Effectiveness and cost-effectiveness of MicroShunt implantation versus standard trabeculectomy for open-angle glaucoma (a SIGHT study): study protocol of a multicentre randomised controlled trial.

BACKGROUND: Trabeculectomy is the "gold standard" initial surgical procedure for open-angle glaucoma worldwide. During the last decade, the introduction of less invasive procedures, including new bleb-forming surgery such as the MicroShunt, has altered the approach of glaucoma management. At present, there is insufficient evidence comparing the effectiveness between these procedures nor versus trabeculectomy. Furthermore, there is no data available on patient impact and cost-effectiveness. This study aims to address this gap in evidence and establish whether MicroShunt implantation is non-inferior compared to trabeculectomy with regard to effectiveness and whether it is cost-effective. METHODS: A multicentre, non-inferiority, randomised controlled trial (RCT) studying open-angle glaucoma with an indication for surgery will be conducted. Patients with previous ocular surgery except for phacoemulsification are excluded, as are patients with ocular comorbidity compromising the visual field or requiring a combined procedure. After informed consent is obtained, patients will be randomly allocated to the intervention, a PRESERFLO™ MicroShunt implantation, or the control group, trabeculectomy, using block randomisation (blocks of 2, 4 or 6 patients). In total, 124 patients will be randomised in a 1:1 ratio, stratified by centre. The primary endpoint will be intraocular pressure (IOP) one year after surgery. Secondary outcomes include IOP-lowering medication use, treatment failure, visual acuity, visual field progression, additional interventions, adverse events, patient-reported outcome measures (PROMs), and cost-effectiveness. Study outcomes will be measured up to 12 months postoperatively. DISCUSSION: This study protocol describes the design of a multicentre non-inferiority randomised controlled trial. To this date, cost-effectiveness studies evaluating the MicroShunt have not been undertaken. This multicentre RCT will provide more insight into whether MicroShunt implantation is non-inferior compared to standard trabeculectomy regarding postoperative IOP and whether MicroShunt implantation is cost-effective. TRIAL REGISTRATION: ClinicalTrials.gov, Identifier: NCT03931564 , Registered 30 April 2019.

A systematically derived overview of the non-ubiquitous pathways and genes that define the molecular and genetic signature of the healthy trabecular meshwork.

PURPOSE: The trabecular meshwork (TM) is situated in the most frontal part of the eye and is thought to play an important role in the regulation of the eye pressure. However, this tissue is rather difficult to harvest for research. The purpose of this study is therefore to integrate the existing gene expression data of the healthy TM to increase sample size and identify its signature genes and pathways. This provides a robust reference for the study of molecular disease processes and supports the selection of candidate target genes for new treatments. METHODS: A systematic search identified microarray data of healthy TM tissue. After quality control, datasets of low quality and deviating samples were excluded. Remaining individuals were jointly normalized and integrated into one database. The average gene expression of each tested gene over all individuals was calculated. The 25% genes with the highest average expression were identified as the most active genes in the healthy TM and used as input for pathway and network analysis. Additionally, ubiquitous pathways and genes were identified and excluded from the results. Lastly, we identified genes which are likely to be TM-specific. RESULTS: The gene expression data of 44 individuals, obtained from 18 datasets, were jointly normalized. Ubiquitous genes (n = 688) and ubiquitous pathways (n = 73) were identified and excluded. Following, 1882 genes and 211 pathways were identified as the signature genes and pathways of the healthy TM. Pathway analysis revealed multiple molecular processes of which some were already known to be active in the TM, for example extracellular matrix and elastic fiber formation. Forty-six candidate TM-specific genes were identified. These consist mainly of pseudogenes or novel transcripts of which the function is unknown. CONCLUSIONS: In this comprehensive meta-analysis we identified non-ubiquitous genes and pathways that form the signature of the functioning of the healthy TM. Additionally, 46 candidate TM-specific genes were identified. This method can also be used for other tissues that are difficult to obtain for study.

Animal models and drug candidates for use in glaucoma filtration surgery: A systematic review.

