Rare and common variants in ROM1 and PRPH2 genes trans-modify Stargardt/ABCA4 disease.

Over 1,500 variants in the ABCA4 locus cause phenotypes ranging from severe, early-onset retinal degeneration to very late-onset maculopathies. The resulting ABCA4/Stargardt disease is the most prevalent Mendelian eye disorder, although its underlying clinical heterogeneity, including penetrance of many alleles, are not well-understood. We hypothesized that a share of this complexity is explained by trans-modifiers, i.e., variants in unlinked loci, which are currently unknown. We sought to identify these by performing exome sequencing in a large cohort for a rare disease of 622 cases and compared variation in seven genes known to clinically phenocopy ABCA4 disease to cohorts of ethnically matched controls. We identified a significant enrichment of variants in 2 out of the 7 genes. Moderately rare, likely functional, variants, at the minor allele frequency (MAF) <0.005 and CADD>25, were enriched in ROM1, where 1.3% of 622 patients harbored a ROM1 variant compared to 0.3% of 10,865 controls (p = 2.41E04; OR 3.81 95% CI [1.77; 8.22]). More importantly, analysis of common variants (MAF>0.1) identified a frequent haplotype in PRPH2, tagged by the p.Asp338 variant with MAF = 0.21 in the matched general population that was significantly increased in the patient cohort, MAF 0.25, p = 0.0014. Significant differences were also observed between ABCA4 disease subgroups. In the late-onset subgroup, defined by the hypomorphic p.Asn1868Ile variant and including c.4253+43G>A, the allele frequency for the PRPH2 p.Asp338 variant was 0.15 vs 0.27 in the remaining cohort, p = 0.00057. Known functional data allowed suggesting a mechanism by which the PRPH2 haplotype influences the ABCA4 disease penetrance. These associations were replicated in an independent cohort of 408 patients. The association was highly statistically significant in the combined cohorts of 1,030 cases, p = 4.00E-05 for all patients and p = 0.00014 for the hypomorph subgroup, suggesting a substantial trans-modifying role in ABCA4 disease for both rare and common variants in two unlinked loci.

Cis-acting modifiers in the ABCA4 locus contribute to the penetrance of the major disease-causing variant in Stargardt disease.

Over 1200 variants in the ABCA4 gene cause a wide variety of retinal disease phenotypes, the best known of which is autosomal recessive Stargardt disease (STGD1). Disease-causing variation encompasses all mutation categories, from large copy number variants to very mild, hypomorphic missense variants. The most prevalent disease-causing ABCA4 variant, present in ~ 20% of cases of European descent, c.5882G > A p.(Gly1961Glu), has been a subject of controversy since its minor allele frequency (MAF) is as high as ~ 0.1 in certain populations, questioning its pathogenicity, especially in homozygous individuals. We sequenced the entire ~140Kb ABCA4 genomic locus in an extensive cohort of 644 bi-allelic, i.e. genetically confirmed, patients with ABCA4 disease and analyzed all variants in 140 compound heterozygous and 10 homozygous cases for the p.(Gly1961Glu) variant. A total of 23 patients in this cohort additionally harbored the deep intronic c.769-784C > T variant on the p.(Gly1961Glu) allele, which appears on a specific haplotype in ~ 15% of p.(Gly1961Glu) alleles. This haplotype was present in 5/7 of homozygous cases, where the p.(Gly1961Glu) was the only known pathogenic variant. Three cases had an exonic variant on the same allele with the p.(Gly1961Glu). Patients with the c.[769-784C > T;5882G > A] complex allele exhibit a more severe clinical phenotype, as seen in compound heterozygotes with some more frequent ABCA4 mutations, e.g. p.(Pro1380Leu). Our findings indicate that the c.769-784C > T variant is major cis-acting modifier of the p.(Gly1961Glu) allele. The absence of such additional allelic variation on most p.(Gly1961Glu) alleles largely explains the observed paucity of affected homozygotes in the population.

