Simultaneous Detection of Common Founder Mutations Using a Cost-Effective Deep Sequencing Panel.

Inherited retinal diseases (IRDs) are a clinically and genetically heterogeneous group of diseases which cause visual loss due to Mendelian mutations in over 250 genes, making genetic diagnosis challenging and time-consuming. Here, we developed a new tool, CDIP (Cost-effective Deep-sequencing IRD Panel) in which a simultaneous sequencing of common mutations is performed. CDIP is based on simultaneous amplification of 47 amplicons harboring common mutations followed by next-generation sequencing (NGS). Following five rounds of calibration of NGS-based steps, CDIP was used in 740 IRD samples. The analysis revealed 151 mutations in 131 index cases. In 54 (7%) of these cases, CDIP identified the genetic cause of disease (the remaining were single-heterozygous recessive mutations). These include a patient that was clinically diagnosed with retinoschisis and found to be homozygous for NR2E3-c.932G>A (p.R311Q), and a patient with RP who is hemizygous for an RPGR variant, c.292C>A (p.H98N), which was not included in the analysis but is located in proximity to one of these mutations. CDIP is a cost-effective deep sequencing panel for simultaneous detection of common founder mutations. This protocol can be implemented for additional populations as well as additional inherited diseases, and mainly in populations with strong founder effects.

Ophthalmology Residents' Experience in Cataract Surgery: Preoperative Risk Factors, Intraoperative Complications, and Surgical Outcomes.

INTRODUCTION: This retrospective study explores the connection between preoperative patient risk factors, the experience of ophthalmology residents, and the outcomes of cataract surgeries performed at Hadassah Medical Center. It is hypothesized that with increased experience, residents may demonstrate greater proficiency in handling surgeries on higher-risk patients, potentially leading to improved surgical outcomes overall. METHODS: Data were examined from 691 consecutive cataract surgeries in 590 patients, conducted by ophthalmology residents at Hadassah Medical Center (January 2018 to February 2022). Demographics, surgeon experience, preoperative cataract risk assessment score, and pre- and postoperative corrected distance visual acuity (CDVA) were analyzed. The risk score was based on cataract density, previous vitrectomy, presence of phacodonesis, small pupil, extreme axial length (> 30 mm or < 21.5 mm) or abnormal axial length (26-30 mm), shallow anterior chamber (< 2.5 mm), poor patient cooperation, oral alpha-1 blocker use, diabetic retinopathy (DR), Fuchs endothelial dystrophy, and having one functioning eye. This study focused on the correlation of risk scores with residents' surgical experience and surgical outcomes. RESULTS: As residents gained experience, surgeries on patients with at least one risk factor increased from 54% (first year) to 75% (second year; p < 0.001) and fluctuated between 75%, 82%, and 77% (third, fourth, and fifth years, respectively), with initial preoperative CDVA declining progressively. Despite handling more complex cases over time, the percentage of intraoperative complications per patient decreased with each year of residents' experience (17%, 13%, 11%, 17%, 6%; respectively). Patients without any risk factor had higher postoperative CDVA than those with one or more risk factors (mean ± standard deviation [SD] in logMAR, 0.16 ± 0.26 vs. 0.27 ± 0.35; p < 0.001) and a higher percentage of CDVA improvement (63% vs. 57%, p = 0.016). CONCLUSIONS: The use of a preoperative risk assessment scoring system to allocate surgeries to residents at varying experience levels may reduce the risk for surgical complications, thereby ensuring patient safety and providing residents with a gradual learning experience.

Development and Evaluation of a New Self-Administered Near Visual Acuity Chart: Accuracy and Feasibility of Usage.