Glaucoma, a degenerative disease of the optic nerve, is the leading cause of irreversible blindness worldwide. Currently, there is no curative treatment. The only proven treatment is lowering intraocular pressure (IOP), the most important risk factor. Glaucoma filtration surgery (GFS) can effectively lower IOP. However, approximately 10% of all surgeries fail yearly due to excessive wound healing, leading to fibrosis. GFS animal models are commonly used for the development of novel treatment modalities. The aim of the present review was to provide an overview of available animal models and anti-fibrotic drug candidates. MEDLINE and Embase were systematically searched. Manuscripts until September 1st, 2021 were included. Studies that used animal models of GFS were included in this review. Additionally, the snowball method was used to identify other publications which had not been identified through the systematic search. Two hundred articles were included in this manuscript. Small rodents (e.g. mice and rats) are often used to study the fibrotic response after GFS and to test drug candidates. Due to their larger eyes, rabbits are better suited to develop medical devices. Novel drugs aim to inhibit specific pathways, e.g. through the use of modulators, monoclonal antibodies, aqueous suppressants or gene therapy. Although most newly studied drugs offer a higher safety profile compared to antimetabolites, their efficacy is in most cases lower when compared to MMC. Current literature on animal models and potential drug candidates for GFS were summarized in this review. Future research should focus on refining current animal models (for example through the induction of glaucoma prior to undertaking GFS) and standardizing animal research to ensure a higher reproducibility and reliability across different research groups. Lastly, novel therapies need to be further optimized, e.g. by conducting more research on the dosage, administration route, application frequency, the option of creating combination therapies, or the development of drug delivery systems for sustained release of anti-fibrotic medication.

History, presence, and future of mitomycin C in glaucoma filtration surgery.

PURPOSE OF REVIEW: Mitomycin C (MMC) is an alkylating agent with extraordinary ability to crosslink DNA, preventing DNA synthesis. By this virtue, MMC is an important antitumor drug. In addition, MMC has become the gold standard medication for glaucoma filtration surgery (GFS). This eye surgery creates a passage for drainage of aqueous humor (AqH) out of the eye into the sub-Tenon's space with the aim of lowering the intraocular pressure. A major cause of failure of this operation is fibrosis and scarring in the sub-Tenon's space, which will restrict AqH outflow. Intraoperative application of MMC during GFS has increased GFS success rate, presumably mainly by reducing fibrosis after GFS. However, still 10% of glaucoma surgeries fail within the first year. RECENT FINDINGS: In this review, we evaluate risks and benefits of MMC as an adjuvant for GFS. In addition, we discuss possible improvements of its use by adjusting dose and method of administration. SUMMARY: One way of improving GFS outcome is to prolong MMC delivery by using a drug delivery system.

Treatment of negative dysphotopsia with supplementary implantation of a sulcus-fixated intraocular lens.

PURPOSE: Our aim was to evaluate the resolution of negative dysphotopsia after supplementary implantation of a sulcus-fixated intraocular lens (IOL). METHODS: This was a retrospective case series. Patients with severe negative dysphotopsia were treated with supplementary implantation of the Rayner Sulcoflex Aspheric (653 L) IOL. Primary outcome measurements were subjectively reported complaints of dysphotopsia, best corrected distance visual acuity (CDVA), iris-IOL distance, anterior chamber depth (ACD) and volume (ACV), angle opening distance and trabecular-iris space area at 500 and 750 µm. RESULTS: A Rayner Sulcoflex IOL was implanted in seven patients (nine eyes) with negative dysphotopsias. Symptoms resolved completely in six eyes, partially in one eye and remained unchanged in two eyes. We did not find any significant changes in CDVA. Angle opening distance, ACD, ACV and iris-IOL distance reduced significantly after Sulcoflex IOL implantation. CONCLUSIONS: Supplementary implantation of a Sulcoflex IOL can successfully treat negative dysphotopsia. The decrease in anterior segment dimensions in combination with the displacement of light rays by the rounded edges of a Sulcoflex IOL may contribute to the resolution of symptoms.

An evidence-based review of prognostic factors for glaucomatous visual field progression.

