Long-Term Ranibizumab Treatment in Neovascular Age-Related Macular Degeneration: A Belgian Subanalysis from the Global Real-World LUMINOUS TM Study

To evaluate long-term, real-world treatment patterns and outcomes of ranibizumab 0.5 mg for neovascular age-related macular degeneration (nAMD) in a Belgian cohort.; This Belgian (BE) cohort of the 5-year global observational LUMINOUS study included 229 patients with nAMD. Outcomes included visual acuity (VA), central retinal thickness (CRT) and safety.; The mean age was 79.5±7.7 years. The majority of patients (67.7%) were female and all patients were Caucasian. Most patients previously received ranibizumab with only 17.5% of patients being treatment-naïve. The injection frequency declined over time irrespective of prior treatment status (p<0.0001), with treatment-naïve eyes receiving a mean of 4.2±2.9 yearly injections and prior-ranibizumab eyes 3.6±2.7. Regression analysis confirmed first-year VA increases for treatment-naïve eyes (p=0.002) followed by a slight decrease of -1.8 letters per year. For prior-ranibizumab eyes, the visual changes over 1 year were statistically non-significant (p=0.90) but declined slightly after year one (p<0.0001). Anatomically, the CRT of treatment-naïve eyes decreased over time from baseline (p<0.0001), whereas the CRT of prior-ranibizumab eyes remained stable (p=0.43). No new safety findings were identified.; LUMINOUS-BE reconfirms the well-characterized benefit-risk profile of ranibizumab for nAMD treatment. The observed low injection frequency reflects a need for more rigorous treatment in real-world settings.; NCT01318941

Clinical autonomic nervous system laboratories in Europe: a joint survey of the European Academy of Neurology and the European Federation of Autonomic Societies

© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Background and purpose: Disorders of the autonomic nervous system (ANS) are common conditions, but it is unclear whether access to ANS healthcare provision is homogeneous across European countries. The aim of this study was to identify neurology-driven or interdisciplinary clinical ANS laboratories in Europe, describe their characteristics and explore regional differences. Methods: We contacted the European national ANS and neurological societies, as well as members of our professional network, to identify clinical ANS laboratories in each country and invite them to answer a web-based survey. Results: We identified 84 laboratories in 22 countries and 46 (55%) answered the survey. All laboratories perform cardiovascular autonomic function tests, and 83% also perform sweat tests. Testing for catecholamines and autoantibodies are performed in 63% and 56% of laboratories, and epidermal nerve fiber density analysis in 63%. Each laboratory is staffed by a median of two consultants, one resident, one technician and one nurse. The median (interquartile range [IQR]) number of head-up tilt tests/laboratory/year is 105 (49-251). Reflex syncope and neurogenic orthostatic hypotension are the most frequently diagnosed cardiovascular ANS disorders. Thirty-five centers (76%) have an ANS outpatient clinic, with a median (IQR) of 200 (100-360) outpatient visits/year; 42 centers (91%) also offer inpatient care (median 20 [IQR 4-110] inpatient stays/year). Forty-one laboratories (89%) are involved in research activities. We observed a significant difference in the geographical distribution of ANS services among European regions: 11 out of 12 countries from North/West Europe have at least one ANS laboratory versus 11 out of 21 from South/East/Greater Europe (p = 0.021). Conclusions: This survey highlights disparities in the availability of healthcare services for people with ANS disorders across European countries, stressing the need for improved access to specialized care in South, East and Greater Europe.info:eu-repo/semantics/publishedVersio

EFAS/EAN survey on the influence of the COVID-19 pandemic on European clinical autonomic education and research

© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.Purpose: To understand the influence of the coronavirus disease 2019 (COVID-19) pandemic on clinical autonomic education and research in Europe. Methods: We invited 84 European autonomic centers to complete an online survey, recorded the pre-pandemic-to-pandemic percentage of junior participants in the annual congresses of the European Federation of Autonomic Societies (EFAS) and European Academy of Neurology (EAN) and the pre-pandemic-to-pandemic number of PubMed publications on neurological disorders. Results: Forty-six centers answered the survey (55%). Twenty-nine centers were involved in clinical autonomic education and experienced pandemic-related didactic interruptions for 9 (5; 9) months. Ninety percent (n = 26/29) of autonomic educational centers reported a negative impact of the COVID-19 pandemic on education quality, and 93% (n = 27/29) established e-learning models. Both the 2020 joint EAN-EFAS virtual congress and the 2021 (virtual) and 2022 (hybrid) EFAS and EAN congresses marked higher percentages of junior participants than in 2019. Forty-one respondents (89%) were autonomic researchers, and 29 of them reported pandemic-related trial interruptions for 5 (2; 9) months. Since the pandemic begin, almost half of the respondents had less time for scientific writing. Likewise, the number of PubMed publications on autonomic topics showed the smallest increase compared with other neurological fields in 2020-2021 and the highest drop in 2022. Autonomic research centers that amended their trial protocols for telemedicine (38%, n = 16/41) maintained higher clinical caseloads during the first pandemic year. Conclusions: The COVID-19 pandemic had a substantial negative impact on European clinical autonomic education and research. At the same time, it promoted digitalization, favoring more equitable access to autonomic education and improved trial design.info:eu-repo/semantics/publishedVersio

