Censoring the Floor Effect in Long-Term Stargardt Disease Microperimetry Data Produces a Faster Rate of Decline.

Purpose: To evaluate progression rate estimation in long-term Stargardt disease microperimetry data by accounting for floor effect. Design: Cohort study. Subjects: Thirty-seven subjects (23 females, 14 males) with biallelic ABCA4 pathogenic or likely pathogenic variants and more than >2 years of longitudinal microperimetry data. Methods: Cross-sectional and longitudinal microperimetry data (Grid A: 18° diameter, Grid B: 6° diameter; Macular Integrity Assessment microperimeter, dynamic range 0-36 decibels [dB]) was extracted from patients with biallelic mutation in the adenosine triphosphate-binding cassette subfamily A member 4 (ABCA4) gene. For each eye, mean sensitivity (MS) and responding point sensitivity (RPS) rates were extracted. Floor censored sensitivity (FCS) progression rate, which accounts for the floor effect at each locus by terminating calculation when scotoma was observed in 2 consecutive visits, was also calculated. In a subset of eyes with ≥1 scotomatous locus at baseline (Grid A), sensitivity progression of loci around the scotoma (edge of scotoma sensitivity [ESS]) was examined against other progression parameters. Paired t test compared progression rate parameters across the same eyes. Main Outcome Measures: Microperimetry grid parameters at baseline and progression rates. Results: A total of 37 subjects with biallelic ABCA4 mutations and >2 years of longitudinal microperimetry data were included in the study. In Grid A, at baseline, the average MS and RPS were 16.5 ± 7.9 and 19.1 ± 5.7 dB, respectively. Similar MS (18.4 ± 7.6 dB) and RPS (20.0 ± 5.5 dB) values were found at baseline for Grid B. In Grid A, overall, MS, RPS, and FCS progression rates were -0.57 ± 1.05, -0.74 ± 1.24, and -1.26 ± 1.65 (all dB/year), respectively. Floor censored sensitivity progression rate was significantly greater than the MS or RPS progression rates. Similar findings were observed in Grid B (MS -1.22 ± 1.42, RPS -1.44 ± 1.44, FCS -2.16 ± 2.24, all dB/year), with paired t test again demonstrated that FCS had a significantly faster rate of decline than MS or RPS. In patients with progression data in both grids, MS, RPS, and FCS progression rates were significantly faster in the smaller Grid B. In 24 eyes with scotoma at baseline, fastest rate of decline was ESS combined with FCS compared with other progression parameters. Conclusions: Incorporation of FCS can reduce confound of floor effect in perimetry analysis and can in turn detect a faster rate of decline. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Expanding the genotypic and phenotypic spectra with a novel variant in the ciliopathy gene, CFAP410, associated with selective cone degeneration.

BACKGROUND: CFAP410 (Cilia and Flagella Associated Protein 410) encodes a protein that has an important role in the development and function of cilia. In ophthalmology, pathogenic variants in CFAP410 have been described in association with cone rod dystrophy, retinitis pigmentosa, with or without macular staphyloma, or with systemic abnormalities such as skeletal dysplasia and amyotrophic lateral sclerosis. Herein, we report a consanguineous family with a novel homozygous CFAP410 c.335_346del variant with cone only degeneration and no systemic features. METHODS: A retrospective analysis of ophthalmic history, examination, retinal imaging, electrophysiology and microperimetry was performed as well as genetic testing with in silico pathogenicity predictions and a literature review. RESULTS: A systemically well 28-year-old female of Pakistani ethnicity with parental consanguinity and no relevant family history, presented with childhood-onset poor central vision and photophobia. Best-corrected visual acuity and colour vision were reduced (0.5 LogMAR, 6/17 Ishihara plates (right) and 0.6 LogMAR, 3/17 Ishihara plates (left). Fundus examination showed no pigmentary retinopathy, no macular staphyloma and autofluorescence was unremarkable. Optical coherence tomography showed subtle signs of intermittent disruption of the ellipsoid zone. Microperimetry demonstrated a reduction in central retinal sensitivity. Electrodiagnostic testing confirmed a reduction in cone-driven responses. Whole-genome sequencing identified an in-frame homozygous deletion of 12 base pairs at c.335_346del in CFAP410. CONCLUSIONS: The non-syndromic cone dystrophy phenotype reported herein expands the genotypic and phenotypic spectra of CFAP410-associated ciliopathies and highlights the need for light of potential future genetic therapies.

