Heterotypic macrophages/microglia differentially contribute to retinal ischaemia and neovascularisation.

AIMS/HYPOTHESIS: Diabetic retinopathy is characterised by neuroinflammation that drives neuronal and vascular degenerative pathology, which in many individuals can lead to retinal ischaemia and neovascularisation. Infiltrating macrophages and activated retina-resident microglia have been implicated in the progression of diabetic retinopathy, although the distinct roles of these immune cells remain ill-defined. Our aim was to clarify the distinct roles of macrophages/microglia in the pathogenesis of proliferative ischaemic retinopathies. METHODS: Murine oxygen-induced retinopathy is commonly used as a model of ischaemia-induced proliferative diabetic retinopathy (PDR). We evaluated the phenotype macrophages/microglia by immunostaining, quantitative real-time RT-PCR (qRT-PCR), flow cytometry and scRNA-seq analysis. In clinical imaging studies of diabetic retinopathy, we used optical coherence tomography (OCT) and OCT angiography. RESULTS: Immunostaining, qRT-PCR and flow cytometry showed expression levels of M1-like macrophages/microglia markers (CD80, CD68 and nitric oxide synthase 2) and M2-like macrophages/microglia markers (CD206, CD163 and macrophage scavenger receptor 1) were upregulated in areas of retinal ischaemia and around neo-vessels, respectively. scRNA-seq analysis of the ischaemic retina revealed distinct ischaemia-related clusters of macrophages/microglia that express M1 markers as well as C-C chemokine receptor 2. Inhibition of Rho-kinase (ROCK) suppressed CCL2 expression and reduced CCR2-positive M1-like macrophages/microglia in areas of ischaemia. Furthermore, the area of retinal ischaemia was reduced by suppressing blood macrophage infiltration not only by ROCK inhibitor and monocyte chemoattractant protein-1 antibody but also by GdCl3. Clinical imaging studies of diabetic retinopathy using OCT indicated potential involvement of macrophages/microglia represented by hyperreflective foci in areas of reduced perfusion. CONCLUSIONS/INTERPRETATION: These results collectively indicated that heterotypic macrophages/microglia differentially contribute to retinal ischaemia and neovascularisation in retinal vascular diseases including diabetic retinopathy. This adds important new information that could provide a basis for a more targeted, cell-specific therapeutic approach to prevent progression to sight-threatening PDR.

Janus Kinase Inhibitors as a Third-Line Therapy for Refractory Endogenous Noninfectious Uveitis.

PURPOSE: Janus kinase (JAK) inhibitors have recently been used to treat patients with biologic refractory noninfectious uveitis (NIU). This narrative review updates the current evidence relevant for their application in patients with refractory NIU. METHODS: A literature search was performed for articles published until October 2023 in the PubMed, Scopus, and CENTRAL databases using the key terms "noninfectious uveitis" and "Janus kinase inhibitor" or "JAK inhibitor" without any exclusion criteria. Published articles were selected based on their clinical focus, relevance for ocular disease, time since publication and study design reflecting their scientific soundness with a critical appraisal of drug safety aspects. RESULTS: Janus kinases are transmembrane signaling proteins. Their inhibition has shown therapeutic potential experimentally and in patients with multiple immune-mediated diseases, including NIU. JAK inhibitors differ from biological agents in that they inhibit not one specific but multiple cytokines. These agents can be ingested orally and seem superior to adalimumab for most indications. While there is no doubt regarding their efficacy in treating immune-mediated inflammatory diseases, reports regarding their safety are increasing, and the findings are generally confusing and contradictory. Since substantiated information about their specific safety profiles in patients with inflammatory eye disease is lacking, their position in the therapeutic algorithm for uveitis has yet to be determined. CONCLUSIONS: In the absence of evidence from controlled clinical trials, JAK inhibitor therapy is still rendered experimental and currently considered only for sight-threatening uveitis. JAK inhibitors may be considered for specific NIU entities for which there is insufficient response or secondary loss of response to conventional or biologic disease-modifying drugs.

