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Background: Artificial intelligence (AI) is a promising new technology that has the potential of diagnosing allergic conjunctival diseases (ACDs). However, its development is slowed by the absence of a tailored image database and explainable AI models. Thus, the purpose of this study was to develop an explainable AI model that can not only diagnose ACDs but also present the basis for the diagnosis., Methods: A dataset of 4942 slit-lamp images from 10 ophthalmological institutions across Japan were used as the image database. A sequential pipeline of segmentation AI was constructed to identify 12 clinical findings in 1038 images of seasonal and perennial allergic conjunctivitis (AC), atopic keratoconjunctivitis (AKC), vernal keratoconjunctivitis (VKC), giant papillary conjunctivitis (GPC), and normal subjects. The performance of the pipeline was evaluated by determining its ability to obtain explainable results through the extraction of the findings. Its diagnostic accuracy was determined for 4 severity-based diagnosis classification of AC, AKC/VKC, GPC, and normal., Results: Segmentation AI pipeline efficiently extracted crucial ACD indicators including conjunctival hyperemia, giant papillae, and shield ulcer, and offered interpretable insights. The AI pipeline diagnosis had a high diagnostic accuracy of 86.2%, and that of the board-certified ophthalmologists was 60.0%. The pipeline had a high classification performance, and the area under the curve (AUC) was 0.959 for AC, 0.905 for normal subjects, 0.847 for GPC, 0.829 for VKC, and 0.790 for AKC., Conclusions: An explainable AI model created by a comprehensive image database can be used for diagnosing ACDs with high degree of accuracy., (Copyright © 2024 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

Our systematic review and meta-analysis elucidates the postoperative complication rates associated with 3 major surgical approaches, including the scleral tunnel, glued, and flanged techniques, for sutureless intrascleral intraocular lens (IOL) fixation. An online search was performed for articles published in PubMed and EMBASE between January 1, 1975, and January 7, 2023. Original studies reporting postoperative complications of sutureless intrascleral IOL fixation were included. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. The initial search yielded 1854 articles, from which 1797 were excluded; 57 and 51 were included in the qualitative synthesis and meta-analysis, respectively. Based on the meta-analysis, the postoperative complication rates of cystoid macular edema (5.7 %), retinal detachment (3.5 %), vitreous hemorrhage (8.8 %), and hypotony (5.5 %) were highest with the scleral tunnel technique. The glued technique had the highest complication rate for corneal edema (14.2 %). The rates of temporarily elevated intraocular pressure (9.9 %), iris capture (5.4 %), haptic exposure (6.5 %), and IOL decentration (7.3 %) were the highest with the flanged technique. The flanged technique had a significantly shorter operative time (median, 17.1 min) compared with the scleral tunnel (42.7 min) and glued (56.5 min) techniques. Postoperative best-corrected visual acuity with the flanged technique was significantly better than that with the other techniques (P = 0.017). This meta-analysis identified high postoperative complication rates related to the impact of surgical manipulations with the scleral tunnel technique and IOL placement stability with the flanged technique. These findings enable surgeons to minimize postoperative complications in high-risk patients., Competing Interests: Disclosure K.N. and A.M.I report personal fees from InnoJin, Inc., outside the submitted work. T.I. reports non-financial support from Lion Corporation 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., personal fees from Santen Pharmaceutical Co., Ltd., and InnoJin, Inc., outside the submitted work. S.N. 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. The remaining authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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.)

Although esophageal cancers invading the muscularis mucosa (pT1a-MM) or submucosa (pT1b-SM) after endoscopic resection (ER) are associated with a risk of lymph node metastasis, details of metastatic recurrence after additional treatment remain unknown. We aimed to identify the risk factors for metastatic recurrence and recurrence patterns in patients receiving additional treatment after ER for esophageal cancer. Between 2006 and 2017, patients with pT1a-MM/pT1b-SM esophageal cancer who underwent ER with additional treatment (esophagectomy, chemoradiotherapy [CRT], and radiation therapy) at 21 institutions in Japan were enrolled. We evaluated the risk factors for metastatic recurrence after ER with additional treatment. Subsequently, the rate and pattern (locoregional or distant) of metastatic recurrence were investigated for each additional treatment. Of the 220 patients who received additional treatment, 57, 125, and 38 underwent esophagectomy, CRT, and radiation therapy, respectively. In the multivariate analysis, lymphatic invasion was the sole risk factor for metastatic recurrence after additional treatment (hazard ratio, 3.50; P = 0.029). Although the risk of metastatic recurrence with additional esophagectomy was similar to that with CRT (hazard ratio, 1.01; P = 0.986), the rate of locoregional recurrence tended to be higher with additional esophagectomy (80.0% (4/5) vs. 36.4% (4/11)), leading to a better prognosis in patients with metastatic recurrence after additional esophagectomy than CRT (survival rate, 80.0% (4/5) vs. 9.1% (1/11)). Patients with lymphatic invasion have a high risk of metastatic recurrence after ER with additional treatment for pT1a-MM/pT1b-SM esophageal cancer. Additional esophagectomy may result in a better prognosis after metastatic recurrence., (© The Author(s) 2024. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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.)

Background/objectives: Dry eye disease (DED) and myopia are common ocular disorders. This systematic review and meta-analysis investigated the association between DED and myopia., Methods: PubMed and EMBASE were searched for articles published between 1984 and 2022. Study quality was assessed using the Joanna Briggs Institute Critical Appraisal Checklist, and analysis was conducted using the DerSimonian-Laird random-effects model., Results: Of the 1,313 studies identified, 15 studies on DED and myopia were included. The meta-analysis revealed that the overall prevalence of subjective DED symptoms in the myopia population was 45.1 % (95 % confidence interval: 0.287-0.616). There was a significant association between DED and myopia. The myopia population had higher Ocular Surface Disease Index scores and shorter tear film breakup times than the non-myopia population. Additionally, the meta-regression analysis showed that spherical equivalent was significantly associated with the prevalence of DED symptoms in adults with myopia., Conclusion: Interventions to prevent DED are required in the myopia population. Enhancing patient awareness and self-management for DED, in addition to early screening and detection, is especially critical for younger populations who are at a higher risk of developing myopia., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: K.N. and A.M.I. received personal fees from InnoJin, Inc., outside the submitted work. S.N. received consulting fee from Chugai Pharmaceutical Co., Ltd., Kowa Company, Ltd., Novartis Pharma KK., Riverfield Inc., travel reimbursements and speaker fees from Alcon Inc., Boehringer Ingelheim Co., Ltd., Bayer Yakuhin Ltd., Canon Inc., JFC Sales Plan Co., Ltd., Kowa Company, Ltd., Mitsubishi Tanabe Pharma Corporation, Machida Holdings Inc., MSD K.K., Novartis Pharma KK., Novo Nordisk Pharma Ltd., Otsuka Pharmaceutical Co., Ltd., Santen Pharmaceutical Co., Ltd., Senju Pharmaceutical Co., Ltd., and Wakamoto Pharmaceutical Co., Ltd. not related to the submitted work. T.I. received non-financial support from Lion Corporation 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. not related to the submitted work. The remaining authors declare no competing interests. The sponsors had no role in the design or execution of the study; data collection and management; the analysis and interpretation of the data; the preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

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.

