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Purpose: To describe atypical varicella zoster virus (VZV) retinitis in a patient with Good syndrome.Methods: A 63-year-old patient with Good syndrome presented with bilateral necrotizing retinitis starting from the posterior pole. He had a history of thymoma status post thymectomy 4 years previously, left-sided sinusitis, and recent pulmonary aspergillosis. Qualitative PCR was performed on aqueous fluid.Results: Immunological investigations revealed reduced levels of CD4+ T cells and immunoglobulins. Qualitative PCR was positive for VZV and negative for cytomegalovirus, herpes simplex virus (HSV)-1, and HSV-2. The patient was treated with oral valacyclovir and three courses of immunoglobulin supplementation. The atypical retinitis showed improvement after therapy.Conclusion: Good syndrome should be considered in a patient with opportunistic infections and history of thymoma in the absence of human immunodeficiency virus. Atypical retinitis can occur in patients with Good syndrome and quantitative PCR is important for accurate diagnosis. [ABSTRACT FROM AUTHOR]

Purpose. To analyze the effect of a resolvin D1 (RvD1) analogue (RvD1a) on dendritic cell maturation, T-cell sensitization, and allograft rejection in corneal allotransplantation. Methods. The receptor expression of RvD1 (ALX/FPR2) on bone marrow–derived dendritic cells (BMDC) was measured using quantitative real-time PCR. We determined BMDC maturation after treatment with RvD1a using ELISA to measure interleukin (IL)-12 protein expression and flow cytometry to assess the expression of CD40, major histocompatibility complex (MHC) II, CD80, and CD86. After corneal transplantation in BALB/c mice, we analyzed T-cell infiltration in the cornea and the draining lymph nodes using flow cytometry. The enzyme-linked immunospot (ELISPOT) assay was used to measure T-cell sensitization via the direct and indirect pathway. Angiogenesis and lymphangiogenesis in the cornea after transplantation were measured using immunohistochemistry. Graft opacity and survival were evaluated by slit lamp biomicroscopy. Results. The receptor for RvD1, lipoxin A4/formyl peptide receptor 2 (ALX/FPR2), was expressed at a significantly lower level on immature than mature dendritic cells (DCs), and RvD1a reduced DC expression of MHC II, CD40, and IL-12 following lipopolysaccharide (LPS) stimulation. Using a murine model of corneal transplantation, RvD1a-treated hosts exhibited significantly reduced allosensitization as demonstrated by decreased frequencies of interferon-gamma–secreting T cells in the draining lymph nodes, and reduced T-cell infiltration into the grafts. Graft survival was significantly enhanced and angiogenesis at the graft site was suppressed in RvD1a-treated hosts compared with vehicle-treated hosts. Conclusions. These results suggest that RvD1 inhibits DC maturation and reduces alloimmune sensitization following transplantation, thereby establishing a novel connection between resolvin D1 and the regulation of DC-mediated, antigen-specific immunity., Version of Record

Purpose: This study investigated the donor characteristics of methicillin‐resistant Staphylococcus aureus (MRSA) contamination in storage medium before transfer of corneas to preservation medium for corneal transplantation, in order to identify donor characteristic risk factors for MRSA contamination. Methods: This retrospective, cross‐sectional study was performed using Juntendo Eye Bank records for all corneal transplantation procedures. Storage medium (EP‐II®) cultures for right eyes were included for the period between July 2008 and December 2017. The following donor characteristics were collected: age, sex, cause of death, history of cataract surgery, death‐to‐enucleation interval, death‐to‐preservation interval, and endothelial cell density (ECD). Donor characteristics were compared between MRSA and non‐MRSA contamination groups. Odds ratios (ORs) for donor‐related risk factors for MRSA contamination were determined using logistic regression. Results: In total, 370 storage medium samples were examined; 222 were positive for bacterial cultures (60.0%) and 36 were MRSA‐positive (9.7%). Donor age was significantly higher in the MRSA contamination group than in the non‐MRSA contamination group (86.1 ± 9.5 years vs 75.9 ± 15.9 years, P < 0.001). Univariate logistic regression analysis showed that MRSA contamination risk factors were older age (OR = 1.07; 95% confidence interval [95% CI]: 1.03‐1.11) and decreased ECD (OR = 0.9993; 95% CI: 0.9986‐0.9992). The fully adjusted OR for every year of age as a risk factor for MRSA contamination was 1.07 (95% CI: 1.03‐1.11). Conclusions: Aging was a risk factor for MRSA contamination in storage medium. Careful pre‐banking assessment of elderly donor corneas is needed to prevent intractable postoperative MRSA infection. [ABSTRACT FROM AUTHOR]

