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Rationale: Corticospinal tract (CST) and corticoreticular pathway (CRP) injury patterns (i.e., the continuity of the nerve fibers) are associated with gait disturbance in post-stroke patients. In this case series study, we examined the case of 3 patients with different CST and CRP injury patterns and analyzed the characteristics of gait disturbance in each patient., Patient Concerns: Patient 1 (P1) was a 73-year-old woman who presented with paralysis of the right upper and lower extremities due to a left lacunar infarction. Patient 2 (P2) was a 41-year-old man who presented with paralysis of the right upper and lower extremities due to a left putamen hemorrhage. Patient 3 (P3) was a 57-year-old man who presented with paralysis of the left upper and lower extremities due to a right putamen hemorrhage., Diagnosis: In P1, the CRP in the affected hemisphere was intact, but the CST was discontinuous. In P2, the CST in the affected hemisphere was intact, but the CRP was discontinuous. P3 was discontinuous in both CST and CRP in the affected hemisphere., Outcomes: Over time, all 3 patients improved to the level of gait independence, but they exhibited different gait patterns. Among them, P3 showed a markedly abnormal gait pattern that included spatiotemporal gait asymmetry, lateral shift of the trunk, and hip hiking., Lessons: This case series study demonstrated that even if both the CST and CRP were injured, gait recovered to some extent (i.e., independent level-ground gait), but the abnormal gait pattern might remain remarkable., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Epidemiological studies demonstrated that cleaning work and frequent use of cleaning products are risk factors for asthma. Laundry detergents have been reported to have epithelial barrier-opening effects. However, whether laundry detergents directly induce airway inflammation and its mechanisms in vivo remain to be elucidated., Methods: Two commercial laundry detergents and two commonly used surfactants for cleaning and cosmetics (sodium lauryl sulfate and sodium dodecyl benzene sulfonate) were intranasally administered to mice. Lungs were analyzed using flow cytometry, histology, ELISA, and quantitative PCR. Human bronchial epithelial cells were stimulated with laundry detergents and analyzed using quantitative PCR and western blotting. Involvement of oxidative stress was assessed using an antioxidant. Dust samples from homes were analyzed to determine their detergent content by measuring their critical micelle concentration (CMC)., Results: The administered laundry detergents and surfactants-induced eosinophilic airway inflammation accompanied by increased IL-33 expression and activation of group 2 innate lymphoid cells (ILC2s). Detergent-induced eosinophilic airway inflammation was significantly attenuated in Rag2 -/- Il2rg -/- , Il33 -/- mice, and also in wild-type mice treated with NAC. Detergent-induced IL-33 expression in airways was attenuated by NAC treatment, both in vivo and in vitro. CMCs were found in all of the tested dust extracts, and they differed significantly among the homes., Conclusion: The laundry detergents and surfactants-induced eosinophilic airway inflammation in vivo through epithelial cell and ILC2 activation. They induced IL-33 expression in airway epithelial cells through oxidative stress. Furthermore, detergent residues were present in house dust and are presumably inhaled into the airway in daily life., (© 2023 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Late braking force (LBF) is often observed in the late stance phase of the paretic lower limb of stroke patients. Nevertheless, the effects and association of LBF remain unclear. We examined the kinetic and kinematic parameters associated with LBF and its effect on walking. Herein, 157 stroke patients were enrolled. Participants walked at a comfortable speed selected by them, and their movements were measured using a 3D motion analysis system. The effect of LBF was analyzed as a linear relationship with spatiotemporal parameters. Multiple linear regression analyses were performed with LBF as the dependent variable and kinetic and kinematic parameters as independent variables. LBF was observed in 110 patients. LBF was associated with decreased knee joint flexion angles during the pre-swing and swing phases. In the multivariate analysis, trailing limb angle, cooperativity between the paretic shank and foot, and cooperativity between the paretic and non-paretic thighs were related to LBF (p < 0.01; adjusted R 2  = 0.64). LBF in the late stance phase of the paretic lower limb reduced gait performance in the pre-swing and swing phases. LBF was associated with trailing limb angle in the late stance, coordination between the paretic shank and foot in the pre-swing phase, and coordination between both thighs., (© 2023. The Author(s).)

Objectives: : It is unclear whether the increased center of mass lateral shift during gait induced by leg length difference induces lateral instability. The purpose of this study was to investigate the effect of leg length discrepancy (LLD) on dynamic gait stability and the compensatory kinematic and dynamic strategies for this effect by using the extrapolated center of mass and margin of stability., Methods: : Nineteen healthy male participants walked without insoles (no LLD condition; 0 cm) and with added insoles (LLD condition; 3 cm). Kinematic and kinetic data were analyzed using a three-dimensional motion analyzer and force plates; the values were compared between the two conditions. Correlation analysis was performed on the parameters and the margin of stability and significant changes were identified., Results: Compared with the no-LLD condition, in the LLD condition, lateral stability was maintained on both the short leg side and the long leg side. Nonetheless, changes in joint angles and muscle activity on the frontal plane were observed on the short leg side, although the correlations were not significant. On the long leg side, a moderate negative correlation was found between the lateral flexion angle of the trunk and the margin of stability ( r =-0.56, P=0.011)., Conclusions: The short leg side may compensate for lateral stability by complex changes in joint angles and muscle activity, and the long leg side may compensate for lateral stability by actively adjusting the trunk lateral flexion angle., Competing Interests: CONFLICTS OF INTEREST: The authors declare that they have no conflicts of interest., (2023 The Japanese Association of Rehabilitation Medicine.)

