The plasticity of biocompatibility.

Biocompatibility concerns the phenomena that occur within the interactions between biomaterials and human patients, which ultimately control the performance of many facets of medical technology. It involves aspects of materials science, many different forms of engineering and nanotechnology, chemistry, biophysics, molecular and cellular biology, immunology, pathology and a myriad of clinical applications. It is not surprising that an overarching framework of mechanisms of biocompatibility has been difficult to elucidate and validate. This essay discusses one fundamental reason for this; we have tended to consider biocompatibility pathways as essentially linear sequences of events which follow well-understood processes of materials science and biology. The reality, however, is that the pathways may involve a great deal of plasticity, in which many additional idiosyncratic factors, including those of genetic, epigenetic and viral origin, exert influence, as do complex mechanical, physical and pharmacological variables. Plasticity is an inherent core feature of the performance of synthetic materials; here we follow the more recent biological applications of plasticity concepts into the sphere of biocompatibility pathways. A straightforward linear pathway may result in successful outcomes for many patients; we may describe this in terms of classic biocompatibility pathways. In other situations, which usually command much more attention because of their unsuccessful outcomes, these plasticity-driven processes follow alternative biocompatibility pathways; often, the variability in outcomes with identical technologies is due to biological plasticity rather than material or device deficiency.

Longer-Term Anti-VEGF Therapy Outcomes in Neovascular Age-Related Macular Degeneration, Diabetic Macular Edema, and Vein Occlusion-Related Macular Edema: Clinical Outcomes in 130 247 Eyes.

PURPOSE: The clinical practice visual acuity (VA) outcomes of anti-VEGF therapy for up to 5 years were assessed in patients with neovascular age-related macular degeneration (nAMD), diabetic macular edema (DME), branch retinal vein occlusion-related macular edema (BRVO-ME), and central retinal vein occlusion-related macular edema (CRVO-ME). DESIGN: A retrospective analysis was performed using the Vestrum Health Retina Database. PARTICIPANTS: Treatment-naive patients with nAMD, DME, BRVO-ME, or CRVO-ME who received anti-VEGF injections between 2014 and 2019 and had follow-up data for ≥12 months. METHODS: Data on age, sex, the number of anti-VEGF treatments, and VA were analyzed. MAIN OUTCOME MEASURES: Mean VA change up to 3 years (BRVO-ME and CRVO-ME) and 5 years (nAMD and DME). RESULTS: At 1, 3, and 5 years, in 67 666, 21 305, and 5208 eyes with nAMD, after a mean of 7.6, 19.5, and 32 injections, there was a mean change of +3.1, -0.2, and -2.2 letters, respectively. At 1, 3, and 5 years, in 40 832, 7728, and 1192 eyes with DME, after a mean of 6.2, 15.4, and 26.0 injections, there was a mean change of +4.7, +3.3, and +3.1 letters, respectively. At 1 and 3 years, in 12 451 and 3027 eyes with BRVO-ME, after a mean of 7.1 and 18.2 injections, there was a mean change of +9.5 and +7.7 letters, respectively. At 1 and 3 years, in 9298 and 2264 eyes with CRVO-ME, after a mean of 7.3 and 18.8 injections, there was a mean change of +8.3 and +6.0 letters, respectively (P < 0.01 for all VA changes of > 1 letter). In all 4 conditions, the mean VA increased with the mean number of anti-VEGF injections, eyes with a baseline VA of 20/40 or better tended to lose VA, and eyes with progressively worse baseline VA experienced a progressively greater VA gain at 3 years. CONCLUSIONS: In practice, patients with nAMD, DME, BRVO-ME, and CRVO-ME showed limited visual outcomes, with patients with nAMD tending to lose VA at 3 and 5 years. Across all 4 disorders, the mean change in VA correlated with treatment intensity at 1, 3, and 5 years. Patients with better baseline VA are more vulnerable to vision loss.

The Technological Basis of a Balloon-Expandable TAVR System: Non-occlusive Deployment, Anchorage in the Absence of Calcification and Polymer Leaflets.

