Adenylyl Cyclase in Ocular Health and Disease: A Comprehensive Review.

Adenylyl cyclases (ACs) are a group of enzymes that convert adenosine-5'-triphosphate (ATP) to cyclic adenosine 3',5' monophosphate (cAMP), a vital and ubiquitous signalling molecule in cellular responses to hormones and neurotransmitters. There are nine transmembrane (tmAC) forms, which have been widely studied; however, the tenth, soluble AC (sAC) is less extensively characterised. The eye is one of the most metabolically active sites in the body, where sAC has been found in abundance, making it a target for novel therapeutics and biomarking. In the cornea, AC plays a role in endothelial cell function, which is vital in maintaining stromal dehydration, and therefore, clarity. In the retina, AC has been implicated in axon cell growth and survival. As these cells are irreversibly damaged in glaucoma and injury, this molecule may provide focus for future therapies. Another potential area for glaucoma management is the source of aqueous humour production, the ciliary body, where AC has also been identified. Furthering the understanding of lacrimal gland function is vital in managing dry eye disease, a common and debilitating condition. sAC has been linked to tear production and could serve as a therapeutic target. Overall, ACs are an exciting area of study in ocular health, offering multiple avenues for future medical therapies and diagnostics. This review paper explores the diverse roles of ACs in the eye and their potential as targets for innovative treatments.

The Role of Insulin-like Growth Factor (IGF) System in the Corneal Epithelium Homeostasis-From Limbal Epithelial Stem Cells to Therapeutic Applications.

The corneal epithelium, comprising three layers of cells, represents the outermost portion of the eye and functions as a vital protective barrier while concurrently serving as a critical refractive structure. Maintaining its homeostasis involves a complex regenerative process facilitated by the functions of the lacrimal gland, tear film, and corneal nerves. Crucially, limbal epithelial stem cells located in the limbus (transitional zone between the cornea and the conjunctiva) are instrumental for the corneal epithelium integrity by replenishing and renewing cells. Re-epithelialization failure results in persistent defects, often associated with various ocular conditions including diabetic keratopathy. The insulin-like growth factor (IGF) system is a sophisticated network of insulin and other proteins essential for numerous physiological processes. This review examines its role in maintaining the corneal epithelium homeostasis, with a special focus on the interplay with corneal limbal stem cells and the potential therapeutic applications of the system components.

Comparison of repeat penetrating keratoplasty, DSAEK and DMEK for the management of endothelial failure of previous PK.

PURPOSE: To compare the clinical outcomes of repeat PK, DSAEK-on-PK or DMEK-on-PK for the management of endothelial failure of previous penetrating keratoplasty. DESIGN: Retrospective, interventional consecutive case series. PARTICIPANTS: 104 consecutive eyes of 100 patients requiring a second keratoplasty for endothelial failure of their primary penetrating keratoplasty performed between September 2016 and December 2020. INTERVENTION: Repeat keratoplasty. MAIN OUTCOME MEASURES: Survival and visual acuity at 12 and 24 months, rebubbling rate and complications. RESULTS: Repeat PK was performed in 61/104 eyes (58.7%), DSAEK-on-PK was performed in 21/104 eyes (20.2%) and DMEK-on-PK was performed in 22/104 eyes (21.2%). Failure rates in the first 12 and 24 months were 6.6% and 20.6% for repeat PKs compared to 19% and 30.6% for DSAEK and 36.4% and 41.3% for DMEK. For those grafts surviving 12 months, the chances of surviving to 24 months were greatest for DMEK-on-PK at 92% vs 85% each for redo PK and DSAEK-on-PK. Visual acuity at one year was logMAR 0.53 ± 0.51 in the redo PK group, 0.25 ± 0.17 for DSAEK-on-PK and 0.30 ± 0.38 for DMEK-on-PK. 24-month outcomes were 0.34 ± 0.28, 0.08 ± 0.16, and 0.36 ± 0.36 respectively. CONCLUSIONS: DMEK-on-PK has a greater failure rate in the first 12 months than DSAEK-on-PK which has a greater failure rate than redo PK. However, the 2-year survival rates in our series for those already surviving 12 months were greatest for DMEK-on-PK. There was no significant difference in visual acuity at 12 or 24 months. Careful patient selection is needed by experienced surgeons to determine which procedure to offer to patients.