Sustained Disease Control in DME Patients upon Treatment Cessation with Brolucizumab.

Background: Treatment cessation due to a dry retina has not been systematically addressed in diabetic macular edema (DME). In three out of four patients receiving 6 mg of brolucizumab in the KITE study, treatment was terminated after the study ended. Methods: The KITE study was a double-masked, multicenter, active-controlled, randomized trial (NCT03481660) in DME patients. Per protocol, patients received five loading injections of Brolucizumab at 6-week intervals, with the option to adjust to 8 weeks in case of disease activity or to extend in the second year to a maximum of 16 weeks in the absence of retinal fluid. Results: After two years, one patient required eight weekly injections, while three patients reached a maximal treatment interval of 16 weeks. The severity of diabetic retinopathy improved in all patients with no dye leakage according to fluorescein angiography (FA) and no retinal fluid according to OCT in three patients. Treatment was paused in these three patients for >36 months, while the fourth patient required continuous treatment at 5-week intervals after switching to other licensed anti-VEGF agents. Conclusions: The adoption of treatment according to individual needs, including considering treatment cessation, may contribute to improved treatment adherence in many patients and be more frequently possible than expected.

The role of age in ocular toxoplasmosis: clinical signs of immunosenescence and inflammaging.

Purpose: This study aimed to investigate the association between age, immune response, and clinical presentation of ocular toxoplasmosis (OT). Design: This was a monocentric, retrospective, observational cohort study. Methods: A review of the medical records of patients with active OT at the Uveitis Center, Charité Universitätsmedizin, was conducted. Baseline parameters included age at presentation, visual acuity, intraocular pressure (IOP), size and location of active lesions, inflammatory activity, antibody index (AI), and complications of intraocular inflammation. The data were presented as the mean ± standard deviation (SD). The level of significance was set at a p-value of <0.05. Results: Between 1998 and 2019, 290 patients with active OT were diagnosed at our tertiary reference center. The mean age of the participants was 37.7 ± 17.1 years, 53.8% of them were female individuals, and 195 patients (70.9%) showed recurrent disease. Older age was associated with lower baseline visual acuity (p = 0.043), poor visual outcome (p = 0.019), increased inflammatory activity (p < 0.005), and larger retinal lesions (p < 0.005). Older patients presented a lower AI (<35 years: 45.1 ± 82.7, median: 12.1; ≥35 years: 18.6 ± 50.5, median: 5.8; p = 0.046), confirmed by a decrease in AI with increasing age (R2 = 0.045; p = 0.024). Finally, AI was correlated with lesion size (multiple linear regression analysis: p = 0.043). Macular involvement (24.3% of patients) was positively correlated with complications (macular/peripapillary edema and retinal detachment, p < 0.005) and poor visual outcome (p < 0.005) and was negatively correlated with inflammatory activity (p < 0.005). Conclusion: We found a strong and clinically relevant impact of age on the clinical presentation and course of OT. While an unspecific inflammatory response increased with age, the specific, local humoral immune response declined. These findings are well in line with the concept of immunosenescence and inflammaging in uveitis.

KESTREL and KITE Phase 3 Studies: 100-Week Results With Brolucizumab in Patients With Diabetic Macular Edema.