Background: Hay fever (HF) presents with various symptoms, including allergic conjunctivitis and rhinitis, and requires cross-organ treatment. This study assessed the impact of the coronavirus disease 2019 (COVID-19) pandemic on HF treatment trends., Methods: This retrospective cohort study utilized data from the JMDC database collected between January 2018 and May 2021. Patients with HF were identified based on the relevant International Classification of Diseases 10th Revision diagnosis codes and the prescription of HF-related medications. The treatment approaches were compared during the cedar and cypress pollen allergy season (January to May in Japan) before and during the COVID-19 pandemic (2018 and 2019, and 2020 and 2021, respectively)., Results: This study included 2,598,178 patients with HF. The numbers of prescribed HF-related claims in 2018, 2019, 2020, and 2021 were 3,332,854, 3,534,198, 2,774,380, and 2,786,681 times, respectively. Oral second-generation antihistamine prescriptions decreased by >10% from 2019 to 2020, with a <10% change in the subsequent year. Anti-allergic eye drop prescriptions also decreased by >10% from 2019 to 2020 but increased by >10% from 2020 to 2021. Compared with 2018, 2019, and 2020, the number of claims in the rhinitis symptoms dominant group was significantly decreased in 2021 (p < 0.001, all). In contrast, the number of claims in the eye symptoms dominant group and the rhinitis and eye symptoms dominant group increased in 2021 compared with that in 2018, 2019, and 2020 (p < 0.001, all)., Conclusion: Changes in HF treatment and related outcomes could be attributed to lifestyle modifications resulting from the COVID-19 pandemic. Measures, such as limiting outdoor activities and adopting mask-wearing practices may have influenced HF symptoms, preventive behaviors, and the overall approach to treating HF., (© 2024 The Author(s). Clinical and Translational Allergy published by John Wiley & Sons Ltd on behalf of European Academy of Allergy and Clinical Immunology.)

Purpose: This study aimed to compare subjective allergic conjunctivitis symptoms and anti-allergic eye drop use patterns between antihistamine-releasing contact lens users and daily disposable soft contact lens users during Japan's hay fever season., Methods: This web-based retrospective cohort study included daily disposable soft contact lens or antihistamine-releasing contact lens users with a history of seasonal allergic conjunctivitis who regularly used daily disposable soft contact lenses since the previous year. The total ocular symptom score (range 0-20) based on 5-item questionnaire scores and time from the start of the hay fever season to the initiation of anti-allergic eye drop treatment were compared between antihistamine-releasing contact lens users and daily disposable soft contact lens users., Results: The study included 24 participants: 17 using daily disposable soft contact lenses and 7 using antihistamine-releasing contact lenses. Antihistamine-releasing contact lens users experienced a greater reduction in total ocular symptom score from 2021 to 2022 compared with daily disposable soft contact lens users (mean total ocular symptom score [standard deviation]: daily disposable soft contact lens: -0.65 [1.4], antihistamine-releasing contact lens: -4.7 [3.6]; n = 24; Mann-Whitney U test, P  = 0.010). Fourteen daily disposable soft contact lens users and five antihistamine-releasing contact lens users eventually required anti-allergic eye drops. Kaplan-Meier analysis revealed a significant delay in the initiation of anti-allergic eye drop treatment among those using antihistamine-releasing contact lenses compared with those using daily disposable soft contact lenses (median days, daily disposable soft contact lenses: 19 days, antihistamine-releasing contact lens: 57 days; n = 24; log-rank test, P  = 0.045)., Conclusions: Antihistamine-releasing contact lenses can potentially mitigate worsening ocular allergic responses during the hay fever season when used appropriately as a preventive measure., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Takenori Inomata reports equipment, drugs, or supplies was provided by Lion Corporation. Takenori Inomata reports equipment, drugs, or supplies was provided by Sony Network Communications Inc. Takenori Inomata reports financial support was provided by Kandenko, Co., Ltd., Johnson & Johnson K.K. Vision Care Company, Yuimedi, Inc., Rohto Pharmaceutical Co., Ltd., Kobayashi Pharmaceutical Co., Ltd., and Fukoku Co., Ltd. Takenori Inomata reports financial support was provided by 10.13039/501100004286Santen Pharmaceutical Co., Ltd., InnoJin, Inc., and Ono Pharmaceutical Co., Ltd. Takenori Inomata reports a relationship with InnoJin, Inc that includes: equity or stocks. Shintaro Nakao reports financial support was provided by 10.13039/100015993Kowa 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. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

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.

Purpose: We report the clinical findings and molecular identification of ocular Thelazia callipaeda from Niigata Prefecture in the Hokuriku area of Japan during winter., Observations: A 77-year-old male visited an ophthalmology clinic in Niigata Prefecture in January 2022 after a 2-week-duration of a conjunctival injection in the left eye and foreign body sensation. Slit-lamp microscopy revealed 11 active nematodes in the left conjunctival sac. Morphological characteristics included longer female body length than male, buccal cavity lacking teeth and lips, and serrated striations along the body surface. The specimens were determined to be T. callipaeda . Genetic analysis of the mitochondrial cytochrome c oxidase subunit 1 ( cox1 ) gene revealed an h9 haplotype., Conclusions and Importance: T. callipaeda infection, especially the h9 haplotype, commonly occurs in western Japan owing to its higher incidence in warmer climates, suggesting the origin of the case. Here, we report a human case of Thelaziasis diagnosed in a cold region of Japan (the Hokuriku area) during winter. This human case of T. callipaeda infection from a cold, previously unassociated region, raises concerns about the potential geographical widening of its distribution, and further investigation may be warranted to prevent its spread., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Objectives: Clinical outcomes of endoscopic submucosal dissection (ESD) for esophageal squamous cell carcinoma (ESCC) with esophageal varices (EVs) are obscure. We aimed to elucidate the clinical outcomes of ESD for ESCC with EVs in a multicenter, retrospective study., Methods: We established a retrospective cohort of 30 patients with ESCC complicating EVs, who underwent ESD at 11 Japanese institutions. Rates of en bloc resection and R0 resection, procedure time, and adverse events were evaluated as indicators of the feasibility and safety of ESD. Additional treatment, recurrence, and metastasis of the lesions were evaluated as indicators of the long-term efficacy of ESD., Results: Portal hypertension was caused by cirrhosis, of which alcohol was the most common cause. En bloc resection was achieved in 93.3% and R0 resection in 80.0% of the patients. The median procedure time was 92 min. Adverse events included a case of uncontrolled intraoperative bleeding leading to discontinuation of ESD and a case of esophageal stricture due to extensive resection. During the follow-up period of a median for 42 months, a patient with local recurrence and another patient with liver metastasis were observed. One patient died of liver failure after receiving chemoradiotherapy as an additional treatment after ESD. No patient died of ESCC., Conclusion: This multicenter, retrospective cohort study demonstrated the safety and efficacy of ESD for ESCC with EVs. Further studies are needed to establish appropriate treatment methods for EVs before ESD and additional treatments for patients with insufficient ESD., (© 2023 Japan Gastroenterological Endoscopy Society.)

