica, psíquica e sexual. Metodologia: Trata-se de uma revisão literária, com utilização das bases de dados: Google Acadêmico, Scielo e Portal Capes, descritores “labioplastia” OR “ninfoplastia” AND “satisfação sexual”, entre os anos 2011-2020, que configuram revisão sistemática e ensaio clínico controlado, nos idiomas inglês, espanhol e português. Foram selecionados 7 artigos com base em relevância clínica e terapêutica.Discussão: A hipertrofia dos pequenos lábios está associada ao desconforto funcional e estético, o que interfere diretamente na vida sexual em relação à satisfação, higiene, dores relacionadas ao uso de roupas justas. Isso afeta a autopercepção feminina e compromete o prazer íntimo da mulher. O padrão estético anatômico para a genitália feminina advém da ideia de que os lábios menores devem ser recobertos pelos lábios maiores, principalmente sobre influência midiática e da indústria pornográfica que preconiza uma genitália pré-puberal. Sendo assim, aquelas que se distanciam desse estereótipo buscam melhorar sua autoimagem e decidem se adequar ao que é socialmente idealizado. Entretanto, uma parcela substancial das mulheres procura a cirurgia com intenção de amenizar sofrimentos álgicos diários, visto que os neurônios somatossensoriais presentes nos lábios menores, em contato prolongado com roupas justas podem desencadear dor. Sendo assim, com a correção cirúrgica da hipertrofia, os lábios menores ficarão protegidos pela vulva, reduzindo a estimulação dolorosa pelo toque por longos períodos com tecidos. Com isso, após a ninfoplastia as pacientes apresentam melhora da função sexual, que deve ser multidimensional e centrada em si, uma vez que a autoconfiança juntamente com a diminuição da dor está diretamente relacionada ao aumento da satisfação sexual.Conclusão: A hipertrofia de pequenos lábios pode interferir no conforto psicológico e no bem estar pessoal e sexual, o que causa conflitos no relacionamento íntimo. Logo, a ninfoplastia de pequenos lábios possibilita eliminar o desconforto social, funcional e estético, sendo evidente a relevância deste procedimento cirúrgico.

Rice-flavor baijiu is a traditional Chinese liquor. The flavor profile and volatiles presented with or without the solid-state saccharification (SSS) were investigated to reveal the effects of SSS process on the quality of rice-flavor baijiu. The liquor prepared with SSS had a sweet flavor. It contained significantly higher contents of β-phenylethyl alcohol, β-phenylethyl acetate, and ethyl lactate with odor active value of >1. The liquor prepared without SSS had a cheese-like flavor. It was confirmed that the cheese-like flavor derived from butanoic acid was only detected in the liquor prepared without SSS. SSS facilitated the biosynthesis of β-phenylethyl alcohol and ethyl lactate by supplying a large amount of phenylalanine and lactic acid at the initial stage of fermentation, and it prevented contamination. These results indicated that the SSS process contributed to produce the characteristic flavor compounds of rice-flavor baijiu. PRACTICAL APPLICATION: Solid-state saccharification (SSS) process of rice-flavor baijiu contributes not only in brewing, but also in the production of the characteristic flavor compounds and the repression of the off-flavor derived from the contamination. Therefore, SSS is a critical process to control the flavor of rice-flavor baijiu.

Objective Nocturnal desaturation is common in patients with chronic respiratory disease and often worsens the prognosis. Therefore, it should be diagnosed accurately and appropriately treated. The aim of this study was to clarify the diversity of nocturnal desaturation. Methods We prospectively enrolled 58 outpatients diagnosed with chronic respiratory disease receiving home oxygen therapy and measured nocturnal SpO2 using a portable oximeter. We classified nocturnal desaturation (3% decrease in SpO2 from baseline) into three patterns: periodic pattern (desaturation duration of

Mycotic aneurysms are sometimes seen in patients with infective endocarditis. We report a case of infective endocarditis with multiple mycotic aneurysms. Although antibiotics were effective, mycotic aneurysms appeared in the cerebral, hepatic, and gastroepiploic arteries. A 55-year-old man presented with mitral valve endocarditis due to Streptococcus oralis. Surgical treatment was deferred because of cerebral hemorrhage. After antibiotic initiation, his fever and C-reactive protein levels declined, and blood culture was negative. However, he experienced repeated cerebral hemorrhage and the number of cerebral mycotic aneurysms increased. Additionally, his spleen ruptured and the number of mycotic aneurysms in the hepatic and gastroepiploic arteries increased. After embolization for mycotic aneurysm and mitral valve replacement, no mycotic aneurysms appeared. Regardless of whether laboratory data improve or not, multiple mycotic aneurysms sometimes appear, and cardiac surgery for infection control should be considered in the early phase.

