Severe Mitral Valve Regurgitation in Infective Endocarditis: A Case Report.

We present a case report of a patient with infective endocarditis. He came to the emergency room with respiratory failure due to severe pneumonia and pulmonary edema. On 2D transesophageal echocardiography, vegetations were seen in both mitral and aortic valves, with mitral valve perforation and severe regurgitation. His clinical presentation and severity of the disease made him suitable for urgent valve repair. He was submitted to mitral valvuloplasty with closure of the valve perforation and insertion of a bioprosthetic aortic valve. Despite significant clinical improvement, a post-surgical complication was noted with new-onset lung injury after cardiopulmonary bypass. This is an interesting case of a patient with suspected retrograde valve involvement, affecting the aortic valve, the mitral-aortic intervalvular fibrosa, and the mitral valve, ending with mitral valve abscess with leaflet perforation and valvular regurgitation.

Patterns of Progression of Nonproliferative Diabetic Retinopathy Using Non-Invasive Imaging.

Purpose: To identify progression of nonproliferative diabetic retinopathy (NPDR) in patients with type 2 diabetes by combining optical coherence tomography angiography (OCTA) metrics and color fundus photography (CFP) images. Methods: This study was a post hoc analysis of a prospective longitudinal cohort study (CORDIS, NCT03696810) with 2-year duration. This study enrolled 122 eyes. Ophthalmological examinations included OCTA and CFP. OCTA metrics included skeletonized vessel density (SVD) and perfusion density (PD) at the superficial capillary plexus (SCP) and deep capillary plexus (DCP). Microaneurysm turnover analysis and Early Treatment Diabetic Retinopathy Study (ETDRS) grading for diabetic retinopathy (DR) severity assessment were performed on 7-field CFP. Results: Eyes graded as ETDRS level 20 showed significant capillary nonperfusion predominantly in the inner ring area in the SCP (P < 0.001), whereas eyes graded as ETDRS level 35 and ETDRS levels 43 and 47 showed significant capillary nonperfusion in both the SCP and DCP in both inner and outer rings (P < 0.001). When evaluating rates of progression in capillary nonperfusion for the 2-year period of follow-up, changes were found predominantly in the DCP for SVD and PD and were better identified in the outer ring area. Microaneurysm turnover contributes to the characterization of NPDR progression by discriminating ETDRS level 35 from ETDRS levels 43 and 47 (P < 0.001), which could not be achieved using only OCTA metrics. Conclusions: Patterns of progression of NPDR can be identified combining OCTA examinations of the superficial and deep retinal capillary plexi of central retina and determination of microaneurysm turnover from fundus photographs. Translational Relevance: Our study reports results from a registered clinical trial that advances understanding of disease progression in NPDR.

Age-Related Macular Degeneration and Extramacular Drusen: Genetic Associations in the Coimbra Eye Study.

Purpose: To explore the association between the genetics of age-related macular degeneration (AMD) and extramacular drusen (EMD) in patients with and without AMD. Methods: We included 1753 eyes (912 subjects) with phenotypic characterization regarding AMD and EMD. Genetic sequencing and the genetic risk score (GRS) for AMD were performed according to the EYE-RISK consortium methodology. To test for differences in the GRS from EMD cases, AMD cases, and controls, a clustered Wilcoxon rank-sum test was used. The association of AMD, EMD, and the GRS was evaluated using logistic regression models adjusted for age and sex. Individual associations of common risk variants for AMD with EMD were explored. Results: EMD were found in 755 eyes: 252 (14.4%) with AMD and 503 (28.7%) without. In total, 122 eyes (7.0%) had only AMD, and 876 (50.0%) were controls. EMD were strongly associated with AMD (odds ratio [OR], 3.333; 95% confidence interval [CI], 2.356-4.623; P < 0.001). The GRS was associated with an increased risk of AMD (OR, 1.416; 95% CI, 1.218-1.646; P < 0.001) but not with EMD. Individually, the common risk variants ARMS2 rs10490924 (P = 0.042), C3 rs2230199 (P = 0.042), and CETP rs5817082 (P = 0.042) were associated with EMD, after adjustment for AMD, sex, and age. Conclusions: We found a strong association between EMD and AMD, suggesting a common pathogenesis. The GRS for AMD was not associated with EMD, but a partially overlapping genetic basis was suggested when assessing individual risk variants. We propose that EMD per se do not represent an increase in the global genetic risk for AMD.

Characterization of central-involved diabetic macular edema using OCT and OCTA.

