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Kenji Inoue,1 Minako Shiokawa,1 Shiho Kunimatsu-Sanuki,2 Goji Tomita,1,3 Kyoko Ishida3 1Inouye Eye Hospital, Tokyo, Japan; 2Nishikasai Inouye Eye Hospital, Tokyo, Japan; 3Department of Ophthalmology, Toho University Ohashi Medical Center, Tokyo, JapanCorrespondence: Kenji Inoue, Inouye Eye Hospital, 4-3 Kanda-surugadai, Chiyoda-ku, Tokyo, 101-0062, Japan, Tel +813-3295-0911 ; Fax +813-3295-0917, Email 2inoue-k@inouye-eye.or.jpPurpose: A fixed-combination eye drop has several advantages over combination therapy, however, the intraocular pressure (IOP)-lowering efficacy and safety of the newly available brimonidine + ripasudil fixed-combination (BRFC) eye drops after switching from brimonidine + ripasudil is yet to be established. Therefore, this study aimed to retrospectively investigate the 6-month safety, usability, and IOP-lowering efficacy of BRFC switched from brimonidine and ripasudil.Patients and Methods: Overall, 69 patients with primary open-angle glaucoma (69 eyes) receiving brimonidine + ripasudil were enrolled in this study. Brimonidine + ripasudil was discontinued, and treatment was switched to BRFC without a washout period. The IOP was compared before and at 3 and 6 months after switching to BRFC. The side effects, discontinued cases, and usability (a questionnaire survey) were also investigated.Results: The IOP was not significantly different after switching to BRFC (15.1 ± 3.3 mmHg at baseline, 15.9 ± 3.6 mmHg after 3 months, and 14.6 ± 3.3 mmHg after 6 months). Adverse reactions occurred in four patients (5.8%): allergic conjunctivitis, two patients; irritation, one patient; and blurred vision, one patient. Treatment was discontinued in five (7.2%) patients owing to allergic conjunctivitis, two patients; increased IOP, two patients; and blurred vision, one patient. In the questionnaire survey, 68 patients with eye pain, 67 with itching, 64 with conjunctival hyperemia, 64 with irritation, and 62 with blurred vision reported no change or improved conditions. Additionally, in response to the question regarding preferences for pre-treatment and fixed combinations, 14 participants (20.2%) favored pre-treatment, while 53 (76.8%) preferred fixed combinations.Conclusion: The IOP was maintained for 6 months, with satisfactory safety and comfort of use, with BRFC switched from brimonidine and ripasudil.Keywords: adverse reactions, brimonidine/ripasudil, intraocular pressure, fixed combination, switching, usability

Takahira Kuno,1,2 Kenji Tamura,1,3 Nobutaka Shimizu,1 Hideo Fukuhara,1 Satoshi Fukata,1 Shingo Ashida,1 Takashi Karashima,1 Hirofumi Satake,3 Kohji Sawada,4 Ichiro Yamasaki,5 Fumito Komatsu,2 Hajime Kuroiwa,6 Motoaki Saito,7 Keiji Inoue1 1Department of Urology, Kochi Medical School, Kochi University, Nankoku, Japan; 2Department of Urology, Tosa Municipal Hospital, Tosa, Japan; 3Department of Urology, Chikamori Hospital, Kochi, Japan; 4Department of Urology, Kochi Prefectural Hata Kenmin Hospital, Sukumo, Japan; 5Department of Urology, Kubokawa Hospital, Takaoka-gun, Japan; 6Integrated Center for Advanced Medical Technologies (ICAM-Tech), Kochi Medical School, Nankoku, Japan; 7Department of Pharmacology, Kochi Medical School, Kochi University, Nankoku, JapanCorrespondence: Kenji Tamura, Email tamurak@kochi-u.ac.jpObjective: The treatment effects of vibegron have not previously been evaluated in a prospective, non-interventional observational study of elderly Japanese patients, particularly those ≥ 80 years old. In addition, no reports have referred to residual urine volume in switching cases. We therefore grouped patients by condition and investigated the treatment effects of vibegron on Overactive Bladder Symptom Score (OABSS), Overactive Bladder Questionnaire Short Form (OAB-q SF), and residual urine volume in each group.Methods: This multicenter, prospective, non-interventional, observational study consecutively enrolled OAB patients with total OABSS score ≥ 3 and OABSS question 3 score ≥ 2. Sixty-three patients from six centers were recruited. Vibegron 50 mg once daily was administered for 12 weeks as first-line monotherapy (first-line group), monotherapy switching from antimuscarinics or mirabegron due to failure of prior therapy (no washout period), or combination therapy with antimuscarinics (second-line group). OABSS, OAB-q SF, and residual urine volume were collected after 4 and 12 weeks. Adverse events were also recorded at each visit.Results: Of the 63 patients registered, 61 were eligible for analysis (first line, n=36; second line, n=25). The OABSS, excluding daytime frequency scores, and OAB-q SF scale showed significant improvement in all conditions. Switching from mirabegron to vibegron significantly reduced residual urine volume. No serious treatment-related adverse events were encountered.Conclusion: Vibegron 50 mg once daily significantly improved OABSS and OAB-q SF even in patients ≥ 80 years old. Notably, switching from mirabegron to vibegron resulted in significant improvements to residual urine volume.Keywords: selective β 3-adrenoreceptor agonist, overactive bladder, residual urine volume, vibegron, mirabegron

Shoko Sakamoto,1,2 Dai Miyawaki,1 Ayako Goto,1 Kaoru Hirai,1,3 Hiroki Hama,1,2 Shin Kadono,1,2 Sayaka Nishiura,1,2 Koki Inoue1 1Department of Neuropsychiatry, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan; 2Department of Neuropsychiatry, Osaka City University Graduate School of Medicine, Osaka, Japan; 3Department of Pediatrics, Osaka Metropolitan University Graduate School of Medicine, Osaka, JapanCorrespondence: Dai Miyawaki, Department of Neuropsychiatry, Osaka Metropolitan University Graduate School of Medicine, Osaka, 545-8585, Japan, Tel +81-6-6645-3821, Fax +81-6-6636-0439, Email miyawakidai@omu.ac.jpPurpose: Internet addiction (IA) has become a global problem and is one of the most common reasons for children to be referred for intervention because IA results in social and educational dysfunction and conflict with parents. IA is associated with various comorbid psychiatric disorders, with notable association between IA and family factors. However, little is known about parental psychopathology. This study aimed to examine the prevalence of IA and association between IA and maternal depression and anxiety in clinical samples after adjusting for comorbidities.Patients and Methods: A cross-sectional study was conducted between April 2020 and August 2021 at the Department of Neuropsychiatry of Osaka Metropolitan University Hospital in Japan. A total of 218 clinically referred children and adolescents (aged 8 to 15 years) were assessed using the Internet Addiction Test, which is one of the most popular questionnaires to evaluate IA, the Child Behavior Checklist (CBCL), and The Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children—Present and Lifetime Version. IA was defined as a total score on the Internet Addiction Test ≥ 50. Of those, for the evaluation of maternal depression and anxiety, the 132 mothers of the children who were referred after January 2021 completed K6 as well.Results: A total of 68 participants (31.2%) presented with IA and had higher total and externalizing scores of CBCL, social anxiety disorder, and oppositional defiant disorder compared to those without IA. IA was associated with the six-item Kessler scale scores of mothers, being raised by single parents, and anxiety disorders after adjusting for age, sex, and family income (95% CI: 1.023– 1.215).Conclusion: Maternal depression and anxiety may be one of the risk factors for children and adolescents to develop IA. Care for maternal depression and anxiety may contribute to intervention for children and adolescents with IA.Keywords: internet addiction, children, maternal depression, oppositional defiant disorder, social anxiety disorder

