Severe ocular Mpox in person living with advanced HIV treated with extended course of tecovirimat.

BACKGROUND: People living with HIV are disproportionately represented among people with severe mpox. Mild and self-limiting conjunctival involvement has been well-documented, and severe ocular complications, including keratitis, corneal scarring, and the associated loss of vision, are increasingly recognized. Tecovirimat is the first-line antiviral therapy for severe mpox, but data around the efficacy of systemic antiviral agents for mpox are limited, particularly in cases of ocular mpox. CASE REPORT: Here, we describe a case of sight-threatening necrotic blepharokeratoconjunctivitis in a person with advanced HIV, requiring an extended course of tecovirimat due to persistent mpox viral shedding for nearly 5 months.

Long-term effect of gene therapy on Leber's congenital amaurosis.

BACKGROUND: Mutations in RPE65 cause Leber's congenital amaurosis, a progressive retinal degenerative disease that severely impairs sight in children. Gene therapy can result in modest improvements in night vision, but knowledge of its efficacy in humans is limited. METHODS: We performed a phase 1-2 open-label trial involving 12 participants to evaluate the safety and efficacy of gene therapy with a recombinant adeno-associated virus 2/2 (rAAV2/2) vector carrying the RPE65 complementary DNA, and measured visual function over the course of 3 years. Four participants were administered a lower dose of the vector, and 8 were administered a higher dose. In a parallel study in dogs, we investigated the relationship among vector dose, visual function, and electroretinography (ERG) findings. RESULTS: Improvements in retinal sensitivity were evident, to varying extents, in six participants for up to 3 years, peaking at 6 to 12 months after treatment and then declining. No associated improvement in retinal function was detected by means of ERG. Three participants had intraocular inflammation, and two had clinically significant deterioration of visual acuity. The reduction in central retinal thickness varied among participants. In dogs, RPE65 gene therapy with the same vector at lower doses improved vision-guided behavior, but only higher doses resulted in improvements in retinal function that were detectable with the use of ERG. CONCLUSIONS: Gene therapy with rAAV2/2 RPE65 vector improved retinal sensitivity, albeit modestly and temporarily. Comparison with the results obtained in the dog model indicates that there is a species difference in the amount of RPE65 required to drive the visual cycle and that the demand for RPE65 in affected persons was not met to the extent required for a durable, robust effect. (Funded by the National Institute for Health Research and others; ClinicalTrials.gov number, NCT00643747.).

IL-4 regulates specific Arg-1(+) macrophage sFlt-1-mediated inhibition of angiogenesis.

One of the main drivers for neovascularization in age-related macular degeneration is activation of innate immunity in the presence of macrophages. Here, we demonstrate that T helper cell type 2 cytokines and, in particular, IL-4 condition human and murine monocyte phenotype toward Arg-1(+), and their subsequent behavior limits angiogenesis by increasing soluble fms-like tyrosine kinase 1 (sFlt-1) gene expression. We document that T helper cell type 2 cytokine-conditioned murine macrophages neutralize vascular endothelial growth factor-mediated endothelial cell proliferation (human umbilical vein endothelial cell and choroidal vasculature) in a sFlt-1-dependent manner. We demonstrate that in vivo intravitreal administration of IL-4 attenuates laser-induced choroidal neovascularization (L-CNV) due to specific IL-4 conditioning of macrophages. IL-4 induces the expression of sFlt-1 by resident CD11b(+) retinal microglia and infiltrating myeloid cells but not from retinal pigment epithelium. IL-4-induced suppression of L-CNV is not prevented when sFlt-1 expression is attenuated in retinal pigment epithelium. IL-4-mediated suppression of L-CNV was abrogated in IL-4R-deficient mice and in bone marrow chimeras reconstituted with myeloid cells that had undergone lentiviral-mediated shRNA silencing of sFlt-1, demonstrating the critical role of this cell population. Together, these data establish how lL-4 directly drives macrophage sFlt-1 production expressing an Arg-1(+) phenotype and support the therapeutic potential of targeted IL-4 conditioning within the tissue to regulate disease conditions such as neovascular age-related macular degeneration.

Novel CCR3 Antagonists Are Effective Mono- and Combination Inhibitors of Choroidal Neovascular Growth and Vascular Permeability.