Background: Visual acuity (VA) assessments are crucial in ophthalmology but traditionally rely on in-clinic evaluations. The emergence of telemedicine has spurred interest in creating dependable self-administered VA tests for use beyond standard clinical environments. This study evaluated the practicality and validity of a self-administered near VA card test against traditional Snellen and Rosenbaum Pocket Vision Screener (RPVS) methods for home monitoring and enhancing clinical workflow. Methods: In a cross-sectional study, a near VA card (Hadassah Self-Visual Acuity Screener (HSVA)) was developed with written and videotaped instructions for self-use. Patients with a minimal best-corrected VA (BCVA) of 1.0 LogMAR in at least one eye were recruited from ophthalmology and optometry clinics. Outcomes included the mean BCVA difference between the self-administered values and those obtained by the examiner, and correlations between BCVA values obtained by the Snellen, RPVS, HSVA, and previous distance BCVA methods according to the patients' electronic medical records. Results: A total of 275 participants (mean age: 42.5 ± 19.4 years; range: 18-89 years; 47% female) were included. Test-retest reliability analysis of the HSVA demonstrated a very good correlation and repeatability (n = 38 patients; Rs = 1.0; p < 0.001). Accuracy analysis revealed the mean LogMAR BCVA values of an additional 237 patients obtained by the Snellen, RPVS, and HSVA methods were similar (p = 0.10). The self-test BCVA results obtained by the HSVA agreed with the masked examiner-tested VA results (n = 67 patients; p = 0.17; Rs = 0.87; ICC = 0.96). Similar results were obtained when stratification by median age (42 years) was performed. Bland-Altman analysis of the HSVA and RPVS methods demonstrated a good agreement. To assess whether the HSVA could predict the VA results in the clinically used charts, multivariate analysis was used and revealed that the HSVA predicted the RPVS results (ß = 0.91; p = 0.001; R2 = 0.88), and the self-test HSVA predicted the Snellen VA results within two lines (ß = 0.93; p = 0.01; R2 = 0.36). Conclusions: The home-based HSVA assessment exhibited high test-retest reliability, accuracy, and alignment with clinical-standard VA tests. Its efficacy in self-testing mirrored examiner-conducted VA assessments and accurately predicted Snellen VA outcomes, indicating the HSVA's suitability for self-monitoring in chronic ocular conditions or when access to conventional examinations is limited. The utility of self-administered VA tests may extend beyond ophthalmology and optometry, potentially benefiting primary care, emergency medicine, and neurology. Further research is needed to explore and validate the practical applications of remote VA testing.

An automated process for bulk downloading optical coherence tomography scans.

OBJECTIVE: To develop an automated method for efficiently downloading a large number of optical coherence tomography (OCT) scans obtained using the Heidelberg Spectralis (Heidelberg Engineering, Heidelberg, Germany) platform. METHODS: The electronic medical records and OCT scans were extracted for all patients with age-related macular degeneration treated at the Hadassah University Hospital Retina Clinic between 2010 and 2021. A macro was created using Visual Basic for Applications (VBA) and Microsoft Excel to automate the export process and anonymize the OCT scans in accordance with hospital policy. OCT scans were extracted as proprietary Heidelberg E2E files. RESULTS: The VBA macro was used to export a total of 94,789 E2E files from 2807 patient records, with an average processing time of 4.32 min per volume scan (SD: 3.57 min). The entire export process took a total of approximately 202 h to complete over a period of 24 days. In a smaller sample, using the macro to download the scans was significantly faster than manually downloading the scans, averaging 3.88 vs. 11.08 min/file, respectively (t = 8.59, p < 0.001). Finally, we found that exporting the files during both off-clinic and working hours resulted in significantly faster processing times compared to exporting the files solely during working hours (t = 5.77, p < 0.001). CONCLUSIONS: This study demonstrates the feasibility of using VBA and Excel to automate the process for bulk downloading data from a specific medical imaging platform. The specific steps and techniques will likely vary depending on the software used and hospital constraints and should be determined for each application.

Best Disease: Global Mutations Review, Genotype-Phenotype Correlation, and Prevalence Analysis in the Israeli Population.

