Effect of physical activity on the relationship between adiposity and cardiac autonomic modulation in female breast cancer survivors: a longitudinal study.

This longitudinal study aimed to analyze the influence of physical activity (PA) on the relationship between body adiposity and cardiac autonomic modulation (CAM) in women survivors of breast cancer. We collected body adiposity through electrical bioimpedance considering body fat percentage (BFP), CAM through heart rate variability (considering RMSSD, SDNN, PNN50, LF (m2), HF (m2), SD1 indexes and SD1/SD2 ratio) and PA through a questionnaire in 64 participants (58.0 ± 9.6 years), recruited through the local association of support for breast cancer and by direct indications from city mastologists. After insertion of PA into the multivariate statistical model, significant attenuation was observed in the relationship between body adiposity and CAM for the indices: SDNN (ß = -0.94; 95 percent CI: -1.93; 0.04; p = .060) and SD1/SD2 (ß = -0.01;95 percent CI = -0.02; 0.001; p = .065). In conclusion, it was observed that PA was able to mitigate the relationships between BFP and CAM (considering SDNN index and SD1/SD2 ratio) in breast cancer survivors.

Association Between Physical Activity Levels in Different Domains and Cardiac Autonomic Modulation in Breast Cancer Survivors: A Cross-sectional Study.

BACKGROUND: Breast cancer survivors frequently present cardiac autonomic dysfunction. Physical activity (PA) has been associated with better cardiac autonomic modulation (CAM) in breast cancer survivors. OBJECTIVE: This study aimed to analyze the association between CAM and PA levels performed in different domains (work and occupation, sport and exercise, and leisure time and commuting) in breast cancer survivors. METHODS: This is a cross-sectional study with 99 breast cancer survivors (age, 55.3 ± 10.4 years). Cardiac autonomic modulation was assessed by heart rate variability, and PA levels at work and occupation, sport and exercise, and leisure time and commuting were assessed using the Baecke PA questionnaire. The sum of these 3 domains provided the total PA. The Mann-Whitney test was used to compare CAM between active and inactive women in different domains of PA. RESULTS: Cardiac autonomic modulation was similar between active and inactive women in the different domains ( P > .05). However, when considering the total PA, active breast cancer survivors presented higher SDNN (average standard deviation of all normal RR intervals) (20.0 ± 13.4 vs 28.8 ± 14.0; P = .008) and SD2 (standard deviation of the long-term intervals between consecutive heartbeats) indices (29.2 ± 17.3 vs 38.7 ± 19.9; P = .005) compared with their inactive counterparts. CONCLUSION: Breast cancer survivors with higher total PA presented better CAM compared with their less active peers. IMPLICATIONS FOR PRACTICE: The results of this study are promising and show the importance of increasing PA levels in different domains for the maintenance of cardiovascular health among breast cancer survivors.

Goat mammary gland metabolism: An integrated Omics analysis to unravel seasonal weight loss tolerance.

Seasonal weight loss (SWL), is a major limitation to animal production. In the Canary Islands, there are two dairy goat breeds with different levels of tolerance to SWL: Majorera (tolerant) and Palmera (susceptible). Our team has studied the response of these breeds to SWL using different Omics tools. The objective of this study was to integrate such results in a data driven approach and using dedicated tools, namely the DIABLO method. The outputs of our analysis mainly separate unrestricted from restricted goats. Metabolites behave as "hub" molecules, grouping interactions with several genes and proteins. Unrestricted goats upregulated protein synthesis, along with arginine catabolism and adipogenesis pathways, which are related with higher anabolic rates and a larger proportion of secretory tissue, in agreement with their higher milk production. Contrarily, restricted goats seemingly increased the synthesis of acetyl-CoA through serine and acetate conversion into pyruvate. This may have occurred to increase fatty acid synthesis and/or to use them as an energy source in detriment to glucose, which was more available in the diet of unrestricted goats. Lastly, restricted Palmera upregulated the expression of PEBP4 and GPD1 genes compared to all other groups, which might support their use as putative biomarkers for SWL susceptibility. SIGNIFICANCE: Seasonal weight loss (SWL) is a major issue influencing animal production in the tropics and Mediterranean. By studying its impact on the mammary gland of tolerant and susceptible dairy goat breeds, using Omics, we aim at surveying the tissue for possible biomarkers that reflect these traits. In this study, data integration of three Omics (transcriptomics, proteomics and metabolomics) was performed using bioinformatic tools, to relate putative biomarkers and evaluate all three levels of information; in a novel approach. This information can enhance selection programs, lowering the impact of SWL on food production systems.

