CTNNA1-associated retinal dystrophy: novel multimodal imaging and electrophysiology features.

Purpose: To describe multimodal imaging and electrophysiology features of CTNNA1-associated retinal dystrophy in a family with p.(Leu318Ser) substitution.

Methods: Three family members including a 48-year-old male proband, his 52-year-old sister, and their 67-year-old mother, were evaluated with multimodal imaging and electrophysiology.

Interleukin-6 from the adipose secretome potentiates differentiation of adipose progenitors through the activation of redox signaling.

Under obesogenic conditions, it is thought that a signal arising from the adipose microenvironment triggers differentiation of adipose progenitor cells (APCs); yet the identity and source of this signal remain unknown. Redox signaling was shown to influence adipogenesis in primary murine APCs treated with pharmacological agents to manipulate the levels of reactive oxygen species (ROS). Increased generation of superoxide ([Formula: see text]) and hydrogen peroxide (HO) via redox cyclers amplified APC differentiation, while differentiation was blunted with ROS scavengers and antioxidants.

Generation of the induced pluripotent stem cell line LEIi023-A from a rod-cone dystrophy patient carrying the dominant PRPF31 c.267del variant.

The human induced pluripotent stem cell line LEIi023-A was generated from a 51-year-old female patient with retinitis pigmentosa 11 (RP11) caused by a single nucleotide deletion in the PRPF31 gene, (NM 015629.3: c.267del, p.

Generation of two induced pluripotent stem cell lines carrying the CDH23 c.1515-12G > A variant.

Autosomal recessive Usher syndrome (USH) is the most common inherited deaf-blindness disease, affecting one in 30,000 people worldwide.Here, we established two lines of induced pluripotent stem cells (iPSC) from a 48-year-old male carrier of a heterozygous NM_022124.6: c.

ROSAH syndrome presenting with recurrent vitreous hemorrhage: a multimodal imaging study.

Background: ROSAH syndrome is an autosomal dominant systemic disease featuring etinal dystrophy, ptic nerve edema, plenomegaly, nhidrosis and migrainous eadache. Ocular manifestation of ROSAH syndrome can simulate posterior uveitis, vasculitis, generalized retinal dystrophy and neuroretinitis.

Purpose: To report a case of a 17-year-old female presenting with recurrent vitreous hemorrhage on a background of dental anomalies and anhidrosis.

Guidelines for the content of statistical analysis plans in clinical trials: protocol for an extension to cluster randomized trials.

Background: Guidance exists to inform the content of statistical analysis plans in clinical trials. Though not explicitly stated, this guidance is generally focused on clinical trials in which the randomization units are individual patients and not groups of patients. There are critical considerations for the analysis of cluster randomized trials, such as accounting for clustering, the risk of imbalances between the arms due to post-randomization recruitment, and the need to use small sample corrections when the number of clusters is small.

Retinal Disease Variability in Female Carriers of Variants Associated with Retinitis Pigmentosa: Clinical and Genetic Parameters.

We sought to investigate the visual function, retinal features, and genotype-phenotype correlations of an Australian cohort of carriers. In this cross-sectional study, we evaluated carriers seen in Melbourne and Perth between 2013 and 2023 and healthy women seen between 2022 and 2023 in Melbourne. Visual acuity tests, fundus-tracked microperimetry, and retinal imaging were performed.

Adipose Tissue Stromal Cells: Rheostats for Adipose Tissue Function and Metabolic Disease Risk.

The transition from metabolically healthy obesity to the development of obesity-associated metabolic syndrome and cardiovascular disease is thought to be triggered by a loss in the functional integrity of adipose tissue. Although mature adipocytes are the primary functional units that carry out lipid partitioning in adipose tissue for the promotion of whole-body energy balance, they are supported by a heterogenous collection of nonadipocytes in the stroma. Research over the past couple of decades has expanded perspectives on the homeostatic and pathological roles of the nonadipocyte compartment.

Elevated Plasma Complement Factors in CRB1-Associated Inherited Retinal Dystrophies.

Purpose: To determine the profile of inflammation-related proteins and complement system factors in the plasma of CRB1-associated inherited retinal dystrophies (CRB1-IRDs).

Methods: We used the Olink Explore 384 Inflammation II panel for targeted proteomics in 30 cases and 29 controls (cohort I) to identify immune pathways involved in CRB1-IRDs. Genotyping was performed in cohort I and a second cohort of 123 patients from 14 countries and 1292 controls (cohort II).

Longitudinal Assessment of Structural and Functional Changes in Rod-cone Dystrophy: A 10-year Follow-up Study.

Purpose: Emerging clinical trials for inherited retinal disease (IRD) require an understanding of long-term progression. This longitudinal study investigated the genetic diagnosis and change in retinal structure and function over 10 years in rod-cone dystrophies (RCDs).

Design: Longitudinal observational follow-up study.

Re-analysis of data from cluster randomised trials to explore the impact of model choice on estimates of odds ratios: study protocol.

Background: There are numerous approaches available to analyse data from cluster randomised trials. These include cluster-level summary methods and individual-level methods accounting for clustering, such as generalised estimating equations and generalised linear mixed models. There has been much methodological work showing that estimates of treatment effects can vary depending on the choice of approach, particularly when estimating odds ratios, essentially because the different approaches target different estimands.

Derivation of two induced pluripotent stem cell lines from a healthy control subject.

Two human induced pluripotent stem cell lines, LEIi021-A and LEIi021-B, were derived from dermal fibroblasts from a healthy control subject from an Australian Aboriginal family with retinitis pigmentosa-11. Reprogramming was performed using episomal vectors expressing OCT4, SOX2, LIN28, L-MYC, KLF4 and mp53DD. Pluripotency markers were expressed in both LEIi021-A and LEIi021-B lines.

Identification of novel 3D-genome altering and complex structural variants underlying retinitis pigmentosa type 17 through a multistep and high-throughput approach.

Introduction: Autosomal dominant retinitis pigmentosa type 17 (adRP, type RP17) is caused by complex structural variants (SVs) affecting a locus on chromosome 17 (chr17q22). The SVs disrupt the 3D regulatory landscape by altering the topologically associating domain (TAD) structure of the locus, creating novel TAD structures (neo-TADs) and ectopic enhancer-gene contacts. Currently, screening for RP17-associated SVs is not included in routine diagnostics given the complexity of the variants and a lack of cost-effective detection methods.

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.

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

Background: (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 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 c.

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.

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.

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.

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.

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.

Rapid Variant Pathogenicity Analysis by CRISPR Activation of 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 expression in fibroblasts derived from patients with retinitis pigmentosa, enabling investigation of pathogenic mechanisms associated with specific variants.

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.

Towards Uncovering the Role of Incomplete Penetrance in Maculopathies through Sequencing of 105 Disease-Associated Genes.

Inherited macular dystrophies (iMDs) are a group of genetic disorders, which affect the central region of the retina. To investigate the genetic basis of iMDs, we used single-molecule Molecular Inversion Probes to sequence 105 maculopathy-associated genes in 1352 patients diagnosed with iMDs. Within this cohort, 39.