Anti-melanoma differentiation-associated gene 5 (MDA5) antibody (Ab) is myositis-specific autoantibody associated with rapidly progressive interstitial lung disease (ILD) and poor prognosis. In this retrospective observational study, we aimed to verify the efficacy and safety of introducing combined immunosuppressive therapy for anti-MDA5 Ab-positive dermatomyositis (DM) from their early stage. We recruited all Japanese patients diagnosed with DM in our clinic between January 2011 and October 2018, who had anti-MDA5 Ab, anti-aminoacyl transfer RNA synthetase Ab or anti-transcriptional intermediary factor 1-γ Ab. Combined immunosuppressive therapy was defined as combination of systemic corticosteroids, i.v. cyclophosphamide and tacrolimus. The difference of clinical features among the three groups was analyzed by multiple comparison analysis. The longitudinal change of the measurements from baseline was examined by Wilcoxon signed-rank test. Association between therapeutic regimens and adverse events was examined by logistic regression analysis. As a result, combined immunosuppressive therapy was most frequently used in the anti-MDA5 Ab-positive group, which significantly improved their forced vital capacity of the lung. Interval time since initial visit until starting treatment was the shortest in the anti-MDA5 Ab-positive group. There was no significant difference in the incidence of death and recurrence among the three groups. Cytomegalovirus reactivation was most common in the anti-MDA5 Ab-positive group, associated with combined immunosuppressive therapy. Collectively, early introduction of combined immunosuppressive therapy was effective for DM patients with anti-MDA5 Ab. At the same time, clinicians should be aware of the risk of cytomegalovirus reactivation during the treatment.

Molecular subtyping in gastrointestinal stromal tumours is a useful method for predicting the efficacy of treatment using tyrosine kinase inhibitors in humans. However, owing to the paucity of reports on mutational analyses, the association between genetic mutations and the therapeutic response to tyrosine kinase inhibitors remains unclear in feline gastrointestinal stromal tumours. In this report, we describe the case of a cat with a gastrointestinal stromal tumour which was unresponsive to tyrosine kinase inhibitors. A mutational analysis revealed that the cat lacked mutations in both the KIT and platelet-derived growth factor receptor-alpha (PDGFRA) genes. Our findings are consistent with the fact that KIT/PDGFRA wild-type gastrointestinal stromal tumours are less responsive to tyrosine kinase inhibitors in humans. This signifies the need for further evaluation and possibly individualised treatment for gastrointestinal stromal tumours in cats on the basis of mutational analyses.

Cataract is a leading cause of blindness and vision impairment globally. Cataract surgery is one of the most frequently performed operations worldwide, but good quality services are not universally available. This scoping review aims to summarise the nature and extent of published literature on interventions to improve the quality of services for age-related cataract globally. We used the dimensions of quality adopted by WHO-effectiveness, safety, people-centredness, timeliness, equity, integration and efficiency-to which we added planetary health. On 17 November 2019 we searched MEDLINE, Embase and Global Health for manuscripts published since 1990, without language or geographic restrictions. We included studies that reported quality-relevant interventions and excluded studies focused on technical aspects of surgery or that only involved children (less than 18 years). Screening of titles/abstracts, full-text review and data extraction were performed by two reviewers independently. Studies were grouped thematically and results synthesised narratively. Most of the 143 included studies were undertaken in high-income countries (n=93, 65%); Twenty-nine intervention groups were identified, most commonly pre-operative education (n=17, 12%) and pain/anxiety management (n=16, 11%). Efficiency was the quality element most often assessed (n=58, 41%) followed by people-centredness (n=40, 28%), while integration (n=4) and timeliness (n=3) were infrequently reported, and no study reported outcomes related to planetary health. Evidence on interventions to improve quality of cataract services shows unequal regional distribution. There is an urgent need for more evidence relevant to low- and middle- income countries as well as across all quality elements, including planetary health. This article is protected by copyright. All rights reserved. [Abstract copyright: This article is protected by copyright. All rights reserved.]

Background and Aim There have been studies on risk factors for stenosis after pyloric endoscopic submucosal dissection (ESD). However, the most appropriate strategies for the management of cases with these risk factors have not been established. This study aimed to investigate post-ESD management by evaluating the timing of stenosis and the effectiveness of endoscopic balloon dilation (EBD) after pyloric ESD. Methods We retrospectively reviewed cases of pyloric ESD. We first reassessed risk factors for stenosis in multivariate analysis and receiver operating characteristic curve and defined patients with the identified risk factors as the risk group. The primary outcome was the timing of stenosis in the risk group assessed by the Kaplan–Meier method. Results We reviewed 159 cases with pyloric ESD and observed pyloric stenosis in 25 cases. Cases with circumferential mucosal defect ≥ 76% were identified as the risk group. The stenosis-free probability in the risk group was 97% (95% confidence interval [CI]: 79–100%), 94% (95% CI: 76–98%), and 85% (95% CI: 66–93%) on days 7, 14, and 21, respectively. It decreased every week thereafter and did not significantly change after day 56. Twenty-three stenosis cases, except for conservative improvement, including six whole circumferential pyloric ESD cases, were improved by EBD without complications. Conclusions Post-ESD stenosis often developed from the third to the eighth week. In all pyloric ESD cases, including whole circumferential pyloric ESD cases, pyloric stenosis was improved following EBD without complications.