PURPOSE: To characterize the occurrence of diabetic macular edema and the presence of abnormal retinal fluid accumulation in nonproliferative diabetic retinopathy (NPDR). METHODS: In this two-year prospective study, a total of 122 eyes with diabetes type 2 underwent optical coherence tomography (OCT) and OCT-Angiography in association with OCT-Fluid imaging, a novel algorithm of OCT analysis allowing quantification of abnormal accumulation of fluid in the retina through low optical reflectivity ratios (LOR). Early Treatment Diabetic Retinopathy Study (ETDRS) grading for diabetic retinopathy (DR) severity assessment was performed using 7-field color fundus photography. Best corrected visual acuity was also recorded. RESULTS: During the 2-year follow-up, 23 eyes (19%) developed central-involved diabetic macular edema (CI-DME) and 2 eyes (2%) developed clinically significant macular edema (CSME). In the two-year period of the study, eyes that developed CI-DME showed a progressive increase in central retinal thickness (CRT) (ß = 7.7 ± 2.1 µm/year, p < 0.001) and in LOR values (ß = 0.009 ± 0.004 ratio/year, p = 0.027). The increase in CRT and abnormal retinal fluid, represented by increased LOR ratios, are associated with increased retinal perfusion in the deep capillary plexus (DCP) (skeletonized vessel density, p = 0.039). In contrast, the eyes with CSME showed decreased retinal perfusion and abnormal fluid located in the outer layers of the retina. CONCLUSIONS: CI-DME and CSME appear to represent different entities. Eyes with CI-DME show increases in abnormal retinal fluid associated with increased retinal vascular perfusion in the DCP. Eyes with CSME are apparently associated with decreased retinal vascular perfusion in the DCP and abnormal fluid in the outer retina.

CENTRAL AND PERIPHERAL INVOLVEMENT OF THE RETINA IN THE INITIAL STAGES OF DIABETIC RETINOPATHY.

PURPOSE: To determine the degree of central microvascular closure using optical coherence tomography angiography in eyes of patients with type 2 diabetes with visible lesions only in the central retina or only in the periphery. METHODS: Cross-sectional study. All 127 eyes underwent ultra-widefield fundus photography 200° examinations with OPTOS California (Optos, Dunfermline, United Kingdom) and Cirrus Angioplex optical coherence tomography angiography 3 × 3 mm acquisitions (ZEISS, Dublin, CA). RESULTS: Twenty-five eyes showed visible lesions only in the central retina, 57 only in the peripheral retina, and 45 presented visible lesions in entire retina. The group with visible lesions only in the periphery showed definite closure in the superficial capillary plexus in 49% of the eyes, whereas the group with visible lesions only in the central seven-early treatment diabetic retinopathy study fields area showed a definite closure in 64%. CONCLUSION: Central capillary closure is already present in the initial stages of diabetic retinopathy even when lesions are only visible in the peripheral retina. Capillary closure in the superficial capillary plexus is three times more frequent than in the deep capillary plexus, demonstrating earlier closure of the superficial capillary plexus. Eyes with visible lesions only in the periphery show a milder form of retinopathy.

Additional measures of macular function beyond visual acuity.

PURPOSE: Visual function is a complex process in which external visual stimuli are interpreted. Patients with retinal diseases and prolonged follow-up times may experience changes in their visual function that are not detected by the standard visual acuity measure, as they are a result of other alterations in visual function. With the advancement of different methods to evaluate visual function, additional measurements have become available, and further standardization suggests that some methods may be promising for use in clinical trials or routine clinical practice. The objectives of this article are to review these additional measurements and to provide guidance on their application. METHODS: The Vision Academy's membership of international retinal disease experts reviewed the literature and developed consensus recommendations for the application of additional measures of visual function in routine clinical practice or clinical trials. RESULTS: Measures such as low-luminance visual acuity, contrast sensitivity, retinal fixation and microperimetry, and reading performance are measures which can complement visual acuity measurements to provide an assessment of overall visual function, including impact on patients' quality of life. Measures such as dark adaptation, color vision testing, binocular vision testing, visual recognition testing, and shape discrimination require further optimization and validation before they can be implemented in everyday clinical practice. CONCLUSION: Additional measurements of visual function may help identify patients who could benefit from earlier diagnosis, detection of disease progression, and therapeutic intervention. New and additional functional clinical trial endpoints are required to fully understand the early stages of macular disease, its progression, and the response to treatment.

Retinal neurodegeneration in eyes with NPDR risk phenotypes: A two-year longitudinal study.

