Pigmentation level of human iPSC-derived RPE does not indicate a specific gene expression profile.

Retinal pigment epithelium (RPE) cells show heterogeneous levels of pigmentation when cultured in vitro. To know whether their color in appearance is correlated with the function of the RPE, we analyzed the color intensities of human-induced pluripotent stem cell-derived RPE cells (iPSC-RPE) together with the gene expression profile at the single-cell level. For this purpose, we utilized our recent invention, Automated Live imaging and cell Picking System (ALPS), which enabled photographing each cell before RNA-sequencing analysis to profile the gene expression of each cell. While our iPSC-RPE were categorized into four clusters by gene expression, the color intensity of iPSC-RPE did not project any specific gene expression profiles. We reasoned this by less correlation between the actual color and the gene expressions that directly define the level of pigmentation, from which we hypothesized the color of RPE cells may be a temporal condition not strongly indicating the functional characteristics of the RPE.

The backs of our eyes are lined with retinal pigment epithelial cells (or RPE cells for short). These cells provide nutrition to surrounding cells and contain a pigment called melanin that absorbs excess light that might interfere with vision. By doing so, they support the cells that receive light to enable vision. However, with age, RPE cells can become damaged and less able to support other cells. This can lead to a disease called age-related macular degeneration, which can cause blindness. One potential way to treat this disease is to transplant healthy RPE cells into eyes that have lost them. These healthy cells can be grown in the laboratory from human pluripotent stem cells, which have the capacity to turn into various specialist cells. Stem cell-derived RPE cells growing in a dish contain varying amounts of melanin, resulting in some being darker than others. This raised the question of whether pigment levels affect the function of RPE cells. However, it was difficult to compare single cells containing various amounts of pigment as most previous studies only analyzed large numbers of RPE cells mixed together. Nakai-Futatsugi et al. overcame this hurdle using a technique called Automated Live imaging and cell Picking System (also known as ALPS). More than 2300 stem cell-derived RPE cells were photographed individually and the color of each cell was recorded. The gene expression of each cell was then measured to investigate whether certain genes being switched on or off affects pigment levels and cell function. Analysis did not find a consistent pattern of gene expression underlying the pigmentation of RPE cells. Even gene expression related to the production of melanin was only slightly linked to the color of the cells. These findings suggests that the RPE cell color fluctuates and is not primarily determined by which genes are switched on or off. Future experiments are required to determine whether the findings are the same for RPE cells grown naturally in the eyes and whether different pigment levels affect their capacity to protect the rest of the eye.

Male-female disparity in clinical features and significance of mild vertebral fractures in community-dwelling residents aged 50 and over.

This investigation examined the clinical implications of mild vertebral fractures in older community-dwelling residents. Focusing on the locomotion health of older individuals, the earlier reported Obuse study enrolled 415 randomly sampled Japanese residents aged between 50 and 89 years, 411 of whom underwent X-ray evaluations for pre-existing vertebral fractures. A blinded assessment of vertebral fractures based on Genant's criteria was conducted on the T5-L5 spine for rating on a severity scale. Grade 1 mild fractures were not linked to age in males, but increased with aging in females. Female participants had fewer Grade 1 and 2 fractures (P = 0.003 and 0.035, respectively) but more Grade 3 fractures (P = 0.013) than did males independently of age (Grade 1, 2, and 3: 25%, 16%, and 9% in females and 40%, 22%, and 6% in males, respectively). Weak negative correlations were observed between the number of fractures and bone mineral density in females for all fracture grades (Spearman's rho: 0.23 to 0.36, P < 0.05). Our study showed that Grade 1 mild vertebral fractures in males lacked pathological significance, while in females they potentially indicated fragility fractures and were related to poor lumbopelvic alignment.

Association between restricted outings and geriatric locomotive function scale score in the general elderly population during the COVID-19 pandemic.