Fujii R, Tamari M, Nonaka Y, Tamiya F, Hosokawa H, Tanaka S. Influence of gait exercise using a walking-assist robot for swing-leg motion in hemiplegic stroke patients: A preliminary study focusing on the immediate effect. Jpn J Compr Rehabil Sci 2022; 13: 49-55., Objective: We analyzed the effect of gait training using a walking-assist robot that assists a subject's knee joint movement and leg swing to achieve toe clearance of the paralyzed-side lower limb during treadmill walking., Methods: The subjects were 10 hemiplegic stroke patients in a rehabilitation ward. The intervention consisted of gait training using the Welwalk WW-1000 (Welwalk) robot for 40 min. Immediately before and after this intervention, a gait analysis of the patients' treadmill walking was performed by a three-dimensional motion capture system. Statistical analyses compared the foot-to-floor distance and the shortening of hip-toe length (SHTL) of the paralyzed side before and after the intervention, and examined the relationship between the change of lower-limb joint kinematics and toe clearance before and after the intervention., Results: The post-intervention SHTL was significantly lower compared to before the intervention, and there was a significant negative correlation between the change in the SHTL and the knee flexion angle from before to after the intervention., Conclusion: Gait exercise using the Welwalk could contribute to the acquisition of more normal leg-swing strategies., Competing Interests: Conflict of interest: The authors declare that there is no conflict of interest., (©Kaifukuki Rehabilitation Ward Association 2022.)

Background: Adrenaline is the first-line medication for managing anaphylaxis. A better understanding of prescription trends for adrenaline auto-injectors (AAIs) is important to improving patient care as well as information on health education interventions and medical guidelines. However, it has been difficult to gather comprehensive data in a sustainable manner. Thus, we aimed to investigate trends in AAI prescriptions in Japan., Methods: We searched the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB), a unique and comprehensive database of health insurance claims, and investigated prescriptions for AAIs for all ages (April 2017 to March 2018). We assessed the annual number of prescriptions per person as well as prescription rates per 100,000 population per year by age, sex, and geographic region., Results: A total of 88,039 subjects (56,109 males, 31,930 female) and 116,758 devices (1.33 AAIs per patient per year) were prescribed AAIs at least once a year for all ages. The prescription rate for AAIs was 69.5 per 100,000 population-years. Patients aged 0-9 years were prescribed AAIs at the rate of 278.9 per 100,000 population-years. Patients aged 0-19 years were 6.4 times more likely to be prescribed AAIs than those over 20 years of age. Males were more frequently prescribed AAIs than females in all age groups, except for those aged 20-24 years. We also evaluated differences in prescription rates by geographic region., Conclusions: This comprehensive evaluation revealed trends in AAI prescriptions, thus helping develop preventive strategies with respect to anaphylaxis in Japan., (Copyright © 2022 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Chronic pruritus, or itch, is common and debilitating, but the neuroimmune mechanisms that drive chronic itch are only starting to be elucidated. Recent studies demonstrate that the IL-33 receptor (IL-33R) is expressed by sensory neurons. However, whether sensory neuron-restricted activity of IL-33 is necessary for chronic itch remains poorly understood., Objectives: We sought to determine if IL-33 signaling in sensory neurons is critical for the development of chronic itch in 2 divergent pruritic disease models., Methods: Plasma levels of IL-33 were assessed in patients with atopic dermatitis (AD) and chronic pruritus of unknown origin (CPUO). Mice were generated to conditionally delete IL-33R from sensory neurons. The contribution of neuronal IL-33R signaling to chronic itch development was tested in mouse models that recapitulate key pathologic features of AD and CPUO, respectively., Results: IL-33 was elevated in both AD and CPUO as well as their respective mouse models. While neuron-restricted IL-33R signaling was dispensable for itch in AD-like disease, it was required for the development of dry skin itch in a mouse model that mirrors key aspects of CPUO pathology., Conclusions: These data highlight how IL-33 may be a predominant mediator of itch in certain contexts, depending on the tissue microenvironment. Further, this study provides insight into future therapeutic strategies targeting the IL-33 pathway for chronic itch., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Platelets are thought to be involved in the pathophysiology of asthma, presumably through direct adhesion to inflammatory cells, including group 2 innate lymphoid cells (ILC2s). Here, we tried to elucidate the effects of platelet adhesion to ILC2s in vitro and in vivo, as well as the mechanisms involved., Methods: Alternaria-induced ILC2-dependent airway inflammation models using wild-type and c-mpl -/- mice were evaluated. Both purified CD41 + and CD41 - ILC2s were cultured with IL-2 and IL-33 to determine in vitro Type 2 (T2) cytokine production and cell proliferation. RNA-seq data of flow-cytometry-sorted CD41 + and CD41 - ILC2s were used to isolate ILC2-specific genes. Flow cytometry was performed to determine the expression of CD41 and adhesion-related molecules on ILC2s in both mouse and human tissues., Results: T2 inflammation and T2 cytokine production from ILC2s were significantly reduced in the c-mpl -/- mice compared to wild-type mice. Platelet-adherent ILC2s underwent significant proliferation and showed enhanced T2 cytokine production when exposed to IL-2 and IL-33. The functions of ILC2-specific genes were related to cell development and function. Upstream regulator analysis identified 15 molecules, that are thought to be involved in ILC2 activation. CD41 expression levels were higher in ILC2s from human PBMCs and mouse lung than in those from secondary lymphoid tissues, but they did not correlate with the P-selectin glycoprotein ligand-1 or CD24 expression level., Conclusion: Platelets spontaneously adhere to ILC2s, probably in the peripheral blood and airways, thereby potentiating ILC2s to enhance their responses to IL-33., (© 2021 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Yamada T, Ohta M, Tamari M. Effect of spasticity of the ankle plantar flexors on the walking speed of hemiplegic stroke patients after maximum walking speed exercises. Jpn J Compr Rehabil Sci 2021; 12: 64-69., Objective: This study examined the effect of ankle plantar flexor spasticity on the walking speed of hemiplegic stroke patients immediately following maximum walking speed exercises., Methods: A total of 23 hemiplegic stroke patients were divided into two groups based on the presence ( n = 13) or absence ( n = 10) of ankle plantar flexor spasticity on the paralyzed side. Gait speed, propulsive force during pre-swing, paretic side ankle plantar flexion movement during pre-swing, paretic side ankle dorsiflexion angle during the stance phase, angular velocity of paretic side dorsiflexion during the stance phase, paretic side trailing limb angle in the terminal stance, paretic side plantar flexion angle in the terminal stance, and the timing of maximum dorsiflexion of the ankle joint on the paretic side were measured before and after the maximum walking speed exercises, using a three-dimensional motion analyzer., Results: In the spasticity group, no significant improvement was observed in any of the categories. In contrast, in the non-spasticity group, significant improvement was observed in all categories, except for the paretic side ankle dorsiflexion angle., Conclusion: This study showed that maximum walking speed exercises immediately improved walking speed in hemiplegic stroke patients without ankle plantar flexor spasticity., (©Kaifukuki Rehabilitation Ward Association 2021.)

