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Takeshi Teshigawara,1– 3 Akira Meguro,3 Nobuhisa Mizuki3 1Department of Ophthalmology, Yokosuka Chuoh Eye Clinic, Yokosuka, Kanagawa, 238-0008, Japan; 2Tsurumi Chuoh Eye Clinic, Yokohama, Kanagawa, 230-0051, Japan; 3Department of Ophthalmology, Yokohama City University School of Medicine, Yokohama, Kanagawa, 236-0004, JapanCorrespondence: Takeshi TeshigawaraDepartment of Ophthalmology, Yokosuka Chuoh Eye Clinic, 2-6 Odaki-cho, Yokosuka, Kanagawa, 238-0008, JapanTel +81 46 827 4001Fax +81 46 827 4141Email teshitake@gmail.comPurpose: Halos are a chief source of patient dissatisfaction after multifocal intraocular lens (IOL) implantation. The primary purpose of this study was to investigate the influence of age, postoperative refraction, and pre- and postoperative pupil size on postoperative halo size with a trifocal diffractive IOL (AcrySof IQ PanOptix) and extended depth-of-focus (EDOF) IOL (TECNIS Symfony) to determine whether these factors could predict postoperative halo size.Patients and Methods: This single-center, open-label study conducted between October 2018 and April 2020 in Yokosuka, Japan included 160 patients: 80 with PanOptix and 80 with Symfony IOLs. Size and intensity of the halos were examined binocularly using a computer-based simulator (Eyeland Design Network GmbH) and scored from 0 (minimum) to 10 (maximum) at 1, 3, and 6 months postoperatively, along with the change in each variable for both IOLs. The respective correlations of halo size with age, postoperative refraction, pre- and postoperative pupil size, and discomfort level due to the halo were also investigated 6 months postoperatively.Results: Halo size and intensity were significantly mitigated between 1, 3, and 6 months postoperatively. Throughout the observation period, halo size was significantly larger with PanOptix than with Symphony (P < 0.05), and halo intensity was significantly higher with Symphony than with PanOptix (P < 0.05). The pre- and postoperative pupil size correlated positively with halo size, while age and postoperative refraction were negatively correlated, for both IOLs.Conclusion: Understanding the features and predictive preoperative factors of halos in different types of multifocal IOLs may be useful in improving patient satisfaction.Keywords: halo size, multifocal intraocular lens, biometric predictable factors, trifocal intraocular lens, extended depth-of-focus intraocular lens, photic phenomena, halo

Takeshi Teshigawara,1– 3 Akira Meguro,3 Nobuhisa Mizuki3 1Yokosuka Chuoh Eye Clinic, Yokosuka, Kanagawa, Japan; 2Tsurumi Chuoh Eye Clinic, Yokohama, Tsurumi, Japan; 3Department of Ophthalmology, Yokohama City University School of Medicine, Yokohama, Kanazawa, JapanCorrespondence: Takeshi TeshigawaraYokosuka Chuoh Eye Clinic, 2-6 Odaki-cho, Yokosuka, Kanagawa 238-0008, JapanTel +81 46 827 4001Fax +81 46 827 4141Email teshitake@gmail.comAbstract: A 68-year-old man with senile cataract underwent femtosecond laser-assisted cataract surgery (FLACS) in his left eye. Only anterior capsulotomy and lens fragmentation were planned with a femtosecond laser. Docking of the patient interface and anterior capsulotomy were completed without any complications. During the lens fragmentation process, the patient could not resist the temptation to squeeze his eyes shut, which caused excessive pressure from the eyelids. As the procedure proceeded, a bubble was formed at the edge of the patient interface and became increasingly larger. In addition, wrinkles in the conjunctiva were observed. As the lens fragmentation was approaching the final stage, the surgeon was reluctant to release the foot pedal to stop the laser emission. Finally, the patient interface lost adhesion to the cornea. Owing to the high repetition rate of the laser, the laser beam slipped into the corneal layers. Under an operating microscope, a grid-pattern laser beam trace was observed in the peripheral part of the cornea. As posterior capsule rupture occurred during the lens removal process, IOL insertion was no longer a suitable option. Therefore, scleral fixation of the implanted intraocular lens was performed without any unexpected events. One year postoperatively, the laser beam trace in the corneal layers could still be identified by slit-lamp examination. Nonetheless, since the laser beam trace was limited to the peripheral part of the cornea, and there was no damage to the central cornea, the visual acuity was 20/20. FLACS has significant benefits, especially in challenging cases of cataract surgery, and has well-established built-in safeguards for complications. However, this case study indicates the possibility of a suction break during laser emission and the preoperative risk factors. It demonstrates that recognizing the signs of suction break is necessary to avoid misplacement of the laser beam on the corneal layers.Keywo/rds: FLACS, complication, safeguard, laser beam trace

