Robert J. Casson

Description:We thank Abihaidar et al. for their insightful comments [1] on our study [2], which are discussed below. Abihaider et al. suggested a primary endpoint of 12-16 weeks. There is evidence to support surgical intervention for full-thickness macular holes (FTMH) within 3 months to optimise anatomical and visual acuity outcomes. Most spontaneous clo-sures are observed within 3 months, while the risk of FTMH progression increases around this time [3]. While more recent evidence suggests FTMH closure may occur up to 13 weeks with carbonic anhydrase inhibitors (CAIs), this data was unavailable during our study period [4]. As all patients were consented for surgery by the third month, extending the study period may have risked adverse outcomes for the participants. The patient (Number 10) referred to by Abihaider et al. [1] continued to re-port subjective metamorphopsia and central blurring vision de spite closure of the hole, which warranted proceeding to surgical intervention by week 12 as per the study protocol. We agree that future RCTs could consider extending the study period to 12 or 16 weeks to investigate the efficacy of CAIs. Additional data regarding the staging of posterior vitreous detachment (PVD) and epiretinal membrane location and epi-centres were important aspects raised by Abihaider et al. [1].Closure with topical therapy was observed in 2 of the 11 stage4 PVD cases (1 dorzolamide group. 1 placebo group), 3 of the 12 stage 3 PVD cases (2 dorzolamide group, 1 placebo group)and 1 of the 9 stage 2 PVD cases (placebo group) (see Table 1).The staging of PVD in our data did not seem to correlate withhigher or lower rates of closure with topical dorzolamidetherapy [2]. Vitreomacular traction (VMT) was present in seven cases, none of which underwent hole closure with topical therapy (three dor zolamide group, four placebo group). Our data supported that FTMH with an additional tractional component in its pathology (as in VMT) is less likely to close spontaneously or with topical dorzolamide therapy (zero of seven cases) [2]. Only three eyes in each group had epiretinal membrane, which were all macular in location. The numbers were too small to comment on the effect of ERM epicentre on this. Furthermore, there is no agreed grading of ERM in the setting of a FTMH, so this was not further elaborated. Duration of FTMH symptoms was only available for 15 of 32 cases (average of 8.44 weeks) [2]. Thus, it was difficult to include this for analysis too. Future clinical trials with larger numbers may provide more analyses on the impact of these factors. We investigated the efficacy of topical dorzolamide on stage 2 FTMH as per Gass classification system, defined as FTMH less than 400 µm. Our reasoning for this patient selection was to further evaluate the findings of Su et al.; a case series of 4 FTMH <300µm that underwent closure with topical dorzol-amide therapy [5]. We agree that investigation of small holes, as defined in the International Vitreomacular Traction Study, would be a worthwhile endeavour.

Description:Genetic testing for paediatric cataract detects a cause in 50%-70% of affected children but is as low as 20% in some reports. We screened 180 cataract-related genes in 22 children (from 20 families) with paediatric cataract from Myanmar using whole-exome sequencing. Pathogenic or likely pathogenic variants were identified in 45% (9/20) of probands in genes MIP, COL2A1, NHS, GJA8, GJA3, CRYGC, CRYBB2, PAX6 and SLC7A8. Variants of uncertain significance likely to be important were identified in three children for a maximum diagnostic rate of 12/20 probands (60%) comparable to other reports. This is the first study to examine the genetics of paediatric cataract in Myanmar.

Description:Inherited retinal diseases (IRDs), such as retinitis pigmentosa, are a heterogenous group of genetic eye diseases characterized by degeneration of photoreceptors. They are the leading cause of blindness in the working age population in high-income countries and are an ideal target for the expanding gene editing tool kit, including rapidly evolving CRISPR/Cas9 technology. In this review, we provide a comprehensive analysis of CRISPR/Cas9 technologies currently being explored as therapeutic interventions for IRDs. Given the challenges posed by the growing complexity and size of gene editing systems, the delivery of these therapeutics to the retina has necessitated innovative approaches. We review current delivery methods, including nanoparticles, virus-like particles and traditional viral vectors, highlighting their advantages and limitations. This review underscores the potential transformative impact of gene editing on genetic disease management, emphasising that advancements in these technologies, coupled with improved pre-clinical models, bring clinically safe and effective treatments for IRDs within view.

Description:Immunohistochemistry has become an essential tool in retinal research. Formaldehyde is the gold standard fixative, but the development of an improved fixative is of keen interest. Herein, we performed a comprehensive evaluation of the compatibility of glyoxal fixation with retinal immunohistochemistry, using wholemounts, cryosections and paraffin-embedded eyes. Immunohistochemistry was performed in normal rat eyes, and, to facilitate localisation of stress-response proteins, eyes subjected to laser-induced retinal injury or injected with the endotoxin lipopolysaccharide. Regarding wholemounts, glyoxal fixation produced retinas that were too fragile to be consistently dissected as pristine wholemounts. In terms of antigenicity, we observed no consistent improvement when glyoxal fixation was used. Some antibodies produced higher signal intensities, but a greater number displayed weaker signal-to-background patterns of labelling compared to formaldehyde fixation. For cryosections and paraffin sections, we likewise found no compelling evidence that immunohistochemical signals were intensified when formaldehyde was replaced by glyoxal. For the 50 antibodies tested, formaldehyde typically produced signal-to-background immunolabelling that was equivalent or superior to glyoxal. In conclusion, the results of this study do not support the use of glyoxal fixation for immunohistochemistry of the rat retina, but with the caveat that improved formulations and protocols may address the limitations exposed herein.

Description:ObjectiveThis study aims to evaluate how extracurricular involvement, such as sports, music, volunteering and teaching, are weighted within standardised curriculum vitae (CV) scoring criteria for medical officers applying to medical and surgical specialty training programs in Australia.MethodsA cross-sectional observational analysis of point allocations for extracurricular involvement was performed, as detailed by publicly available standardised CV scoring criteria for medical and surgical training programs. The analysis includes all specialty training programs in Australian and New Zealand listed by the Australian Health Practitioner Regulation Agency that publish these criteria for the 2023 intake.ResultsOf the 47 reviewed specialty training programs, 14 publish publicly available standardised CV scoring criteria, and 8 of these allocate points for extracurricular involvement. The mean weighting for extracurricular involvement was 11.5% (range 4.5-20%), compared with 42.5% for research. The allocation of points varies by training program and subdomain.ConclusionThe weighting of extracurricular involvement within standardised CV scoring criteria is limited and varied among specialty training programs, despite alignment with non-cognitive competencies emphasised by training frameworks. Current emphasis on academic achievements may disadvantage applicants with limited access to research opportunities. Greater clarity and consistency in evaluating non-academic attributes may support fairer, more holistic selection processes.