Leaflet durability and costs restrict contemporary trans-catheter aortic valve replacement (TAVR) largely to elderly patients in affluent countries. TAVR that are easily deployable, avoid secondary procedures and are also suitable for younger patients and non-calcific aortic regurgitation (AR) would significantly expand their global reach. Recognizing the reduced need for post-implantation pacemakers in balloon-expandable (BE) TAVR and the recent advances with potentially superior leaflet materials, a trans-catheter BE-system was developed that allows tactile, non-occlusive deployment without rapid pacing, direct attachment of both bioprosthetic and polymer leaflets onto a shape-stabilized scallop and anchorage achieved by plastic deformation even in the absence of calcification. Three sizes were developed from nickel-cobalt-chromium MP35N alloy tubes: Small/23 mm, Medium/26 mm and Large/29 mm. Crimp-diameters of valves with both bioprosthetic (sandwich-crosslinked decellularized pericardium) and polymer leaflets (triblock polyurethane combining siloxane and carbonate segments) match those of modern clinically used BE TAVR. Balloon expansion favors the wing-structures of the stent thereby creating supra-annular anchors whose diameter exceeds the outer diameter at the waist level by a quarter. In the pulse duplicator, polymer and bioprosthetic TAVR showed equivalent fluid dynamics with excellent EOA, pressure gradients and regurgitation volumes. Post-deployment fatigue resistance surpassed ISO requirements. The radial force of the helical deployment balloon at different filling pressures resulted in a fully developed anchorage profile of the valves from two thirds of their maximum deployment diameter onwards. By combining a unique balloon-expandable TAVR system that also caters for non-calcific AR with polymer leaflets, a powerful, potentially disruptive technology for heart valve disease has been incorporated into a TAVR that addresses global needs. While fulfilling key prerequisites for expanding the scope of TAVR to the vast number of patients of low- to middle income countries living with rheumatic heart disease the system may eventually also bring hope to patients of high-income countries presently excluded from TAVR for being too young.

Biocompatibility pathways and mechanisms for bioactive materials: The bioactivity zone.

This essay analyzes the scientific evidence that forms the basis of bioactive materials, covering the fundamental understanding of bioactivity phenomena and correlation with the mechanisms of biocompatibility of biomaterials. This is a detailed assessment of performance in areas such as bone-induction, cell adhesion, immunomodulation, thrombogenicity and antimicrobial behavior. Bioactivity is the modulation of biological activity by characteristics of the interfacial region that incorporates the material surface and the immediate local host tissue. Although the term 'bioactive material' is widely used and has a well understood general meaning, it would be useful now to concentrate on this interfacial region, considered as 'the bioactivity zone'. Bioactivity phenomena are either due to topographical/micromechanical characteristics, or to biologically active species that are presented in the bioactivity zone. Examples of topographical/micromechanical effects are the modulation of the osteoblast - osteoclast balance, nanotopographical regulation of cell adhesion, and bactericidal nanostructures. Regulation of bioactivity by biologically active species include their influence, especially of metal ions, on signaling pathways in bone formation, the role of cell adhesion molecules and bioactive peptides in cell attachment, macrophage polarization by immunoregulatory molecules and antimicrobial peptides. While much experimental data exists to demonstrate the potential of such phenomena, there are considerable barriers to their effective clinical translation. This essay shows that there is solid scientific evidence of the existence of bioactivity mechanisms that are associated with some types of biomaterials, especially when the material is modified in a manner designed to specifically induce that activity.

Long-Term Stability and Biocompatibility of Pericardial Bioprosthetic Heart Valves.