BACKGROUND: Restrictions in daily activities due to coronavirus infection countermeasures reduced opportunities for physical activity and social participation in people of all ages. This study investigated the associations of restricted outings on locomotive function during the COVID-19 pandemic using a cohort of middle-aged and elderly community-dwelling residents. METHODS: Registered citizens of 50-89 years old were targeted for this investigation. We established 8 groups based on age (50's, 60's, 70's, and 80's) and gender (male and female) after random sampling from the basic resident registry of Obuse town in 2014. All participants were surveyed by a 25-question geriatric locomotive function scale (GLFS-25) at the time of checkup before the COVID-19 pandemic. Then, in 2021 and 2022 after government restrictions on outings were lifted for COVID-19 pandemic, all participants were mailed questionnaires including the GLFS-25. A total of 296 (143 male and 153 female) participants who responded at least once were included. We evaluated the changes in opportunities to go out between pre- and post-pandemic time points and the impact on GLFS-25 scores. RESULTS: In total, 128 (43.2%) respondents had fewer opportunities to go out than the previous year. Pre- and post-pandemic GLFS-25 scores in the decreased outing (+) group were significantly worse than in the decreased outing (-) group (both p < 0.01). The final multivariate model revealed GLFS-25 score worsening beta coefficient of 0.27 for age (+10 years), 3.97 for male, 4.54 for decreased outings, and 4.46 for spinal canal stenosis. CONCLUSIONS: In this randomly sampled Japanese cohort based on a resident registry, restricted outings during the COVID-19 pandemic was a significant independent factor associated with lower locomotive function.

Robotic search for optimal cell culture in regenerative medicine.

Induced differentiation is one of the most experience- and skill-dependent experimental processes in regenerative medicine, and establishing optimal conditions often takes years. We developed a robotic AI system with a batch Bayesian optimization algorithm that autonomously induces the differentiation of induced pluripotent stem cell-derived retinal pigment epithelial (iPSC-RPE) cells. From 200 million possible parameter combinations, the system performed cell culture in 143 different conditions in 111 days, resulting in 88% better iPSC-RPE production than that obtained by the pre-optimized culture in terms of the pigmentation scores. Our work demonstrates that the use of autonomous robotic AI systems drastically accelerates systematic and unbiased exploration of experimental search space, suggesting immense use in medicine and research.

Inducing human retinal pigment epithelium-like cells from somatic tissue.

Regenerative medicine relies on basic research outcomes that are only practical when cost effective. The human eyeball requires the retinal pigment epithelium (RPE) to interface the neural retina and the choroid at large. Millions of people suffer from age-related macular degeneration (AMD), a blinding multifactor genetic disease among RPE degradation pathologies. Recently, autologous pluripotent stem-cell-derived RPE cells were prohibitively expensive due to time; therefore, we developed a faster reprogramming system. We stably induced RPE-like cells (iRPE) from human fibroblasts (Fibs) by conditional overexpression of both broad plasticity and lineage-specific transcription factors (TFs). iRPE cells displayed critical RPE benchmarks and significant in vivo integration in transplanted retinas. Herein, we detail the iRPE system with comprehensive single-cell RNA sequencing (scRNA-seq) profiling to interpret and characterize its best cells. We anticipate that our system may enable robust retinal cell induction for basic research and affordable autologous human RPE tissue for regenerative cell therapy.

Prevalence and associated factors of primary elbow osteoarthritis in the Japanese general elderly population: a Japanese cohort survey randomly sampled from a basic resident registry.

BACKGROUND: The epidemiology of primary elbow osteoarthritis (PEOA) remains unknown. We aimed to evaluate the prevalence and associated factors of PEOA in a cross-sectional resident cohort from a municipal registry of a Japanese town. METHODS: A total of 415 residents over 50 years of age were randomly sampled from a Japanese town and were adjusted for age and gender. Those with diseases that could potentially cause a secondary osteoarthritis of the elbow were excluded. The remaining 318 subjects (150 men and 168 women) underwent bidirectional radiography of the elbow. Subjects were diagnosed with PEOA if one of their elbows was Kellgren-Lawrence (KL) grade 2 or greater. In addition, motion pain and tenderness at the elbow were examined by orthopedic surgeons. Associated factors for the PEOA were statistically analyzed. RESULTS: The prevalence of PEOA was 25.2% (male, 27.3%; female, 23.2%), and the prevalence of symptomatic PEOA was 0.9%. The age-stratified prevalence of PEOA was as follows: 50-59, 6.2% (male, 5.0%; female, 7.3%); 60-69, 15.4% (male, 17.5%; female, 13.7%); 70-79, 29.5% (male, 35.3%; female, 25.0%); and 80-89, 55.9% (male, 55.6%; female, 56.3%). Age and body mass index were revealed as associated factors that increased the prevalence of PEOA with KL grade 2 or greater. The use of vibrating tools was demonstrated as an independent associated factor that increased the prevalence of PEOA with KL grade 4 in addition to the 2 aforementioned factors. CONCLUSIONS: The prevalence of PEOA in Japanese subjects was 25.2% for those aged 50-89 years with a mean age of 69.2 years, most of which was asymptomatic OA without motion pain or tenderness at the elbow. Age and body mass index increased the prevalence of PEOA with KL grade 2 or greater. The prevalence of PEOA increased with age, but the disease was self-accommodated by most people.