Kenji Inoue,1 Ryoko Komori,1 Shiho Kunimatsu-Sanuki,2 Kyoko Ishida,3 Goji Tomita1,3 1Inouye Eye Hospital, Tokyo, Japan; 2Nishikasai Inouye Eye Hospital, Tokyo, Japan; 3Department of Ophthalmology, Toho University Ohashi Medical Center, Tokyo, JapanCorrespondence: Kenji Inoue, Inouye Eye Hospital, 4-3 Kanda-surugadai, Chiyoda-ku, Tokyo, 101-0062, Japan, Tel +813-3295-0911, Fax +813-3295-0917, Email 2inoue-k@inouye-eye.or.jpPurpose: To investigate the current use of fixed-combination eye drops by patients with glaucoma in Japan.Patients and Methods: A total of 5303 outpatients (5303 eyes) with glaucoma or ocular hypertension were enrolled in the survey at 78 private practices from March 8 to 14, 2020. The medications they used were investigated. The use of fixed-combination medications was analyzed, stratified by the number of medications used. The results were compared to those of the survey performed in 2016 via χ2 tests.Results: Fixed-combination medications were used by 55.6%, 79.8%, 84.9%, 91.3%, and 94.1% of patients in the two-, three-, four-, five, and six-medications groups. The use of prostaglandin analog/β-blocker (PG/β), carbonic anhydrase inhibitor/β-blocker (CAI/β), and α-2-adrenergic agonist/β-blocker (α 2/β) fixed-combination medications were 42.8%, 12.0%, and 0.8% in the two-medications group; 36.2%, 41.6%, and 2.0% in the three-medications group; and 23.5%, 60.1%, and 1.3% in the four-medications group, respectively. The most commonly used fixed-combination medications were PG/β in the two-medications group and CAI/β in the groups using three or more medications. Compared to those in the survey performed in 2016, there were increases (both P < 0.0001) in the use of PG/β fixed-combination medication in the two- (28.7% to 42.8%) and three-medications (21.7% to 36.2%) groups, and none in the use of CAI/β fixed-combination medication. There was little use of α 2/β fixed-combination medication, probably because it was launched only three months before the survey.Conclusion: The proportion of fixed-combination medications increased as the number of medications per patient increased.Keywords: intraocular pressure, PG/β fixed combination, CAI/β fixed combination, α 2/β fixed combination, multicenter

Shoko Sakamoto,1,2 Dai Miyawaki,1,3 Ayako Goto,1 Kaoru Hirai,1,4 Hiroki Hama,1,2 Shin Kadono,1,2 Sayaka Nishiura,1,2 Koki Inoue1 1Department of Neuropsychiatry, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan; 2Department of Neuropsychiatry, Osaka City University Graduate School of Medicine, Osaka, Japan; 3Department of Child and Adolescent Psychiatry, Osaka City General Hospital, Osaka, Japan; 4Department of Pediatrics, Osaka Metropolitan University Graduate School of Medicine, Osaka, JapanCorrespondence: Dai Miyawaki, Department of Child and Adolescent Psychiatry, Osaka City General Hospital, Osaka, Japan, Email miyawakidai@omu.ac.jp

Preceding a core-collapse supernova (CCSN), various processes produce an increasing amount of neutrinos of all flavors characterized by mounting energies from the interior of massive stars. Among them, the electron antineutrinos are potentially detectable by terrestrial neutrino experiments such as KamLAND and Super-Kamiokande (SK) via inverse beta decay interactions. Once these pre-supernova (pre-SN) neutrinos are observed, an early warning of the upcoming CCSN can be provided. In light of this, KamLAND and SK, both located in the Kamioka mine in Japan, have been monitoring pre-SN neutrinos since 2015 and 2021, respectively. Recently, we performed a joint study between KamLAND and SK on pre-SN neutrino detection. A pre-SN alert system combining the KamLAND detector and the SK detector was developed and put into operation, which can provide a supernova alert to the astrophysics community. Fully leveraging the complementary properties of these two detectors, the combined alert is expected to resolve a pre-SN neutrino signal from a 15 M ⊙ star within 510 pc of the Earth at a significance level corresponding to a false alarm rate of no more than 1 per century. For a Betelgeuse-like model with optimistic parameters, it can provide early warnings up to 12 hr in advance.

Satoko Kawarasaki,1 Honami Sawazaki,1 Hiroaki Iijima,2 Su-Ping Ng,1 Jungin Kwon,1 Shinsuke Mohri,1 Mari Iwase,1 Huei-Fen Jheng,1 Haruya Takahashi,1 Wataru Nomura,1,3 Kazuo Inoue,1,3 Teruo Kawada,1,3 Tsuyoshi Goto1,3 1Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji 611-0011, Japan; 2Ikuyaku. Integrated Value Development Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan; 3Research Unit for Physiological Chemistry, The Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto 606-8317, JapanCorrespondence: Tsuyoshi GotoLaboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji 611-0011, JapanTel +81-774-38-3753Fax +81-774-38-3752Email goto.tsuyoshi.6x@kyoto-u.ac.jpPurpose: Sodium-glucose co-transporter-2 (SGLT2) inhibitors have various pleiotropic effects, including body weight reduction, and therefore have the potential to be used in various applications. However, such effects have not been fully investigated; thus, non-clinical studies using animal models are needed. In animal experiments, SGLT2 inhibitors are usually administered by oral or dietary methods. However, the detailed characteristics of these dosing methods, especially to induce their pleiotropic effects, have not been reported. Therefore, we compared the preventive effects of canagliflozin, an SGLT2 inhibitor, on body weight gain following oral gavage and dietary administration methods in a mouse model of diet-induced obesity.Methods: Canagliflozin was dosed by oral gavage or dietary administration for 9 weeks to 6-week-old C57BL/6N mice fed a high-fat diet, and parameters related to obesity were evaluated.Results: The suppression of body weight gain, fat mass, and hepatic lipid content was observed following both dosing methods, whereas the effect on body weight tended to be stronger in the dietary administration group. In adipose tissue, fatty acid synthase expression was significantly decreased in the dietary administration group, and its expression was significantly correlated with fat mass. However, the expression of genes related to fatty acid oxidation was unchanged, indicating that the preventive effect on body weight gain was mediated mainly through the suppression of lipid synthesis rather than the promotion of lipid oxidation.Conclusion: Canagliflozin prevented body weight gain through the suppression of lipid synthesis via both dosing methods, although there were some differences in the efficacy. The findings of our study can help to identify new mechanisms of action of SGLT2 inhibitors and potential applications.Keywords: SGLT2 inhibitor, obesity, dosing method