A Comprehensive Report of Intrinsically Disordered Regions in Inherited Retinal Diseases.

BACKGROUND/PURPOSE: A comprehensive review of the degree of disorder in all genes in the Retinal Information Network (RetNet) Database is implicated in inherited retinal diseases (IRDs). Their association with a missense variation was evaluated. METHODS: IRD genes from RetNet were included in this study. Publicly available data on the genome aggregation database (gnomAD) were used to analyze the number of total and pathogenic missense variants. Metapredict, an accurate and high-performance predictor that reproduces consensus disorder scores, was used to calculate disorder. MAIN OUTCOME MEASURES: The main outcome measures were percent disorder, percent pathogenicity, number of total missense variants, and percent total missense variation. RESULTS: We included 287 RetNet genes with relevant data available from gnomAD. Mean percent disorder was 26.3% ± 26.0%, mean percent pathogenicity was 5.2% ± 11.0%, mean number of total missense variants was 424.4 ± 450.0, and mean percent total missense was 50.0% ± 13.4%. The percent disorder followed a bimodal distribution with the highest number of occurrences in the 0 to 10th disorder decile. The five outlier proteins in the first disorder decile with a higher-than-expected number of total missense variation were identified (HMCN1, ADGRV, USH2A, DYNC2H1, LAMA1, and SLC38A8). When excluded, % total missense was significantly associated with percent disorder (R = 0.238 and p = 0.0240). CONCLUSIONS: This novel study examining all genes implicated in IRDs found that the majority genes had a disorder in the 0 to 10th decile and were relatively intolerant to missense variation. This may have future utility when interpreting variants of undetermined significance and missense variants.

Expanding the phenotypic and genotypic spectrum of patients with HGSNAT-related retinopathy.

BACKGROUND: Variants in HGSNAT have historically been associated with syndromic mucopolysaccharidosis type IIIC (MPSIIIC) but more recent studies demonstrate cases of HGSNAT-related non-syndromic retinitis pigmentosa. We describe and expand the genotypic and phenotypic spectrum of this disease. MATERIALS AND METHODS: This is a retrospective, observational, case series of 11 patients with pericentral retinitis pigmentosa due to variants in HGSNAT gene without a syndromic diagnosis of MPSIIIC. We reviewed ophthalmologic data extracted from medical records, genetic testing, color fundus photos, fundus autofluorescence (FAF), and optical coherence tomography (OCT). RESULTS: Of the 11 patients, the mean age was 52 years (range: 26-78). The mean age of ophthalmologic symptoms onset was 45 years (range: 15-72). The visual acuity varied from 20/20 to 20/80 (mean 20/30 median 20/20). We described five novel variants in HGSNAT: c.715del (p.Arg239Alafs *37), c.118 G>A (p.Asp40Asn), c.1218_1220delinsTAT, c.1297A>G (p.Asn433Asp), and c.1726 G>T (p.Gly576*). CONCLUSIONS: HGSNAT has high phenotypic heterogeneity. Data from our cohort showed that all patients who had at least one variant of c.1843 G>A (p.Ala615Thr) presented with the onset of ocular symptoms after the fourth decade of life. The two patients with onset of ocular symptoms before the fourth decade did not carry this variant. This may suggest that c.1843 G>A variant is associated with a later onset of retinopathy.

Molecular and Clinical Characterization of CNGA3 and CNGB3 Genes in Brazilian Patients Affected with Achromatopsia.

