A comprehensive analysis of the effects of the deaminase AID on the transcriptome and methylome of activated B cells.

Beyond its well-characterized functions in antibody diversification, the cytidine deaminase AID can catalyze off-target DNA damage and has been hypothesized to edit RNA and mediate DNA demethylation. To comprehensively examine the effects of AID on the transcriptome and the pattern of DNA methylation ('methylome'), we analyzed AID-deficient (Aicda(-/-)), wild-type and AID-overexpressing activated B cells by high-throughput RNA sequencing (RNA-Seq) and reduced-representation bisulfite sequencing (RRBS). These analyses confirmed the known role of AID in immunoglobulin isotype switching and also demonstrated few other effects of AID on gene expression. Additionally, we detected no evidence of AID-dependent editing of mRNA or microRNA. Finally, the RRBS data did not support the proposed role for AID in regulating DNA methylation. Thus, despite evidence of its additional activities in other systems, antibody diversification seems to be the sole physiological function of AID in activated B cells.

Concordance between Self-Reported Visual Difficulty and Objective Visual Impairment: The National Health and Aging Trends Study.

PURPOSE: To examine the performance of self-reported visual difficulty (VD) in predicting objective visual impairment (VI) in older adults and explore factors that influence discordance. DESIGN: Cross-sectional analysis of the National Health and Aging Trends Study (2022). METHODS: Participants reporting blindness or difficulties with distance or near vision were characterized as having VD. Presenting binocular distance visual acuity (VA), near VA, and contrast sensitivity (CS) were assessed. Objective VI was defined as having VI in distance VA (worse than 20/40), near VA (worse than 20/40), or CS (worse than 1.55 logCS). Receiver operating characteristic analysis was used to compare performance of VD in predicting VI. To investigate factors that influence discordance, we limited our sample to adults with VI and used a multivariable logistic regression model to identify factors associated with not reporting VD. Similar analyses were performed to explore factors associated with reporting VD in adults without VI. MAIN OUTCOME MEASURES: Discordance factors. RESULTS: Four thousand nine hundred ninety-nine adults were included in the 2022 cohort. Visual difficulty achieved an area under the curve (AUC) of 56.0 (95% confidence interval [CI], 55.2-56.9) in predicting VI, with a sensitivity of 15.8 (95% CI, 14.2-17.5) and specificity of 96.3 (95% CI, 95.5-96.9). Characteristics associated with not reporting VD in adults with VI included female gender (odds ratio [OR], 0.64 [95% CI, 0.42-0.99]), Hispanic ethnicity (OR, 0.49 [95% CI, 0.31-0.78), higher income (≥75 000, OR, 1.99 [95% CI, 1.14-3.45]), ≥4 comorbidities (OR, 0.46 [95% CI, 0.29-0.72]), and depressive symptoms (OR, 0.49 [95% CI, 0.25-0.93]). Factors associated with self-reporting VD in the absence of VI included Hispanic ethnicity (OR, 2.11 [95% CI, 1.15-3.86]), higher income (≥$75 000, OR, 0.27 [95% CI, 0.12-0.63]), and anxiety symptoms (OR, 3.05 [95% CI, 1.56-5.97]). CONCLUSIONS: Self-reported VD is a distinct measure assessing disability and has limited ability in predicting objective VI. Caution is advised when using self-reported VD as a surrogate measure for objective VI in epidemiological studies, although it may still be an effective way to capture risk of current or future disability. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Utilizing visual symptoms to distinguish dry eye from glaucoma, cataract, and suspect glaucoma patients: a cross-sectional study.