Takeshi Teshigawara,1– 3 Akira Meguro,3 Nobuhisa Mizuki3 1Yokosuka Chuoh Eye Clinic, Yokosuka, Kanagawa, Japan; 2Tsurumi Chuoh Eye Clinic, Yokohama, Tsurumi, Japan; 3Department of Ophthalmology, Yokohama City University School of Medicine, Yokohama, Kanazawa, JapanCorrespondence: Takeshi TeshigawaraYokosuka Chuoh Eye Clinic, 2-6 Odaki-Cho, Yokosuka, Kanagawa 238-0008, JapanTel +81 46 827 4001Fax +81 46 827 4141Email teshitake@gmail.comAbstract: Posterior capsule opacification (PCO) is the most common cause of deterioration of vision and contrast sensitivity and glare after cataract surgery. Neodymium (Nd): yttrium aluminum garnet (YAG) laser capsulotomy is an effective and standard procedure to treat these symptoms. The incidence rate of PCO requiring Nd:YAG laser treatment varies and depends on published studies, ranging from 2.2% to 10.0%. Although Nd:YAG laser treatment is largely safe, it still has complications, such as transient increase of intraocular pressure, anterior uveitis, intraocular lenses pitting, cystoid macula edema, endophthalmitis, and retinal detachment. We encountered a rare complication related to Nd:YAG laser treatment, where the laser accidentally hits the cornea. This occurred because the PCO was mistaken for the corneal layers during the laser procedure. This report presents the 3-year post-treatment process, and the findings herein may help raise the awareness of the possibility of this rare complication and provide measures for its treatment.Keywords: cornea, laser treatment, complication, PCO

Mami Ishihara, Akira Meguro, Mizuho Ishido, Masaki Takeuchi, Etsuko Shibuya, Nobuhisa Mizuki Department of Ophthalmology and Visual Science, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, JapanCorrespondence: Mami Ishihara; Akira Meguro Tel +81-45-787-2683Fax +81-45-781-9755Email mamitaiga7@gmail.com; akmeguro@yokohama-cu.ac.jpPurpose: Angiotensin-converting enzyme (ACE) is conventionally used as a biomarker in the diagnosis of uveitis associated with sarcoidosis, but its sensitivity is relatively low. In this study, we investigated whether serum soluble interleukin-2 receptor (sIL-2R) is also useful as a diagnostic marker, in addition to ACE, in the detection of uveitis associated with sarcoidosis.Patients and Methods: Data were analyzed from 126 patients with uveitis (52 sarcoidosis and 74 non-sarcoid uveitis) and 12 with primary intraocular lymphoma (PIOL) who had their serum sIL-2R and ACE levels measured.Results: Serum sIL-2R level was elevated in 69.2% of patients with sarcoid uveitis, 5.4% of those with non-sarcoid uveitis, and 16.7% of those with PIOL. The sensitivity and specificity of an elevated sIL-2R level for the detection of sarcoidosis were 69.2% and 93.0%, respectively. In contrast, serum ACE levels were elevated only in patients with sarcoid uveitis, with a sensitivity of 44.2% and specificity of 100%. Furthermore, serum sIL-2R and/or ACE level was elevated in 75.0% of patients with sarcoid uveitis, which is higher than those who had elevated serum ACE level only (44.2%, P = 0.0025). The sensitivity and specificity of elevated sIL-2R and/or ACE in detecting sarcoid uveitis were 75.0% and 93.0%, respectively. The PPV was 0.87, and the NPV was 0.86.Conclusion: Compared with the sensitivity of serum ACE levels alone, combined measurement of both serum sIL-2R and ACE levels improves sensitivity in the detection of uveitis associated with sarcoidosis. Nevertheless, serum ACE alone remains useful thanks to its high specificity in the differentiation of uveitis patients, with sarcoidosis from those without sarcoidosis.Keywords: sarcoid uveitis, soluble interleukin-2 receptors, sIL-2R, angiotensin-converting enzyme, ACE, primary intraocular lymphoma, PIOL