Background: Assessing changes in quality of life in patients with hay fever-related allergic conjunctivitis requires validated and clinically meaningful metrics. A minimal clinically important difference (MCID) that can be applied to assess Domain II of the Japanese Allergic Conjunctival Disease Quality of Life Questionnaire (JACQLQ) in a smartphone app setting has yet to be determined., Objective: This cross-sectional observational study aimed to determine MCIDs for the app-based JACQLQ in assessing hay fever-related allergic conjunctivitis., Methods: This study used data from a crowdsourced, cross-sectional, observational study conducted via the smartphone app "AllerSearch" between February 1, 2018, and May 1, 2020. Participants were recruited through digital media and social networking platforms and voluntarily provided electronic informed consent. Participants completed the JACQLQ, which includes items on daily activity and psychological well-being, as well as a visual analog scale to measure stress levels related to hay fever. Data were collected through the app, ensuring comprehensive user input. MCIDs were determined using both anchor- and distribution-based methods. The face scale of the JACQLQ Domain III and stress level scale for hay fever were used as anchors to estimate the MCID; ranges were derived from these MCID estimates. In the distribution-based method, MCIDs were calculated using half the SD and SE of the JACQLQ Domain II scores. SEs were derived from the intraclass correlation coefficient of an app-based JACQLQ test-retest reliability metric., Results: A total of 17,597 individuals were identified, of which 15,749 individuals provided electronic consent. After excluding those with incomplete data, 7590 participants with hay fever were included in the study (mean age 35.3, SD 13.9 years; n=4331, 57.1% of women). MCID ranges calculated using the anchor-based method were 1.0-6.9, 1.2-5.6, and 2.1-12.6 for daily activity, psychological well-being, and total JACQLQ Domain II scores, respectively. Using the distribution-based method, the intraclass correlation coefficients were odds ratio (OR) 0.813 (95% CI 0.769-0.849) for daily activity, OR 0.791 (95% CI 0.743-0.832) for psychological well-being, and OR 0.841 (95% CI 0.791-0.864) for total JACQLQ Domain II scores. In addition, the distribution-based method resulted in 2 MCIDs based on half the SD and SE of measurement for daily activity (4.8 and 4.2), psychological well-being (3.4 and 3.1), and total JACQLQ Domain II (7.8 and 6.4) scores. The final suggested MCID ranges for daily activity, psychological well-being, and total JACQLQ Domain II scores were 4.2-6.0, 3.1-4.7, and 6.4-10.5, respectively., Conclusions: MCID ranges for the JACQLQ estimation could help to standardize the app-based quality of life assessment for patients with hay fever-related allergic conjunctivitis. These MCIDs enhanced the precision of remote symptom monitoring and facilitated timely, data-driven interventions, ultimately improving the overall management and outcomes of allergic conjunctivitis through mobile health platforms., (©Ken Nagino, Jaemyoung Sung, Akie Midorikawa-Inomata, Yasutsugu Akasaki, Takeya Adachi, Nobuyuki Ebihara, Ken Fukuda, Atsuki Fukushima, Kenta Fujio, Yuichi Okumura, Atsuko Eguchi, Keiichi Fujimoto, Hurramhon Shokirova, Alan Yee, Yuki Morooka, Tianxiang Huang, Kunihiko Hirosawa, Shintaro Nakao, Hiroyuki Kobayashi, Takenori Inomata. Originally published in JMIR Formative Research (https://formative.jmir.org), 26.11.2024.)