BACKGROUND: The diagnosis of dry eye and other common ophthalmological conditions can be supported using patient reported symptoms, which is increasingly useful in contexts such as telemedicine. We aim to ascertain visual symptoms that differentiate dry eye from cataract, glaucoma, or glaucoma suspects. METHODS: Adults with dry eye, glaucoma, cataract, and suspected glaucoma (controls) completed a questionnaire to rate the frequency and severity of 28 visual symptoms. Univariate, followed by multivariable logistic regression with backward stepwise selection (p < 0.05), determined the individual symptoms and set of symptoms best distinguishing dry eye from each of the other conditions. RESULTS: Mean age of 353 patients (94 glaucoma suspect controls, 79 glaucoma, 84 cataract, and 96 dry eye) was 64.1 years (SD = 14.1); 67% were female and 68% White. Dry eye patients reported more frequent light sensitivity (OR = 15.0, 95% CI = 6.3-35.7) and spots in vision (OR = 2.8, 95% CI = 1.2-6.3) compared to glaucoma suspect controls. Compared to glaucoma patients, dry eye patients experienced more frequent light sensitivity (OR = 9.2, 95% CI = 2.0-41.7), but less frequent poor peripheral vision (OR = 0.2, 95% CI = 0.06-0.7), difference in vision between eyes (OR = 0.09, 95% CI = 0.01-0.7), and missing patches of vision (OR = 0.06, 95% CI = 0.009-0.3). Compared to cataract patients, dry eye patients reported more frequent spots in vision (OR = 4.5, 95% CI = 1.5-13.4) and vision variability across the week (OR = 4.7, 95% CI = 1.2-17.7) and were less likely to report worsening vision (OR = 0.1, 95% CI = 0.03-0.4) and blindness (OR = 0.1, 95% CI = 0.02-0.8). CONCLUSION: Visual symptoms may serve as a complementary tool to distinguish dry eye from various ocular conditions, though the symptoms that best distinguish dry eye differ across comparisons. Differentiating how patients visually perceive common eye diseases may be used in a variety of clinical settings to rule out specific conditions.

Patient-Reported Symptoms Demonstrating an Association with Severity of Visual Field Damage in Glaucoma.

PURPOSE: To determine which patient-reported symptoms best distinguish patients with and without glaucoma and explain the most variance in visual field (VF) damage and to compare the amount of variance that can be explained by symptoms versus retinal nerve fiber layer (RNFL) thickness. DESIGN: Cross-sectional study. PARTICIPANTS: Adults diagnosed with glaucoma or suspicion of glaucoma (controls). METHODS: Worse-eye VF damage was defined on the basis of perimetric testing. Thickness of RNFL was defined by OCT imaging. Patients rated their visual symptoms on questions collated from several published questionnaires, rating the frequency and severity of 28 symptoms on a scale of 1 (never/not at all) to 4 (very often/severe). Multivariable regression models identified patient-reported symptoms that contributed the highest variance in VF damage. MAIN OUTCOME MEASURES: Patient-reported symptoms that explained the most variance in VF damage and amount of variance in VF damage explained by patient-reported symptoms and RNFL. RESULTS: A total of 170 patients (mean age: 64 years; 58% female; 47% employed) completed testing, including 95 glaucoma suspects and 75 glaucoma patients. In glaucoma patients, median mean deviation of VF damage in the worse eye was -19.3 and ranged from -5.3 to -34.7 decibels. Symptoms more common among glaucoma patients compared with glaucoma suspects included better vision in 1 eye, blurry vision, glare, sensitivity to light, cloudy vision, missing patches of vision, and little peripheral vision. Worse severity ratings for the symptom "little peripheral vision" explained the most variance in VF damage (43%). A multivariable model including the frequency of cloudy vision, severity of having little peripheral vision, missing patches, 1 eye having better vision, and vision worsening, plus sociodemographic features, explained 62% of the variance in VF damage. Comparatively, a multivariable model of worse-eye RNFL thickness and sociodemographic features explained 42% of the variance in VF damage, whereas a model including only sociodemographic features explained 8% of the variance in VF damage. CONCLUSIONS: Five patient-reported symptoms explain a significant amount of the variance in VF damage. Asking patients about their symptoms may optimize patient-physician communication and be a useful adjunct to clinical testing in some patients to estimate disease severity.

APOE4 Allele, Sex, and Dementia Risk in Parkinson's Disease: Lessons From a Longitudinal Cohort.