PURPOSE: To report the 100-week outcomes from the KESTREL and KITE trials. DESIGN: Two phase 3, double-masked, active-controlled, randomized trials. METHODS: Patients with diabetic macular edema (DME) were randomized 1:1:1 to brolucizumab 3 mg/6 mg (BRO3/BRO6) or aflibercept 2 mg (AFL) in KESTREL (N = 566) or 1:1 to BRO6 or AFL in KITE (N = 360). BRO3/BRO6 arms received 5 loading doses every 6 weeks (q6w) followed by q12w dosing, with an option to adjust to q8w at predefined disease activity assessment visits. In KITE, at week 72, based on the disease stability assessment, treatment intervals could be extended by 4 weeks in the BRO6 arm. AFL arms received 5 monthly loading doses followed by fixed q8w dosing. RESULTS: At week 100, change from baseline in BCVA (letters) was +8.8 for BRO6 and +10.6 for AFL in KESTREL; and +10.9 for BRO6 and +8.4 for AFL in KITE. In both studies, fewer BRO6 subjects had intraretinal fluid and/or subretinal fluid than AFL subjects. Results were achieved with 32.9% (KESTREL) and 47.5% (KITE) of BRO6 subjects maintained on q12w and q12w/q16w dosing, respectively. Intraocular inflammation rates for BRO6 vs AFL were 4.2% vs 1.1% (KESTREL) and 2.2% vs 1.7% (KITE), of which retinal vasculitis rates were 0.5% vs 0% in KESTREL, with no cases in KITE. Retinal vascular occlusion rates were 1.6% vs 0.5% (KESTREL) and 0.6% in both treatment arms in KITE. CONCLUSIONS: Results show the long-term efficacy and durability of brolucizumab in improving visual and anatomical outcomes in DME; the overall safety profile of brolucizumab remained unchanged through year 2.

Intravitreal Dexamethasone as a Rescue for Anti-Vascular Endothelial Growth Factor Therapy in Neovascular Age-Related Macular Degeneration with Persistent Disease Activity and High Treatment Demand.

Purpose: To assess the impact of switching to, or adding, an intravitreal dexamethasone implant (Dex; Ozurdex®) in anti-vascular endothelial growth factor (VEGF) therapy on disease stability and treatment intervals in eyes with neovascular age-related macular degeneration (nAMD) and persistent disease activity and high treatment demand. Methods: This retrospective noncomparative multicenter longitudinal case series included pseudophakic eyes with nAMD and persistent retinal fluid despite regular anti-VEGF therapy (ranibizumab or aflibercept) that received at least 1 intravitreal Dex implant. Visual acuity, central retinal thickness (CRT), and intraocular pressure were recorded before, and after, the addition of Dex to anti-VEGF therapy. Results: Sixteen eyes of 16 patients met the inclusion criteria of persistent fluid despite anti-VEGF therapy, under treatment intervals of ≤7 weeks in 14 instances. Patients were 80.9 ± 7.4 years old and had received 25.5 ± 17.4 anti-VEGF injections before Dex over a period of 36.4 ± 21.9 months before switching. The treatment interval increased from 5.5 ± 3.2 weeks between the last anti-VEGF and first Dex injection to 11.7 ± 7.3 weeks thereafter (P = 0.022). CRT remained stable (385.3 ± 152.1, 383.9 ± 129.7, and 458.3 ± 155.2 µm before switching as well as 12 and 24 months after switching; P = 0.78 and P = 0.36, respectively). An insignificant mean short-term early increase in visual acuity was not sustained over time. Conclusions: The addition of Dex resulted in a relevant and sustained increase in treatment intervals, whereas CRT and visual acuity remained stable in these difficult-to-treat eyes. It may be discussed whether inflammation or other steroid-responsive factors play a significant role in cases of nAMD with nonsatisfactory responses to anti-VEGF.

Correlation of Aqueous, Vitreous, and Serum Protein Levels in Patients With Retinal Diseases.