Achromatopsia (ACHM) is a congenital cone photoreceptor disorder characterized by reduced visual acuity, nystagmus, photophobia, and very poor or absent color vision. Pathogenic variants in six genes encoding proteins composing the cone phototransduction cascade (CNGA3, CNGB3, PDE6C, PDE6H, GNAT2) and of the unfolded protein response (ATF6) have been related to ACHM cases, while CNGA3 and CNGB3 alone are responsible for most cases. Herein, we provide a clinical and molecular overview of 42 Brazilian patients from 38 families affected with ACHM related to biallelic pathogenic variants in the CNGA3 and CNGB3 genes. Patients' genotype and phenotype were retrospectively evaluated. The majority of CNGA3 variants were missense, and the most prevalent CNGB3 variant was c.1148delC (p.Thr383Ilefs*13), resulting in a frameshift and premature stop codon, which is compatible with previous publications in the literature. A novel variant c.1893T>A (p.Tyr631*) in the CNGB3 gene is reported for the first time in this study. A great variability in morphologic findings was observed in our patients, although no consistent correlation with age and disease stage in OCT foveal morphology was found. The better understanding of the genetic variants landscape in the Brazilian population will help in the diagnosis of this disease.

Improved Rod Sensitivity as Assessed by Two-Color Dark-Adapted Perimetry in Patients With RPE65-Related Retinopathy Treated With Voretigene Neparvovec-rzyl.

Purpose: The purpose of this study was to evaluate rod-mediated function with two-color dark-adapted perimetry (2cDAP) in patients with RPE65-related retinopathy treated with voretigene neparvovec-rzyl. Methods: Following dilation and dark adaptation, 2cDAP and FST were performed. The 2cDAP was measured on an Octopus 900 perimeter (Haag-Streit) with cyan (500 nm wavelength) and red (650 nm wavelength) stimuli. Hill of vision (HOV) analysis was performed on 2cDAP perimetry with Visual Field Modeling and Analysis (VFMA). Full field threshold stimulus testing (FST) was also measured as a secondary measure of rod-mediated function, and assessed on a Diagnosys Espion with the ColorDome stimulator (Diagnosys LLC). Results: Eight eyes from 4 patients who were treated with voretigene bilaterally had rod function assessed by 2cDAP testing at least 1 year after treatment. There was statistically significant improvement in 2cDAP following gene augmentation therapy. HOV VFMA analysis showed widespread improvements that extended beyond the treatment bleb and statistically significant improvement in HOV analysis volumetric measurements post-treatment to cyan and red stimuli. FST testing performed in six eyes from three patients demonstrated statistically significant improvement to all chromatic stimuli following treatment. Conclusions: These findings demonstrated statistically significant improvement in 2cDAP and FST following treatment with voretigene. Translational Relevance: These findings provide a sensitive method of assessing rod-mediated function in a topographic manner that may be useful in future clinical trials for inherited retinal dystrophies.

Comparison of Quality of Life in Breast Cancer Survivors with and without Persistent Depressive Symptoms: A 12-Month Follow-Up Study.

Although breast cancer treatments reduce mortality, their adverse effects can increase depression which impacts one's quality of life (QoL). Physical activity (PA) seems to improve the QoL of breast cancer survivors (BCS). However, an unanswered question is the influence of PA on the QoL in BCS with depressive symptoms. Thus, we analyzed the influence of PA on the QoL in BCS with persistent depressive symptoms during 12 months of follow-up. The sample included 70 female BCS. Depression and QoL domains (i.e., functional capacity, physical limitations, body pain, general health status, vitality, social and emotional aspects, and mental health) were assessed at baseline and follow-up periods by the Hospital Anxiety and Depression Scale and SF-36, respectively. Habitual PA was assessed by Baecke's questionnaire. Our results indicate a prevalence of 17.1% of depressive symptoms. Non-depressives BCS improved their physical limitations and general health status domains over time, but there were no observed differences in depressive BCS. BCS with persistent depressive symptoms (baseline and follow-up) showed worse QoL scores than non-depressives in all domains, regardless of confounding factors. When adjusted for PA, the difference between BCS depressives and non-depressives lost its significance in the functional capacity domain. In conclusion, habitual PA practice positively influenced the functional capacity domain of the QoL in BCS.

A possible ocular biomarker for response to hyperornithinemia in gyrate atrophy: the effect of pyridoxine, lysine, and arginine-restricted diet in a patient with advanced disease.