The significance of information and communication technology education via tablets in college of physical therapy.

[Purpose] This study aimed to clarify whether collaborative learning could be promoted via information and communication technology education using tablets at college of physical therapy. [Participants and Methods] An online survey was conducted to evaluate collaborative learning among 81 first-year students at the Department of Physical Therapy actively using tablets in classes (six specific categories). [Results] The Friedman test had significant results, and a significant primary effect was observed between each questionnaire item. Following this, the Bonferroni test was performed for multiple comparisons, with significant differences were observed among certain items. [Conclusion] We reported employing tablets in the classroom positively impacted collaborative learning. Here, among the evaluations of collaborative learning, the items with the best results corresponded mainly to communication activation between students.

Serine and Lipid Metabolism in Macular Disease and Peripheral Neuropathy.

BACKGROUND: Identifying mechanisms of diseases with complex inheritance patterns, such as macular telangiectasia type 2, is challenging. A link between macular telangiectasia type 2 and altered serine metabolism has been established previously. METHODS: Through exome sequence analysis of a patient with macular telangiectasia type 2 and his family members, we identified a variant in SPTLC1 encoding a subunit of serine palmitoyltransferase (SPT). Because mutations affecting SPT are known to cause hereditary sensory and autonomic neuropathy type 1 (HSAN1), we examined 10 additional persons with HSAN1 for ophthalmologic disease. We assayed serum amino acid and sphingoid base levels, including levels of deoxysphingolipids, in patients who had macular telangiectasia type 2 but did not have HSAN1 or pathogenic variants affecting SPT. We characterized mice with low serine levels and tested the effects of deoxysphingolipids on human retinal organoids. RESULTS: Two variants known to cause HSAN1 were identified as causal for macular telangiectasia type 2: of 11 patients with HSAN1, 9 also had macular telangiectasia type 2. Circulating deoxysphingolipid levels were 84.2% higher among 125 patients with macular telangiectasia type 2 who did not have pathogenic variants affecting SPT than among 94 unaffected controls. Deoxysphingolipid levels were negatively correlated with serine levels, which were 20.6% lower than among controls. Reduction of serine levels in mice led to increases in levels of retinal deoxysphingolipids and compromised visual function. Deoxysphingolipids caused photoreceptor-cell death in retinal organoids, but not in the presence of regulators of lipid metabolism. CONCLUSIONS: Elevated levels of atypical deoxysphingolipids, caused by variant SPTLC1 or SPTLC2 or by low serine levels, were risk factors for macular telangiectasia type 2, as well as for peripheral neuropathy. (Funded by the Lowy Medical Research Institute and others.).

Ex vivo anti-microbial efficacy of various formaldehyde releasers against antibiotic resistant and antibiotic sensitive microorganisms involved in infectious keratitis.

BACKGROUND: Corneal infections with antibiotic-resistant microorganisms are an increasingly difficult management challenge and chemically or photochemically cross-linking the cornea for therapy presents a unique approach to managing such infections since both direct microbial pathogens killing and matrix stabilization can occur simultaneously. The present study was undertaken in order to compare the anti-microbial efficacy, in vitro, of 5 candidate cross-linking solutions against 5 different microbial pathogens with relevance to infectious keratitis. METHODS: In vitro bactericidal efficacy studies were carried out using 5 different FARs [diazolidinyl urea (DAU), 1,3-bis(hydroxymethyl)-5,5-dimethylimidazolidine-2,4-dione (DMDM), sodium hydroxymethylglycinate (SMG), 2-(hydroxymethyl)-2-nitro-1,3-propanediol (NT = nitrotriol), 2-nitro-1-propanol (NP)] against 5 different microbial pathogens including two antibiotic-resistant species [methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), Pseudomonas aeruginosa (PA), and Candida albicans (CA)]. Standard in vitro antimicrobial testing methods were used. RESULTS: The results for MSSA were similar to those for MRSA. DAU, DMDM, and SMG all showed effectiveness with greater effects generally observed with longer incubation times and higher concentrations. Against MRSA, 40 mM SMG at 120 min showed a > 95% kill rate, p < 0.02. Against VRE, 40 mM DAU for 120 min showed a > 94% kill rate, p < 0.001. All FARs showed bactericidal effect against Pseudomonas aeruginosa, making PA the most susceptible of the strains tested. Candida showed relative resistance to these compounds, requiring high concentrations (100 mM) to achieve kill rates greater than 50%. CONCLUSION: Our results show that each FAR compound has different effects against different cultures. Our antimicrobial armamentarium could potentially be broadened by DAU, DMDM, SMG and other FARs for antibiotic-resistant keratitis. Further testing in live animal models are indicated.