INTRODUCTION: Diabetic retinopathy (DR) is both a microangiopathy and a neurodegenerative disease. However, the connections between both changes are not well known. PURPOSE: To characterise the longitudinal retinal ganglion cell layer + inner plexiform layer (GCL + IPL) changes and their association with microvascular changes in type-2 diabetes (T2D) patients with nonproliferative diabetic retinopathy (NPDR). METHODS: This two-year prospective study (CORDIS, NCT03696810) included 122 T2D individuals with NPDR identified as risk phenotypes B and C, which present a more rapid progression. Phenotype C was identified by decreased VD ≥ 2SD in healthy controls, and phenotype B, identified by subclinical macular oedema with only minimal vascular closure. The GCL + IPL thickness, vessel density, perfusion density and area of intercapillary spaces (AIS) were assessed by optical coherence tomography (OCT) and OCT angiography (OCTA). Linear mixed effects models were employed to evaluate the retinal GCL + IPL progression and its associations. RESULTS: Regarding GCL + IPL thickness, T2D individuals presented on average 80.1 ± 7.49 µm, statistically significantly lower than the healthy control group, 82.5 ± 5.71 (p = 0.022), with only phenotype C differing significantly from controls (p = 0.006). GCL + IPL thickness steadily decreased during the two-year period in both risk phenotypes, with an annual decline rate of -0.372 µm/year (p < 0.001). Indeed, phenotype C showed a higher rate of progression (-0.459 µm/year, p < 0.001) when compared to phenotype B (-0.296 µm/year, p = 0.036). Eyes with ETDRS grade 20 showed GCL + IPL thickness values comparable to those of healthy control group (83.3 ± 5.80 and 82.7 ± 5.50 µm, respectively, p = 0.880), whereas there was a progressive decrease in GCL + IPL thickness in ETDRS grades 35 and 43-47 associated with the increase in severity of the retinopathy (-0.276 µm/year, p = 0.004; -0.585 µm/year, p = 0.013, respectively). Furthermore, the study showed statistically significant associations between the progressive thinning of GCL + IPL and the progressive increase in retinal capillary non-perfusion, with particular relevance for AIS (p < 0.001). CONCLUSIONS: Our findings showed that, in eyes with NPDR and at risk for progression, retinal neurodegeneration occurs at different rates in different risk phenotypes, and it is associated with retinal microvascular non-perfusion.

Retinal Capillary Nonperfusion in Preclinical Diabetic Retinopathy.

INTRODUCTION: The aim of the study was to identify retinal microvascular changes using optical coherence tomography angiography (OCTA) in type 2 diabetes (T2D) patients with preclinical retinopathy identified by ultra-widefield fundus photography (UWF-FP). METHODS: This is a cross-sectional observational study. All patients underwent UWF-FP 200° examinations with OPTOS California (Optos, Dunfermline, UK) and Cirrus AngioPlex® spectral-domain (SD)-OCTA 3 × 3 mm acquisitions (ZEISS, Dublin, CA, USA). The absence of visible lesions was identified using UWF-FP. RESULTS: One hundred and ninety three eyes of individuals with T2D with no visible lesions in the fundus and identified in a screening setting were included in the study. Skeletonized vessel density (SVD), perfusion density (PD), and areas of capillary nonperfusion (CNP) values on SD-OCTA were significantly decreased when compared with healthy population (p < 0.001). SVD and CNP values of the superficial capillary plexus (SCP) were more frequently decreased (35% and 45%, respectively) than SVD values of the deep capillary plexus (DCP) (9% and 15%, respectively), demonstrating that diabetic microvascular changes occur earlier in the SCP than in the DCP. The ischemic phenotype, identified by a definite decrease in SVD or CNP in the SCP may, therefore, be identified in the preclinical stage of diabetic retinal disease. CONCLUSIONS: Retinal capillary nonperfusion detected by OCTA metrics of SVD and CNP can be identified in the central retina in eyes with T2D before development of visible lesions in the retina. Our findings confirm the relevance of OCTA to identify macular microvascular changes in the initial stages of diabetic retinopathy, allowing the identification of its ischemic phenotype very early in the disease process.

Interaction between genetics and the adherence to the Mediterranean diet: the risk for age-related macular degeneration. Coimbra Eye Study Report 8.