PURPOSE: To examine which prognostic factors are associated with glaucomatous visual field progression. DESIGN: Knowledge of prognostic factors helps clinicians to select patients at risk of glaucomatous visual field progression and intensify their treatment. METHODS: By consulting relevant databases, we identified 2733 articles published up to September 2010, of which 85 articles investigating prognostic factors for visual field progression in patients with open-angle glaucoma (OAG) were eligible. We summarized results for each factor in tables, noting the direction of the association between the prognostic factor and progression, and the accompanying P value. Four authors, working blind to the factors, independently judged the extent to which a prognostic factor was associated with glaucomatous visual field progression. If there were different associations for normal-tension glaucoma (NTG) studies, they were judged separately. Consensus was reached during group meetings. MAIN OUTCOME MEASURES: A ranking of all studied prognostic factors for glaucomatous visual field progression according to their likelihood of being prognostic. RESULTS: A total of 103 different prognostic factors were investigated in 85 articles. The following factors were clearly associated with glaucomatous visual field progression: age, disc hemorrhages (for NTG), baseline visual field loss, baseline intraocular pressure (IOP), and exfoliation syndrome. An association was unlikely for family history of glaucoma, atherosclerosis, systemic hypertension, visual acuity, sex (for NTG), systolic blood pressure, myopic refractive error (for NTG), and Raynaud's phenomenon. CONCLUSIONS: The factors we found clearly associated with progression could be used in clinical practice and for developing clinical prediction models. For many other factors, further research is necessary.

Magnetically actuated glaucoma drainage device for regulating intraocular pressure after implantation.

The key risk factor for glaucoma is increased intraocular pressure (IOP). Glaucoma drainage devices implanted in the eye can reduce IOP and thus stop disease progression. However, most devices currently used in clinical practice are passive and do not allow for postsurgical IOP control, which may result in serious complications such as hypotony (i.e., excessively low IOP). To enable noninvasive IOP control, we demonstrate a novel, miniature glaucoma implant that will enable the repeated adjustment of the hydrodynamic resistance after implantation. This is achieved by integrating a magnetic microvalve containing a micropencil-shaped plug that is moved using an external magnet, thereby opening or closing fluidic channels. The microplug is made from biocompatible poly(styrene-block-isobutylene-block-styrene) (SIBS) containing iron microparticles. The complete implant consists of an SIBS drainage tube and a housing element containing the microvalve and fabricated with hot embossing using femtosecond laser-machined glass molds. Using in vitro and ex vivo microfluidic experiments, we demonstrate that when the microvalve is closed, it can provide sufficient hydrodynamic resistance to overcome hypotony. Valve function is repeatable and stable over time. Due to its small size, our implant is a promising, safe, easy-to-implant, minimally invasive glaucoma surgery device.

A Degradable Sustained-Release Drug Delivery System for Bleb-Forming Glaucoma Surgery.

Fibrosis of the filtering bleb is one of the main causes of failure after bleb-forming glaucoma surgery. Intraoperative application of mitomycin C (MMC) is the current gold standard to reduce the fibrotic response. However, MMC is cytotoxic and one-time application is often insufficient. A sustained-release drug delivery system (DDS), loaded with MMC, may be less cytotoxic and equally or more effective. Two degradable (polycaprolactone (PCL) and polylactic-co-glycolic acid (PLGA)) MMC-loaded DDSs are developed. Release kinetics are first assessed in vitro followed by rabbit implants in conjunction with the PRESERFLO MicroShunt. As a control, the MicroShunt is implanted with adjunctive use of a MMC solution. Rabbits are euthanized at postoperative day (POD) 28 and 90. The PLGA and PCL DDSs release (on average) 99% and 75% of MMC, respectively. All groups show functioning blebs until POD 90. Rabbits implanted with a DDS show more inflammation with avascular thin-walled blebs when compared to the control. However, collagen is more loosely arranged. The PLGA DDS shows less inflammation, less foreign body response (FBR), and more complete degradation at POD 90 when compared to the PCL DDS. Further optimization with regard to dosage is required to reduce side effects to the conjunctiva.

