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INTRODUCTION: The aim of this study was to evaluate the current management of RPE65 biallelic mutation-associated inherited retinal degeneration (RPE65-IRD) in Europe since market authorization of voretigene neparvovec (VN, LuxturnaTM) in 2018. By July 2022, over 200 patients have been treated outside the USA, of whom about 90% in Europe. We conducted among all centers of the European Vision Institute Clinical Research Network (
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Qualidade de Vida , Degeneração Retiniana , Humanos , Pré-Escolar , Criança , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Seguimentos , Degeneração Retiniana/genética , Degeneração Retiniana/terapia , Projetos de Pesquisa , Europa (Continente) , MutaçãoRESUMO
INTRODUCTION: An increasing number of gene-specific therapies are being developed for inherited retinal degenerations (IRDs). Identification of well-characterized patients is an emerging need. We conducted the second multinational survey among the
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Degeneração Retiniana , Adulto , Humanos , Degeneração Retiniana/diagnóstico , Degeneração Retiniana/genética , Degeneração Retiniana/terapia , Seguimentos , Testes Visuais , Projetos de Pesquisa , Europa (Continente)RESUMO
Thrombosis results in heparin-induced thrombocytopenia (HIT) from cellular activation involving Fc receptors. In this study, the FcγRIIA 131RR genotype was found to increase the risk of thrombosis in HIT patients (odds ratio: 5.9; 95% confidence interval: 1.7-20). When platelet aggregation tests (PATs) were performed with platelet-rich plasma (PRP), a shorter lag time was measured in 131RR donors compared to individuals with the HR and HH genotypes in response to HIT plasma or 5B9, a recently developed humanized monoclonal antibody to PF4/heparin. Importantly, this difference was no longer detectable when PATs were performed with washed platelets or immunoglobulin (Ig)G-depleted PRP. Moreover, polyclonal IgG or monoclonal IgG1 added to IgG-depleted PRP increased the lag time in response to 5B9. HH platelets were also sensitive to IgG2, which in contrast, failed to inhibit the response of 131RR platelets to 5B9. Finally, higher tissue factor messenger RNA levels were measured in the whole blood of 131RR donors after activation by HIT antibodies, with increased phospholipid procoagulant activity. These results demonstrate that HIT patients homozygous for the FcγRIIA 131R allele have a higher risk of thrombosis, probably due to increased cell activation by antibodies to PF4/heparin, with a lower inhibitory effect of endogenous IgG, especially from the IgG2 subclass.
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Anticoagulantes/efeitos adversos , Heparina/efeitos adversos , Imunoglobulina G/imunologia , Ativação Plaquetária , Receptores de IgG/imunologia , Trombocitopenia/complicações , Trombose/etiologia , Genótipo , Humanos , Imunoglobulina G/sangue , Polimorfismo Genético , Receptores de IgG/genética , Trombocitopenia/sangue , Trombocitopenia/induzido quimicamente , Trombocitopenia/imunologia , Trombose/sangue , Trombose/genética , Trombose/imunologiaRESUMO
A rapid lateral flow immunoassay (LFIA) (STic Expert(®) HIT), recently developed for the diagnosis of heparin-induced thrombocytopenia (HIT), was evaluated in a prospective multicentre cohort of 334 consecutive patients. The risk of HIT was estimated by the 4Ts score as low, intermediate and high in 28·7%, 61·7% and 9·6% of patients, respectively. Definite HIT was diagnosed in 40 patients (12·0%) with positive results on both enzyme-linked immunosorbent assay (Asserachrom(®) HPIA IgG) and serotonin release assay. The inter-reader reproducibility of results obtained was excellent (kappa ratio > 0·9). The negative predictive value of LFIA with plasma samples was 99·6% with a negative likelihood ratio (LR) of 0·03, and was comparable to those of the particle gel immunoassay (H/PF4-PaGIA(®) ) performed in 124 cases. Positive predictive value and positive LR were 44·4% and 5·87, respectively, and the results were similar for serum samples. The probability of HIT in intermediate risk patients decreased from 11·2% to 0·4% when the LFIA result was negative and increased to 42·5% when it was positive. In conclusion, the STic Expert(®) HIT combined with the 4Ts score is a reliable tool to rule out the diagnosis of HIT.