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.

High Astigmatism After Conventional Diameter Deep Anterior Lamellar Keratoplasty in Keratoconus Can Be Successfully Managed With Repeat Wide Diameter Deep Anterior Lamellar Keratoplasty.

PURPOSE: The aim of this study was to describe a new surgical technique to replace a conventional diameter (≤8 mm) deep anterior lamellar keratoplasty (DALK) graft with associated high astigmatism refractory to corneal-based astigmatic procedure/intolerance to contact lenses with a larger diameter (≥9 mm) DALK graft to improve best spectacle-corrected visual acuity (BSCVA). METHODS: Two eyes from 2 keratoconic patients at Southend University Hospital between December 2019 and June 2021 with a minimum follow-up of 17 months were evaluated. The primary outcome of interest was Snellen BSCVA with a secondary outcome of topographic cylinder. RESULTS: Patient 1 had undergone initial 8 mm diameter DALK, with residual keratometric astigmatism of nearly 12 diopters (D) postoperatively despite numerous astigmatic interventions, with a BSCVA of 6/60, before undergoing 9 mm diameter repeat modified DALK. After suture removal and subsequent in-the-wound blunt manual relaxing incisions, the patient had a final keratometric astigmatism of 3.5 D, manifest refraction of plano/-3.50 × 175, and a BSCVA of 6/9. Patient 2 had undergone initial 7.75 mm diameter DALK, with residual keratometric astigmatism of 10.5 D with a BSCVA of counting fingers. The patient underwent 9 mm repeat modified DALK with final residual keratometric astigmatism of 3.1 D after suture removal, manifest refraction of -1.00/-2.75 × 25, and BSCVA of 6/9. CONCLUSIONS: Wide diameter DALK (>9 mm) is effective in the management of conventional diameter DALK (≤8 mm) associated high astigmatism in keratoconus. Creation of a peripheral posterior stromal shoulder also allows safe further titration of residual astigmatism if needed.

Safety and clinical outcomes of omitting same and next day review after DMEK performed with an inferior peripheral iridotomy.

BACKGROUND/OBJECTIVES: To determine the incidence of day one postoperative complications after Descemet Membrane Endothelial Keratoplasty (DMEK) performed with intraoperative inferior peripheral iridotomy (PI), and whether their early detection influences postoperative intervention. SUBJECTS/METHODS: 70 eyes of 70 consecutive patients that underwent DMEK from August 2019 to August 2021 at a single UK centre were retrospectively analysed. Cases that did not have an inferior PI were excluded. Any action taken at day one and week one postoperative review was noted. RESULTS: No pupil block or other major adverse events were found at day one review. At one week, 14 eyes (20%) required re-bubbling, all of which had been fully attached at the day one review. CONCLUSIONS: This series suggests that inferior PI performed alongside DMEK alone or triple DMEK effectively minimizes the risk of pupil block. Since no early complications occurred in this cohort requiring immediate intervention, it may be safe to defer review of these patients to a later time point.

Intravitreal dexamethasone to manage post endothelial keratoplasty cystoid macular oedema refractory to topical therapy.