Discovery of innate lymphoid cells (ILCs), which are non-T and non-B lymphocytes that have no antigen-specific receptors, changed the classical concept of the mechanism of allergy, which had been explained mainly as antigen-specific acquired immunity based on IgE and Th2 cells. The discovery led to dramatic improvement in our understanding of the mechanism of non-IgE-mediated allergic inflammation. Numerous studies conducted in the past decade have elucidated the characteristics of each ILC subset in various organs and tissues and their ontogeny. We now know that each ILC subset exhibits heterogeneity. Moreover, the functions and activating/suppressing factors of each ILC subset were found to differ among both organs and types of tissue. Therefore, in this review, we summarize our current knowledge of ILCs by focusing on the organ/tissue-specific features of each subset to understand their roles in various organs. We also discuss ILCs' involvement in human inflammatory diseases in various organs and potential therapeutic/preventive strategies that target ILCs., (© 2021 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

ETS variant transcription factor 4 (ETV4) is a recently identified transcription factor that regulates gene expression-based biomarkers of asthma and IL6 production in an airway epithelial cell line. Given that ETV4 has not yet been implicated in asthma genetics, we performed genetic association studies of adult asthma in the ETV4 region using two independent Japanese cohorts (a total of 1532 controls and 783 cases). SNPs located between ETV4 and mesenchyme homeobox 1 (MEOX1) were significantly associated with adult asthma, including rs4792901 and rs2880540 (P = 5.63E-5 and 2.77E-5, respectively). The CC haplotype of these two SNPs was also significantly associated with adult asthma (P = 8.43E-7). Even when both SNPs were included in a logistic regression model, the association of either rs4792901 or rs2880540 remained significant (P = 0.013 or 0.007, respectively), suggesting that the two SNPs may have independent effects on the development of asthma. Both SNPs were expression quantitative trait loci, and the asthma risk alleles at both SNPs were correlated with increased levels of ETV4 mRNA expression. In addition, the asthma risk allele at rs4792901 was associated with increased serum IL6 levels (P = 0.041) in 651 healthy adults. Our findings imply that ETV4 is involved in the pathogenesis of asthma, possibly through the heightened production of IL6., (© 2021. The Author(s).)

Classically, skin was considered a mere structural barrier protecting organisms from a diversity of environmental insults. In recent decades, the cutaneous immune system has become recognized as a complex immunologic barrier involved in both antimicrobial immunity and homeostatic processes like wound healing. To sense a variety of chemical, mechanical, and thermal stimuli, the skin harbors one of the most sophisticated sensory networks in the body. However, recent studies suggest that the cutaneous nervous system is highly integrated with the immune system to encode specific sensations into evolutionarily conserved protective behaviors. In addition to directly sensing pathogens, neurons employ novel neuroimmune mechanisms to provide host immunity. Therefore, given that sensation underlies various physiologies through increasingly complex reflex arcs, a much more dynamic picture is emerging of the skin as a truly systemic organ with highly coordinated physical, immunologic, and neural functions in barrier immunology.

Pulmonary alveolar proteinosis (PAP) is a devastating lung disease caused by abnormal surfactant homeostasis, with a prevalence of 6-7 cases per million population worldwide. While mutations causing hereditary PAP have been reported, the genetic basis contributing to autoimmune PAP (aPAP) has not been thoroughly investigated. Here, we conducted a genome-wide association study of aPAP in 198 patients and 395 control participants of Japanese ancestry. The common genetic variant, rs138024423 at 6p21, in the major-histocompatibility-complex (MHC) region was significantly associated with disease risk (Odds ratio [OR] = 5.2; P = 2.4 × 10 -12 ). HLA fine-mapping revealed that the common HLA class II allele, HLA-DRB1*08:03, strongly drove this signal (OR = 4.8; P = 4.8 × 10 -12 ), followed by an additional independent risk allele at HLA-DPβ1 amino acid position 8 (OR = 0.28; P = 3.4 × 10 -7 ). HLA-DRB1*08:03 was also associated with an increased level of anti-GM-CSF antibody, a key driver of the disease (β = 0.32; P = 0.035). Our study demonstrated a heritable component of aPAP, suggesting an underlying genetic predisposition toward an abnormal antibody production.

Background: The aim of this study was to evaluate the safety and efficacy of low-dose everolimus treatment in patients with tuberous sclerosis complex (TSC)-associated angiomyolipoma (AML) with renal dysfunction or low body weight., Methods: We investigated a total of 50 adult patients underwent everolimus treatment for AML associated with TSC. For patients with renal dysfunction (serum creatinine level ≥ 1.5 mg/dl) or low body weight (body weight < 35 kg), 5 mg of everolimus was administered daily (low-dose group). For patients without renal dysfunction or low body weight, 10 mg of everolimus was administered daily (conventional-dose group). The treatment effects and adverse events were compared between the two groups., Results: There were 20 patients in the low-dose group, and 30 in the conventional-dose group. The average reduction rate of the AML volume in the low-dose group was 52%, whereas it was 60% in the conventional-dose group. No significant differences were found in the average reduction rate between the groups (P = 0.24). The average blood everolimus trough levels were 7.7 ± 3.1 ng/mL in the low-dose group and 12.2 ± 5.7 ng/mL in the conventional-dose group. The level was significantly higher in the conventional-dose group than in the low-dose group (P = 0.004). The incidences of stomatitis and irregular menstruation were significantly lower in the low-dose group than in the conventional-dose group (P = 0.009, P = 0.045, respectively)., Conclusions: The present study demonstrates that low-dose everolimus treatment is safe and effective for TSC-associated AML. This treatment was well tolerated and adverse events were mild in all cases.