Purpose: To review all reported disease-causing mutations in BEST1, perform genotype-phenotype correlation, and estimate disease prevalence in the Israeli population. Methods: Medical records of patients diagnosed with Best disease and allied diseases from nine Israeli medical centers over the past 20 years were collected, as were clinical data including ocular findings, electrophysiology results, and retina imaging. Mutation detection involved mainly whole exome sequencing and candidate gene analysis. Demographic data were obtained from the Israeli Bureau of Statistics (January 2023). A bibliometric study was also conducted to gather mutation data from online sources. Results: A total of 134 patients were clinically diagnosed with Best disease and related conditions. The estimated prevalence of Best disease was calculated to be 1 in 127,000, with higher rates among Arab Muslims (1 in 76,000) than Jews (1 in 145,000). Genetic causes were identified in 76 individuals (57%), primarily showing autosomal-dominant inheritance due to BEST1 mutations (58 patients). Critical conserved domains were identified consisting of a high percentage of dominant missense mutations, primarily in transmembrane domains and the intracellular region (Ca2+ binding domain) of the BEST1 protein. Conclusions: This study represents the largest cohort of patients with Best disease reported in Israel and globally. The prevalence in Israel is akin to that in Denmark but is lower than that in the United States. Critical conserved domains within the BEST1 protein are pivotal for normal functioning, and even minor missense alterations in these areas lead to a dominant disease manifestation. Genetic testing is indispensable as the gold standard for Best disease diagnosis due to the variable clinical presentation of the disease.

Whole exome sequencing of 491 individuals with inherited retinal diseases reveals a large spectrum of variants and identification of novel candidate genes.

BACKGROUND: Inherited retinal diseases (IRDs) include a range of vision loss conditions caused by variants in different genes. The clinical and genetic heterogeneity make identification of the genetic cause challenging. Here, a cohort of 491 unsolved cases from our cohort of Israeli and Palestinian families with IRDs underwent whole exome sequencing (WES), including detection of CNVs as well as single nucleotide variants (SNVs). METHODS: All participants underwent clinical examinations. Following WES on DNA samples by 3 billion, initial SNV analysis was performed by 3 billion and SNV and CNV analysis by Franklin Genoox. The CNVs indicated by the programme were confirmed by PCR followed by gel electrophoresis. RESULTS: WES of 491 IRD cases revealed the genetic cause of disease in 51% of cases, of which 11% were due wholly or in part to CNVs. In two cases, we clarified previously incorrect or unclear clinical diagnoses. This analysis also identified ESRRB and DNM1 as potential novel genes. CONCLUSION: This analysis is the most extensive one to include CNVs to examine IRD causing genes in the Israeli and Palestinian populations. It has allowed us to identify the causative variant of many patients with IRDs including ones with unclear diagnoses and potential novel genes.

Effect of mydriasis on chord mu value in cataract surgery candidates.

PURPOSE: This study investigates the relationship between pupil size during biometry examinations and the chord mu value in candidates for cataract surgery. METHODS: Retrospective analysis of ocular biometry measurements was performed on consecutive cataract surgery candidates above 50 years of age, examined between 2018 and 2020 at a single tertiary referral center. Statistical analysis assessed the association between pupil size and the chord mu value. The population was categorized into groups based on pupil size, and an analysis was conducted on the barycenter positions of the iris and pupil center for each group. RESULTS: The analysis included 2877 patients. A weak positive correlation was observed between the chord mu value and pupil size using Pearson's test (r = 0.160, p < 0.01). Group stratification by pupil size indicated temporal and inferior shifts in pupil center barycenter as pupil size increased, reflecting asymmetrical pupil dilation during mydriasis. A moderate positive correlation between the chord mu value and chord alpha value was identified (Pearson's test, r = 0.641, p < 0.01). As expected, no correlation was found between chord alpha value and pupil size. CONCLUSIONS: Chord mu values were higher in patients with mydriatic pupils, likely due to asymmetric pupil dilation and center displacement. Evaluating chord mu values requires considering pupil status and conducting biometry under standardized lighting to prevent misinterpretation caused by pharmacological dilation. This caution is crucial to avoid erroneously excluding eligible patients from multifocal IOL implants. Alternatively, the chord alpha value could serve as a more appropriate alternative in such scenarios.

CCR1 mediates Müller cell activation and photoreceptor cell death in macular and retinal degeneration.