Cervical Spinal Alignment Change Accompanying Spondylosis Exposes Harmonization Failure with Total Spinal Balance: A Japanese Cohort Survey Randomly Sampled from a Basic Resident Registry.

The relationship between spinal posture and quality of life has garnered considerable attention with the increase in older community-dwelling residents. However, details of this association remain insufficient. A recent Japanese population cohort epidemiological locomotion survey (the Obuse study) revealed that the C2-C7 cervical sagittal vertical axis (CSVA) began to increase in males from their 60s, but not in females. This study aimed to clarify the pathology of these cervical spondylotic changes. A total of 411 participants (202 male and 209 female) aged between 50 and 89 years were selected by random sampling from a cooperating town's resident registry. All participants underwent lateral X-ray photography in a standing position for the measurement of several sagittal spinal alignment parameters, including CSVA, C2-C7 cervical lordosis (CL), T1 slope (T1S), and sagittal vertical axis (SVA). The presence of cervical spondylotic changes was also recorded. Associations of cervical sagittal spinal alignment with cervical spondylosis and between cervical and total sagittal spinal alignment were examined. The prevalence of cervical spondylosis was significantly higher in males (81%) than in females (70%) (p = 0.01). CL was significantly smaller in cervical spondylosis subjects when adjusted by age (3.4 degrees less; p = 0.01). T1S minus CL displayed a moderate positive correlation with CSVA in both males and females (r = 0.49 and 0.48, respectively, both p < 0.01). In males only, CSVA and CL showed weak positive correlations with SVA (r = 0.31 and 0.22, respectively, both p < 0.01) independently of age. Cervical spinal misalignment was more clearly associated with diminished SF-8TM scores in females than in males. In community-dwelling elderly residents, cervical sagittal spinal alignment change accompanying cervical spondylosis manifested as hypofunction to compensate for whole-spine imbalance.

Efficacy of denosumab therapy for a 12-year-old female patient with Williams syndrome with osteoporosis and history of fractures: a case report.

BACKGROUND: A decrease in bone mineral density is common in patients with Williams syndrome. However, appropriate management for osteoporosis in Williams syndrome patients has not been established. We report the case of a 12-year-old female patient with Williams syndrome, who underwent denosumab treatment for osteoporosis. CASE PRESENTATION: A 12-year-old Japanese female patient with Williams syndrome was shown to have very low bone mineral density. Bone mineral density was evaluated before treatment and at 5, 9, 17, 23, and 29 months of treatment by dual-energy X-ray absorptiometry. After denosumab therapy for 29 months, lumbar and total hip bone mineral density values had increased by 51.6% and 37.6%, respectively. No new fractures occurred during the observation period. CONCLUSIONS: To the best of our knowledge, this is the first experience with denosumab treatment in Williams syndrome patients with osteoporosis. Based on our findings, denosumab may be an effective treatment option for Williams syndrome patients with osteoporosis.

Associations of LRP5 and MTHFR Gene Variants with Osteoarthritis Prevalence in Elderly Women: A Japanese Cohort Survey Randomly Sampled from a Basic Resident Registry.