Development and child health in a world of synthetic chemicals.

Chemical pollution is one of today's most significant threats to the developmental potential of children worldwide. Maternal exposure to toxicants can perturb sensitive windows of fetal development, indirectly through promoting antenatal disorders, abnormal placental adaptation, or directly through maternal-fetal transport. Current evidence clearly shows that persistent organic chemicals promote hypertensive disorders of pregnancy, placental abnormalities, and fetal growth restriction, whereas findings are less consistent for phthalates and bisphenols. Prospective birth cohorts strongly support a link between adverse neurodevelopmental outcomes and prenatal exposure to flame retardants and organophosphate pesticides. Emerging evidence reveals a potential association between in utero exposure to bisphenols and childhood behavioral disorders, while childhood metabolic health is more consistently associated with postnatal exposure to phthalates and bisphenols. IMPACT: Synthesizes emerging evidence linking modern forms of chemical pollution to antenatal disorders, fetal growth restriction and childhood disorders. Highlights potential developmental impacts of emerging pollutants of concern now ubiquitous in our environment but without regulatory restrictions.

Non-syndromic OTX2-associated pattern dystrophy: a 10-year multimodal imaging study.

PURPOSE: To report novel multimodal imaging features and long-term follow-up of Orthodenticle Homeobox 2 (OTX2)-associated pattern Gdystrophy. METHODS: A 14-year-old boy referred with glaucoma suspect and macular pigmentation underwent fundus autofluorescence imaging, optical coherence tomography, fluorescein and indocyanine green angiography, visual field test, microperimetry and electrophysiology over a ten-year period. Next-generation sequencing panel identified a de novo heterozygous likely pathogenic OTX2 variant, c.259G>A, [p.(Glu87Lys)]. RESULTS: Visual acuity was 20/40 OD and 20/30 OS. Examination showed bilateral enlarged optic nerve heads and increased disc cupping, multiple cilioretinal arteries, a pigmentary maculopathy with stellate-shaped region of hypoautofluorescence, shallow serous macular detachment, subretinal deposits and temporal avascular retina. Angiography showed no source of leakage and absence of retinal neovascularisation despite extensive peripheral non perfusion. Electrophysiological assessments demonstrated mild progressive rod and cone pathway abnormalities, reduced light-adapted b:a ratio, and reduced Arden ratio on electro-oculogram. Ten-year follow-up confirmed a stable disease course despite persistent submacular fluid. There was no associated pituitary structural abnormality or dysfunction. CONCLUSIONS: This case study contributes to further understanding of OTX2-associated pattern dystrophy, highlighting its stability over 10 years. Further investigation into inter-individual and intrafamilial variability is warranted.

Generation of two induced pluripotent stem cell lines from an Usher syndrome type 1B patient with the homozygous c.496del MYO7A variant.

Usher syndrome (USH) is the most common cause of inherited deaf-blindness. Here, we produced the LEIi020-A and LEIi020-B induced pluripotent stem cell (iPSC) lines from dermal fibroblasts derived from a patient with USH1B caused by inheritance of homozygous c.496del variants in MYO7A using episomal plasmids encoding OCT4, SOX2, KLF4, L-MYC, LIN28, mir302/367 microRNA and shRNA for TP53. Both iPSC lines expressed pluripotency markers, demonstrated trilineage differentiation potential and displayed a 46,XY karyotype. These cell lines represent a valuable resource for the production of retinal and otic tissues to support research into the pathogenesis and treatment of USH1B.

Establishment of an induced pluripotent stem cell line LEIi019-A from an early-onset retinal dystrophy patient with the autosomal dominant OTX2 c.259G>A variant.

The human induced pluripotent stem cell (iPSC) line LEIi019-A was generated from a patient with early-onset pattern dystrophy caused by a heterozygous mutation NM_001270525.1:c.259G>A (p.Glu87Lys) in OTX2. Patient-derived dermal fibroblasts were reprogrammed using episomal plasmids containing reprogramming factors OCT4, SOX2, KLF4, MYCL, LIN28, TP53 shRNA and miR-302/367. The iPSC line expressed pluripotency markers, displayed a normal 46,XY karyotype and demonstrated the ability to differentiate into the three primary germ layers, retinal organoids and retinal pigment epithelial cells.

Retinal Characteristics of Female Choroideremia Carriers: Multimodal Imaging, Microperimetry, and Genetics.