This retrospective study aimed to determine the optimal cutoff values of the Dry Eye-Related Quality-of-Life Score (DEQS) questionnaire for diagnosing dry eye disease (DED) and classifying DED severities. Participants completed the DEQS questionnaire, the Japanese version of the Ocular Surface Disease Index (J-OSDI) questionnaire, and DED examinations. DED was diagnosed according to the 2016 Asia Dry Eye Society diagnostic criteria based on DED symptoms (J-OSDI ≥ 13 points) and tear film breakup time ≤ 5 s. Receiver operating characteristic (ROC) analysis was used to calculate the optimal cutoff values of the DEQS summary score for detecting DED and grading its severity. Among 427 patients, 296 (69.3%) and 131 (30.7%) were diagnosed with DED and non-DED, respectively. ROC analysis determined an optimal cutoff value of 15.0 points for DED diagnosis, with 83.5% sensitivity, 87.0% specificity, and an area under the curve of 0.915. The positive and negative predictive values for DEQS ≥ 15.0 points were 93.6% and 69.9%, respectively. DEQS cutoff values of 15.0, 20.0, and 26.8 points could be accepted for severity classification of DED subjective symptoms in clinical use and represent mild, moderate, and severe DED, respectively. Conclusively, the optimal cutoff values of DEQS enable DED detection and subjective symptom severity classification., (© 2024. The Author(s).)

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.)

Background/objective: To test the feasibility of a dry eye disease (DED) symptom stratification algorithm previously established for the general population among patients visiting ophthalmologists., Subject/methods: This retrospective cross-sectional study was conducted between December 2015 and October 2021 at a university hospital in Japan; participants who underwent a comprehensive DED examination and completed the Japanese version of the Ocular Surface Disease Index (J-OSDI) were included. Patients diagnosed with DED were stratified into seven clusters using a previously established symptom-based stratification algorithm for DED. Characteristics of the patients in stratified clusters were compared., Results: In total, 426 participants were included (median age [interquartile range]; 63 [48-72] years; 357 (83.8%) women). Among them, 291 (68.3%) participants were diagnosed with DED and successfully stratified into seven clusters. The J-OSDI total score was highest in cluster 1 (61.4 [52.2-75.0]), followed by cluster 5 (44.1 [38.8-47.9]). The tear film breakup time was the shortest in cluster 1 (1.5 [1.1-2.1]), followed by cluster 3 (1.6 [1.0-2.5]). The J-OSDI total scores from the stratified clusters in this study and those from the clusters identified in the previous study showed a significant correlation (r = 0.991, P < 0.001)., Conclusions: The patients with DED who visited ophthalmologists were successfully stratified by the previously established algorithm for the general population, uncovering patterns for their seemingly heterogeneous and variable clinical characteristics of DED. The results have important implications for promoting treatment interventions tailored to individual patients and implementing smartphone-based clinical data collection in the future., (© 2023. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

Background: Dry eye (DE) and hay fever (HF) show synergistic exacerbation of each other's pathology through inflammatory pathways., Objective: This study aimed to investigate the association between DE and HF comorbidity and the related risk factors., Methods: A cross-sectional observational study was conducted using crowdsourced multidimensional data from individuals who downloaded the AllerSearch smartphone app in Japan between February 2018 and May 2020. AllerSearch collected the demographics, medical history, lifestyle and residential information, HF status, DE symptoms, and HF-related quality of life. HF symptoms were evaluated using the nasal symptom score (0-15 points) and nonnasal symptom score (0-12 points). HF was defined by the participants' responses to the questionnaire as HF, non-HF, or unknown. Symptomatic DE was defined as an Ocular Surface Disease Index total score (0-100 points), with a threshold score of 13 points. HF-related quality of life was assessed using the Japanese Allergic Conjunctival Disease Standard Quality of Life Questionnaire (0-68 points). We conducted a multivariable linear regression analysis to examine the association between the severity of DE and HF symptoms. We subsequently conducted a multivariable logistic regression analysis to identify the factors associated with symptomatic DE (vs nonsymptomatic DE) among individuals with HF. Dimension reduction via Uniform Manifold Approximation and Projection stratified the comorbid DE and HF symptoms. The symptom profiles in each cluster were identified using hierarchical heat maps., Results: This study included 11,284 participants, classified into experiencing HF (9041 participants), non-HF (720 participants), and unknown (1523 participants) groups. The prevalence of symptomatic DE among individuals with HF was 49.99% (4429/9041). Severe DE symptoms were significantly associated with severe HF symptoms: coefficient 1.33 (95% CI 1.10-1.57; P<.001) for mild DE, coefficient 2.16 (95% CI 1.84-2.48; P<.001) for moderate DE, and coefficient 3.80 (95% CI 3.50-4.11; P<.001) for severe DE. The risk factors for comorbid symptomatic DE among individuals with HF were identified as female sex; lower BMI; medicated hypertension; history of hematologic, collagen, heart, liver, respiratory, or atopic disease; tomato allergy; current and previous mental illness; pet ownership; living room and bedrooms furnished with materials other than hardwood, carpet, tatami, and vinyl; discontinuation of contact lens use during the HF season; current contact lens use; smoking habits; and sleep duration of <6 hours per day. Uniform Manifold Approximation and Projection stratified the heterogeneous comorbid DE and HF symptoms into 14 clusters. In the hierarchical heat map, cluster 9 was comorbid with the most severe HF and DE symptoms, and cluster 1 showed severe HF symptoms with minimal DE-related symptoms., Conclusions: This crowdsourced study suggested a significant association between severe DE and HF symptoms. Detecting DE among individuals with HF could allow effective prevention and interventions through concurrent treatment for ocular surface management along with HF treatment., (©Takenori Inomata, Jaemyoung Sung, Masahiro Nakamura, Masao Iwagami, Yasutsugu Akasaki, Kenta Fujio, Masahiro Nakamura, Nobuyuki Ebihara, Takuma Ide, Masashi Nagao, Yuichi Okumura, Ken Nagino, Keiichi Fujimoto, Atsuko Eguchi, Kunihiko Hirosawa, Akie Midorikawa-Inomata, Kaori Muto, Kumiko Fujisawa, Yota Kikuchi, Shuko Nojiri, Akira Murakami. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 12.09.2023.)

