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Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread rapidly since 2019, and the number of reports regarding long COVID has increased. Although the distribution of long COVID depends on patient characteristics, epidemiological data on Japanese patients are limited. Hence, this study aimed to investigate the distribution of long COVID in Japanese patients. This study is the first nationwide Japanese prospective cohort study on long COVID., Methods: This multicenter, prospective cohort study enrolled hospitalized COVID-19 patients aged ≥18 years at 26 Japanese medical institutions. In total, 1200 patients were enrolled. Clinical information and patient-reported outcomes were collected from medical records, paper questionnaires, and smartphone applications., Results: We collected data from 1066 cases with both medical records and patient-reported outcomes. The proportion of patients with at least one symptom decreased chronologically from 93.9% (947/1009) during hospitalization to 46.3% (433/935), 40.5% (350/865), and 33.0% (239/724) at 3, 6, and 12 months, respectively. Patients with at least one long COVID symptom showed lower quality of life and scored higher on assessments for depression, anxiety, and fear of COVID-19. Female sex, middle age (41-64 years), oxygen requirement, and critical condition during hospitalization were risk factors for long COVID., Conclusions: This study elucidated the symptom distribution and risks of long COVID in the Japanese population. This study provides reference data for future studies of long COVID in Japan., Competing Interests: Conflict of Interest Norihiro Harada reports personal fees from AstraZeneca K.K., GlaxoSmithKline, Kyorin, Novartis Japan, Sanofi and grants from AstraZeneca, Daikin, Kyorin, SRL Medisearch, outside the submitted work. Other authors have no conflicts of interest., (Copyright © 2023. Published by Elsevier B.V.)

This study provides the first evidence that a Li ion can form ionic plastic crystals using crown ether with a bis-(trifluoromethanesulphonyl) amide (TFSA) anion. 1 H, 7 Li, and 13 C nuclear-magnetic-resonance (NMR) measurements of the 15-crown-5-Li-TFSA complex revealed that the constituents underwent isotropic reorientation in the plastic crystalline phase. The NMR data of the 12-crown-4-Li-TFSA salt showed that the complex is a rotator crystal (the complexes are denoted as [Li 15C5] and [Li 12C4] in this paper). The X-ray diffraction (XRD) reflection patterns of the [Li 15C5] crystal recorded in the highest-temperature solid phase (plastic phase) could be indexed to a cubic structure. Conversely, [Li 12C4] could be fitted to a trigonal structure. In this study, [M (3 n )C n ] (M = Li, Na, K; n = 4-6) complexes were also prepared, and NMR, DSC, XRD, and electrical conductivity measurements were performed. Based on these results, we additionally revealed that the [Na 15C5] and [K (15C5) 2 ] complexes are also new rotator crystals. Single-crystal XRD measurements also revealed that the [Na 15C5] compound has two stable sites in the crystal. Activation energies of molecular motions in the [M (3 n )C n ] crystals were estimated using 1 H NMR relaxation time ( T 1 and T 2 ) measurements. The electrical conductivity measurements of [Li 12C4], [Li 15C5], and [Na 15C5] showed high ionic conductivities (∼10 -2 S cm -1 ).

Autoreactive B cells are assumed to play a critical role in pemphigus; however, the characteristics of these cells are not yet fully understood. In this study, 23 pemphigus vulgaris or pemphigus foliaceus samples were used to isolate circulating desmoglein (DSG)-specific B cells. Transcriptome analysis of the samples was performed at the single-cell level to detect genes involved in disease activity. DSG1- or DSG3-specific B cells from three patients' differentially expressed genes related to T cell costimulation (CD137L) as well as B-cell differentiation (CD9, BATF, TIMP1) and inflammation (S100A8, S100A9, CCR3), compared with nonspecific B cells from the same patients. When the DSG1-specific B cells before and after treatment transcriptomes of the patient with pemphigus foliaceus were compared, there were changes in several B-cell activation pathways not detected in non-DSG1-specific B cells. This study clarifies the transcriptomic profile of autoreactive B cells in patients with pemphigus and documents the gene expression related to disease activity. Our approach can be applied to other autoimmune diseases and has the potential for future detection of disease-specific autoimmune cells., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background/objectives: Glucose tolerance is controlled by the internal clock and is worse in the evening. From a chrononutrition perspective, diabetes prevention requires evaluating the antidiabetic effects of the timing of functional ingredients and nutrient intake. The purpose of this study was to investigate the timing effects of acute mulberry leaf extract (MLE) intake on postprandial glucose levels in young adults., Subjects/methods: Twelve young adults underwent four trials. Blood samples were collected in a fasting state and at 30, 60, 120, and 180 min after eating a mixed meal. The study had a randomised, placebo-controlled, double-blind trial design involving: (1) morning placebo trial (08:00 h; MP trial), (2) evening placebo trial (18:00 h; EP trial), (3) morning MLE trial (08:00 h; MM trial), and (4) evening MLE trial (18:00 h; EM trial)., Results: The incremental area under the blood glucose curve (iAUC) in the EM trials was significantly lower than that in the EP trials (P = 0.010). The postprandial glucose concentrations 120 min after the meal were significantly lower in the EM trials than those in the EP trials (P = 0.006). The postprandial insulin concentrations at 120 min were significantly lower in the MM trials than those in the MP trials (P = 0.034). Moreover, the postprandial insulin concentrations 180 min after the meal were significantly lower in the EM trials than those in the EP trials (P = 0.034)., Conclusions: MLE intake in the evening, but not in the morning, was effective in improving glucose tolerance., Trial Registration: Clinical trial reference: UMIN 000045301; website of trial registry: https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000051340 ., (© 2023. The Author(s).)

Pemphigus is an autoimmune disease that causes blistering and erosion of the skin and mucous membranes because of autoantibodies against desmoglein, which plays an important role in adhesion between epidermal keratinocytes. Treatment of pemphigus has long been centered on corticosteroids, and the guidelines for management of pemphigus have recommended high-dose systemic corticosteroids as the first-line treatment. While guideline-based treatment has been shown to be beneficial in patients with pemphigus, it has also become clear that this treatment is accompanied by significant burden and risk. The challenge for future pemphigus treatment is to maximize efficacy while minimizing risk during the course of the disease. In this regard, treatment targeting B cells is expected to become increasingly important as autoreactive B cells in pemphigus patients are thought to play a major role in the production of autoantibodies, which form the basis of the pathogenesis. The recent expansion of insurance coverage to rituximab, a monoclonal antibody against CD20, for refractory pemphigus in the USA, Europe, and Japan has opened up a new era of pemphigus treatment by enabling treatment strategies with drugs targeting B cells in patients. Here, we discuss the current status and future prospects of pemphigus treatment, focusing on rituximab and Bruton's tyrosine kinase inhibitors, which are expected to become essential drugs for pemphigus treatment in the future., (© 2022 The Author. The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.)