PURPOSE: To describe visual function and retinal features of female carriers of choroideremia (CHM), using multimodal imaging and microperimetry. DESIGN: Cross-sectional cohort study. PARTICIPANTS AND CONTROLS: Choroideremia carriers seen in Australia (Melbourne or Perth) or the United Kingdom (Oxford or Cambridge) between 2012 and 2023. Healthy age-matched controls seen in Melbourne, Australia, between 2022 and 2023. METHODS: Participants had visual acuity, fundus-tracked microperimetry, OCT, and fundus autofluorescence imaging performed. Choroideremia carriers were either genetically or clinically confirmed (i.e., obligate carriers). Choroideremia carriers were grouped according to their retinal phenotype and compared with healthy controls. Statistical analyses were performed on StataBE (v18.0). MAIN OUTCOME MEASURES: Best-corrected visual acuity (BCVA), low-luminance visual acuity (LLVA), average retinal sensitivity, volume of macular hill of vision (HoV), inner retinal thickness, and photoreceptor complex (PRC) thickness. RESULTS: Eighty-six eyes of 43 CHM carriers and 60 eyes of 30 healthy controls were examined using multimodal imaging and microperimetry. Median age was 54 and 48.5 years for CHM carriers and controls, respectively (P = 0.18). Most CHM carriers (86%) were genetically confirmed. Choroideremia carriers and controls had strong intereye correlation between eyes for BCVA and average retinal sensitivity (P < 0.001). Low-luminance visual acuity and macular HoV tests were sensitive tests to detect changes in CHM carriers with mild phenotypes (i.e., fine and coarse). Choroideremia carriers with geographic or male-pattern phenotypes had reduced BCVA, LLVA, retinal sensitivity, and retinal thinning, compared with healthy controls. Retinal thickening of the inner retina was observed in the central 1°, despite generalized thinning of the PRC in the central 7°, indicating retinal remodeling in CHM carriers, compared with controls. There were no genotype-phenotype correlations observed. CONCLUSIONS: Female carriers of CHM with severe retinal phenotypes (i.e., geographic or male pattern) have significantly decreased visual function and retinal structural changes when compared with age-matched controls and those carriers with milder phenotypes. Low-luminance visual acuity and volumetric measures of the macular HoV were found to be the most sensitive functional tests to detect milder retinal disease (fine and coarse phenotypes) in CHM carriers. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Retinal Dystrophies Associated With Peripherin-2: Genetic Spectrum and Novel Clinical Observations in 241 Patients.

Purpose: To describe the clinical, electrophysiological and genetic spectrum of inherited retinal diseases associated with variants in the PRPH2 gene. Methods: A total of 241 patients from 168 families across 15 sites in 9 countries with pathogenic or likely pathogenic variants in PRPH2 were included. Records were reviewed for age at symptom onset, visual acuity, full-field ERG, fundus colour photography, fundus autofluorescence (FAF), and SD-OCT. Images were graded into six phenotypes. Statistical analyses were performed to determine genotype-phenotype correlations. Results: The median age at symptom onset was 40 years (range, 4-78 years). FAF phenotypes included normal (5%), butterfly pattern dystrophy, or vitelliform macular dystrophy (11%), central areolar choroidal dystrophy (28%), pseudo-Stargardt pattern dystrophy (41%), and retinitis pigmentosa (25%). Symptom onset was earlier in retinitis pigmentosa as compared with pseudo-Stargardt pattern dystrophy (34 vs 44 years; P = 0.004). The median visual acuity was 0.18 logMAR (interquartile range, 0-0.54 logMAR) and 0.18 logMAR (interquartile range 0-0.42 logMAR) in the right and left eyes, respectively. ERG showed a significantly reduced amplitude across all components (P < 0.001) and a peak time delay in the light-adapted 30-Hz flicker and single-flash b-wave (P < 0.001). Twenty-two variants were novel. The central areolar choroidal dystrophy phenotype was associated with 13 missense variants. The remaining variants showed marked phenotypic variability. Conclusions: We described six distinct FAF phenotypes associated with variants in the PRPH2 gene. One FAF phenotype may have multiple ERG phenotypes, demonstrating a discordance between structure and function. Given the vast spectrum of PRPH2 disease our findings are useful for future clinical trials.

Rapid Variant Pathogenicity Analysis by CRISPR Activation of CRB1 Gene Expression in Patient-Derived Fibroblasts.