PURPOSE This study aimed to compare patients with early oral cavity squamous cell carcinoma (OCSCC) (tumor category [T] 1-2, node-negative, and no distant metastasis) treated with traditional elective neck dissection (ND) with those managed by sentinel lymph node biopsy (SLNB) using survival and neck function and complications as end points. METHODS Sixteen institutions in Japan participated in the study (trial registration number: UMIN000006510). Patients of age ≥ 18 years with histologically confirmed, previously untreated OCSCC (Union for International Cancer Control TNM Classification of Malignant Tumors 7th edition T1-2, node-negative no distant metastasis), with ≥ 4 mm (T1) depth of invasion, were randomly assigned to undergo standard selective ND (ND group; n = 137) or SLNB-navigated ND (SLNB group; n = 134). The primary end point was the 3-year overall survival rate, with a 12% noninferiority margin; secondary end points included postoperative neck functionality and complications and 3-year disease-free survival. Sentinel lymph nodes underwent intraoperative multislice frozen section analyses for the diagnosis. Patients with positive sentinel lymph nodes underwent either one-stage or second-look ND. RESULTS Pathologic metastasis-positive nodes were observed in 24.8% (34 of 137) and 33.6% (46 of 134) of patients in the ND and SLNB groups, respectively ( P = .190). The 3-year overall survival in the SLNB group (87.9%; lower limit of one-sided 95% CI, 82.4) was noninferior to that in the ND group (86.6%; lower limit 95% CI, 80.9; P for noninferiority < .001). The 3-year disease-free survival rate was 78.7% (lower limit 95% CI, 72.1) and 81.3% (75.0) in the SLNB and ND groups, respectively ( P for noninferiority < .001). The scores of neck functionality in the SLNB group were significantly better than those in the ND group. CONCLUSION SLNB-navigated ND may replace elective ND without a survival disadvantage and reduce postoperative neck disability in patients with early-stage OCSCC.

Background: Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is a rare autosomal dominant disease progressively affecting cognitive and motor functions, most often caused by mutations in the colony-stimulating factor 1 receptor gene (CSF1R). / Aim: To elucidate the mechanism of disease progression, changes in white matter lesions and cortical cerebral blood flow (CBF) were evaluated in cases during various stages of the disease. ...

This study aimed to investigate the associations between objectively measured sleep timing and habitual dietary intake among university students. We hypothesized that a later chronotype and larger social jetlag (SJL) are associated with an undesirable dietary intake. The 82 healthy university students included in this study were asked to undertake a seven-day wrist activity recording. All the participants also completed a self-administered questionnaire during the recording period, including questions on demographic characteristics and habitual dietary intakes. Dietary intake and the score for adherence to the Japanese Food Guide Spinning Top (food guide score) over the previous month were evaluated using a self-reported diet history questionnaire. Nocturnal sleep timing and total sleep time for each night were estimated using the recorded wrist activity. Chronotype was calculated as weekend (WE) mid-sleep time corrected for catch-up sleep on weekdays (WDs). SJL was calculated by subtracting WD mid-sleep time from WE mid-sleep time. Multivariable linear regression showed that a later chronotype was significantly (P < .05) associated with a lower consumption of eggs, greater consumption of grains, and lower food guide score. Multivariable linear regression also showed significant (P < .05) associations of a larger value in SJL with a lower total energy intake, lower consumption of grains, and greater consumption of sugar and confectioneries. The results suggest that chronotype and SJL may be differently associated with undesirable dietary intake in young adults. These findings have important implications for developing novel strategies, focusing on sleep timing, for improving dietary intakes and preventing lifestyle-related diseases.

Ultrasound assessment of the carotid artery provides prognostic information on coronary events. This study examined whether ultrasound assessments of plaque echolucency of the carotid artery are useful for identifying patients with coronary artery disease (CAD) who are at high risk but could benefit from lipid-lowering therapy for secondary prevention.Ultrasound assessment of carotid plaque echolucency with integrated backscatter (IBS) analysis was performed in 393 chronic CAD patients with low-density lipoprotein cholesterol (LDL-C) levels100 mg/dL on statin therapy. All patients were prospectively followed up for a maximum of 96 months or until the occurrence of one of the following coronary events: cardiac death, nonfatal myocardial infarction, or unstable angina pectoris requiring unplanned revascularization.During the follow-up period, 45 coronary events occurred. Patients were stratified by IBS (≤-16.3 or-16.3 dB, median value) and LDL-C level (70 or 70-99 mg/dL). Multivariate Cox proportional hazards analysis showed that patients with lower IBS and LDL-C 70-99 mg/dL had significantly higher probabilities of coronary events compared with those with higher IBS and LDL-C70 mg/dL, after adjustment for a baseline model of risk factors (hazard ratio 5.15; 95% confidence interval 1.21-22.0, p = 0.03). In contrast, patients with lower IBS and LDL-C70 mg/dL had an improved prognosis comparable with those with higher IBS. Addition of LDL-C levels to the baseline model of risk factors improved net reclassification improvement (NRI) and integrated discrimination improvement (IDI) in patients with lower IBS (NRI, 0.44, p = 0.04; and IDI, 0.035, p 0.01), but not in those with higher IBS.Evaluation of echolucency of the carotid artery was useful for selecting CAD patients at high risk of secondary coronary events but who could benefit from lipid-lowering therapy.