OBJECTIVE: Osteoarthritis (OA) is a common and degenerative joint disorder in the elderly. A greater importance of understanding the relationship between genetic factors and OA prevalence has emerged with population aging. We therefore investigated the associations of several bone disease-related genetic variants with the prevalence of OA and osteoporosis in Japanese elderly women from the Obuse study cohort, which was randomly sampled from a basic town resident registry. METHODS AND RESULTS: In total, 206 female participants (mean ± standard deviation age: 69.7 ± 11.0 years) who completed OA, bone mineral density, and genotype assessments were included. The number of patients diagnosed as having knee/hip OA and osteoporosis was 59 (28.6%) and 30 (14.6%), respectively. Fisher's exact testing revealed significant relationships between the minor T allele of LDL receptor related protein 5 (LRP5) rs3736228 and the prevalence of knee/hip OA and osteoporosis. The respective odds ratios (ORs) of the TT genotype for knee/hip OA and osteoporosis were 7.28 (95% confidence interval [CI] 2.22-28.08) and 5.24 (95% CI 0.95-26.98). An additional subgroup analysis for knee OA revealed that the frequency of the common C allele of methylenetetrahydrofolate reductase (MTHFR) rs1801133 had a statistically significant protective association with the prevalence of knee OA (OR 0.58, 95% CI 0.35-0.97). CONCLUSION: In sum, the present study demonstrated significant associations of LRP5 rs3736228 and MTHFR rs1801133 with knee/hip OA and osteoporosis prevalences and knee OA prevalence, respectively, in Japanese elderly women. These results will help further the understanding of OA pathogenesis and related genetic risk factors.

A ROCK Inhibitor Promotes Graft Survival during Transplantation of iPS-Cell-Derived Retinal Cells.

Currently, retinal pigment epithelium (RPE) transplantation includes sheet and single-cell transplantation, the latter of which includes cell death and may be highly immunogenic, and there are some issues to be improved in single-cell transplantation. Y-27632 is an inhibitor of Rho-associated protein kinase (ROCK), the downstream kinase of Rho. We herein investigated the effect of Y-27632 in vitro on retinal pigment epithelium derived from induced pluripotent stem cells (iPS-RPE cells), and also its effects in vivo on the transplantation of iPS-RPE cell suspensions. As a result, the addition of Y-27632 in vitro showed suppression of apoptosis, promotion of cell adhesion, and higher proliferation and pigmentation of iPS-RPE cells. Y-27632 also increased the viability of the transplant without showing obvious retinal toxicity in human iPS-RPE transplantation into monkey subretinal space in vivo. Therefore, it is possible that ROCK inhibitors can improve the engraftment of iPS-RPE cell suspensions after transplantation.

Reference values for bone metabolism in a Japanese cohort survey randomly sampled from a basic elderly resident registry.

The aim of this study was to provide definitive reference values for bone mineral density (BMD) and bone turnover markers in the general elderly population. Registered citizens of 50 to 89 years old were targeted for this survey. After random sampling from the resident registry of Obuse town, we established eight groups based on age (50 s, 60 s, 70 s, and 80 s) and gender. A total of 411 people were enrolled. We used a dual-energy x-ray absorptiometry device to measure and evaluate BMD. The bone formation marker bone alkaline phosphatase (BAP) was measured as a bone turnover marker. Bone quality marker pentosidine, and bone resorption markers including urinary total deoxypyridinoline (DPD), tartrate-resistant acid phosphatase 5b (TRACP-5b), 25-hydroxyvitamin D (25[OH]D), and whole parathyroid hormone (PTH) were also measured as bone turnover markers. Sixty-three people (15.3%) were diagnosed as osteoporosis. BMD decreased with age in the femoral neck and total hip. On the other hand, there was no characteristic change with age in the lumber spine. As for bone markers, pentosidine and DPD increased with aging, although 25(OH)D, whole PTH, and BAP showed no characteristic associations with gender and aging. In terms of the relationship between low BMD and bone markers, there was a significant independent association between low BMD and TRACP-5b in females. In conclusions, hip BMD decreased with aging in men and women. However, there was no characteristic decline with aging in the lumbar spine. All bone markers showed no significant independent characteristics associated with age or gender in a multivariate analysis model, except for a significant association between low BMD and TRACP-5b in females. TRACP-5b was a potentially useful marker for the detection of low BMD.

Values for the Japanese Orthopaedic Association Back Pain Evaluation Questionnaire in the general elderly population: A Japanese cohort survey randomly sampled from a basic resident registry.