Kenji Inoue,1 Junji Inoue,2 Shiho Kunimatsu-Sanuki,2 Norie Nozaki,3 Kosuke Shimizu,4 Kyoko Ishida,5 Goji Tomita1,5 1Inouye Eye Hospital, Chiyoda-Ku, Tokyo, Japan; 2Nishikasai Inouye Eye Hospital, Edogawa-Ku, Tokyo, Japan; 3Omiya Inouye Eye Clinic, Saitama-Shi, Saitama, Japan; 4Sapporo Inouye Eye Clinic, Sapporo-Shi, Sapporo, Japan; 5Department of Ophthalmology, Toho University Ohashi Medical Center, Meguro-ku, Tokyo, JapanCorrespondence: Kenji InoueInouye Eye Hospital, Chiyoda-Ku, Tokyo, JapanTel +81 03 3295 0911Fax +81 03 3295 0917Email 2inoue-k@inouye-eye.or.jpPurpose: To retrospectively evaluate the short-term efficacy of omidenepag isopropyl (EYBELIS 0.002%) by assessing its intraocular pressure (IOP)-lowering capability and safety in patients with normal-tension glaucoma (NTG).Patients and Methods: Fifty-four NTG patients (54 eyes) who were newly administrated with omidenepag isopropyl were enrolled in the study. The subjects comprised 22 men and 32 women, and the mean age of the subjects was 55.0 ±  14.1 years. The mean deviation value using the Humphrey visual field test program (30– 2 SITA Standard) was − 5.03 ±  3.38 dB. The following data were retrieved from the medical records and used for retrospective analyses: IOP at baseline 1– 2 months and 3– 4 months after administration. The frequency of non-responder patients who had less than 10% IOP reduction was evaluated. Patients were observed for adverse reactions and dropouts at each time point.Results: IOP at baseline, after 1– 2 months and after 3– 4 months was 15.7 ±  2.6 mmHg, 13.5 ±  2.3 mmHg, and 13.6 ±  2.4 mmHg, respectively. There was a significant decrease in IOP after administration (p< 0.0001). Eleven patients (22.4%) were non-responders. Adverse reactions occurred in 4 patients (7.4%), including conjunctival hyperemia in 3 patients (after 1 week, 2 weeks, and 1 month, respectively) and eye pain in 1 patient (after 1 month). Five patients (9.3%) dropped out of the study because of an adverse reaction in 3 patients, insufficient IOP reduction in 1 patient, and discontinuation of follow-up of 1 patient at our institution.Conclusion: After administration of omidenepag isopropyl, IOP in patients with NTG was significantly decreased. However, adverse reactions occurred in 7.4% of patients.Keywords: intraocular pressure, adverse reactions, EP2 receptor agonist, conjunctival hyperemia

Kenji Inoue,1 Hua Piao,1 Mayumi Iwasa,1 Kyoko Ishida,2 Goji Tomita2 1Inouye Eye Hospital, Tokyo, Japan; 2Department of Ophthalmology, Toho University Ohashi Medical Center, Tokyo, JapanCorrespondence: Kenji InoueInouye Eye Hospital, Chiyoda-ku, Tokyo, JapanTel +81 3 3295 0911Fax +81 3 3295 0917Email inoue-k@inouye-eye.or.jpPurpose: To investigate the short-term intraocular pressure-lowering efficacy and safety of switching from a fixed combination of latanoprost/timolol to a fixed combination of latanoprost/carteolol.Patients and Methods: The subjects were 30 eyes of 30 adult patients with primary open-angle glaucoma, normal-tension glaucoma, or ocular hypertension who were using a latanoprost-/timolol-fixed combination with insufficient intraocular pressure-lowering efficacy or adverse reactions. The subjects were switched from once-daily latanoprost/timolol to once-daily latanoprost/carteolol with no washout interval. Intraocular pressure, tear film break-up time, corneal epithelial defects, conjunctival hyperemia, blood pressure, and pulse rate were measured and compared before and 1 and 3 months after switching. Patients were monitored for adverse reactions at each visit, and dropouts were recorded.Results: The mean intraocular pressure at 1 month (15.9± 3.1 mmHg) and 3 months (16.3± 3.8 mmHg) was not significantly different from that at baseline (16.1± 3.1 mmHg). The tear film break-up time and corneal epithelial defects were significantly improved after switching (p< 0.01 and p< 0.0001, respectively). There was a significant decrease in systolic blood pressure after 1 month and diastolic pressure after 3 months (p< 0.05). There was no significant change in pulse rate during the study. Adverse reactions (blurred vision, blepharitis, and conjunctival hyperemia) occurred in 3 patients (10.0%). Four patients (13.3%) discontinued treatment during the 3-month study period.Conclusion: A switch from a fixed combination of latanoprost/timolol to that of latanoprost/carteolol can maintain intraocular pressure and adherence with once-daily administration while improving tear film break-up time and corneal epithelial defects.Keywords: adverse reactions, eye drops, glaucoma, intraocular pressure

Manja Vollmann,1 Ayako Matsuda,2 Judith R Kroep,3 Kunihiko Kobayashi,4 Kaoru Kubota,5 Kenichi Inoue,6 Kazue Yamaoka,7 Hein Putter,8 Rajen Ramai,9 Johannes WR Nortier,3 Maarten J Fischer,10 Ad A Kaptein10 1Socio-Medical Sciences ESHPM, Erasmus University Rotterdam, Rotterdam, the Netherlands; 2Department of Hygiene and Public Health, Teikyo University School of Medicine, Tokyo, Japan; 3Medical Oncology, Leiden University Medical Center, Leiden, the Netherlands; 4Saitama International Medical Center Saitama, Saitama, Japan; 5Nippon Medical School Hospital, Tokyo, Japan; 6Saitama Cancer Center, Saitama, Japan; 7Teikyo University Graduate School of Public Health, Tokyo, Japan; 8Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, the Netherlands; 9Respiratory Medicine, Leiden University Medical Centre, Leiden, the Netherlands; 10Medical Psychology, Leiden University Medical Center, Leiden, the NetherlandsCorrespondence: Ad A KapteinDepartment of Medical Psychology, Leiden University Medical Center, PO Box 9600, Leiden 2300 RC, the NetherlandsEmail a.a.kaptein@lumc.nlPurpose: Examine illness perceptions, functional health and quality of life of lung cancer patients throughout chemotherapy treatment.Patients and Methods: Longitudinal design with baseline measure 12 days after the first chemotherapy and follow-up measure 3 months later, where illness perceptions (BIPQ), functional health, and quality of life (EORTC QLQ-C-30) were measured. A total of 21 patients with non-small-cell lung cancer took part. Non-parametric testing was performed given the pilot nature of the study and the associated relatively small sample size.Results: Small to medium changes in illness perceptions and functional health between the two measurement points were detected, with both becoming more positive. More negative illness perceptions at the beginning of the treatment were associated with less functioning and lower quality of life at both beginning and end of treatment.Conclusion: Addressing illness perceptions seems a clinically relevant approach in improving functioning and quality of life of patients with non-small-cell lung cancer.Keywords: lung cancer, illness perceptions, quality of life, longitudinal design, patient reported outcomes

Particle dark matter could belong to a multiplet that includes an electrically charged state. WIMP dark matter (χ0) accompanied by a negatively charged excited state (χ−) with a small mass difference (e.g. < 20 MeV) can form a bound-state with a nucleus such as xenon. This bound-state formation is rare and the released energy is O(1−10) MeV depending on the nucleus, making large liquid scintillator detectors suitable for detection. We searched for bound-state formation events with xenon in two experimental phases of the KamLAND-Zen experiment, a xenon-doped liquid scintillator detector. No statistically significant events were observed. For a benchmark parameter set of WIMP mass mχ0=1 TeV and mass difference Δm=17 MeV, we set the most stringent upper limits on the recombination cross section times velocity 〈σv〉 and the decay-width of χ− to 9.2×10−30 cm3/s and 8.7×10−14 GeV, respectively at 90% confidence level.