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Heparina/efeitos adversos , Imunoensaio/métodos , Nanopartículas/química , Trombocitopenia/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Trombocitopenia/induzido quimicamenteRESUMO
Heparin-induced thrombocytopenia (HIT) is due primarily to IgG antibodies specific to platelet factor 4/heparin complexes (PF4/Hs) that activate platelets via FcγRIIA. CD148 is a protein tyrosine phosphatase that regulates Src kinases and collagen-induced platelet activation. Three polymorphisms affecting CD148 (Q276P, R326Q, and D872E) were studied in HIT patients and 2 control groups, with or without antibodies to PF4/Hs. Heterozygote status for CD148 276P or 326Q alleles was less frequent in HIT patients, suggesting a protective effect of these polymorphisms. Aggregation tests performed with collagen, HIT plasma, and monoclonal antibodies cross-linking FcγRIIA showed consistent hyporesponsiveness of platelets expressing the 276P/326Q alleles. In addition, platelets expressing the 276P/326Q alleles exhibited a greater sensitivity to the Src family kinases inhibitor dasatinib in response to collagen or ALB6 cross-linking FcγRIIA receptors. Moreover, the activatory phosphorylation of Src family kinases was considerably delayed as well as the phosphorylation of Linker for activation of T cells and phospholipase Cγ2, 2 major signaling proteins downstream from FcγRIIA. In conclusion, this study shows that CD148 polymorphisms affect platelet activation and probably exert a protective effect on the risk of HIT in patients with antibodies to PF4/Hs.
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Heparina/efeitos adversos , Ativação Plaquetária/genética , Polimorfismo de Nucleotídeo Único , Receptores de IgG/fisiologia , Trombocitopenia/genética , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Genótipo , Heparina/imunologia , Heparina/metabolismo , Humanos , Masculino , Fator Plaquetário 4/imunologia , Fator Plaquetário 4/metabolismo , Polimorfismo de Nucleotídeo Único/fisiologia , Proteínas Tirosina Fosfatases/genética , Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/genética , Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/fisiologia , Receptores de IgG/genética , Receptores de IgG/metabolismo , Fatores de Risco , Trombocitopenia/sangue , Trombocitopenia/etiologiaRESUMO
BACKGROUND: Rare Eye Diseases (RED) are the leading cause of visual impairment and blindness for children and young adults in Europe. This heterogeneous group of conditions includes over 900 disorders ranging from relatively prevalent disorders such as retinitis pigmentosa to very rare entities such as developmental eye anomalies. A significant number of patients with RED have an underlying genetic etiology. One of the aims of the European Reference Network for Rare Eye Diseases (ERN-EYE) is to facilitate improvement in diagnosis of RED in European member states. MAIN BODY: Technological advances have allowed genetic and genomic testing for RED. The outcome of genetic testing allows better understanding of the condition and allows reproductive and therapeutic options. The increase of the number of clinical trials for RED has provided urgency for genetic testing in RED. A survey of countries participating in ERN-EYE demonstrated that the majority are able to access some forms of genomic testing. However, there is significant variability, particularly regarding testing as part of clinical service. Some countries have a well-delineated rare disease pathway and have a national plan for rare diseases combined or not with a national plan for genomics in medicine. In other countries, there is a well-established organization of genetic centres that offer reimbursed genomic testing of RED and other rare diseases. Clinicians often rely upon research-funded laboratories or private companies. Notably, some member states rely on cross-border testing by way of an academic research project. Consequently, many clinicians are either unable to access testing or are confronted with long turnaround times. Overall, while the cost of sequencing has dropped, the cumulative cost of a genomic testing service for populations remains considerable. Importantly, the majority of countries reported healthcare budgets that limit testing. SHORT CONCLUSION: Despite technological advances, critical gaps in genomic testing remain in Europe, especially in smaller countries where no formal genomic testing pathways exist. Even within larger countries, the existing arrangements are insufficient to meet the demand and to ensure access. ERN-EYE promotes access to genetic testing in RED and emphasizes the clinical need and relevance of genetic testing in RED.
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Oftalmopatias , Doenças Raras , Criança , Europa (Continente) , Testes Genéticos , Genômica , Humanos , Doenças Raras/diagnóstico , Doenças Raras/genéticaRESUMO
Professor Michael Larsen, who is a member of the ERN-EYE Ontology Study Group and co-chair of Workgroup on Retinal Rare Eye Diseases (WG1), was inadvertently omitted from the author list in the Acknowledgements section of the original article [1].