INTRODUCTION: The effect of APOE4 allele on dementia risk is well established in Alzheimer's disease and Parkinson's disease (PD). However, it is unknown if sex modifies this relationship. We sought to determine the effect of sex on the relationship between APOE4 status and incident cognitive decline in PD. METHODS: Data from the prospectively collected longitudinal National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS) and Neuropathology Data Set (NDS) were analyzed. The NACC develops and maintains data from approximately 29 National Institutes of Aging-funded Alzheimer's Disease Research Centers. Further details may be found at the NACC web site (www.alz.washington.edu). The visit at which diagnosis of PD was made was termed the baseline visit. All patients with a PD diagnosis but without dementia at the baseline visit were included in the analyses. RESULTS: Presence of APOE4 allele was associated with higher odds (OR = 7.4; P < .001) of subsequent diagnosis of dementia and with a faster time to developing dementia (P = .04). Those with APOE4 allele were more likely to have neuropathology associated with Alzheimer's disease than those without APOE4 allele. We did not find any difference by sex. There were no differences between Lewy body pathology or neuron loss in the substantia nigra between the 2 groups. Sex was not associated with dementia risk in PD (OR = 0.53, P = .15) or with the time to dementia onset (P = .22). Sex did not modify the relationship between the APOE4 allele and dementia onset in PD patients (P = .12). CONCLUSIONS: APOE4 allele status in PD may be a predictor of cognitive decline in PD but does not appear to be modified by sex.

Evaluation of away-from-home excursion patterns after falling among individuals with glaucoma: a longitudinal study.

BACKGROUND: Unintentional falls among older adults are associated with an ensuing decline in physical activity. Our objective is to evaluate the associations between fall status and changes in excursions after a fall. METHODS: Prospective cohort study of older adults with glaucoma or suspected glaucoma who reported falls for 1 year and wore a GPS device for 1-week at the baseline and 1 year later. GPS data were quantified into average: daily excursions, daily time away from home, and time per excursion. Fall status was categorized as fallers, injurious fallers, recurrent fallers, and recurrent injurious fallers. Multivariable negative binomial regression and generalized estimating equations models were employed to evaluate relationship between excursion parameters and fall status. RESULTS: A total of 192 eligible participants were included in the analyses. Approximately half were males (50.5%) with a mean age of 70.1 years and one-fourth were Black (28.1%). There were no significant associations between fall status and end-of-study excursion parameters (p > 0.06 for all), and visual field damage did not modify these relationships (p > 0.07 for all). For instance, patients with multiple falls during a one-year study period did not demonstrate more daily excursions (incident rate ratio [IRR] = 1.16, 95% confidence interval [CI] = 0.85 to 1.57), longer time per excursion (IRR = 0.79, 95% CI =0.59 to 1.06), or more average daily time away (IRR = 1.05, 95% CI = 0.84 to 1.30) conducted at the end-of-the study. Excursion parameters at the final assessment were not significantly different from those at baseline (p > 0.09 for all) and the changes did not vary by fall status (p > 0.23 for all). CONCLUSIONS: Older adults with glaucoma did not modify their travel away from home after experiencing a fall. Additional research is necessary to understand how often maintenance of travel outside the home after a fall reflects proper compensation for greater fall risk or continued activity despite the risk of falling.

Patterns of Daily Physical Activity across the Spectrum of Visual Field Damage in Glaucoma Patients.