BACKGROUND: Loss of function variants in the ornithine aminotransferase (OAT) gene cause accumulation of ornithine levels, leading to gyrate atrophy. The benefit of ornithine-lowering therapies has been documented in a mouse model and young patients, however, the effect in adults with advanced disease has not been well described. MATERIALS AND METHODS: Case report of an adult patient with advanced gyrate atrophy, who underwent treatment with pyridoxine and an arginine-restricted diet for four years. RESULTS: A 51-year-old female with advanced chorioretinal degeneration presented with hyperornithinemia (961 vs. normal 18-135 µmol/L) and compound heterozygous pathogenic variants in OAT (p.Tyr299* and p.Ala270Pro). Treatment with pyridoxine and arginine-diet restriction yielded a maximal reduction in ornithine levels by 71% (275 µmol/L). Optical coherence tomography (OCT) showed a reduction in ellipsoid zone (EZ) thickness that correlated with lower ornithine levels and reversed with higher ornithine levels. While her best-corrected visual acuity remained unchanged, the progressive decline in her visual fields appeared to stabilize during a one-year period when ornithine levels were below 500 µmol/L. CONCLUSIONS: In this report, we demonstrate that chorioretinal degeneration appears to stabilize in an adult patient with gyrate atrophy in association with a partial reduction in ornithine levels. We also observed a correlation with reduced EZ thickness on OCT and propose this may be a novel biomarker for ornithine reduction therapies. Our case study characterizes the potential retinal structure-function benefits of ornithine-lowering treatments even in cases of advanced chorioretinal degeneration. Thus, we recommend a low threshold for treating all patients with gyrate atrophy.

A DOUBLE HYPERAUTOFLUORESCENT RING IN A 33-YEAR-OLD-FEMALE PATIENT.

PURPOSE: To describe the clinical phenotype and molecular diagnosis of a patient with atypical presentation of enhanced S-cone syndrome. METHODS: This is a case report of a patient who underwent best-corrected visual acuity, slit-lamp exam, fundus examination, autofluorescence, optical coherence tomography, kinetic perimetry, and full-field electroretinography. Genetic testing was performed via next-generation sequencing. RESULTS: A 33-year-old female patient presented with mild nyctalopia, but normal rod function measured by electroretinogram and foveoschisis on optical coherence tomography. She also presented a double hyperautofluorescent ring on autofluorescence. Genetic testing found a pathogenic variant c.925C>G (p.Arg309Gly) and a likely pathogenic variant c.299C>T (p.Arg77Trp) in NR2E3 gene. CONCLUSION: Enhanced S-cone syndrome may present without the pathognomonic findings of decreased rod function on electroretinogram, suggesting the importance of genetic testing in retinal diseases for diagnosis.

Impact of dietary Chlorella vulgaris and feed enzymes on health status, immune response and liver metabolites in weaned piglets.

In this study, we analysed the impact of dietary inclusion of Chlorella vulgaris and carbohydrases on general health, redox status, immune response, liver lipids and metabolites in weaned piglets. Forty-four male piglets were allocated into four diets: control (n = 11), CH (control diet with 5% CH, n = 10), CH+R (control diet with 5% CH plus 0.005% Rovabio Excel AP, n = 10), and CH+M (control diet with 5% CH plus 0.01% of a pre-selected four-CAZyme mixture, n = 11). After 15 days of trial, animals were slaughtered and samples of blood and liver collected. Spectrophotometry methods and commercial kits were used to determine blood parameters and gas and liquid chromatography for hepatic fatty acid and chlorophylls profiles, respectively. While total, LDL- and VLDL-cholesterol were increased by CH, the opposite was recorded for HDL-cholesterol (p < 0.001). Piglets fed CH-based diets presented an increase of IgG and a decrease of IgM (p < 0.001) which along with lymphocytes exacerbation contributed for piglets' survival after weaning. n-6 PUFA were reduced in piglets fed CH and the opposite occurred for n-3 PUFA (p < 0.001), thus benefiting n-6/n-3 ratio in the liver. Chlorophylls amount was not changed by the use of Rovabio or enzymatic mixture. The discriminant analysis applied to hepatic parameters revealed a clear separation between control and CH-based diets but failed to discriminate feed enzymes. Our findings indicate health promoting effects of CH as feed ingredient in piglets' nutrition at weaning, without negatively impacting on animals' performance.