The benefit of rituximab (RTX) for systemic sclerosis-associated interstitial lung disease (SSc-ILD) has been shown in previous clinical trials. However, predictors of RTX efficacy have not been clarified. We investigated whether B-cell responsiveness to RTX is related to therapeutic effect. Ten SSc-ILD patients treated with RTX in an independent clinical trial (Japan Registry of Clinical Trials, jRCTs031180373) were included in this analysis. Peripheral B-cell counts were examined retrospectively before RTX administration (baseline) and at 2, 4, 12, and 24 weeks after the first RTX administration, along with percent-predicted forced vital capacity (%FVC) before and 24 weeks after RTX treatment. Relative to baseline, the percentage of residual peripheral blood B cells at 2 weeks after RTX was negatively correlated with the %FVC improvement at the 24-week assessment (r = -0.41, p = 0.04). In the subgroup with less than 5% B-cell persistence at week 2, %FVC at the 24-week assessment was significantly improved compared to baseline (p = 0.02). In another subgroup with more than 5% residual B cells, %FVC was not significantly different after 24 weeks compared to baseline (p = 0.41). In conclusion, the removal rate of B cells after 2 weeks of RTX treatment may be a useful surrogate marker of subsequent SSc-ILD improvement.

Objective Galectin-10 (Gal-10) is a key molecule involved in eosinophil-mediated suppression of T-cell immune response. Systemic sclerosis (SSc) is characterized by T helper (Th) 2/Th17 immune response and impaired function of regulatory T cells, but the pathological role of Gal-10 has not been studied so far. Therefore, we investigated the clinical correlation of serum Gal-10 levels in SSc patients. Methods Serum Gal-10 levels were determined by enzyme-linked immunosorbent assay in 38 patients with diffuse cutaneous SSc (dcSSc), 30 with limited cutaneous SSc and 20 healthy controls. Clinical correlations of serum Gal-10 levels were examined. Results Serum Gal-10 levels were significantly lower in SSc patients than in healthy controls, especially in dcSSc patients, and inversely correlated with skin score, the percentage of predicted diffusion lung capacity for carbon monoxide and estimated right ventricular systolic pressure (RVSP). Furthermore, serum Gal-10 levels had negative correlations with leucocyte counts and inflammatory parameters. Multivariate regression analysis identified C-reactive protein and RVSP as explanatory parameters for serum Gal-10 levels. Conclusion Decreased serum Gal-10 levels may reflect the impairment of eosinophil-mediated regulatory system for T-cell immune response in SSc, possibly contributing to pulmonary vascular involvement leading to pulmonary arterial hypertension.

Elevation of ALP is an abnormal feature in TAFRO syndrome, but the cause is unknown. This article is the first report that histologically showed intrahepatic cholangitis may be the cause of ALP elevation in TAFRO syndrome.

Impaired social facilitation was reported in autism spectrum disorder (ASD) children. However, behavioral analysis methods of social facilitation for ASD model have not been reported. We developed a novel breeding home cage for social facilitation. Voluntary exercise of more social C57BL/6 J mice was significantly increased in the presence of observer mouse compared to that in the absence of observer mouse. In contrast, the presence of observer mouse did not affect voluntary exercise of less social BALB/cCrSlc mice. These suggest that BALB/cCrSlc mice, a mouse model of ASD, exhibited impaired social facilitation. Our method would provide novel clues for ASD pathophysiology.

Summary Background & aims Improving sleep quality is important for an aging society. However, no study has been conducted on the association between dietary variety and sleep efficiency among older Japanese adults using longitudinal data. The current study is a longitudinal study that aimed to elucidate the association between dietary variety and sleep efficiency in older Japanese adults. Methods This study was conducted among older adults (≥70 years old in 2016) in the metropolitan area of Tokyo, Japan, between 2016 and 2018. Dietary variety score (DVS) and sleep efficiency were determined for all participants and were used to assess dietary habits and sleep quality, respectively. A cross-lagged panel analysis was used to consider the prospective associations between DVS and sleep efficiency, and this analysis was performed before and after adjusting for possible covariates in the 2016 data. Results After adjusting for age, sex, body mass index, current drinking status, current smoking status, exercise habits, living (alone or with others) style, the Japanese version of the Geriatric Depression Scale (Short Form), sleep duration and retiring time the DVS in 2016 predicted the sleep efficiency in 2018 (β = 0.130, p Conclusion The possibility that DVS can predict sleep efficiency 2 years later was demonstrated.