BACKGROUND/OBJECTIVES: To describe the visual and clinical outcomes of patients with post endothelial keratoplasty (EK) cystoid macular oedema (CMO) refractory to topical treatment with intravitreal sustained-release dexamethasone implant (Ozurdex). SUBJECTS/METHODS: 131 eyes from 111 patients undergoing solitary or combined EK (52 DSAEK (40.0%) and 79 DMEK (60.0%)) at Southend University Hospital between January 2020 and February 2022 with a minimum follow-up of 6 months were evaluated. Patients suspected of having CMO underwent spectral-domain macular optical coherence tomography (SD-OCT) Patients with diabetes were not included in this series. RESULTS: CMO was identified in 5.3% (n = 7) of cases, with 2 of these patients responding to topical corticosteroid treatment. The remaining 5 patients underwent intravitreal dexamethasone implant, with 1 patient requiring repeat implant due to CMO recurrence. All presented within 2 months postoperatively. 4 out of 5 eyes treated with intravitreal dexamethasone achieved a Snellen BCVA ≤6/9.5. 1 patient had an uncontrolled rise in intraocular pressure (IOP) despite maximal medical treatment requiring an urgent PreserFlo Ab-Externo MicroShunt. CONCLUSIONS: The use of intravitreal sustained-release dexamethasone implant in the management of post EK CMO refractory to topical therapy is effective and safe in most cases, but patients should be monitored and treated promptly for any secondary IOP response.

Analysis of microbial keratitis incidence, isolates and in-vitro antimicrobial susceptibility in the East of England: a 6-year study.

BACKGROUND/OBJECTIVES: To report the incidence, microbiological profile and in-vitro antimicrobial susceptibilities of microbial keratitis (MK) in the East of England (EoE) over a 6-year period. SUBJECTS/METHODS: A retrospective study of patients diagnosed with MK who underwent corneal scraping at participating trusts, within the EoE, between 01/01/2015-01/07/2020. Analysis was performed on MK isolate profiles, in-vitro anti-microbial sensitivities and trends over time. RESULTS: The mean incidence of IK, in the EoE, was estimated at 6.96 per 100 000 population/year. 1071 corneal scrapes were analysed, 460 were culture positive (42.95%) of which 87.2% were bacteria (50.3% gram-positive and 49.7% gram-negative), 2.4% polymicrobial, 9.3% fungi and 1.1% acanthamoeba. The most common organisms were pseudomonas spp (29.57%). There was a non-statistically significant trend (NST) in increasing incidence of pseudomonas spp, staph aureus and serratia (p = 0.719, p = 0.615, and p = 0.099 respectively) and a declining NST in Fungi (p = 0.058). Susceptibilities in-vitro to, penicillin classes, fluoroquinolone and aminoglycosides were 76.7% and 89.4%, 79.2% and 97.2% and 95.4 and 96.1% to gram-positive and gram-negative bacteria respectively. Gram-negative organisms were increasingly resistant to cephalosporins with a 19.2% reduction in sensitivity over time. (p = 0.011). Ceftriaxone showed the greatest decrease in sensitivity of 41.67% (p = 0.006). CONCLUSION: In the EoE, MK is relatively prevalent though likely underestimated. Profiles are similar to other UK regions with the exception of a higher fungal and lower acanthamoeba incidence. Common first and second-line antimicrobial selection provides, on the whole, good coverage. Nevertheless, anti-microbial resistance, to cephalosporins, was observed so selection should be carefully considered when treating MK empirically.

A lack of an association between COVID-19 vaccination and corneal graft rejection: results of a large multi-country population based study.

PURPOSE: The aim of the study was to present the rates of corneal transplant rejection from 2018 to 2022 at both Moorfields Eye Hospital UK, and Ospedali Privati Forli (OPF) "Villa Igea", Italy and evaluate the purported association between COVID-19 vaccination and rejection. METHODS: We performed a retrospective review of rejection cases presenting to the two units. Monthly rates were correlated against regional vaccination programme rates. At OPF, conditional Poisson regression model was employed to estimate the incidence risk ratio (IRR) of graft rejection following COVID-19 vaccination risk period compared with the control period. RESULTS: Between January 2018 and March 2022, there were 471 (Moorfields), 95 (OPF) episodes of rejection. From the start of vaccination programme in the UK in late January 2021, the median number of graft rejections per month at Moorfields was 6 (range: 5-9), which was not significantly different to post-lockdown, pre-vaccination programme (March 2020-January 2021), p = 0.367. At OPF, the median rates of rejection before and after initiation of the vaccination programme were not significantly different (p = 0.124). No significant increase in incidence rate of rejection in the risk period following COVID-19 vaccination was found (IRR = 0.53, p = 0.71). CONCLUSION: No notable increase in rates of transplant rejection was noted in year 2021 when COVID-19 vaccination was broadly implemented. The apparent temporal relationship between COVID-19 vaccination and corneal graft rejection highlighted in several case reports may not represent a causative association.