BACKGROUND: Age-related macular degeneration (AMD) is a multifactorial degenerative disease of the macula. Different factors, environmental, genetic and lifestyle, contribute to its onset and progression. However, how they interconnect to promote the disease, or its progression, is still unclear. With this work, we aim to assess the interaction of the genetic risk for AMD and the adherence to the Mediterranean diet in the Coimbra Eye Study. METHODS: Enrolled subjects (n = 612) underwent ophthalmological exams and answered a food questionnaire. Adherence to the Mediterranean diet was assessed with mediSCORE. An overall value was calculated for each participant, ranging from 0 to 9, using the sum of 9 food groups, and a cut off value of ≥ 6 was considered high adherence. Rotterdam Classification was used for grading. Participants' genotyping was performed in collaboration with The European Eye Epidemiology Consortium. The genetic risk score (GRS) was calculated for each participant considering the number of alleles at each variant and their effect size. Interaction was assessed with additive and multiplicative models, adjusted for age, sex, physical exercise, and smoking. RESULTS: The AMD risk was reduced by 60% in subjects with high adherence to the Mediterranean diet compared to subjects with low adherence to the Mediterranean diet. Combined effects of having low adherence to the Mediterranean diet and high GRS led to almost a 5-fold increase in the risk for AMD, compared to low GRS and high adherence to the Mediterranean diet. The multiplicative scale suggested a multiplicative interaction, although not statistically significant [odds ratio (OR) = 1.111, 95% CI 0.346-3.569, P = 0.859]. The additive model showed a causal positive effect of the interaction of GRS and adherence to the Mediterranean diet: relative excess risk due to interaction (RERI) = 150.9%, (95% CI: - 0.414 to 3.432, P = 0.062), attributable proportion due to interaction (AP) = 0.326 (95% CI: - 0.074 to 0.726, P = 0.055) and synergy index (SI) = 1.713 (95% CI: 0.098-3.329, P = 0.019). High GRS people benefited from adhering to the Mediterranean diet with a 60% risk reduction. For low-GRS subjects, a risk reduction was also seen, but not significantly. CONCLUSIONS: Genetics and Mediterranean diet interact to protect against AMD, proving there is an interplay between genetics and environmental factors. TRIAL REGISTRATION: The AMD Incidence (NCT02748824) and Lifestyle and Food Habits Questionnaire in the Portuguese Population Aged 55 or More (NCT01715870) studies are registered at www. CLINICALTRIALS: gov . Five-year Incidence of Age-related Macular Degeneration in the Central Region of Portugal (AMD IncidencePT); NCT02748824: date of registration: 22/04/16. Lifestyle and Food Habits Questionnaire in the Portuguese Population Aged 55 or More; NCT01715870: date of registration: 29/10/12.

Stereoelectroencephalography Implantation Using Frameless Neuronavigation and Varioguide: Prospective Analysis of Accuracy and Safety in a Case Series of 11 Patients.

BACKGROUND: Stereoencephalography (SEEG) is becoming a widespread diagnostic procedure for drug-resistant epilepsy investigation. Techniques include frame-based and robot-assisted implantation, and more recently, frameless neuronavigated systems (FNSs). Despite its recent use, the accuracy and safety of FNS are still under investigation. OBJECTIVE: To assess in a prospective study the accuracy and safety of a specific FNS use for SEEG implantation. METHODS: Twelve patients who underwent SEEG implantation using FNS (Varioguide [Brainlab]) were included in this study. Data were collected prospectively and included demographic data, postoperative complications, functional results, and implantation characteristics (i.e., duration and number of electrodes). Further analysis included accuracy at entry point and target using measurements of the euclidean distance between planned and actual trajectories. RESULTS: Eleven patients underwent SEEG-FNS implantation from May 2019 to March 2020. One patient did not undergo surgery because of a bleeding disorder. The mean target deviation was 4.06 mm, and mean entry point deviation was 4.2 mm, with insular electrodes significantly more deviated. Results excluding insular electrodes showed a mean target deviation of 3.66 mm and a mean entry point deviation of 3.77 mm. No severe complications occurred; a few mild to moderate adverse events were reported (1 superficial infection, 1 seizure cluster, and 3 transient neurologic impairments). The mean implantation duration by electrodes was 18.5 minutes. CONCLUSIONS: Implantation of depth electrodes for SEEG using FNS seems to be safe, but larger prospective studies are needed to validate these results. Accuracy is sufficient for noninsular trajectories but warrant caution for insular trajectories with statistically significantly less accuracy.

Serum glial fibrillary acidic protein and neurofilament light chain as biomarkers of retinal neurodysfunction in early diabetic retinopathy: results of the EUROCONDOR study.