Three-Year Safety Results of SAR422459 (EIAV-ABCA4) Gene Therapy in Patients With ABCA4-Associated Stargardt Disease: An Open-Label Dose-Escalation Phase I/IIa Clinical Trial, Cohorts 1-5.

PURPOSE: To report on the safety of the first 5 cohorts of a gene therapy trial using recombinant equine infectious anemia virus expressing ABCA4 (EIAV-ABCA4) in adults with Stargardt dystrophy due to mutations in ABCA4. DESIGN: Nonrandomized multicenter phase I/IIa clinical trial. METHODS: Patients received a subretinal injection of EIAVABCA4 in the worse-seeing eye at 3 dose levels and were followed for 3 years after treatment. MAIN OUTCOME MEASURES: The primary end point was ocular and systemic adverse events. The secondary end points were best-corrected visual acuity, static perimetry, kinetic perimetry, total field hill of vision, full field electroretinogram, multifocal ERG, color fundus photography, short-wavelength fundus autofluorescence, and spectral domain optical coherence tomography. RESULTS: The subretinal injections were well tolerated by all 22 patients across 3 dose levels. There was 1 case of a treatment-related ophthalmic serious adverse event in the form of chronic ocular hypertension. The most common adverse events were associated with the surgical procedure. In 1 patient treated with the highest dose, there was a significant decline in the number of macular flecks as compared with the untreated eye. However, in 6 patients, hypoautofluorescent changes were worse in the treated eye than in the untreated eye. Of these, 1 patient had retinal pigment epithelium atrophy that was characteristic of tissue damage likely associated with bleb induction. No patients had any clinically significant changes in best-corrected visual acuity, static perimetry, kinetic perimetry, total field hill of vision, full field electroretinogram, or multifocal ERG attributable to the treatment. CONCLUSIONS: Subretinal treatment with EIAV-ABCA4 was well tolerated with only 1 case of ocular hypertension. No clinically significant changes in visual function tests were found to be attributable to the treatment. However, 27% of treated eyes showed exacerbation of retinal pigment epithelium atrophy on fundus autofluorescence. There was a significant reduction in macular flecks in 1 treated eye from the highest dose cohort. Additional follow-up and continued investigation in more patients will be required to fully characterize the safety and efficacy of EIAV-ABCA4.

A patient with X-linked retinoschisis and exudative retinal detachment associated with a pathogenic hemizygous variant c.304c>T in RS1.

BACKGROUND: X-linked retinoschisis (XLRS) is a rare retinal dystrophy due to pathogenic variants in the RS1 gene. The hallmark of the disease is a foveal spoke-wheel appearance. The purpose of this report is to expand the phenotypic spectrum of XLRS reporting a patient with atypical phenotype of XLRS associated with Coats-like phenotype. MATERIALS AND METHODS: This is a case report of a patient diagnosed with XLRS who underwent ophthalmologic multimodal imaging and next-generation sequencing panel. RESULTS: The proband is a 14-year-old male patient who presented at Instituto Suel Abujamra with a history of Coats Disease in the right eye treated with retinal laser in both eyes two years ago. His best-corrected visual acuity was count finger at 1 foot in the right eye and 20/40 in the left eye. Fundus exam showed an extensive area of exudation and retinal detachment in the right eye and cystic change at the fovea in a spoke-wheel pattern in the left eye. The next-generation sequencing panel targeting inherited retinal diseases with 236 genes found a pathogenic hemizygous variant c.304C>T (p.Arg102Trp) in RS1 that has already been reported. CONCLUSIONS: The association of peripheral vascular incompetence and XLRS has already been described. Retinal exudation in the setting of XLRS is probably the result of vascular disruption and compromise. The loss of retinoschisin function that leads to foveal retinoschisis may also lead to vascular anomalies.

Association Between Different Domains of Physical Activity and Body Adiposity Indicators in Breast Cancer Survivors.