Dai Miyawaki,1 Ayako Goto,1 Yoshihiro Iwakura,1,2 Kaoru Hirai,1 Yusuke Miki,1 Naomi Asada,1,2 Hiroki Terakawa,1 Koki Inoue1 1Department of Neuropsychiatry, Osaka City University Graduate School of Medicine, Osaka, Japan; 2Department of Child and Adolescent Psychiatry, Osaka City General Hospital, Osaka, Japan Abstract: Early-onset obsessive-compulsive disorder (OCD) is more severe than later-onset OCD. There are no reports of any early-onset OCD patients being cured, especially with respect to preschoolers. In this case report, we describe the successful treatment and cure of a 6-year-old preschool girl with severe OCD since the age of 3. At the age of 3, the patient began to fear contamination and danger to herself and her family, leading to excessive hand-washing, and several months later, ritualized checking. The OCD symptoms waxed and waned for about 3 years and thereafter worsened gradually over a few weeks, culminating in a refusal to eat and dress. At the age of 6, after a week of inpatient pediatric treatment with no improvement, the patient was transferred to Osaka City University Hospital to seek psychiatric treatment. The patient fully recovered from OCD following family-based cognitive-behavioral therapy (CBT) and short-term use of low-dose fluvoxamine in an inpatient setting. After treatment, the OCD symptoms disappeared with complete remission for over 3 years. Now, aged 9, the patient has good global functioning and is well adjusted in her daily life with no need for any treatment. To the best of our knowledge, this is the first report of preschool-onset OCD with long-term complete remission with inpatient treatment in a preschooler with severe OCD. Some preschoolers with very early-onset OCD may have good prognosis without continuous pharmacotherapy, although the symptoms with the onset are severe enough to require hospitalization. Preschool-onset OCD is likely to be misdiagnosed as separation anxiety disorder. Our findings suggest that family-based CBT, which is the treatment of choice for preschool-onset OCD, can be applicable to inpatient treatment. Early detection and intensive intervention of OCD in preschoolers may improve the chance of remission. Keywords: very early-onset OCD, differential diagnosis, family-based cognitive-behavioral therapy, inpatient treatment

Kenji Inoue, Taku Kawashima, Seiki Katakura, Kyoko Shidara, Takayuki Fujimoto, Hiromi Kohmoto, Minako Shiokawa, Ryo Moriyama, Ryoko Okayama Inouye Eye Hospital, Tokyo, Japan Purpose: To evaluate the efficacy and safety of tafluprost/timolol fixed combination (TTFC). Study design: A prospective clinical study. Methods: Twenty-eight patients (28 eyes) with primary open-angle glaucoma, who had used tafluprost and timolol gel for at least 3 months with good adherence, were enrolled. Concomitant administration of tafluprost and timolol was switched to TTFC without a washout period. The intraocular pressure (IOP), blood pressure, pulse rate, and ocular signs were compared between before switching (baseline), and 4 and 8 weeks after switching. A questionnaire survey was also performed 4 weeks after switching to investigate ocular comfort and patient preferences. Results: The IOP showed no significant change after switching to TTFC (14.8 ± 2.8, 14.6 ± 3.4, and 14.8 ± 3.7 mmHg at baseline, Week 4, and Week 8, respectively). The pulse rate and systolic blood pressure showed no changes, but diastolic blood pressure was significantly lower at Week 8. At baseline, fluorescein staining revealed corneal abnormalities in 3 patients, which resolved by Week 8 in 1 patient. Hyperemia was noted in 2 patients at baseline, and this also resolved by Week 8 in 1 patient. Three patients discontinued study treatment for the following reasons (1 patient each): blurred vision; ocular irritation, eyelid erythema, and asthenopia; and loss to follow-up from Week 8. The questionnaire survey revealed no significant differences between the 2 treatments, although more patients preferred TTFC. Conclusion: Among 28 patients enrolled, only 2 patients discontinued the study treatment due to adverse reactions. In patients whose adherence was considered relatively good to concomitant therapy, switching to TTFC achieved similar IOP control with good safety and a high level of patient acceptance. Keywords: tafluprost/timolol fixed combination, switching, intraocular pressure, adverse reactions

Shiro Amano, Kenji Inoue Inouye Eye Hospital, Chiyoda-ku, Tokyo, Japan Purpose: To prospectively evaluate the effect of topical diquafosol sodium on eyes with dry eye disease (DED) and meibomian gland dysfunction (MGD).Patients and methods: The subjects were consecutive patients diagnosed with both DED and MGD at Inouye Eye Hospital between March and September of 2016. The subjects were administered topical 3% diquafosol sodium ophthalmic solution six times a day for 3 months. At each study visit, subjects underwent slit-lamp examination and completed MGD symptoms and dry eye-related quality of life score (DEQS) questionnaires. Meibum quality (meibum score) and meibomian gland loss (meiboscore) were evaluated. Tear lipid layer thickness was measured in both eyes with an ocular surface interferometer immediately after clinic arrival and 20 minutes after instillation of one drop of topical diquafosol.Results: Thirteen patients (3 men, 10 women) with a mean age of 69.5±8.3 years completed the 3-month study. The number of telangiectasia and plugged meibomian gland orifices significantly decreased from baseline after 1 month of diquafosol use. The meibum score and the meiboscore significantly decreased from baseline at 3 months. Also, the lipid layer thickness was greater after diquafosol administration than before administration at baseline and 1, 2, and 3 months by 12.2, 11.5, 9.5, and 17.0 nm, respectively, but this difference was only significant at 3 months (p=0.039). The DEQS ocular symptom (p=0.065) and MGD questionnaire (p=0.081) scores tended to be lower than baseline at 3 months.Conclusion: Diquafosol sodium ophthalmic solution improves DED- and MGD-related signs in eyes with MGD. Keywords: diquafosol, meibomian gland dysfunction, dry eye

Keisuke Miki,1 Ryoji Maekura,1 Seigo Kitada,1 Mari Miki,1 Kenji Yoshimura,1 Hiroshi Yamamoto,2 Toshiko Kawabe,2 Hiroyuki Kagawa,1 Yohei Oshitani,1 Akitoshi Satomi,1 Kohei Nishida,1 Nobuhiko Sawa,1 Kimiko Inoue2 1Department of Respiratory Medicine, 2Department of Rehabilitation Medicine, National Hospital Organization, Toneyama National Hospital, Toyonaka, Japan Background: COPD patients undergoing pulmonary rehabilitation (PR) show various responses. The purpose of this study was to investigate the possible mechanisms and predictors of the response to PR in COPD patients.Methods: Thirty-six stable COPD patients underwent PR including a 4-week high-intensity exercise training program, and they were evaluated by cardiopulmonary exercise testing. All patients (mean age 69 years, severe and very severe COPD 94%) were classified into four groups by whether the exercise time (Tex) or the peak oxygen uptake (VO2) increased after PR: two factors increased (both the Tex and the peak VO2 increased); two factors decreased; time only increased (the Tex increased, but the peak VO2 economized); and VO2 only increased (the Tex decreased, but the peak VO2 increased). Within all patients, the relationships between baseline variables and the post-to-pre-change ratio of the time–slope, Tex/(peak minus resting VO2), were investigated.Results: Compared with the two factors increased group (n=11), in the time only increased group (n=18), the mean differences from pre-PR at peak exercise in 1) minute ventilation (VE) (P=0.004), VO2 (P