AIMS: Neurodegeneration and glial activation are primary events in the pathogenesis of diabetic retinopathy. Serum glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) are biomarkers of underlying neuroinflammatory and neurodegenerative disease processes. The aim of the present study was to assess the usefulness of these serum biomarkers for the identification and monitoring of retinal neurodysfunction in subjects with type 2 diabetes. METHODS: A case-control study was designed including 38 patients from the placebo arm of the EUROCONDOR clinical trial: 19 with and 19 without retinal neurodysfunction assessed by multifocal electroretinography. GFAP and NfL were measured by Simoa. RESULTS: Serum levels of GFAP and NfL directly correlated with age (r = 0.37, p = 0.023 and r = 0.54, p < 0.001, respectively). In addition, a direct correlation between GFAP and NfL was observed (r = 0.495, p = 0.002). Serum levels of GFAP were significantly higher at baseline in those subjects in whom neurodysfunction progressed after the 2 years of follow-up (139.1 ± 52.5 pg/mL vs. 100.2 ± 54.6 pg/mL; p = 0.04). CONCLUSIONS: GFAP could be a useful serum biomarker for retinal neurodysfunction. Monitoring retinal neurodysfunction using blood samples would be of benefit in clinical decision-making. However, further research is needed to validate this result as well as to establish the best cutoff values.

Second surgery after vertical paramedian hemispherotomy for epilepsy recurrence.

Background: Vertical Paramedian Hemispherotomy (VPH) is considered an effective surgical treatment for drug-resistant epilepsy with 80% of patients experiencing seizure freedom or worthwhile improvement. Identifying persistent connective tracts is challenging in failed VPH. Methods: We reviewed our series of consecutive patients undergoing VPH for hemispheric drug-resistant epilepsy and included cases with recurrent epileptic seizures undergoing second surgery with at least 6 months of postoperative follow-up. The cases were extensively assessed to propose a targeted complementary resection. Results: Two children suffering from seizure recurrence following hemispherotomy leading to second surgery were included. After complete assessment, persisting amygdala residue was suspected responsible for the epilepsy recurrence in both patients. Complementary resection of the amygdala residue led to seizure freedom for both patients (Engel IA/ILAE Class 1) without complication. Different diagnostic tools are used to assess patients after failed hemispherotomy including routine EEG, prolonged video EEG, MRI (particularly DTI sequences), SPECT or PET scans and clinical evaluation. These tools allow to rule out epileptic foci in the contralateral hemisphere and to localize a potentially persisting epileptogenic zone. Assessment of these patients should be as systematic and integrated as the initial workup. Although our two patients suffered from Rasmussen's encephalitis, seizure recurrence after VPH has been described in other pathologies. Conclusion: Lying deep and medially in the surgical corridor of VPH, the amygdala can be incompletely resected and cause recurrent epilepsy. Complementary selective resection of the amygdala residue may safely lead to success in epilepsy control.

The Importance of the Hypogastric Artery Preservation during Treatment for Aortoiliac Aneurysms: A Prospective Single-Center Study.

BACKGROUND: To determine the importance of the hypogastric artery for the outcomes of survival, endoleaks, reinterventions, buttock claudication (BC), and perioperative mortality rate (PMR) in patients with aortoiliac aneurysms (AIA) receiving endovascular or open surgical (OS) repair. METHODS: This was a prospective consecutive cohort study of patients with AIA who underwent endovascular treatment or OS repair during the period of 2010-2021. Endovascular repair was performed with use of aortoiliac endoprosthesis associated with internal iliac artery (IIA) coil embolization and/or with iliac branch endoprosthesis (IBE) in order to preserve the IIA. The AIA OS repairs were performed with the artery ligation in order to exclude the IIA, or in some cases, the exclusion of the IIA was performed with an endosuture in the proximal stump of the artery. Three groups were identified in the postprocedural period: group 0 (no hypogastric arteries (HAs) preserved), group 1 (1 hypogastric artery preserved), and group 2 (2 hypogastric arteries preserved). RESULTS: A total of 91 patients were submitted to OS or endovascular surgery. Regarding the HA patency, there were 17 patients in group 0, 45 patients in group 1, and 29 patients in group 2. There were 17 cases of bowel ischemia (BI) (94.1% in group 0, 5.9% in group 1, and no cases in group 2, P < 0.001) most of them in group 0, with statistical significance, 12 cases of BC (91.7% in group 0, 8.3% in group 1, and no cases in group 2, P < 0.001), most of them in group 0, with statistical significance. The perioperative mortality was 14.3%, 13 patients (9 patients - 52.9% group 0, 3 patients - 6.7% group 1, and 1 patient - 3.4% group 2, P < 0.001). The linear regression analysis for survival rates showed that BI [P = 0.026 to hazard ratio (HR) = 1.69], emergency aortoiliac repair (P < 0.001, HR = 8.86), and number of HAs (P < 0.001, HR = 5.46) in postoperative were related to poorer survival rates in both univariate and multivariate analysis. The linear regression analysis showed that the number of HAs (P < 0.001, HR = 3.61) in postoperative, emergency aortoiliac repair (P = 0.002, HR 3.233), and cardiac disease (P = 0.048, HR = 3.84) were related to BI. CONCLUSIONS: In conclusion, the number of HA is crucial for adequate and safe outcomes after abdominal aortic aneurysm (AAA) repair. The main factors related to death were BI, emergency aortoiliac repair, and the number of HAs preserved. Moreover, the main factors related to BI were the number of HAs in postoperative, emergency aortoiliac repair, and cardiac disease.

