Purpose: Mutations in Topoisomerase I-binding RS protein (TOPORS) have been previously documented and have been described to result in pathological autosomal dominant retinitis pigmentosa (adRP). In our study, we describe the various genotypes and clinical/phenotypic manifestations of TOPORS-related mutations of our unique patient population in Rural Appalachia. Methods: The medical records of 416 patients with inherited retinal disease at the West Virginia University Eye Institute who had undergone genetic testing between the years of 2015-2022 were reviewed. Patients found to have pathologic RP and mutations related to TOPORS were then analyzed. Results: In total, 7 patients (ages 12-70) were identified amongst three unique families. All patients were female in our study. The average follow-up period was 7.7 years. A mother (70 yr) and daughter (51 yr) had a novel heterozygous nonsense point mutation in TOPORS c.2431C > T, p.Gln811X (Exon 3) that led to premature termination of the desired protein resulting in early onset vision loss, cataract formation, and visual field restriction. The mother developed a full-thickness macular hole which was successfully repaired. Five other patients were found to have previously described TOPORS mutations. Visual field loss was progressive with age in both cohorts. Conclusions: Seven patients at our institution were identified to have mutations in TOPORS resulting in autosomal dominant retinitis pigmentosa. Two patients were found to have novel truncating mutations in the TOPORS gene resulting in profound night blindness and visual field loss, recurrent macular edema, and in one individual, epiretinal membrane formation leading to a macular hole which was able to be successfully repaired.

Retinitis pigmentosa 1-like 1 (RP1L1) is a component of photoreceptor cilia. Pathogenic variants in RP1L1 cause photoreceptor diseases, suggesting that RP1L1 plays an important role in photoreceptor biology, although its exact function is unknown. To date, RP1L1 variants have been associated with occult macular dystrophy (cone degeneration) and retinitis pigmentosa (rod degeneration). Here, we summarize the reported RP1L1-associated photoreceptor pathogenic mutations. The association between RP1L1 and other diseases (mainly several tumors) is also summarized and RP1L1 is included in a wider range of diseases. Finally, it is necessary to further explore the influence mechanism of RP1L1 gene on the health of photoreceptors and how it participates in the occurrence and development of tumors.

Blindness poses a growing global challenge, with approximately 26% of cases attributed to degenerative retinal diseases. While gene therapy, optogenetic tools, photosensitive switches, and retinal prostheses offer hope for vision restoration, these high-cost therapies will benefit few patients. Understanding retinal diseases is therefore key to advance effective treatments, requiring in vitro models replicating pathology and allowing quantitative assessments for drug discovery. Pluripotent stem cells (PSCs) provide a unique solution given their limitless supply and ability to differentiate into light-responsive retinal tissues encompassing all cell types. This review focuses on the history and current state of photoreceptor and retinal pigment epithelium (RPE) cell generation from PSCs. We explore the applications of this technology in disease modelling, experimental therapy testing, biomarker identification, and toxicity studies. We consider challenges in scalability, standardisation, and reproducibility, and stress the importance of incorporating vasculature and immune cells into retinal organoids. We advocate for high-throughput automation in data acquisition and analyses and underscore the value of advanced micro-physiological systems that fully capture the interactions between the neural retina, RPE, and choriocapillaris.

OBJECTIVE: To report visual acuity (VA) outcomes, intraoperative and postoperative complications of isolated cataract surgery in eyes with retinitis pigmentosa (RP), compared with non-RP-affected eyes.
METHODS: Retrospective clinical cohort study.
METHODS: A total of 113,389 eyes underwent cataract surgery between July 2003 and March 2015 at 8 clinical sites in the United Kingdom. Eyes with RP as the only comorbid pathology and eyes without any ocular comorbidities (controls) undergoing cataract surgery were compared. VA at 4 to 12 weeks postoperatively and rates of intraoperative and postoperative complications are reported.
RESULTS: Seventy-two eyes had RP. The mean age in the RP group was 57 ± 15 compared to 75 ± 10 in controls (P < .001). Females represented 46% of RP cases and 60% of controls (P = .06). Preoperative VA (mean LogMAR = 1.03 vs 0.59, P < .001) and postoperative VA (0.71 vs 0.14, P < .001) were worse in RP group. The mean VA gain was 0.25 ± 0.60 LogMAR in RP vs 0.43 ± 0.48 LogMAR in controls (P < .001). There were no significant differences in the rate of intraoperative pupil expansion use, posterior capsular tears, or zonular dialysis. Postoperative cystoid macular edema developed in 6.9% of RP eyes and 1% of controls (P < .001). The need for IOL repositioning or exchange was not statistically different between the two groups.
CONCLUSIONS: Cataract surgery can improve vision in eyes with RP and cataract. Intraoperative complications were similar to control eyes; however, RP eyes experienced more frequent postoperative cystoid macular edema.