Factors predictive of cystoid macular oedema following endothelial keratoplasty: a single-centre review of 2233 cases.

AIMS: To describe the incidence of postoperative cystoid macular oedema (CMO) after endothelial keratoplasty (EK) and to identify its contributory risk factors. METHODS: 2233 patients undergoing EK at Ospedali Privati Forlì 'Villa Igea', between January 2005 to October 2018 for Descemet stripping automated endothelial keratoplasty (DSAEK) and June 2014 to August 2018 for Descemet membrane endothelial keratoplasty (DMEK) with a minimum follow-up of 18 months were evaluated. Univariate and multivariate analyses were conducted to identify and quantify contributory risk factors. Receiver operating characteristic (ROC) curve analysis were performed to determine ideal cut-off points of continuous variables. RESULTS: CMO was identified in 2.82% (n=63) of the cases. CMO occurred in 2.36% of DSAEK eyes and in 5.56% of DMEK eyes (p=0.001). Average onset of CMO was 4.27±6.63 months (range: 1-34 months) postoperatively. Compared with those who did not develop CMO, a higher proportion of patients in the CMO group had diabetes (24.2% vs 9.8%, p<0.001) (OR=3.16, 95% CI: 1.72 to 5.81, p<0.001), a higher proportion of patients who underwent DMEK rather than DSAEK (28.6% vs 14.1%, p=0.001) (OR=2.42, 95% CI: 1.35 to 4.33, p=0.003) and were older (70.5±10.0 vs 67.1±14.3 years, p=0.01). Using the cut-off of 67 years as identified by ROC curve analysis, subjects aged >67 years (OR=2.35, 95% CI: 1.30 to 4.26, p=0.005) were more likely to develop CMO. There were no other significant differences between the groups. CONCLUSIONS: Older age (>67 years), diabetes mellitus and DMEK have been identified as independent risk factors for postoperative CMO following EK. Close observation is necessary during the first postoperative year after EK, particularly in patients with risk factors.

Selective Laser Trabeculoplasty for Steroid-Induced Ocular Hypertension following Endothelial Keratoplasty.

Purpose: To examine the safety and efficacy of selective laser trabeculoplasty (SLT) in patients responding to topical steroids with elevated intraocular pressure following endothelial keratoplasty.Methods: Patients that underwent Descemet Membrane Endothelial Keratoplasty (DMEK) or Descemet Stripping Automated Endothelial Keratoplasty (DSAEK) were offered SLT as first-line therapy if they presented with steroid response and met inclusion criteria. Patient demographics, best-corrected visual acuity (BCVA), steroid and glaucoma regimens were recorded before and after SLT.Results: Twelve eyes of eight patients were recruited to the study. All patients demonstrated a reduction in IOP and only one patient remained on anti-glaucoma drops after SLT. The mean (±SD) reduction in IOP following SLT was 8.8 (±4.9) mmHg (p < 0.0001). BCVA remained stable and no adverse events following treatment were observed.Conclusions: SLT may be a safe and effective treatment option that reduces topical antihypertensive burden while allowing continuance of corticosteroids in steroid-responsive eyes at high risk of rejection following endothelial keratoplasty. Larger randomized studies are needed to compare SLT efficacy with topical medication in this patient group and to review any impact on graft survival and glaucoma progression.