Society 5.0, proposed as part of the 5th Science and Technology Basic Plan by Japan's National Institute of Advanced Industrial Science and Technology, is a human-centered society where cyberspace and physical space are integrated, to resolve social challenges and promote economic growth. In Society 5.0, medicine will undergo extensive digital transformation (DX), and digital health technology is expected to expand markedly, becoming part of routine clinical practice. Prompt diagnosis of dry eye disease (DED) and uninterrupted monitoring of such patients with healthcare barriers is currently an unmet need. DX of DED evaluation and management can boost the current quality of DED care. Software as Medical Devices (SaMDs), i.e., software programs developed through evidence-based research to provide diagnostic, therapeutic, and preventive services, and particularly medical devices based on smartphone applications (apps), have attracted attention. We have striven to actualize the DX of ophthalmic care and evaluation, denoted by our ongoing development of SaMDs to assist DED diagnosis. To illustrate healthcare using the Internet of Medical Things, we here present the research and development process of our smartphone app-based SaMD for DED diagnosis assistance., Competing Interests: The DryEyeRhythm application was created using Apple's ResearchKit (Cupertino, CA, USA) along with OHAKO, Inc. (Tokyo, Japan) and Medical Logue, Inc. (Tokyo, Japan). TI reports non-financial support from Lion Corp. and Sony Network Communications Inc.; grants from Johnson & Johnson Vision Care Inc., Yuimedi Inc., ROHTO Pharmaceutical Co. Ltd., Kobayashi Pharmaceutical Co. Ltd., Kandenko Co. Ltd., and Fukoku Co. Ltd.; and personal fees from Santen Pharmaceutical Co. Ltd., InnoJin Inc., and Ono Pharmaceutical Co. Ltd., outside the submitted work. YO, KN, and AMI received personal fees from InnoJin Inc., outside the submitted work. SN report grants from Kowa Co. Ltd.; Mitsubishi Tanabe Pharma Corp.; Alcon Japan, Ltd.; Santen Pharmaceutical Co. Ltd.; Machida Endoscope Co. Ltd.; Wakamoto Pharmaceutical Co. Ltd.; Bayer Yakuhin Ltd.; Senju Pharmaceutical Co. Ltd.; Nippon Boehringer Ingelheim Co. Ltd.; Chugai Pharmaceutical Co. Ltd.; Hoya Corp.; and Novartis Pharma KK, outside the submitted work. The remaining authors have no conflicts of interest to declare., (© 2024 The Juntendo Medical Society.)

Purpose: Long-term ramifications of the coronavirus disease 2019 pandemic on various care-seeking characteristics of patients with diabetic retinopathy remain unclear. This study aimed to identify risk factors for dropout from regular fundus examinations (RFEs) in patients with diabetic retinopathy in Japan., Methods: We extracted demographic and health checkup data (April 2018 to March 2021) from the JMDC database. Patients with diabetes identified using diagnosis-related and medication codes were included. The dropout and continuation groups included patients who discontinued and continued to undergo RFEs during the coronavirus disease 2019 pandemic, respectively., Results: The number of RFEs was significantly lower during the mild lockdown period (April and May 2020) than during the prepandemic period. Of the 14,845 patients with diabetes, 2333 (15.7%) dropped out of RFEs during the pandemic, whereas before the pandemic, of the 11,536 patients with diabetes, 1666 (14.4%) dropped out of RFEs (P = 0.004). Factors associated with dropout in the multivariate logistic regression analysis included younger age, male sex, high triglyceride levels, high γ-glutamyl transpeptidase levels, smoking habit, alcohol consumption, weight gain of more than 10 kg since the age of 20 years, and certain stages of lifestyle improvement. Factors associated with continuation included low body mass index and high glycosylated hemoglobin levels., Conclusions: Our findings can assist in identifying patients with diabetes at risk of dropout., Translational Relevance: These results have implications for public health and identifying patients with diabetes at risk of dropout. Education and tailored monitoring regimens could be pivotal role in fostering adherence.