Choroidal neovascularization (CNV) is a defining feature of wet age-related macular degeneration. We examined the functional role of CCR3 in the development of CNV in mice and primates. CCR3 was associated with spontaneous CNV lesions in the newly described JR5558 mice, whereas CCR3 ligands localized to CNV-associated macrophages and the retinal pigment epithelium/choroid complex. Intravitreal injection of neutralizing antibodies against vascular endothelial growth factor receptor 2, CCR3, CC chemokine ligand 11/eotaxin-1, and CC chemokine ligand 24/eotaxin-2 all reduced CNV area and lesion number in these mice. Systemic administration of the CCR3 antagonists GW766994X and GW782415X reduced spontaneous CNV in JR5558 mice and laser-induced CNV in mouse and primate models in a dose-dependent fashion. Combination treatment with antivascular endothelial growth factor receptor 2 antibody and GW766994X yielded additive reductions in CNV area and hyperpermeability in mice. Interestingly, topical GW766994X and intravitreal anti-CCR3 antibody yielded strong systemic effects, reducing CNV in the untreated, contralateral eye. Contrarily, ocular administration of GW782415X in primates failed to substantially elevate plasma drug levels or to reduce the development of grade IV CNV lesions. These findings suggest that CCR3 signaling may be an attractive therapeutic target for CNV, utilizing a pathway that is at least partly distinct from that of vascular endothelial growth factor receptor. The findings also demonstrate that systemic exposure to CCR3 antagonists may be crucial for CNV-targeted activity.

Spectral sensitivity measurements reveal partial success in restoring missing rod function with gene therapy.

Restored rod visual function after gene therapy can be established unequivocally by demonstrating that, after dark adaptation, spectral sensitivity has the shape characteristic of rods and that this shape collapses to a cone-like shape before rods have recovered after an intense bleach. We used these tests to assess retinal function in eight young adults and children with early-onset severe retinal dystrophy from Phase II of a clinical gene-therapy trial for RPE65 deficiency that involved the subretinal delivery of a recombinant adeno-associated viral vector carrying RPE65. We found substantial improvements in rod sensitivity in two participants: dark-adapted spectral sensitivity was rod-like after treatment and was cone-like before rods had recovered after a bleach. After 40 min of dark adaptation, one participant showed up to 1,000-fold sensitivity improvements 4 months after treatment and the second up to 100-fold improvements 6 months after treatment. The dark-adapted spectral sensitivities of the other six participants remained cone-like and showed little improvement in sensitivity.

The relevance of chemokine signalling in modulating inherited and age-related retinal degenerations.

Systemic monocytes, tissue resident macrophages, dendritic cells and microglia have specific roles in immune surveillance and maintenance of tissue homeostasis and are key regulator and effector cells of the local immune response to acute and chronic tissue injury.Two major signalling pathways that differentially define trafficking behaviour and activation of systemic and local myeloid cell populations in response to exogenous and endogenous inflammatory stimuli are the Ccl2-Ccr2 and the Cx3cl1-Cx3cr1 chemokine pathways.Alterations in these pathways have been implicated in controlling myeloid cell activation during normal ageing and in age-related retinal degenerations, including age-related macular degeneration (AMD).We review the evidence for how altered chemokine signalling in acute and chronic inflammatory conditions regulate local and systemic myeloid cell responses in the retina and how this may contribute to or attenuate pathology in inherited and age-related retinal diseases. We discuss the role of environmental factors (e.g. light exposure) and the influence of genetic factors on the manifestation of pathology in experimental models and in human patients and how we envisage harnessing this knowledge for the development of targeted, more broadly applicable anti-inflammatory treatment strategies for a wide range of retinal degenerations.

Attitudes and understanding of premium intraocular lenses in cataract surgery: a public health sector patient survey.