Inherited retinal diseases (IRDs) are a heterogeneous group of blinding genetic disorders caused by pathogenic variants in genes expressed in the retina. In this study, we sought to develop a method for rapid evaluation of IRD gene variant pathogenicity by inducing expression of retinal genes in patient-derived fibroblasts using CRISPR-activation (CRISPRa). We demonstrate CRISPRa of CRB1 expression in fibroblasts derived from patients with retinitis pigmentosa, enabling investigation of pathogenic mechanisms associated with specific variants. We show the CRB1 c.4005 + 1G>A variant caused exon 11 skipping in CRISPR-activated fibroblasts and retinal organoids (ROs) derived from the same RP12 patient. The c.652 + 5G>C variant was shown to enhance exon 2 skipping in CRISPR-activated fibroblasts and differentially affected CRB1 isoform expression in fibroblasts and ROs. Our study demonstrates an accessible platform for transcript screening of IRD gene variants in patient-derived fibroblasts, which can potentially be applied for rapid pathogenicity assessments of any gene variant.

Assessing efficacy in non-inferiority trials with non-adherence to interventions: Are intention-to-treat and per-protocol analyses fit for purpose?

BACKGROUND: Non-inferiority trials comparing different active drugs are often subject to treatment non-adherence. Intention-to-treat (ITT) and per-protocol (PP) analyses have been advocated in such studies but are not guaranteed to be unbiased in the presence of differential non-adherence. METHODS: The REMoxTB trial evaluated two 4-month experimental regimens compared with a 6-month control regimen for newly diagnosed drug-susceptible TB. The primary endpoint was a composite unfavorable outcome of treatment failure or recurrence within 18 months post-randomization. We conducted a simulation study based on REMoxTB to assess the performance of statistical methods for handling non-adherence in non-inferiority trials, including: ITT and PP analyses, adjustment for observed adherence, multiple imputation (MI) of outcomes, inverse-probability-of-treatment weighting (IPTW), and a doubly-robust (DR) estimator. RESULTS: When non-adherence differed between trial arms, ITT, and PP analyses often resulted in non-trivial bias in the estimated treatment effect, which consequently under- or over-inflated the type I error rate. Adjustment for observed adherence led to similar issues, whereas the MI, IPTW and DR approaches were able to correct bias under most non-adherence scenarios; they could not always eliminate bias entirely in the presence of unobserved confounding. The IPTW and DR methods were generally unbiased and maintained desired type I error rates and statistical power. CONCLUSIONS: When non-adherence differs between trial arms, ITT and PP analyses can produce biased estimates of efficacy, potentially leading to the acceptance of inferior treatments or efficacious regimens being missed. IPTW and the DR estimator are relatively straightforward methods to supplement ITT and PP approaches.

NADPH oxidase 1 promotes hepatic steatosis in obese mice and is abrogated by augmented skeletal muscle mass.

Exercise as a lifestyle modification is a frontline therapy for nonalcoholic fatty liver disease (NAFLD), but how components of exercise attenuate steatosis is unclear. To uncouple the effect of increased muscle mass from weight loss in obesity, myostatin knockout mice were bred on a lean and obese db/db background. Myostatin deletion increases gastrocnemius (Gastrocn.) mass and reduces hepatic steatosis and hepatic sterol regulatory element binding protein 1 (Srebp1) expression in obese mice, with no impact on adiposity or body weight. Interestingly, hypermuscularity reduces hepatic NADPH oxidase 1 (Nox1) expression but not NADPH oxidase 4 (Nox4) in db/db mice. To evaluate a deterministic function of Nox1 on steatosis, Nox1 knockout mice were bred on a lean and db/db background. NOX1 deletion significantly attenuates hepatic oxidant stress, steatosis, and Srebp1 programming in obese mice to parallel hypermuscularity, with no improvement in adiposity, glucose control, or hypertriglyceridemia to suggest off-target effects. Directly assessing the role of NOX1 on SREBP1, insulin (Ins)-mediated SREBP1 expression was significantly increased in either NOX1, NADPH oxidase organizer 1 (NOXO1), and NADPH oxidase activator 1 (NOXA1) or NOX5-transfected HepG2 cells versus ?-galactosidase control virus, indicating superoxide is the key mechanistic agent for the actions of NOX1 on SREBP1. Metabolic Nox1 regulators were evaluated using physiological, genetic, and diet-induced animal models that modulated upstream glucose and insulin signaling, identifying hyperinsulinemia as the key metabolic derangement explaining Nox1-induced steatosis in obesity. GEO data revealed that hepatic NOX1 predicts steatosis in obese humans with biopsy-proven NAFLD. Taken together, these data suggest that hypermuscularity attenuates Srebp1 expression in db/db mice through a NOX1-dependent mechanism.NEW & NOTEWORTHY This study documents a novel mechanism by which changes in body composition, notably increased muscle mass, protect against fatty liver disease. This mechanism involves NADPH oxidase 1 (NOX1), an enzyme that increases superoxide and increases insulin signaling, leading to increased fat accumulation in the liver. NOX1 may represent a new early target for preventing fatty liver to stave off later liver diseases such as cirrhosis or liver cancer.