Takeshi Teshigawara,1–3 Akira Meguro,3 Sanae Sanjo,1 Seiichiro Hata,4 Nobuhisa Mizuki31Department of Ophthalmology, Yokosuka Chuoh Eye Clinic, Yokosuka, Kanagawa, Japan; 2Department of Ophthalmology, Tsurumi Chuoh Eye Clinic, Yokohama, Kanagawa, Japan; 3Department of Ophthalmology, Yokohama City University School of Medicine, Yokohama, Kanagawa, Japan; 4Department of Ophthalmology, Yokohama Sky Eye Clinic, Yokohama, Kanagawa, JapanAbstract: Zonulopathy is a major concern if found during cataract surgery as it can cause further complications. Such complications may occur during continuous curvilinear capsulorhexis (CCC), lens fragmentation and intraocular lens (IOL) implantation. Femtosecond laser-assisted cataract surgery (FLACS) devices, such as the LenSX (Alcon Laboratories) are advantageous because they can detect the area and largest point of zonulopathy via anterior segment optical coherent tomography (AS-OCT) before the manual part of the procedure. CCC and lens fragmentation can also minimize further zonular stress. A symmetrical CCC is ideal for IOL implantation in the sulcus with optic capture. In the present study, we did not detect significant zonular dehiscence preoperatively in either of the eyes of our 68-year-old patient when using AS-OCT (CASIA2 Tomey). However, LenSx AS-OCT revealed zonular dehiscence in both eyes, perioperatively. We created CCC and lens fragmentation without causing stress to the zonules. In the subsequent manual part of procedure, we found zonular dehiscence in the same area as indicated by LenSx AS-OCT, which extended to approximately 200° in the right eye and 180° in the left. After lens fragmentation by LenSx, we successfully removed the lens without further zonular dialysis. However, zonular dialysis (>180°) in the right eye was too large to insert an IOL, either in the capsule or the sulcus. Therefore, we performed scleral IOL implantation. In the left eye, we avoided using capsular tension ring (CTR) for IOL placement to avoid further iatrogenic damage to the zonule. Instead, an IOL was inserted into the sulcus with optic capture to reduce the possibility of further stress to the zonula and phimosis. Post-surgically, the patient regained good eyesight in both eyes. This case illustrates the advantages of FLACS in addressing zonulopathy. The consistent creation of CCC and lens fragmentation by FLACS may increase success rates, even in unexpectedly challenging cases.Keywords: femtosecond laser-assisted cataract surgery, phacodonesis, zonular dialysis, optic capture, anterior segment optical coherent tomography