PURPOSE: To define and quantify patterns of objectively measured daily physical activity by level of visual field (VF) damage in glaucoma patients including: (1) activity fragmentation, a metric of health and physiologic decline, and (2) diurnal patterns of activity, a measure of rest and activity rhythms. DESIGN: Prospective cohort study. PARTICIPANTS: Older adults diagnosed with glaucoma or suspected glaucoma. METHODS: Degree of VF damage was defined by the average VF sensitivity within the integrated VF (IVF). Each participant wore a hip accelerometer for 1 week to measure daily minute-by-minute activity for 7 consecutive days. Activity fragmentation was calculated as the reciprocal of the average activity bout duration in minutes, with higher fragmentation indicating more transient, rather than sustained, activity. Multivariate linear regression was used to test for cross-sectional associations between VF damage and activity fragmentation. Multivariate linear mixed-effects models were used to assess the associations between VF damage and accumulation of activity across 6 3-hour intervals from 5 am to 11 pm. MAIN OUTCOME MEASURES: Activity fragmentation and amount of activity (steps) over the course of the day. RESULTS: Each 5-dB decrement in IVF sensitivity was associated with 16.3 fewer active minutes/day (P < 0.05) and 2% higher activity fragmentation (P < 0.05), but not with the number of active bouts per day (P = 0.30). In time-of-day analyses, lower IVF sensitivity was associated with fewer steps over the 11 am to 2 pm, 2 pm to 5 pm, and 5 pm to 8 pm periods (106.6, 93.1, and 89.2 fewer steps, respectively; P < 0.05 for all), but not over other periods. The activity midpoint (the time at which half of the daily activity is completed) did not vary across level of VF damage. CONCLUSIONS: At worse levels of VF damage, glaucoma patients demonstrate shorter, more fragmented bouts of physical activity throughout the day and lower activity levels during typical waking hours, reflecting low physiologic functioning. Further work is needed to establish the temporality of this association and whether glaucoma patients with such activity patterns are at a greater risk of adverse health outcomes associated with activity fragmentation.

The Impact of Weather and Seasons on Falls and Physical Activity among Older Adults with Glaucoma: A Longitudinal Prospective Cohort Study.

Understanding periods of the year associated with higher risk for falling and less physical activity may guide fall prevention and activity promotion for older adults. We examined the relationship between weather and seasons on falls and physical activity in a three-year cohort of older adults with glaucoma. Participants recorded falls information via monthly calendars and participated in four one-week accelerometer trials (baseline and per study year). Across 240 participants, there were 406 falls recorded over 7569 person-months, of which 163 were injurious (40%). In separate multivariable regression models incorporating generalized estimating equations, temperature, precipitation, and seasons were not significantly associated with the odds of falling, average daily steps, or average daily active minutes. However, every 10 °C increase in average daily temperature was associated with 24% higher odds of a fall being injurious, as opposed to non-injurious (p = 0.04). The odds of an injurious fall occurring outdoors, as opposed to indoors, were greater with higher average temperatures (OR per 10 °C = 1.46, p = 0.03) and with the summer season (OR = 2.69 vs. winter, p = 0.03). Falls and physical activity should be understood as year-round issues for older adults, although the likelihood of injury and the location of fall-related injuries may change with warmer season and temperatures.

Evidence-Based Criteria for Determining Peripapillary OCT Reliability.

PURPOSE: To assess the impact of OCT signal strength (SS) and artifact on retinal nerve fiber layer (RNFL) measurement reliability and to understand whether glaucoma severity modifies this relationship. DESIGN: Retrospective, longitudinal cohort study. PARTICIPANTS: Two thousand nine hundred ninety-two OCT scans from 474 eyes of 241 patients with glaucoma or glaucoma suspect status. METHODS: We extracted mean RNFL thickness and SS and manually graded scans for artifact. To analyze the effect of SS and artifact on OCT reliability, we (1) created a multilevel linear model using measured RNFL thickness values and demographic and clinical data to estimate the true (predicted) RNFL thickness, (2) calculated model residuals (ΔRNFL) as our reliability measure, and (3) created a second multilevel linear model with splines and interaction terms that modeled overall and quadrant specific reliability (ΔRNFL) as the outcome, using SS and artifact as predictors. MAIN OUTCOME MEASURES: Impact of SS and artifact on ΔRNFL. RESULTS: For SS between 10 and 3, the impact of decreases in SS on OCT reliability is modest (-0.67 to -1.25 ΔRNFL per 1-point decrease in SS; P < 0.05). But at less than 3, changes in SS have a large impact on reliability (-15.70 to -16.34 ΔRNFL per 1-point decrease in SS; P < 0.05). At SS between 10 and 3, decreases in SS tend to have a larger impact on reliability in eyes with severe glaucoma (-1.25 per 1-point decrease in SS; P < 0.05) compared with eyes with mild or moderate glaucoma (-0.67 to -0.75 per 1-point decrease in SS; P < 0.05). The presence of artifact has a significant impact on OCT reliability independent of the effects of SS (-4.76 ΔRNFL; P < 0.05). Artifact affects reliability solely in the quadrant in which it occurs, with artifact in one quadrant showing no impact on ΔRNFL in the opposite quadrant (P > 0.05). CONCLUSIONS: Signal strength decreases down to 3 have relatively mild impacts on OCT reliability. At less than 3, the impact of further decreases in SS on reliability are substantial. The effect of SS on reliability is greater in severe glaucoma. Artifacts result in a decrease in reliability independent of the effect of SS. We propose evidence-based guidelines to guide physicians on whether to trust the results of an OCT scan.