The Influence of Design Modifications and Microstructured Surface Topographies on Bleb Survival after Glaucoma Tube Shunt Implantation.

Lowering intraocular pressure (IOP) by placement of a glaucoma shunt is an effective treatment for glaucoma. However, fibrosis of the outflow site can hamper surgical outcome. In this study, the antifibrotic effect of adding an endplate (with or without microstructured surface topographies) to a microshunt made of poly(styrene-block-isobutylene-block-styrene) is investigated. New Zealand white rabbits are implanted with a control implant (without endplate) and modified implants. Afterward, bleb morphology and IOP is recorded for 30 days. After killing of the animals, eyes are collected for histology, Addition of an endplate extended bleb survival, Topography-990 has the longest recorded bleb-survival time. Histology reveals that the addition of an endplate increases the presence of myofibroblasts, macrophages, polymorphonuclear cells, and foreign body giant cells compared to the control. However, an increased capsule thickness and inflammatory response are observed in the groups with surface topographies, The addition of an endplate results in prolonged bleb survival, demonstrating that engineering of the shape of glaucoma implants could prolong bleb functionality. Future research should further elaborate the effect of surface topographies on long-term bleb survival, since an increased presence of pro-fibrotic cells and increased capsule thickness are observed compared to the control.

Clinical applications for intraoperative optical coherence tomography: a systematic review.

In this systematic review, we provide an overview of the current state of intraoperative optical coherence tomography (iOCT). As iOCT technology is increasingly utilized, its current clinical applications and potential uses warrant attention. Here, we categorize the findings of various studies by their respective fields, including the use of iOCT in vitreoretinal surgery, corneal surgery, glaucoma surgery, cataract surgery, and pediatric ophthalmology. The trend observed in recent decades towards performing minimally invasive ophthalmic surgery has caused practitioners to recognize the limitations of using a conventional surgical microscope for intraoperative visualization. Thus, the superior visualization provided by iOCT can improve the safety of these surgical techniques and promote the development of new minimally invasive ophthalmic surgeries. Landmark prospective studies found that iOCT can significantly affect surgical decision making and can cause a subsequent change in surgical strategy, and the use of iOCT has potential to improve surgical outcome. Despite these advantages, however, iOCT is still a relatively new technique, and beginning users of iOCT can encounter limitations that can preclude their reaching the full potential of iOCT and in this respect several improvements are needed.

Effect of combined water drinking test and dark room provocative testing in Caucasian eyes with narrow angles.

PURPOSE: To assess the usefulness of water drinking test and dark room provocative testing (WDT + DRPT) in current clinical practice by evaluating input parameters from Swept-source Optical Coherence Tomography (SS-OCT) images, and to determine if clinical factors like axial length, central endothelial cell count (CECC) and retinal nerve fibre layer thickness (RNFL) thickness are associated with a positive WDT + DRPT. METHODS: SS-OCT examination was performed in consecutive subjects presenting as new patients in the outpatient clinic aged > 40 years. If at least one eye met the inclusion criteria (anterior chamber angles <20° and anterior chamber depth < 2.5 mm on SS-OCT), subjects were included in this study and WDT + DRPT was carried out. The eye with the smallest angle was analysed. The difference in parameters between eyes with a positive (≥8 mmHg) and negative (<8 mmHg) increase in intraocular pressure (IOP) after WDT + DRPT were statistically analysed. Second, the correlation between IOP increase after WDT + DRPT and anterior chamber angle parameters (RNFL thickness, CECC and axial length) was studied. RESULTS: A total of 95 subjects with a mean age of 64 years were included. There was an association between IOP increase after WDT + DRPT and anterior chamber angle characteristics, however this was not of clinical significance. No positive results after WDT + DRPT were found in patients with anterior chamber angles ≥ 20°. CONCLUSIONS: The present findings indicate that this combined provocative test has no definite correlative or predictive value in angle closure disease. Further, the test is not useful in predicting early diagnosis or possible CECC or RNFL loss.

A model for designing intraocular pressure-regulating glaucoma implants.