Takeshi Teshigawara,1–3 Akira Meguro,3 Nobuhisa Mizuki3 1Yokosuka Chuoh Eye Clinic, Yokosuka, Kanagawa, Japan; 2Tsurumi Chuoh Eye Clinic, Yokohama, Kanagawa, Japan; 3Department of Ophthalmology, Yokohama City University School of Medicine, Yokohama, Kanagawa, Japan Purpose: To evaluate the influence of pupil dilation on predicted postoperative refraction (PPR) and recommended intraocular lens (IOL) power to obtain target postoperative refraction calculated by using the third- and fourth-generation IOL power calculation formulas with a new optical biometer.Methods: This retrospective study included 162 eyes with cataract that underwent uneventful phacoemulsification with IOL implantation. PPR, recommended IOL power, anterior chamber depth (ACD), and lens thickness (LT) were measured pre- and post-pupil dilation. The change in PPR detected by using third-generation (Hoffer Q and SRK/T) and fourth-generation formulas (Haigis and Holladay 2) and the changes in ACD and LT were evaluated pre- and postdilation. The influence of dilation on the recommended IOL power calculated by each formula was analyzed.Result: ACD and LT significantly changed from pre- to postdilation. The mean absolute change in PPR between pre- and postdilation was significantly higher for fourth-generation formulas compared with third-generation formulas. The change in PPR between pre- and postdilation showed a significantly positive correlation with change in ACD and a significantly negative correlation with change in LT with fourth-generation formulas, but not with third-generation formulas. The discrepancy rate of recommended IOL power between pre- and postdilation calculated by fourth-generation formulas was significantly higher than that calculated by third-generation formulas.Conclusion: ACD and LT significantly changed by dilation. PPR and recommended IOL power significantly changed more by dilation when using fourth-generation formulas compared with third-generation formulas. Given the significant correlations of the change in PPR (between the pre- and postdilation) in the fourth-generation formulas and the changes in ACD and LT, the latter changes may be key in influencing dilation in the fourth-generation power calculation. Knowledge of the influence of dilation on fourth-generation formulas could help improve IOL calculation. Keywords: pupil dilation, IOL power calculation, predicted postoperative refraction

Takeshi Teshigawara,1–3 Akira Meguro,3 Kazuro Yabuki,4 Seiichiro Hata,5 Nobuhisa Mizuki3 1Yokosuka Chuoh Eye Clinic, Yokosuka, Kanagawa, Japan; 2Tsurumi Chuoh Eye Clinic, Yokohama, Kanagawa, Japan; 3Department of Ophthalmology, Yokohama City University School of Medicine, Yokohama, Kanagawa, Japan; 4Department of Ophthalmology, Saiseikai Yokohamashi Nanbu Hospital, Yokohama, Kanagawa, Japan; 5Yokohama Sky Eye Clinic, Yokohama Kanagawa, Japan Abstract: At present, only one design is available for trifocal intraocular lens (IOL); unfortunately, this particular design is not suitable for implantation in the sulcus with optic capture when posterior capsule rupture (PCR) occurs. Although three-piece bifocal IOLs can be implanted in the sulcus, this form of IOL can be vulnerable to tilt and decentration, thus causing aberration and photopic phenomena, such as halos and glares. However, visual axis centered optic capture using femtosecond laser-assisted cataract surgery (FLACS) is able to manage such complex operations. In the present study, we implanted a three-piece +4.0 D bifocal IOL into the sulcus of a patient who experienced PCR using optic capture and FLACS following the straightforward implantation of a one-piece trifocal IOL in the other eye. Defocus curves showed that the weakness of the trifocal IOL (nearest distances) was compensated for by the strength of the +4.0 D bifocal IOL, whereas the weakness of the +4.0 D bifocal IOL (middle distance) was compensated for by the strength of the trifocal IOL. Therefore, this combination provided the patient with a wider range of depth of focus. The contrast sensitivity in both eyes was within the normal range. Photopic phenomena were comparable with the bilateral implantation of the trifocal IOL. Anterior segment optical coherence tomography showed that tilt and decentration in the trifocal IOL implanted in the bag was significantly higher than the +4.0 D bifocal IOL implanted in the visual axis centered optic capture. This case showed that the intraindividual implantation of a single-piece trifocal IOL in the bag and a three-piece +4.0 D bifocal IOL in the sulcus, using a combination of optic capture and FLACS, is promising particularly in cases of PCR and can provide a wider range of vision without losing visual quality. Keywords: multifocal intraocular lens, mixing and matching, optic capture, femtosecond laser-assisted cataract surgery, posterior capsule rupture