Competing Interests: Conflicts of Interest: Inomata T, reports non-financial support from Lion Corporation and Sony Network Communications Inc., grants from Johnson & Johnson Vision Care, Inc., Kandenko, Co., Ltd., Yuimedi, Inc., Rohto Pharmaceutical Co., Ltd., Kobayashi Pharmaceutical Co., Ltd., Kandenko Co., Ltd., and Fukoku Co., Ltd., personal fees from Santen Pharmaceutical Co., Ltd., InnoJin, Inc., and Ono Pharmaceutical Co., Ltd., outside the submitted work; Okumura Y and Nagino K, report personal fees from InnoJin, Inc., outside the submitted work; Nakao S, reports grants from Kowa Company. Ltd., Mitsubishi Tanabe Pharma Corporation, Alcon Japan, Ltd., Santen Pharmaceutical Co., Ltd., Machida Endoscope Co., Ltd., Wakamoto Pharmaceutical Co., Ltd., Bayer Yakuhin, Ltd., Senju Pharmaceutical Co., Ltd. Nippon Boehringer Ingelheim Co., Ltd., Chugai Pharmaceutical Co., Ltd., Hoya Corporation, and Novartis Pharma K.K., outside the submitted work; Hirosawa K, None; Sung J, None; Morooka Y, None; Huang T, None; Akasaki Y, None; Omori K, None.

Background: In 2022, the "New Capitalism Grand Design and Implementation Plan" was adopted in Japan, emphasizing the promotion and environmental development of startups. Given this context, an investigation into the startup and investment landscape in the allergy sector, both domestically and internationally, becomes imperative., Methods: We analyzed 156 allergy-related startups from Japan, the US, and Europe from 2010 to 2021. Data on corporate information and investment trends were extracted from databases and VC websites., Results: The total investment reached approximately 7.2 billion USD, with a ratio of 20:6:1 for the US, Europe, and Japan, respectively. The US showed a decline post its peak from 2016-2018, while Europe and Japan experienced growth. Notably, the US primarily invested in biopharmaceuticals for atopic dermatitis and food allergies, Europe in asthma-related apps, and Japan in healthcare apps and cross-border startups., Discussion and Conclusion: While Japan's investment environment in the allergy sector remains in its nascent stages and has room for development, the US and Europe are evidently ahead. Considering the rise of startups and funding limitations in Japan, external funding from regions like the US becomes a potential avenue. These findings are anticipated to contribute to the strategic activation of startups in allergy research and development.

Background: In the enhancement of allergy care involving multidisciplinary and multiple medical departments, there is a perceived need for education that targets not only specialists but also non-specialists. However, research on the need for and methods of such education remains inadequate., Objective: To design a remote allergy care education program for all medical practitioners and to validate its necessity and utility., Methods: The Empowering Next Generation Allergist/immunologist toward Global Excellence Task Force (ENGAGE-TF), supported by the Japanese Society of Allergology, initiated a virtual educational program called 'Outreach Lectures' in collaboration with Keio University and Fukui University. This initiative was widely promoted through social media and various institutions, and a survey was conducted through its mailing list., Results: 1139 responses were obtained. More than half were physicians from non-allergy specialties, representing a diverse range of healthcare professions. Over 70% expressed being 'very satisfied,' and over 60% found the difficulty level 'appropriate.' Free-form feedback revealed differences in learning focus based on profession and learning approach based on years of experience., Conclusion: The high participation rate (90%) of non-specialist physicians underscores the demand for addressing allergic conditions in primary care. The effectiveness of virtual / recurrent education, particularly for healthcare professionals with over 11 years of experience, was implied. Further follow-up investigation focusing on quantitative and objective assessment of educational effectiveness is indispensable.