Potentiation of Adipogenesis by Reactive Oxygen Species Is a Unifying Mechanism in the Proadipogenic Properties of Bisphenol A and Its New Structural Analogues.

Aims: Structural analogues of bisphenol A (BPA), including bisphenol S (BPS) and bisphenol F (BPF), are emerging environmental toxicants as their presence in the environment is rising since new regulatory restrictions were placed on BPA-containing infant products. The adipogenesis-enhancing effect of bisphenols may explain the link between human exposure and metabolic disease; however, underlying molecular pathways remain unresolved. Results: Exposure to BPS, BPF, BPA, or reactive oxygen species (ROS) generators enhanced lipid droplet formation and expression of adipogenic markers after induction of differentiation in adipose-derived progenitors isolated from mice. RNAseq analysis in BPS-exposed progenitors revealed modulation in pathways regulating adipogenesis and responses to oxidative stress. ROS were higher in bisphenol-exposed cells, while cotreatment with antioxidants attenuated adipogenesis and abolished the effect of BPS. There was a loss of mitochondrial membrane potential in BPS-exposed cells and mitochondria-derived ROS contributed to the potentiation of adipogenesis by BPS and its analogues. Male mice exposed to BPS during gestation had higher whole-body adiposity, as measured by time domain nuclear magnetic resonance, while postnatal exposure had no impact on adiposity in either sex. Innovation: These findings support existing evidence showing a role for ROS in regulating adipocyte differentiation and are the first to highlight ROS as a unifying mechanism that explains the proadipogenic properties of BPA and its structural analogues. Conclusion: ROS act as signaling molecules in the regulation of adipocyte differentiation and mediate bisphenol-induced potentiation of adipogenesis. Antioxid. Redox Signal. 40, 1-15.

Analysis of the Outer Retinal Bands in ABCA4 and PRPH2-Associated Retinopathy using OCT.

PURPOSE: To evaluate the outer retinal bands using OCT in ABCA4- and PRPH2-associated retinopathy and develop a novel imaging biomarker to differentiate between these 2 genotypes. DESIGN: Multicenter case-control study. PARTICIPANTS: Patients with a clinical and genetic diagnosis of ABCA4- or PRPH2-associated retinopathy and an age-matched control group. METHODS: Macular OCT was used to measure the thickness of the outer retinal bands 2 and 4 by 2 independent examiners at 4 retinal loci. MAIN OUTCOME MEASURES: Outcome measures included the thicknesses of band 2, band 4, and the band 2/band 4 ratio. Linear mixed modeling was used to make comparisons across the 3 groups. Receiver operating characteristic (ROC) analysis determined the optimal cutoff for the band 2/band 4 ratio to distinguish PRPH2- from ABCA4-associated retinopathy. RESULTS: We included 45 patients with ABCA4 variants, 45 patients with PRPH2 variants, and 45 healthy controls. Band 2 was significantly thicker in patients with PRPH2 compared with ABCA4 (21.4 vs. 15.9 µm, P < 0.001) variants, whereas band 4 was thicker in patients with ABCA4 variants than those with PRPH2 variants (27.5 vs. 21.7 µm, P < 0.001). Similarly, the band 2/band 4 ratio was significantly different (1.0 vs. 0.6 for PRPH2 vs. ABCA4, P < 0.001). The area under the ROC curve was 0.87 for either band 2 (> 18.58 µm) or band 4 (< 26.17 µm) alone and 0.99 (95% confidence interval: 0.97-0.99) for the band 2/band 4 ratio with a cutoff threshold of 0.79, providing 100% specificity. CONCLUSIONS: We report an altered outer retinal band profile whereby the band 2/band 4 ratio was able to discriminate between PRPH2- and ABCA4-associated retinopathy. This may have future clinic utility in predicting the genotype and provide further insight into the anatomic correlate of band 2. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Cluster randomized controlled trial analysis at the cluster level: The clan command.