Reliability of laser-assisted hindfoot alignment evaluation.

[Purpose] A goniometer is frequently used for static measurement of hindfoot alignment. However, although goniometer measurements require experience, their reliability and validity remain controversial. We developed a hindfoot alignment measurement method by laser as an alternative measure. The purpose of this study was to examine the reliability of laser-assisted hindfoot alignment evaluation. [Participants and Methods] Two non-expert examiners (without medical knowledge), briefly trained in the use of laser-assisted hindfoot alignment evaluation, evaluated hindfoot alignment in 12 healthy participants. [Results] The ICC of the intra-rater reliability was 0.74 for both examiners and the ICC for inter-rater reliability was 0.43. [Conclusion] The good intra-rater and moderate inter-rater reliability of laser-assisted hindfoot alignment evaluation, when used by non-professionals, suggest the laser-assisted hindfoot alignment evaluation may be appropriate for use in clinical practice settings.

Optimal foot-position of caregiver based on muscle activity of lower back and lower limb while providing sit-to-stand support.

[Purpose] In caregivers, low load posture is necessary to prevent lower back pain during patient handling activities such as sit-to-stand support. This study focused on the foot-position of caregivers as an adjustable and useful parameter. A wide stance decreases the stress on the lumbar vertebra. However, this foot-position increases loading of the spinae erector muscles. The aim of this study was to investigate the relationship of anterior-posterior and lateral-medial distances between feet and activity of the spinae erector muscles to determine the optimal foot-position for reducing stress on the lumbar vertebra without increasing spinae erector muscle load. [Participants and Methods] Five young male participants were asked to provide sit-to-stand support 10 times using nine normalized foot-positions with different anterior-posterior and lateral-medial distances. Surface electromyograms of the erector spinae and lower limb muscles were measured during sit-to-stand support. [Results] The results showed that the optimal foot-position (anterior-posterior 55%, lateral-medial 20% of body height) increased muscle activity within the lower limb muscles compared with the lower back muscles and did not increase loads on the erector spinae muscle. [Conclusion] Optimizing foot-position can reduce stress on the lumbar vertebra without increasing load on the spinae erector muscles.

A case-control collapsing analysis identifies retinal dystrophy genes associated with ophthalmic disease in patients with no pathogenic ABCA4 variants.

PURPOSE: Variants in the ABCA4 gene are causal for a variety of retinal dystrophy phenotypes, including Stargardt disease (STGD1). However, 15% of patients who present with symptoms compatible with STGD1/ABCA4 disease do not have identifiable causal ABCA4 variants. We hypothesized that a case-control collapsing analysis in ABCA4-negative patients with compatible symptoms would provide an objective measure to identify additional disease genes. METHODS: We performed a genome-wide enrichment analysis of "qualifying variants"-ultrarare variants predicted to impact protein function-in protein-coding genes in 79 unrelated cases and 9028 unrelated controls. RESULTS: Despite modest sample size, two known retinal dystrophy genes, PRPH2 and CRX, achieved study-wide significance (p < 1.33 × 10-6) under a dominant disease model, and eight additional known retinal dystrophy genes achieved nominal significance (p < 0.05). Across these ten genes, the excess of qualifying variants explained up to 36.8% of affected individuals. Furthermore, under a recessive model, the cone-rod dystrophy gene CERKL approached study-wide significance. CONCLUSION: Our results indicate that case-control collapsing analyses can efficiently identify pathogenic variants in genes in non-ABCA4 retinal dystrophies. The genome-wide collapsing analysis framework is an objective discovery method particularly suitable in settings with overlapping disease phenotypes.