Mononuclear cells are involved in the pathogenesis of retinal diseases, including age-related macular degeneration (AMD). Here, we examined the mechanisms that underlie macrophage-driven retinal cell death. Monocytes were extracted from patients with AMD and differentiated into macrophages (hMdɸs), which were characterized based on proteomics, gene expression, and ex vivo and in vivo properties. Using bioinformatics, we identified the signaling pathway involved in macrophage-driven retinal cell death, and we assessed the therapeutic potential of targeting this pathway. We found that M2a hMdɸs were associated with retinal cell death in retinal explants and following adoptive transfer in a photic injury model. Moreover, M2a hMdɸs express several CCRI (C-C chemokine receptor type 1) ligands. Importantly, CCR1 was upregulated in Müller cells in models of retinal injury and aging, and CCR1 expression was correlated with retinal damage. Lastly, inhibiting CCR1 reduced photic-induced retinal damage, photoreceptor cell apoptosis, and retinal inflammation. These data suggest that hMdɸs, CCR1, and Müller cells work together to drive retinal and macular degeneration, suggesting that CCR1 may serve as a target for treating these sight-threatening conditions.

Genome-wide association study and genomic risk prediction of age-related macular degeneration in Israel.

Purpose: The risk of developing age-related macular degeneration(AMD) is influenced by genetic background. In 2016, International AMD Genomics Consortium(IAMDGC) identified 52 risk variants in 34 loci, and a polygenic risk score(PRS) based on these variants was associated with AMD. The Israeli population has a unique genetic composition: Ashkenazi Jewish(AJ), Jewish non-Ashkenazi, and Arab sub-populations. We aimed to perform a genome-wide association study(GWAS) for AMD in Israel, and to evaluate PRSs for AMD. Methods: For our discovery set, we recruited 403 AMD patients and 256 controls at Hadassah Medical Center. We genotyped all individuals via custom exome chip. We imputed non-typed variants using cosmopolitan and AJ reference panels. We recruited additional 155 cases and 69 controls for validation. To evaluate predictive power of PRSs for AMD, we used IAMDGC summary statistics excluding our study and developed PRSs via either clumping/thresholding or LDpred2. Results: In our discovery set, 31/34 loci previously reported by the IAMDGC were AMD associated with P<0.05. Of those, all effects were directionally consistent with the IAMDGC and 11 loci had a p-value under Bonferroni-corrected threshold(0.05/34=0.0015). At a threshold of 5x10 -5 , we discovered four suggestive associations in FAM189A1 , IGDCC4 , C7orf50 , and CNTNAP4 . However, only the FAM189A1 variant was AMD associated in the replication cohort after Bonferroni-correction. A prediction model including LDpred2-based PRS and other covariates had an AUC of 0.82(95%CI:0.79-0.85) and performed better than a covariates-only model(P=5.1x10 -9 ). Conclusions: Previously reported AMD-associated loci were nominally associated with AMD in Israel. A PRS developed based on a large international study is predictive in Israeli populations.

Subretinal autofluorescent deposits: A review and proposal for clinical classification.

Subretinal autofluorescent deposits (SADs) may be found in the posterior pole, associated with very various conditions. These disorders usually present a typical pattern of autofluorescent lesions seen on short-wavelength fundus autofluorescence. We describe SADs according to their putative pathophysiological origin and also according to their clinical pattern, i.e., number, shape, and usual location. Five main putative pathophysiological origins of SADs were identified in disorders associated with an intrinsic impairment of phagocytosis and protein transportation, with excess of retinal pigment epithelium phagocytic capacity, with direct or indirect retinal pigment epithelium injury, and/or disorders associated with long-standing serous retinal detachment with mechanical separation between the retinal pigment epithelium and the photoreceptor outer segments. Clinically, however, they could be classified into eight subclasses of SADs, as observed on fundus autofluorescence as follows: single vitelliform macular lesion, multiple roundish or vitelliform lesions, multiple peripapillary lesions, flecked lesions, leopard-spot lesions, macular patterned lesions, patterned lesions located in the same area as the causal disorder, or nonpatterned lesions. Thus, if multimodal imaging may be required to diagnose the cause of SADs, the proposed classification based on noninvasive, widely available short-wavelength fundus autofluorescence could guide clinicians in making their diagnosis decision tree before considering the use of more invasive tools.

Beyond the Complement Cascade: Insights into Systemic Immunosenescence and Inflammaging in Age-Related Macular Degeneration and Current Barriers to Treatment.