This was a multicenter clinical trial of rituximab, a chimeric monoclonal IgG antibody directed against CD20, for the treatment of refractory pemphigus vulgaris and pemphigus foliaceus. In total, 20 patients were treated with two doses of rituximab (1000 mg; 2 weeks apart) on days 0 and 14. The primary end point was the proportion of patients who achieved complete or partial remission on day 168 following the first rituximab dose. Of the 20 enrolled patients, 11 (55%) and four (20%) achieved complete and partial remission, respectively; therefore, remission was achieved in a total of 15 patients (75.0% [95% confidence interval, 50.9%-91.3%]). It was demonstrated that the remission rate was greater than the prespecified threshold (5%). In addition, a significant improvement in clinical score (Pemphigus Disease Area Index) and decrease in serum anti-desmoglein antibody level were observed over time. Four serious adverse events (heart failure, pneumonia, radial fracture, and osteonecrosis) were recorded in two patients, of which only pneumonia was considered causally related with rituximab. The level of peripheral blood CD19-positive B lymphocytes was decreased on day 28 after rituximab treatment and remained low throughout the study period until day 168. Our results confirm the efficacy and safety of rituximab therapy for refractory pemphigus in Japanese patients., (© 2022 The Authors. The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.)

Pemphigus and pemphigoid are autoimmune blistering diseases that affect mucosa and skin. Several clinical scoring systems, including the pemphigus disease area index (PDAI) and the bullous pemphigoid disease area index (BPDAI), have been validated for managing disease activity and severity. Current guidelines recommend that treatment response be evaluated with clinical scores and that additional second-line therapies be considered if initial treatment is insufficient for disease control. However, there have been few studies analyzing correlations between PDAI/BPDAI transitions and initial treatment effects. To investigate whether PDAI/BPDAI transitions during the treatment initiation phase correlate with initial treatment responses and whether such information can be used as a guide for necessary additional treatment, we retrospectively analyzed 67 pemphigus patients and 47 pemphigoid patients who received initial treatment at Keio University between 2012 and 2018. The clinical symptoms were evaluated weekly with PDAI/BPDAI. The patients were divided into two groups: in group A, disease was controlled only with oral corticosteroids and immunosuppressants (initial treatment), whereas in group B additional therapies were required due to insufficient responses. In pemphigus, the PDAI ratio of day 7/day 0 was significantly reduced in group A compared to group B (0.548 vs 0.761, P < 0.01) after initial treatment had started. In pemphigoid, the ratios of day 7/day 0 of BPDAI (erosion/blister) and BPDAI (urticaria/erythema) significantly decreased in group A compared to group B (0.565 vs 0.901 and 0.350 vs 0.760, respectively, P < 0.05). Receiver operating characteristic analyses on PDAI, BPDAI (erosion/blister) and BPDAI (urticaria/erythema) revealed that the cut-off values in the ratios of day 7/day 0 were 0.762, 0.675, and 0.568, respectively. Our results suggest that PDAI/BPDAI transitions during the initial phase of the treatments may be useful to predict the outcome of the treatment provided and the necessity of additional therapies to achieve disease control., (© 2022 Japanese Dermatological Association.)

Intravenous Ig (IVIG) is a treatment option for intractable cases of pemphigus vulgaris (PV), an autoimmune blistering disease caused by autoantibodies against desmoglein 3 (DSG3). To investigate the efficacy of IVIG on autoantibody secretion, we produced PV model mice by adoptive transfer of immunized Dsg3 -/- splenocytes to Rag2 -/- mice. We found that circulating anti-DSG3 IgG ELISA titer decreased in PV model mice after 5 days of treatment with IVIG compared with PBS-treated mice, whereas the F(ab') 2 fragment did not suppress the anti-DSG3 IgG titer. enzyme-linked immunospot assay revealed that IVIG treatment reduced the frequency of anti-DSG3 antibody-secreting cells in the spleen but not in lymph nodes and bone marrow. Moreover, this reduction was observed only in the splenic B220 - fraction but not in the B220 + fraction. Furthermore, IVIG decreased the serum levels of anti-DSG3 IgG, even after a significant reduction of its titer, owing to antibody-mediated CD20 + B cell depletion. In addition, IVIG suppressed anti-DSG3 IgG production in B220 - CD138 + plasma cells derived from PV model mice ex vivo. These results indicate that IVIG reduced autoantibody production in B220 - cells containing plasma cells in PV model mice, and this function may indicate one of the mechanisms of action of IVIG on PV., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Pemphigus vulgaris is an autoimmune blistering disease caused by IgG targeting desmoglein 3 (Dsg3), an adhesion molecule of keratinocytes. Anti-Dsg3 IgG production is prevented in healthy individuals, but it is unclear how Dsg3-specific B cells are regulated. To clarify the immunological condition regulating Dsg3-specific B cells, a pathogenic anti-Dsg3 Ig (AK23) knock-in mouse was generated. AK23 knock-in B cells developed normally without undergoing deletion or acquiring an anergic phenotype in vivo. The knock-in B cells showed Ca 2+ influx upon IgM cross-linking and differentiated into AK23-IgG + B cells after LPS and IL-4 stimulation in vitro that induced a pemphigus phenotype after adoptive transfer into Rag2 -/- mice. However, the knock-in mouse itself produced AK23-IgM but little IgG without blisters in vivo. Dsg3 immunization and skin inflammation caused AK23-IgG production and a pemphigus phenotype in vivo. Furthermore, Fcgr2b deficiency or haploinsufficiency spontaneously induced AK23-IgG production and a pemphigus phenotype with poor survival rates in AK23 knock-in mice. To assess Fcgr2b involvement in Ig class-switch efficiency, postswitch transcripts of B cells were quantified and significantly higher in Fcgr2b -/- and Fcgr2b +/- mice than wild-type mice in a gene dose-dependent manner. Finally, RNA sequencing revealed reduced expression of FCGR2B and FcγRIIB-related genes in patient B cells. These results indicated that Dsg3-specific B cells do not spontaneously perform pathogenic class switching in vivo, and pemphigus phenotype induction was prevented under normal conditions. Attenuated FcγRIIB signaling is also one of the drivers for pathogenic class switching and is consistent with immunological features identified from clinical samples. This study unveiled a characteristic immune state silencing autoreactive B cells in mice., (Copyright © 2022 by The American Association of Immunologists, Inc.)

Antigen-specific peripheral tolerance is crucial to prevent the development of organ-specific autoimmunity. However, its function decoupled from thymic tolerance remains unclear. We used desmoglein 3 (Dsg3), a pemphigus antigen expressed in keratinocytes, to analyze peripheral tolerance under physiological antigen-expression conditions. Dsg3-deficient thymi were transplanted into athymic mice to create a unique condition in which Dsg3 was expressed only in peripheral tissue but not in the thymus. When bone marrow transfer was conducted from high-avidity Dsg3-specific T cell receptor-transgenic mice to thymus-transplanted mice, Dsg3-specific CD4 + T cells developed in the transplanted thymus but subsequently disappeared in the periphery. Additionally, when Dsg3-specific T cells developed in Dsg3 -/- mice were adoptively transferred into Dsg3-sufficient recipients, the T cells disappeared in an antigen-specific manner without inducing autoimmune dermatitis. However, Dsg3-specific T cells overcame this disappearance and thus induced autoimmune dermatitis in Treg-ablated recipients but not in Foxp3 -mutant recipients with dysfunctional Tregs. The molecules involved in disappearance were sought by screening the transcriptomes of wild-type and Foxp3 -mutant Tregs. OX40 of Tregs was suggested to be responsible. Consistently, when OX40 expression of Tregs was constrained, Dsg3-specific T cells did not disappear. Furthermore, Tregs obtained OX40L from dendritic cells in an OX40 -dependent manner in vitro and then suppressed OX40L expression in dendritic cells and Birc5 expression in Dsg3-specific T cells in vivo. Lastly, CRISPR/Cas9-mediated knockout of OX40 signaling in Dsg3-specific T cells restored their disappearance in Treg-ablated recipients. Thus, Treg-mediated peripheral deletion of autoreactive T cells operates as an OX40 -dependent regulatory mechanism to avoid undesired autoimmunity besides thymic tolerance., Competing Interests: The authors declare no competing interest.