'Posture-Less' DMEK: Is Posturing After Descemet Membrane Endothelial Keratoplasty Actually Necessary?

PURPOSE: To evaluate the clinical results of Descemet membrane endothelial keratoplasty (DMEK) without any intraoperative or postoperative posturing. DESIGN: Retrospective, noncomparative, and interventional case series. METHODS: One hundred thirty-four (134) consecutive eyes of 101 patients requiring DMEK for any cause of endothelial failure were included. Descemet membrane endothelial keratoplasty was performed with an intraoperative inferior PI. After unscrolling and centration of the graft, the anterior chamber was near completely filled with 20% SF6. After filling the eye with gas there was no intraoperative tamponade time, and patients did not posture postoperatively. Main outcome measures were: graft detachment rate, rebubbling rate, primary and secondary failure rates, rejection rate, intraoperative and postoperative complications, and visual acuity 3 and 12 months after surgery. RESULTS: Five of 134 (3.7%) developed graft detachment greater than one-third of the graft area, and 19 of 134 (14.2%) developed graft detachment less than one-third of the graft area. A rebubble procedure was performed in 19 of 134 (14.2%); of those, the average number of rebubbling procedures performed was 1.13 (range, 1-2). Primary failure occurred in 6 of 134 (4.5%).Twelve-month graft survival occurred in 122 of 134 eyes (91.0%), with secondary failure within the first 12 months accounting for failure of 6 of 134 (4.5%). Nine of 134 (6.7%) cases had a recorded episode of endothelial rejection. The average time for rejection episode was 9.5 months (range, 1-20 months) after surgery. CONCLUSIONS: A total of 134 'posture-less' DMEKs did not suffer very high rates of graft detachment, rebubbling, or other postoperative complications, even with immediate erect posturing after surgery.

Early Endothelialization of Ab Interno Stromal Tectonic Patch in the Management of Corneal Perforation Secondary to Bacterial Keratitis.

PURPOSE: The purpose of this study was to describe a novel surgical technique using an ab interno stromal patch to treat corneal perforation and to present the histological findings of the patch after its removal during definitive mushroom keratoplasty. METHODS: The endothelium had already been removed with the submerged cornea using backgrounds away (SCUBA) technique. RESULTS: The patient was managed successfully with a sutureless ab interno stromal tectonic patch. Two months later, definitive mushroom keratoplasty was performed and the patch was sent for histological examination. Immunohistochemistry revealed a reactive endothelium covering the posterior surface of the graft. Nine months later, her best-corrected visual acuity was 6/9. CONCLUSIONS: This is the first case to our knowledge demonstrating that stromal tectonic grafts without the endothelium can successfully attach to the host tissue and seal a perforation. The stroma may undergo reendothelialization and begin to restore vision, even before penetrating keratoplasty.

Sutureless Tectonic Mini-Descemet's Stripping Automated Endothelial Keratoplasty ("mini-DSAEK") for the management of corneal perforations.

PURPOSE: To report the outcomes of a new technique, pull-through sutureless 'mini-DSAEK', to manage corneal perforations secondary to different aetiologies including trauma, neurotrophic ulcer following penetrating keratoplasty (PK), herpes simplex keratitis and microbial keratitis. METHODS: In this retrospective case series, we report the clinical outcomes of five cases of sutureless tectonic mini-DSAEK performed in patients presenting with large corneal perforations to Southend University Hospital between November 2019 and October 2020. One corneal perforation was sufficiently peripheral for the tectonic mini-DSAEK graft to be successfully positioned outside of the central visual axis. Four corneal perforations were central or paracentral for which the tectonic grafts involved the visual axis. RESULTS: Anterior chambers remained deep and formed with no evidence of leak in all subsequent follow ups in all patients representing 100% tectonic success. All tectonic grafts remained attached except one partially detached graft. One patient underwent uneventful phacoemulsification with intraocular lens implant 8 months after the primary intervention with excellent visual outcome. Two patients underwent two-piece mushroom PK and one patient underwent triple procedure (cataract extraction + intraocular lens + PK) for visual rehabilitation 2-6 months after the primary intervention with good visual outcome. CONCLUSION: Sutureless tectonic pull-through mini-DSAEK is a useful technique in the management of corneal perforations, with a number of advantages compared with conventional techniques.