In this article, we introduce a new command, clan, that conducts a cluster-level analysis of cluster randomized trials. The command simplifies adjusting for individual- and cluster-level covariates and can also account for a stratified design. It can be used to analyze a continuous, binary, or rate outcome.

High maternal adiposity during pregnancy programs an imbalance in the lipidome and predisposes to diet-induced hepatosteatosis in the offspring.

BACKGROUND: Exposure to high maternal adiposity in utero is a significant risk factor for the later-life development of metabolic syndrome (MetS), including non-alcoholic fatty liver disease (NAFLD). We have previously shown that high pre-pregnancy adiposity programs adipose tissue dysfunction in the offspring, leading to spillover of fatty acids into the circulation, a key pathogenic event in obesity-associated MetS. Herein, we hypothesized that programming of adipose tissue dysfunction in offspring born to overweight dams increases the risk for developing NAFLD. RESULTS: Females heterozygous for leptin receptor deficiency (Hetdb) were used as a model of high pre-pregnancy adiposity. Female wild-type (Wt) offspring born to Hetdb pregnancies gained significantly more body fat following high-fat/fructose diet (HFFD) compared with Wt offspring born to Wt dams. HFFD increased circulating free fatty acids (FFA) in male offspring of control dams, while FFA levels were similar in HFFD-fed offspring from Wt dams and CD or HFFD-fed Wt offspring from Hetdb dams. Despite female-specific protection from diet-induced FFA spillover, both male and female offspring from Hetdb dams were more susceptible to diet-induced hepatosteatosis. Lipidomic analysis revealed that CD-offspring of overweight dams had decreased hepatic polyunsaturated FA (PUFA) levels compared with control offspring. Changes to saturated FA (SFA) and the de novo lipogenic (DNL) index were diet driven; however, there was a significant effect of the intrauterine environment on FA elongation and Δ9 desaturase activity. CONCLUSION: High maternal adiposity during pregnancy programs a susceptibility to diet-induced hepatosteatosis.

Driving with retinitis pigmentosa.

BACKGROUND: To establish the proportion of patients with retinitis pigmentosa (RP) meeting the Australian fitness to drive (FTD) visual standards. METHODOLOGY: A prospective consecutive case series of patients with a clinical or genetic diagnosis of RP. Data on age at symptom onset, current driving status, inheritance pattern, better eye visual acuity (BEVA), binocular Esterman visual field (BEVF) parameters, genotype and ability to meet the driving standards based on BEVA and BEVF were collected. Outcome measures included the proportion of RP patients overall meeting the standards and clinical predictors for passing. A sub-analysis was performed on those RP patients who reported to drive. Change in BEVA and BEVF parameters across age in specific genotype groups was assessed. RESULTS: Overall, 228 patients with RP had a BEVF assessment. Only 39% (89/228) met the driving standards. Younger age at the time of testing was the only significant predictor (p < 0.01) for passing. Of the 55% of RP patients who reported to drive, 52% (65/125) met the standards, decreasing to 14% in the 56- to 65-year-old age group. RP patients harbouring mutations in HK1 or RHO genes may have slower rates of decline in their VF parameters. CONCLUSION: Nearly 40% of RP patients met the driving standards. However, almost 50% of RP drivers were unaware of their failure to meet the current standards. BEVF testing is essential in the assessment of RP patients who are still driving. Phenotype and genotype predictors for passing the standards warrant further investigation.Abbreviation: FTD, fitness to drive; IRD, inherited retinal disease; RP, retinitis pigmentosa; RHO, rhodopsin; HK1, hexokinase 1; PRPF31 pre-mRNA processing factor 31; RPGR, retinitis pigmentosa GTPase regulator; VF, visual field; BEVA, better eye visual acuity; BEVF, binocular Esterman visual field.

Maternal obesity and programming of metabolic syndrome in the offspring: searching for mechanisms in the adipocyte progenitor pool.