Background/aims: This study aimed to assess the efficacy and sterility of stored platelet-rich plasma (PRP) eye-drops for corneal epithelial wound healing compared with those of autologous serum (AS) eye-drops., Methods: At our single institution, PRP and AS eye-drops were prepared using peripheral blood obtained from six healthy volunteers and stored at 4°C. Platelet and leucocyte counts and transforming growth factor (TGF)-β1, epidermal growth factor (EGF), and fibronectin levels were assessed during storage for up to 4 weeks. Sterility was assessed by culturing 4-week poststorage samples. PRP, AS, and phosphate-buffered saline (PBS) eye-drop efficacies were compared using corneal epithelial wound healing assays in vitro and in vivo and monitoring wound areas under a microscope every 3 hours., Results: Higher platelet and lower leucocyte counts were seen in PRP than in whole blood on the day of preparation. After storage, TGF-β1, EGF, and fibronectin levels were significantly higher in PRP than in AS eye-drops. In vitro and in vivo , PRP eye-drops used on the day of preparation significantly promoted corneal epithelial wound healing compared with PBS. Moreover, PRP eye-drops stored for 4 weeks significantly promoted corneal wound healing compared with PBS and AS eye-drops., Conclusion: PRP eye-drops stored at 4°C for 4 weeks promoted corneal epithelial wound healing with higher levels of growth factors than those observed in AS eye-drops, while maintaining sterility, suggesting that this preparation satisfies the unmet medical needs in the treatment of refractory keratoconjunctival epithelial disorders., Competing Interests: Competing interests: YO, TI,and AM have a patent pending for the manufacturing method of PRP eye-drops (pending patent application 2020-164360)., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

With approximately one million diagnosed cases and over 700,000 deaths recorded annually, gastric cancer (GC) is the third most common cause of cancer-related deaths worldwide. GC is a heterogeneous tumor. Thus, optimal management requires biomarkers of prognosis, treatment selection, and treatment response. The Cancer Genome Atlas program sub-classified GC into molecular subtypes, providing a framework for treatment personalization using traditional chemotherapies or biologics. Here, we report a comprehensive study of GC vascular and immune tumor microenvironment (TME)-based on stage and molecular subtypes of the disease and their correlation with outcomes. Using tissues and blood circulating biomarkers and a molecular classification, we identified cancer cell and tumor archetypes, which show that the TME evolves with the disease stage and is a major determinant of prognosis. Moreover, our TME-based subtyping strategy allowed the identification of archetype-specific prognostic biomarkers such as CDH1 -mutant GC and circulating IL-6 that provided information beyond and independent of TMN staging, MSI status, and consensus molecular subtyping. The results show that integrating molecular subtyping with TME-specific biomarkers could contribute to improved patient prognostication and may provide a basis for treatment stratification, including for contemporary anti-angiogenesis and immunotherapy approaches., Competing Interests: Declarations Conflict of Interest DGD received consultant fees from Innocoll Pharmaceuticals and research grants from Exelixis, Bayer, BMS, and Surface Oncology. No reagents or funding from these companies were used in this study. The other authors declare no conflicts of interest.

During the 5 th Science, Technology, and Innovation Basic Plan, the Japanese government proposed a novel societal concept -Society 5.0- that promoted a healthcare system characterized by its capability to provide unintrusive, predictive, longitudinal care through the integration of cyber and physical space. The role of Society 5.0 in managing our quality of vision will become more important in the modern digitalized and aging society, both of which are known risk factors for developing dry eye. Dry eye is the most common ocular surface disease encountered in Japan with symptoms including increased dryness, eye discomfort, and decreased visual acuity. Owing to its complexity, implementation of P4 (predictive, preventive, personalized, participatory) medicine in managing dry eye requires a comprehensive understanding of its pathology, as well as a strategy to visualize and stratify its risk factors. Using DryEyeRhythm ® , a mobile health (mHealth) smartphone software (app), we established a route to collect holistic medical big data on dry eye, such as the subjective symptoms and lifestyle data for each individual. The studies to date aided in determining the risk factors for severe dry eye, the association between major depressive disorder and dry eye exacerbation, eye drop treatment adherence, app-based stratification algorithms based on symptomology, blink detection biosensoring as a dry eye-related digital phenotype, and effectiveness of app-based dry eye diagnosis support compared to traditional methods. These results contribute to elucidating disease pathophysiology and promoting preventive and effective measures to counteract dry eye through mHealth., Competing Interests: The DryEyeRhythmⓇ application was created using Apple's ResearchKit (Cupertino, CA, USA) along with OHAKO, Inc. (Tokyo, Japan) and Medical Logue, Inc. (Tokyo, Japan). TI, YO, and AMI are the owners of InnoJin, Inc. (Tokyo, Japan), which developed DryEyeRhythmⓇ. TI reported receiving grants from Johnson & Johnson Vision Care, SEED Co., Ltd., Novartis Pharma K.K., and Kowa Company, Ltd., outside the submitted work, as well as personal fees from Santen Pharmaceutical Co., Ltd., and InnoJin, Inc. The remaining authors declare no competing interests., (© 2023 The Juntendo Medical Society.)