Background: An orosomucoid-like 3 (ORMDL3)/gasdermin B (GSDMB) gene locus on chromosome 17q is consistently associated with childhood-onset asthma, which is highly atopic. As some evidence suggests the relationship between asthma and allergic sensitization reflects asthma patient susceptibility to augmented IgE responses driven by common environmental allergens rather than an increased asthma risk after allergen exposure, we aimed to determine any relationships between this locus region and childhood-onset adult asthma with regard to serum total IgE levels or allergic sensitization., Methods: We conducted a case-control association study using three independent Japanese populations (3869 total adults) and analyzed the ORs for association of rs7216389, an expression quantitative trait locus for ORMDL3/GSDMB, with adult asthma according to onset age. Additionally, associations between the rs7216389 genotype and total serum IgE levels or allergic sensitization was examined., Results: Rs7216389 was associated with both childhood-onset adult asthma (OR for asthmatic patients afflicted at the age of 10 years or younger = 1.61, p = 0.00021) and asthmatic patients with higher levels of total serum IgE (OR for asthmatic patients with IgE ≥1000IU/mL = 1.55, p = 0.0033). In both healthy controls and in the combined healthy and asthmatic individuals, rs7216389 was correlated with increased total serum IgE levels (p < 0.0005), but not allergic sensitization (p > 0.1)., Conclusions: ORMDL3/GSDMB is an important susceptibility gene for childhood-onset adult asthma in Japanese populations and this association is linked to elevated total serum IgE levels but not to allergic sensitization., (Copyright © 2020 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Silica crystals (silica), which are a major mineral component of volcanic ash and desert dust, contribute to the pathogenesis of pulmonary disorders such as asthma and fibrosis. Although administration of silica or sand dust to rodents exacerbates development of ovalbumin-induced or house dust mite-induced asthma-like airway inflammation, the detailed mechanisms remain unclear. Here, using murine models, we found that silica can induce IL-33 expression in pulmonary epithelial cells. IL-33, but not IL-25 or TSLP, and type 2 cytokines such as IL-5 and IL-13 were critically involved in silica's exacerbation of OVA-induced airway eosinophilia in mice. Innate lymphoid cells (ILCs), but not T, B or NKT cells, were also involved in the setting. Moreover, a scavenger receptor that recognized silica was important for silica's exacerbating effect. These observations suggest that IL-33 induced in epithelial cells by silica activates ILCs to produce IL-5 and/or IL-13, contributing to silica's exacerbation of OVA-induced airway eosinophilia in mice. Our findings provide new insight into the underlying mechanisms of exacerbation of pulmonary disorders such as asthma following inhalation of silica-containing materials such as volcanic ash and desert dust., Competing Interests: Declaration of competing interest The authors declare that they have no known competing interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Eosinophilic airway inflammation is one of the cardinal features of allergic airway diseases such as atopic asthma and allergic rhinitis. These childhood-onset conditions are mediated by allergen and allergen-specific IgE and often accompanied by other allergic diseases including food allergy and eczema. They can develop consecutively in the same patient, which is referred to as an allergic march. In contrast, some phenotypes of asthma, nonsteroidal anti-inflammatory drugs-exacerbated airway disease (N-ERD), chronic rhinosinusitis with nasal polyps (CRSwNP)/eosinophilic CRS and allergic bronchopulmonary aspergillosis/mycosis (ABPA/ABPM) are adult-onset airway diseases, which are characterized by prominent peripheral blood eosinophilia. Most of these conditions, except for ABPA/ABPM, are nonatopic, and the coexistence of multiple diseases, including an adult-onset eosinophilic systemic disease, eosinophilic granulomatosis with polyangiitis (EGPA), is common. In this review, we focus on eosinophil biology, genetics and clinical characteristics and the pathophysiology of adult-onset eosinophilic asthma, N-ERD, CRSwNP/eosinophilic CRS, ABPA/ABPM and EGPA, while exploring the common genetic, immunological and pathological conditions among these adult-onset eosinophilic diseases., (© 2020 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Purpose: Previous literature has shown that standing stability relies on the vestibular system; however, the neural correlates underlying standing stability remains unclear. This study aimed to investigate the neural correlates of standing stability using functional magnetic resonance imaging (fMRI) following galvanic vestibular stimulation (GVS)., Materials and Methods: Forty-five healthy right-handed healthy volunteers were included. Postural stability was measured using the modified Clinical Test of Sensory Interaction and Balance (mCTSIB), which measures swaying speed and area on hard and soft surfaces when the volunteer's eyes are open and closed. Functional activation as determined by the blood oxygenation level-dependent (BOLD) response, was measured during GVS using fMRI. We investigated the association between BOLD responses during GVS and postural stability., Results: Relative to rest, participants showed significantly higher BOLD signal during GVS in the parietal operculum, central operculum, and the opercular part of the inferior frontal gyrus. Moreover, functional activation in the central operculum was negatively correlated with standing stability, indexed using swaying speed when volunteers stood on a foam surface with their eyes closed., Conclusions: Our findings suggest that the neural correlates of standing stability involve greater functional activation in the central operculum.

Background: Adult-onset asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous diseases caused by complex gene-environment interactions. A functional single nucleotide polymorphism of cadherin-related family member 3 (CDHR3), known as a receptor of rhinovirus-C, is associated with childhood-onset asthma especially in atopic individuals., Objective: Here, we identified risk factors for adult-onset asthma and COPD, focusing on the impact of the CDHR3 variant in atopic individuals., Methods: We conducted a longitudinal, retrospective, observational cohort study of 1523 healthy adults with baseline examinations at Tsukuba Medical Center Hospital in 2008 and retrospectively identified new-onset, physician-diagnosed asthma or COPD from 2009 to 2018. We assessed risk factors by the Cox regression analysis. The impact of CDHR3 variant rs6967330 was also examined in individuals with pre-existing atopy., Results: Over 10 study years, 103 people developed airway diseases (79 asthma and 24 COPD; 52 females, average onset-age 55 years old, range 38-80). Higher body mass index (BMI) and lower forced expiratory volume in one second/forced vital capacity (FEV 1 /FVC) ratio were significant risk factors (BMI: HR 1.072 [95% CI 1.005-1.14], P = .034; FEV 1 /FVC ratio: HR 1.091 [1.044-1.14], P = .00011). Restriction to atopic individuals saw the A allele at rs6967330 and lower FEV 1 /FVC ratio to associate with adult-onset disease (A allele: HR 2.89 [1.57-5.20], P = .00062; FEV 1 /FVC ratio: HR 1.10 [1.04-1.17], P = .0010)., Conclusion and Clinical Relevance: Genetic susceptibility to rhinovirus-C infection in atopic individuals is a risk factor for chronic airway diseases even in later life., (© 2020 John Wiley & Sons Ltd.)

