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Norihiko Yokoi,1 Aoi Komuro,1 Chie Sotozono,1 Shigeru Kinoshita2 1Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan; 2Department of Frontier Medical Science and Technology for Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan Purpose: Surgical punctal occlusion is indispensable for the treatment of severe dry eye in cases where punctal-plug insertion is not applicable due to an enlarged or deformed punctum. However, permanent punctal occlusion is difficult in some cases. In our aim to establish a more reliable punctal occlusion, we have devised a new surgical approach for punctal occlusion.Patients and methods: This study involved 20 puncta of 12 eyes of 12 patients (1 male and 11 females; mean age: 65.2 years) with severe aqueous-tear-deficient dry eye. A new surgical procedure for punctal occlusion using fibrous tissue from under the lacrimal caruncle into the diathermy-induced deepithelialized canaliculus as supporting tissue for punctal closure was performed. In all patients, the assessment of eye symptoms, as well as the condition of punctal occlusion by slit-lamp biomicroscopy, tear volume (tear-meniscus radius [TMR] measurement by meniscometry), the condition of precorneal tear film (graded by interferometry [IG]), measurement of fluorescein breakup time (FBUT), and scoring of ocular surface staining (fluorescein score of area [FSA] and density [FSD], and lissamine green score [LGS]) were performed, and the preoperative and 6-month-postoperative values were compared.Results: In regard to the postoperative improvement of symptoms, 11 patients showed remarkable improvement, 1 patient showed improvement, and no reopening of the closed punctum was found in any patient. Test values were all significantly improved post surgery (all: P

Motoko Kawashima,1 Miki Uchino,1,2 Norihiko Yokoi,3 Yuichi Uchino,1,2 Murat Dogru,1 Aoi Komuro,3 Yukiko Sonomura,3 Hiroaki Kato,3 Shigeru Kinoshita,3 Kazuo Tsubota1 1Department of Ophthalmology, Keio University School of Medicine, Shinjuku-ku, 2Ryogoku Eye Clinic, Sumida-ku, Tokyo, 3Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan Purpose: To investigate the association of dry eye disease with sleep quality. Methods: In 2011, a cross-sectional survey was conducted among all the employees, mainly young and middle-aged Japanese office workers, who used visual display technology, at a company in Osaka, Japan (N=672; age range =26–64 years). The participants were classified according to the Japanese dry eye diagnosis criteria by dry eye examination results including the Schirmer test, fluorescein and lissamine green staining, tear film break-up time, and symptom questionnaire into three groups as follows: definite dry eye disease, probable dry eye disease, and no dry eye disease. To determine sleep quality, Japanese version of the Pittsburgh Sleep Quality Index (global score) was implemented. The global score (range =0–21) was calculated by summing seven sleep variable scores (scale, 0–3); scores ≥5.5 indicated poor sleep. Results: The total mean global score was 5.1±2.3 (completed N=383); 45% of the dry eye disease participants reported having poor sleep quality, while 34% of the no dry eye disease participants did so, with a significant difference found in the global score (P=0.002). Furthermore, a statistically significant association was observed between the global score and dry eye disease (P=0.005). Conclusion: Poor sleep quality is associated with dry eye disease, especially with dry eye symptoms. Keywords: dry eye, sleep quality, symptom, questionnaire, Pittsburgh Sleep Quality Index, tear film break-up time, visual display terminals

Abstract Lymphocytic myocarditis (LM) is primarily triggered by various factors including viral infections and subsequent immune responses. While rare, some patients with LM experience recurrence with a life‐threatening fulminant form. Although combining steroids and immunosuppressants, such as azathioprine and mycophenolate mofetil, has demonstrated favourable outcomes in patients with LM, their efficacy is limited to the chronic phase. Indeed, various immunosuppressants have been used for LM with fulminant manifestation; however, their evidence remains lacking. In our case series, two patients with LM experienced fulminant relapses during steroid tapering, and another presented persistent cardiac enzymes elevation despite steroid therapies. Consequently, we initiated calcineurin inhibitors alongside steroids, resulting in well‐controlled clinical courses without further recurrence of LM and significant adverse effects. Our cases suggest calcineurin inhibitors as therapeutic options for managing steroid‐resistant LM with fulminant relapse.