The use of bioprostheses for heart valve therapy has gradually evolved over several decades and both surgical and transcatheter devices are now highly successful. The rapid expansion of the transcatheter concept has clearly placed a significant onus on the need for improved production methods, particularly the pre-treatment of bovine pericardium. Two of the difficulties associated with the biocompatibility of bioprosthetic valves are the possibilities of immune responses and calcification, which have led to either catastrophic failure or slow dystrophic changes. These have been addressed by evolutionary trends in cross-linking and decellularization techniques and, over the last two decades, the improvements have resulted in somewhat greater durability. However, as the need to consider the use of bioprosthetic valves in younger patients has become an important clinical and sociological issue, the requirement for even greater longevity and safety is now paramount. This is especially true with respect to potential therapies for young people who are afflicted by rheumatic heart disease, mostly in low- to middle-income countries, for whom no clinically acceptable and cost-effective treatments currently exist. To extend longevity to this new level, it has been necessary to evaluate the mechanisms of pericardium biocompatibility, with special emphasis on the interplay between cross-linking, decellularization and anti-immunogenicity processes. These mechanisms are reviewed in this paper. On the basis of a better understanding of these mechanisms, a few alternative treatment protocols have been developed in the last few years. The most promising protocol here is based on a carefully designed combination of phases of tissue-protective decellularization with a finely-titrated cross-linking sequence. Such refined protocols offer considerable potential in the progress toward superior longevity of pericardial heart valves and introduce a scientific dimension beyond the largely disappointing 'anti-calcification' treatments of past decades.

Visual acuity outcomes and anti-VEGF therapy intensity in macular oedema due to retinal vein occlusion: a real-world analysis of 15 613 patient eyes.

BACKGROUND/AIMS: To assess visual acuity (VA) outcomes and antivascular endothelial growth factor (anti-VEGF) therapy intensity in retinal vein occlusion (RVO)-related macular oedema (ME). METHODS: A retrospective study was completed in treatment-naïve patients with RVO-related ME from 2013 to 2019, using the Vestrum Health Retina Database. RESULTS: Mean baseline age was 72.4 years and 54% were women. In 6 months, in 8876 eyes with branch retinal vein occlusion (BRVO)-related ME, after a mean of 4.5 anti-VEGF injections, VA increased by 9.4 letters (95% confidence interval (CI) for change in VA +8.94 to +9.78, p<0.001) from a baseline of 55.1 letters. In 6737 eyes with central retinal vein occlusion (CRVO)-related ME, after a mean of 4.6 anti-VEGF injections over 6 months, VA improved by 9.2 letters (95% CI +8.50 to +9.87, p<0.001) from a baseline of 37.2 letters. In 1 year, VA gain was similar (BRVO: 7.4 injections, +8.1 letters, 95% CI +7.55 to +8.57, p<0.001; CRVO: 7.6 injections, +7.1 letters, 95% CI +6.31 to +7.95, p<0.001). In 6 months and 1 year, mean letters gain increased with number of anti-VEGF injections. Patient eyes with baseline VA of 20/40 or better tended to lose VA in 1 year. CONCLUSION: Mean change in VA correlates with treatment intensity, but patients with better VA at presentation are susceptible to vision loss, reflecting a ceiling effect. Assessed with the same database, VA gains compare favourably with 1-year VA gains in neovascular age-related macular degeneration and diabetic ME, but exhibit a larger gap when compared with corresponding randomised controlled trials.

Visual acuity outcomes and anti-VEGF therapy intensity in diabetic macular oedema: a real-world analysis of 28 658 patient eyes.

BACKGROUND/AIM: To assess visual acuity (VA) outcomes and antivascular endothelial growth factor (anti-VEGF) treatment intensity in diabetic macular oedema (DMO). METHODS: Retrospective analysis was performed in treatment-naïve patients with DMO from 2013 to 2018 using a database of aggregated de-identified electronic medical records (Vestrum Health). RESULTS: At 1 year, 28 658 patient eyes underwent a mean of 6.4 anti-VEGF injections, gaining a mean of +4.2 letters (95% confidence interval for mean gain: +4.0 to +4.5 letters, p<0.001). When stratified by anti-VEGF medication and by years 2013-2018, no clinically meaningful differences in injection frequency or 1-year VA change resulted. At 1 year, 50% of eyes received ≤6 injections, while <20% received 10-13 injections, representing monthly treatment. Mean letters gained at 1 year generally showed a linear relationship with mean number of anti-VEGF injections, beyond two injections. Eyes with good baseline VA (≥20/40) generally were at risk of VA loss at 1 year; those with moderately severe baseline impairment (20/70 to 20/200) who received ≥10 injections improved by a mean of +10.3 letters. CONCLUSION: In clinical practice, patients with DMO undergo fewer anti-VEGF injections and exhibit worse visual gains compared with patients in randomised clinical trials. Visual outcomes correlate with treatment intensity at 1 year, with ceiling effects related to baseline VA.