Genome-wide identification of microRNA targets in human ES cells reveals a role for miR-302 in modulating BMP response.

MicroRNAs are important regulators in many cellular processes, including stem cell self-renewal. Recent studies demonstrated their function as pluripotency factors with the capacity for somatic cell reprogramming. However, their role in human embryonic stem (ES) cells (hESCs) remains poorly understood, partially due to the lack of genome-wide strategies to identify their targets. Here, we performed comprehensive microRNA profiling in hESCs and in purified neural and mesenchymal derivatives. Using a combination of AGO cross-linking and microRNA perturbation experiments, together with computational prediction, we identified the targets of the miR-302/367 cluster, the most abundant microRNAs in hESCs. Functional studies identified novel roles of miR-302/367 in maintaining pluripotency and regulating hESC differentiation. We show that in addition to its role in TGF-ß signaling, miR-302/367 promotes bone morphogenetic protein (BMP) signaling by targeting BMP inhibitors TOB2, DAZAP2, and SLAIN1. This study broadens our understanding of microRNA function in hESCs and is a valuable resource for future studies in this area.

Recognition of 5' triphosphate by RIG-I helicase requires short blunt double-stranded RNA as contained in panhandle of negative-strand virus.

Antiviral immunity is triggered by immunorecognition of viral nucleic acids. The cytosolic helicase RIG-I is a key sensor of viral infections and is activated by RNA containing a triphosphate at the 5' end. The exact structure of RNA activating RIG-I remains controversial. Here, we established a chemical approach for 5' triphosphate oligoribonucleotide synthesis and found that synthetic single-stranded 5' triphosphate oligoribonucleotides were unable to bind and activate RIG-I. Conversely, the addition of the synthetic complementary strand resulted in optimal binding and activation of RIG-I. Short double-strand conformation with base pairing of the nucleoside carrying the 5' triphosphate was required. RIG-I activation was impaired by a 3' overhang at the 5' triphosphate end. These results define the structure of RNA for full RIG-I activation and explain how RIG-I detects negative-strand RNA viruses that lack long double-stranded RNA but do contain blunt short double-stranded 5' triphosphate RNA in the panhandle region of their single-stranded genome.

Let-7 and MicroRNA-148 Regulate Parathyroid Hormone Levels in Secondary Hyperparathyroidism.

Secondary hyperparathyroidism commonly complicates CKD and associates with morbidity and mortality. We profiled microRNA (miRNA) in parathyroid glands from experimental hyperparathyroidism models and patients receiving dialysis and studied the function of specific miRNAs. miRNA deep-sequencing showed that human and rodent parathyroids share similar profiles. Parathyroids from uremic and normal rats segregated on the basis of their miRNA expression profiles, and a similar finding was observed in humans. We identified parathyroid miRNAs that were dysregulated in experimental hyperparathyroidism, including miR-29, miR-21, miR-148, miR-30, and miR-141 (upregulated); and miR-10, miR-125, and miR-25 (downregulated). Inhibition of the abundant let-7 family increased parathyroid hormone (PTH) secretion in normal and uremic rats, as well as in mouse parathyroid organ cultures. Conversely, inhibition of the upregulated miR-148 family prevented the increase in serum PTH level in uremic rats and decreased levels of secreted PTH in parathyroid cultures. The evolutionary conservation of abundant miRNAs in normal parathyroid glands and the regulation of these miRNAs in secondary hyperparathyroidism indicates their importance for parathyroid function and the development of hyperparathyroidism. Specifically, let-7 and miR-148 antagonism modified PTH secretion in vivo and in vitro, implying roles for these specific miRNAs. These findings may be utilized for therapeutic interventions aimed at altering PTH expression in diseases such as osteoporosis and secondary hyperparathyroidism.