Introdução: A pandemia por COVID-19 propiciou o desenvolvimento de sintomas de distúrbios psicológicos e alterações comportamentais. Objetivos: Evidenciar as manifestações psíquicas e comportamentais mais prevalentes durante a pandemia. Métodos: Realizou-se uma revisão sistemática nas bases PubMed, Biblioteca Virtual em Saúde, Scopus, Science Direct, Web of Science e SciELO com artigos publicados até maio de 2020. Incluíram-se estudos: tipo coorte, caso-controle, relato de casos coorte, transversal, estudo ecológico, ensaio clínico randomizado, ensaio clínico comunitário, ensaio clínico não randomizado. Realizados em seres humanos tendo a manifestação de sintomas psíquicos e alterações comportamentais no período de pandemia. Excluíram-se estudos que não referiam a sintomas de distúrbios psicológicos e alterações comportamentais, estudos secundários, teses e dissertações. Resultados: Dos 3264 artigos, 14 foram selecionados. Conclusão: O isolamento social é um fator de risco para o desenvolvimento de manifestações psíquicas e alterações comportamentais. Entretanto é necessário novos estudos sobre a temática no contexto pandêmico atual.

This study examined olfactory dysfunction in LATY136F knock-in mice and its pathogenic mechanism.The olfactory function of LATY136F knock-in mice was assessed by a behavioral test using cycloheximide solution, which has been used as a mice repellant because of its peculiar smell and unpleasant taste. The tests were administered to each group of LATY136F knock-in mice and WT mice at 8, 12, 16, 20, and 24 weeks of age. After the behavioral tests to evaluate olfactory function, the mice were sacrificed for evaluations by immunohistochemistry.Behavioral tests to evaluate olfactory function showed that the LATY136F knock-in mice had a statistically significant level of olfactory dysfunction (P0.05). Histological analysis showed that the thickness of the olfactory epithelium in these mice was thinner than that in the age-matched wild type mice. There was no IgG4-RD like lesion in the olfactory epithelium of LATY136F knock-in mice. Olfactory marker protein and growth-associated protein 43 expressions in the olfactory epithelium of the LATY136F knock-in mice were markedly lesser than those in the wild type mice (P0.05).The present study demonstrated that olfactory disturbances occurred in LATY136F knock-in mice. Furthermore, the mechanism was suggested to be reduced regeneration of the olfactory epithelium.

Castleman disease (CD) includes a group of rare and heterogeneous disorders with characteristic lymph node histopathological abnormalities. CD can occur in a single lymph node station, which is referred to as unicentric CD (UCD). CD can also involve multicentric lymphadenopathy and inflammatory symptoms (multicentric CD [MCD]). MCD includes human herpesvirus-8 (HHV-8)–associated MCD, POEMS-associated MCD, and HHV-8−/idiopathic MCD (iMCD). The first-ever diagnostic and treatment guidelines were recently developed for iMCD by an international expert consortium convened by the Castleman Disease Collaborative Network (CDCN). The focus of this report is to establish similar guidelines for the management of UCD. To this purpose, an international working group of 42 experts from 10 countries was convened to establish consensus recommendations based on review of treatment in published cases of UCD, the CDCN ACCELERATE registry, and expert opinion. Complete surgical resection is often curative and is therefore the preferred first-line therapy, if possible. The management of unresectable UCD is more challenging. Existing evidence supports that asymptomatic unresectable UCD may be observed. The anti–interleukin-6 monoclonal antibody siltuximab should be considered for unresectable UCD patients with an inflammatory syndrome. Unresectable UCD that is symptomatic as a result of compression of vital neighboring structures may be rendered amenable to resection by medical therapy (eg, rituximab, steroids), radiotherapy, or embolization. Further research is needed in UCD patients with persisting constitutional symptoms despite complete excision and normal laboratory markers. We hope that these guidelines will improve outcomes in UCD and help treating physicians decide the best therapeutic approach for their patients.

AIM Systemic sclerosis (SSc) is an autoimmune connective tissue disease, in which extensive fibrotic change and vasculopathy affect the skin and various internal organs. It also involves the joints, causing stiffness, arthralgia, and arthritis. Although arthropathy is commonly observed in SSc, its underlying mechanism remains unknown. CXCL12, also known as stromal cell derived factor 1, is associated with inflammation, mesenchymal cell recruitment, angiogenesis, and collagen production, and is implicated in the development of various joint diseases. To assess the potential contribution of CXCL12 to SSc development, we investigated the clinical association of serum CXCL12 levels in patients with SSc. METHOD We conducted a cross-sectional analysis of 68 patients with SSc and 20 healthy controls recruited in a single center over 9 years. Serum CXCL12 levels were measured by enzyme-linked immunosorbent assay. RESULTS Serum CXCL12 levels were significantly higher in patients with SSc than in healthy controls (median 1554.0 pg/mL, 25th-75th centiles 1313.0-1914.0 pg/mL vs 967.4 pg/mL, 608.8-1271.0 pg/mL, P < 0.001). Patients with SSc with elevated CXCL12 levels had significantly more cases of arthropathy than those with normal CXCL12 levels (85.7% vs 25.0%, P = 0.01). Furthermore, patients with SSc with elevated CXCL12 levels showed an increased trend in the prevalence of limited range of motion of the finger joints compared with those with normal CXCL12 levels (60.0% vs 18.6%, P =0 .07). Moreover, serum CXCL12 levels were significantly correlated with the titers of rheumatoid factor in patients with SSc (r = .41, P = 0.001). CONCLUSION Elevated serum CXCL12 levels may be related to the development of SSc arthropathy.