Strategic Outlook toward 2030: Japan's Research for Allergy and Immunology (Strategy 2030) is the national research strategy based on Japan's Basic Law on Measures Against Allergic Diseases, a first of its kind worldwide. This strategy was established by a multi-disciplinary committee consisting of administrators of the Ministry of Health, Labour and Welfare of Japan, young and senior experts from various research societies and associations, and representatives of patient and public groups. Whereas the issues of transition, integration, and international collaboration have yet to be solved in this research realm in Japan, identification of unmet needs, digitization of information and transparent procedures, and strategic planning for complex problems (a process dubbed MIERUKA by the Toyota Way) are crucial to share and tackle the same vision and goals. The committee developed three specific actions focusing on preemptive treatment, interdisciplinarity and internationality, and life stage. The real success of Strategy 2030 is made by the spontaneous contributions of doctors, dentists, veterinarians, and other medical professionals; basic and clinical research scientists, research supporters, and pharmaceutical/medical device companies; manufacturers of food, healthcare, and home appliances; and patients, their families, and the public. The hope is to establish a stable society in which people can live long, healthy lives, as free as possible from allergic and immunological diseases, at each individual life stage. This article is based on a Japanese review first reported in Arerugi, introduces the developmental process and details of Strategy 2030., (Copyright © 2020 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

[Purpose] The aim of this study was to determine if gait index predicts the efficacy of weight-support treadmill training (BWSTT) in hemiplegic stroke patients. [Participants and Methods] In total, 21 patients who had sustained a hemiplegic stroke, on an average 71 days prior, and could walk independently on level ground were included in the study. BWSTT was performed under 20% of bodyweight unloading at the maximum speed possible for each participant to a perceived level of fatigue of 15 on the 20-point Borg scale. The immediate effects of BWSTT were evaluated as the change in the following variables, calculated from 5 level ground gait cycles; walking speed and rate, root mean square, coefficient of variability, auto-correlation coefficient, and single leg stance time ratio. All indices were calculated from the triaxial accelerometer attached to the waist of the participant. Linear regression was used to identify predictive variables of BWSTT effectiveness. [Results] Only single leg stance time ratio on level ground was extracted as a predictor of BWSTT effectiveness. [Conclusion] Single leg stance time ratio was a predictive factor of improved gait symmetry after BWSTT and therefore, could be used as a factor to select patients who might benefit from BWSTT as a component of stroke rehabilitation., Competing Interests: There are no conflicts of interest to declare., (2020©by the Society of Physical Therapy Science. Published by IPEC Inc.)

The overwhelming majority of participants in current genetic studies are of European ancestry. To elucidate disease biology in the East Asian population, we conducted a genome-wide association study (GWAS) with 212,453 Japanese individuals across 42 diseases. We detected 320 independent signals in 276 loci for 27 diseases, with 25 novel loci (P < 9.58 × 10 -9 ). East Asian-specific missense variants were identified as candidate causal variants for three novel loci, and we successfully replicated two of them by analyzing independent Japanese cohorts; p.R220W of ATG16L2 (associated with coronary artery disease) and p.V326A of POT1 (associated with lung cancer). We further investigated enrichment of heritability within 2,868 annotations of genome-wide transcription factor occupancy, and identified 378 significant enrichments across nine diseases (false discovery rate < 0.05) (for example, NKX3-1 for prostate cancer). This large-scale GWAS in a Japanese population provides insights into the etiology of complex diseases and highlights the importance of performing GWAS in non-European populations.

Background: Tuberous sclerosis complex (TSC) is a rare autosomal dominant disorder forming hamartomas throughout the body. Facial angiofibromas (FAs) occur in 75% of TSC patients, which are often enlarged, impairing the appearance of the face, and reducing the patient's quality of life (QOL). The aim of this study was to characterize the impact of topical sirolimus treatment on the health-related QOL in patients with FA associated with TSC., Methods: We investigated a total of 33 patients who received sirolimus gel treatment for FA associated with TSC and assessed the changes in the health-related QOL using the Medical Outcomes Study 36-Item Short Form (SF-36) Health Survey. SF-36 surveys were performed before and after 3 months of treatment. The conditions of the patients after using the sirolimus gel were categorized into the following three categories: "improved," "unchanged," and "aggravated." Adverse events were investigated using the CTCAE v5.0-JCOG., Results: The median age of the patients was 25 (range 14-55) years. After 3 months of sirolimus gel treatment, three scale scores of the SF-36, vitality (VT), social function (SF), and mental health (MH), were significantly improved compared to before the treatment. The VT and SF in patients who had improved FA were significantly better than those in the other patients. There were no significant differences in any scale scores between patients with and without adverse events at 3 months after the initiation of sirolimus gel treatment., Conclusions: This is the first report regarding improved health-related quality of life in patients treated with sirolimus gel for FA associated with TSC by using the SF-36. The three scale scores associated with mental health were significantly improved compared to before the treatment. The health-related QOL in patients receiving sirolimus gel treatment is more strongly affected by the treatment efficacy than adverse events. Sirolimus gel treatment improves the health-related QOL in patients with FA associated with TSC.

[Purpose] Reports on the amount of unloading maximizing walking ability in patients with stroke are limited. The effect of body weight-supported treadmill training (BWSTT) in patients with stroke has not been clarified. We aimed to investigate the effects of unloading rate during BWSTT on the gait of patients with stroke and the relationship between BWSTT and walking ability on flat ground. [Participants and Methods] We performed BWSTT in 17 patients at three unloading rates: 0%, 20%, and 40%. Then, we examined the walking speed and rate, number of steps, single-leg support time ratio, and root mean square before and after unloading. Furthermore, we examined the relationship between walking ability on flat ground and immediate effects of BWSTT at each unloading rate. [Results] We observed no significant improvement under all conditions. However, walking ability improved at unloading rates of 20% and 40%, with poor temporal symmetry while walking on flat ground. [Conclusion] Our results revealed that BWSTT has diverse effects depending on the unloading rate and the ability to walk on flat ground. In particular, it tends to be highly effective for those who have poor sway and symmetry, which may serve as an index for prescribing BWSTT., (2020©by the Society of Physical Therapy Science. Published by IPEC Inc.)