BACKGROUND: To analyze the relationship between different physical activity (PA) domains and adiposity indicators in breast cancer survivors. METHODS: This is a cross-sectional study, composed of 115 breast cancer (BC) survivors. Measurements of weight, height, waist circumference (WC), and hip circumference were objectively collected, as well as the analysis of body fat percentage through bioelectrical impedance analysis. The PA level was assessed by the Baecke questionnaire including domains related to occupational activity, leisure-time activity, and transportation, while the time spent in sedentary behavior was assessed through self-reported screen-time. Socioeconomic status was assessed through the Brazilian criteria for economic classification and considered as a covariate. RESULTS: BC survivors with higher PA levels in leisure-time activity/sport presented reductions in body fat percentage (ß = 1.13%; CI = -2.06; -0.21), BMI (ß = 0.80 kg/m²; CI = -1.50; -0.11), WC (ß = 1.89 cm; CI = -3.54; -0.23), and waist-to-height ratio (ß = 0.13 cm; CI = -0.23; -0.02). Similar values were observed in PA during transportation and in total. There was no correlation between PA at work and adiposity indicators. CONCLUSION: Different PA domains were inversely related to body adiposity in BC survivors.

Carbohydrate tolerance in Amazon tambaqui (Colossoma macropomum) revealed by NMR-metabolomics - Are glucose and fructose different sugars for fruit-eating fish?

In the present study, two approaches were followed to evaluate the metabolic responses of tambaqui (Colossoma macropomum), a frugivorous species, to intraperitoneal (IP) administration of glucose (GLU) and fructose (FRU) in fed (FED) and 10-day fasted (FAST) fish. Glucose and fructose tolerance tests were performed to assess the carbohydrate utilization and complementary NMR-metabolomics analyses were done to elucidate the impacts of sugar mobilization on the metabolic profile of plasma, liver and muscle. Blood was sampled from FED groups at 0, 3, 6 and 24 h; and at 0 and 24 h from FAST groups. Significant differences were observed in the hyperglycaemic peak between sugars at 3 h (GLU - 13.7 ± 2.0 mM vs. FRU - 8.7 ± 1.1 mM; saline 6.3 ± 0.6 mM) and on the return to normoglycaemia (GLU - 8.5 ± 2.2 mM vs. FRU - 5.2 ± 0.9 mM; saline 4.9 ± 0.6 mM) 6 h after IP on the FRU fish. The NMR-metabolomics approach allowed to conclude that tambaqui seems to be more responsive to the feeding regime (FED vs. FAST) than to the injected sugar (FRU vs. GLU). From the studied tissues, plasma showed no significant variations between feeding regimes at 24 h after IP, while muscle and liver revealed some variations on the final metabolome profile between FED and FAST groups. The metabolome variations between feeding regimes are indicative of changes on the amino acid utilization. Fish from FAST group seem to utilize amino acids as energy source rather than for protein synthesis and muscle growth. Variations on glucose concentration in muscle can also indicate different utilization of the sugars depending on the feeding regime.

Association between cardiac autonomic modulation and sedentary behavior in breast cancer survivors: a 12-month cohort study.

PURPOSE: This study aimed to analyze the longitudinal influence of sitting time (ST) on cardiac autonomic modulation (CAM) and resting heart rate (RHR) in a 12-month cohort of 67 breast cancer survivors. METHODS: CAM was assessed by heart rate variability with heart monitor which also assessed RHR, and ST was self-reported. The relationship between the variables was analyzed by the Pearson correlation and its magnitude by linear regression. RESULTS: At baseline, no associations were found between ST and CAM or RHR. In the delta analyses, a decrease in RMSSD, SD1, and HF(ms2) was associated with sitting time. At 12-month follow-up, there was an increase in the ST and a decrease in RHR. ST was negatively related with CAM (RMSSD, PNN50, and SD1), but no association was observed between ST and RHR. CONCLUSION: The increase in ST was associated with worsening of CAM after 12-month follow-up. Promoting reduction in ST will be an important strategy against cardiovascular impairment in breast cancer survivors.

Injection pressure levels for creating blebs during subretinal gene therapy.