OBJECTIVES: To investigate patient understanding of, and attitudes to, premium (toric, extended depth of focus/multifocal) intraocular lenses (premIOLs) in public health sector patients undergoing cataract surgery (CS) in the UK. METHODS: A 12 question survey with Likert scale questions was designed, to assess patient attitudes to post-operative spectacle dependence, refractive target and desirability of spectacle independence whilst considering possible complications of dysphotopsias and need for premIOL exchange/adjustment. RESULTS: 360 surveys were collected. CS had not been performed in 66.5%. Separate spectacles were worn for reading and distance in 28.8%, 19.2% had varifocals, 11.2% bifocals, 22.9% reading glasses only and 1.6% computer glasses only. Contact lenses were not worn in 95.7%. Only 41.6% were drivers. Most patients (85.8%) did not mind wearing glasses after CS, with 78.9% preferring reading glasses, compared with 29.7% preferring distance glasses. Most patients (75.3%) were not familiar with premIOLs, with 58.9% not willing to consider them in the context of a 2% risk of debilitating dysphotopsia and 54.2% rejecting a 5% risk of second surgery. CONCLUSIONS: There is a lack of awareness of premIOLs in public health sector (NHS) patients in the UK, suggesting limitations in the "fully informed" consent process for CS. Most NHS CS patients are currently willing to wear spectacles after CS, especially reading glasses. There is reluctance in such patients to consider premIOLs on a background of small risks of debilitating dysphotopsias and increased risks of a second operation.

Ccl2, Cx3cr1 and Ccl2/Cx3cr1 chemokine deficiencies are not sufficient to cause age-related retinal degeneration.

Monocytes, macrophages, dendritic cells and microglia play critical roles in the local immune response to acute and chronic tissue injury and have been implicated in the pathogenesis of age-related macular degeneration. Defects in Ccl2-Ccr2 and Cx3cl1-Cx3cr1 chemokine signalling cause enhanced accumulation of bloated subretinal microglia/macrophages in senescent mice and this phenomenon is reported to result in the acceleration of age-related retinal degeneration. The purpose of this study was to determine whether defects in CCL2-CCR2 and CX3CL1-CX3CR1 signalling pathways, alone or in combination, cause age-dependent retinal degeneration. We tested whether three chemokine knockout mouse lines, Ccl2(-/-), Cx3cr1(-/-) and Ccl2(-/-)/Cx3cr1(-/-), in comparison to age-matched C57Bl/6 control mice show differences in subretinal macrophage accumulation and loss of adjacent photoreceptor cells at 12-14 months of age. All mouse lines are derived from common parental strains and do not carry the homozygous rd8 mutation in the Crb1 gene that has been a major confounding factor in previous reports. We quantified subretinal macrophages by counting autofluorescent lesions in fundus images obtained by scanning laser ophthalmoscopy (AF-SLO) and by immunohistochemistry for Iba1 positive cells. The accumulation of subretinal macrophages was enhanced in Ccl2(-/-), but not in Cx3cr1(-/-) or Ccl2(-/-)/Cx3cr1(-/-) mice. We identified no evidence of retinal degeneration in any of these mouse lines by TUNEL staining or semithin histology. In conclusion, CCL2-CCR2 and/or CX3CL1-CX3CR1 signalling defects may differentially affect the trafficking of microglia and macrophages in the retina during ageing, but do not appear to cause age-related retinal degeneration in mice.

Dupilumab-Induced, Tralokinumab-Induced, and Belantamab Mafodotin-Induced Adverse Ocular Events-Incidence, Etiology, and Management.

ABSTRACT: Emerging monoclonal antibody therapies are assuming greater importance in the management of severe and refractory forms of immunity-driven and oncological disorders. However, some have been found to induce adverse ocular events (AOEs) leading to discontinuation of treatment or additional multidisciplinary management. We present the current knowledge concerning AOEs associated with 3 monoclonal antibody therapies: dupilumab, tralokinumab, and belantamab mafodotin. We examine the manifestations of their AOEs, proposed pathophysiological mechanisms, and current treatment recommendations. We identified and reviewed all studies for dupilumab, tralokinumab, and belantamab mafodotin using the keywords "dupilumab," "tralokinumab," "belantamab mafodotin," "conjunctivitis," and "keratopathy" from January 2016 to November 2021. Conjunctivitis was the most frequently reported AOE in patients with atopic dermatitis receiving dupilumab or tralokinumab. Mild cases were managed with warm compresses for associated meibomian gland dysfunction, artificial tears, and antihistamine/mast cell stabilizer eye drops. In more severe cases, additional anti-inflammatory therapy, with corticosteroid eye drops or ointments, or topical calcineurin inhibitors-such as tacrolimus or ciclosporin-were required. Patients with resistant or refractory multiple myeloma treated with belantamab mafodotin often developed keratopathy, which could necessitate contact lens fitting, or for cycles of belantamab mafodotin to be delayed.