Background: Food allergy is a growing health problem worldwide because of its increasing prevalence, life-threatening potential, and shortage of effective preventive treatments. In an outbreak of wheat allergy in Japan, thousands of patients had allergic reactions to wheat after using soap containing hydrolyzed wheat protein (HWP)., Objectives: The aim of the present study was to investigate genetic variation that can contribute to susceptibility to HWP allergy., Methods: We conducted a genome-wide association study of HWP allergy in 452 cases and 2700 control subjects using 6.6 million genotyped or imputed single nucleotide polymorphisms. Replication was assessed by genotyping single nucleotide polymorphisms in independent samples comprising 45 patients with HWP allergy and 326 control subjects., Results: Through the genome-wide association study, we identified significant associations with the class II HLA region on 6p21 (P = 2.16 × 10 -24 for rs9271588 and P = 2.96 × 10 -24 for HLA-DQα1 amino acid position 34) and with the RBFOX1 locus at 16p13 (rs74575857, P = 8.4 × 10 -9 ). The associations were also confirmed in the replication data set. Both amino acid polymorphisms (HLA-DQβ1 amino acid positions 13 and 26) located in the P4 binding pockets on the HLA-DQ molecule achieved the genome-wide significance level (P < 5.0 × 10 -8 )., Conclusions: Our data provide the first demonstration of genetic risk for HWP allergy and show that this genetic risk is mainly represented by multiple combinations of HLA variants., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Introduction: The color variations of ornamental flowers are often generated by ion-beam and gamma irradiation mutagenesis. However, mutation rates differ significantly even among cultivars of the same species, resulting in high cost and intensive labor for flower color breeding., Objectives: We aimed to establish a metabolome-based strategy to identify biomarkers and select promising parental lines with high mutation rates using Chrysanthemum as the case study., Methods: The mutation rates associated with flower color were measured in 10 chrysanthemum cultivars with pink, yellow, or white flowers after soft X-ray irradiation at the floret-formation stage. The metabolic profiles of the petals of these cultivars were clarified by widely targeted metabolomics and targeted carotenoid analysis using liquid chromatography-tandem quadrupole mass spectrometry. Metabolome and carotenoid data were subjected to an un-supervised principal component analysis (PCA) and a supervised logistic regression with least absolute shrinkage and selection operator (LASSO)., Results: The PCA of the metabolic profile data separated chrysanthemum cultivars according to flower color rather than mutation rates. By contrast, logistic regression with LASSO generated a discrimination model to separate cultivars into two groups with high or low mutation rates, and selected 11 metabolites associated with mutation rates that can be biomarkers candidates for selecting parental lines for mutagenesis., Conclusion: This metabolome-based strategy to identify metabolite markers for mutation rates associated with flower color might be applied to other ornamental flowers to accelerate mutation breeding for generating new cultivars with a wider range of flower colors.

Background: Group 2 innate lymphoid cells (ILC2s) play critical roles in induction and exacerbation of allergic airway inflammation. Thus clarification of the mechanisms that underlie regulation of ILC2 activation has received significant attention. Although innate lymphoid cells are divided into 3 major subsets that mirror helper effector T-cell subsets, counterpart subsets of regulatory T cells have not been well characterized., Objective: We sought to determine the factors that induce regulatory innate lymphoid cells (ILCregs)., Methods: IL-10 + ILCregs induced from ILC2s by using retinoic acid (RA) were analyzed with RNA-sequencing and flow cytometry. ILCregs were evaluated in human nasal tissue from healthy subjects and patients with chronic rhinosinusitis with nasal polyps and lung tissue from house dust mite- or saline-treated mice., Results: RA induced IL-10 secretion by human ILC2s but not type 2 cytokines. IL-10 + ILCregs, which were converted from ILC2s by means of RA stimulation, expressed a regulatory T cell-like signature with expression of IL-10, cytotoxic T lymphocyte-associated protein 4, and CD25, with downregulated effector type 2-related markers, such as chemoattractant receptor-homologous molecule on T H 2 cells and ST2, and suppressed activation of CD4 + T cells and ILC2s. ILCregs were rarely detected in human nasal tissue from healthy subjects or lung tissue from saline-treated mice, but numbers were increased in nasal tissue from patients with chronic rhinosinusitis with nasal polyps and in lung tissue from house dust mite-treated mice. Enzymes for RA synthesis were upregulated in airway epithelial cells during type 2 inflammation in vivo and by IL-13 in vitro., Conclusion: We have identified a unique immune regulatory and anti-inflammatory pathway by which RA converts ILC2s to ILCregs. Interactions between airway epithelial cells and ILC2s play an important roles in the generation of ILCregs., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Hyperprogression has recently been recognized as a new pattern of progression in patients undergoing immune checkpoint inhibitor treatment. Here, we report two cases that showed hyperprogression during the initial phase of pembrolizumab treatment for metastatic urothelial carcinoma. The first patient, who received pembrolizumab as a second-line treatment, developed severe respiratory failure due to the rapid progression of lung metastases on the ninth day after the third pembrolizumab treatment. The second patient developed jaundice and hepatic dysfunction due to the progression of a metastatic lymph node of the liver hilum after the first administration of pembrolizumab. She developed multiple brain metastases with intraventricular bleeding on the 10th day after the second administration of pembrolizumab. It is important to be aware that hyperprogression sometimes occurs quite a while after starting treatment, and that both pseudoprogression and hyperprogression may occur in the early stage of treatment., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The chitinase-like protein YKL-40 plays a major role in inhibiting the inflammasome. Deregulation of inflammasome activation is emerging as a key modulator of pathologic airway inflammation in patients with asthma. We determined whether cis-expression quantitative trait loci (eQTLs) of the gene that encodes YKL-40, chitinase 3-like 1 (CHI3L1), are involved in the onset of asthma or in specific asthma phenotypes., Methods: This case-control study, which was conducted at the University of Tsukuba, Japan, included a total of 2709 adults from the Tsukuba genome-wide association study (GWAS) cohort (734 healthy volunteers and 237 asthma patients), the Tsukuba replication cohort (375 healthy adult volunteers and 381 adult asthma patients), and the Hokkaido replication cohort (554 healthy adult volunteers and 428 adult asthma patients). Among 34 cis-eQTLs in CHI3L1 in the lung, rs946261 was associated with adult asthma in these Japanese cohorts. The genetic impact of rs946261 on asthma was also examined according to the age at onset and adult asthma clusters., Results: In the Tsukuba GWAS cohort, the C allele at rs946261 was significantly associated with reduced expression of CHI3L1 mRNA in the lung and with development of asthma (odds ratio (OR) 1.27; P = 0.036). The association was also observed following analysis of the three Japanese cohorts (OR 1.16; P = 0.013). A stronger association was found with late-onset asthma that developed at 41 years of age or later (OR 1.24; 95% confidence interval (CI) 1.07-1.45; P = 0.0058) and with a specific asthma phenotype characterized by late onset, less atopy, and mild airflow obstruction (OR 1.29; 95% CI 1.03-1.61; P = 0.027)., Conclusions: The genotype consisting of the cis-eQTL allele that reduces expression of CHI3L1 was specifically associated with late-onset adult asthma. Given the important role of YKL-40 in many pathophysiological processes, including cell growth, migration, chemotaxis, reorganization, and tissue remodeling, it may be involved in an important pathogenic role in the establishment of inflammation and remodeling in asthmatic airways. Our findings may indicate the presence of a specific endotype related to exaggerated activation of YKL-40 in the pathogenesis of late-onset adult asthma.