Purpose: To further establish aqueous humor (AH) as a clinically suitable source of protein biomarkers in retinal diseases by evaluating the correlation of a large panel of proteins between AH, vitreous humor (VH), and serum (SE). Methods: We enrolled 60 subjects (eyes) with various non-infectious retinal diseases. AH, VH, and SE proteins were analyzed using the Olink Target 96 platform (1196 protein assays in total). We compared these three matrices in terms of quantification overlap, principal component analysis, and correlation. Results: In the AH, VH, and SE samples, 841, 917, and 1133 proteins, respectively, were consistently quantified above the limit of detection in more than 30% of patients. AH and VH shared 812 of these proteins. AH and VH samples overlapped along principal component 1, but SE samples were distinct. We identified 490 proteins with significant (false discovery rate [FDR]-adjusted P < 0.05) and relevant correlations (correlation coefficient > 0.5) between AH and VH, compared to only 33 and 40 proteins for VH and SE and for AH and SE, respectively. Conclusions: Due to a close correlation between protein concentrations in the AH and VH and a clear difference from the SE, AH has the potential to serve as a substitute for VH and may hold significance in identifying protein biomarkers and novel targets related to retinal diseases. Translational Relevance: This study further supports AH as a clinically suitable source of protein biomarkers in retinal diseases. In addition, the identified AH and VH correlations can inform the selection of protein biomarker candidates in future translational research.

Association of inflammation-related markers and diabetic retinopathy severity in the aqueous humor, but not serum of type 2 diabetic patients.

Diabetic retinopathy (DR) is a frequent microvascular complication of diabetes mellitus, and inflammatory pathways have been linked to its pathogenesis. In this retrospective, observational pilot study, we aimed to compare the concentrations of four inflammation-related proteins, ZAG, Reg-3a, elafin and RBP-4, in the serum and aqueous humor of healthy controls and diabetic patients with different stages of DR. The concentrations of VEGF-A, IL-8, IL-6 were determined in parallel as internal controls. In the serum, we did not find significant differences in the concentrations of target proteins. In the aqueous humor, higher levels of ZAG, RBP-4, Reg-3a and elafin were observed in advanced nonproliferative DR (NPDR)/ proliferative DR (PDR) compared to controls. The levels of ZAG and RBP-4 were also higher in advanced NPDR/PDR than in nonapparent DR. Normalization of target protein concentrations to the aqueous humor total protein demonstrates that a spill-over from serum due to breakage of the blood-retina barrier only partially accounts for increased inflammation related markers in later stages. In conclusion, we found elevated levels of Reg-3a, RBP-4, elafin and ZAG in advanced stages of diabetic retinopathy. Higher levels of pro-inflammatory proteins, Reg-3a and RBP-4, might contribute to the pathogenesis of diabetic retinopathy, as the parallel increased concentrations of anti-inflammatory molecules elafin and ZAG might indicate a compensatory mechanism.

Efficacy of TNF-Alpha Inhibitors to Control Inflammation and Prevent Secondary Complications in Non-Infectious Uveitis: A Real-Life Experience from Switzerland.

PURPOSE: To evaluate the efficacy of systemic tumor necrosis factor-alpha inhibitors (TNFi) in the treatment of non-infectious uveitis (NIU). METHODS: This Swiss multicenter retrospective cohort study included patients with NIU requiring TNFi during the period from 2001 to 2018. Risk factors for the occurrence of new complications were identified using Cox regression analysis and hazard ratios (HR). RESULTS: Seventy-one patients (126 eyes; mean age 40.6 ± 14.4 years, mean duration of uveitis 46.0 ± 61.8 months) were followed for 40.2 ± 17.3 months after addition of TNFi. Under TNFi, visual acuity improved from 0.2 ± 0.3 to 0.1 ± 0.3 logMAR (p < 0.001). The portion of patients under systemic corticosteroids decreased from 81.7% to 25.4% (p < 0.001), while that for conventional synthetic disease-modifying anti-rheumatic drugs insignificantly decreased from 63.4% to 50.7% (p > 0.05). In 80.2% of eyes, complications were present at baseline with epiretinal gliosis (39.7%), cataract (41.3%) and macular edema (ME; 27.8%) being the most common. New complications under TNFi were encountered in 49.2% of eyes, also including recurrence (5 eyes) or new onset of ME (14 eyes). The need for switching of TNFi was associated with further complications (HR 3.78, p = 0.012). CONCLUSION: Although the efficacy and tolerability of TNFi in a real-life setting are favorable, treatment is often initiated late, i.e., after many eyes have already developed complications. Even with TNFi, new complications, particularly ME, cannot be completely avoided. Further research is needed to assess the impact of earlier initiation of TNFi therapy.