Decellularization and engineered crosslinking: a promising dual approach towards bioprosthetic heart valve longevity.

OBJECTIVES: While decellularization has previously significantly improved the durability of bioprosthetic tissue, remnant immunogenicity may yet necessitate masking through crosslinking. To alleviate the fears of reintroducing the risk of calcific degeneration, we investigated the application of rationally designed crosslinking chemistry, capable of abrogating mineralization in isolation, in decellularized tissue. METHODS: Bovine and porcine pericardium were decellularized using the standard Triton X/sodium deoxycholate/DNAse/RNAse methodology and thereafter combined incrementally with components of a four-stage high-density dialdehyde-based fixation regimen. Mechanical properties prior to, and calcium levels following, subcutaneous implantation for 6 and 10 weeks in rats were assessed. RESULTS: Enhanced four-stage crosslinking, independent of decellularization, or decellularization followed by any of the crosslinking regimens, achieved sustained, near-elimination of tissue calcification. Decellularization additionally resulted in significantly lower tissue stiffness and higher fatigue resistance in all groups compared to their non-decellularized counterparts. CONCLUSIONS: The dual approach of combining decellularization with enhanced crosslinking chemistry in xenogeneic pericardial tissue offers much promise in extending bioprosthetic heart valve longevity.

Visual Acuity Outcomes and Anti-Vascular Endothelial Growth Factor Therapy Intensity in Neovascular Age-Related Macular Degeneration Patients: A Real-World Analysis of 49 485 Eyes.

PURPOSE: This study assessed anti-vascular endothelial growth factor (VEGF) therapy intensity and its relationship with visual acuity (VA) change in real-world neovascular age-related macular degeneration (nAMD) patients. DESIGN: This retrospective analysis was performed on a large database of aggregated, longitudinal, de-identified electronic medical records from a geographically and demographically diverse sample of patients of United States retina specialists (Vestrum Health Retina Database). PARTICIPANTS: Treatment-naïve nAMD patients who underwent anti-VEGF injections between January 1, 2012, and October 31, 2016, were eligible if follow-up data were available before October 31, 2017. METHODS: Age, gender, anti-VEGF treatment type, number of treatments, and VA were extracted from the database. MAIN OUTCOME MEASURE: Mean VA change assessed at 1 year and stratified based on number of anti-VEGF injections received over 1 year. RESULTS: In this analysis, 49 485 eyes were included. The mean age was 80.9 years, and 64% were female. Mean baseline VA was 53.8 letters (Snellen equivalent, 20/80). At 1 year, after a mean of 7.3 anti-VEGF injections, there was a mean gain of 1 letter (0.95 letter; 95% confidence interval [CI] for change in VA, +0.77 to +1.13 letter; P < 0.001). When stratified by anti-VEGF agent, the mean VA changes were nearly identical at 1 year. There was a linear relationship between mean letters gained and mean number of injections, between 4 and 10 injections over 1 year, with 4 or fewer or 10 or more injections associated with loss of vision or a plateau, respectively. Greater mean 1-year change in VA also trended with worse baseline VA; those patients with better VA at presentation tended to be particularly vulnerable to vision loss. Those who received the fewest injections tended to be older and have worse baseline VA. CONCLUSIONS: Real-world nAMD patients receive fewer anti-VEGF injections and experience worse visual outcomes compared with patients receiving fixed, frequent therapy in randomized controlled trials. Mean change in VA correlates with treatment intensity at 1 year, but with ceiling effects related to treatment intensity and baseline VA. Older patients and those with poor baseline VA may be particularly prone to undertreatment.