Corneal astigmatic outcomes after femtosecond laser-assisted cataract surgery combined with surface penetrating arcuate keratotomies.

AIM: To evaluate corneal astigmatic outcomes of femtosecond laser-assisted arcuate keratotomies (FAKs) combined with femtosecond-laser assisted cataract surgery (FLACS) over 12mo follow-up. METHODS: Totally 145 patients with bilateral cataracts and no ocular co-morbidities were recruited to a single-centre, single-masked, prospective randomized controlled trial (RCT) comparing two monofocal hydrophobic acrylic intraocular lenses. Eyes with corneal astigmatism (CA) of >0.8 dioptres (D) received unpaired, unopened, surface penetrating FAKs at the time of FLACS. Visual acuity, subjective refraction and Scheimpflug tomography were recorded at 1, 6, and 12mo. Alpins vectoral analyses were performed. RESULTS: Fifty-one patients (61 eyes), mean age 68.2±9.6y [standard deviation (SD)], received FAKs. Sixty eyes were available for analysis, except at 12mo when 59 attended. There were no complications due to FAKs. Mean pre-operative CA was 1.13±0.20 D. There was a reduction of astigmatism at all post-operative visits (residual CA 1mo: 0.85±0.42 D, P=0.0001; 6mo: 0.86±0.35 D, P=0001; and 12mo: 0.90±0.39, P=0.0001). Alpins indices remained stable over 12mo. Overall, the cohort was under-corrected at all time points. At 12mo, 61% of eyes were within ±15 degrees of pre-operative astigmatic meridian. CONCLUSION: Unpaired unopened penetrating FAKs combined with on-axis phacoemulsification are safe but minimally effective. CA is largely under-corrected in this cohort using an existing unmodified nomogram. The effect of arcuate keratotomies on CA remained stable over 12mo.

Impact of cessation of regular cataract surgery during the COVID pandemic on the rates of posterior capsular rupture and post-operative cystoid macular oedema.

BACKGROUND/OBJECTIVES: During the COVID-19, elective cataract surgery (CS) was significantly curtailed. We investigated whether consequent reduction of micro-surgical skills practice might lead to higher operative complications. METHODS: Single-centre, electronic note review of consecutive patients undergoing CS during three periods: 1st February 2019 to 13th January 2020 (P1) prior to pandemic; 3rd June 2020 to 11th January 2021 after 1st lockdown (P2); and 25th January to 30th July 2021 (P3) after/during second lockdown. RESULTS: 2276 operations occurred during P1, 999 during P2, 846 during P3. During P1, posterior capsular rupture (PCR) rate was 1.67%, similar to P2 (1.30%, p = 0.54), but lower than P3 (3.55%, p = 0.002). There was no difference in PCR risk percentage scores between routine and PCR cases during P1 (1.90% vs 2.03%, p = 0.83), P2 (2% vs 2.18%, p = 0.18), or P3 (1.87% vs. 2.71%, p = 0.08). During P2 and P3, there was a higher rate of cystoid macular oedema (CMO) compared with P1 (4.9% and 6.86% vs. 1.93%, p = 0.0001), with no differences in proportion of diabetics or cases with CMO in combination with PCR. There was no difference in surgeons grade experiencing PCR. CONCLUSIONS: In P3 following 9 months of curtailed elective CS, PCR rates were increased across all surgeon grades, occurring in cases with similar risk percentage scores. CMO rates were increased during COVID and not related to proportion of diabetics or increased PCR rates. The reduction in elective CS during the pandemic was associated with more complications, perhaps due to attenuation of microsurgical skills.

Time and Motion Studies to assess surgical productivity in cataract theatre lists within the National Health Service: Immediate Sequential Bilateral Cataract Surgery versus Delayed Sequential Bilateral Cataract Surgery.