Kenji Inoue,1 Minako Shiokawa,1 Kyoko Ishida,2 Goji Tomita2 1Inouye Eye Hospital, Tokyo, Japan; 2Department of Ophthalmology, Toho University Ohashi Medical Center, Tokyo, Japan Purpose: To evaluate the safety and efficacy of switching from dorzolamide 1.0%/timolol maleate 0.5% fixed-combination (DTFC) eye drops to brinzolamide 1.0%/timolol maleate 0.5% fixed-combination (BTFC) eye drops in patients with primary open-angle glaucoma or ocular hypertension. Methods: A total of 35 eyes of 35 patients with primary open-angle glaucoma or ocular hypertension using DTFC eye drops were included. Participants discontinued DTFC drops and immediately began using BTFC drops. All other eye drops currently being used were continued. Intraocular pressure (IOP) 1 and 3 months after switching medications was compared with baseline IOP. One month after switching medications, participant preference and adherence were evaluated. Adverse reactions were monitored at each study visit. Results: The IOP was 17.9±2.6 mmHg at baseline and 18.3±4.1 mmHg and 17.8±3.4 mmHg 1 month and 3 months after switching medications, respectively (P=0.633). The frequency of missing a dose was not different before (6.1%) and after (6.1%) switching to BTFC. Significantly fewer participants reported stinging after switching to BTFC (15.2%) than while using DTFC (51.5%, P

Izumi Kanayama,1 Hirofumi Miyaji,1 Hiroko Takita,2 Erika Nishida,1 Maiko Tsuji,3 Bunshi Fugetsu,4,5 Ling Sun,4,5 Kana Inoue,1 Asako Ibara,1 Tsukasa Akasaka,6 Tsutomu Sugaya,1 Masamitsu Kawanami1 1Department of Periodontology and Endodontology, 2Support Section for Education and Research, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan; 3Mitsubishi Gas Chemical Company, Inc., Tokyo, Japan; 4Division of Frontier Research, Research Department, Creative Research Institution Sousei, 5Graduate School of Environmental Science, 6Department of Biomedical, Dental Materials and Engineering, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan Background: Graphene oxide (GO) is a single layer carbon sheet with a thickness of less than 1 nm. GO has good dispersibility due to surface modifications with numerous functional groups. Reduced graphene oxide (RGO) is produced via the reduction of GO, and has lower dispersibility. We examined the bioactivity of GO and RGO films, and collagen scaffolds coated with GO and RGO. Methods: GO and RGO films were fabricated on a culture dish. Some GO films were chemically reduced using either ascorbic acid or sodium hydrosulfite solution, resulting in preparation of RGO films. The biological properties of each film were evaluated by scanning electron microscopy (SEM), atomic force microscopy, calcium adsorption tests, and MC3T3-E1 cell seeding. Subsequently, GO- and RGO-coated collagen scaffolds were prepared and characterized by SEM and compression tests. Each scaffold was implanted into subcutaneous tissue on the backs of rats. Measurements of DNA content and cell ingrowth areas of implanted scaffolds were performed 10 days post-surgery.Results: The results show that GO and RGO possess different biological properties. Calcium adsorption and alkaline phosphatase activity were strongly enhanced by RGO, suggesting that RGO is effective for osteogenic differentiation. SEM showed that RGO-modified collagen scaffolds have rough, irregular surfaces. The compressive strengths of GO- and RGO-coated scaffolds were approximately 1.7-fold and 2.7-fold greater, respectively, when compared with the non-coated scaffold. Tissue ingrowth rate was 39% in RGO-coated scaffolds, as compared to 20% in the GO-coated scaffold and 16% in the non-coated scaffold.Conclusion: In summary, these results suggest that GO and RGO coatings provide different biological properties to collagen scaffolds, and that RGO-coated scaffolds are more bioactive than GO-coated scaffolds. Keywords: GO, RGO, tissue engineering, regenerative scaffold, cell ingrowth, biomaterials

Kenji Inoue,1 Ryoko Okayama,1 Risako Higa,1 Goji Tomita2 1Inouye Eye Hospital, Tokyo, 2Second Department of Ophthalmology, Toho University School of Medicine, Tokyo, Japan Purpose: We prospectively investigated the intraocular pressure (IOP)-reducing effect, the visual field-maintenance effect, and the adverse reactions caused by administration of ­latanoprost/timolol maleate fixed-combination eyedrops for 3 years.Subjects and methods: The subjects were 162 patients (162 eyes) with glaucoma or ocular hypotension who were using latanoprost and timolol maleate eyedrops concomitantly. The latanoprost and timolol maleate eyedrop regimen was discontinued without any washout period and subsequently changed to a latanoprost–timolol maleate fixed-combination eyedrop regimen. IOP values before the change and at 6, 12, 18, 24, 30, and 36 months after the change were measured and compared. The Humphrey visual field test was conducted before the change and at 12, 24, and 36 months after the change, and mean-deviation values were compared. Adverse reactions were assessed at every checkup.Results: The IOPs before the change and at 6–36 months after the change were 15.2±3.3 mmHg and 14.3–15.2 mmHg, respectively, and a significant decrease was observed at 36 months after the change (P

Kenji Inoue,1 Minako Shiokawa,1 Takayuki Fujimoto,1 Goji Tomita21Inouye Eye Hospital, Tokyo, Japan; 22nd Department of Ophthalmology, Toho University School of Medicine, Tokyo, JapanPurpose: To evaluate the effects of bimatoprost 0.03% single treatment for 3 years on intraocular pressure (IOP) and visual field performance.Methods: We monitored the IOP of 62 patients with normal-tension glaucoma every 1–3 months. The Humphrey visual field test was performed every 6 months after treatment and the results obtained were compared to those before treatment. In addition, visual field performance was evaluated using trend and event analysis.Results: The mean ± standard deviation (SD) of IOP after treatment with bimatoprost for 3 years (13.6±3.1 mmHg) was significantly lower than that before treatment (16.8±2.4 mmHg, P

Kenji Inoue Inouye Eye Hospital, Tokyo, Japan Abstract: Glaucoma is a chronic, progressive disease in which retinal ganglion cells ­disappear and subsequent, gradual reductions in the visual field ensues. Glaucoma eye drops have hypotensive effects and like all other medications are associated with adverse effects. Adverse reactions may either result from the main agent or from preservatives used in the drug vehicle. The preservative benzalkonium chloride, is one such compound that causes frequent adverse reactions such as superficial punctate keratitis, corneal erosion, conjunctival allergy, and conjunctival injection. Adverse reactions related to main hypotensive agents have been divided into those affecting the eye and those affecting the entire body. In particular, β-blockers frequently cause systematic adverse reactions, including bradycardia, decrease in blood pressure, irregular pulse and asthma attacks. Prostaglandin analogs have distinctive local adverse reactions, including eyelash bristling/lengthening, eyelid pigmentation, iris pigmentation, and upper eyelid deepening. No systemic adverse reactions have been linked to prostaglandin analog eye drop usage. These adverse reactions may be minimized when they are detected early and prevented by reducing the number of different eye drops used (via fixed combination eye drops), reducing the number of times eye drops are administered, using benzalkonium chloride-free eye drops, using lower concentration eye drops, and providing proper drop instillation training. Additionally, a one-time topical medication can be given to patients to allow observation of any adverse reactions, thereafter the preparation of a topical medication with the fewest known adverse reactions can be prescribed. This does require precise patient monitoring and inquiries about patient symptoms following medication use. Keywords: glaucoma eye drops, adverse reactions, preservatives, main agent