The coronavirus disease (COVID-19) pandemic has emphasized the paucity of non-contact and non-invasive methods for the objective evaluation of dry eye disease (DED). However, robust evidence to support the implementation of mHealth- and app-based biometrics for clinical use is lacking. This study aimed to evaluate the reliability and validity of app-based maximum blink interval (MBI) measurements using DryEyeRhythm and equivalent traditional techniques in providing an accessible and convenient diagnosis. In this single-center, prospective, cross-sectional, observational study, 83 participants, including 57 with DED, had measurements recorded including slit-lamp-based, app-based, and visually confirmed MBI. Internal consistency and reliability were assessed using Cronbach's alpha and intraclass correlation coefficients. Discriminant and concurrent validity were assessed by comparing the MBIs from the DED and non-DED groups and Pearson's tests for each platform pair. Bland-Altman analysis was performed to assess the agreement between platforms. App-based MBI showed good Cronbach's alpha coefficient, intraclass correlation coefficient, and Pearson correlation coefficient values, compared with visually confirmed MBI. The DED group had significantly shorter app-based MBIs, compared with the non-DED group. Bland-Altman analysis revealed minimal biases between the app-based and visually confirmed MBIs. Our findings indicate that DryEyeRhythm is a reliable and valid tool that can be used for non-invasive and non-contact collection of MBI measurements, which can assist in accessible DED detection and management., (© 2023. Springer Nature Limited.)

Background: Using traditional patient-reported outcomes (PROs), such as paper-based questionnaires, is cumbersome in the era of web-based medical consultation and telemedicine. Electronic PROs may reduce the burden on patients if implemented widely. Considering promising reports of DryEyeRhythm, our in-house mHealth smartphone app for investigating dry eye disease (DED) and the electronic and paper-based Ocular Surface Disease Index (OSDI) should be evaluated and compared to determine their equivalency., Objective: The purpose of this study is to assess the equivalence between smartphone app-based and paper-based questionnaires for DED., Methods: This prospective, nonblinded, randomized crossover study enrolled 34 participants between April 2022 and June 2022 at a university hospital in Japan. The participants were allocated randomly into 2 groups in a 1:1 ratio. The paper-app group initially responded to the paper-based Japanese version of the OSDI (J-OSDI), followed by the app-based J-OSDI. The app-paper group responded to similar questionnaires but in reverse order. We performed an equivalence test based on minimal clinically important differences to assess the equivalence of the J-OSDI total scores between the 2 platforms (paper-based vs app-based). A 95% CI of the mean difference between the J-OSDI total scores within the ±7.0 range between the 2 platforms indicated equivalence. The internal consistency and agreement of the app-based J-OSDI were assessed with Cronbach α coefficients and intraclass correlation coefficient values., Results: A total of 33 participants were included in this study. The total scores for the app- and paper-based J-OSDI indicated satisfactory equivalence per our study definition (mean difference 1.8, 95% CI -1.4 to 5.0). Moreover, the app-based J-OSDI total score demonstrated good internal consistency and agreement (Cronbach α=.958; intraclass correlation=0.919; 95% CI 0.842 to 0.959) and was significantly correlated with its paper-based counterpart (Pearson correlation=0.932, P<.001)., Conclusions: This study demonstrated the equivalence of PROs between the app- and paper-based J-OSDI. Implementing the app-based J-OSDI in various scenarios, including telehealth, may have implications for the early diagnosis of DED and longitudinal monitoring of PROs., (©Ken Nagino, Yuichi Okumura, Yasutsugu Akasaki, Kenta Fujio, Tianxiang Huang, Jaemyoung Sung, Akie Midorikawa-Inomata, Keiichi Fujimoto, Atsuko Eguchi, Shokirova Hurramhon, Alan Yee, Maria Miura, Mizu Ohno, Kunihiko Hirosawa, Yuki Morooka, Akira Murakami, Hiroyuki Kobayashi, Takenori Inomata. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 03.08.2023.)

Background: Multidisciplinary efforts to prospectively collect and analyze symptoms of hay fever are limited. We aimed to identify the characteristics of nasal and ocular symptoms of hay fever, using the AllerSearch smartphone application., Methods: This mobile health-based prospective observational study using the AllerSearch smartphone application was conducted between February 1, 2018, and May 1, 2020. Individuals who downloaded AllerSearch from Japan and provided comprehensive self-assessments (including 17 items related to quality of life [QoL]-related items) were included. The characteristics and risk factors for allergic rhinitis (AR) and allergic conjunctivitis (AC) were identified using hierarchical heat maps and multivariate logistic regression., Results: Of the 9041 participants with hay fever, 58.8% had AR and AC, 22.2% had AR, and 5.7% had AC. The AR-AC comorbid cohort showed worse symptoms of hay fever and QoL scores than the other cohorts. Factors (odds ratio, 95% confidence interval) associated with AR-AC included a lower age (0.98, 0.97-0.98), female sex (1.31, 1.19-1.45), liver disease (1.58, 1.26-2.35), dry eye disease (1.45, 1.30-1.63), unknown dry eye disease status (1.46, 1.31-1.62), contact lens use discontinuation during the hay fever season (1.69, 1.28-2.23), and bedroom flooring material other than hardwood, carpet, tatami, or vinyl (1.91, 1.16-3.14)., Conclusions: Analysis of medical big data for hay fever performed using a mobile health app helped identify risk factors and characteristics of AC, AR, and AR-AC. Phenotyping of highly variable symptoms of hay fever, such as nasal and ocular symptoms, can facilitate better-quality clinical care., (Copyright © 2023 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

Topic: Numerous smartphone applications have been devised for diagnosis, treatment, and symptom management in ophthalmology. Despite the importance of systematic evaluation of the purpose, target disease, effectiveness, and utility of smartphone applications to their effective utilization, few studies have formally evaluated their validity, reliability, and clinical utility., Clinical Relevance: This report identifies smartphone applications with potential for clinical implementation in ophthalmology and summarizes the evidence on their practical utility., Methods: We searched PubMed and EMBASE on July 28, 2022, for articles reporting original data on the effectiveness of treatment, disease detection, diagnostic accuracy, disease monitoring, and usability of smartphone applications in ophthalmology published between January 1, 1987, and July 25, 2022. Their quality was assessed using the Joanna Briggs Institute Critical Appraisal Checklist., Results: The initial search yielded 510 articles. After removing 115 duplicates and 285 articles based on inclusion and exclusion criteria, the full texts of the remaining 110 articles were reviewed. Furthermore, 71 articles were included in the final qualitative synthesis. All studies were determined to be of high (87.3%) or moderate (12.7%) quality. In terms of respective application of interest, 24 (33.8%) studies assessed diagnostic accuracy, 17 (23.9%) assessed disease detection, and 3 (4.2%) assessed intervention efficacy. A total of 48 smartphone applications were identified, of which 27 (56.3%) were publicly available. Seventeen (35.4%) applications included functions for ophthalmic examinations, 13 (27.1%) included functions aimed at disease detection, 10 (20.8%) included functions to support medical personnel, five (10.4%) included functions related to disease education, and three (6.3%) included functions to promote treatment adherence for patients. The largest number of applications targeted amblyopia (18.8%), followed by retinal disease (10.4%). Two (4.2%) smartphone applications reported significant efficacy in treating diseases., Conclusion: In this systematic review, a comprehensive appraisal is presented on studies related to diagnostic accuracy, disease detectability, and efficacy of smartphone applications in ophthalmology. Forty-eight applications with potential clinical utility are identified. Appropriate smartphone applications are expected to enable early detection of undiagnosed diseases via telemedicine and prevent visual dysfunction via remote monitoring of chronic diseases., Financial Disclosures: Proprietary or commercial disclosure may be found after the references., (© 2023 by the American Academy of Ophthalmology.)