BACKGROUND: It is now understood that it is the quality rather than the absolute amount of adipose tissue that confers risk for obesity-associated disease. Adipose-derived stem cells give rise to adipocytes during the developmental establishment of adipose depots. In adult depots, a reservoir of progenitors serves to replace adipocytes that have reached their lifespan and for recruitment to increase lipid buffering capacity under conditions of positive energy balance. MAIN: The adipose tissue expandability hypothesis posits that a failure in de novo differentiation of adipocytes limits lipid storage capacity and leads to spillover of lipids into the circulation, precipitating the onset of obesity-associated disease. Since adipose progenitors are specified to their fate during late fetal life, perturbations in the intrauterine environment may influence the rapid expansion of adipose depots that occurs in childhood or progenitor function in established adult depots. Neonates born to mothers with obesity or diabetes during pregnancy tend to have excessive adiposity at birth and are at increased risk for childhood adiposity and cardiometabolic disease. CONCLUSION: In this narrative review, we synthesize current knowledge in the fields of obesity and developmental biology together with literature from the field of the developmental origins of health and disease (DOHaD) to put forth the hypothesis that the intrauterine milieu of pregnancies complicated by maternal metabolic disease disturbs adipogenesis in the fetus, thereby accelerating the trajectory of adipose expansion in early postnatal life and predisposing to impaired adipose plasticity.

Microperimetry and Adaptive Optics Imaging Reveal Localized Functional and Structural Changes in Asymptomatic RPGR Mutation Carriers.

Purpose: Female carriers of RPGR mutations demonstrate no significant retinal dysfunction or structural change despite a characteristic tapetal-like reflex. In this study, we examined localized changes of pointwise sensitivity (PWS) and cone density (CD) using microperimetry (MP) and adaptive optics (AO) imaging in female carriers of RPGR mutations. Methods: In this cross-sectional case-control study, MP (MAIA, 10-2 test grid) and AO imaging (rtx1) were performed in female carriers of RPGR mutations and unrelated age-matched healthy controls. PWS at 68 loci located 1 degree to 9 degrees away from the preferred retinal locus and CD at 12 loci located 1 degree to 3 degrees away from the foveal center were measured. Severity of defect was defined by standard deviation (SD) from age-matched healthy control means: normal (<1 SD from normal average), moderate defect (1-2 SD from normal average), and severe defect (>2 SD from normal average). Results: Twelve patients from seven unrelated families were enrolled. Seven patients were asymptomatic, 5 of whom had visual acuity 20/20 or better in both eyes. PWS and CD were available in 12 and 8 patients, respectively. Severe PWS and CD defect in at least 1 test location was observed in 10 of 12 patients and 7 of 8 patients, respectively. Among the five asymptomatic patients who had normal visual acuity, severe PWS and CD defects were observed in three of five and four of five patients, respectively. Conclusions: MP and AO imaging revealed early functional and structural changes in asymptomatic RPGR mutation carriers and should be considered in clinical assessment of these patients.

Longitudinal Analysis of Functional and Structural Outcome Measures in PRPH2-Associated Retinal Dystrophy.

PURPOSE: To establish disease progression rates in total lesion size (TLS), decreased autofluorescence (DAF) area, total macular volume (TMV), and mean macular sensitivity (MMS) in PRPH2-associated retinal dystrophy. DESIGN: Single-center, retrospective chart review. PARTICIPANTS: Patients with heterozygous pathogenic or likely pathogenic PRPH2 variants. METHODS: Patients who underwent serial ultrawide-field (UWF) fundus autofluorescence (FAF), OCT, and Macular Integrity Assessment microperimetry with at least 1 year of follow-up were included. Linear correlation was performed in eyes of all patients to determine the rate of change over time. MAIN OUTCOME MEASURES: Outcome measures included changes in TLS, DAF area, TMV, and MMS. RESULTS: Twelve patients (mean age, 55) from 10 unrelated families attended 100 clinic visits, which spanned over a mean (SD) of 4.7 (2.0) years. Mean (SD) TLS and DAF radius expansion were 0.14 (0.12) and 0.10 (0.08) mm/year, respectively. Mean (SD) TMV change was -0.071 (0.040) mm3/year with no interocular difference (P = 0.20) and strong interocular correlation (r2 = 0.88, P < 0.01). Mean (SD) MMS change was -0.10 (1.25) dB/year. Mean macular sensitivity declined in 4 and improved in 6 patients. Mean macular sensitivity was subnormal despite a TMV within the normal range. CONCLUSIONS: Serial measurements of UWF-FAF-derived TLS and DAF showed slow expansion. Total macular volume might be a more sensitive measure than MMS in detecting disease progression.