Functional Outcomes of Brolucizumab-Induced Intraocular Inflammation Involving the Posterior Segment-A Meta-Analysis and Systematic Review.

Early poor outcomes of intraocular inflammation (IOI) after intravitreal brolucizumab (IVB) have negatively affected the use of brolucizumab in clinical routine. We wished to identify factors related to the treatment details of IOI involving the posterior segment resulting from IVB for neovascular AMD (nAMD), if these were reported in detail. Articles were retrieved from PubMed, Scopus, ClinicalTrials, and CENTRAL using the following search terms: AND AND . The risk of bias was rated using the JBI Critical Appraisal Tool. We included 31 reports (41 patients and 46 eyes). Patients were 75.9 ± 8.5 years, and 58.5% were female. IOI occurred 41.7 ± 37.5 (median 37.0) days after treatment initiation with 2.0 ± 1.3 (1-6) IVB injections. A mean change in visual acuity of -14.6 ± 21.0 (median -6.5) letters was reported. The mean time from first IOI signs to the initiation of any anti-inflammatory treatment was 3.3 ± 6.2 days, with 63% of the patients receiving systemic corticosteroids as standard treatment. Finally, a period effect was observed, with a change in visual acuity of -25.3 ± 27.1 and -2.6 ± 7.3 letters in the chronologically first and last third, respectively, of treated eyes (effect size: r = 0.71; p = 0.006). Functional outcomes markedly improved with increasing experience in managing IOI.

IOP-lowering and drug-sparing effects of trabectome surgery with or without cyclodialysis ab interno.

PURPOSE: To compare the postoperative intraocular pressure (IOP) after ab interno trabeculectomy (AIT; trabectome surgery) alone or combined with cyclodialysis ab interno (AITC). PATIENTS AND METHODS: Forty-three eyes with insufficiently controlled open-angle glaucoma were included in this consecutive case series. All eyes received AIT, combined with phacoemulsification and IOL-implantation in phakic instances, with or without additional cyclodialysis ab interno. Postoperative visual acuity, IOP, number of IOP-lowering medications and complications were registered over 12 months. RESULTS: A total of 19 eyes (14 patients) received AIT and 24 (19 patients) received AITC. Both groups were comparable for baseline IOP (AIT: 19.7 ± 8.2 mmHg; AITC: 19.4 ± 6.8 mmHg; p = 0.96), there was a comparable IOP reduction after 6 months (AIT: - 3.8 ± 12.3, median (interquartile range (IQR)): - 3.8 (- 7.8-4.8) mmHg; AITC: - 4.9 ± 8.3, median (IQR): - 2.0 (- 10.8-2.0) mmHg; p = 0.95) and 12 months (AIT: - 4.3 ± 6.6, median (IQR): - 4.0 (- 8.0 to - 1.0) mmHg; AITC: - 3.7 ± 6.7, median (IQR): - 1.5 (- 5.5 to - 0.5) mmHg; p = 0.49). While final visual acuity was similar between the groups, they differed regarding topical IOP-lowering medications (baseline: AIT 2.9 ± 1.2 and AITC 2.9 ± 1.2; 1 year after surgery: AIT 2.6 ± 1.5 (p = 0.16) and AITC 1.3 ± 1.3; p < 0.001)). Depending on the definition, a complete or qualified success of 33.4-45.8% was achieved in AITC compared to 15.8-21.1% in AIT. CONCLUSION: The additional suprachoroidal outflow when AIT is combined with cyclodialysis ab interno (AITC) seems to result in an additional drug sparing effect for at least 1 year without critical safety signals. Thus, AITC might be further investigated prospectively prior to advocating its use in routine minimally invasive glaucoma surgery.