Background: Discontinuation of contact lens use is mainly caused by contact lens-associated dry eye. It is crucial to delineate contact lens-associated dry eye's multifaceted nature to tailor treatment to each patient's individual needs for future personalized medicine., Objective: This paper aims to quantify and stratify individual subjective symptoms of contact lens-associated dry eye and clarify its risk factors for future personalized medicine using the smartphone app DryEyeRhythm (Juntendo University)., Methods: This cross-sectional study included iPhone (Apple Inc) users in Japan who downloaded DryEyeRhythm. DryEyeRhythm was used to collect medical big data related to contact lens-associated dry eye between November 2016 and January 2018. The main outcome measure was the incidence of contact lens-associated dry eye. Univariate and multivariate adjusted odds ratios of risk factors for contact lens-associated dry eye were determined by logistic regression analyses. The t-distributed Stochastic Neighbor Embedding algorithm was used to depict the stratification of subjective symptoms of contact lens-associated dry eye., Results: The records of 4454 individuals (median age 27.9 years, SD 12.6), including 2972 female participants (66.73%), who completed all surveys were included in this study. Among the included participants, 1844 (41.40%) were using contact lenses, and among those who used contact lenses, 1447 (78.47%) had contact lens-associated dry eye. Multivariate adjusted odds ratios of risk factors for contact lens-associated dry eye were as follows: younger age, 0.98 (95% CI 0.96-0.99); female sex, 1.53 (95% CI 1.05-2.24); hay fever, 1.38 (95% CI 1.10-1.74); mental illness other than depression or schizophrenia, 2.51 (95% CI 1.13-5.57); past diagnosis of dry eye, 2.21 (95% CI 1.63-2.99); extended screen exposure time >8 hours, 1.61 (95% CI 1.13-2.28); and smoking, 2.07 (95% CI 1.49-2.88). The t-distributed Stochastic Neighbor Embedding analysis visualized and stratified 14 groups based on the subjective symptoms of contact lens-associated dry eye., Conclusions: This study identified and stratified individuals with contact lens-associated dry eye and its risk factors. Data on subjective symptoms of contact lens-associated dry eye could be used for prospective prevention of contact lens-associated dry eye progression., (©Takenori Inomata, Masahiro Nakamura, Masao Iwagami, Akie Midorikawa-Inomata, Jaemyoung Sung, Keiichi Fujimoto, Yuichi Okumura, Atsuko Eguchi, Nanami Iwata, Maria Miura, Kenta Fujio, Ken Nagino, Satoshi Hori, Kazuo Tsubota, Reza Dana, Akira Murakami. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 26.06.2020.)

CD4 + CD25 + Foxp3 + Regulatory T cells (Tregs) play a critical role in immune tolerance. The plasticity and functional adaptability of Tregs in an inflammatory microenvironment has been demonstrated in autoimmunity. Here, using a double transgenic mouse model that permits Foxp3 lineage tracing, we investigated the phenotypic plasticity of Foxp3 + Tregs in a well-characterized murine model of corneal transplantation. In order to subvert the normal immune privilege of the cornea and foster an inflammatory milieu, host mice were exposed to desiccating stress prior to transplantation. Treg frequencies and function were decreased following desiccating stress, and this corresponded to decreased graft survival. A fraction of Tregs converted to IL-17 + or IFNγ + 'exFoxp3' T cells that were phenotypically indistinguishable from effector Th17 or Th1 cells, respectively. We investigated how Foxp3 expression is modulated in different Treg subsets, demonstrating that neuropilin-1 - peripherally-derived Tregs are particularly susceptible to conversion to IL-17 + /IFNγ + exFoxp3 cells in response to cues from their microenvironment. Finally, we show that IL-6 and IL-23 are implicated in the conversion of Tregs to exFoxp3 cells. This report demonstrates that the pathological conversion of Tregs contributes to the loss of corneal immune privilege.