Autoimmune bullous diseases (AIBDs) are skin disorders which are mainly induced by autoantibodies against desmosomal or hemidesmosomal structural proteins. Previous studies using patients' samples and animal disease models identified target antigens and elucidated the mechanisms of blister formation. Pemphigus has been the subject of more active clinical and basic research than any other AIBD. These efforts have revealed the pathogenesis of pemphigus, which in turn has led to optimal diagnostic methods and novel therapies, such as rituximab. In bullous pemphigoid (BP), studies with passive-transfer mouse models using rabbit anti-mouse BP180 antibodies and studies with passive-transfer or active mouse models using autoantigen-humanized mice elucidated the immune reactions to BP180 in vivo. Recently, dipeptidyl peptidase-4 inhibitors have attracted attention as a trigger for BP. For epidermolysis bullosa acquisita (EBA), investigations using mouse models are actively under way and several molecules have been identified as targets for novel therapies. In this review, we give an overview and discussion of the recent progress in our understanding of the pathogenesis of pemphigus, BP, and EBA. Further studies on the breakdown of self-tolerance and on the identification of key molecules that are relevant to blister formation may expand our understanding of the etiology of AIBDs and lead to the development of novel therapeutic strategies., Competing Interests: Declaration of competing interests The authors have no conflicts of interest to declare., (Copyright © 2021 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

Purpose: To investigate whether a correction based on a Humphrey field analyzer (HFA) 24-2/30-2 visual field (VF) can improve the prediction performance of a deep learning model to predict the HFA 10-2 VF test from macular optical coherence tomography (OCT) measurements., Methods: This is a multicenter, cross-sectional study. The training dataset comprised 493 eyes of 285 subjects (407, open-angle glaucoma [OAG]; 86, normative) who underwent HFA 10-2 testing and macular OCT. The independent testing dataset comprised 104 OAG eyes of 82 subjects who had undergone HFA 10-2 test, HFA 24-2/30-2 test, and macular OCT. A convolutional neural network (CNN) DL model was trained to predict threshold sensitivity (TH) values in HFA 10-2 from retinal thickness measured by macular OCT. The predicted TH values was modified by pattern-based regularization (PBR) and corrected with HFA 24-2/30-2. Absolute error (AE) of mean TH values and mean absolute error (MAE) of TH values were compared between the CNN-PBR alone model and the CNN-PBR corrected with HFA 24-2/30-2., Results: AE of mean TH values was lower in the CNN-PBR with HFA 24-2/30-2 correction than in the CNN-PBR alone (1.9dB vs. 2.6dB; P = 0.006). MAE of TH values was lower in the CNN-PBR with correction compared to the CNN-PBR alone (4.2dB vs. 5.3 dB; P < 0.001). The inferior temporal quadrant showed lower prediction errors compared with other quadrants., Conclusions: The performance of a DL model to predict 10-2 VF from macular OCT was improved by the correction with HFA 24-2/30-2., Translational Relevance: This model can reduce the burden of additional HFA 10-2 by making the best use of routinely performed HFA 24-2/30-2 and macular OCT.

Introduction: The rapid spread of COVID-19 posed a global burden. Substantial number of people died of the disease in the acute phase of infection. In addition, a significant proportion of patients have been reported to suffer from post-acute phase symptoms, sequelae of COVID-19, which may negatively influence the quality of daily living and/or socioeconomic circumstances of the patients. However, no previous study has comprehensively and objectively assessed the quality of life of patients by using existing international scales. Further, evidence of socioeconomic consequences among patients with COVID-19 is scarce. To address the multidimensional issues from sequelae of COVID-19, evidence from comprehensive surveys beyond clinical perspectives is critical that investigates health, and social determinants of disease progression as well as socioeconomic consequences at a large scale., Methods and Analysis: In this study, we plan to conduct a nationwide and comprehensive survey for the sequelae of COVID-19 in a total of 1000 patients diagnosed at 27 hospitals throughout Japan. This study will evaluate not only the health-related status of patients from clinical perspectives but also the Health-related Quality of Life (HRQoL) scores, socioeconomic status and consequences to discuss the sequelae of the disease and the related risk factors. The primary endpoint is the frequency of long-term complications of COVID-19 infection. The secondary endpoints are risk factors for progression to sequelae of COVID-19 infection. The study will provide robust and important evidence as a resource to tackle the issues from the sequelae of COVID-19 from the multi-dimensional perspectives., Ethics and Dissemination: This trial was approved by the Keio University School of Medicine Ethics Committee (20200243, UMIN000042299). The results of this study will be reported at a society meeting or published in a peer-reviewed journal., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: We constructed a multitask learning model (latent space linear regression and deep learning [LSLR-DL]) in which the 2 tasks of cross-sectional predictions (using OCT) of visual field (VF; central 10°) and longitudinal progression predictions of VF (30°) were performed jointly via sharing the deep learning (DL) component such that information from both tasks was used in an auxiliary manner (The Association for Computing Machinery's Special Interest Group on Knowledge Discovery and Data Mining [SIGKDD] 2021). The purpose of the current study was to investigate the prediction accuracy preparing an independent validation dataset., Design: Cohort study., Participants: Cross-sectional training and testing data sets included the VF (Humphrey Field Analyzer [HFA] 10-2 test) and an OCT measurement (obtained within 6 months) from 591 eyes of 351 healthy people or patients with open-angle glaucoma (OAG) and from 155 eyes of 131 patients with OAG, respectively. Longitudinal training and testing data sets included 7984 VF results (HFA 24-2 test) from 998 eyes of 592 patients with OAG and 1184 VF results (HFA 24-2 test) from 148 eyes of 84 patients with OAG, respectively. Each eye had 8 VF test results (HFA 24-2 test). The OCT sequences within the observation period were used., Methods: Root mean square error (RMSE) was used to evaluate the accuracy of LSLR-DL for the cross-sectional prediction of VF (HFA 10-2 test). For the longitudinal prediction, the final (eighth) VF test (HFA 24-2 test) was predicted using a shorter VF series and relevant OCT images, and the RMSE was calculated. For comparison, RMSE values were calculated by applying the DL component (cross-sectional prediction) and the ordinary pointwise linear regression (longitudinal prediction)., Main Outcome Measures: Root mean square error in the cross-sectional and longitudinal predictions., Results: Using LSLR-DL, the mean RMSE in the cross-sectional prediction was 6.4 dB and was between 4.4 dB (VF tests 1 and 2) and 3.7 dB (VF tests 1-7) in the longitudinal prediction, indicating that LSLR-DL significantly outperformed other methods., Conclusions: The results of this study indicate that LSLR-DL is useful for both the cross-sectional prediction of VF (HFA 10-2 test) and the longitudinal progression prediction of VF (HFA 24-2 test)., (© 2021 by the American Academy of Ophthalmology.)