Comparative RNA-sequencing analysis of myocardial and circulating small RNAs in human heart failure and their utility as biomarkers.

Heart failure (HF) is associated with high morbidity and mortality and its incidence is increasing worldwide. MicroRNAs (miRNAs) are potential markers and targets for diagnostic and therapeutic applications, respectively. We determined myocardial and circulating miRNA abundance and its changes in patients with stable and end-stage HF before and at different time points after mechanical unloading by a left ventricular assist device (LVAD) by small RNA sequencing. miRNA changes in failing heart tissues partially resembled that of fetal myocardium. Consistent with prototypical miRNA-target-mRNA interactions, target mRNA levels were negatively correlated with changes in abundance for highly expressed miRNAs in HF and fetal hearts. The circulating small RNA profile was dominated by miRNAs, and fragments of tRNAs and small cytoplasmic RNAs. Heart- and muscle-specific circulating miRNAs (myomirs) increased up to 140-fold in advanced HF, which coincided with a similar increase in cardiac troponin I (cTnI) protein, the established marker for heart injury. These extracellular changes nearly completely reversed 3 mo following initiation of LVAD support. In stable HF, circulating miRNAs showed less than fivefold differences compared with normal, and myomir and cTnI levels were only captured near the detection limit. These findings provide the underpinning for miRNA-based therapies and emphasize the usefulness of circulating miRNAs as biomarkers for heart injury performing similar to established diagnostic protein biomarkers.

Identification of the RNA recognition element of the RBPMS family of RNA-binding proteins and their transcriptome-wide mRNA targets.

Recent studies implicated the RNA-binding protein with multiple splicing (RBPMS) family of proteins in oocyte, retinal ganglion cell, heart, and gastrointestinal smooth muscle development. These RNA-binding proteins contain a single RNA recognition motif (RRM), and their targets and molecular function have not yet been identified. We defined transcriptome-wide RNA targets using photoactivatable-ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) in HEK293 cells, revealing exonic mature and intronic pre-mRNA binding sites, in agreement with the nuclear and cytoplasmic localization of the proteins. Computational and biochemical approaches defined the RNA recognition element (RRE) as a tandem CAC trinucleotide motif separated by a variable spacer region. Similar to other mRNA-binding proteins, RBPMS family of proteins relocalized to cytoplasmic stress granules under oxidative stress conditions suggestive of a support function for mRNA localization in large and/or multinucleated cells where it is preferentially expressed.

Comprehensive profiling of circulating microRNA via small RNA sequencing of cDNA libraries reveals biomarker potential and limitations.

We profiled microRNAs (miRNAs) in cell-free serum and plasma samples from human volunteers using deep sequencing of barcoded small RNA cDNA libraries. By introducing calibrator synthetic oligonucleotides during library preparation, we were able to calculate the total as well as specific concentrations of circulating miRNA. Studying trios of samples from newborn babies and their parents we detected placental-specific miRNA in both maternal and newborn circulations and quantitated the relative contribution of placental miRNAs to the circulating pool of miRNAs. Furthermore, sequence variation in the placental miRNA profiles could be traced to the specific placenta of origin. These deep sequencing profiles, which may serve as a model for tumor or disease detection, allow us to define the repertoire of miRNA abundance in the circulation and potential uses as biomarkers.

The influence of a peer-based HIV prevention intervention on conversation about HIV prevention among people who inject drugs in Baltimore, Maryland.

STEP into Action assessed the efficacy of a peer-based HIV prevention intervention in reducing HIV risk behaviors among people who inject drugs (PWIDs) in Baltimore. This analysis examined the effect of the intervention on the change in frequency of conversation about HIV prevention topics over time. 114 participants were randomized into an experimental and 113 into a control group. Data was collected prospectively at 6, 12, and 18 months. The experimental group talked more frequently about HIV prevention topics compared to the control group at 6-month visit. At 18 months relative risk ratios (RRR) remained statistically significant for conversation about the danger of needle sharing (RRR = 3.21) and condom use (RRR = 2.81). The intervention resulted in an increased conversation about HIV prevention among PWIDs, but the sustainability past 6 months remained a challenge; suggesting that interventions should be designed to constantly reinforce communication about HIV prevention among PWIDs.