Identification of additional risk loci for stroke and small vessel disease: a meta-analysis of genome-wide association studies

BACKGROUND: Genetic determinants of stroke, the leading neurological cause of death and disability, are poorly understood and have seldom been explored in the general population. Our aim was to identify additional loci for stroke by doing a meta-analysis of genome-wide association studies. METHODS: For the discovery sample, we did a genome-wide analysis of common genetic variants associated with incident stroke risk in 18 population-based cohorts comprising 84 961 participants, of whom 4348 had stroke. Stroke diagnosis was ascertained and validated by the study investigators. Mean age at stroke ranged from 45·8 years to 76·4 years, and data collection in the studies took place between 1948 and 2013. We did validation analyses for variants yielding a significant association (at p<5 × 10(-6)) with all-stroke, ischaemic stroke, cardioembolic ischaemic stroke, or non-cardioembolic ischaemic stroke in the largest available cross-sectional studies (70 804 participants, of whom 19 816 had stroke). Summary-level results of discovery and follow-up stages were combined using inverse-variance weighted fixed-effects meta-analysis, and in-silico lookups were done in stroke subtypes. For genome-wide significant findings (at p<5 × 10(-8)), we explored associations with additional cerebrovascular phenotypes and did functional experiments using conditional (inducible) deletion of the probable causal gene in mice. We also studied the expression of orthologs of this probable causal gene and its effects on cerebral vasculature in zebrafish mutants. FINDINGS: We replicated seven of eight known loci associated with risk for ischaemic stroke, and identified a novel locus at chromosome 6p25 (rs12204590, near FOXF2) associated with risk of all-stroke (odds ratio [OR] 1·08, 95% CI 1·05-1·12, p=1·48 × 10(-8); minor allele frequency 21%). The rs12204590 stroke risk allele was also associated with increased MRI-defined burden of white matter hyperintensity-a marker of cerebral small vessel disease-in stroke-free adults (n=21 079; p=0·0025). Consistently, young patients (aged 2-32 years) with segmental deletions of FOXF2 showed an extensive burden of white matter hyperintensity. Deletion of Foxf2 in adult mice resulted in cerebral infarction, reactive gliosis, and microhaemorrhage. The orthologs of FOXF2 in zebrafish (foxf2b and foxf2a) are expressed in brain pericytes and mutant foxf2b(-/-) cerebral vessels show decreased smooth muscle cell and pericyte coverage. INTERPRETATION: We identified common variants near FOXF2 that are associated with increased stroke susceptibility. Epidemiological and experimental data suggest that FOXF2 mediates this association, potentially via differentiation defects of cerebral vascular mural cells. Further expression studies in appropriate human tissues, and further functional experiments with long follow-up periods are needed to fully understand the underlying mechanisms