Importance: Neonatal linear immunoglobulin A (IgA) bullous dermatosis (LABD) is a rare disease that can be fatal when associated with respiratory failure. All previously reported cases of neonatal LABD have been in newborns with healthy asymptomatic mothers, and the pathogenic IgA was of unknown origin., Objective: To clarify the origin of IgA associated with LABD in neonates born of healthy asymptomatic mothers., Design, Setting, and Participants: This case study analyzed the laboratory findings of a single breast-fed newborn male with neonatal LABD admitted to the Keio University Hospital in Tokyo and his healthy asymptomatic mother. The healthy newborn developed life-threatening blisters and erosions of the skin and mucous membranes on day 4 after birth. Blood serum, skin, and maternal breast milk were examined for IgA autoantibodies., Main Outcomes and Measures: Histopathologic and immunofluorescence analyses of specimens (serum, skin, and breast milk) from the patient and his mother., Results: Histopathologic evaluation of the newborn's skin revealed subepidermal blisters with neutrophil infiltrates, and immunofluorescence testing showed linear IgA deposition along the basement membrane zone (BMZ), which lead to the diagnosis of neonatal LABD. Indirect immunofluorescence using normal human skin after treatment with 1-mol/L sodium chloride showed the patient to have circulating IgA binding to the dermal side of BMZ. Immunohistochemical staining proved the deposition of secretory IgA in the neonatal skin by demonstrating the presence of J chain-not been seen in other LABD cases-indicating that the autoantibodies producing the blisters were derived from the maternal breast milk. Although no circulating IgA against the skin was detected in mother's sera, the breast milk contained IgA that reacted with the dermal side of the BMZ. No new blister formation was observed after cessation of breastfeeding., Conclusions and Relevance: The results of this case study suggest a passive transfer of pathogenic IgA to a newborn from an asymptomatic mother via breast milk. In prior reports, no serum from asymptomatic mothers of newborns with LABD had IgA autoantibodies binding to skin components; however, in this case, we found that the maternal breast milk contained IgA autoantibodies associated with neonatal LABD. In neonatal LABD, maternal breast milk should be examined for IgA autoantibodies and breast milk feeding should be discontinued as soon as neonatal LABD is suspected.

Background: The treatment of pemphigus is based on systemic corticosteroid use and adjuvant therapies, but some patients are resistant to conventional therapy. Tirabrutinib is a highly selective oral Bruton's tyrosine kinase inhibitor that may be clinically effective in treating pemphigus by suppressing B-cell signaling., Objective: We investigated the efficacy and safety of tirabrutinib in patients with refractory pemphigus., Methods: This was a multicenter, open-label, single-arm phase 2 study of Japanese patients with refractory pemphigus receiving appropriate treatment with an oral corticosteroid and adjuvant therapies. Patients received postprandial oral tirabrutinib 80 mg once daily for 52 weeks. After 16 weeks of tirabrutinib treatment, the corticosteroid dose was tapered to ≤10 mg/day of prednisolone equivalent., Results: In total, 16 patients were evaluated (mean age, 52.5 years; 50 % male). The complete remission rate after 24 weeks of treatment (primary endpoint) was 18.8 % (3/16; 95 % confidence interval, 6.6 %-43.0 %). By Week 52, eight patients (50.0 %) achieved complete remission and 10 patients (62.5 %) achieved remission. Over 52 weeks of treatment, the mean prednisolone dose decreased from 17.03 to 7.65 mg/day. Incidences of adverse events (AEs) and adverse drug reactions were 87.5 % and 43.8 %, respectively. A relationship with tirabrutinib was ruled out for all serious AEs and Grade ≥3 AEs., Conclusion: Treatment with tirabrutinib enabled remission and reduced oral corticosteroid exposure over time and did not result in any major safety concerns in patients with refractory pemphigus. Thus, oral tirabrutinib may be a new treatment option for patients with refractory pemphigus., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background/aim: To train and validate the prediction performance of the deep learning (DL) model to predict visual field (VF) in central 10° from spectral domain optical coherence tomography (SD-OCT)., Methods: This multicentre, cross-sectional study included paired Humphrey field analyser (HFA) 10-2 VF and SD-OCT measurements from 591 eyes of 347 patients with open-angle glaucoma (OAG) or normal subjects for the training data set. We trained a convolutional neural network (CNN) for predicting VF threshold (TH) sensitivity values from the thickness of the three macular layers: retinal nerve fibre layer, ganglion cell layer+inner plexiform layer and outer segment+retinal pigment epithelium. We implemented pattern-based regularisation on top of CNN to avoid overfitting. Using an external testing data set of 160 eyes of 131 patients with OAG, the prediction performance (absolute error (AE) and R 2 between predicted and actual TH values) was calculated for (1) mean TH in whole VF and (2) each TH of 68 points. For comparison, we trained support vector machine (SVM) and multiple linear regression (MLR)., Results: AE of whole VF with CNN was 2.84±2.98 (mean±SD) dB, significantly smaller than those with SVM (5.65±5.12 dB) and MLR (6.96±5.38 dB) (all, p<0.001). Mean of point-wise mean AE with CNN was 5.47±3.05 dB, significantly smaller than those with SVM (7.96±4.63 dB) and MLR (11.71±4.15 dB) (all, p<0.001). R 2 with CNN was 0.74 for the mean TH of whole VF, and 0.44±0.24 for the overall 68 points., Conclusion: DL model showed considerably accurate prediction of HFA 10-2 VF from SD-OCT., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

We aimed to develop a model to predict visual field (VF) in the central 10 degrees in patients with glaucoma, by training a convolutional neural network (CNN) with optical coherence tomography (OCT) images and adjusting the values with Humphrey Field Analyzer (HFA) 24-2 test. The training dataset included 558 eyes from 312 glaucoma patients and 90 eyes from 46 normal subjects. The testing dataset included 105 eyes from 72 glaucoma patients. All eyes were analyzed by the HFA 10-2 test and OCT; eyes in the testing dataset were additionally analyzed by the HFA 24-2 test. During CNN model training, the total deviation (TD) values of the HFA 10-2 test point were predicted from the combined OCT-measured macular retinal layers' thicknesses. Then, the predicted TD values were corrected using the TD values of the innermost four points from the HFA 24-2 test. Mean absolute error derived from the CNN models ranged between 9.4 and 9.5 B. These values reduced to 5.5 dB on average, when the data were corrected using the HFA 24-2 test. In conclusion, HFA 10-2 test results can be predicted with a OCT images using a trained CNN model with adjustment using HFA 24-2 test.