Tatsukata Kawagoe,1 Masao Ota,1,2 Akira Meguro,1 Masaki Takeuchi,1 Takahiro Yamane,1 Haruna Shimazaki,3 Masaru Takeuchi,3 Eiichi Okada,4 Takeshi Teshigawara,1,5,6 Nobuhisa Mizuki1 1Department of Ophthalmology and Visual Science, Yokohama City University Graduate School of Medicine, Yokohama, 2Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, 3Department of Ophthalmology, National Defense Medical College, Tokorozawa, 4Okada Eye Clinic, Yokohama, 5Yokosuka Chuoh Eye Clinic, Yokosuka, 6Tsurumi Chuoh Eye Clinic, Yokohama, Japan Purpose: The crystallin beta A4 (CRYBA4) gene variant, rs2009066, was previously reported to be associated with high myopia in a southern Chinese population. In the present study, we investigated whether CRYBA4 variants were associated with high myopia in a Japanese population.Methods: We recruited 1,063 Japanese patients with high myopia (spherical equivalent [SE] ≤–9.00 D in both eyes) and 1,009 healthy Japanese subjects (SE >–1.00 D). We genotyped rs2009066 and three tagging single-nucleotide polymorphisms (SNPs), rs16982456, rs2071861, and rs4276, in the CRYBA4 region.Results: We did not find any significant association between these four SNPs and high myopia in an allele analysis. However, rs2009066 and rs2071861, which were in strong linkage disequilibrium (LD; r2=0.86), showed a marginal association with high myopia in the recessive genotype model of risk alleles (rs2009066 G allele: P=0.032, odds ratio [OR] =1.31; rs2071861 A allele: P=0.037, OR =1.31). Nevertheless, this association became insignificant after correcting for multiple testing (Pc >0.05).Conclusion: This study showed no significant association between CRYBA4 variants and high myopia in a Japanese population. Our findings did not correspond with a previous study. Further genetic studies with other populations are needed to elucidate a potential contribution of the CRYBA4 region in the development of high myopia. Keywords: high myopia, CRYBA4, association study, polymorphism

Abstract Background Black/African American women with breast cancer have a disproportionately higher risk of mortality compared to other race groups, although their overall incidence of disease is lower. Despite this, advance care planning (ACP) and consequent code status documentation remain low in this vulnerable patient population. Code status orders (i.e., Full code, Do Not Attempt Resuscitation [DNAR], Do Not Intubate [DNI]) allow consideration of patient preferences regarding the use of aggressive treatments, such as cardiopulmonary resuscitation and intubation. The aim of this study is to characterize presence of code status orders and determine whether race affects code status documentation after the first encounter for breast cancer. Methods Data were derived from 7524 women with breast cancer from the University of Chicago Medical Center (UCMC) between 2016 and 2021. Cox regression was used to estimate the effects of race and adjusted for age, ethnicity, inpatient stays, metastatic breast cancer, marital status, and body mass index. Results The sample included 60.5% White, 3.6% Asian/Mideast Indian, 28.9% Black/African American, and 7.0% other or unknown race. Results indicate that code status orders after the first breast cancer encounter were uncommon (7.2%). Black/African American race (HR = 2.74; 95% CI: 1.75, 4.28) emerged as a significant factor associated with any code status orders compared to other race groups even when adjusting for covariates. Conclusions Code status documentation in this sample of women with breast cancer was low overall, yet rates were higher among Black/African American patients compared to other race groups. In fact, race remains a significant predictor of code status documentation even when accounting for indirect measures of cancer severity. This could be denoting the racial disparities (e.g., higher cancer malignancy such as triple negative breast cancer) in breast cancer mortality risk. Future research is needed to identify factors unique to Black/African American women that would increase code status documentation so that goal concordant care can be prioritized among patients with breast cancer.