The Pharmaceuticals and Medical Devices Agency (PMDA) has approved hundreds of new drugs in recent years. We retrospectively analyzed the new drugs approved in Japan from 2008 to 2019, and identify the first-in-world approvals and clarify the current drug lag. The new drug and the drug lag were defined as a drug with a new active substance and a difference between the approval date in Japan and the international birth date, respectively. Among 400 new drugs approved in Japan during the last 12 years, 80 (20.0%) were first approved in Japan, and 320 were outside Japan (the United States: 202, 50.5%; Europe: 82, 20.5%; other regions: 36, 9.0%). Of these, 45 new drugs have not yet been approved outside Japan, and the remaining 355 have been globally approved in Japan and overseas. The number of new drug approvals were the largest in oncology followed by metabolic/endocrine and infectious diseases. The median drug lags (year) among all 400 new drugs and 355 new drugs with global approvals were 4.3 and 4.7 in the first tertile (2008-2011), 1.5 and 2.6 in the second tertile (2012-2015), and reduced to 1.3 and 2.2 in the third tertile (2016-2019), respectively. Substantial drug lag remains in neurology, psychiatry, and therapeutic areas where the number of new drug approvals was relatively small. Collectively, one-fifth of the new drugs approved in Japan are first-in-world approvals. Drug lag has been greatly decreased, although it still exists.

Damage-associated molecular patterns (DAMPs) have drawn much attention as a member of disease-associated molecules in systemic sclerosis (SSc). In this study, we investigated the potential contribution of S100A12, a member of DAMPs, to the development of SSc by evaluating S100A12 expression in the lesional skin and the clinical correlation of serum S100A12 levels. S100A12 expression was markedly elevated in the epidermis of SSc-involved skin at protein levels and in the bulk skin at mRNA levels. The deficiency of transcription factor Fli1, a predisposing factor of SSc, enhanced S100A12 expression and Fli1 occupied the S100A12 promoter in normal human keratinocytes. Serum S100A12 levels were higher in SSc patients, especially in those with diffuse cutaneous involvement, than in healthy controls and positively correlated with skin score. Furthermore, the presence of interstitial lung disease significantly augmented serum levels of S100A12. Importantly, serum S100A12 levels correlated inversely with both per cent forced vital capacity and per cent diffusing capacity for carbon monoxide and positively with serum levels of KL-6 and surfactant protein-D. Collectively, these results indicate a possible contribution of S100A12 to skin sclerosis and interstitial lung disease associated with SSc, further supporting the critical roles of DAMPs in the pathogenesis of this disease.

Introduction The combination of ipilimumab plus nivolumab has been used as first-line therapy for metastatic renal cell carcinoma. While it is well known that hemodialysis patients have a higher rate of renal cell carcinoma compared to the general population, no reports have described the safety of ipilimumab-nivolumab in metastatic renal cell carcinoma patients on hemodialysis. Case presentation A 73-year-old man with a 21-year history of dialysis was referred to our department in 2019 for bilateral renal tumors and multiple lung nodules. He had already been diagnosed with bilateral renal tumors in 2015, without undergoing surgery due to comorbidities. In May 2019, contrast-enhanced computed tomography revealed multiple lung metastases in addition to the existing renal tumors; consequently, he was treated with four doses of nivolumab-ipilimumab with no adverse events. Conclusion The combination of ipilimumab plus nivolumab was safely used in a hemodialysis patient with metastatic renal cell carcinoma.

Background Electroconvulsive therapy (ECT) is a well-established treatment for psychiatric disorders, including depression and psychosis. ECT has been reported to be effective in treating such psychiatric symptoms in patients with Parkinson's disease (PD) and has been also reported to be effective in treating motor symptoms. The aim of the study is to summarize previous clinical studies investigating the efficacy of ECT for symptoms in patients with PD. Methods A systematic review and meta-analysis of any study designs assessing motor and/or non-motor symptoms in patients with PD before and after ECT. Co-primary outcomes were set as motor manifestations assessed using the Unified Parkinson's Disease Rating Scale or other rating scales, and non-motor symptoms included depression and psychosis. Secondary outcomes were wearing-off phenomenon and cognitive function. The impact of ECT on those symptoms was examined by comparing the severity of the symptoms before and after ECT using a random effect model and was expressed in standardized mean difference. Results Of 1219 identified citations, 14 studies (n = 129; 1 randomized controlled study, 9 prospective observational studies, and 4 retrospective studies) were analyzed. The findings were as follows: ECT significantly improved motor manifestations in patients with PD, and the improvement was significant in the subpopulation without psychiatric symptoms; ECT significantly improved depression and psychosis; and ECT significantly relieved wearing-off phenomenon and did not worsen cognitive functioning. Conclusion The current meta-analysis suggests the potential benefit of ECT on motor and non-motor symptoms in presumably complicated and difficult-to-treat subgroups. © 2020 International Parkinson and Movement Disorder Society.