Specifications for Innovative, Enabling Biomaterials Based on the Principles of Biocompatibility Mechanisms.

In any engineering discipline, whenever products are designed, manufactured and ultimately utilized for the benefits of society, a series of specifications for the product are defined, and maybe refined, in order that they perform as effectively as possible, with due attention being paid to the safety, and economic aspects. These specifications are established with respect to all of the relevant properties, including those determined by mechanical, physical, chemical, manufacturing and environmental conditions, and the resulting design and materials selection reflects the optimal balance. In areas of medical technology, these specifications should be based on both functionality, which determines whether a device can actually perform as intended, and biocompatibility, which determines how the device interacts, both acutely and chronically, with the body. Unfortunately, whilst so much progress has been made with the development of superior functionality for the treatment and diagnosis of so many disease states, this is not the same for biocompatibility, where the single most-important currently adopted specification is that the device should do no harm, which falls far short of the ideal requirement. This paper addresses the profound need for biomaterials specifications to be based on the mechanisms of biocompatibility.

Biocompatibility in regenerative nanomedicine.

Biocompatibility is a very common word that is used within biomaterial science and used for description of the interactions between the foreign material and the body. However, the meaning of biocompatibility as well as the mechanisms that collectively constitutes is still unclear. With the advance of nanotechnology, new concerns have been observed related to biocompatibility of these biomaterials. Due to their small size and variability of their physical and chemical properties, nanoparticles' (NP) distribution within the body and interactions with the target cells and tissues are highly variable. Here, we tried to provide an overview about NPs, the concept of biocompatibility and biocompatibility-related issues in nanomedicine and several different NPs.

Challenges With the Development of Biomaterials for Sustainable Tissue Engineering.

The field of tissue engineering has tantalizingly offered the possibility of regenerating new tissue in order to treat a multitude of diseases and conditions within the human body. Nevertheless, in spite of significant progress with in vitro and small animal studies, progress toward realizing the clinical and commercial endpoints has been slow and many would argue that ultimate goals, especially in treating those conditions which, as yet, do not have acceptable conventional therapies, may never be reached because of flawed scientific rationale. In other words, sustainable tissue engineering may not be achievable with current approaches. One of the major factors here is the choice of biomaterial that is intended, through its use as a "scaffold," to guide the regeneration process. For many years, effective specifications for these biomaterials have not been well-articulated, and the requirements for biodegradability and prior FDA approval for use in medical devices, have dominated material selection processes. This essay argues that these considerations are not only wrong in principle but counter-productive in practice. Materials, such as many synthetic bioabsorbable polymers, which are designed to have no biological activity that could stimulate target cells to express new and appropriate tissue, will not be effective. It is argued here that a traditional 'scaffold' represents the wrong approach, and that tissue-engineering templates that are designed to replicate the niche, or microenvironment, of these target cells are much more likely to succeed.

Adipose-derived Stem Cells Attenuates Diabetic Osteoarthritis via Inhibition of Glycation-mediated Inflammatory Cascade.