Landmark genetic studies have revealed the effect of complement biology and its regulation on the pathogenesis of age-related macular degeneration (AMD). Limited phase 3 clinical trial data showing a benefit of complement inhibition in AMD raises the prospect of more complex mediators at play. Substantial evidence supports the role of para-inflammation in maintaining homeostasis in the retina and choroid. With increasing age, a decline in immune system regulation, known as immunosenescence, has been shown to alter the equilibrium maintained by para-inflammation. The altered equilibrium results in chronic, sterile inflammation with aging, termed 'inflammaging', including in the retina and choroid. The chronic inflammatory state in AMD is complex, with contributions from cells of the innate and adaptive branches of the immune system, sometimes with overlapping features, and the interaction of their secretory products with retinal cells such as microglia and retinal pigment epithelium (RPE), extracellular matrix and choroidal vascular endothelial cells. In this review, the chronic inflammatory state in AMD will be explored by immune cell type, with a discussion of factors that will need to be overcome in the development of curative therapies.

Suppressing Inflammation for the Treatment of Diabetic Retinopathy and Age-Related Macular Degeneration: Dazdotuftide as a Potential New Multitarget Therapeutic Candidate.

Diabetic retinopathy (DR) and age-related macular degeneration (AMD) are major causes of blindness globally. The primary treatment option for DME and neovascular AMD (nAMD) is anti-vascular endothelial growth factor (VEGF) compounds, but this treatment modality often yields insufficient results, and monthly injections can place a burden on the health system and patients. Although various inflammatory pathways and mediators have been recognized as key players in the development of DR and AMD, there are limited treatment options targeting these pathways. Molecular pathways that are interlinked, or triggers of multiple inflammatory pathways, could be promising targets for drug development. This review focuses on the role of inflammation in the pathogenesis of DME and AMD and presents current anti-inflammatory compounds, as well as a potential multitarget anti-inflammatory compound (dazdotuftide) that could be a candidate treatment option for the management of DME and AMD.

The pseudohypopyon stage in adult-onset foveomacular vitelliform dystrophy.

PURPOSE: To gain insight into the pathogenesis of adult-onset foveomacular vitelliform dystrophy (AFVD) via assessment of its pseudohypopyon stage (PHS). METHODS: Retrospectively, data were collected in a tertiary center from established cohorts of a genetically evaluated AFVD and best vitelliform macular dystrophy (BVMD) eyes in the pseudohypopyon stage. Best-corrected visual acuity (BCVA, LogMAR), lesion characterization, including lesion dimensions, liquefaction areas and patterns (altitudinal or lateral), and ellipsoid zone integrity were analyzed from spectral-domain optical coherence tomography images. RESULTS: Out of 167 eyes of 90 AFVD patients and 56 eyes of 28 BVMD patients, 8 eyes of six AFVD patients and five eyes of four BVMD patients were at the PHS were included. The mean LogMAR BCVA ± SD was 0.21 ± 0.20 and 0.41 ± 0.10 in AFVD and BVMD diseases, respectively (p = 0.13). Seven AFVD eyes (87.5%) demonstrated lateral liquefaction, while all BVMD eyes demonstrated an altitudinal pattern (p = 0.005). Maximal horizontal lesion diameters were 1.41 ± 0.46 mm and 2.64 ± 0.77 mm in AFVD and BVMD, respectively (p = 0.02). AFVD patients were older (69 ± 14) than BVMD patients (22 ± 13; p = 0.009). CONCLUSION: The pseudohypopyon stage in AFVD is often characterized by a lateral liquefaction pattern, unlike the altitudinal pattern characterizing BVMD. Age, lesion size, or pathogenesis pathways may underline the different pseudohypopyon stage patterns in AFVD and BVMD.

Incidence and Risk Factors of Visual Impairment in Patients with Angioid Streaks and Macular Neovascularization.