MFSD7b belongs to the Major Facilitator Superfamily of transporters that transport small molecules. Two isoforms of MFSD7b have been identified and they are reported to be heme exporters that play a crucial role in maintaining the cytosolic and mitochondrial heme levels, respectively. Mutations of MFSD7b (also known as FLVCR1) have been linked to retinitis pigmentosa, posterior column ataxia, and hereditary sensory and autonomic neuropathy. Although MFSD7b functions have been linked to heme detoxification by exporting excess heme from erythroid cells, it is ubiquitously expressed with a high level in the kidney, gastrointestinal tract, lungs, liver, and brain. Here, we showed that MFSD7b functions as a facilitative choline transporter. Expression of MFSD7b slightly but significantly increased choline import, while its knockdown reduced choline influx in mammalian cells. The influx of choline transported by MFSD7b is dependent on the expression of choline metabolizing enzymes such as choline kinase (CHKA) and intracellular choline levels, but it is independent of gradient of cations. Additionally, we showed that choline transport function of Mfsd7b is conserved from fly to man. Employing our transport assays, we showed that missense mutations of MFSD7b caused reduced choline transport functions. Our results show that MFSD7b functions as a facilitative choline transporter in mammalian cells.

UNASSIGNED: Calcitonin gene-related peptide (CGRP) antagonists are recently approved for the treatment of migraine.
UNASSIGNED: The main aim of the current study was to find out the association of CGRP antagonists with RP using data mining algorithms integrated with network pharmacological approaches.
UNASSIGNED: The individual case safety reports were extracted using OpenVigil2.1-MedDRA-V17 (2004Q1-2022Q3), the United States Adverse Event Reporting System (US FAERS). The data mining algorithms i.e. reporting odds ratio (ROR) with 95% confidence and proportionality reporting ratio (PRR) with associated chi-square value were calculated along with a minimum of three ICSRs to identify the signal. Further, the network was constructed using Cytoscape 3.7.2. Finally, molecular docking was performed using Glide, Schrodinger Inc.
UNASSIGNED: The PRR ≥2 with a linked chi-square value ≥4, add up of co-occurrence ≥3, and a lower limit of 95% confidence interval of ROR exceeding 2 indicates a positive signal of RP. Further, the network pharmacological and molecular docking results have shown the involvement of insulin-like growth factor 1-receptor (IGF1R) pathways.
UNASSIGNED: The RP is recognized as a novel signal with all CGRP antagonists.

OBJECTIVE: Assessment of construct validity and reliability of a novel patient-reported outcome (PRO) instrument for assessing the severity and impact of RP in SSc.
METHODS: An international multicentre study validation study of the 27-item Assessment of Systemic Sclerosis-Associated Raynaud\'s Phenomenon (ASRAP) and 10-item short-form (ASRAP-SF) questionnaires. The relationship between ASRAP questionnaires and demographics, clinical phenotype and legacy instruments for assessing SSc-RP severity, disability and pain was assessed. Repeatability was evaluated at 1 week. Anchor-based statements of health status facilitated assessment of ASRAP thresholds of meaning.
RESULTS: A total of 420 SSc subjects were enrolled. There was good correlation between ASRAP (and ASRAP-SF) with RP visual analogue scale (VAS) and Scleroderma Health Assessment Questionnaire RP VAS (rho range 0.648-0.727, P < 0.001). Correlation with diary-based assessment of SSc-RP attack frequency and duration was lower (rho range 0.258-0.504, P < 0.001). ASRAP questionnaires had good correlation with instruments for assessing disability, hand function, pain and global health assessment (rho range 0.427-0.575, P < 0.001). Significantly higher ASRAP scores were identified in smokers, patients with active digital ulceration (DU), previous history of DU and calcinosis (P < 0.05 for all comparisons). There was excellent repeatability at 1 week among patients with stable SSc-RP symptoms (intra-class coefficients of 0.891 and 0.848, P < 0.001). Patient-acceptable symptom state thresholds for ASRAP and ASRAP-SF were 45.34 and 45.77, respectively. A preliminary Minimally Important Clinical Difference threshold of 4.17 (95% CI 0.53, 7.81, P = 0.029) was estimated.
CONCLUSIONS: ASRAP and ASRAP-SF questionnaires are valid and reliable novel PRO instruments for assessing the severity and impact of SSc-RP.