Diabetes mellitus (DM) is well-known to exert complications such as retinopathy, cardiomyopathy and neuropathy. However, in recent years, an elevated osteoarthritis (OA) complaints among diabetics have been observed, portending the risk of diabetic OA. Since formation of advanced glycation end products (AGE) is believed to be the etiology of various diseases under hyperglycemic conditions, we firstly established that streptozotocin-induced DM could potentiate the development of OA in C57BL/6J mouse model, and further explored the intra-articularly administered adipose-derived stem cell (ADSC) therapy focusing on underlying AGE-associated mechanism. Our results demonstrated that hyperglycemic mice exhibited OA-like structural impairments including a proteoglycan loss and articular cartilage fibrillations in knee joint. Highly expressed levels of carboxymethyl lysine (CML), an AGE and their receptors (RAGE), which are hallmarks of hyperglycemic microenvironment were manifested. The elevated oxidative stress in diabetic OA knee-joint was revealed through increased levels of malondialdehyde (MDA). Further, oxidative stress-activated nuclear factor kappa B (NF-κB), the marker of proinflammatory signalling pathway was also accrued; and levels of matrix metalloproteinase-1 and 13 were upregulated. However, ADSC treatment attenuated all OA-like changes by 4 weeks, and dampened levels of CML, RAGE, MDA, NF-κB, MMP-1 and 13. These results suggest that during repair and regeneration, ADSCs inhibited glycation-mediated inflammatory cascade and rejuvenated cartilaginous tissue, thereby promoting knee-joint integrity in diabetic milieu.

A truly non-occlusive stent-graft moulding balloon for thoracic endovascular aortic repair.

Endovascular treatment of thoracic aortic pathologies has recently progressed towards more proximal pathologies, including those of the aortic arch and ascending aorta where there is a higher risk for stent-graft migration during the deployment or the moulding procedure due to the beating and ejecting heart. Typical measures to prevent dislodgement of the balloon or the stent-graft during the procedure are rapid pacing or pharmacologically induced hypotension. We present a circular and fully non-occlusive stent-graft moulding balloon that does not require any reduction of cardiac output or hypotension during inflation, moulding and deflation of the balloon.

PREDICTIVE FACTORS FOR PROLIFERATIVE VITREORETINOPATHY FORMATION AFTER UNCOMPLICATED PRIMARY RETINAL DETACHMENT REPAIR.

PURPOSE: To determine predictive factors of proliferative vitreoretinopathy (PVR) formation after uncomplicated primary retinal detachment repair. METHODS: Retrospective, single-center, case-control study of 74 consecutive patients with (37 eyes) and without (37 eyes) PVR formation after undergoing uncomplicated primary surgery for retinal detachment repair. Logistic regression was used to assess factors associated with PVR formation. RESULTS: Retinal detachment involving the macula was 4.2 times (adjusted odds ratio; 95% confidence interval, 1.4-12.9; P = 0.0119) more likely to have PVR formation compared with those without. Patients who were current or former smokers were 3.6 times (adjusted odds ratio; 95% confidence interval, 1.1-11.7; P = 0.0352) more likely to have PVR formation compared with nonsmokers. Compared with 25-gauge (g) vitrectomy, larger gauge vitrectomy (20 g or 23 g) was 3.6 times (adjusted odds ratio; 95% confidence interval, 1.2-11.3; P = 0.0276) more likely to have PVR formation. Duration of retinal detachment symptoms, high myopia, lens status, lattice degeneration, location of retinal break, number of retinal breaks, and surgical technique (e.g., scleral buckle with or without vitrectomy versus vitrectomy alone) were not found to be predictive of PVR formation. CONCLUSION: Cigarette smoking and macular involvement are significant risk factors predictive of PVR formation after uncomplicated primary retinal detachment repair.

Global Unmet Needs in Cardiac Surgery.

More than 6 billion people live outside industrialized countries and have insufficient access to cardiac surgery. Given the recently confirmed high prevailing mortality for rheumatic heart disease in many of these countries together with increasing numbers of patients needing interventions for lifestyle diseases due to an accelerating epidemiological transition, a significant need for cardiac surgery could be assumed. Yet, need estimates were largely based on extrapolated screening studies while true service levels remained unknown. A multi-author effort representing 16 high-, middle-, and low-income countries was undertaken to narrow the need assessment for cardiac surgery including rheumatic and lifestyle cardiac diseases as well as congenital heart disease on the basis of existing data deduction. Actual levels of cardiac surgery were determined in each of these countries on the basis of questionnaires, national databases, or annual reports of national societies. Need estimates range from 200 operations per million in low-income countries that are nonendemic for rheumatic heart disease to >1,000 operations per million in high-income countries representing the end of the epidemiological transition. Actually provided levels of cardiac surgery range from 0.5 per million in the assessed low- and lower-middle income countries (average 107 ± 113 per million; representing a population of 1.6 billion) to 500 in the upper-middle-income countries (average 270 ± 163 per million representing a population of 1.9 billion). By combining need estimates with the assessment of de facto provided levels of cardiac surgery, it emerged that a significant degree of underdelivery of often lifesaving open heart surgery does not only prevail in low-income countries but is also disturbingly high in middle-income countries.