BACKGROUND: Japanese Orthopaedic Association Back Pain Evaluation Questionnaire (JOABPEQ) is widely used as a patient-based evaluation tool for lumbar spine disease in Japan. However, there are currently few established JOABPEQ reference values for the general population. This study proposes population-based reference values for JOABPEQ using a randomly sampled Japanese cohort. METHODS: Registered citizens of 50-89 years old were targeted for this survey. We established 8 groups based on age (50's, 60's, 70's, and 80's) and gender (male and female) after random sampling from the basic resident registry of Obuse town in 2014. A total of 414 participants (202 males and 212 females) were enrolled for calculations of average JOABPEQ scores for each age and gender group. We also evaluated for correlations between JOABPEQ domain scores and visual analogue scale (VAS) scores for low back pain. RESULTS: Median reference JOABPEQ scores stratified by age and gender were determined in this study. Lumbar function, walking ability, and social life function deteriorated significantly with age in both genders, with remarkable declines for the social life function domain. VAS scores for low back pain were not significantly correlated with JOABPEQ item scores. CONCLUSIONS: This first resident cohort of Japanese individuals determined median JOABPEQ scores by age and gender, which might serve as reference values for future studies.

Differences in Bone Mineral Density and Bone Turnover Markers Between Subjects With and Without Diffuse Idiopathic Skeletal Hyperostosis.

STUDY DESIGN: Japanese resident cohort study based on a municipal registry. OBJECTIVE: This study of a community-dwelling elderly Japanese population employed random sampling from the basic resident registry of a rural town for subject selection to investigate the differences in bone mineral density (BMD) and bone turnover markers between subjects with and without diffuse idiopathic skeletal hyperostosis (DISH). SUMMARY OF BACKGROUND DATA: DISH is a condition characterized by the calcification and ossification of soft tissues. Although some reports have addressed BMD in DISH, the precise status of BMD and bone metabolism in individuals with DISH remains unclear. METHODS: Eight groups based on age (50s, 60s, 70s, and 80s) and sex after random sampling from the resident registry of Obuse town were established. A total of 411 participants (202 males and 209 females) were enrolled for the evaluation of BMD and bone turnover markers. All subjects underwent a single whole-spine lateral radiographic examination for the existence of DISH. The BMD and bone turnover markers of subjects with and without DISH were analyzed for associations with the disorder using multivariate analysis. RESULTS: DISH was detected in 66 (16.1%) participants in our population cohort. According to multivariate analysis, increased lumbar and hip BMD were significantly related to DISH (odds ratio: 7.47 and 22.8, respectively). CONCLUSION: This study clarified the differences in BMD and bone turnover markers between subjects with and without DISH on a general population basis. Multivariate analysis revealed increased lumbar and hip BMD to be significantly associated with DISH, with no remarkable findings for bone turnover markers. LEVEL OF EVIDENCE: 4.

HLA-Matched Allogeneic iPS Cells-Derived RPE Transplantation for Macular Degeneration.

Immune attacks are key issues for cell transplantation. To assess the safety and the immune reactions after iPS cells-derived retinal pigment epithelium (iPS-RPE) transplantation, we transplanted HLA homozygote iPS-RPE cells established at an iPS bank in HLA-matched patients with exudative age-related macular degeneration. In addition, local steroids without immunosuppressive medications were administered. We monitored immune rejections by routine ocular examinations as well as by lymphocytes-graft cells immune reaction (LGIR) tests using graft RPE and the patient's blood cells. In all five of the cases that underwent iPS-RPE transplantation, the presence of graft cells was indicated by clumps or an area of increased pigmentation at 6 months, which became stable with no further abnormal growth in the graft during the 1-year observation period. Adverse events observed included corneal erosion, epiretinal membrane, retinal edema due to epiretinal membrane, elevated intraocular pressure, endophthalmitis, and mild immune rejection in the eye. In the one case exhibiting positive LGIR tests along with a slight fluid recurrence, we administrated local steroid therapy that subsequently resolved the suspected immune attacks. Although the cell delivery strategy must be further optimized, the present results suggest that it is possible to achieve stable survival and safety of iPS-RPE cell transplantation for a year.

Association between musculoskeletal function deterioration and locomotive syndrome in the general elderly population: a Japanese cohort survey randomly sampled from a basic resident registry.