Background: TYRO3 is a member of the TAM (TYRO3, AXL, MERTK) receptor tyrosine kinase family and functions to limit type 2 immune responses implicated in allergic sensitization. Recent studies have shown that multiple intronic variants of TYRO3 were associated with asthma, implying that genetic variation could contribute to errant immune activation. We therefore hypothesized that expression quantitative trait loci (eQTLs) of the TYRO3 gene influence the development of allergic diseases (including asthma and allergic rhinitis) in Japanese populations., Methods: We performed a candidate gene case-control association study of 8 eQTLs of TYRO3 on atopy, asthma, and allergic rhinitis using 1168 unrelated Japanese adults who had GWAS genotyping. We then examined the genetic impact of rs2297377 (TYRO3) on atopy and allergic rhinitis in 2 other independent Japanese populations., Results: A meta-analysis of 3 Japanese populations (a total of 2403 Japanese adults) revealed that rs2297377 was associated with atopy and allergic rhinitis (OR = 1.29 and 1.31; P = 0.00041 and 0.0010, respectively). The risk allele at rs2297377 correlated with decreased expression of TYRO3 mRNA. The gene-gene interaction between HLA-DPB1 and TYRO3 was not significant with regard to sensitization. The estimated proportion of atopy and allergic rhinitis cases attributable to the risk genotype was 14% and 16%, respectively., Conclusions: Our study identified TYRO3 as an important susceptibility gene to atopy and allergic rhinitis in Japanese., (Copyright © 2018 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Background: The aim of this study was to evaluate the effects and the utility of second-line everolimus treatment for regrown renal angiomyolipoma (AML) with tuberous sclerosis complex (TSC) after transcatheter arterial embolization (TAE)., Methods: We investigated a total of 14 patients who underwent second-line everolimus treatment for TSC-AML that regrew after TAE, and assessed their effects and adverse events. Everolimus treatment was performed for AML with a maximum diameter of 4 cm. To determine the reduction ratio of AML, the volume of AML was measured using multislice helical computed tomography. Adverse events were evaluated according to CTCAE v4.0-JCOG. We further compared the treatment effect and adverse events with those in patients receiving first-line everolimus treatment., Results: The AML volume decreased in all patients, with a ≥ 50% volume decrease in 57% (8 of 14) of the cases, and the mean reduction rate was 53%. We observed no significant difference in the mean reduction rate of AML between second-line everolimus treatment for regrown TSC-AML after TAE and first-line everolimus treatment for TSC-AML. The adverse events were mild and consistent with those reported in our previous study., Conclusion: Although further studies are needed, everolimus appears to be effective as second-line treatment for TSC-AML that regrew after TAE and a beneficial treatment option for TSC-AML.

Many risk factors related to the development of non-alcoholic fatty liver disease (NAFLD) have been proposed, including the most well-known of diabetes and obesity as well as periodontitis. As periodontal pathogenic bacteria produce endotoxins, periodontal treatment can result in endotoxemia. The aim of this study was to investigate the effects of intravenous, sonicated Porphyromonas gingivalis ( Pg ) injection on glucose/lipid metabolism, liver steatosis, and gut microbiota in mice. Endotoxemia was induced in C57BL/6J mice (8 weeks old) by intravenous injection of sonicated Pg ; Pg was deactivated but its endotoxin remained. The mice were fed a high-fat diet and administered sonicated Pg (HFPg) or saline (HFco) injections for 12 weeks. Liver steatosis, glucose metabolism, and gene expression in the liver were evaluated. 16S rRNA gene sequencing with metagenome prediction was performed on the gut microbiota. Compared to HFco mice, HFPg mice exhibited impaired glucose tolerance and insulin resistance along with increased liver steatosis. Liver microarray analysis demonstrated that 1278 genes were differentially expressed between HFco and HFPg mice. Gene set enrichment analysis showed that fatty acid metabolism, hypoxia, and TNFα signaling via NFκB gene sets were enriched in HFPg mice. Although sonicated Pg did not directly reach the gut, it changed the gut microbiota and decreased bacterial diversity in HFPg mice. Metagenome prediction in the gut microbiota showed enriched citrate cycle and carbon fixation pathways in prokaryotes. Overall, intravenous injection of sonicated Pg caused impaired glucose tolerance, insulin resistance, and liver steatosis in mice fed high-fat diets. Thus, blood infusion of Pg contributes to NAFLD and alters the gut microbiota.