BACKGROUND: To compare productivity of National Health Service cataract lists performing unilateral cataract (UC) surgery vs Immediate Sequential Bilateral Cataract Surgery (ISBCS). METHODS: Five 4-hour lists with ISBCS cases and five with UC were observed using time and motion studies (TMS). Individual tasks and timings of each staff member in theatre was recorded by two observers. All operations were performed by consultant surgeons under local anaesthesia (LA). RESULTS: Median number of eyes operated per 4-hour list was 8 (range 6-8) in the ISBCS group and 5 (5-7) in the UC group (p = 0.028). Mean total theatre time (defined as time between the entry of the first patient and the exit of the last patient from theatre) was 177.12 (SD 73.62) minutes in the ISBCS group and 139.16 (SD 47.73) minutes in the UC group (p = 0.36). Mean time to complete two consecutive unilateral cataract surgery operations was 48.71 minutes compared to 42.23 minutes for a single ISBCS case (13.30% time saved). Based on our collected TMS data, a possible 5 consecutive ISBCS cases and 1 UC (total 11 cataract surgeries) could be performed during a four-hour theatre session, with a theatre utilisation quotient of 97.20%, contrasting to nine consecutive UC, with a theatre utilisation quotient of 90.40%. DISCUSSION: Performing consecutive ISBCS cases under LA on routine cataract surgery lists can increase surgical efficiency. TMS are a useful way to investigate surgical productivity and test theoretical models for efficiency improvements.

Effect of gene therapy on visual function in Leber's congenital amaurosis.

Early-onset, severe retinal dystrophy caused by mutations in the gene encoding retinal pigment epithelium-specific 65-kD protein (RPE65) is associated with poor vision at birth and complete loss of vision in early adulthood. We administered to three young adult patients subretinal injections of recombinant adeno-associated virus vector 2/2 expressing RPE65 complementary DNA (cDNA) under the control of a human RPE65 promoter. There were no serious adverse events. There was no clinically significant change in visual acuity or in peripheral visual fields on Goldmann perimetry in any of the three patients. We detected no change in retinal responses on electroretinography. One patient had significant improvement in visual function on microperimetry and on dark-adapted perimetry. This patient also showed improvement in a subjective test of visual mobility. These findings provide support for further clinical studies of this experimental approach in other patients with mutant RPE65. (ClinicalTrials.gov number, NCT00643747 [ClinicalTrials.gov].).

Corneal transplantation after failed grafts: Options and outcomes.

Corneal transplantation is the most commonly performed human tissue transplantation procedure worldwide. Because of the large number of transplants, corneal graft failure has become one of the most common indications for corneal transplantation. The relatively recently developed lamellar transplant techniques have brought about specific potential complications leading to graft failure that may require different approaches to repeat transplantation other than penetrating keratoplasty. On the other hand, these new lamellar techniques also provide novel ways of rescuing failed penetrating grafts, with potential advantages over successive penetrating keratoplasties, such as reduced intraoperative risks and faster visual rehabilitation. We summarize the incidence and risk factors of graft failure for penetrating and lamellar (stromal and endothelial) corneal transplants and discuss the various surgical alternatives currently available to rescue such failed grafts, with a focus on the reported outcomes and limitations.

Visual and refractive outcomes and glistenings occurrence after implantation of 2 hydrophobic acrylic aspheric monofocal IOLs.

PURPOSE: To compare the Clareon IOL with the Tecnis PCB00 IOL in terms of visual performance, refractive outcomes, glistenings occurrence, and quality-of-life outcomes. SETTING: Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom. DESIGN: Single-center, single-masked, prospective, randomized controlled trial. METHODS: One hundred thirty-nine patients with bilateral cataracts were randomized to receive the Clareon (C IOL) or Tecnis (T IOL) IOL. Visual acuity, refraction, central corneal thickness (CCT), endothelial cell loss, contrast sensitivity, mesopic gap acuity, evaluation of glistenings, and rates of perioperative and postoperative complications were recorded. Quality-of-life outcomes were measured with the EuroQOL-5 dimensions questionnaire and the patient-reported outcome measures (PROMs) questionnaire. Optimized A-constants were available for the T IOL but not for the C IOL. RESULTS: Seventy-one patients (140 eyes) received the C IOLs and 68 patients (134 eyes) received the T IOLs. Data were analyzed for the first implanted eye. At 12 months, mean uncorrected distance visual acuity (logarithm of the minimum angle of resolution) was 0.02 ± 0.10 and 0.01 ± 0.08 (mean ± SD; P = .49; 95% CI, -0.02 to 0.04) in the C IOL and T IOL groups, respectively. Corrected distance visual acuity was -0.02 ± 0.09 and -0.03 ± 0.06, respectively (P = .45; 95% CI, -0.02 to 0.04). The increase in CCT was 14 ± 19 and 16 ± 28 µm, respectively (P = .63; 95% CI, -10.16 to 6.16). Mean absolute refraction spherical equivalent error from target refraction was 0.41 ± 0.28 for the C IOL and 0.25 ± 0.2 for the T IOL groups (P = .002; 95% CI, 0.08 to 0.24). Glistenings were minimal (median grade 0), with no difference in grades between groups (P = .2). PROMs improved postoperatively and were similar in both groups. CONCLUSIONS: There were no differences in visual outcomes between the Clareon IOL and Tecnis PCB00 IOL. Glistenings were rarely observed in either IOL with no difference in grades. There was no difference in perioperative or postoperative complications. Surgeon optimization of the A-constant for the Clareon IOL is recommended.