BACKGROUND: Locomotive syndrome (LoS) is defined as the loss of mobility due to age-related impairment of motor organs. The purpose of this study was to evaluate the prevalence and severity of LoS, muscular strength and balancing ability, and prevalence of sarcopenia in relation to the presence of LoS according to sex and age groups ranging between 50 and 89 years. METHODS: Male and female participants between the ages of 50-89 were randomly selected in the resident registry of a cooperating town. Calls for participation continued until approximately 50 consenting participants were successfully recruited for each age group and sex. A total of 413 participants (203 male and 210 female) were enrolled for undergoing a LoS risk test and measuring their physical function. Physical function was compared to participants with or without LoS. RESULTS: A total of 312 patients (75.5%) were diagnosed as LoS, of which 144 (46.2%) were male and 168 (53.8%) were female. The severity of LoS for the 312 patients were 210 (67.3%) for stage 1 and 102 (32.7%) for stage 2. The prevalence of LoS in males were 37, 59, 91, and 100% in the 50s, 60s, 70s, and 80s age strata, respectively. The prevalence of LoS in females were 71, 62, 89, and 98% in the 50s, 60s, 70s, and 80s age strata, respectively. The prevalence of sarcopenia was significantly higher as the age strata in males grew higher. Knee extension strength was significantly lower for participants in their 50s and females in addition to females in their 60s with LoS. The 31 patients diagnosed as sarcopenia included 29 (93.5%) with LoS, 11 (35.4%) classified as LoS stage 1, and 18 (58.1%) classified as stage 2. CONCLUSIONS: The prevalence of LoS was high in participants over 70 years of age. In males, the prevalence of sarcopenia was higher as the age strata grew higher. Patients with LoS exhibited lower knee extension strength. We believe that some measures to prevent or improve LoS may require exercise to increase the muscle strength of the lower limbs.

Fragility fractures and delayed wound healing after tooth extraction in Japanese older adults.

INTRODUCTION: Fragility fractures can cause delayed wound healing after tooth extraction, which contributes to an increased risk of osteomyelitis of the jaw. We evaluated whether a history of fragility fracture was associated with increased risk of delayed wound healing after tooth extraction in older adults in Japan. MATERIALS AND METHODS: Of 5352 people aged 50-89 years in the 2014 basic resident registry of the town of Obuse, the present study included 376 subjects (190 men and 186 women) who completed a structured questionnaire and measurement of the bone mineral densities (BMDs) of the bilateral femoral neck. Delayed wound healing after tooth extraction was self-reported. Fragility fractures were confirmed via examination of hospital medical records. Logistic regression analyses adjusted for age and gender were used to evaluate association of clinical variables with delayed would healing after tooth extractions. Odds ratios (ORs) and the 95% confidence intervals (CIs) of all possible associated variables for the presence of delayed wound healing were calculated. RESULTS: Subjects with a history of fragility fractures had a significantly higher risk of delayed wound healing compared with those without previous fragility fractures (OR 2.68; 95% CI 1.11-6.46, p = 0.028). This association still remained after adjusted for all other variables (OR 2.70; 95% CI 1.10-6.60, p = 0.030). Delayed wound healing was not significantly associated with the BMD of the femoral neck. CONCLUSIONS: History of fragility fracture may be associated with increased risk of delayed wound healing after tooth extraction in Japanese men and women aged 50-89 years.

Prevalence of Diffuse Idiopathic Skeletal Hyperostosis in the General Elderly Population: A Japanese Cohort Survey Randomly Sampled From a Basic Resident Registry.

STUDY DESIGN: This is a Japanese resident cohort study based on a municipal registry. OBJECTIVES: In this study of an aged Japanese population, we used random sampling from the basic resident registry of a rural town for subject selection to investigate the prevalence of diffuse idiopathic skeletal hyperostosis (DISH) and effect of subject-related factors. SUMMARY OF BACKGROUND: DISH is a condition characterized by the calcification and ossification of soft tissues. Interest is mounting on DISH as the elderly rate increases, but its pathogenetic mechanism remains unknown. DATA: A total of 413 aged people randomly sampled from the resident registry of Obuse town. MATERIALS AND METHODS: We established 8 groups on the basis of age (50s, 60s, 70s, and 80s) and sex after random sampling from the resident registry of Obuse town. A total of 411 participants (202 male and 209 female) were enrolled and underwent a single whole-spine lateral radiographic examination. We assessed for the existence of DISH and analyzed the effects of clinical factors using multivariate analysis. RESULTS: A total of 72 (17.5%) participants were identified to have DISH in our population cohort. The prevalence of DISH tended to increase with age, being 3.1% in subjects in their 50s, 14.0% in their 60s, 24.3% in their 70s, and 29.0% in their 80s. According to multivariate analysis, hypertension (HT), male, bone mineral density (BMD), and aging were independent factors associated with DISH. The odds ratios of HT, male, and BMD were 1.93, 2.88, and 19.1, respectively. CONCLUSIONS: This is the first study examining DISH in detail according to age and sex groups on a general population basis. Multivariate analysis revealed HT, male, BMD, and aging to be independent factors associated with DISH in the healthy community-dwelling elderly.