In this paper, we propose a novel heart rate (HR) estimation method using simultaneously recorded RGB and near-infrared (NIR) face videos to improve the robustness of camera-based remote HR estimation against illumination fluctuations and head motions. The key to robust HR estimation is constructing the histogram of HRs for a considered time window by voting candidate HRs that are estimated using different spatial face patches, spectral modalities (i.e., RGB and NIR), and temporal short-time sub-windows. The histogram voting is performed only for the candidate HRs that pass through a reliability check of HR estimation. The final HR estimate for the considered time window is then obtained by detecting the most frequently voted HR bin and performing parabola fitting using its neighboring bins. By spatially, spectrally, and temporally fusing the candidate HRs for majority voting, our method can automatically exploit suitable video sub-regions less affected by illumination fluctuations and head motions to enable robust HR estimation. Through the experiments on 168 RGB-NIR video recordings, we demonstrate that our fusion-based method achieves improved HR estimation accuracy compared with existing methods.

Background Venous compliance decreases with aging and/or physical inactivity, which is thought to be involved partly in the pathogenesis of cardiovascular disease such as hypertension. This suggests that it is important to maintain high venous compliance from a young age in order to prevent cardiovascular disease. Both nutrient and exercise could play an important role in the improvement and maintenance of vascular health. Indeed, habitual endurance exercise is known to improve the venous compliance, although little is known about the effect of diet on venous compliance. Considering that higher consumption of vegetables could contribute to the arterial vascular health and the decreased blood pressure, it is hypothesized that venous compliance may be greater as vegetable intake is higher. Thus, the purpose of this study was to clarify the association between vegetable intake and venous compliance in healthy young adults. Methods Dietary intake was assessed in 94 subjects (male: n = 44, female: n = 50) using a self-administered diet history questionnaire (DHQ). Intakes of nutrients and food groups that were obtained from the DHQ were adjusted according to total energy intake using the residual method. Based on the adjusted intake of food groups, total vegetable intake was calculated as the sum of green/yellow and white vegetables consumed. Calf volume was measured using venous occlusion plethysmography with a cuff deflation protocol. Calf venous compliance was calculated as the numerical derivative of the cuff pressure–calf volume curve. In addition, circulatory responses (heart rate and systolic and diastolic blood pressure) at resting and maximal oxygen uptake were assessed in all subjects. Results Mean value of total vegetables intake was 162.2 ± 98.2 g/day. Simple linear regression analysis showed that greater venous compliance was significantly associated with higher total vegetable consumption (r = 0.260, P = 0.011) and green/yellow vegetable intake (r = 0.351, P = 0.001) but not white vegetable intake (r = 0.013, P = 0.902). These significant associations did not change in the multivariate linear regression models which were adjusted by sex and maximal oxygen uptake. Conclusion These findings suggest that higher consumption of vegetables, especially of the green/yellow vegetables, may be associated with greater venous compliance in young healthy adults.

Background Although animal studies showed that Follistatin-like 1 (FSTL1) exerts cardioprotective effects against ischemic injury, little is known in humans. We examined whether FSTL1 is secreted in an infarcted myocardium and whether its production is associated with left ventricular (LV) remodeling in survivors of acute myocardial infarction. Methods and Results FSTL1 levels were measured by enzyme-linked immunosorbent assay in plasma collected from the aortic root and the anterior interventricular vein in 93 patients with anterior acute myocardial infarction. Measurement of FSTL1 levels and left ventriculography were repeated during the early phase (2 weeks) and the chronic phase (6 months) after MI. A persistent increment in FSTL1 levels from the aortic root to the anterior interventricular vein, reflecting FSTL1 production in the infarcted myocardium at both the early and chronic phases, was seen in 22 patients (24%). A linear regression analysis revealed that a persistent transmyocardial increment in FSTL1 levels was significantly associated with percent changes in LV end-diastolic volume index, LV end-systolic volume index, and LV ejection fraction from the early to the chronic phase (r = 0.44, 0.51, and −0.43, respectively, all P Conclusions The persistent production of FSTL1 in the infarcted myocardium was associated with adverse LV remodeling in survivors of acute myocardial infarction.

Introduction: Lubiprostone is an effective treatment of chronic constipation (CC). However, as with other stimulant or osmotic laxatives, adverse events (AEs) can make it difficult to continue treatment. This article investigates AE risk factors associated with lubiprostone. Methods: We retrospectively analyzed all 1,338 Japanese patients with CC treated at our hospital from October 2013 to July 2017. All patients were diagnosed with constipation as defined by the Roma III criteria. Enrolled patients received lubiprostone orally (24 or 48 μg daily), after which we investigated the incidence of AEs. The causative factors for diarrhea and nausea, the most common AEs, were examined by the backward logistic regression model. Results: Two hundred eight (15.5%) experienced at least 1 AE. No serious AEs were associated with the study drug. The AEs reported by >1% of patients overall were diarrhea (6.1%) and nausea (4.2%). We performed a multivariate logistic regression using a backward variable selection method to investigate AE risk factors. Factors associated with higher incidence of diarrhea were patient age of 65 years or more (odds ratio: [95% confidence interval]; p value) (2.09: [1.05–4.16]; 0.035). Factors associated with greater likelihood of nausea included female gender (1.99: [1.10–3.61]; 0.023), and the chief complaint was a patient complaining of abdominal pain and fullness (2.07: [1.01–4.22]; 0.046). Conclusions: Understanding AE risk factors can help avoid unnecessary AEs and promote more effective treatment.