Deep MicroRNA sequencing reveals downregulation of miR-29a in neuroblastoma central nervous system metastasis.

Central nervous system (CNS) is an increasingly common site of isolated metastasis for patients with Stage 4 neuroblastoma. To explore the microRNA (miRNA) profile of this metastatic process, miRNA sequencing was performed to identify miRNA sequence families with differential expression between tumor pairs (pre-CNS primary and CNS metastasis) from 13 patients with Stage 4 neuroblastoma. Seven miRNA sequence families had distinct expression in CNS metastases when compared with their corresponding pre-CNS primaries. MiR-7 was upregulated (3.75-fold), and miR-21, miR-22, miR-29a, miR-143, miR-199a-1-3p, and miR-199a-1-5p were downregulated (3.5-6.1-fold), all confirmed by quantitative reverse transcription-PCR. MiR-29a, previously shown to be downregulated in a broad spectrum of solid tumors including neuroblastoma, had the most significant decrease in all 13 CNS metastases (P = 0.001). Its known onco-targets CDC6, CDK6, and DNMT3A, as well as B7-H3, an inhibitory ligand for T cells, and natural killer cells, were found to have higher differential expression in these 13 CNS metastases when compared with their paired primaries. Additionally, miR-29a expression in primary tumors was significantly lower among patients who eventually relapsed in the CNS. Irrespective of the amplification status of MYCN, which is known to be associated with metastasis, pre-CNS primaries, and CNS metastases had significantly lower miR-29a expression than non-CNS primary tumors. Among MYCN amplified cell lines, those from CNS relapse also had lower miR-29a expression than non-CNS relapse. These findings raised the hypothesis that miR-29a could be a biomarker for neuroblastoma CNS metastasis, and its downregulation may play a pivotal role in CNS progression.

Longitudinal Changes in Visual Acuity and Contrast Sensitivity and Incident Dementia.

PURPOSE: To evaluate the impact of baseline and change in vision on the risk of developing dementia. DESIGN: Retrospective cohort study. METHODS: This longitudinal analysis utilized data from the 2021 and 2022 National Health and Aging Trends Study. Binocular presenting vision was assessed, including distance (DVA) and near (NVA) visual acuity, and contrast sensitivity (CS). Dementia status was defined based on: (1) medical diagnosis of dementia, (2) dementia score, or (3) poor cognitive test performance. RESULTS: Of the 2,159 adults included in this study, weighted mean (SD) age was 77.9 years (5.2), with the majority being female (weighted: 54%), and White (88%). The baseline median (interquartile range [IQR]) DVA was 0.08 (0-0.20) logMAR, NVA was 0.17 (0.09-0.26) logMAR, and CS was 1.80 (1.65-1.85) logCS. Over the 1-year follow up period, 192 (6.6%) adults developed dementia. In time-to-event analyses, baseline DVA (HR: 1.08 [95% CI: 1.02-1.14], per 0.1 logMAR), NVA (HR: 1.07 [95% CI: 1.01-1.13], per 0.1 logMAR), and CS (HR: 1.09 [95% CI: 1.03-1.15], per 0.1 logCS) were associated with greater likelihood of incident dementia. Further, change in CS (HR: 1.14 [95% CI: 1.04-1.25], per 0.1 logCS worse/year), but not VA, was associated with greater likelihood of incident dementia. CONCLUSIONS: Worse baseline VA and CS are associated with greater likelihood of incident dementia. Further, worsening CS over time, but not VA, was associated with higher likelihood of incident dementia. Future work is needed to study interventions targeted at improving vision deficits and examine their impact on decreasing dementia risk.

Characterizing Longitudinal Changes in Fear of Falling and Quality of Life in Patients with Varying Levels of Visual Field Damage.