Isolation of tumor-specific T cells and their antigen receptors (TCRs) from malignant pleural effusions (MPE) may facilitate the development of TCR-transduced adoptive cellular immunotherapy products for advanced lung cancer patients. However, the characteristics and markers of tumor-specific T-cells in MPE are largely undefined. To this end, to establish the phenotypes and antigen specificities of CD8+ T cells, we performed single-cell RNA and TCR sequencing of samples from three advanced lung cancer patients. Dimensionality reduction on a total of 4,983 CD8+ T cells revealed 10 clusters including naïve, memory, and exhausted phenotypes. We focused particularly on exhausted T cell clusters and tested their TCR reactivity against neoantigens predicted from autologous cancer cell lines. Four different TCRs specific for the same neoantigen and one orphan TCR specific for the autologous cell line were identified from one of the patients. Differential gene expression analysis in tumor-specific T cells relative to the other T cells identified CXCL13, as a candidate gene expressed by tumor-specific T cells. In addition to expressing CXCL13, tumor-specific T cells were present in a higher proportion of T cells co-expressing PDCD1(PD-1)/TNFRSF9(4-1BB). Furthermore, flow cytometric analyses in advanced lung cancer patients with MPE documented that those with high PD-1/4-1BB expression have a better prognosis in the subset of 57 adenocarcinoma patients (p = .039). These data suggest that PD-1/4-1BB co-expression might identify tumor-specific CD8+ T cells in MPE, which are associated with patients’ prognosis. (233 words)

Introduction: Isolated h-type tracheoesophageal fistula (H-TEF) without esophageal discontinuity is rare and poses challenges in selecting a surgical approach due to the height of the fistula within the thoracic cavity. Case presentation: A female neonate was born prematurely at 31 weeks of gestation with a weight of 1200 g. She was intubated at birth due to respiratory distress. She was later diagnosed with CHARGE syndrome. Nasogastric tube feedings were initiated shortly after birth. Air bubbles could be seen coming out the nasogastric tube, which were suspicious for a tracheoesophageal fistula (TEF). A contrast esophagogram confirmed an h-type TEF at the level of the second thoracic vertebral body. When the patient was five months old and had a weight of 3 Kg, she was taken to the operating room for a thoracoscopic repair of the TEF. She was placed in complete left lateral position. Four 5-mm ports were placed in the right hemithorax. The right vagus nerve was identified. We first created a pleural flap with the mediastinal pleura. Blunt dissection of the esophagus and the trachea allowed clear identification of the TEF. A vessel loop was placed around the TEF. The TEF was divided. The esophageal end the tracheal sides of the TEF were closed with interrupted stitches. The pleural flap was interposed between the two stumps. The operation took 238 minutes. The postoperative period was uneventful, and she had no recurrence of the TEF. She underwent a tracheostomy one month later, and a laparoscopic fundoplication three months after that. She was discharged home at one year of age. Conclusion: Thoracoscopy appears to be a suitable approach for the repair of high thoracic h-type TEF.