Brolucizumab in Pretreated Neovascular Age-Related Macular Degeneration: Case Series, Systematic Review, and Meta-Analysis.

BACKGROUND: Recalcitrant neovascular age-related macular degeneration (rnAMD) despite intensive intravitreal anti-neovascular endothelial growth factor (VEGF) treatment, can be handled by switching to another anti-VEGF agent. This first systematic review and meta-analysis presents long-term data after switching from another anti-VEGF agent to brolucizumab. METHODS: Retrospective case series over two years of patients switched to brolucizumab, and a systematic review and meta-analysis of peer-reviewed studies presenting patients switched to brolucizumab. Weighted mean differences based on the random-effects models were calculated for best-corrected visual acuity (BCVA) and central subfield thickness (CST). RESULTS: The systematic review draws on 1200 eyes switched to brolucizumab. The meta-analysis showed a clinically irrelevant decrease in BCVA after one and two months, together with significant decreases in CST for up to one year after the switch but lacking power over 2 years. Of twelve eyes (twelve patients) in our case series, five continued treatment for two years without experiencing significant changes. CONCLUSIONS: After switch to brolucizumab, a significant morphological improvement with CST reduction was shown in eyes with rnAMD. The small worsening of BCVA may be owing to the chronically active nature of rnAMD. Brolucizumab thus remains a treatment option in rnAMD despite its potential side effects.

Brolucizumab in Neovascular Age-Related Macular Degeneration and Diabetic Macular Edema: Ophthalmology and Diabetology Treatment Aspects.

Anti-vascular endothelial growth factor (anti-VEGF) therapies have become the standard of care in the treatment of neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME), resulting in a remarkable decrease in disease-related vision loss. However, the need for regular injections places a significant burden on patients, caregivers, and the healthcare system and improvements in vision may not be maintained long term. As a result of its drying potency and duration of action, brolucizumab, an intravitreal anti-VEGF therapy approved for the treatment of nAMD and DME, could decrease injection frequency for patients and provide an efficacious treatment; however, balancing its benefits and risks can be challenging. There have been reports of intraocular inflammation (IOI) in patients treated with brolucizumab, which, if left untreated, may result in severe vision loss. Recent evidence, however, indicates that early recognition of IOI and prompt and aggressive systemic corticosteroid treatment in response to posterior segment involvement can lead to favorable outcomes in these relatively rare but severe cases. A series of consensus meetings were conducted in 2022 between Swiss medical retina experts and diabetologists, discussing the current data for brolucizumab and exploring various challenges to its use, including the associated risk of IOI. The outcome is a collation of practical insights and guidance for ophthalmologists on the use of brolucizumab in patients with nAMD and DME, including patient selection and assessment, treatment regimen and monitoring, and the recognition and management of adverse events.

Pathophysiological Considerations in Periorbital Necrotizing Fasciitis: A Case Report.

BACKGROUND: Periorbital necrotizing fasciitis (PNF) is a rare complication of bacterial infection, associated with irreversible inflammatory destruction of soft tissues like subcutaneous tissue and superficial fascia. PNF can cause visual loss, septic shock and death within hours to days. Since the infection progresses rapidly from a local disease to septic shock, prompt identification and decisive interventions are mandatory. AIM: Considering pathophysiology, differential diagnosis, and treatment options, we report a case of PNF and its outcome. METHODS: A 69 years old male with febrile periorbital swelling had been diagnosed with bilateral PNF, caused by dual infection with Streptococcus pyogenes (S. pyogenes) and Staphylococcus aureus (S. aureus) based on conjunctival swabs. RESULTS: The superantigens produced by S. pyogenes have been identified as key to the rapid dissemination of infection and severity of systemic manifestations. CONCLUSION: A combination of intravenous antibiotics and regular surgical debridements resulted in a beneficial outcome in our patient.