Relationship between surface electromyography of the spinae erector muscles and subjectively adjusted step length in the supporting standing-up motion.

[Purpose] Caregivers experience low back pain owing to frequent patient handling motions such as supporting the body while standing up. To prevent low back pain in caregivers, low load posture while engaging in patient handling motions is required. We determined the relationship between surface electromyography of the erector spinae muscles and subjective step length as "long" and "short" during the supporting standing-up motions of caregivers. [Participants and Methods] Ten young male participants were asked to perform supporting standing-up motion 10 times using two-step lengths comprised of subjective long and short steps. During supporting standing-up motion, we measured surface electromyograms of the erector spinae muscles and calculated the integral electromyographic values. [Results] The subjective long/short-step length normalized by body height did not differ across the participants. In addition, the subjective long-step length was longer than the subjective short-step length in all the participants. Integral electromyographic values for both the left and right erector spinae muscles in the short-step length were significantly lower than those in the long-step length when the data obtained from all the participants were used. [Conclusion] We considered that the load of the erector spinae muscle will be reduced if the short-step instead of the long-step instruction is given. In the future, instructions based on the subjective step-length variation in caregivers must be considered.

New estimation model of the initial lower limb angle to improve angle estimation during the extension phase of standing-up movement.

[Purpose] An estimation model of the knee and ankle joint angles during the extension phase was proposed in the previous study. However, it had limited use because of the fixed initial lower limb angle before standing up. This study aimed to propose a new estimation model of the initial lower limb angle to improve the angle estimation during extension phase. [Subjects and Methods] Seven healthy male volunteers were enrolled. The new estimation model approximated the initial lower limb angle using a force sensor plate that measured the plantar pressure of the subjects. The estimated angle and force were compared to those obtained by a motion capture system and force plate. [Results] The new estimation model of initial lower limb angle showed no significant difference compared with the true values obtained by motion capture, except for the subject who had a greater foot-pressure measurement error compared with the force plate measurement, with maximum errors of 5.98° and 6.31°, respectively. [Conclusion] The proposed model in this study can estimate the initial lower limb angle before standing and can be applied to the angle estimation model during the extension phase of the standing-up movement.

Novel method for evaluation of frontal plane knee alignment using bony prominences in patients with osteoarthritis.

[Purpose] Angle measurement using images of bony prominences (AMI) determines frontal plane knee alignment from the skin surface without using radiation. The purpose of this study was to assess the validity and reliability of images obtained with the AMI method. [Participants and Methods] The study included 21 patients with osteoarthritis. We measured the functional axis of the lower limb, obtained via full-leg radiography and correlated the findings with the angle of dissection and the angle measured with the AMI method. Additionally, we assessed the reliability of the AMI method. [Results] The angle obtained using the AMI method and the radiographic anatomic axis (the full-leg radiograph)/the mechanical axis were well correlated. The AMI method also showed high reliability. [Conclusion] The AMI method is a valid and reliable alternative to full-leg radiography for imaging of functional and anatomical knee axes. As AMI does not use special equipment or involve radiation exposure, the method can be used in outside medical facilities and can be repeated over time without increased risk to patients.

Notch signaling functions in lymphatic valve formation.