Takahiro Terami,1 Jun Wada,1 Kentaro Inoue,1 Atsuko Nakatsuka,1,2 Daisuke Ogawa,1,2 Sanae Teshigawara,1 Kazutoshi Murakami,1,3 Akihiro Katayama,1 Jun Eguchi,1 Hirofumi Makino11Department of Medicine and Clinical Science, 2Department of Diabetic Nephropathy, 3Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, JapanPurpose: Urinary angiotensinogen has been reported as a marker for the activation of intrarenal renin–angiotensin system (RAS) in various kidney diseases. To investigate the importance of urinary angiotensinogen in diabetic nephropathy, we compared the urinary levels of angiotensinogen, albumin, and α1-microglobulin.Materials and methods: Japanese patients with type 2 diabetes at various stages of nephropathy (n=85) were enrolled, and we measured albumin/creatinine ratio (ACR) and urinary excretion of angiotensinogen and α1-microglobulin. We also compared the clinical data of the patients treated with or without angiotensin II receptor blockers or angiotensin-converting enzyme inhibitors (RAS inhibitors [+], n=51; RAS inhibitors [−], n=34).Results: Urinary angiotensinogen levels positively correlated with ACR (r =0.367, P=3.84×10-4) and urinary α1-microglobulin (r=0.734, P=1.32 × 10-15), while they negatively correlated with estimated glomerular filtration ratio (eGFR) (r=−0.350, P=1.02 × 10-3) and high-density lipoprotein cholesterol (r=−0.216, P=0.049). Multiple regression analysis was carried out to predict urinary angiotensinogen levels by employing eGFR, ACR, and urinary α1-microglobulin as independent variables; only urinary α1-microglobulin entered the regression equation at a significant level. Although ACR was higher in the RAS inhibitors (+) group, urinary α1-microglobulin and angiotensinogen did not show significant increase in the RAS inhibitors (+) group.Conclusion: Urinary angiotensinogen is well correlated with urinary α1-microglobulin and reflected the tubular injuries which may be associated with the intrarenal RAS activation in patients with type 2 diabetes.Keywords: diabetic nephropathy, urinary biomarkers, renin–angiotensin system, angiotensinogen, α1-microglobulin, albumin

Kenji Inoue,1 Ayumi Tanaka,1 Goji Tomita2 1Inouye Eye Hospital, 22nd Department of Ophthalmology, Toho University School of Medicine, Tokyo, Japan Purpose: To evaluate the effects of tafluprost treatment for 3 years on intraocular pressure (IOP) and visual field performance. Methods: The IOP of 55 patients with normal-tension glaucoma was monitored every 1–3 months for 3 years. The Humphrey visual field test was performed every 6 months after treatment and results compared with before-treatment results. Visual field performance was also evaluated by trend and event analysis. Results: After 3 years’ tafluprost single-use vials treatment, the IOP (12.8 ± 2.8 mmHg [mean ± standard deviation]) was significantly lower than before treatment (15.7 ± 2.2 mmHg; P < 0.0001). When comparing before-treatment Humphrey visual field test findings with those after 3 years of treatment, no change was found in the mean deviation and pattern standard deviation. Visual field performance had worsened in four patients and three patients according to trend analysis and event analysis, respectively. Adverse reactions appeared in ten cases and one patient (1.8%) discontinued treatment due to an adverse reaction. Conclusion: Tafluprost single-use vials treatment was effective in reducing IOP over the 3 years of this study, but visual field performance worsened by 10.3%–13.8% in patients with normal-tension glaucoma. Safety was satisfactory. Keywords: intraocular pressure, visual field, trend analysis, event analysis

Michitaka Sugahara, Takayuki Fujimoto, Kyoko Shidara, Kenji Inoue, Masato Wakakura Inouye Eye Hospital, Tokyo, Japan Introduction: Here, we describe a patient who presented with anterior ischemic optic neuropathy (AION) and subsequently developed uveitis. Case: A 69-year-old man was referred to our hospital and initially presented with best-corrected visual acuities (BCVA) of 20/40 (right eye) and 20/1000 (left eye) and relative afferent pupillary defect. Slit-lamp examination revealed no signs of ocular inflammation in either eye. Fundus examination revealed left-eye swelling and a pale superior optic disc, and Goldmann perimetry revealed left-eye inferior hemianopia. The patient was diagnosed with nonarteritic AION in the left eye. One week later, the patient returned to the hospital because of vision loss. The BCVA of the left eye was so poor that the patient could only count fingers. Slit-lamp examination revealed 1+ cells in the anterior chamber and the anterior vitreous in both eyes. Funduscopic examination revealed vasculitis and exudates in both eyes. The patient was diagnosed with bilateral panuveitis, and treatment with topical betamethasone was started. No other physical findings resulting from other autoimmune or infectious diseases were found. No additional treatments were administered, and optic disc edema in the left eye improved, and the retinal exudates disappeared in 3 months. The patient's BCVA improved after cataract surgery was performed. Conclusion: Panuveitis most likely manifests after the development of AION. Keywords: anterior ischemic optic neuropathy, uveitis

Norio Watanabe,1,* Atsushi Nishida,2,* Shinji Shimodera,3 Ken Inoue,4 Norihito Oshima,5 Tsukasa Sasaki,6 Shimpei Inoue,3 Tatsuo Akechi,1 Toshi A Furukawa,7 Yuji Okazaki81Department of Psychiatry and Cognitive-Behavioral Medicine, Nagoya City University Graduate School of Medical Sciences, Nagoya, 2Department of Schizophrenia Research, Tokyo Institute of Psychiatry, Tokyo, 3Department of Neuropsychiatry, Kochi Medical School, Kochi, 4Department Public Health, Fujita Health University School of Medicine, Aichi, 5Office for Mental Health Support, Division for Counseling and Support, University of Tokyo, Tokyo, 6Health Service Center, University of Tokyo, Tokyo, 7Department of Cognitive-Behavioral Medicine, Kyoto University Graduate School of Medicine/School of Public Health, Kyoto, 8Department of Psychiatry, Tokyo Metropolitan Matsuzawa Hospital, Tokyo, Japan *These authors contributed equally to this workBackground: The aim of this study was to determine the prevalence of and factors associated with poor help-seeking among adolescents who self-harm and to explore the resources used for help.Methods: A cross-sectional survey using an anonymous questionnaire was conducted in 47 junior and 30 senior high schools in Japan. Adolescent self-harm was defined as an adolescent who had harmed himself or herself in the previous year, as in previous studies reported in Western countries. Poor help-seeking was defined as not consulting anyone despite reporting current psychological or somatic complaints. Information about sociodemographic and psychological factors possibly associated with help-seeking, such as suicidal thoughts, depression, anxiety, and psychotic-like experiences, was also collected. Regression analyses were performed to examine associated factors.Results: A total of 18,104 students (8620 aged 12–15 years, 9484 aged 15–18 years), accounting for 93% of all students in the relevant student classes, participated in the study. Two hundred and seventy-six (3.3%) junior and 396 (4.3%) senior high school students reported having self-harmed. Of these, 40.6% of adolescents in junior and 37.6% in senior high schools were classified as poor help-seeking. Poor help-seeking with regard to self-harm was significantly more common in those who reported not having consulted anyone about psychological problems (odds ratio 9.2, 95% confidence interval 4.6–18.4 in juniors; odds ratio 9.9, confidence interval 5.5–17.9 in seniors) and in those with current suicidal ideation (odds ratio 2.0, confidence interval 1.0–3.7 in juniors; odds ratio 1.9, confidence interval 1.1–3.4 in seniors). Family members were approached significantly less often as a resource for help by students who self-harmed than by those who did not, and school nurses were more often consulted by those who did self-harm.Conclusion: Around 40% of adolescents who self-harmed in the previous year did not seek help. School-based mental health should screen students at risk of self-harm, and educate school nurses about preventative care.Keywords: self-harm, adolescence, help-seeking, prevention, Japan