Long-term Efficacy of TNF-alpha Inhibitors on Persistent Uveitic Macular Edema: A Swiss Multicenter Cohort Study.

PURPOSE: To assess the efficacy of tumor necrosis factor-alpha inhibitors (TNFi) on uveitic macular edema (ME) unresponsive to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs). METHODS: This multicenter retrospective study included patients with uveitic ME persisting despite csDMARDs. The effect of an additional TNFi on central retinal thickness (CRT), best corrected visual acuity (BCVA) and corticosteroid need was evaluated. RESULTS: Thirty-five eyes (26 patients, mean age 42.9 ± 15.2 years) were included. CRT decreased from 425 ± 137 µm to 294 ± 66 µm (p < .001) and 280 ± 48 µm (p < .001) at 1 and 4 years of follow-up, respectively. BCVA improved from 0.28 ± 0.22 to 0.21 ± 0.48 (1 year, p = .013) and 0.08 ± 0.13 logMAR (4 years, p = .002). The proportion of patients requiring systemic corticosteroids decreased from 88.5% to 34.8% (1 year) and 15.4% (4 years). CONCLUSION: The addition of a TNFi resulted in an improvement of CRT and BCVA for up to 4 years in uveitic ME but rescue treatments were needed for some patients.

Aqueous Humor Apolipoprotein Concentration and Severity of Diabetic Retinopathy in Type 2 Diabetes.

An imbalance of plasma apolipoproteins has been linked to diabetic retinopathy (DR); however, there is scarce information regarding their presence in the aqueous humor (AH) and their role in DR. Here, we aimed at analysing the relationship between apolipoprotein concentrations in human AH and the severity of DR. Concentrations of apolipoproteins were measured retrospectively in patients with type 2 diabetes mellitus (T2DM) without DR (n = 23), with mild to moderate nonproliferative DR (NPDR) (n = 13), and advanced NPDR/proliferative DR (PDR) (n = 14) using a multiplex immunoassay. Compared to the non-apparent DR group, the concentrations of seven apolipoproteins were elevated in advanced NPDR/PDR (Apo AI 5.8-fold, Apo AII 4.5-fold, Apo CI 3.3-fold, Apo CIII 6.8-fold, Apo D 3.3-fold, Apo E 2.4-fold, and Apo H 6.6-fold). No significant differences were observed in apolipoprotein concentrations between patients with non-apparent DR and healthy controls (n = 17). In conclusion, the AH concentrations of apolipoproteins AI, AII, CI, CIII, D, E, and H increased in advancing stages of DR, suggesting their role in the pathogenesis of DR, which deserves further examination.

Long-Term Outcomes in Children with Congenital Toxoplasmosis-A Systematic Review.

Even in the absence of manifestations at birth, children with congenital toxoplasmosis (CT) may develop serious long-term sequelae later in life. This systematic review aims to present the current state of knowledge to base an informed decision on how to optimally manage these pregnancies and children. For this, a systematic literature search was performed on 28 July 2022 in PubMed, CENTRAL, ClinicalTrials.gov, Google Scholar and Scopus to identify all prospective and retrospective studies on congenital toxoplasmosis and its long-term outcomes that were evaluated by the authors. We included 31 research papers from several countries. Virulent parasite strains, low socioeconomic status and any delay of treatment seem to contribute to a worse outcome, whereas an early diagnosis of CT as a consequence of prenatal screening may be beneficial. The rate of ocular lesions in treated children increases over time to 30% in European and over 70% in South American children and can be considerably reduced by early treatment in the first year of life. After treatment, new neurological manifestations are not reported, while ocular recurrences are observed in more than 50% of patients, with a mild to moderate impact on quality of life in European cohorts when compared to a significantly reduced quality of life in the more severely affected South American children. Though CT is rare and less severe in Europe when compared with South America, antenatal screening is the only effective way to diagnose and treat affected individuals at the earliest possible time in order to reduce the burden of disease and achieve satisfying outcomes.