Subretinal delivery of adeno-associated virus serotype 2 results in minimal immune responses that allow repeat vector administration in immunocompetent mice.

BACKGROUND: Adeno-associated virus serotype 2 (AAV2) vectors show considerable promise for ocular gene transfer. However, one potential barrier to efficacious long-term therapy is the development of immune responses against the vector or transgene product. METHODS: We evaluated cellular and humoral responses in mice following both single and repeated subretinal administration of AAV2, and examined their effects on RPE65 and green fluorescent protein transgene expression. RESULTS: Following subretinal administration of vector, splenocytes and T-cells from draining lymph nodes showed minimal activation following stimulation by co-culture with AAV2. Neutralizing antibodies (NAbs) were not detected in the ocular fluids of any mice receiving AAV2 or in the serum of mice receiving a lower dose. NAbs were present in the serum of a proportion of mice receiving a higher dose of the vector. Furthermore, no differences in immunoglobulin titre in serum or ocular fluids against RPE65 protein or AAV2 capsid between treated and control mice were detected. Histological examination showed no evidence of retinal toxicity or leukocyte infiltration compared to uninjected eyes. Repeat administration of low-dose AAV.hRPE65.hRPE65 to both eyes of RPE65(-/-) mice resulted in transgene expression and functional rescue, but re-administration of high-dose AAV2 resulted in boosted NAb titres and variable transgene expression in the second injected eye. CONCLUSIONS: These data, which were obtained in mice, suggest that, following subretinal injection, immune responses to AAV2 are dose-dependent. Low-dose AAV2 is well tolerated in the eye, with minimal immune responses, and transgene expression after repeat administration of vector is achievable. Higher doses lead to the expression of NAbs that reduce the efficacy of repeated vector administration.

Influence of Socioeconomic Deprivation on Visual Acuity in Patients Undergoing Corneal Transplantation.

PURPOSE: To determine whether there is an association between socioeconomic status and best-corrected visual acuity (BCVA) in patients undergoing corneal transplantation in the United Kingdom. METHODS: Retrospective cohort study of 4306 patients registered on the national United Kingdom Transplant Registry and undergoing penetrating keratoplasty, anterior lamellar keratoplasty, or endothelial keratoplasty in 2002, 2008, and 2013. Socioeconomic status was determined by applying a validated deprivation index to generate a score based on 5 categories. Patients' demographic details, preoperative BCVA, copathology, surgical center volume, and socioeconomic status were analyzed for univariate effects of categorical and continuous variables. Binary logistic regression was used to determine whether preoperative BCVA was affected by socioeconomic status after adjusting for other factors. RESULTS: A larger percentage of the most deprived group was female in each period compared with the least deprived, but this was only significant in 2002 (48.7% vs. 40.3%; P = 0.04). There was no interaction between socioeconomic status and the preoperative BCVA in the grafted eye. However, BCVA in the fellow eye was poorer for the most economically deprived patients compared with the least deprived in 2013 (P = 0.01). CONCLUSIONS: We found no evidence of a relationship between socioeconomic deprivation and BCVA in the transplant recipient eye. However, there was clear evidence of an association between socioeconomic deprivation and reduced acuity in fellow eyes, for which barriers to access or low patient demand may be possible contributors.