OBJECTIVE: Measurement of digital perfusion, sometimes coupled with a cold challenge, has been widely used as an objective outcome in trials evaluating drug therapies in RP, in addition to patient-reported outcomes or to establish the proof-of-concept in preliminary studies. However, whether digital perfusion is a valid surrogate for clinical outcomes in RP trials has never been explored. The principal aim of this study was to evaluate the potential surrogacy of digital perfusion, by combining individual-level and trial-level data.
METHODS: We used individual data from a series of n-of-1 trials, and trial data from a network meta-analysis. We estimated individual-level surrogacy through coefficients of determination between digital perfusion and clinical outcomes (R2ind). We further calculated the coefficients of determination between treatment effect on the clinical outcomes and on digital perfusion, at the individual level (R2TEind) and at the trial level (R2trial), using non-weighted linear regression, with their 95% CI calculated through bootstrapping.
RESULTS: Results from 33 patients and 24 trials were included in the final analysis. At the individual level, there was no correlation between digital perfusion and clinical outcomes at rest and in response to various cooling tests (the highest R2ind was 0.03 [-0.07, 0.09]), and R2TEind was also very low 0.07 (0, 0.29). At the trial level, the highest value of R2trial was 0.1 (0, 0.477).
CONCLUSIONS: Digital perfusion, at rest or in response to a cold challenge, and whatever the method used, does not fulfil the criteria of a valid surrogate for existing patient-reported outcomes in RP trials.

We report the synthesis of Sr1·875Ce0·025CoO4-δ and Sr1·875Ce0·025Co0·75Ni0·25O4+δ for the first time, each compound was synthesised using Co-precipitation and Sol-Gel methods, at 1050 °C for 144 and 120 h respectively. Oxygen stoichiometry was determined using Iodometric titration, we have noticed oxygen hypostoichiometry for Ce-doped compound and hyperstoichiometry state after Ni-doping. Electrical properties were studied for sintered pellets, Electrical resistance was measured in the range (-0.5-+0.5 v). Specific electrical resistivity and electrical conductivity were calculated from resistance measurements. It was found that the Ce-doped compound has about three times higher conductivity (σC1 = 0.000000058423295 s cm-1) Compared with the Ni-doped one (σN2 = 0.000000022384787 s cm-1). Electrical Capacitance was measured at 1 kHz frequency, the relative dielectric constant εr, and the loss tangent tanδ were calculated accordingly. The results showed that the Ni-doped compound has higher capacitance but lower εr and dissipation factor values.

UNASSIGNED: SSc is a CTD characterized by excessive fibrosis of the skin and internal organs, along with microvascular damage, and is often associated with typical autoantibodies. The aim of this study was to analyse the correlation between specific autoantibody profiles, clinical and paraclinical features in Moroccan patients with SSc.
UNASSIGNED: We analysed the presence of specific autoantibodies in 46 SSc patients using IIF on HEp-2 cells and immunodot. We then correlated the types of autoantibodies with clinical and laboratory manifestations.
UNASSIGNED: Among our patients, 86.9% were females. The mean age of patients at diagnosis was 50.21 years, with an average delay to diagnosis of 5 years. The main clinical manifestations found were RP (89.2%), sclerodactyly (84.8%), proximal scleroderma (67.4%), gastrointestinal involvement (50%) and interstitial lung disease (30.4%). According to the specific autoantibody profile, 14 patients were anti-topo I positive (30.4%), 8 anti-RNP (68 kDa/A/C) positive (17.4%) and 6 anti-RNA polymerase III positive (13%). We found a significant association of anti-RNA polymerase III with sclerodactyly and pulmonary arterial hypertension (P < 0.05). We also found an association between anti-topo I and interstitial lung disease in 30.4% of patients. There was no significant association between the positivity for the autoantibodies and other diagnosed clinical manifestations.
UNASSIGNED: Some clinical manifestations of SSc might be positively correlated with the presence of specific autoantibodies. Environmental factors, ethnicity and gene interaction might also influence this correlation.