OBJECTIVE: To estimate the incidence and risk factors of visual impairment and complications in eyes with macular neovascularization (MNV) because of angioid streaks (ASs). DESIGN: Longitudinal multicenter retrospective cohort study. SUBJECTS: Patients with AS-associated MNV treated with anti-VEGF agents and a follow-up of > 3 months. METHODS: Clinical and MNV characteristics were collected at baseline. Visual acuity (VA) values and the presence of atrophy or fibrosis were collected at each visit. MAIN OUTCOME MEASURES: Rate of VA change over time and associated factors; the incidence rate of moderate-to-severe visual impairment (MSVI) and blindness and hazard ratio (HR) of candidate risk factors for MSVI; the incidence rate of fibrosis and macular atrophy. RESULTS: Overall, 84 eyes of 66 patients (39 men, 58%) with a mean (standard deviation) age of 55.7 (13.8) years were followed for a mean (standard deviation) of 67.7 (48.5) months. The median number of anti-VEGF doses per eye was 13. The average rate (95% confidence interval [CI]) of visual loss was +0.04 (0.02-0.06) logarithm of the minimum angle of resolution/year (P < 0.001); the visual loss was faster in nonnaive eyes (P = 0.007) and those with better baseline VA (P < 0.001); it was slower in eyes with pattern dystrophy-like features (P = 0.04). The incidence rates (95% CI) of MSVI and blindness were 10.4 (6.88-15)/100-eye-years and 2.33 (1.12-4.29)/100-eye-years. A higher number of injections (HR [95% CI] = 0.45 [0.19-0.94] for receiving ≥ 13 injections vs. < 13; P = 0.03) was protective against MSVI. The incidence rates (95% CI) of fibrosis and macular atrophy were 24.1 (17.5-32.3)/100-eye-years and 14.3 (10.1-19.6)/100-eye-years. CONCLUSIONS: Eyes with MNV-related AS had a high rate of visual impairment and propensity to macular fibrosis and atrophy. A higher number of injections yielded better chances of maintaining good VA, suggesting the need for intensive treatment. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Evaluation of three biometric devices: ocular parameters and calculated intraocular lens power.

Cataract surgery is among the most common medical procedures, and accurate ocular biometry measurements are key for successful visual outcome. The current study evaluated data obtained by the Eyestar 900, Anterion, IOLMaster700 biometers and the Pentacam corneal topographer. Compared values were axial length (AL), anterior chamber depth (ACD), steep- and flat-K, cylinder and axis. Clinical impact was assessed by calculating intraocular lens (IOL) power using the mean values of every parameter and the Barrett and Kane formulas, stratified by device and amount of cylinder. IOL was re-calculated for each device substituting Pentacam K-values. This study included 196 eyes (98 participants) of cataract surgery candidates. When comparing the IOLMaster to the Eyestar (157 eyes), no difference was found in mean AL or ACD measurements (P > 0.05). Steep-K measurements differed between these devices and the Pentacam (P = 0.01). AL and ACD measurements differed between the IOLMaster and Anterion (38 eyes; P < 0.05). Strong correlations (range 0.72-0.99) were found between all four devices. Bland-Altman analysis demonstrated excellent agreement between biometry devices other than ACD between the IOLMaster and Eyestar. Calculated IOL power was 0.50-1.00 diopter (D) lower with the IOLMaster. Cylinder power was 0.75D higher in all biometers when Pentacam K-values were substituted.

Interest of Widefield-Optical Coherence Tomography Angiography for Diagnosis and Follow-Up of Retinal Neovascularisation in Proliferative Diabetic Retinopathy.

Aim: The primary aim was to evaluate the use of optical coherence tomography angiography (OCTA) versus fluorescein angiography (FA) for detecting and monitoring retinal neovascularization (NV) in patients with proliferative diabetic retinopathy (PDR) receiving treatment with anti-vascular endothelial growth factor (anti-VEGF). Methods: Treatment-naïve patients with PDR, willing to begin anti-VEGF treatment without laser from 9/2018-2/2020 were included. FA and OCTA scans were obtained at baseline, and a second OCTA scan was performed after 6 months of anti-VEGF therapy. We calculated sensitivity and specificity for two masked graders with respect to identifying NV on OCTA versus FA. Using ImageJ software, we also measured the change in NV size, at baseline and 6-month follow-up. Results: Ten eyes in eight patients were included, of which three eyes in three patients received a 6-month follow-up examination. Mean age was 51.7 ± 11.2 years, and 75% of patients were male. Overall, 21 NV sites in the 10 eyes were identified both clinically and on FA. Using OCTA scans, the sensitivity and specificity for both graders were extremely high, ranging from 95.2% to 100%. At 6-month follow-up, NV size decreased by 69.8%. Conclusion: These results suggest that OCTA may provide a suitable alternative to FA for visualizing, measuring, and monitoring changes in retinal NV in patients with PDR who receive anti-VEGF therapy.