Glaucoma is a group of eye conditions that damage the optic nerve, the health of which is vital for vision. The key risk factor for the development and progression of this disease is increased intraocular pressure (IOP). Implantable glaucoma drainage devices have been developed to divert aqueous humor from the glaucomatous eye as a means of reducing IOP. The artificial drainage pathway created by these devices drives the fluid into a filtering bleb. The long-term success of filtration surgery is dictated by the proper functioning of the bleb and overlying Tenon's and conjunctival tissue. To better understand the influence of the health condition of these tissues on IOP, we have developed a mathematical model of fluid production in the eye, its removal from the anterior chamber by a particular glaucoma implant-the PRESERFLO® MicroShunt-, drainage into the bleb and absorption by the subconjunctival vasculature. The mathematical model was numerically solved by commercial FEM package COMSOL. Our numerical results of IOP for different postoperative conditions are consistent with the available evidence on IOP outcomes after the implantation of this device. To obtain insight into the adjustments in the implant's hydrodynamic resistance that are required for IOP control when hypotony or bleb scarring due to tissue fibrosis take place, we have simulated the flow through a microshunt with an adjustable lumen diameter. Our findings show that increasing the hydrodynamic resistance of the microshunt by reducing the lumen diameter, can effectively help to prevent hypotony. However, decreasing the hydrodynamic resistance of the implant will not sufficiently decrease the IOP to acceptable levels when the bleb is encapsulated due to tissue fibrosis. Therefore, to effectively reduce IOP, the adjustable glaucoma implant should be combined with a means of reducing fibrosis. The results reported herein may provide guidelines to support the design of future glaucoma implants with adjustable hydrodynamic resistances.

Wound Healing Response After Bleb-Forming Glaucoma Surgery With a SIBS Microshunt in Rabbits.

Purpose: The PreserFlo MicroShunt is an innovative implant for the surgical treatment of glaucoma. Although usually effective, surgeries can still fail due to fibrosis. This study was conducted to gain insight into the histological aspects of the fibrotic response and find potential targets to reduce postoperative fibrosis. Methods: Fifteen New Zealand White rabbits were implanted with a microshunt and followed up for 40 days. Animals were euthanized at postoperative days (PODs) 1, 5, and 40 to collect eyes for histological evaluation. Bleb formation and ocular health were assessed by slit-lamp (SL) biomicroscopy and optical coherence tomography (OCT). Intraocular pressure (IOP) was measured using rebound tonometry. Results: Blebs failed after approximately 2 weeks based on bleb survival and IOP measurements. No severe complications were observed with OCT and SL. Histology revealed a wide variety of cells, in the bleb and around the microshunt, including polymorphonuclear leucocytes (PMNs), myofibroblasts, and foreign body giant cells, at different PODs. Conclusions: Implantation of a poly(styrene-b-isobutylene-b-styrene) microshunt in rabbits resulted in the occurrence of a wide variety of cells during the wound-healing response. Future research should further elucidate the potential of these (earlier often overlooked) cells to target the fibrotic response in vivo-for example, by developing novel antifibrotic drugs, methods for sustained delivery of medications, or augmenting material properties. Translational Relevance: Current antifibrotic therapies aim to inhibit myofibroblasts; however, a wide variety of cells are involved in the fibrotic response. Future research focusing on these cells could offer novel methods for reducing the fibrotic response after glaucoma surgery.

Safety and Effectiveness of the PRESERFLO® MicroShunt in Primary Open-Angle Glaucoma: Results from a 2-Year Multicenter Study.