Successful Treatment of Pediatric Posttraumatic Tibiofibular Synostosis by Resection and Peroneal Artery Perforator Adipofascial Flap: A Case Report.

CASE: Pediatric posttraumatic tibiofibular synostosis (PPTFS) is a rare postfracture complication that often leads to growth abnormalities. There are very few reports demonstrating the long-term efficacy of surgical treatment. An 11-year-old boy with PPTFS displayed progressive prominence of the fibular head and shortening of the lateral malleolus subsequent to a fracture suffered at the age of 5 years. He was treated by synostosis resection and a peroneal artery perforator adipofascial flap. Eight years postoperatively, the synostosis had not recurred, and his earlier growth abnormalities were nearly normal. CONCLUSIONS: Peroneal artery perforator adipofascial flap is effective for pregrowth spurt PPTFS.

Base-Resolution Methylome of Retinal Pigment Epithelial Cells Used in the First Trial of Human Induced Pluripotent Stem Cell-Based Autologous Transplantation.

The first-in-human trial of induced pluripotent stem cell (iPSC)-based autologous transplantation was successfully performed on a female patient with age-related macular degeneration. Here we delineated the base-resolution methylome of the iPSC-derived retinal pigment epithelium (iRPE) used in this trial. The methylome of iRPE closely resembled that of native RPE (nRPE), although partially methylated domains (PMDs) emerged in iRPE but not nRPE. Most differentially methylated regions between iRPE and nRPE appeared to originate from (de)methylation errors during differentiation, whereas errors at reprogramming resulted in aberrant genomic imprinting and X chromosome reactivation. Moreover, non-CpG methylation was prominent in nRPE but not iRPE. Intriguingly, xenotransplantation to mouse remodeled the iRPE methylome to demethylate a subset of suppressed genes and accumulate non-CpG methylation, but failed to resolve PMDs and hypermethylated CpG islands. Although the impacts of these alterations remain elusive, our findings should provide a useful guide for methylome analyses of other iPSC-derived cells.

Association Between Sagittal Spinal Alignment and Physical Function in the Japanese General Elderly Population: A Japanese Cohort Survey Randomly Sampled from a Basic Resident Registry.

BACKGROUND: The extension of healthy life expectancy has become increasingly important because of rising health-care costs and decreases in the quality of life in the elderly population. Although reports have surfaced on an association between sagittal spinal alignment and physical performance, such studies on the healthy population are limited. This study investigated the relationship between sagittal spinal alignment and physical function in the general elderly population. METHODS: Registered citizens who were 50 to 89 years of age were targeted for this survey. We established 8 groups based on age (50 to 59 years, 60 to 69 years, 70 to 79 years, and 80 to 89 years) and sex (male and female) after random sampling from the resident registry of the town of Obuse in 2014. A total of 412 people (203 male and 209 female) were enrolled for the measurement and analysis of radiographic parameters of sagittal spinal alignment and physical performance tests. RESULTS: Physical function score values decreased with age, with moderate to strong correlations. Within age subgroups, worsened spinal alignment in standing whole-spinal radiographs indicated diminished physical performance results. The impact of the sagittal vertical axis was especially prominent; as the sagittal vertical axis was shifted forward by 1 standard deviation, 1-leg standing time became shortened by 3.8 seconds. Two-step scores were significantly associated with sagittal vertical axis, global tilt, cervical sagittal vertical axis, and pelvic tilt. CONCLUSIONS: Our investigation of sagittal spinal alignment on physical function in a Japanese elderly cohort revealed significant negative correlations between spinal alignment and physical performance after excluding the influence of age and sex. Posture change in the community-dwelling elderly population is an important sign of physical function impairment. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.