The relationship between vitamin D status, intake and exercise performance in UK University-level athletes and healthy inactive controls.

The potential ergogenic effects of vitamin D (vitD) in high performing athletes has received considerable attention in the literature and media. However, little is known about non-supplemented university athletes and students residing at a higher latitude. This study aimed to investigate the effects of vitD (biochemical status and dietary intake) on exercise performance in UK university athletes and sedentary students. A total of 34 athletes and 16 sedentary controls were studied during the spring and summer months. Serum vitD status and sunlight exposure were assessed using LC-MS/MS and dosimetry, respectively. Muscular strength of the upper and lower body was assessed using handgrip and knee extensor dynamometry (KE). Countermovement jump (CMJ) and aerobic fitness were measured using an Optojump and VO2max test, respectively. Statistical analysis was performed using paired/ independent t-tests, ANCOVA and Pearson/ Spearman correlations, depending on normality. VitD status increased significantly over the seasons, with athletes measuring higher status both in spring (51.7±20.5 vs. 37.2±18.9 nmol/L, p = 0.03) and summer (66.7±15.8 vs 55.6±18.8 nmol/L, p = 0.04) when compared to controls, respectively. Notably, 22% of the subjects recruited were vitD deficient during the spring term only (<25nmol/L, n 9). Subjects with 'insufficient' vitD status (<50nmol/L) elicited significantly lower CMJ when contrasted to the vitD 'sufficient' (>50nmol/l) group (p = 0.055) and a lower VO2 max (p = 0.05) in the spring and summer term (p = 0.05 and p = 0.01, respectively). However, an ANCOVA test showed no significant difference detected for either CMJ or VO2max following adjustments for co-variates. In conclusion, we provide novel information on the vitD status, dietary intake, physical fitness and sunlight exposure of UK young adults across two separate seasons, for which there is limited data at present.

Tectonic Mini-DSAEK Facilitates Closure of Corneal Perforation in Eyes With Healthy Endothelium.

PURPOSE: The purpose of this study was to report a surgical technique for closure of a traumatic corneal perforation in a patient with healthy endothelium. METHODS: A 69-year-old male patient presented to Southend University Hospital with a 2.5 mm round temporal corneal perforation caused by a metallic foreign body from an industrial accident. Best-corrected visual acuity at presentation was 6/36. The patient received a tectonic small diameter Descemet stripping automated endothelial keratoplasty (mini-DSAEK) to close the perforation. The patient subsequently developed traumatic cataract and underwent cataract surgery 8 months later. Clinical outcomes at 1 week, 1 month, 3 months, 6 months, and 9 months were evaluated. The primary outcomes of interest were successful sustained closure of the perforation and surgical complications, with secondary outcomes of best-spectacle corrected visual acuity (BSCVA, Snellen) and keratometric astigmatism (KA, Pentacam). RESULTS: The anterior chamber was reformed by the graft, restoring the globe's mechanical integrity. The bare stroma reepithelized by 1 week. Neither intraoperative nor postoperative surgical complications were reported. The anterior chamber remained deep and formed during subsequent follow-ups through 9 months. At the 9-month follow-up, final best spectacle-corrected visual acuity was 6/6-1 (Snellen fraction). Keratometric astigmatism was 1.1 diopters. CONCLUSIONS: Tectonic mini-Descemet stripping automated endothelial keratoplasty is a safe technique in the management of corneal perforations too large for tissue adhesives, with a low astigmatic profile and rapid visual recovery.