Characterisation of progression of macular oedema in the initial stages of diabetic retinopathy: a 3-year longitudinal study.

BACKGROUND/OBJECTIVES: To characterise the prevalence and three-year progression of centre-involving diabetic macular oedema (CI-DMO) in minimal to moderate non-proliferative diabetic retinopathy, using optical coherence tomography (OCT) and measurements of retinal fluid using tissue optical reflectivity ratios (OCT-Leakage). METHODS/METHODS: Seventy-four eyes from 74 patients were followed in a 3-year prospective longitudinal observational cohort of type 2 diabetes (T2D) patients using spectral-domain optical coherence tomography (SD-OCT), OCT-Angiography (OCT-A) and OCT-Leakage (OCT-L). Eyes were examined four times with 1-year intervals. Sixteen eyes (17.8%) were excluded from the analysis due to quality control standards. Retinal oedema was measured by central retinal thickness and retinal fluid by using optical reflectivity ratios obtained with the OCT-L algorithm. Vessel density was measured by OCT-A. Thinning of the ganglion cell and inner plexiform layers (GCL + IPL) was examined to identify retinal neurodegenerative changes. Diabetic retinopathy ETDRS classification was performed using the seven-field ETDRS protocol. RESULTS: CI-DMO was identified in the first visit in 9% of eyes in ETDRS groups 10-20, 10% of eyes in ETDRS group 35 and 15% of eyes in ETDRS groups 43-47. The eyes with CI-DMO and subclinical CI-DMO showed a progressive increase in retinal extracellular fluid during the 3-year period of follow-up. The eyes with CI-DMO and increased retinal extracellular fluid accumulation were associated with vision loss. CONCLUSIONS: The prevalence of subclinical CI-DMO and CI-DMO in the initial stages of NPDR occurs independently of severity grading of the retinopathy, showing progressive increase in retinal extracellular fluid and this increase is associated with vision loss (82% 9 out of 11 cases).

Perspectives of diabetic retinopathy-challenges and opportunities.

Diabetic retinopathy (DR) may lead to vision-threatening complications in people living with diabetes mellitus. Decades of research have contributed to our understanding of the pathogenesis of diabetic retinopathy from non-proliferative to proliferative (PDR) stages, the occurrence of diabetic macular oedema (DMO) and response to various treatment options. Multimodal imaging has paved the way to predict the impact of peripheral lesions and optical coherence tomography-angiography is starting to provide new knowledge on diabetic macular ischaemia. Moreover, the availability of intravitreal anti-vascular endothelial growth factors has changed the treatment paradigm of DMO and PDR. Areas of research have explored mechanisms of breakdown of the blood-retinal barrier, damage to pericytes, the extent of capillary non-perfusion, leakage and progression to neovascularisation. However, knowledge gaps remain. From this perspective, we highlight the challenges and future directions of research in this field.

Different Risk Profiles for Progression of Nonproliferative Diabetic Retinopathy: A 2-Year Study.