Collecting lymphatic ducts contain intraluminal valves that prevent backflow. In mice, lymphatic valve morphogenesis begins at embryonic day 15.5 (E15.5). In the mesentery, Prox1 expression is high in valve-forming lymphatic endothelial cells, whereas cells of the lymphatic ducts express lower levels of Prox1. Integrin α9, fibronectin EIIIA, Foxc2, calcineurin and the gap junction protein Cx37 are required for lymphatic valve formation. We show that Notch1 is expressed throughout the developing mesenteric lymphatic vessels at E16.5, and that, by E18.5, Notch1 expression becomes highly enriched in the lymphatic valve endothelial cells. Using a Notch reporter mouse, Notch activity was detected in lymphatic valves at E17.5 and E18.5. The role of Notch in lymphatic valve morphogenesis was studied using a conditional lymphatic endothelial cell driver either to delete Notch1 or to express a dominant-negative Mastermind-like (DNMAML) transgene. Deletion of Notch1 led to an expansion of Prox1(high) cells, a defect in Prox1(high) cell reorientation and a decrease in integrin α9 expression at sites of valve formation. Expression of DNMAML, which blocks all Notch signaling, resulted in a more severe phenotype characterized by a decrease in valves, failure of Prox1(high) cells to cluster, and rounding of the nuclei and decreased fibronectin-EIIIA expression in the Prox1(high) cells found at valve sites. In human dermal lymphatic endothelial cells, activation of Notch1 or Notch4 induced integrin α9, fibronectin EIIIA and Cx37 expression. We conclude that Notch signaling is required for proper lymphatic valve formation and regulates integrin α9 and fibronectin EIIIA expression during valve morphogenesis.

An estimation of knee and ankle joint angles during extension phase of standing up motion performed using an inertial sensor.

[Purpose] Motion capture system is difficult to use in daily life. The aim of this study was to propose an estimation model for knee and ankle joint angle measurements and locate body center of gravity (COG) of the extension phase during standing-up motion. [Subjects and Methods] Seven healthy male volunteers were enrolled. An estimation model was proposed for the knee and ankle joint angle measurements by combining the angle and acceleration of the trunk, based on readings from the inertial sensor attachment on the subject's chest, during the extension phase. Joint angles and COG position were compared to those obtained by a motion capture system. [Results] The joint angles and COG position demonstrated high correlation coefficients which represent strong correlation between the proposed model and the motion capture system. The proposed model could estimate the joint angle during extension phase, with a maximum error of 4.58 degrees, as well as COG position in the horizontal and vertical directions with maximum errors of 4.48 cm and 3.19 cm, respectively. [Conclusion] The proposed system could be used instead of motion capture system to estimate knee and ankle joint angles; however, the estimation of the COG position was insufficient because of lacked accuracy.

Analysis of crutch position in the horizontal plane to confirm the stability of the axillary pad for safe double-crutch walking.

[Purpose] The aim of this study was to analyze the crutch position in the horizontal plane to confirm the stability of the axillary pad during double-crutch walking. [Subjects] Twelve healthy young subjects (6 males and 6 females). [Methods] The subjects were asked to walk in a straight line, using double crutches, for a distance of 5 m, 5 times. Crutch position data were obtained using four infrared reflective markers attached to both crutches (two markers each on both crutches). The crutch angles of each subject were compared across three time points during the crutch stance phase (crutch contact, mid stance, and crutch off). [Results] Crutch angles of each of the two crutches were significantly different across the crutch stance phase of 11 of the 12 subjects. Phasic differences were shown by 4 of the 12 subjects, and a strong correlation was observed between the left and right crutch angles of all subjects. [Conclusion] External rotation of the crutch throughout the stance phase was very important for keeping the axillary pad in the axilla, not only for single-crutch walking, but also for double-crutch walking. In addition, symmetry of the crutch positioning is one of the most important factors for safe double-crutch walking.

Gene therapy in patient-specific stem cell lines and a preclinical model of retinitis pigmentosa with membrane frizzled-related protein defects.