Endophthalmitis after Intravitreal Injection of Vascular Endothelial Growth Factor Inhibitors: Management and Visual Outcomes.

PURPOSE: We describe the presentation of patients developing endophthalmitis after intravitreal injection with vascular endothelial growth factor (VEGF) inhibitors. Moreover, we evaluate the management by comparing the outcomes of immediate tap and injection of intravitreal antibiotics (TAI) versus initial surgical pars plana vitrectomy (PPV). Finally, we analyze the predictive factors of visual outcomes at 6-month follow-up. DESIGN: Retrospective, single-center, nonrandomized interventional study. PARTICIPANTS: Patients developing endophthalmitis after receiving an intravitreal injection of anti-VEGF agent between 2006 and 2016. METHODS: All patients received a vitreous biopsy sent for cultures before the initiation of treatment: TAI group versus PPV with intravitreal antibiotics (PPV group). MAIN OUTCOME MEASURES: Best-corrected visual acuity (BCVA) at 6-month follow-up after treatment for endophthalmitis. RESULTS: A total of 258 357 intravitreal injections occurred over the course of the 10-year period, of which 40 patients (0.016%) had endophthalmitis within 3 weeks after injection. In total, 34 patients (85.0%) had pain and 25 patients (62.5%) had hypopyon on initial examination. Among 24 culture-positive cases, 66.7% of the causative organisms were coagulase-negative Staphylococcus, followed by Streptococcus species (10.0%). The best-corrected visual acuity (BCVA) (logarithm of the minimum angle of resolution [logMAR]) at 6-month follow-up was significantly worse for patients who had a positive culture for Streptococcus species (4.0; standard deviation [SD], 0.8) (approximately light perception) compared with those who had a positive culture for coagulase-negative Staphylococcus (0.4; SD, 0.3) (∼20/50) (P < 0.0001). Compared with the TAI group, a higher proportion of samples were culture-positive in the PPV group (90.9% vs. 48.3%, P = 0.03). There was no statistically significant difference in BCVA at 6-month follow-up between the TAI and PPV groups. Younger age (<85 years) and lower intraocular pressure (IOP) (≤25 mmHg) at presentation were predictive of achieving a BCVA of 20/400 or better at 6-month follow-up after treatment. Initial management (TAI vs. PPV), duration of symptoms, presence of pain, presence of hypopyon, presenting BCVA, and culture status (positive vs. negative) were not found to be predictive of visual outcomes at 6-month follow-up. CONCLUSIONS: No significant difference in BCVA at 6-month follow-up was detected between the TAI and PPV groups. Younger age and lower IOP at presentation were associated with better visual outcomes at 6-month follow-up.

Real-world Outcomes of Anti-Vascular Endothelial Growth Factor Therapy in Diabetic Macular Edema in the United States.