PURPOSE: To investigate the relationship between baseline visual field (VF) severity and rates of visual field loss with changes in quality of life (QoL) and fear of falling (FoF) in adults with glaucoma. METHODS: Prospective cohort study, including participants from the Falls In Glaucoma Study. Quality of life and FoF were assessed annually using the Glaucoma Quality of Life-15 Questionnaire, and the University of Illinois at Chicago FoF Questionnaire, respectively, with higher Rasch-analyzed scores (in logits) indicating better QoL and greater FoF. Mean deviation (MD) values of each eye were collected, with better-eye MD taken as the primary exposure. Change rates in better-eye MD, QoL, and FoF were computed using linear regression. Separate regression models were employed to explore the relationship between baseline better-eye MD and its rate of change with rates of change in QoL and FoF. RESULTS: The mean (standard deviation) rate of change in better-eye MD was -0.08 dB/year (0.5), rate of QoL change was -0.08 logits/year (0.4), and rate of FoF change was 0.16 logits/year (0.7). At baseline, better-eye MD (per dB worse) was significantly associated with worse baseline QoL (ß = -0.10 logits [95% confidence interval [CI]: -0.13, -0.08]) and greater FoF (ß = 0.06 logits [95% CI: 0.01, 0.10]). Baseline better-eye MD was associated with no significant change in QoL ( -0.004 logits/year, 95% CI: -0.02, 0.01) or FoF (-0.0001 logits/year, 95% CI: -0.02, 0.02) over time. Change rates in better-eye MD showed significant associations with faster increases in FoF over time (ß = 0.26 logits/year [95% CI: 0.06, 0.45]; per dB loss/year), but not with changes in QoL (P = 0.79). CONCLUSIONS: Patients with glaucoma generally showed worsening of QoL and FoF over time, though the degree of change was modest and not related to the degree of damage at baseline. Faster rates of better-eye MD change alone were associated with faster increases in FoF. Further studies are needed to evaluate the reasons (visual and nonvisual) for changes in QoL and functionality over time and find ways in which QoL and mobility can be improved for those with VF damage. FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

The Quantitative Impact of Visual Function on Accelerometer-measured Physical Activity in Older United States Adults: A Nationwide Cross-sectional Analysis.

Purpose: To explore the impact of objective vision measures on novel metrics of objectively-measured physical activity (PA) in a nationally representative sample of United States (US) older adults. Design: Cross-sectional analysis using data from the National Health and Aging Trends Study. Participants: Adults had their distance and near visual acuity (VA) and contrast sensitivity (CS) tested. Any objective vision impairment (VI), defined as any VI in distance VA, near VA, or CS, was the primary exposure. Physical activity data were collected using the Actigraph CentrePoint Insight Watch worn for 7 days. Methods: Multivariable regression models were used to investigate the association between vision and PA measures. All analyses accounted for the survey design and models were adjusted for age, sex, race, living arrangement, education, and comorbidities. Main Outcome Measures: Physical activity metrics included (1) total daily activity (active minutes per day, number of active bouts, and mean length of active bouts), (2) activity fragmentation, and (3) time until 75% activity. An active bout was defined as ≥ 1 consecutive active minute. Activity fragmentation was defined as the probability of an active minute being followed by a sedentary minute, with higher values indicating more fragmented activity. Time until 75% activity was defined as the time taken to complete 75% of daily PA starting from their first active bout. Results: Among 723 participants, sampled from 10 443 338 older adults in the US, 30% had any objective VI. Any objective VI was significantly associated with lower number of active minutes per day (7.8% fewer [95% confidence interval {CI}: -13.6% to -1.7%]), shorter active bouts (7.0% shorter [95% CI: -12.3% to -1.4%]), and greater activity fragmentation (2.5% [95% CI: 0.8% to 4.2%]), while no associations were found with number of active bouts. Time until 75% activity did not significantly differ between adults with any objective VI and those without (P = 0.34). Conclusions: Older US adults with any objective VI displayed lower total daily activity, as well as more fragmented, shorter periods of PA, despite having a similar number of active bouts compared to their normally sighted counterparts. Implementing interventions that increase bout duration may help promote PA in adults with VI. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.