Abstract Background The relationship between inflammatory response, fish consumption, and mortality risk in older individuals is unclear. We investigated whether C-reactive protein (CRP) levels ≥ 0.1 mg/dL, fish intake, and inflammatory responses are associated with all-cause mortality risk in older adults. Methods This prospective cohort study included older adults aged 85–89 years from the Kawasaki Aging and Wellbeing Project, who did not require daily care. Cohort was recruited from March 2017 to December 2018 (follow-up ended on December 31, 2021). Dietary assessment was conducted using the Brief Self-Administered Diet History Questionnaire. Multivariate Cox proportional hazards regression was used to estimate the hazard ratio (HR) and 95% confidence interval (CI) for all-cause mortality in the CRP ≥ 0.1 mg/dL group; the CRP

Shintaro Okui,1 Akira Meguro,1 Masaki Takeuchi,1,2 Takahiro Yamane,1 Eiichi Okada,3 Yasuhito Iijima,4 Nobuhisa Mizuki1 1Department of Ophthalmology and Visual Science, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan; 2Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA; 3Okada Eye Clinic, Yokohama, Kanagawa, Japan; 4Aoto Eye Clinic, Yokohama, Kanagawa, Japan Purpose: Many studies have investigated the relationship of the lumican gene (LUM) rs3759223 variant with the risk of high myopia, but the results have been inconsistent and inconclusive. In this study, we investigated whether LUM rs3759223 is associated with high myopia in a Japanese population.Methods: We recruited 1,585 Japanese patients with high myopia (spherical equivalent [SE]

Atsushi Yoshino,1 Natalia Polouliakh,1–3 Akira Meguro,1 Masaki Takeuchi,1,4 Tatsukata Kawagoe,1 Nobuhisa Mizuki1 1Department of Ophthalmology and Visual Science, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, 2Sony Computer Science Laboratories Inc., Fundamental Research Laboratories, 3Systems Biology Institute, Tokyo, Japan; 4Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA Abstract: Components of fish roe possess antioxidant and antiaging activities, making them potentially very beneficial natural resources. Here, we investigated chum salmon eggs (CSEs) as a source of active ingredients, including vitamins, unsaturated fatty acids, and proteins. We incubated human dermal fibroblast cultures for 48 hours with high and low concentrations of CSE extracts and analyzed changes in gene expression. Cells treated with CSE extract showed concentration-dependent upregulation of collagen type I genes and of multiple antioxidative genes, including OXR1, TXNRD1, and PRDX family genes. We further conducted in silico phylogenetic footprinting analysis of promoter regions. These results suggested that transcription factors such as acute myeloid leukemia-1a and cyclic adenosine monophosphate response element-binding protein may be involved in the observed upregulation of antioxidative genes. Our results support the idea that CSEs are strong candidate sources of antioxidant materials and cosmeceutically effective ingredients. Keywords: fish egg, antiaging, gene expression analysis, antioxidative gene, phylogenetic footprinting analysis

Nobuyuki Kanemaki,1 Akira Meguro,2 Takahiro Yamane,2 Masaki Takeuchi,2,3 Eiichi Okada,4 Yasuhito Iijima,5 Nobuhisa Mizuki2 1Veterinary Teaching Hospital, Azabu University, Sagamihara, 2Department of Ophthalmology and Visual Science, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan; 3Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA; 4Okada Eye Clinic, 5Aoto Eye Clinic, Yokohama, Kanagawa, Japan Purpose: Many studies have investigated the relationship of paired box 6 (PAX6) gene polymorphisms with the risk of high myopia, but the results across studies remain inconsistent and ambiguous. In the present work, we investigated whether PAX6 polymorphisms are associated with high myopia in a Japanese population.Methods: A total of 1,585 Japanese patients with high myopia (spherical equivalent [SE]