Kenji Inoue,1 Mayumi Iwasa,1 Masato Wakakura,1 Goji Tomita21Inouye Eye Hospital, 2Toho University Ohashi Medical Center, Tokyo, JapanBackground: The purpose of this study was to evaluate the effects of benzalkonium (BAK)-free travoprost monotherapy administered for 3 years on intraocular pressure and visual field performance.Methods: The intraocular pressure of 76 patients with normal tension glaucoma was monitored every 1–3 months. A Humphrey visual field test was performed every 6 months after treatment and compared with the results before treatment. Visual field performance was also evaluated by trend and event analysis.Results: Thirty cases discontinued within 3 years. Mean intraocular pressure after 3 years of travoprost treatment (14.1 ± 2.4 mmHg) was significantly lower than that before treatment (16.8 ± 2.6 mmHg, P ‹ 0.0001). There was no change in the mean deviation and pattern standard deviation as measured by Humphrey visual field test after 3 years of treatment compared with before treatment. Visual field performance was worse in one patient (2.8%) by trend analysis and five patients (13.9%) by event analysis. Treatment was discontinued in six cases (7.9%) due to the appearance of adverse reactions.Conclusion: BAK-free travoprost monotherapy was effective in reducing intraocular pressure for at least 3 years; however, visual field performance worsened in 2.8%–13.9% of patients with normal tension glaucoma.Keywords: BAK-free travoprost, intraocular pressure, visual field, trend analysis, event analysis

Kenji Inoue,1 Takayuki Fujimoto,1 Risako Higa,1 Ryo Moriyama,1 Hiromi Kohmoto,1 Haruka Nagumo,1 Masato Wakakura,1 Goji Tomita21Inouye Eye Hospital, Chiyoda-ku, Tokyo, 2Second Department of Ophthalmology, Toho University School of Medicine, Meguro-ku, Tokyo, JapanBackground: The purpose of this prospective study was to investigate the intraocular pressure (IOP)-lowering effect and safety of latanoprost 0.005% + timolol maleate 0.5% fixed combination eyedrops, now available in Japan.Materials and methods: Thirty-one patients diagnosed with primary open-angle glaucoma who had an insufficient intraocular pressure (IOP) decrease with latanoprost 0.005% eyedrop monotherapy were enrolled. The latanoprost 0.005% eyedrops were discontinued, and administration of latanoprost 0.005%/timolol maleate 0.5% fixed combination eyedrops was initiated without any washout period. IOP was compared before and at months 1, 3, and 6 after the switch. The incidence of adverse reactions was investigated at every follow-up visit.Results: Mean IOP was 17.3 ± 2.7 mmHg before the switch, 15.5 ± 2.6 mmHg one month after the switch, 14.9 ± 2.4 mmHg 3 months after the switch, and 15.1 ± 2.2 mmHg 6 months after the switch, indicating that IOP decreased significantly after the change. The IOP reduction rate was 9.9% ± 11.5% after one month, 13.1% ± 10.9% after 3 months, and 11.2% ± 11.8% after 6 months. Two patients (6.5%) discontinued therapy due to adverse reactions (one case each of itchiness and bradycardia).Conclusion: When latanoprost 0.005% eyedrop monotherapy was replaced by latanoprost 0.005% + timolol maleate 0.5% fixed combination eyedrops, IOP decreased significantly without increasing the frequency of administration, and safety was satisfactory.Keywords: latanoprost 0.005%, timolol maleate 0.5%, fixed combination, eyedrops, intraocular pressure, switch

Kenji Inoue1, Ryoko Okayama1, Risako Higa1, Masato Wakakura1, Goji Tomita21Inouye Eye Hospital, 4-3 Kanda-Surugadai, Chiyoda-ku, 2Second Department of Ophthalmology, Toho University School of Medicine, Meguro-ku, Tokyo, JapanBackground: Latanoprost 0.005% + timolol maleate 0.5% combined eyedrops were recently made available in Japan. We prospectively investigated the intraocular pressure (IOP)-lowering effect, visual preservation effect, and adverse reactions of a one-year administration of this fixed combination.Methods: The subjects included 162 eyes from 162 patients diagnosed with either primary open-angle glaucoma or ocular hypertension and using an unfixed combination of latanoprost 0.005% and timolol maleate 0.5%. The unfixed combination was discontinued and replaced with the latanoprost 0.005% + timolol maleate 0.5% fixed combination with no washout period. IOP was measured before (baseline) and 3, 6, 9, and 12 months after the change. The mean deviation value of Humphrey field analysis was compared. Adverse reactions were examined at every follow-up.Results: No significant differences were found between mean IOP values obtained at baseline (mean ± standard deviation, 15.2 ± 3.3 mmHg) 3 months (15.1 ± 3.2 mmHg), 6 months (15.3 ± 3.1 mmHg), 9 months (15.3 ± 3.1 mmHg), and 12 months (15.1 ± 3.2 mmHg) after the change from the unfixed to the fixed combination of eyedrops (P = 0.212). In addition, no significant differences were observed between mean deviation values obtained at baseline (–9.11 ± 6.94 dB) and 12 months (–10.08 ± 7.24 dB) after the change (P = 0.114). Thirty-one patients discontinued the fixed combination within 12 months of replacement, due to an insufficient IOP decrease (20 patients, 12.3%) and adverse reactions (11 patients, 6.8%).Conclusion: Following replacement of two eyedrop medications (latanoprost 0.005% and timolol maleate 0.5%) by one fixed combination (latanoprost 0.005% + timolol maleate 0.5%), IOP and visual field were preserved. However, 20% of the patients discontinued the new treatment because of an insufficient IOP decrease and complaints of adverse reactions.Keywords: latanoprost 0.005%, timolol maleate 0.5%, fixed combination, intraocular pressure, safety, visual field