Abstract Background The risk of subsequent cardiovascular disease (CVD) is high in cancer survivors. Although metabolic syndrome is an established risk factor for CVD, its association with cancer survivors has not yet been established. This study aimed to clarify whether metabolic syndrome is associated with subsequent CVD risk in patients with cancer using a nationwide epidemiological dataset. Methods We retrospectively analysed 53 510 patients with a history of breast, colorectal, or stomach cancer, which is reportedly a major site for developing cancer in Japan. Study participants were categorized into two groups based on the presence of metabolic syndrome, defined using the Japanese criteria (high waist circumference and ≥2 metabolic parameters including elevated blood pressure, elevated triglycerides, reduced high‐density lipoprotein cholesterol, or elevated fasting plasma glucose). The clinical outcomes were collected between 2005 and 2021. The primary endpoint was defined as the composite CVD outcome, including myocardial infarction, angina pectoris, stroke, and heart failure. Results The median patient age was 54 years, and 37.5% of the patients were men. Metabolic syndrome was observed in 5558 (10.4%) patients. Over a mean follow‐up period of 973 ± 791 days, 3085 composite CVD outcomes were recorded. Multivariable Cox regression analyses showed that metabolic syndrome was associated with a greater risk of developing CVD events (HR = 1.29, 95% CI = 1.15–1.45). Metabolic syndrome was also associated with an increased risk of CVD in patients with a follow‐up period ≥1 year (HR = 1.33, 95% CI = 1.15–1.53). This relationship was also observed when metabolic syndrome was defined according to the International Diabetes Federation criteria (HR = 1.34, 95% CI = 1.21–1.49) and the National Cholesterol Education Program Adult Treatment Panel III criteria (HR = 1.32, 95% CI = 1.19–1.46). Subgroup analyses showed that the relationship between metabolic syndrome and incident CVD was more pronounced in the non‐obese participants than in the obese participants. Conclusions Metabolic syndrome is associated with a greater risk of developing CVD, even among cancer survivors.

Gene therapies, which include viral-vector gene delivery, genome editing, and genetically modified cell therapy, are innovative treatments with the potential to address the underlying genetic causes of disorders and to provide life-changing value in terms of curing disease. Although adeno-associated virus (AAV)-based gene therapy is one of the most advanced types of gene therapy, far fewer AAV-based gene therapy studies have been conducted in Asia than in North America and Europe. The 6th Asia Partnership Conference of Regenerative Medicine (APACRM) was held on April 20, 2023 in Tokyo, Japan. APACRM Working Group 3 comprehensively analyzed the regulatory processes that occur prior to the initiation of clinical trials as well as the regulatory requirements for AAV-based gene therapies for six Asian countries or regions (China, India, Japan, Singapore, South Korea, and Taiwan). In this article, we report the outcomes of this conference, summarizing the regulatory requirements for initiating clinical trials for AAV-based gene therapies in terms of the laws, regulations, and guidelines for gene therapy; consultations or reviews required by the health authorities; points to consider for scientific reviews by the health authorities; and specific challenges to address when developing gene therapy products in these locations. Finally, we present several policy recommendations, including simplifying the regulatory review system for multiple scientific review areas; simplifying the regulatory consultation system; and providing training programs and regulatory guidance to support the advancement of gene therapy development in Asia.

Cerebral small vessel disease and brain white matter injury are worsened by cardiovascular risk factors including obesity. Molecular pathways in cerebral endothelial cells activated by chronic cerebrovascular risk factors alter cell-cell signaling, blocking endogenous and post-ischemic white matter repair. Using cell-specific translating ribosome affinity purification (RiboTag) in white matter endothelia and oligodendrocyte progenitor cells (OPCs), we identify a coordinated interleukin-chemokine signaling cascade within the oligovascular niche of subcortical white matter that is triggered by diet-induced obesity (DIO). DIO induces interleukin-17B (IL-17B) signaling that acts on the cerebral endothelia through IL-17Rb to increase both circulating and local endothelial expression of CXCL5. In white matter endothelia, CXCL5 promotes the association of OPCs with the vasculature and triggers OPC gene expression programs regulating cell migration through chemokine signaling. Targeted blockade of IL-17B reduced vessel-associated OPCs by reducing endothelial CXCL5 expression. In multiple human cohorts, blood levels of CXCL5 function as a diagnostic and prognostic biomarker of vascular cognitive impairment.

Background With the advent of cranial orthoses as therapeutic medical devices for the treatment of severe positional head deformities in Japan, an increasing number of patients are being treated with them. However, assessing the effectiveness of a treatment is often difficult due to the use of different metrics. This study aimed to evaluate the effectiveness of cranial orthoses for deformational plagiocephaly using two- (2D) and three-dimensional (3D) evaluation metrics.