Defects in Membrane Frizzled-related Protein (MFRP) cause autosomal recessive retinitis pigmentosa (RP). MFRP codes for a retinal pigment epithelium (RPE)-specific membrane receptor of unknown function. In patient-specific induced pluripotent stem (iPS)-derived RPE cells, precise levels of MFRP, and its dicistronic partner CTRP5, are critical to the regulation of actin organization. Overexpression of CTRP5 in naïve human RPE cells phenocopied behavior of MFRP-deficient patient RPE (iPS-RPE) cells. AAV8 (Y733F) vector expressing human MFRP rescued the actin disorganization phenotype and restored apical microvilli in patient-specific iPS-RPE cell lines. As a result, AAV-treated MFRP mutant iPS-RPE recovered pigmentation and transepithelial resistance. The efficacy of AAV-mediated gene therapy was also evaluated in Mfrp(rd6)/Mfrp(rd6) mice--an established preclinical model of RP--and long-term improvement in visual function was observed in AAV-Mfrp-treated mice. This report is the first to indicate the successful use of human iPS-RPE cells as a recipient for gene therapy. The observed favorable response to gene therapy in both patient-specific cell lines, and the Mfrp(rd6)/Mfrp(rd6) preclinical model suggests that this form of degeneration caused by MFRP mutations is a potential target for interventional trials.

Analysis of Crutch Position in the Horizontal Plane to Estimate the Stability of the Axillary Pad in the Axilla during Single-crutch Walking.

[Purpose] The aim of this study was to estimate the stability of the axillary pad in the axilla during single-crutch walking through kinematic analysis of the crutch position in the horizontal plane. [Subjects] The subjects were 19 healthy young males. [Methods] The subjects were instructed to walk 5 m in a straight line while using a single crutch. This was repeated 10 times. Repeated-measures analysis of variance and Tukey's honest significance test were used to compare crutch angles across three time points during crutch stance (crutch contact, mid stance and crutch off) for each subject. [Results] A statistically significant effect of time was found in 17 of the 19 subjects. Sixteen of these 17 subjects rotated the crutch externally from crutch contact to crutch off. [Conclusion] External rotation of the crutch throughout the stance phase is important to enable the axillary pad to be held tightly against the chest wall. These results may lead to alterations of the instructions for crutch use and the prevention of falls.

Effects of self-monitoring using an accelerometer on physical activity of older people with long-term care insurance in Japan: a randomized controlled trial.

PURPOSE: This study aimed to investigate the effects of a self-monitoring intervention to promote an increase in physical activity, as measured by step count, and reduce sedentary behavior in older people covered by the long-term care insurance system (LTCI) in Japan. METHODS: This was a randomized controlled trial conducted at a daycare center from October 2022 to January 2023. Fifty-two older adults with LTCI who were able to walk with or without aids were assigned to an intervention (n = 26) group and control (n = 26) group. During the 5-week follow-up period, the intervention group received education on physical activity and self-monitoring such as goal setting, self-management and feedback. The primary outcome was step count, and the secondary outcome was sedentary behavior. RESULTS: Participants who completed the study to the end of the 5-week follow-up and drop-out participants for whom outcome data were available were included in the final analysis of 57 participants, n = 24 (79.8 ± 8.8 years, male 25.5%) in the intervention group and n = 23 (82.5 ± 8.5 years, male 39.1%) in the control group. Comparisons between the two groups at baseline showed no significant differences. In the results of a two-way mixed analysis of variance (ANOVA) including 2 (group: control, intervention) × 2 (term: baseline, 5-week follow-up) factors, an interaction was observed in the number of steps, sedentary behavior, and light physical activity (p < 0.05). CONCLUSION: Self-monitoring of physical activity using an accelerometer may be effective in increasing the number of steps and light physical activity and in reducing sedentary behavior in older people with LTCI. CLINICAL TRIAL REGISTRATION: UMIN000052044, registered on 2023/08/29.

Scleral growth stunting via sub-Tenon injection of cross-linking solutions in live rabbits.