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries

Expression of defensin in the human hair follicle

Abstract Haarfollikel stellen eine Unterbrechung der kontinuierlichen Barriere der Haut dar. Als Reservoir für topisch applizierte Substanzen, aber auch für eine mikrobielle Kolonisation ist u. a. das Infundibulum ein Ort intensiver Interaktion mit Umweltfaktoren. Antimikrobielle Peptide wie β-Defensine sind wichtige Abwehr- und Botenstoffe und haben zusätzliche regulatorische Funktionen. Ziel dieser Arbeit war es, die Expressionsmuster von β-Defensinen in Vellus (VHF)- und Terminalhaarfollikeln (THF) vergleichend zu analysieren und hieraus Schlussfolgerungen bezüglich weitergehender biologischer Funktionen zu ziehen. Haarfollikel-tragende Gewebeschnitte menschlicher Haut des behaarten Kopfes und der Retroaurikularregion wurden mittels immunhistochemischer und immunfluoreszierender Färbungen hinsichtlich der Expression der β-Defensine hBD-1, hBD-2, hBD-3 untersucht. Insgesamt wurden 148 Kryostatschnitte beurteilt (hBD-1 = 51, hBD-2 = 54, hBD-3 = 43). Die Auswertung der Lokalisation und Intensität der Färbungen erfolgte semiquantitativ unter Berücksichtigung der anatomischen Schicht des Follikels sowie der Tiefe der Kompartimente in der Haut, unterteilt in Infundibulum, Isthmus, infraseboglandulären und suprabulbären Bereich, Haarbulbus und Talgdrüse. In Bereichen, in denen von einer hohen immunologischen Aktivität ausgegangen werden kann, fanden wir in unserer Untersuchung eine entsprechend starke konstitutive Expression der drei β-Defensine, so in der distalen äußeren Wurzelscheide (ÄWS), um den Haarkanal herum und im Bereich der Einmündung der Talgdrüsengänge. Im Weiteren ergab sich ein deutlich differenziertes Bild. Eine maximale Expression von hBD-3 fand sich in der ÄWS im proximalen Follikel. Im Gegensatz dazu ließen sich hBD-1 und hBD-2 vorwiegend im distalen Follikel nachweisen. In der inneren Wurzelscheide des Haarfollikels wurden die drei β-Defensine in allen Haartypen sehr ausgeprägt exprimiert, aber mit unterschiedlichen Verteilungen. Als Besonderheit war in der Medulla (THF) eine stärkere Expression von hBD-1 und hBD-2 zu finden. Auch in der fibrösen Hülle und in der Grenzzone zwischen der äußeren und inneren Wurzelscheide konnte eine starke Immunfärbung von hBD-3 dargestellt werden. Sowohl in VHF als auch in THF wurden alle untersuchten β-Defensine exprimiert. Obwohl die Größendimensionen der Follikeltypen sehr unterschiedlich sind und eine unterschiedliche mikrobielle Kolonisierung angenommen werden muss, fanden sich keine grundsätzlichen Unterschiede in den Expressionsmustern. Die Funktion der Expression der immunstimulatorischen Moleküle hBD-1, hBD-2 und hBD-3 im distalen Haarfollikel entspricht der aus der interfollikulären Epidermis bekannten Funktion im Rahmen der natürlichen Immunabwehr. Die Expression von hBD-2 sowie hBD-3 in klar definierten Kompartimenten der tieferen Haarfollikelabschnitte weist neben der antimikrobiellen auf eine zusätzliche regulatorische Funktion hin. Molekulare Verknüpfungen mit Signalwegen, die u. a. an der Aufrechterhaltung des bulbären Immunprivilegs beteiligt sind, sind beschrieben, so dass die vorliegenden Befunde wichtige Anknüpfungspunkte für weitergehende Untersuchungen ergeben.Abstract (englisch) Hair-follicles constitute disruptions of the continuous skin-barrier. Being a reservoir for topically applied substances but also for microbial colonization the infundibulum serves as a place of intensive interaction with environmental factors. Antimicrobial peptides like β-defensines are important defence- and messenger-molecules with regulative functions. The aim of this thesis was to compare the expression-pattern of β-defensines in vellus (VHF)- and terminal hair-follicles (THF) to draw conclusions regarding additional biological functions. Tissue-sections bearing hair-follicles of human hairy scalp and of the retroauricular area were analyzed for the expression of the β-defensines hBD-1, hBD-2 und hBD-3 using immunohistochemic and immunofluorescent stainings. A total of 148 cryosections were assessed (hBD-1=51, hBD-2=54, hBD-3=43). The semiquantitative evaluation of the localization and intensity of the stainings includes the anatomical layer of the follicle and the depth of the skin compartment, segmented into infundibulum, isthmus, infra-sebaceousglandular and supra-bulbar areas, hair- bulb and sebaceous gland. In areas of presumably high immunological activity i. e. in the distal part of the outer root sheath (ORS), around the hair- channel and near the junction of the sebaceous gland-ducts we detected a high constitutive expression of the three β-defensines. Further examinations revealed a more differentiated pattern. The highest expression of hBD-3 was found in the ORS of the proximal follicle, whereas hBD-1 und hBD-2 could be predominantly detected in the distal follicles. The three β-defensines were strongly expressed in the inner root-sheat of the hair-follicle of all hair- types, but with different distributions. As a special feature there was a stronger expression of hBD-1 and hBD-2 in the medulla. Additionally a strong immunological staining of hBD-3 was detected in the fibrotic cover and in border-zone between outer and inner ORS. All examined β-defensines were expressed in VHF as well as in THF. In spite of the different size dimension of the follicle-types and the presumably different microbial colonization no principal differences in the expression-patterns could be found. The function of the expression of the immunstimulatory molecules hBD-1, hBD-2 und hBD-3 in the distal hair-follicles is equivalent to the one in the interfollicular epidermis within the scope of the natural immune-defence. The expression of hBD-2 and hBD-3 in clearly defined compartments of deeper hair-follicle-parts refers to a regulative function beyond the antimicrobial properties. Molecular links to signal-pathways which are involved in the maintenance of the bulbar immune-privilege are described, revealing important links for further studies