Abstract A double-check process helps prevent errors and ensures quality control. However, it may lead to decreased personal accountability, reduced effort, and declining quality checks. Introducing an artificial intelligence (AI)-based system in such scenarios could effectively address the risk of oversights. This study introduces an innovative AI-integrated workflow for cervical cytology screening that substantially improves efficiency and reduces the burden on cytologists. The AI model prioritizes cases for review based on anomaly scores and streamlines the first screening process to approximately 10 s per case. The model enhances the identification of high-risk cases via detailed microscopic observation, high anomaly scores cases, and a targeted review of low-score cases. The workflow highlights its capability for rapid, accurate, and less labor-intensive evaluations, demonstrating the potential to transform cervical cancer screening. This study highlights the importance of AI in modern medical diagnostics, particularly in areas with a high demand for accuracy and efficiency.

IntroductionThere are limited data on prevalence of dementia in centenarians and near-centenarians (C/NC), its determinants, and whether the risk of dementia continues to rise beyond 100.MethodsParticipant-level data were obtained from 18 community-based studies (N = 4427) in 11 countries that included individuals ≥95 years. A harmonization protocol was applied to cognitive and functional impairments, and a meta-analysis was performed.ResultsThe mean age was 98.3 years (SD = 2.67); 79% were women. After adjusting for age, sex, and education, dementia prevalence was 53.2% in women and 45.5% in men, with risk continuing to increase with age. Education (OR 0.95;0.92-0.98) was protective, as was hypertension (odds ratio [OR] 0.51;0.35-0.74) in five studies. Dementia was not associated with diabetes, vision and hearing impairments, smoking, and body mass index (BMI).DiscussionAmong the exceptional old, dementia prevalence remains higher in the older participants. Education was protective against dementia, but other factors for dementia-free survival in C/NC remain to be understood.

Masao Yoshida,1,* Akira Meguro,2,* Atsushi Yoshino,2 Naoko Nomura,2 Eiichi Okada,3 Nobuhisa Mizuki21Department of Public Health, Kyorin University School of Medicine, Mitaka, Tokyo, Japan; 2Department of Ophthalmology and Visual Science, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan; 3Okada Eye Clinic, Yokohama, Kanagawa, Japan*These authors contributed equally to this workPurpose: Polymorphisms in the insulin-like growth factor 1 (IGF1) gene were previously associated with high or extreme myopia in Caucasian and Chinese populations. In the present study, we investigated whether IGF1 polymorphisms are associated with high myopia in a Japanese population.Methods: A total of 446 Japanese patients with high myopia (≤–9.00 diopters) and 481 Japanese healthy controls (+1.50 diopters to –1.50 diopters) were recruited. We genotyped seven tagging single-nucleotide polymorphisms (SNPs) in IGF1 and assessed allelic and haplotypic diversity in cases and controls.Results: There were no statistically significant differences in the allele frequencies of IGF1 SNPs and genotypes between cases and controls (P>0.05). However, the A allele of rs5742629 and the G allele of rs12423791 were associated with a moderately increased risk of high myopia (odds ratio [OR] =1.20 and OR =1.21, respectively) with borderline statistical significance (P=0.0502, corrected P (Pc) =0.21 and P=0.064, Pc=0.29, respectively). The haplotype consisting of the A allele of rs5742629 and the G allele of rs12423791 was marginally associated with the risk of high myopia (P=0.041; OR =1.21); this association was not significant after correction (Pc=0.19).Conclusion: We found that the IGF1 SNPs are not significantly associated with high myopia in our Japanese population. Our results are in contrast to a previous study in which extreme myopia cases had significantly higher frequencies of the G allele of rs5742629 and the C allele of rs12423791 than controls. Therefore, the IGF1 SNPs may not be important factors for susceptibility to high myopia in all populations. Further genetic studies are needed to elucidate the possible contributions of the IGF1 region to the development of high myopia.Keywords: high myopia, IGF1, association study, polymorphism