Background: Hay fever is a common allergic disease, with an estimated worldwide prevalence of 14.4% and a variety of symptoms. This study assessed the minimal clinically important difference (MCID) of nasal symptom score (NSS), non-nasal symptom score (NNSS), and total symptoms score (TSS) for app-based hay-fever monitoring., Methods: MCIDs were calculated based on the data from a previous large-scale, crowdsourced, cross-sectional study using AllerSearch, an in-house smartphone application. MCIDs were determined with anchor-based and distribution-based methods. The face scale score of the Japanese Allergic Conjunctival Disease Standard Quality of Life Questionnaire Domain III and the daily stress level due to hay fever were used as anchors for determining MCIDs. The MCID estimates were summarized as MCID ranges., Results: A total of 7590 participants were included in the analysis (mean age: 35.3 years, 57.1% women). The anchor-based method produced a range of MCID values (median, interquartile range) for NSS (2.0, 1.5-2.1), NNSS (1.0, 0.9-1.2), and TSS (2.9, 2.4-3.3). The distribution-based method produced two MCIDs (based on half a standard deviation, based on a standard error of measurement) for NSS (2.0, 1.8), NNSS (1.3, 1.2), and TSS (3.0, 2.3). The final suggested MCID ranges for NSS, NNSS, and TSS were 1.8-2.1, 1.2-1.3, and 2.4-3.3, respectively., Conclusions: MCID ranges for app-based hay-fever symptom assessment were obtained from the data collected through a smartphone application, AllerSearch. These estimates may be useful for monitoring the subjective symptoms of Japanese patients with hay fever through mobile platforms., (© 2023 The Authors. Clinical and Translational Allergy published by John Wiley & Sons Ltd on behalf of European Academy of Allergy and Clinical Immunology.)

Background: Although additional treatment is considered for patients with esophageal squamous cell carcinoma (ESCC) invading into the muscularis mucosa (pT1a-MM) or submucosa (pT1b-SM) after endoscopic submucosal dissection (ESD), the actual benefits of this method remain to be elucidated., Aims: We aimed to evaluate the prognostic benefits of additional treatment in such patients., Methods: Between 2006 and 2017, we enrolled patients with pT1a-MM/pT1b-SM ESCC after ESD at 21 institutions in Japan. Overall survival (OS) and disease-specific survival (DSS) were compared between the additional treatment and follow-up groups after propensity score matching, to reduce the bias of baseline characteristics. A subgroup analysis was performed according to the pathological findings: category A, pT1a-MM but negative for lymphovascular invasion (LVI) and vertical margin (VM); category B, tumor invasion into the submucosa ≤ 200 μm but negative for LVI and VM; category C, others., Results: Of 593 patients with pT1a-MM/pT1b-SM ESCC after ESD, 101 matched pairs were extracted after propensity score matching. The OSs were similar between the additional treatment and follow-up groups (80.6% vs. 78.6% in 5 years; P = 0.972). In a subgroup analysis, the OS in the additional treatment group was significantly lower than that in the follow-up group (65.7% vs. 95.2% in 5 years; P = 0.037) in category A, whereas OS did not significantly differ in category C (76.8% vs. 69.5% in 5 years; P = 0.360)., Conclusions: Additional treatment after ESD in patients with pT1a-MM/pT1b-SM ESCC was not associated with an improved prognosis., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Dry eye disease (DED) is one of the most common ocular surface diseases. Numerous patients with DED remain undiagnosed and inadequately treated, experiencing various subjective symptoms and a decrease in quality of life and work productivity. A mobile health smartphone app, namely, the DEA01, has been developed as a noninvasive, noncontact, and remote screening device, in the context of an ongoing paradigm shift in the health care system, to facilitate a diagnosis of DED., Objective: This study aimed to evaluate the capabilities of the DEA01 smartphone app to facilitate a DED diagnosis., Methods: In this multicenter, open-label, prospective, and cross-sectional study, the test method will involve using the DEA01 smartphone app to collect and evaluate DED symptoms, based on the Japanese version of the Ocular Surface Disease Index (J-OSDI), and to measure the maximum blink interval (MBI). The standard method will then involve a paper-based J-OSDI evaluation of subjective symptoms of DED and tear film breakup time (TFBUT) measurement in an in-person encounter. We will allocate 220 patients to DED and non-DED groups, based on the standard method. The primary outcome will be the sensitivity and specificity of the DED diagnosis according to the test method. Secondary outcomes will be the validity and reliability of the test method. The concordance rate, positive and negative predictive values, and the likelihood ratio between the test and standard methods will be assessed. The area under the curve of the test method will be evaluated using a receiver operating characteristic curve. The internal consistency of the app-based J-OSDI and the correlation between the app-based J-OSDI and paper-based J-OSDI will be assessed. A DED diagnosis cutoff value for the app-based MBI will be determined using a receiver operating characteristic curve. The app-based MBI will be assessed to determine a correlation between a slit lamp-based MBI and TFBUT. Adverse events and DEA01 failure data will be collected. Operability and usability will be assessed using a 5-point Likert scale questionnaire., Results: Patient enrollment will start in February 2023 and end in July 2023. The findings will be analyzed in August 2023, and the results will be reported from March 2024 onward., Conclusions: This study may have implications in identifying a noninvasive, noncontact route to facilitate a diagnosis of DED. The DEA01 may enable a comprehensive diagnostic evaluation within a telemedicine setting and facilitate early intervention for undiagnosed patients with DED confronting health care access barriers., Trial Registration: Japan Registry of Clinical Trials jRCTs032220524; https://jrct.niph.go.jp/latest-detail/jRCTs032220524., International Registered Report Identifier (irrid): PRR1-10.2196/45218., (©Ken Nagino, Yuichi Okumura, Masahiro Yamaguchi, Jaemyoung Sung, Masashi Nagao, Kenta Fujio, Yasutsugu Akasaki, Tianxiang Huang, Kunihiko Hirosawa, Masao Iwagami, Akie Midorikawa-Inomata, Keiichi Fujimoto, Atsuko Eguchi, Yukinobu Okajima, Koji Kakisu, Yuto Tei, Takefumi Yamaguchi, Daisuke Tomida, Masaki Fukui, Yukari Yagi-Yaguchi, Yuichi Hori, Jun Shimazaki, Shuko Nojiri, Yuki Morooka, Alan Yee, Maria Miura, Mizu Ohno, Takenori Inomata. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 13.03.2023.)