PURPOSE: To assess the safety and effectiveness of the PRESERFLO® MicroShunt (formerly InnFocus MicroShunt) in patients with primary open-angle glaucoma (POAG). DESIGN: The MicroShunt, a controlled ab externo glaucoma filtration surgery device, was investigated in a 2-year, multicenter, single-arm study. PARTICIPANTS: Eligible patients were aged 18-85 years with POAG inadequately controlled on maximal tolerated medical therapy with intraocular pressure (IOP) ≥18 and ≤35 mmHg or when glaucoma progression warranted surgery. METHODS: The MicroShunt was implanted as a stand-alone procedure with adjunctive use of topical mitomycin C (MMC; 0.2-0.4 mg/ml) for 2-3 minutes. MAIN OUTCOME MEASURES: The primary effectiveness outcome was IOP reduction and success (not requiring reoperation or pressure failures [IOP > 21 mmHg and < 20% reduction in IOP]) at year 1. Additional end points at year 2 included IOP reduction, success, glaucoma medications, adverse events (AEs), and reoperations. Results are reported in the overall population and subgroups of patients receiving 0.2 or 0.4 mg/ml MMC. RESULTS: In 81 patients, mean (± standard deviation [SD]) IOP decreased from 21.7 ± 3.4 mmHg at baseline to 14.5 ± 4.6 mmHg at year 1 and 14.1 ± 3.2 mmHg at year 2 (P < 0.0001). Overall success (with and without supplemental glaucoma medication use) at year 1 was 74.1%. Mean (± SD) number of medications decreased from 2.1 ± 1.3 at baseline to 0.5 ± 0.9 at year 2 (P < 0.0001), and 73.8% of patients were medication free. Most common nonserious AEs were increased IOP requiring medication or selective laser trabeculoplasty (25.9%) and mild-to-moderate keratitis (11.1%). There were 6 (7.4%) reoperations and 5 (6.2%) needlings by year 2. In an analysis (post hoc) according to MMC concentration, overall success was 78.1% (0.2 mg/ml) and 74.4% (0.4 mg/ml; P = 0.710). In the 0.2 and 0.4 mg/ml MMC groups, 51.9% and 90.3% of patients were medication free, respectively (P = 0.001). There was a trend toward lower IOP and higher medication reduction in the 0.4 mg/ml MMC subgroup. CONCLUSIONS: In this study, mean IOP and glaucoma medication reductions were significant and sustained over 2 years postsurgery. No long-term, sight-threatening AEs were reported. Further studies may confirm potential risk/benefits of higher MMC concentration.

Conventional glaucoma implants and the new MIGS devices: a comprehensive review of current options and future directions.

Glaucoma is a progressive optic neuropathy that is the second leading cause of preventable blindness worldwide, after cataract formation. A rise in the intraocular pressure (IOP) is considered to be a major risk factor for glaucoma and is associated with an abnormal increase of resistance to aqueous humour outflow from the anterior chamber. Glaucoma drainage devices have been developed to provide an alternative pathway through which aqueous humour can effectively exit the anterior chamber, thereby reducing IOP. These devices include the traditional aqueous shunts with tube-plate design, as well as more recent implants, such as the trabeculectomy-modifying EX-PRESS® implant and the new minimally invasive glaucoma surgery (MIGS) devices. In this review, we will describe each implant in detail, focusing on their efficacy in reducing IOP and safety profile. Additionally, a critical and evidence-based comparison between these implants will be provided. Finally, we will propose potential developments that may help to improve the performance of current devices.

Contributing ocular comorbidity to end-of-life visual acuity in medically treated glaucoma patients, ocular hypertension and glaucoma suspect patients.

AIM: To assess the visual acuity at the end of life in glaucoma suspect patients, ocular hypertension, and patients treated for glaucoma and to find factors contributing to a reduced visual acuity in this cohort of deceased patients. METHODS: In a cohort of 3883 medically treated glaucoma patients, glaucoma suspect, or patients with ocular hypertension assembled in 2001-2004, 1639 were deceased. Patient data were collected from electronic and paper patient files. The files of 1378 patients were studied and the last measured visual acuity and ocular comorbidities influencing the visual acuity were extracted. RESULTS: Our results show that only 37.2% of patients had no visual impairment in either eye, 30.5% was visually impaired or blind in both eyes and 4.1% was blind in both eyes, all based on VA. The most common contributing factors for severe visual impairment or blindness (prevalence ≥ 1%) were: glaucoma, retinal vein occlusion, dry and exudative age-related macular degeneration, past retinal detachment, amblyopia, diabetic retinopathy, anterior ischemic optic neuropathy, trauma, decompensated cornea, past keratitis, enucleation, corneal transplantation, and macular hole. CONCLUSIONS: Despite the current advanced treatment modalities for glaucoma, 30.5% of patients had a VA < 0.5 in both eyes and 4.1% was blind in both eyes. However, this disability cannot be confidently attributed only to glaucoma. Besides glaucoma, most common contributing factors were among others retinal and macular diseases. Patient management in glaucoma should be based on more than lowering the intraocular pressure to prevent blindness at the end of life.