To compare the occurrence of disc hemorrhages (DH) and glaucoma progression in open-angle glaucoma (OAG) patients with different glaucomatous disc types. Prospective, hospital-based, observational cohort study. OAG patients examined between 2000 and 2005, whose discs were classified as typical myopic glaucomatous (MG), generalized enlargement of cup (GE), or focal glaucomatous (FG) disc type were included and followed for 5 years. The first occurrence of DH during follow-up was analyzed using Kaplan-Meier analysis and difference in DH occurrence based on glaucomatous disc type using the Cox proportional-hazards model to adjust for effects of confounding factors. For inter-group comparison of glaucoma progression, the change rate of the mean deviation, Collaborative Initial Glaucoma Treatment Study scores, and fundus photographs were used. Thirty-nine patients with MG-, 18 with FG-, and 17 with GE-disc types were included. No significant inter-group difference was seen in the rate of glaucoma progression. The five-year probability of DH occurrence was much lower with MG- than with FG- or GE-disc types (P < 0.0220). The central corneal thickness (P = 0.0024) and mean intraocular pressure and its variations (P = 0.0450, 0.0219) contributed to DH occurrence. The MG-disc type demonstrated a much lower DH occurrence during follow-up than other disc types.

Anti-desmoglein (Dsg) 1 and Dsg3 IgG autoantibodies in pemphigus foliaceus and pemphigus vulgaris cause blisters through loss of desmosomal adhesion. It is controversial whether blister formation is due to direct inhibition of Dsg, intracellular signaling events causing desmosome destabilization, or both. Recent studies show that heterophilic binding between Dsg and desmocollin (Dsc) is the fundamental adhesive unit of desmosomes. To eliminate cellular contributions to potential pathogenicity of pemphigus antibodies, bead assays coated with recombinant Dsg1, Dsc1, Dsg3, or Dsc3 ectodomains were developed. A mixture of Dsg beads and Dsc beads formed large aggregates, confirming that the heterophilic binding is dominant. The pathogenic anti-Dsg1 and anti-Dsg3 mAbs, which bind the transadhesive interface, blocked the aggregation of Dsg1/Dsc1 and Dsg3/Dsc3 beads, respectively, whereas nonpathogenic mAbs did not. All sera tested from eight patients with pemphigus foliaceus and eight patients with mucosal pemphigus vulgaris with active disease inhibited the adhesion of Dsg1/Dsc1 and Dsg3/Dsc3 beads, respectively. When paired sera obtained from seven patients with pemphigus foliaceus and six patients with pemphigus vulgaris in active disease and remission were compared, the former inhibited aggregation better than the latter. These findings strongly suggest that steric hindrance of heterophilic transinteraction between Dsg and Dsc is important for disease pathology in both pemphigus foliaceus and pemphigus vulgaris., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To predict the visual field (VF) of glaucoma patients within the central 10° from optical coherence tomography (OCT) measurements using deep learning and tensor regression., Design: Cross-sectional study., Methods: Humphrey 10-2 VFs and OCT measurements were carried out in 505 eyes of 304 glaucoma patients and 86 eyes of 43 normal subjects. VF sensitivity at each test point was predicted from OCT-measured thicknesses of macular ganglion cell layer + inner plexiform layer, retinal nerve fiber layer, and outer segment + retinal pigment epithelium. Two convolutional neural network (CNN) models were generated: (1) CNN-PR, which simply connects the output of the CNN to each VF test point; and (2) CNN-TR, which connects the output of the CNN to each VF test point using tensor regression. Prediction performance was assessed using 5-fold cross-validation through the root mean squared error (RMSE). For comparison, RMSE values were also calculated using multiple linear regression (MLR) and support vector regression (SVR). In addition, the absolute prediction error for predicting mean sensitivity in the whole VF was analyzed., Results: RMSE with the CNN-TR model averaged 6.32 ± 3.76 (mean ± standard deviation) dB. Significantly (P < .05) larger RMSEs were obtained with other models: CNN-PR (6.76 ± 3.86 dB), SVR (7.18 ± 3.87 dB), and MLR (8.56 ± 3.69 dB). The absolute mean prediction error for the whole VF was 2.72 ± 2.60 dB with the CNN-TR model., Conclusion: The Humphrey 10-2 VF can be predicted from OCT-measured retinal layer thicknesses using deep learning and tensor regression., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: We recently reported on the usefulness of retinal artery trajectory in estimating the magnitude of retinal stretch due to myopia. The purpose of the present study was to elucidate the relationship between the peripapillary retinal artery angle (PRAA) and thickness of the macular ganglion cell-inner plexiform layer (GCIPL)., Methods: This r included 138 healthy eyes of 79 subjects older than 20 years of age without any known eye disease. GCIPL thickness was separated into eight sectors according to quadrant and eccentricity from the fovea. The PRAA was calculated as the angle between the superior and inferior retinal arteries. Relationships between whole GCIPL thickness (average and sectorial) and the values of PRAA and axial length (AL) were investigated using a linear mixed model., Results: Average GCIPL thickness in the whole scanned area decreased significantly with narrowing of the PRAA with and without adjusting for AL. Sectorized macular GCIPL thickness also decreased significantly, with narrowing of the PRAA in seven out of the eight with the adjustment of AL, the exception being the inferior peripheral temporal sector., Conclusions: Macular GCIPL thickness decreased significantly with narrowing of the PRAA on average and in seven out of eight sectors.

Purpose: To compare structure-function relationships based on the Drasdo and Sjöstrand retinal ganglion cell displacement models., Methods: Single eyes from 305 patients with glaucoma and 55 heathy participants were included in this multicenter, cross-sectional study. The ganglion cell and inner plexiform layer (GCIPL) thickness was measured using spectral domain optical coherence tomography. Visual field measurements were performed using the Humphrey 10-2 test. All A-scan pixels (128 × 512 pixels) were allocated to the closest 10-2 location with both displacement models using degree and millimeter scales. Structure-function relationships were investigated between GCIPL thickness and corresponding visual sensitivity in nonlong (160 eyes) and long (200 eyes) axial length (AL) groups., Results: In both the nonlong and long AL groups, compared with the no-displacement model, both the Drasdo and the Sjöstrand models showed that the structure-function relationship around the fovea improved (P < 0.05). The magnitude of improvement in the area was either comparable between the model or was larger for the Drasdo model than the Sjöstrand model (P < 0.05). Meanwhile, structure-function relationships outside the innermost retinal region that were based on the Drasdo and Sjöstrand models were comparable to or were even worse than (in the case of the Drasdo model) those obtained using the no-displacement model., Conclusions: Structure-function relationships evaluated based on both the Drasdo and Sjöstrand models significantly improved around the fovea, particularly when using the Drasdo model. This was not the case in other areas.