BACKGROUND: Scleral cross-linking is a potential method to inhibit axial elongation of the eye, preventing the progression of pathological myopia. Formaldehyde releasers, which are common preservatives found in cosmetics and ophthalmic solutions, have been shown to be not only effective in cross-linking corneal collagen in vitro and in vivo, but also have minimal toxicity effects on the eye. The present study aims to evaluate the efficacy of scleral cross-linking using sodium hydroxymethylglycinate (SMG) to inhibit eye growth using an in vivo rabbit model. METHODS: A cross-linking solution containing 40 mM SMG was delivered to the sub-Tenon's space behind the equator. The application regimen included a two-quadrant injection performed five times over 2 weeks on New Zealand White rabbits (n=5, group 1), and one-time injection followed for up to 5 days on Dutch-Belted rabbits (n=6, group 2). Group 1 was monitored serially for axial length changes using B-scan ultrasound for 5-6 weeks. Group 2 was injected with a higher viscosity solution formulation. Both groups were evaluated for thermal denaturation temperature changes of the sclera postmortem. RESULTS: Axial growth was limited by 10%-20% following SMG treatment as compared with the untreated eye. Thermal denaturation analysis showed increased heat resistance of the treated eyes in the areas of injection. Overall, the SMG treatment inhibited eye growth with few side effects from the injections. CONCLUSIONS: Cross-linking solutions delivered via sub-Tenon injection provide a potential method for limiting axial length growth in progressive myopia and could be used as a potential treatment for myopia.

Differences in Improvement of Physical Function in Older Adults with Long-Term Care Insurance with and without Falls: A Retrospective Cohort Study.

(1) Background: This study examined the differences in changes in physical function with and without falls after daycare use among frail older adults with long-term care insurance (LTCI). (2) Methods: In this retrospective cohort study, 82 of 96 consecutive daycare center users met the inclusion criteria. The participants were divided into two groups based on the presence or absence of falls 6-12 months after use. Participant characteristics in the fall and non-fall groups and physical function at baseline and six months in each group were compared. Using analysis of covariance, we analyzed physical function and its changes between the two groups, and cut-off values were calculated using receiver operating characteristic curves. (3) Results: Gait speed, timed up-and-go test, and 30 s chair stand test (CS30) improved significantly over six months in the no-fall group (n = 70) and all participants (n = 82) (p < 0.01). Gait speed in the fall group (n = 12) improved significantly over six months (p = 0.04). The fall group had significantly lower adjusted ΔCS30 scores than the no-fall group (p = 0.03), with a cutoff value of 2 (p = 0.024). (4) Conclusions: In older adults with LTCI, physical function with and without falls after daycare use differed by ΔCS30, with a cutoff value of 2.

iPSC-derived retinal pigmented epithelial cells from patients with macular telangiectasia show decreased mitochondrial function.

Patient-derived induced pluripotent stem cells (iPSCs) provide a powerful tool for identifying cellular and molecular mechanisms of disease. Macular telangiectasia type 2 (MacTel) is a rare, late-onset degenerative retinal disease with an extremely heterogeneous genetic architecture, lending itself to the use of iPSCs. Whole-exome sequencing screens and pedigree analyses have identified rare causative mutations that account for less than 5% of cases. Metabolomic surveys of patient populations and GWAS have linked MacTel to decreased circulating levels of serine and elevated levels of neurotoxic 1-deoxysphingolipids (1-dSLs). However, retina-specific, disease-contributing factors have yet to be identified. Here, we used iPSC-differentiated retinal pigmented epithelial (iRPE) cells derived from donors with or without MacTel to screen for novel cell-intrinsic pathological mechanisms. We show that MacTel iRPE cells mimicked the low serine levels observed in serum from patients with MacTel. Through RNA-Seq and gene set enrichment pathway analysis, we determined that MacTel iRPE cells are enriched in cellular stress pathways and dysregulation of central carbon metabolism. Using respirometry and mitochondrial stress testing, we functionally validated that MacTel iRPE cells had a reduction in mitochondrial function that was independent of defects in serine biosynthesis and 1-dSL accumulation. Thus, we identified phenotypes that may constitute alternative disease mechanisms beyond the known serine/sphingolipid pathway.