Variable responsiveness to zileuton, a leukotriene antagonist used to treat asthma, may be due in part to genetic variation. While individual SNPs were previously associated with zileuton-related lung function changes, specific quantitative trait loci (QTLs) and biological pathways that may contribute have not been identified. In this study, we investigated the hypothesis that genetic variation within biological pathways is associated with zileuton response. We performed an integrative QTL mapping and pathway enrichment study to investigate data from a GWAS of zileuton response, in addition to mRNA expression profiles and leukotriene production data from lymphoblastoid cell lines (LCLs) (derived from asthmatics) that were treated with zileuton or ethanol (control). We identified 1060 QTLs jointly associated with zileuton-related differential LTB 4 production in LCLs and lung function change in patients taking zileuton, of which eight QTLs were also significantly associated with persistent LTB 4 production in LCLs following zileuton treatment (i.e., 'poor' responders). Four nominally significant trans-eQTLs were predicted to regulate three candidate genes (SELL, MTF2, and GAL), the expression of which was significantly reduced in LCLs following zileuton treatment. Gene and pathway enrichment analyses of QTL associations identified multiple genes and pathways, predominantly related to phosphatidyl inositol signaling via PI3K. We validated the PI3K pathway activation status in a subset of LCLs demonstrating variable zileuton-related LTB 4 production, and show that in contrast to LCLs that responded to zileuton, the PI3K pathway was activated in poor responder LCLs. Collectively, these findings demonstrate a role for the PIK3 pathway and its targets as important determinants of differential responsiveness to zileuton.

Chitin, which is a major component of house dust mites (HDM), fungi, crustaceans, etc., can activate immune cells, suggesting that it contributes to development of allergic disorders such as asthma. Although the pathophysiological sensitization route of asthmatic patients to allergens is considered via the respiratory tract, the roles of intranasally-administered chitin in development of asthma remain unclear. After ovalbumin (OVA) challenge, development of airway inflammation was profoundly exacerbated in mice sensitized with OVA in the presence of chitin. The exacerbation was dependent on IL-33, but not IL-25, thymic stromal lymphopoietin or IL-17A. Chitin enhanced IL-33-dependent IL-1β production by dendritic cells (DCs). Furthermore, chitin- and IL-33-stimulated DC-derived IL-1β promoted OVA-specific Th2 cell activation, resulting in aggravation of OVA-induced airway inflammation. These findings indicate the adjuvant activity of chitin via a new mechanism and provide important clues for development of therapeutics for allergic disorders caused by HDM, fungi and crustaceans.

Background: Direct contact of food proteins with eczematous lesions is thought to be the main cause of epicutaneous sensitization. To further investigate the development and pathogenesis of food allergy in vivo, a good mouse model of epicutaneous sensitization is needed. However, a fundamental problem in that regard is that the optimal age for epicutaneous sensitization of mice is unknown. In this study, we attempted to elucidate that optimal age., Methods: Dorsal skin of wild-type BALB/c female mice (1, 3, 8 and 24 weeks old) was shaved, depilated and tape-stripped. A Finn chamber containing a 20-μl-aliquot of 20-mg/ml (OVA) was applied to the tape-stripped skin on 3 consecutive days/week, for 3 weeks. The body temperature was measured after intraperitoneal OVA challenge. Serum OVA-specific IgE titers and OVA-induced cytokine production by spleen cells were measured by ELISA. Dendritic cells (DCs) that migrated to the draining lymph nodes were quantified by FITC-labeled OVA and flow cytometry. The mRNA expression levels in the dorsal skin were measured by qPCR., Results: A significant age-dependent body temperature decline was observed after OVA challenge. The serum OVA-specific IgE titer, OVA-induced cytokine production (i.e., IL-4, IL-5 and IL-13) by spleen cells, and number of FITC-OVA-engulfing DCs increased with age. In addition, mRNA for IL-33, but not TSLP or IL-25, was significantly induced in the skin by tape-stripping and increased with age., Conclusions: Twenty-four-week-old mice showed the greatest DC migration, Th2 polarization, IgE production and body temperature decline. Skin-derived IL-33 is likely to play key roles in those changes., (Copyright © 2018 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

[Purpose] To clarify the relationship between white matter fiber damage and the Ability for Basic Movement Scale (ABMS) II in patients with stroke in a diffusion tensor tract-based spatial statistic study. [Subjects and Methods] Twelve patients with stroke (seven men and five women, mean age ± SD: 61.6 ± 8.5 years) were evaluated using the ABMS II. The patients were divided into the ABMS II good group and the ABMS II poor group. Tract-based spatial statistical analysis was performed using diffusion tensor images in both groups. [Results] Patients in the ABMS II good group had significantly higher fractional anisotropy values of the anterior thalamic radiation (ATR), superior longitudinal fasciculus (SLF), inferior occipitofrontal fasciculus (IOF), and uncinate fasciculus (UF) of the lesion-containing hemisphere than patients in the ABMS II poor group. [Conclusion] ATR, SLF, and IOF damage may affect ABMS II scores in patients with stroke.

Psoriasis vulgaris (PsV) is an autoimmune disease of skin and joints with heterogeneity in epidemiologic and genetic landscapes of global populations. We conducted an initial genome-wide association study and a replication study of PsV in the Japanese population (606 PsV cases and 2,052 controls). We identified significant associations of the single nucleotide polymorphisms with PsV risk at TNFAIP3-interacting protein 1and the major histocompatibility complex region (P = 3.7 × 10 -10 and 6.6 × 10 -15 , respectively). By updating the HLA imputation reference panel of Japanese (n = 908) to expand HLA gene coverage, we fine-mapped the HLA variants associated with PsV risk. Although we confirmed the PsV risk of HLA-C*06:02 (odds ratio = 6.36, P = 0.0015), its impact was relatively small compared with those in other populations due to rare allele frequency in Japanese (0.4% in controls). Alternatively, HLA-A*02:07, which corresponds to the cysteine residue at HLA-A amino acid position 99 (HLA-A Cys99), demonstrated the most significant association with PsV (odds ratio = 4.61, P = 1.2 × 10 -10 ). In addition to HLA-A*02:07 and HLA-C*06:02, stepwise conditional analysis identified an independent PsV risk of HLA-DQβ1 Asp57 (odds ratio = 2.19, P = 1.9 × 10 -6 ). Our PsV genome-wide association study in Japanese highlighted the genetic architecture of PsV, including the identification of HLA risk variants., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)