PURPOSE: This study assessed real-world visual acuity (VA) outcomes of anti-vascular endothelial growth factor (anti-VEGF) therapy for diabetic macular edema (DME). DESIGN: This retrospective analysis was performed on a large database of aggregated, longitudinal electronic medical records from a geographically and demographically diverse sample of patients of United States retina specialists (Vestrum Health Retina Database). PARTICIPANTS: DME patient eyes that underwent ≥3 monthly anti-VEGF injections within 4 months of the first injection and between January 2011 and March 2017 were eligible if follow-up data were available prior to March 2018. METHODS: The eyes were divided into 3 groups based on choice of initial intravitreal anti-VEGF agent (aflibercept, bevacizumab, or ranibizumab). These eyes were then subdivided into 3 cohorts, depending on length of follow-up (6, 12, or 24 months), with each cohort being mutually exclusive. MAIN OUTCOME MEASURES: VA outcomes and number of treatments were assessed on each cohort and stratified by baseline VA. RESULTS: A total of 15,608 DME patient eyes were included in this analysis. In the 12-month cohort, of 1379 eyes initially treated with aflibercept, the mean 12-month improvement was +5.5 letters (95% confidence interval [CI] +4.5 to +6.6 letters, P < 0.001) after 7.5 injections on average, with similar outcomes for bevacizumab (3109 eyes, +5.5 letters, 95% CI +4.7 to +6.3 letters, P < 0.001, average 7.9 injections), and for ranibizumab (1352 eyes, +4.0 letters, 95% CI +2.9 to +5.2 letters, P < 0.001, average 7.7 injections). The mean numbers of corticosteroid, macular, and panretinal laser treatment sessions were similar in each group. In the 12-month cohort, when stratified by baseline VA of 20/201 or worse, 20/71 to 20/200, 20/41 to 20/70, and 20/40 or better, the final mean letters gained or lost were +28.0, +10.2, +2.8, and -2.5 in the aflibercept group, +36.0, +7.8, +2.9, and -2.0 letters in the bevacizumab group, and +30.5, +7.9, +1.6, and -2.7 letters in the ranibizumab group, respectively. CONCLUSIONS: Real-world VA outcomes following anti-VEGF therapy for DME were meaningfully inferior to those noted in randomized, controlled trials. Eyes with better baseline VA experienced fewer letters gained compared with those with worse baseline VA. The initial choice of anti-VEGF agent did not correlate with visual outcomes.

Real-world Outcomes of Anti-Vascular Endothelial Growth Factor Therapy in Neovascular Age-Related Macular Degeneration in the United States.

PURPOSE: Real-world visual outcomes of anti-vascular endothelial growth factor (anti-VEGF) therapy for neovascular age-related macular degeneration (nAMD) have been reported in cohorts outside of the United States. This study sought to assess the relationship between presenting visual acuity (VA) and visual outcomes, as well as the potential impact of loss to follow-up, in real-world anti-VEGF-treated nAMD patients from the United States. DESIGN: Retrospective study of aggregated, longitudinal electronic medical records obtained from a geographically diverse sample of US retina specialists and included in the Vestrum Health Retina Database. PARTICIPANTS: Inclusion criteria were a diagnosis of nAMD, no previous treatment, and ≥3 monthly anti-VEGF injections in the first 4 months from diagnosis in patients diagnosed between January 2011 and July 2013. METHODS: To model loss to follow-up, mutually exclusive cohorts of nAMD patients with loss to follow-up after specific time points of 6 and 12 months (i.e., no follow-up beyond) were compared with a separate cohort of patients who completed 24 months of follow-up ending prior to July 2015 (n = 2213). MAIN OUTCOME MEASURE: VA outcomes were assessed on each cohort as a whole, with additional stratification by baseline VA. RESULTS: The 6-, 12-, and 24-month cohorts received means of 5.4, 7.3, and 12.1 injections and showed no change, no change, and a mean change of +3.1 letters from baseline (95% confidence interval 1.8-4.4 letters, P < 0.01), respectively. When stratified by baseline VA, nearly all groups lose VA at their respective follow-up periods, except for those with baseline VA of 20/200 or worse. CONCLUSIONS: Real-world nAMD patients in the United States receive fewer anti-VEGF injections and experience worse visual outcomes compared with patients in randomized clinical trials, consistent with non-US studies. Patients with better VA at presentation tend to be particularly vulnerable to vision loss. Compared with other patients, those ultimately lost to follow-up have worse visual outcomes at, or prior to, their final visit, suggesting that loss to follow-up may lead to overestimation of visual outcomes in clinical studies of nAMD.