ABSTRACT Background Despite the high recurrence rate of non‐muscle‐invasive bladder cancer (NMIBC), there are limitations in accurately predicting recurrence after transurethral resection of bladder tumor (TURBT) based on clinicopathological factors alone. However, prediction of recurrence using biomolecular characteristics of bladder tumors has not been applied to clinical practice. The objective of this study was to establish a new gene expression scoring system for identifying patients at high risk of recurrence. Methods NMIBC and normal bladder samples were subjected to microarray analysis to obtain gene expression profiles. We identified 6 genes that were specifically upregulated in bladder cancer and also in recurrent cases. All patients were randomly grouped into a discovery cohort (n = 59) and a validation cohort (n = 30). Gene expression score (GES) was defined as the mean Z‐score of the 6 genes specific for recurrent bladder cancer. Results The intravesical recurrence rate of the high GES group (n = 38) was higher than the low GES group (n = 21). GES was significantly associated with recurrence‐free survival in the validation cohort as well. In prognostic analysis, the European Organization for Research and Treatment of Cancer (EORTC) risk classification was not related to recurrence after TURBT in either univariate or multivariate analysis. On the other hand, the GES we developed was an independent factor for recurrence in NMIBC. Conclusions A novel gene expression scoring system was shown to predict recurrence in NMIBC patients after TURBT and might be helpful in clinical decision‐making for NMIBC patients.

Dysfunction of primary cilia leads to genetic disorder, ciliopathies, which shows various malformations in many vital organs such as brain. Multiple tongue deformities including cleft, hamartoma, and ankyloglossia are also seen in ciliopathies, which yield difficulties in fundamental functions such as mastication and vocalization. Here, we found these tongue anomalies in mice with mutation of ciliary protein. Abnormal cranial neural crest-derived cells (CNCC) failed to evoke Hh signal for differentiation of mesoderm-derived cells into myoblasts, which resulted in abnormal differentiation of mesoderm-derived cells into adipocytes. The ectopic adipose subsequently arrested tongue swelling formation. Ankyloglossia was caused by aberrant cell migration due to lack of non-canonical Wnt signaling. In addition to ciliopathies, these tongue anomalies are often observed as non-familial condition in human. We found that these tongue deformities could be reproduced in wild-type mice by simple mechanical manipulations to disturb cellular processes which were disrupted in mutant mice. Our results provide hints for possible future treatment in ciliopathies.

Venous thromboembolism is a serious safety concern in women using combined oral contraceptives; ethinyl estradiol (EE) is widely used as an estrogen. Estetrol (E4) is a native estrogen with selective tissue activity and exclusively produced by the fetal liver. This study used a multicenter, randomized, open-label, active-controlled, parallel-group design to evaluate the effects of E4 combined with drospirenone (DRSP) on coagulation and fibrinolysis in Japanese patients with endometriosis. Participants were randomized to receive either E4 15 mg/DRSP 3 mg or EE 20 µg/DRSP 3 mg for 12 weeks. E4/DRSP and EE/DRSP were administered orally once a day in a cyclic regimen, ie, 24-day active use followed by a 4-day hormone-free period, and a flexible extended regimen, respectively, and blood coagulation and fibrinolysis markers were measured. The effect on coagulation and fibrinolysis was considerably less in the E4/DRSP group than in the EE/DRSP group. Major anticoagulant proteins, protein S (free, total) and tissue factor pathway inhibitor (free), were reduced following EE/DRSP treatment. Consequently, thrombin generation determined by the activated protein C sensitivity ratio was increased by approximately 4-fold in the EE/DRSP group than in the E4/DRSP group. Eventually, the fibrinolysis cascade was triggered to compensate for disturbed coagulation, and D-dimer levels were 4.7-fold higher in the EE/DRSP group than in the E4/DRSP group. This study demonstrated that the effect of E4/DRSP on the blood coagulation and fibrinolysis cascades was significantly less than that of EE/DRSP in participants with endometriosis, a disease of women of advanced and reproductive age (jRCT2080225090, https://jrct.niph.go.jp/en-latest-detail/jRCT2080225090 ).