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.)

We investigated and characterized the prevalence of dry eye disease (DED) in Parkinson's disease (PD). PubMed and EMBASE databases were searched for relevant studies between January 1, 1979 and March 10, 2022. Quality was assessed using the Joanna Briggs Institute Critical Appraisal Checklist. Study-specific estimates were combined using the DerSimonian-Laird random-effects model. Prevalence of subjective DED symptoms in patients with PD and mean differences in blink rate, corneal thickness, tear film breakup time, and tear secretion volume on Schirmer test I were compared to those in controls. Of 383 studies, 13 (1519 patients with PD) and 12 were included in qualitative and quantitative syntheses, respectively. Meta-analysis revealed a 61.1% prevalence of subjective DED symptoms in PD and that, compared with controls, patients with PD had significantly lower blink rate, thinner corneal thickness, shorter tear film breakup time, and lower tear secretion volumes on Schirmer test I, without and with anesthesia., (© 2022. The Author(s).)

Objectives: We aimed to clarify the prognostic factors for patients with esophageal squamous cell carcinoma (ESCC) invading into the muscularis mucosa (pT1a-MM) or submucosa (pT1b-SM) after endoscopic submucosal dissection (ESD)., Methods: This retrospective study enrolled such patients at 21 institutions in Japan between 2006 and 2017. We evaluated 15 factors, including pathological risk categories for ESCC-specific mortality, six non-cancer-related indices, and treatment strategies., Results: In the analysis of 593 patients, the 5-year overall and disease-specific survival rates were 83.0% and 97.6%, respectively. In a multivariate Cox analysis, male sex (hazard ratio [HR] 3.56), Charlson comorbidity index (CCI) ≥3 (HR 2.53), ages of 75-79 (HR 1.61) and ≥80 years (HR 2.04), prognostic nutrition index (PNI) <45 (HR 1.69), and pathological intermediate-risk (HR 1.63) and high-risk (HR 1.89) were prognostic factors. Subsequently, we developed a clinical risk classification for non-ESCC-related mortality based on the number of prognostic factors (age ≥75 years, male sex, CCI ≥3, PNI <45): low-risk, 0; intermediate-risk, 1-2; and high-risk, 3-4. The 5-year non-ESCC-related mortality rates for patients without additional treatment were 0.0%, 10.2%, and 45.8% in the low-, intermediate-, and high-risk groups, respectively. Meanwhile, the 5-year ESCC-specific mortality rates for the pathological low-, intermediate-, and high-risk groups were 0.3%, 5.3%, and 18.2%, respectively., Conclusions: We clarified prognostic factors for patients with pT1a-MM/pT1b-SM ESCC after ESD. The combined assessment of non-ESCC- and ESCC-related mortalities by the two risk classifications might help clinicians in deciding treatment strategies for such patients., (© 2022 Japan Gastroenterological Endoscopy Society.)

Background: Hay fever is a highly prevalent, heterogenous, and multifactorial disease. Patients may benefit from longitudinal assessments using mobile health (mHealth) principles. We have previously attempted to establish an effective mHealth platform for patients with hay fever through AllerSearch, our in-house smartphone app that assesses electronic patient-reported outcomes through a questionnaire on hay fever and provides evidence-based advice. To be used by the public, an investigation on its reliability and validity is necessary., Objective: The aim of this paper is to assess the reliability and validity of subjective symptom data on hay fever collected through our app, AllerSearch., Methods: This study used a prospective observational design. The participants were patients aged ≥20 years recruited from a single university hospital between June 2, 2021, and January 26, 2022. We excluded patients who could not use smartphones as well as those with incomplete data records and outlier data. All participants answered the Japanese Allergic Conjunctival Disease Standard Quality of Life Questionnaire (JACQLQ), first in the paper-and-pencil format and subsequently on AllerSearch on the same day. The JACQLQ comprises the following three domains: Domain I, with 9 items on ocular or nasal symptoms; Domain II, with 17 items on daily activity and psychological well-being; and Domain III, with 3 items on overall condition by face score. The concordance rate of each domain between the 2 platforms was calculated. The internal consistency of Domains I and II of the 2 platforms was assessed using Cronbach alpha coefficients, the concurrent validity of Domains I and II was assessed by calculating Pearson correlation coefficients, and the mean differences between the 2 platforms were assessed using Bland-Altman analysis., Results: In total, 22 participants were recruited; the data of 20 (91%) participants were analyzed. The average age was 65.4 (SD 12.8) years, and 80% (16/20) of the participants were women. The concordance rate of Domains I, II, and III between the paper-based and app-based JACQLQ was 0.78, 0.85, and 0.90, respectively. The internal consistency of Domains I and II between the 2 platforms was satisfactory (Cronbach alpha of .964 and .919, respectively). Pearson correlation analysis yielded a significant positive correlation between Domains I and II across the 2 platforms (r=0.920 and r=0.968, respectively). The mean difference in Domains I and II between the 2 platforms was 3.35 units (95% limits of agreement: -6.51 to 13.2)., Conclusions: Our findings indicate that AllerSearch is a valid and reliable tool for the collection of electronic patient-reported outcomes to assess hay fever, contributing to the advantages of the mHealth platform., (©Yasutsugu Akasaki, Takenori Inomata, Jaemyoung Sung, Yuichi Okumura, Kenta Fujio, Maria Miura, Kunihiko Hirosawa, Masao Iwagami, Masahiro Nakamura, Nobuyuki Ebihara, Masahiro Nakamura, Takuma Ide, Ken Nagino, Akira Murakami. Originally published in JMIR Formative Research (https://formative.jmir.org), 23.08.2022.)

This study aimed to determine the characteristics and clinical ocular manifestations of acute corneal graft rejection after coronavirus disease 2019 (COVID-19) vaccination. We conducted an online search of the PubMed and EMBASE databases. Data on recipients' characteristics, corneal transplantation types, interval between vaccination and allograft rejection, clinical manifestations, and graft rejection medication were extracted. Thirteen articles on 21 patients (23 eyes) with acute corneal graft rejection after COVID-19 vaccination, published between April and December 2021, were included. The median (interquartile range) age at the onset of rejection was 68 (27-83) years. Types of transplantation included penetrating keratoplasty (12 eyes), Descemet membrane endothelial keratoplasty (six eyes), Descemet stripping automated endothelial keratoplasty (four eyes), and living-related conjunctival-limbal allograft (one eye). The interval between vaccination and rejection ranged from 1 day to 6 weeks. Corneal edema was the leading clinical manifestation (20 eyes), followed by keratic precipitates (14 eyes) and conjunctival or ciliary injection (14 eyes). Medications included frequently applied topical corticosteroids (12 eyes), followed by a combination of topical and oral corticosteroids (four eyes). In addition, the clinical characteristics of corneal allograft rejection after COVID-19 vaccination were identified. Corneal transplant recipients may require further vaccination, necessitating appropriate management and treatment.