INTRODUCTION: Characterization of 2-year progression of different risk phenotypes in eyes with mild and moderate nonproliferative diabetic retinopathy (NPDR) in type 2 diabetes (T2D). METHODS: A 2-year prospective longitudinal cohort study (CORDIS, NCT03696810) was conducted. Ophthalmological examinations were performed including best corrected visual acuity, color fundus photography and optical coherence tomography (OCT and OCTA). OCT metrics, central retinal thickness and ganglion cell layer + inner plexiform layer (GCL + IPL) thickness were analyzed. OCTA metrics, vessel density (VD), perfusion density (PD) and area of intercapillary spaces (AIS) were obtained from superficial and deep capillary plexus (SCP, DCP). Only phenotype C identified by decreased VD ≥ 2 SD of healthy controls and phenotype B identified by subclinical macular edema with decreased VD < 2 SD of healthy controls were included. RESULTS: One hundred twenty-two eyes from T2D individuals were included in study; 65 eyes (53%) were classified as phenotype B and 57 eyes (47%) as phenotype C. For phenotype B, progression was associated with thinning of the GCL + IPL (ETDRS 35, 1 year p = 0.013, 2 year p < 0.001; ETDRS 43-47, 2 year p = 0.003) and vessel closure involving mainly the DCP for both ETDRS grades (ETDRS 35, 1 year p = 0.025, 2 year p = 0.034; ETDRS 43-47, 1 year p = 0.011). For phenotype C there was also progressive thinning of the GCL + IPL (ETDRS 35, in both years p ≤ 0.001; ETDRS 43-47, 1 year p = 0.002, 2 year p = 0.001), with vessel closure involving mainly SCP (ETDRS 35, 1 year p = 0.012, 2 year p = 0.023 in full-retina), which appeared to stabilize at maximal values in ETDRS grade 43-47 at the end of 2 years. ETDRS severity changes at the end of the 2-year period showed that worsening was associated with phenotype C with changes involving predominantly the SCP (VD, p = 0.005; PD, p = 0.008; AIS, p = 0.005). CONCLUSIONS: Association between ETDRS classification of NPDR severity and identification of different risk phenotypes offers new perspective to predict disease progression in T2D individuals with NPDR.

Common and rare genetic risk variants in age-related macular degeneration and genetic risk score in the Coimbra eye study.

PURPOSE: To determine the contribution of common and rare genetic variants in age-related macular degeneration (AMD) in a Portuguese population from the Coimbra Eye Study (CES), and the genetic risk score (GRS). METHODS: Participants underwent ophthalmologic examination and imaging. A centralized reading centre performed AMD staging. Genetic sequencing was carried out with the EYE-RISK assay. Sixty-nine single nucleotide polymorphisms (SNPs) were genotyped and tested for association with AMD. Case-control and progression-to-AMD analyses were performed using logistic regression to assess allelic odds ratio (OR) at a 95% confidence interval (CI) for each variant. GRS was calculated for cases/controls and progressors/non-progressors. Cumulative impact of rare variants was compared between cases/controls using logistic regression. RESULTS: In case-control analysis (237 cases/640 controls) variants associated with risk of disease were: ARMS2 rs10490924, ARMS2_HTRA1 rs3750846, CFH rs35292876, SLC16A8 rs8135665, TGFBR1 rs1626340. Major risk variants ARMS2/HTRA1 rs3750846, CFH rs570618 and C3 rs2230199 had unexpected lower allele frequency (AF), and the highest risk-conferring variant was a rare variant, CFH rs35292876 (OR, 2.668; p-value = 0.021). In progression-to-AMD analysis (137 progressors/630 non-progressors), variants associated with risk of progression were ARMS2 rs10490924, ARMS2_HTRA1 rs3750846, CFH rs35292876. GRS of cases/controls was 1.124 ± 1.187 and 0.645 ± 1.124 (p-value < 0.001), and of progressors/non-progressors was 1.190 ± 1.178 and 0.669 ± 1.141 (p-value < 0.001). Higher proportion of pathogenic rare CFH variants was observed in cases (OR, 9.661; p-value < 0.001). CONCLUSIONS: Both common and rare variants were associated with AMD, but a CFH rare variant conferred the highest risk of disease while three major risk variants had a lower-than-expected AF in our population originary from a geographic region with lower prevalence of AMD. GRS was still significantly higher in AMD patients. Damaging CFH rare variants were cumulatively more common in AMD cases.

Characterization of two-year progression of different phenotypes of nonproliferative diabetic retinopathy.

INTRODUCTION: To characterize the two-year progression of risk phenotypes of nonproliferative diabetic retinopathy (NPDR) in type 2 diabetes (T2D) Phenotype C, or ischemic phenotype, identified by decreased skeletonized retinal vessel density (VD), ≥ 2 SD over normal values, and Phenotype B, or edema phenotype, identified by increased retinal thickness, i.e. subclinical macular edema, and no significant decrease in VD. METHODS: A prospective longitudinal cohort study (CORDIS, NCT03696810) was conducted with 4 visits (baseline, 6-months, one-year and two-year). Ophthalmological examinations included best corrected visual acuity, color fundus photography (CFP) and optical coherence tomography (OCT) and OCT Angiography. Early Treatment Diabetic Retinopathy Study grading was performed at the baseline and last visits based on 7-fields CFP. RESULTS: One hundred and twenty-two eyes from T2D individuals with NPDR fitted in the categories of phenotype B and C and completed the two-years follow-up. Sixty-five (53%) of the eyes were classified as phenotype B and 57 (47%) eyes as phenotype C. Neurodegeneration represented by thinning of the ganglion cell layer and inner plexiform layer was present in both phenotypes and showed significant progression over the two-year period (p<0.001). In phenotype C, significant progression in the two-year period was identified in decreased skeletonized VD (p=0.01), whereas in phenotype B microvascular changes involved preferentially decreases in perfusion density (PD, p=0.012). Phenotype B with changes in VD and PD (flow) and preferential involvement of the deep capillary plexus (p<0.001) is associated with development of center-involved macular edema. DISCUSSION: In the two-year period of follow-up both phenotypes B and C showed progression in retinal neurodegeneration, with changes at the microvascular level characterized by decreases in PD in phenotype B and decreases in VD in phenotype C.