Repeatability, reproducibility, and agreement of three tonometers for measuring intraocular pressure in rabbits.

The aim of this study was to evaluate repeatability, reproducibility, and agreement of three commonly used tonometers in animal research (TonoLab, TonoVet, and TonoPEN AVIA) in a cohort of 24 rabbits. Additionally, the impact of sedation on IOP was investigated in 21 New Zealand White rabbits with the TonoVet tonometer. Repeatability was determined using the coefficient of variation (CoV) for two observers. For the TonoLab (6.55%) and TonoVet (6.38%) the CoV was lower than for the TonoPEN AVIA (10.88%). The reproducibility was highest for the TonoVet (0.2 ± 3.3 mmHg), followed by the TonoLab (0 ± 12.89 mmHg) and lowest for the TonoPEN AVIA (- 1.48 ± 10.3 mmHg). The TonoLab and TonoVet showed the highest agreement (r = 0.85, R2 = 0.73). After sedation, a significant IOP reduction (often > 25%) was observed. Our results show that among the three tonometers tested, the TonoVet tonometer is best for use in rabbits while the TonoLab should be avoided. The impact of sedation on IOP was substantial and should be taken into account during experimentation.

XEN® Gel Stent compared to PRESERFLO™ MicroShunt implantation for primary open-angle glaucoma: two-year results.

PURPOSE: To evaluate the long-term efficacy and safety of two minimally invasive glaucoma surgery implants with a subconjunctival drainage approach: the XEN45 Gel Stent® (Xen) implant and the PRESERFLO™ MicroShunt (MicroShunt). METHODS: Retrospective comparative case series of primary open-angle glaucoma (POAG) patients with at least 6 months of follow-up after a MicroShunt or Xen implantation augmented with mitomycin C. RESULTS: Forty-one eyes of 31 patients underwent Xen implantation, and 41 eyes of 33 patients, MicroShunt implantation. Baseline characteristics were similar, except for more combined surgeries with phacoemulsification in the Xen group (37% vs. 2%). Mean baseline IOP ± standard deviation dropped from 19.2 ± 4.4 to 13.8 ± 3.8 mmHg (n = 26) in the Xen group and from 20.1 ± 5.0 to 12.1 ± 3.5 (n = 14) in the MicroShunt group at 24 months of follow-up (p = 0.19, t-test). The number of IOP-lowering medications dropped from 2.5 ± 1.4 to 0.9 ± 1.2 in the Xen group and from 2.3 ± 1.5 to 0.7 ± 1.1 in the MicroShunt group. The probability of qualified success was 73% and 79% at 24 months of follow-up for the Xen and MicroShunt groups, respectively. Postoperative complications were usually mild and self-limiting. The number of bleb needling and secondary glaucoma surgery procedures was similar in both groups; however, in the Xen group more additional MicroPulse® transscleral cyclophotocoagulation procedures were performed. CONCLUSION: Xen Gel Stent and PreserFlo MicroShunt implantations achieved comparable results in POAG eyes in terms of IOP-lowering and surgical success, with a similar high safety profile.

Small RNA Sequencing of Aqueous Humor and Plasma in Patients With Primary Open-Angle Glaucoma.