Retinal damage has been associated with increased injection pressure during subretinal gene therapy delivery in various animal models, yet there are no human clinical data regarding the pressures required to initiate and propagate subretinal blebs. This study characterized the intraoperative pressure levels for subretinal gene therapy delivery across eight retinal conditions. A total of 116 patients with retinal degenerative diseases have been treated with subretinal gene therapy at OHSU-Casey Eye Institute as of June 2020; seventy patients (60.3%) were treated using a pneumatic-assisted subretinal delivery system. All retinal blebs were performed using a 41-gauge injection cannula, and use of a balanced salt solution (BSS) "pre-bleb" prior to gene therapy delivery was performed at the discretion of the surgeon. Patient age and intraoperative data for BSS and vector injections were analyzed in a masked fashion for all patients who received pneumatic-assisted subretinal gene therapy. The median age of the patients was 35 years (range 4-70). No significant differences in injection pressures were found across the eight retinal conditions. In this study, patient age was shown to affect maximum injection pressures required for bleb propagation, and the relationship between age and pressure varied based on retinal condition. These data have important implications in optimizing surgical protocols for subretinal injections.

Effect of Pharmacological Pupil Dilation on Dark-Adapted Perimetric Sensitivity in Healthy Subjects Using an Octopus 900 Perimeter.

Purpose: To determine whether dilation status has a clinically meaningful effect on sensitivity in normal subjects undergoing two-color dark-adapted perimetry, which can be useful to assess rod function. Methods: A perimeter measured naturally and pharmacologically dilated scotopic sensitivities using a test grid consisting of 16 points across the horizontal meridian ranging from 60° temporal to 45° nasal using cyan (500 nm wavelength) or red (650 nm wavelength) stimuli. The primary outcome was average overall sensitivity based on dilation status, which was compared using a linear mixed effect model for each color stimuli. A difference of 2 dB or more was considered clinically significant. Results: Twenty-nine eyes from 15 subjects (nine female) ages 23 to 63 with no known retinal pathology were included. Pharmacologically dilated eyes were 0.54 dB (95% confidence interval [CI], 0.05 dB to 1.03 dB; P = 0.032) more sensitive to a red stimulus than naturally dilated eyes, but this was not statistically significant after correction for multiple comparisons. Pharmacologically dilated eyes were 0.03 dB (95% CI, -0.20 dB to 0.14 dB; P = 0.734) less sensitive to a cyan stimulus compared to naturally dilated eyes. Conclusions: These findings show no clinically significant differences in sensitivity of scotopic perimetry in eyes without retinal pathology based on dilation status for both cyan and red stimuli. Translational Relevance: In this study, pharmacological dilation did not have a clinically meaningful effect on sensitivity, suggesting that this is not necessary when using two-color dark-adapted perimetry to assess for rod function.

Variable expressivity of BEST1-associated autosomal dominant vitreoretinochoroidopathy (ADVIRC) in a three-generation pedigree.

OBJECTIVE: Autosomal dominant vitreoretinochoroidopathy (ADVIRC) is associated with pathogenic variants in BEST1, which typically causes visual impairment in the late stage of disease. We present a pedigree with variable expressivity and the youngest case in the literature with visual impairment in early childhood. METHODS AND ANALYSIS: This is a retrospective, observational, case series describing multigenerational members of one family affected with ADVIRC. Patients underwent examination, ultra-widefield fundus photography and angiography, optical coherence tomography, full-field electroretinography (ffERG) and full-field perimetry. RESULTS: Three affected members of the pedigree, one from each successive generation, were found to harbour a mutation, c.715G>A:p.Val239Met, in BEST1. The proband characterised in this report is, to our knowledge, the youngest documented case of ADVIRC in early childhood. Yet, this patient has the most severe retinal dysfunction compared with the father and paternal grandmother, whom exhibit classic characteristics of ADVIRC. Longitudinal data from the paternal grandmother showed that there was a rapid decline in ffERG responses (photopic decline worse than scotopic) from the fourth to fifth decade of life, which correlated with severe concentric constriction of visual fields. CONCLUSION: This multigenerational case series provides new insights into the ADVIRC disease spectrum and rate of progression. While ADVIRC typically causes a slowly progressive disease, we show that variable phenotypic expressivity is possible among affected members of the same family with the same mutation in BEST1. Thus, ADVIRC must also be considered in the differential diagnosis of paediatric patients with severe retinal dystrophy in early childhood.