Many hereditary disorders in dogs have equivalents in humans and thus attract attention as natural animal models. Breed predisposition to certain diseases often provides promising clues to explore novel hereditary disorders in dogs. Recently, cases of gastrointestinal (GI) polyps in Jack Russell Terriers (JRTs) have increased in Japan. In 21 affected JRTs, polyps were found in either or both the stomach and colorectum, with a predilection for the gastric antrum and rectum. Multiple polyps were found in 13 of 21 examined dogs, including 5 dogs with both gastric and colorectal polyps. Some dogs were found to have GI polyps at an early age, with the youngest case being 2.3 years old. Histopathologically, 43 of 46 GI polyps (93.5%) were diagnosed as adenomas or adenocarcinomas. Immunohistochemical analysis revealed cytoplasmic and nuclear accumulation of β-catenin in the tumor cells. As in the case of human patients with familial adenomatous polyposis, all examined JRTs with GI polyps (n = 21) harbored the identical heterozygous germline APC mutations, represented by a 2-bp substitution (c.[462A>T; 463A>T]). The latter substitution was a non-sense mutation (p.K155X) resulting in a truncated APC protein, thus suggesting a strong association with this cancer-prone disorder. Somatic mutation and loss of the wild-type APC allele were detected in the GI tumors of JRTs, suggesting that biallelic APC inactivation was involved in tumor development. This study demonstrated that despite differences in the disease conditions between human and dog diseases, germline APC mutation confers a predisposition to GI neoplastic polyps in both dogs and humans.

Background Some Okinawan vegetables have been reported to have anti-diabetic activity; however, no prospective cohort study has clarified whether consumption of Okinawan vegetables is associated with a risk of type 2 diabetes. This study aimed to determine the association between consumption of Okinawan vegetables and risk of type 2 diabetes through a large-scale, population-based, prospective study in Japan. Methods We examined 10,732 participants (4,714 men and 6,018 women) aged 45-74 years who resided in Okinawa. Participants were asked to answer a 147-item food frequency questionnaire. We calculated the overall amount of Okinawan vegetables consumed and the amount of seven specific kinds of Okinawan vegetables consumed. The odds ratios (ORs) for self-reported type 2 diabetes during 5 years of follow-up were estimated via multivariate logistic regression analysis. Results During the 5-year period, 216 new cases (123 men and 93 women) of type 2 diabetes were reported. Comparing the highest tertile to the lowest tertile of intake, the overall amount of Okinawan vegetables consumed was not associated with risk of type 2 diabetes in men (OR 1.22; 95% confidence interval [CI], 0.74-2.01, P-trend = 0.53) or in women (OR 0.96; 95% CI, 0.57-1.62, P-trend = 0.89). The consumption of seven specific kinds of Okinawan vegetables was also not associated with the risk of type 2 diabetes. Conclusions The consumption of total Okinawan vegetables was not associated with the risk of type 2 diabetes.

Background and Aim Esophageal endoscopic submucosal dissection (ESD) is often technically difficult due to intraoperative body movements. The level of sedation can be increased to suppress body movements, but this may not be successful in all cases. Using local analgesics for submucosal injection during ESD may aid in conscious sedation. This study evaluated the feasibility of the lidocaine injection method (LIM) during esophageal ESD. Methods Twenty‐nine patients with superficial esophageal cancer were enrolled in this study at Osaka Saiseikai Nakatsu Hospital, and 1% lidocaine + 0.4% hyaluronate sodium was injected into the submucosa underneath the lesion during esophageal ESD. The main outcome was body movements that disturbed the procedure. Results Most patients were male (90%), with a median age of 70 years (interquartile range [IQR]: 66–75 years old), and the median lesion size was 17 mm (IQR: 12–21 mm). The median injection volume of lidocaine was 70 mg (IQR: 55–79 mg). All lesions were successfully removed en bloc. In all cases, there were no body movements that disturbed the procedure. Regarding adverse events of sedation, five patients (17%) had hypotension, four patients (14%) had bradycardia, and seven patients (24%) had hypoxemia during ESD. Convulsions or arrhythmia as adverse events associated with lidocaine were not observed. Conclusions Esophageal ESD with LIM did not cause body movements that disturbed the procedure. LIM may help create a stable conscious sedation method for esophageal ESD., Esophageal endoscopic submucosal dissection (ESD) is often technically difficult due to intraoperative body movements. Esophageal ESD using the lidocaine injection method (LIM) did not cause body movements that disturbed the procedure in our study. LIM may help create a stable conscious sedation method for esophageal ESD.