Dry eye disease (DED) after cataract surgery is associated with various risk factors, while causing a wide range of heterogeneous symptoms including decreased quality of vision. This systematic review and meta-analysis aimed to determine the prevalence and characteristics of DED after cataract surgery. We searched PubMed and EMBASE and included studies on patients with DED after cataract surgery, between January 2011 and June 2020. Study-specific estimates (DED prevalence rates after cataract surgery in patients without preexisting DED) were combined using one-group meta-analysis in a random-effects model. We included 36 studies published between 2013 and 2020. We included nine of these in the meta-analysis of DED prevalence after cataract surgery. Overall 37.4% (95% CI 22.6-52.3; 206/775) of patients without preexisting DED developed DED after cataract surgery. The risk factors for DED after cataract surgery included age, female sex, systemic diseases, systemic medications, psychiatric conditions, preexisting DED, meibomian gland dysfunction, preservatives in eye drops, surgery techniques, and lifestyle. DED severity peak occurred 1 day postoperatively and persisted for at least 1-12 months following cataract surgery; therefore, consistent follow-up for DED is warranted for at least 1 month after cataract surgery. Topical administration of preservative-free diquafosol tetrasodium solution and preoperative meibomian gland treatment were effective in preventing and treating DED following cataract surgery. As more than one-third of patients develop DED after cataract surgery, careful DED management and treatment is needed after cataract surgery to improve satisfaction and vision quality., (© 2022. The Author(s).)

Purpose: Undiagnosed or inadequately treated dry eye disease (DED) decreases the quality of life. We aimed to investigate the reliability, validity, and feasibility of the DryEyeRhythm smartphone application (app) for the diagnosis assistance of DED., Methods: This prospective, cross-sectional, observational, single-center study recruited 82 participants (42 with DED) aged ≥20 years (July 2020-May 2021). Patients with a history of eyelid disorder, ptosis, mental disease, Parkinson's disease, or any other disease affecting blinking were excluded. Participants underwent DED examinations, including the Japanese version of the Ocular Surface Disease Index (J-OSDI) and maximum blink interval (MBI). We analyzed their app-based J-OSDI and MBI results. Internal consistency reliability and concurrent validity were evaluated using Cronbach's alpha coefficients and Pearson's test, respectively. The discriminant validity of the app-based DED diagnosis was assessed by comparing the results of the clinical-based J-OSDI and MBI. The app feasibility and screening performance were evaluated using the precision rate and receiver operating characteristic curve analysis., Results: The app-based J-OSDI showed good internal consistency (Cronbach's α = 0.874). The app-based J-OSDI and MBI were positively correlated with their clinical-based counterparts (r = 0.891 and r = 0.329, respectively). Discriminant validity of the app-based J-OSDI and MBI yielded significantly higher total scores for the DED cohort (8.6 ± 9.3 vs. 28.4 ± 14.9, P < 0.001; 19.0 ± 11.1 vs. 13.2 ± 9.3, P < 0.001). The app's positive and negative predictive values were 91.3% and 69.1%, respectively. The area under the curve (95% confidence interval) was 0.910 (0.846-0.973) with concurrent use of the app-based J-OSDI and MBI., Conclusions: DryEyeRhythm app is a novel, non-invasive, reliable, and valid instrument for assessing DED., (Copyright © 2022 Elsevier Inc. All rights reserved.)

This systematic review aimed to determine the comorbid dry eye (DE) and allergic conjunctivitis (AC) prevalence. We searched PubMed and EMBASE for articles published until 22 March 2022, combining the terms "(dry eye OR keratoconjunctivitis sicca) AND allergic conjunctivitis." Study-specific estimates (DE and AC incidence rates among patients with AC and DE, respectively) were combined using the one-group meta-analysis in a random-effects model. The initial search yielded 700 studies. Five articles reporting AC incidence among individuals with DE and six articles reporting DE incidence among individuals with AC were included in the qualitative synthesis. In these nine articles, the total sample size was 7254 patients. The DE incidence among individuals with AC was 0.9-97.5%; the AC incidence among individuals with DE was 6.2-38.0%. One-group meta-analysis using a random-effects model showed that 47.2% (95% confidence interval: 0.165-0.779; 320/1932 cases) of patients with AC had comorbid DE and 17.8% (95% confidence interval: 0.120-0.236; 793/4855 cases) of patients with DE had comorbid AC, as defined by each article. Complimentary screening and treatment for patients with DE and AC may improve long-term outcomes and prevent chronic ocular damage in highly susceptible populations.

We investigated the effects of anti-CD80/86 antibodies in a murine high-risk corneal transplantation rejection model. A mixed lymphocyte reaction (MLR) assay was conducted with anti-CD80/86 antibodies. Inflammatory cytokine levels in the culture supernatant were measured using an enzyme-linked immunosorbent assay. Interferon (IFN)-γ-producing CD4 + T cell frequencies in the MLR were assessed using flow cytometry. In vivo, high-risk corneal allograft survival and IFN-γ-producing CD4 + T cell frequencies in corneal grafts were assessed with intraperitoneal injection of anti-CD80/86 antibodies compared to phosphate-buffered saline (PBS). RNA-sequencing was performed on corneal grafts 2 weeks post-transplantation. Anti-CD80/86 antibodies significantly decreased T-cell proliferation, IFN-γ + -producing CD4 + T cell frequencies, and IFN-γ, interleukin (IL)-1β, IL-2, IL-10, and tumor necrosis factor-α production in the MLR compared to PBS injection. Intraperitoneal injection of anti-CD80/86 antibodies significantly prolonged corneal graft survival and decreased IFN-γ + -producing CD4 + T cell frequencies compared to PBS injection. Gene set enrichment analysis showed that the gene sets mainly enriched in the control group were related to allograft rejection and inflammatory response compared to PBS injection. Anti-CD80/86 antibodies significantly prolonged corneal graft survival by inhibiting T-cell proliferation and inflammatory response., (© 2022. The Author(s).)

Different pathophysiologic mechanisms are involved in the initiation, development, and outcome of dry eye disease (DED). Animal models have proven valuable and efficient in establishing ocular surface microenvironments that mimic humans, thus enabling better understanding of the pathogenesis. Several dry eye animal models, including lacrimal secretion insufficiency, evaporation, neuronal dysfunction, and environmental stress models, are related to different etiological factors. Other models may be categorized as having a multifactorial DED. In addition, there are variations in the methodological classification, including surgical lacrimal gland removal, drug-induced models, irradiation impairment, autoimmune antibody-induced models, and transgenic animals. The aforementioned models may manifest varying degrees of severity or specific pathophysiological mechanisms that contribute to the complexity of DED. This review aimed to summarize various dry eye animal models and evaluate their respective characteristics to improve our understanding of the underlying mechanism and identify therapeutic prospects for clinical purposes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhu, Inomata, Shih, Okumura, Fujio, Huang, Nagino, Akasaki, Fujimoto, Yanagawa, Miura, Midorikawa-Inomata, Hirosawa, Kuwahara, Shokirova, Eguchi, Morooka, Chen and Murakami.)