Autoimmune bullous skin diseases, such as pemphigus and pemphigoid, may enable clarification of the mechanisms of immune regulation in the skin. Pemphigus and pemphigoid are mediated by essentially IgG autoantibodies against structural proteins of the desmosomes at cell-cell junctions and hemidesmosomes at epidermal-dermal junctions, respectively, and are characterized by blisters and erosions in the skin and/or mucous membranes. Intensive investigation over the last 3 decades has identified their target antigens and developed serological diagnostic tools as well as mouse models to help us understand their pathophysiology. Based on these advances, several new therapeutic approaches have become available, and more effective and less toxic targeted approaches are under development., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Several European countries recently developed international diagnostic and management guidelines for pemphigus, which have been instrumental in the standardization of pemphigus management., Objective: We now present results from a subsequent Delphi consensus to broaden the generalizability of the recommendations., Methods: A preliminary survey, based on the European Dermatology Forum and the European Academy of Dermatology and Venereology guidelines, was sent to a panel of international experts to determine the level of consensus. The results were discussed at the International Bullous Diseases Consensus Group in March 2016 during the annual American Academy of Dermatology conference. Following the meeting, a second survey was sent to more experts to achieve greater international consensus., Results: The 39 experts participated in the first round of the Delphi survey, and 54 experts from 21 countries completed the second round. The number of statements in the survey was reduced from 175 topics in Delphi I to 24 topics in Delphi II on the basis of Delphi results and meeting discussion., Limitations: Each recommendation represents the majority opinion and therefore may not reflect all possible treatment options available., Conclusions: We present here the recommendations resulting from this Delphi process. This international consensus includes intravenous CD20 inhibitors as a first-line therapy option for moderate-to-severe pemphigus., (Copyright © 2020. Published by Elsevier Inc.)

The pemphigoid group is a category of autoimmune subepidermal blistering diseases in which autoantibodies deposit linearly at the epidermal basement membrane zone (BMZ). The main subtypes of pemphigoid mediated by immunoglobulin G autoantibodies are bullous pemphigoid (BP), mucous membrane pemphigoid (MMP) and epidermolysis bullosa acquisita (EBA). To establish the first guidelines approved by the Japanese Dermatological Association for the management of pemphigoid diseases, the Committee for Guidelines for the Management of Pemphigoid Diseases (Including EBA) was founded as part of the Study Group for Rare Intractable Skin Diseases under the Ministry of Health, Labor and Welfare Research Project on Overcoming Intractable Diseases. These guidelines aim to provide current information for the management of BP, MMP and EBA in Japan. Based on evidence, the guidelines summarize the clinical and immunological manifestations, pathophysiologies, diagnostic criteria, disease severity determination criteria, treatment algorithms and treatment recommendations. Because of the rarity of these diseases, there are few clinical studies with a high degree of evidence, so several parts of these guidelines were established based on the opinions of the Committee. To further optimize these guidelines, periodic revision in line with the new evidence is necessary., (© 2019 Japanese Dermatological Association.)

Autoimmune diseases are devastating conditions in which the immune system is directed against the host, leading to life-threatening destruction of organs. Although autoantigens are ill-defined in most autoimmune diseases, this is not the case in the skin. Autoimmune bullous diseases have been extensively studied with detailed characterization of autoantigens, the epitopes that are targeted, and the mechanisms of action that mediate autoimmune tissue destruction. Pemphigus is an autoimmune bullous disease caused by circulating IgG that targets two desmosomal proteins, desmoglein 1 and 3, which are crucial for cell-cell adhesion of keratinocytes. Binding of auto-antibodies to desmogleins impairs keratinocyte adhesion, leading to severe blistering disease. Mouse models that recapitulate the human disease have been instrumental in elucidating the detailed pathophysiology. Taking advantage of the fact that desmogleins are specifically targeted in pemphigus, studying humoral and cellular autoimmunity against these autoantigens provides us with an opportunity to understand not only the effector mechanisms of B and T cells in mediating pathology but also how autoreactive lymphocytes are regulated during development in the thymus and post-development in the periphery. This review introduces pemphigus and its subtypes as prototypic autoimmune diseases from which recent basic and translational developments should provide insight into how autoimmunity develops., (© The Japanese Society for Immunology. 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: With the increased use of targeted therapies in oncology, dermatological adverse events (dAEs) have drawn attention. Because the face is crucial for human identity and social interactions, facial dAEs have significant impact on a patient's quality of life. This study aimed to explore patients' experience with regard to the management of targeted oncological therapy-induced facial dAEs., Methods: In this qualitative study, 20 patients at a university hospital in Japan with advanced/metastatic cancer and targeted therapy-induced facial dAEs were individually interviewed to collect data. Thematic analysis was used to analyze the data., Results: Patients with cancer and targeted oncological therapy-induced facial dAEs who were referred to the Department of Dermatology had certain expectations from specialist services. Three key themes were identified: professional input and advice, empathetic commitment to individual management, and integrated care across specialties., Conclusions: The referred patients with cancer and facial dAEs needed more in-depth information and advice from dermatological services and were reassured by the empathetic commitment to individual management in integrated care across specialties. These findings suggest that attention to the patient's perspective with a "sick person first" attitude and a collaborative effort across different specialties is important to minimize the effects of facial dAEs on the quality of life of patients with cancer.

Purpose: We sought to construct and evaluate a deep learning (DL) model to diagnose early glaucoma from spectral-domain optical coherence tomography (OCT) images., Design: Artificial intelligence diagnostic tool development, evaluation, and comparison., Methods: This multi-institution study included pretraining data of 4316 OCT images (RS3000) from 1371 eyes with open angle glaucoma (OAG) regardless of the stage of glaucoma and 193 normal eyes. Training data included OCT-1000/2000 images from 94 eyes of 94 patients with early OAG (mean deviation > -5.0 dB) and 84 eyes of 84 normal subjects. Testing data included OCT-1000/2000 from 114 eyes of 114 patients with early OAG (mean deviation > -5.0 dB) and 82 eyes of 82 normal subjects. A DL (convolutional neural network) classifier was trained using a pretraining dataset, followed by a second round of training using an independent training dataset. The DL model input features were the 8 × 8 grid macular retinal nerve fiber layer thickness and ganglion cell complex layer thickness from spectral-domain OCT. Diagnostic accuracy was investigated in the testing dataset. For comparison, diagnostic accuracy was also evaluated using the random forests and support vector machine models. The primary outcome measure was the area under the receiver operating characteristic curve (AROC)., Results: The AROC with the DL model was 93.7%. The AROC significantly decreased to between 76.6% and 78.8% without the pretraining process. Significantly smaller AROCs were obtained with random forests and support vector machine models (82.0% and 67.4%, respectively)., Conclusion: A DL model for glaucoma using spectral-domain OCT offers a substantive increase in diagnostic performance., (Copyright © 2018 Elsevier Inc. All rights reserved.)

This was a multicenter study of rituximab, a chimeric monoclonal immunoglobulin G antibody directed against CD20, for the treatment of refractory autoimmune bullous diseases (pemphigus and pemphigoid). Ten patients (three with pemphigus vulgaris, six with pemphigus foliaceus and one with bullous pemphigoid) were treated with a single cycle of rituximab (four weekly infusions at a dose of 375 mg/m 2 of body surface area). The primary end-points were the number of serious adverse events and rate of complete remission at 40 weeks. Five patients (50%) achieved complete remission with minimal therapy (defined as no active lesions with lower doses of systemic corticosteroids compared to that with prednisolone 10 mg/day). Improvements in clinical scores (Pemphigus Disease Area Index) and decreases in autoantibody titers in the sera were observed in the four pemphigus patients who failed to achieve complete remission. This suggests that rituximab was effective in nine of 10 cases. Two serious adverse events (Pneumocystis carinii pneumonia and septic shock due to infectious arthritis) were observed and adequately treated with hospitalization. CD19-positive B lymphocytes in the peripheral blood decreased on day 29 following rituximab treatment, and remained at low levels throughout the observation period (280 days). Our results confirmed the efficacy of rituximab therapy for refractory autoimmune bullous diseases in Japan., (© 2018 Japanese Dermatological Association.)