Relatively mild blue cone monochromacy phenotype caused by various haplotypes in the L- and M-cone opsin genes.

Purpose: Blue cone monochromacy (BCM) is an X-linked retinopathy caused by mutations in the red and green cone opsin genes. The aim of this study was to establish the clinical, genetic, and electrophysiological characteristics of a specific form of BCM. Methods: Patients harboring mutations in the OPN1LW/OPN1MW genes underwent a full clinical examination, including ocular examination, color vision, full-field electroretinography, color fundus and autofluorescence photography, and optical coherence tomography. Genetic analysis was performed using whole-exome sequencing, duplex PCR, PCR/restriction fragment length polymorphism, and Sanger sequencing. IBM SPSS Statistics v. 21.0 was used for the data analysis. Results: Twenty-five patients harboring various haplotypes in exon 3 of the OPN1LW/OPN1MW genes were recruited. They showed a milder incomplete phenotype of BCM than the typical BCM control group. They presented significantly better visual acuity (logarithm of the minimum angle of resolution [logMAR] 0.48 ± 0.26 vs. 1.10 ± 0.54; p < 0.0001) and a highly myopic refraction (-7.81 ± 5.81 D vs. -4.78 ± 5.27 D; p = 0.0222) compared with the BCM control group. The study group had higher 30-Hz cone flicker responses (28.60 ± 15.02 µv; n = 24), whereas the BCM group had none (0.66 ± 2.12 µv; n = 21; p < 0.0001). The Lanthony 15-HUE desaturated test was variable for the exon 3 haplotype group, with a tendency toward the deutan-protan axis. Conclusions: The present study included genetic and clinical data from the largest cohort of patients with exon 3 haplotypes that were previously shown to cause missplicing of the OPN1LW and OPN1MW genes. Analysis of the clinical data revealed better best-corrected visual acuity, more severe myopia, and higher 30-Hz cone flicker responses in the patients with exon 3 haplotypes than in those with typical BCM.

Clinical impact of the worldwide shortage of verteporfin (Visudyne®) on ophthalmic care.

INTRODUCTION: Since July 2021, a worldwide shortage of verteporfin (Visudyne®) occurred: an essential medicine required for photodynamic therapy (PDT). PDT with verteporfin has a broad range of indications in ophthalmology, including chronic central serous chorioretinopathy, polypoidal choroidal vasculopathy and choroidal haemangioma. For these disorders, PDT is either the first-choice treatment or regarded as a major treatment option. MATERIALS AND METHODS: A questionnaire was sent to key opinion leaders in the field of medical retina throughout the world, to assess the role of PDT in their country and the effects of the shortage of verteporfin. In addition, information on the application of alternative treatments during shortage of verteporfin was obtained, to further assess the impact of the shortage. RESULTS: Our questionnaire indicated that the shortage of verteporfin had a major impact on ophthalmic care worldwide and was regarded to be a serious problem by most of our respondents. However, even though there is ample evidence to support the use of PDT in several chorioretinal diseases, we found notable differences in its use in normal patient care throughout the world. Various alternative management strategies were noted during the verteporfin shortage, including lowering the dose of verteporfin per patient, the use of alternative treatment strategies and the use of a centralized system for allocating the remaining ampoules of verteporfin in some countries. CONCLUSION: The shortage of verteporfin has had a large effect on the care of ophthalmic patients across the world and may have resulted in significant and irreversible vision loss. Mitigation strategies should be developed in consultation with all stakeholders to avoid future medication shortages of verteporfin and other unique ophthalmic medications. These strategies may include mandatory stock keeping, compulsory licensing to an alternative manufacturer or incentivizing the development of competition, for example through novel public-private partnerships.