Multidimensional integrative data analysis of digital phenotyping is crucial for elucidating the pathologies of multifactorial and heterogeneous diseases, such as the dry eye (DE). This crowdsourced cross-sectional study explored a novel smartphone-based digital phenotyping strategy to stratify and visualize the heterogenous DE symptoms into distinct subgroups. Multidimensional integrative data were collected from 3,593 participants between November 2016 and September 2019. Dimension reduction via Uniform Manifold Approximation and Projection stratified the collected data into seven clusters of symptomatic DE. Symptom profiles and risk factors in each cluster were identified by hierarchical heatmaps and multivariate logistic regressions. Stratified DE subgroups were visualized by chord diagrams, co-occurrence networks, and Circos plot analyses to improve interpretability. Maximum blink interval was reduced in clusters 1, 2, and 5 compared to non-symptomatic DE. Clusters 1 and 5 had severe DE symptoms. A data-driven multidimensional analysis with digital phenotyping may establish predictive, preventive, personalized, and participatory medicine., (© 2021. The Author(s).)

Corneal transplantation is one of the most successful forms of solid organ transplantation; however, immune rejection is still a major cause of corneal graft failure. Both innate and adaptive immunity play a significant role in allograft tolerance. Therefore, immune cells, cytokines, and signal-transduction pathways are critical therapeutic targets. In this analysis, we aimed to review the current literature on various immunotherapeutic approaches for corneal-allograft rejection using the PubMed, EMBASE, Web of Science, Cochrane, and China National Knowledge Infrastructure. Retrievable data for meta-analysis were screened and assessed. The review, which evaluated multiple immunotherapeutic approaches to prevent corneal allograft rejection, showed extensive involvement of innate and adaptive immunity components. Understanding the contribution of this immune diversity to the ocular surface is critical for ensuring corneal allograft survival.

Background: We aimed to elucidate the risk of metastatic recurrence after endoscopic resection (ER) without additional treatment for esophageal squamous cell carcinomas (ESCCs) with tumor invasion into the muscularis mucosa (pT1a-MM) or submucosa (T1b-SM)., Methods: We retrospectively enrolled patients with pT1a-MM/pT1b-SM ESCC after ER at 21 institutions in Japan between 2006 and 2017. We compared metastatic recurrence between patients with and without additional treatment, stratified into category A (pT1a-MM with negative lymphovascular invasion [LVI] and vertical margin [VM]), B (tumor invasion into the submucosa ≤ 200 µm [pT1b-SM1] with negative LVI and VM), and C (others). Subsequently, using multivariate Cox analysis, we evaluated risk factors for metastatic recurrence after ER without additional treatment., Results: We enrolled 593 patients, and metastatic recurrence occurred in 38 patients. Metastatic recurrence after additional treatment was significantly lower than that after no additional treatment in category C (9.1% vs. 23.6% in 5 years, p = 0.001), whereas no significant difference was noted in categories A (0.0% vs. 2.6%) and B (0.0% vs. 4.3%). In patients without additional treatment after ER, risk factors for metastatic recurrence were lymphatic invasion (hazard ratio [HR], 5.61), positive VM (HR, 4.55), and tumor invasion into the submucosa > 200 μm (HR, 3.25), and, but near half of the patients with metastatic recurrence had no further recurrence after salvage treatment, resulting in excellent 5-year disease-specific survival in categories A (99.6%) and B (100.0%)., Conclusions: Closed follow-up with no additional treatment may be an acceptable option after ER in pT1a-MM/pT1b-SM1 ESCC with negative LVI and VM., (© 2021. Japanese Society of Gastroenterology.)

Purpose: To investigate the effects of ex vivo-induced bone marrow myeloid-derived suppressor cells (BM-MDSCs) on allogeneic immune responses in corneal transplantation., Methods: Bone marrow cells from C57BL/6J (B6) mice were cultured with IL-6 and GM-CSF for four days. The ex vivo induction of the BM-MDSCs was assessed using flow cytometry, inducible nitric oxide synthase (iNOS) mRNA expression using reverse transcription-quantitative polymerase chain reaction, and nitric oxide (NO) production in allogeneic stimulation. T-cell proliferation and regulatory T-cell (Treg) expansion were investigated on allogeneic stimulation in the presence of ex vivo-induced BM-MDSCs. IFN-γ, IL-2, IL-10, and TGF-β1 protein levels were measured using enzyme-linked immunosorbent assays. After subconjunctival injection of ex vivo-induced BM-MDSCs, the migration of the BM-MDSCs into corneal grafts, allogeneic corneal graft survival, neovascularization, and lymphangiogenesis were assessed using flow cytometry, slit-lamp microscopy, and immunohistochemistry., Results: The combination of GM-CSF and IL-6 significantly induced BM-MDSCs with increased iNos mRNA expression. The ex vivo-induced BM-MDSCs promoted NO release in allogeneic stimulation in vitro. The ex vivo-induced BM-MDSCs inhibited T-cell proliferation and promoted Treg expansion. Decreased IFN-γ and increased IL-2, IL-10, and TGF-β1 production was observed in coculture of ex vivo-induced BM-MDSCs. Injected ex vivo-induced BM-MDSCs were confirmed to migrate into the grafts. The injected BM-MDSCs also prolonged corneal graft survival and prevented angiogenesis and lymphangiogenesis., Conclusions: The ex vivo-induced BM-MDSCs have suppressive effects on allogeneic immune responses and prolong corneal allograft survival via the iNOS pathway, indicating that they may be a potential therapeutic tool for corneal transplantation.

Corneal neovascularization (CNV) causes higher-order aberrations, corneal edema, ocular inflammation, and corneal transplant rejection, thereby decreasing visual acuity. In this study, we investigated the effects of topical administration of the kappa opioid receptor agonist nalfurafine (TRK-820) on CNV. To induce CNV, intrastromal corneal sutures were placed on the corneal stroma of BALB/c mice for 2 weeks. Nalfurafine (0.1 µg/2 μL/eye) was topically administered to the cornea once or twice daily after CNV induction. The CNV score, immune cell infiltration, and mRNA levels of angiogenic and pro-inflammatory factors in neovascularized corneas were evaluated using slit-lamp microscopy, immunohistochemistry, flow cytometry, and polymerase chain reaction. The mRNA expression of the kappa opioid receptor gene Oprk1 was significantly upregulated following CNV induction. Topical administration of nalfurafine twice daily significantly suppressed CNV and lymphangiogenesis, as well as reduced the mRNA levels of angiogenic and pro-inflammatory factors in the neovascularized corneas. Moreover, nalfurafine administration twice daily reduced the numbers of infiltrating leukocytes, neutrophils, macrophages, and interferon-γ-producing CD4 + T cells in the neovascularized corneas. In this study, we demonstrated that topical administration of nalfurafine suppressed local CNV in a mouse model along with the activation of KOR, suggesting that nalfurafine may prevent and control CNV in humans.