The 5th Scientific Conference of the International Pemphigus and Pemphigoid Foundation (IPPF), "Pemphigus and Pemphigoid: A New Era of Clinical and Translational Science" was held in Orlando, Florida, on May 15-16, 2018. Scientific sessions covered recent, ongoing, and future clinical trials in pemphigus and bullous pemphigoid, disease activity and quality of life instruments, and the IPPF Natural History Study. Furthermore, the meeting provided an opportunity to hear firsthand from patients, investigators, and industry about their experience enrolling for clinical trials.

Pemphigus and pemphigoid are characterized as autoimmune blistering diseases in which immunoglobulin G autoantibodies cause blisters and erosions of the skin or mucosa or both. Recently, understanding of the pathophysiology of pemphigus and pemphigoid has been furthered by genetic analyses, characterization of autoantibodies and autoreactive B cells, and elucidation of cell-cell adhesion between keratinocytes. For the management of pemphigus and pemphigoid, the administration of systemic corticosteroids still represents the standard treatment strategy; however, evidence of the efficacy of therapies not involving corticosteroids, such as those employing anti-CD20 antibodies, is increasing. The goal should be to develop antigen-specific immune suppression-based treatments., Competing Interests: No competing interests were disclosed.Competing interests: Soner Uzun has published with Jun Yamagami once in the last 3 years on an international consensus paper on the diagnosis and management of pemphigus (doi: http://dx.doi.org/10.1016/j.jaad.2018.02.021).No competing interests were disclosed.

The purpose of the study was to investigate whether the structure-function relationship in glaucomatous and normative eyes is improved by considering photoreceptor layer thickness. Humphrey 10-2 visual fields (VF) and optical coherence tomography were carried out in 615 eyes of 391 subjects, including 100 eyes of 53 healthy controls and 515 eyes of 338 glaucoma patients. The relationship between mean VF sensitivity and the thickness of the retinal nerve fiber layer (RNFL) and ganglion cell layer and inner plexiform layer (GCL + IPL) was analyzed using linear mixed models, by glaucoma status and degree of myopia. The structure-function relationship was also analyzed by supplementing the RNFL and GCL + IPL thickness with the thicknesses of: (i) the inner nuclear layer and outer plexiform layer (INL + OPL); (ii) the outer nuclear layer and inner segment of photoreceptor layer (ONL + ISL); (iii) the outer segment layer of photoreceptor and retinal pigment epithelium (OSL + RPE). The model included total thickness of RNFL, GCL + IPL and OSL + RPE was highly more optimal than the model that only included the total thickness of RNFL and GCL + IPL, in all subsets of eyes by glaucoma status and degree of myopia.

Vancomycin (VCM) is known to induce linear IgA bullous dermatosis (LAD). However, in contrast to conventional LAD, in which circulating IgA autoantibodies against basement membrane proteins are commonly detected, patient sera from VCM-induced LAD yields negative results in indirect immunofluorescence microscopy, and the targeted autoantigen remains undetermined. By using sera from a typical patient with VCM-induced LAD, we identified that co-incubation of sera with VCM resulted in linear IgA deposition at the basement membrane zone by indirect immunofluorescence. Patient sera reacted with the dermal side of 1 mol/L NaCl-split skin and with the recombinant noncollagenous (i.e., NC1) domain of type VII collagen by both immunoblot and ELISA in the presence of VCM. The investigation of an additional 13 patients with VCM-induced LAD showed that 10 out of the 14 sera (71.4%) reacted with the NC1 domain of type VII collagen by ELISA when spiked with VCM, whereas only 4 (28.6%) tested positive without it. The enhancement of reactivity to NC1 by VCM, as determined by optical density via ELISA, was observed in 10 out of the 14 sera (71.4%). These findings indicate that type VII collagen is a target autoantigen in VCM-induced LAD and that VCM mediates IgA autoreactivity against type VII collagen, providing an insight into mechanisms involved in drug-induced autoimmune disease., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To investigate the structure-function mapping in the central 10° by relating Humphrey field analyzer (HFA) 10-2 visual field (VF) and circumpapillary retinal nerve fiber layer (cpRNFL) thickness from spectral-domain optical coherence tomography (SD-OCT). We also compared the obtained results with a previously reported mapping between 10-2 VF and the optic disc., Methods: In 151 eyes of 151 POAG patients and 35 eyes from 35 healthy participants, cpRNFL thickness measurements were obtained using SD-OCT and the 10-2 VF was measured with the HFA. The relationship between visual sensitivity and cpRNL thickness values in the temporal 180° was analyzed using least absolute shrinkage and selection operator (LASSO) regression. The optic disc angle corresponding to each VF test point was then derived using the coefficients from the optimal LASSO regression., Results: The structure-function map obtained was largely consistent with the mapping reported previously; superior central VF test points correspond to a more vulnerable area of the optic disc, more distant toward the inferior pole from the center of the temporal quadrant (9:00 o'clock for the right eye) while inferior VF test points correspond closer to the center of the temporal quadrant. The prediction error tended to be large in the 'more vulnerable area' in the map reported previously., Conclusions: The structure-function map obtained largely confirms the previously reported map; however, some important differences were observed.

The purpose of the present study was to investigate the effect of different durations of half-time re-warm up (RW) on intermittent sprint performance. Using a randomized crossover design, 13 healthy men performed three trials, which consisted of two, 40-min intermittent exercises separated by a 15-min half-time. Half-time interventions were 15 min of seated rest (Control), 7 min of cycling at 70% of maximal heart rate (HR max ) (7 min RW), and 3 min of cycling at 70% of HR max (3 min RW). The second 40-min intermittent exercise as an exercise performance test was the Cycling Intermittent-Sprint Protocol (CISP), which consisted of 10 s of rest, 5 s of maximal sprint, and 105 s of low-intensity exercise at 50% of VO 2max , with the cycles repeated over the 40-min duration. The mean work during the maximal sprint in the initial 10 min of the CISP was higher in the both RW trials than in the control trial (control: 3638 ± 906 J, 7 min RW: 3808 ± 949 J, p < 0.05, 3 min RW: 3827 ± 960 J, p < 0.05). There were no significant differences among three trials for mean work at 10-20, 20-30, and 30-40 min of the CISP. In the initial 10 min of the CISP, the change in oxygenated hemoglobin concentration during the 105 s of exercise at 50% of VO 2max , oxygen uptake, carbon dioxide production, and respiratory exchange ratio were higher in both RW trials than in the control trial (p < 0.05). The rating of perceived exertion after half-time interventions was higher in both RW trials than in the control trial (p < 0.05). In conclusion, the 3 min RW increased intermittent sprint performance after the half-time, compared with a traditional passive half-time practice, and was as effective in improving intermittent sprint performance as the 7 min RW.

This corrects the article DOI: 10.1038/nrdp.2018.13.