Kenji Inoue1, Akira Setogawa1, Risako Higa1, Ryo Moriyama1, Masato Wakakura1, Goji Tomita21Inouye Eye Hospital, Chiyoda-ku, Tokyo, Japan; 22nd Department of Ophthalmology, Toho University School of Medicine, Tokyo, JapanIntroduction: Travoprost 0.004%/timolol maleate 0.5% fixed combination eye drops are available in Japan. We prospectively investigated the intraocular pressure (IOP)-decreasing effect of travoprost 0.004%/timolol maleate 0.5% fixed combination eye drops and the adherence of patients to the administration protocol.Materials and methods: We studied 43 eyes from 43 patients diagnosed with primary open-angle glaucoma, who were using prostaglandin analogs and ß-blockers. The prostaglandin analogs and ß-blockers were discontinued, and the treatment regimen was changed to travoprost 0.004%/timolol maleate 0.5% fixed combination eye drops without any washout period. IOP before and at 1 month, 3 months, and 6 months after the treatment change was evaluated and compared. A questionnaire about protocol adherence was administered 1 month after the treatment change.Results: IOP was 15.7 ± 2.9 mmHg before the change, 15.5 ± 2.7 mmHg at 1 month after the change, 15.3 ± 3.6 mmHg at 3 months after the change, and 15.8 ± 3.2 mmHg at 6 months after the change, and none of the differences were significant (P = 0.191). The responses to the questionnaire showed that cases where eye drop administration was forgotten decreased after the treatment change. Moreover, because of changes in eye drops, 19.0% of patients had irritation. More than half (54.8%) of the patients preferred travoprost 0.004%/timolol maleate 0.5% fixed combination eye drops. Seven patients (16.3%) discontinued eye drop use because of adverse reactions within 6 months after the change.Conclusion: When the treatment regimen was changed from prostaglandin analogs and ß-blockers to travoprost 0.004%/timolol maleate 0.5% fixed combination eye drops, administration protocol adherence increased and IOP was preserved; however, adverse reactions appeared in about 16% of the cases.Keywords: travoprost 0.004%/timolol maleate 0.5% fixed combination, ß-blockers, prostaglandin analog, change, intraocular pressure

Kenji Inoue1, Minako Shiokawa1, Michitaka Sugahara1, Risako Higa1, Masato Wakakura1, Goji Tomita21Inouye Eye Hospital, Tokyo, Japan; 2Second Department of Ophthalmology, Toho University School of Medicine, Tokyo, JapanPurpose: To prospectively investigate adverse reactions to bimatoprost in Japanese patients with glaucoma or ocular hypertension. We also examined patient attitudes to adverse reactions via a questionnaire.Methods: Fifty-two Japanese patients with glaucoma or ocular hypertension were enrolled. Iridial, eyelid, and eyelash photographs were taken before and at 6 months after bimatoprost treatment. Increase in eyelid pigmentation, iridial pigmentation, eyelash growth and bristle, and vellus hair of the lid was assessed from the photographs. Questionnaires completed by patients provided insight into their subjective judgment of adverse reactions.Results: Increase in eyelash bristle (53.8%), iris pigmentation (50.0%), eyelash growth (46.2%), vellus hair of the lid (40.4%), and eyelid pigmentation (7.7%) was evident after bimatoprost treatment. The objective and subjective assessments were in agreement in terms of increase in eyelash bristle, eyelash growth, and increase in vellus hair of the lid.Conclusion: Most patients were conscious of these adverse reactions. Before administering bimatoprost, sufficient explanation of potential adverse reactions should be provided; after initiating treatment, careful observation is required.Keywords: bimatoprost, adverse reaction, eyelid pigmentation, changes in eyelashes, iris pigmentation

Cosmic-ray muons produce various radioisotopes when passing through material. These spallation products can be backgrounds for rare event searches such as in solar neutrino, double-β decay, and dark matter search experiments. The KamLAND-Zen experiment searches for neutrinoless double-β decay in 745 kg of xenon dissolved in liquid scintillator. The experiment includes dead-time-free electronics with a high efficiency for detecting muon-induced neutrons. The production yields of different radioisotopes are measured with a combination of delayed coincidence techniques, newly developed muon reconstruction, and xenon spallation identification methods. The observed xenon spallation products are consistent with results from the fluka and geant4 simulation codes.

We report a measurement of the strange axial coupling constant gAs using atmospheric neutrino data at KamLAND. This constant is a component of the axial form factor of the neutral-current quasielastic (NCQE) interaction. The value of gAs significantly changes the ratio of proton and neutron NCQE cross sections. KamLAND is suitable for measuring NCQE interactions as it can detect nucleon recoils with low-energy thresholds and measure neutron multiplicity with high efficiency. KamLAND data, including the information on neutron multiplicity associated with the NCQE interactions, makes it possible to measure gAs with a suppressed dependence on the axial mass MA, which has not yet been determined. For a comprehensive prediction of the neutron emission associated with neutrino interactions, we establish a simulation of particle emission via nuclear deexcitation of C12, a process not considered in existing neutrino Monte Carlo event generators. Energy spectrum fitting for each neutron multiplicity gives gAs=-0.14-0.26+0.25, which is the most stringent limit obtained using NCQE interactions without MA constraints. The two-body current contribution considered in this analysis relies on a theoretically effective model and electron scattering experiments and requires future verification by direct measurements and future model improvement.

The KamLAND-Zen experiment has provided stringent constraints on the neutrinoless double-beta (0νββ) decay half-life in ^{136}Xe using a xenon-loaded liquid scintillator. We report an improved search using an upgraded detector with almost double the amount of xenon and an ultralow radioactivity container, corresponding to an exposure of 970 kg yr of ^{136}Xe. These new data provide valuable insight into backgrounds, especially from cosmic muon spallation of xenon, and have required the use of novel background rejection techniques. We obtain a lower limit for the 0νββ decay half-life of T_{1/2}^{0ν}>2.3×10^{26}  yr at 90% C.L., corresponding to upper limits on the effective Majorana neutrino mass of 36-156 meV using commonly adopted nuclear matrix element calculations.

Hisato Ohno, Kenji InoueInouye Eye Hospital, Tokyo, JapanAbstract: We report five cases of unexplained retinal hemorrhage after 23-gauge sutureless vitrectomy. A 23-gauge sutureless vitrectomy was performed for four cases of macular holes (MH) and one case of macular hole retinal detachment (MHRD). Retinal hemorrhages were observed on the first day after surgery and disappeared within several months without leaving any recognizable damage. We speculate that the retinal hemorrhages might have resulted from repeated collapse of the globe through a cannula under air perfusion, but other causes such as retinal vein congestion by face-down positioning are also possible.Keywords: retinal hemorrhage, vitrectomy, postoperative, macular hole, sutureless surgery

Kenji Inoue1, Kei Noguchi1, Masato Wakakura1, Goji Tomita21Inouye Eye Hospital, Tokyo; 22nd Department of Ophthalmology, Toho University School of Medicine, Tokyo, JapanPurpose: To prospectively evaluate the diurnal variation of intraocular pressure (IOP) during unoprostone treatment in 13 healthy volunteers.Method: IOP was measured by Goldmann applanation tonometry by the same observer every 3 hours from 9 am to 9 am the next morning. Unoprostone was then instilled at 9 am and 9 pm daily for 1 month. After 1 month, IOP was measured again with unoprostone instilled at 9 am and 9 pm during IOP measurement. We then compared the average daily IOP before and after the treatment (paired t-test).Results: After 1 month of treatment, the average IOP decreased at every time point but one (12 pm, 3 pm, 6 pm, 9 pm, 12 am, 3 am, and 9 am, but not at 6 am). There were no adverse reactions and none of the subjects discontinued unoprostone.Conclusion: The hypotensive effects of unoprostone persist throughout the day, but this study suggests that the effects may be weaker at nighttime and early in the morning.Keywords: unoprostone, intraocular pressure, diurnal variation, healthy volunteer