Phenotypic Expression of CFH Rare Variants in Age-Related Macular Degeneration Patients in the Coimbra Eye Study.

Purpose: To determine the association between rare genetic variants in complement factor H (CFH) and phenotypic features in age-related macular degeneration (AMD) patients from the Coimbra Eye Study (CES). Methods: AMD patients from the Incidence CES (NCT02748824) underwent ophthalmologic examination and color fundus photography, spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence, and near-infrared imaging. Multimodal phenotypic characterization was carried out in a centralized reading center. The coding and splice-site regions of the CFH gene were sequenced through single-molecule molecular inversion probe-based next-generation sequencing in association with the EYE-RISK consortium. Variants with minor allele frequency <0.05 resulting in splice-site or protein change were selected. Differences in phenotypic features between carriers and noncarriers were analyzed using generalized estimated equations logistic regression models, considering intereye correlations. Results: We included 39 eyes of 23 patients carrying rare CFH variants and 284 eyes of 188 noncarriers. Carrier status was associated with having higher drusen burden in the macula in the inner Early Treatment Diabetic Retinopathy Study circle (odds ratio [OR], 5.44 [95% confidence interval {CI}, 1.61-18.37]; P = 0.006), outer circle (OR, 4.37 [95% CI, 1.07-17.77]; P = 0.04), and full grid (OR, 4.82 [95% CI, 1.13-20.52]; P = 0.033). In SD-OCT, a lower total macular volume and lower inner retinal layers' volume (OR, 0.449 [95% CI, 0.226-0.894]; P = 0.023; OR, 0.496 [95% CI, 0.252-0.979]; P = 0.043) and pigment epithelial detachments (PEDs) (OR, 5.24 [95% CI, 1.08-25.44]; P = 0.04) were associated with carrying a rare CFH variant. Carriers with subretinal drusenoid deposits (SDD) had the rare variant P258L in all cases except one. Conclusions: We identified in our cohort phenotypic differences between carriers and noncarriers of rare variants in the CFH gene. Carriers had more severe disease, namely superior drusen burden, PEDs, and thinner retinas. The rare variant P258L may be associated with SDD. Carriers are probably at increased risk of progression.

Outcome of Patients with Surgical Site Infection after Craniotomy.

Background: The management of surgical site infection (SSI) after craniotomy remains challenging with few existing recommendations. Patients and Methods: We reviewed the medical files of patients who underwent surgery between 2009 and 2018 to manage infection after craniotomy at our tertiary hospital. The Cox proportional hazards model and the Renyi test were used to investigate the association between relapse or all-cause mortality and selected variables. We compared infections with and without intra-cranial involvement using the Fisher test and the Wilcoxon rank sum test. Results: Seventy-seven episodes of infection were identified in 58 patients. The proportion of relapse was estimated to be 32.2% (± standard deviation [SD] 6.9) at five years. Intra-cranial infection was present in 15.6% of the cases (n = 12). Bone flap was removed in the majority of cases (93.5%) and the overall median duration of antibiotic therapy was six weeks (interquartile range [IQR] 6-12 weeks). Staphylococcus aureus was associated with a higher risk of relapse (p = 0.037). The administration of parenteral antibiotic agents (p = 0.012) and bone flap removal (p = 0.0051) were correlated with less relapse. In contrast, immunosuppressive drug use and radiotherapy were correlated with a higher risk of relapse (p = 0.014 and p = 0.031, respectively) and a higher all-cause mortality (p = 0.0093 and p < 0.0001, respectively). We found no difference between infections with and without intra-cranial involvement. Conclusions: Bone flap removal and parenteral antibiotic agents remain important in the management of SSI after craniotomy and were associated with less relapse in our study. More studies are needed to better determine the optimal treatment of this infection.