Traumatic retinopathy presenting as acute macular neuroretinopathy

Aim: Traumatic retinopathy presenting as acute macular neuroretinopathy (AMNR) is an uncommon disease causing paracentral scotomas after indirect trauma. Methods: We report on five patients (six eyes) with AMNR with a temporary reduction of visual acuity and persistent paracentral scotomas after indirect trauma. The findings were documented using multimodal imaging and the follow-up was up to 32months. Results: Initially, fundoscopy was unremarkable in all patients while visual acuity (Snellen equivalents) varied between 0.03 and 1.0, and a paracentral scotoma was present in all patients. During follow-up, visual acuity recovered to 1.0 in all patients while the paracentral scotomas persisted. Spectral-domain optical coherence tomography revealed a disruption of the inner/outer segment junction within the macular lesion and changes in the outer nuclear layer, which slowly recovered partly during the follow-up. Conclusions: These findings suggest that indirect trauma can cause changes in the outer retina resembling those seen in AMNR, resulting in persisting paracentral scotomas

Late side-effects of radiotherapy for subfoveal choroidal neovascularization.

Radiation therapy for subfoveal neovascularization has not yet proved its efficiency, but, to our knowledge, no exudative complication of this treatment has been reported. We describe a late side effect observed in 16 eyes after a mean follow up of 33 months, characterized by major extension and exudation of the choroidal new vessels. In several cases, development of elongated, club like new vessels was observed at the border of the neovascular membrane. At the end of the follow-up, 4 eyes had an exudative retinal detachment affecting half of the retina or more and visual acuity was < or = 1/50 in 94% of the cases (including a case with no light perception and 2 cases with only light perception).SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Effect of pegaptanib sodium 0.3 mg intravitreal injections (Macugen) in intraocular pressure: posthoc analysis from VISION study

Objective To assess the rate of pegaptanib-associated sustained intraocular pressure (IOP) elevation. Methods A posthoc analysis was conducted on all IOP measurements, except the immediate 30-min postinjection, from all subjects randomised to pegaptanib 0.3 mg or sham injections continuously in the first 2 years of the Vascular endothelial growth factor Inhibition Study in Ocular Neovascularisation (V.I.S.I.O.N.) study. Measurements were taken with Goldmann applanation tonometer or Tonopen, except at baseline and in cases of an IOP reading > 30 mm Hg when a Goldmann applanation tonometer was mandatory. Results Of 221 subjects, IOP measurements >= 22 mm Hg were seen in 28/114 and 23/107 subjects of the pegaptanib and sham subgroups, respectively (p=0.6338) and measurements >= 24 mm Hg were observed in eight and eight subjects in the pegaptanib and sham groups, respectively. More than two measurements >= 22 mm Hg occurred in six and 10 subjects (p=0.3025), and more than two measurements >= 24 mm Hg were observed in one and four subjects in the pegaptanib and sham groups, respectively. One patient with sustained IOP elevation in the pegaptanib study group, and four in the sham group, had IOP lowering medication added during the course of the study. No subject required glaucoma surgery. Conclusions In V.I.S.I.O.N., after 2 years, there was no evidence of sustained IOP elevation associated with pegaptanib 0.3 mg us

Photodynamic therapy of subfoveal neovascular membrane in type 2A idiopathic juxtafoveolar retinal telangiectasis.

PURPOSE: To evaluate the effect of photodynamic therapy on subfoveal neovascular membrane related to type 2A idiopathic juxtafoveolar retinal telangiectasia. DESIGN: Interventional case series. METHODS: Retrospective review of four eyes of four patients who underwent photodynamic therapy for subfoveal neovascular membrane secondary to idiopathic juxtafoveolar retinal telangiectasia. Ocular photodynamic therapy with verteporfin was performed in all cases using standard protocols. Results are given in terms of final visual acuity and neovascular membrane activity based on clinical examination, fluorescein and indocyanin green angiography, and, in two cases, optical coherence tomography. RESULTS: Baseline visual acuity of 20/30 and 20/40 (x2) was maintained in three patients after one, two, and three sessions of photodynamic therapy respectively, and a follow-up of 23, 21, and 9 months. Leakage specific to the subfoveal neovascular membrane ceased on the fluorescein angiography. In the other patient, the final vision decreased from 20/50 to 20/200 after four sessions of photodynamic therapy and a follow-up of 14 months. Although there was still mild persistent leakage on the fluorescein angiography, neovascular membrane size was unchanged, and no subretinal fluid was demonstrated on optical coherence tomography. CONCLUSIONS: Data from this case series suggest that photodynamic therapy may be effective in managing subfoveal neovascular membrane associated with idiopathic juxtafoveolar retinal telangiectasia, which usually carries a poor visual prognosis. Prospective study is required to confirm the beneficial effect of this treatment