Purpose: Identify differentially expressed microRNAs (miRNAs) in aqueous humor (AH) and blood of primary open-angle glaucoma (POAG) patients by using small RNA sequencing. These may provide insight into POAG pathophysiology or serve as diagnostic biomarker. Methods: AH and plasma of nine POAG patients and 10 cataract control patients were small RNA sequenced on Illumina NovaSeq 6000. Identification of gene transcripts targeted by differentially expressed miRNAs was done with miRWalk and MirPath. These targets were used for pathway analysis and Gene Ontology enrichment. Diagnostic potential was evaluated by receiver operating characteristics analysis. Results: We identified 715 miRNAs in plasma and 62 miRNAs in AH. Plasma miRNA profile did not differ between POAG and control. In contrast, in AH, seven miRNAs were differentially expressed. Hsa-miR-30a-3p, hsa-miR-143-3p, hsa-miR-211-5p, and hsa-miR-221-3p were upregulated, whereas hsa-miR-92a-3p, hsa-miR-451a, and hsa-miR-486-5p were downregulated in POAG. Compared to previous studies, hsa-mir-143-3p, hsa-miR-211-5p, and hsa-miR-221-3p were reported previously, strengthening their involvement in POAG whereas hsa-miR-30a-3p, hsa-miR-92a-3p, and hsa-miR-486-5p are implicated in POAG for the first time. Identified gene transcripts were involved in several pathways, some implicated in glaucoma before (e.g., TGF-ß and neurotrophin signaling), whereas others are new (e.g., prolactin and apelin signaling). In respect to diagnostics, AH concentration of hsa-mir-143-3p had an area under the curve (AUC) of 0.889. Combined with hsa-miR-221-3p, AUC improved to 0.96. Conclusions: Small RNA sequencing identified seven differentially expressed miRNAs in AH of POAG patients. The differentially expressed miRNAs may be useful as POAG biomarkers or could become targets for new therapeutic strategies.

The intraocular pressure-lowering effect of prostaglandin analogs combined with topical ß-blocker therapy: a systematic review and meta-analysis.

OBJECTIVE: To estimate the intraocular pressure (IOP)-lowering effect of prostaglandin analogs (PGAs) when added to topical ß-blocker (BB) therapy. DESIGN: Systematic review and meta-analyses of randomized clinical trials. PARTICIPANTS: Twenty-nine articles reporting on 33 study arms and 3 control arms. METHODS: Articles published between January 1, 1990, and August 18, 2009, were identified in relevant databases. The pooled IOP-lowering effects at the 1- to 3-month follow-ups were calculated by performing random effects meta-analyses. MAIN OUTCOME MEASURES: Absolute and relative change in IOP for mean diurnal curve and highest and lowest IOP decrease on the diurnal IOP curve. RESULTS: Adding 0.005% latanoprost in the evening to 0.5% timolol twice daily resulted in a pooled change of -6.3 mmHg (95% CI, -7.1 to -5.5 mmHg, mean IOP curve); switching to the fixed combination of 0.5% timolol and 0.005% latanoprost in the morning resulted in a pooled change of -2.8 mmHg (95% CI, -3.3 to -2.3 mmHg, mean IOP curve). Starting with any fixed combination of 0.5% timolol and a PGA in the morning resulted in a pooled change of -8.4 mmHg (95% CI, -9.1 to -7.6 mmHg, mean IOP curve) and varied between -9.1 mmHg (95% CI, -9.9 to -8.2 mmHg, highest) and -7.9 mmHg (95% CI, -8.5 to -7.2 mmHg, lowest); starting with any fixed combination of 0.5% timolol and a PGA in the evening resulted in a pooled change of -8.6 (95% CI, -9.2 to -8.0 mmHg, mean IOP curve) and varied between -10.1 mmHg (95% CI, -11.0 to -9.2 mmHg, highest) and -7.3 mmHg (95% CI, -8.1 to -6.4 mmHg, lowest). CONCLUSIONS: The concomitant use of latanoprost and timolol leads to a larger additional IOP reduction when compared with the fixed combination. There is no difference in mean IOP-lowering effect between evening and morning dosing of a fixed combination of timolol and a PGA, although the largest IOP decreases are seen with evening dosing. These findings are explained by differences in study design. When time points of IOP measurements close to the peak or trough moment of a drug are included, the IOP-lowering effect will be overestimated or underestimated, respectively. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.