Azathioprine (AZP) is used as a corticosteroid (CS)-sparing medication to treat autoimmune blistering diseases. In this study, we examined the efficacy of AZP and the feasibility of using AZP monotherapy (without CS) to treat pemphigus and pemphigoid. We performed a retrospective study of 10 Japanese patients (seven with pemphigus and three with pemphigoid) with mild to moderate disease activity who had been treated using AZP. The treatment efficacy was evaluated based on decreases in the disease activity scores and autoantibody titers. The results demonstrate that seven out of 10 cases (70%) were treated successfully using AZP monotherapy with no severe adverse effects. The disease activity scores of the successfully-treated patients decreased to zero after 1-37.5 months (average, 11.9) and the average disease activity scores in these cases decreased significantly at 2 months (38.2 ± 36.6%) compared with the scores of the three patients who required additional systemic CS therapy (77.5 ± 3.5%) (P < 0.05). Additionally, the autoantibody titers of five cases treated successfully using AZP decreased by half at 6 months. In conclusion, our findings suggest that AZP monotherapy is a viable treatment option for mild to moderate pemphigus and pemphigoid., (© 2017 Japanese Dermatological Association.)

Yanaoka, T, Yamagami, J, Kidokoro, T, Kashiwabara, K, and Miyashita, M. Halftime rewarm-up with intermittent exercise improves the subsequent exercise performance of soccer referees. J Strength Cond Res 32(1): 211-216, 2018-This study investigated the effect of halftime rewarm-up (RW) with intermittent exercise on the subsequent exercise performance of soccer referees, determined by the Yo-Yo Intermittent Recovery Test level 1 (Yo-Yo IR1). Using a randomized cross-over design, 10 male referees were required to complete 2 trials. The trials consisted of the Loughborough Intermittent Shuttle Test, halftime, and Yo-Yo IR1 periods. During halftime, participants either rested on a chair (Control) or performed a halftime RW exercise for 15 minutes. The halftime RW protocol comprised 2.15 minutes of seated rest, followed by 2.15 minutes of running at 70% of the maximum heart rate (HRmax)-this cycle of recovery and running was repeated for a total of 13 minutes. The halftime RW protocol started at 1 minute after the commencement of the halftime period and concluded 1 minute before its end. The Yo-Yo IR1 performance, blood glucose, free fatty acids (FFAs), triglycerides (TGs), creatine kinase (CK), and lactate concentrations, the rating of perceived exertion, mean HR, and HRmax were analyzed. The Yo-Yo IR1 performance was higher in the halftime RW trial than in the control trial (3,095 ± 326 vs. 2,904 ± 421 m, P ≤ 0.05). The mean HR and HRmax, blood glucose, FFA, TG, CK, and lactate concentrations did not differ between the trials. The rating of perceived exertion during the halftime RW, but not after the Yo-Yo IR1 period, was higher than that in the control trial. In conclusion, this study showed that halftime RW with intermittent exercise improves the subsequent exercise performance.

Transmembrane collagen XVII (COL17) is a hemidesmosomal component of basal keratinocytes that can be targeted by autoantibodies in autoimmune blistering disorders, including linear IgA dermatosis (LAD). COL17 can be physiologically cleaved within the juxtamembranous extracellular NC16A domain, and LAD autoantibodies preferentially react with the processed ectodomains, indicating that the processing induces neoepitopes. However, the details of how neoepitopes develop have not been elucidated. In this study, we show that C-terminal processing of COL17 also plays a role in inducing neoepitopes for LAD autoantibodies. First, the mAb hC17-ect15 targeting the 15th collagenous domain of COL17 was produced, which showed characteristics similar to LAD autoantibodies. The mAbs preferentially reacted with C-terminally deleted (up to 682 amino acids) recombinant COL17, suggesting that C-terminal processing shows neoepitopes on the 15th collagenous domain. The LAD autoantibodies also react with C-terminal deleted COL17. Therefore, neoepitopes for LAD autoantibodies also develop after C-terminal processing. Finally, the passive transfer of the mAb hC17-ect15 into human COL17-expressing transgenic mice failed to induce blistering disease, suggesting that neoepitope-targeting antibodies are not always pathogenic. In summary, this study shows that C-terminal processing induces dynamic structural changes and neoepitopes for LAD autoantibodies on COL17., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Aim: Autoimmune bullous disease (ABD) is induced by autoantibodies against cell adhesion molecules, and blistering may occur on the mucous membranes of the eyes, nose, mouth, oral cavity, laryngopharynx, and esophagus. Endoscopic prevalence and features of ABD-associated esophageal lesions are not well known. We conducted the present study to assess the endoscopic prevalence of ABD-associated mucosal lesions., Methods: Endoscopic prevalence of mucosal lesions, particularly laryngopharyngeal and esophageal lesions, was used as the primary endpoint to assess the significance of upper gastrointestinal endoscopy, and clinical and endoscopic features were secondary endpoints., Results: Of 123 ABD patients, 50.4% had apparent oral or laryngopharyngeal lesions and 30.8% had laryngopharyngeal lesions. Esophageal lesions were detected through normal observation in 16.8% of affected patients, whereas 40.6% exhibited epidermolysis or blood blisters by mechanical inducement, regardless of esophageal mucosal lesion detection by normal observation. Additionally, 56.0% exhibited the Nikolsky sign with mechanical inducement. Of the 123 patients, 29.2% did not have exposed skin lesions. Of these patients, 77.7% had oral cavity or laryngopharyngeal lesions, 36.1% had esophageal lesions, and 58.3% exhibited the Nikolsky sign on esophageal mucosa., Conclusion: It is important to determine the endoscopic characteristics and findings of ABD. ABD can be suspected from endoscopic findings., (© 2017 Japan Gastroenterological Endoscopy Society.)

Purpose: To assess the thickness of the photoreceptor layer in the macular region in glaucomatous eyes., Method: Humphrey 10-2 visual field (VF) testing was carried out and mean threshold (mTH) was calculated in 118 eyes from 118 patients with open angle glaucoma. Macular optical coherence tomography (OCT) measurements (RS 3000, Nidek Co.ltd., Aichi, Japan) were also carried out in all eyes. Thickness measurements were recorded in the outer segment and retinal pigment epithelium (OS+RPE), the nerve fiber layer (NFL), the ganglion cell layer and inner plexiform layer (GCL+IPL), the inner nuclear layer and outer plexiform layer (INL+OPL) and the outer nuclear layer and inner segment (ONL+IS). The relationship between mTH and the thickness of these five different layers was investigated. Additionally, the influence of OS+RPE on mTH was investigated using partial correlation eliminating the effect of other variables of NFL, GCL+IPL, INL+OPL, ONL+IS, age, gender and axial length., Results: The thickness of the OS+RPE layer was significantly decreased with the decrease of mTH (coefficient = 0.63 p <0.001). Partial correlation analysis suggested OS+RPE thickness is significantly (coefficient = 0.31, p <0.001) related to mTH, independent from NFL, GCL+IPL, INL+OPL, ONL+IS, age, gender and axial length., Conclusions: The thickness of the RPE+OS layer appears to be related to visual sensitivity in glaucoma.