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BACKGROUND: The optical accessibility of the eye and technological advances in ophthalmic diagnostics have put ophthalmology at the forefront of data-driven medicine. The focus of this study is rare eye disorders, a group of conditions whose clinical heterogeneity and geographic dispersion make data-driven, evidence-based practice particularly challenging. Inter-institutional collaboration and information sharing is crucial but the lack of standardised terminology poses an important barrier. Ontologies are computational tools that include sets of vocabulary terms arranged in hierarchical structures. They can be used to provide robust terminology standards and to enhance data interoperability. Here, we discuss the development of the ophthalmology-related component of two well-established biomedical ontologies, the Human Phenotype Ontology (HPO; includes signs, symptoms and investigation findings) and the Orphanet Rare Disease Ontology (ORDO; includes rare disease nomenclature/nosology). METHODS: A variety of approaches were used including automated matching to existing resources and extensive manual curation. To achieve the latter, a study group including clinicians, patient representatives and ontology developers from 17 countries was formed. A broad range of terms was discussed and validated during a dedicated workshop attended by 60 members of the group. RESULTS: A comprehensive, structured and well-defined set of terms has been agreed on including 1106 terms relating to ocular phenotypes (HPO) and 1202 terms relating to rare eye disease nomenclature (ORDO). These terms and their relevant annotations can be accessed in http://www.human-phenotype-ontology.org/ and http://www.orpha.net/ ; comments, corrections, suggestions and requests for new terms can be made through these websites. This is an ongoing, community-driven endeavour and both HPO and ORDO are regularly updated. CONCLUSIONS: To our knowledge, this is the first effort of such scale to provide terminology standards for the rare eye disease community. We hope that this work will not only improve coding and standardise information exchange in clinical care and research, but also it will catalyse the transition to an evidence-based precision ophthalmology paradigm.
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Ontologias Biológicas , Oftalmopatias/classificação , Medicina de Precisão/métodos , Doenças Raras/classificação , Biologia Computacional/métodos , Medicina Baseada em Evidências , HumanosRESUMO
A new ELISA (Zymutest HIA®), based on incubation of diluted plasma with protamine/heparin (PRT/H) complexes without and with platelet factor 4 (PF4) provided by a platelet lysate, was used to detect heparin-dependent antibodies in a cohort of 232 cardiac surgery (CS) patients and in 47 patients with heparin-induced thrombocytopenia (HIT). Significant binding of IgG/A/M to PRT/H complexes was demonstrated in 59 CS patients (25.4%), with similar absorbances whether platelet lysate was added to the plasma or not, and significant reactivity to PF4/H in 29 of them. Antibodies to PRT or heparin alone were present in 15 and two of these patients, respectively. Importantly, antibodies to PRT/H were detected in only three of the 47 HIT patients, who had also undergone recent CS. The Zymutest HIA® was positive in another 41 CS patients (17%), but only or mainly when their plasma was tested with platelet lysate, with significant levels of antibodies to PF4/H in 40 of them without detectable reactivity to PRT or heparin alone. Slight antibody binding to PRT/H complexes was also measured in six of these 41 patients. Therefore, a total of 35 CS patients exhibited dual antibody reactivity towards PRT/H and PF4/H complexes. Serotonin release assay performed with PRT alone was positive in 17 CS patients with antibodies to PRT/H, but all had normal platelet count evolution without thrombosis postoperatively. In conclusion, antibodies to PRT/H are frequently present in CS patients postoperatively (25.4%), and can activate platelets in vitro, but their clinical impact remains questionable.
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Anticorpos/imunologia , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Heparina/química , Ativação Plaquetária/efeitos dos fármacos , Protaminas/química , Trombocitopenia/induzido quimicamente , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Ponte Cardiopulmonar/efeitos adversos , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/cirurgia , Ensaio de Imunoadsorção Enzimática , Feminino , Heparina/efeitos adversos , Heparina/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeos/química , Protaminas/imunologia , Serotonina/metabolismo , Trombocitopenia/imunologia , Trombose/imunologia , Resultado do Tratamento , Adulto JovemRESUMO
INTRODUCTION: Heparin-induced thrombocytopenia (HIT) results from an atypical immune response with synthesis of IgG antibodies (Abs) to platelet factor 4/heparin complexes (PF4/H), and probably involves both B and T cells. We investigated whether 3 single nucleotide polymorphisms (SNPs), rs1800896 (-1082G/A), rs1800871 (-819C/T) and rs1800872 (-592C/A) and the polymorphic CA repeat microsatellites IL10R [5325CA(11_15)] and IL10G [8134CA(14_29)] are associated with the synthesis of Abs to PF4/heparin and HIT. MATERIALS AND METHODS: Eighty-two patients with definite HIT and two control groups were studied. The first control group (Ab(neg)) consisted of 85 patients without Abs to PF4/heparin after cardiopulmonary bypass (CPB). The second control group (Ab(pos)) consisted of 84 patients who had developed significant levels of PF4-specific antibodies after CPB, but without HIT. RESULTS: Allele frequencies of the 3 SNPs were similar in HIT patients and controls. Fourteen alleles in IL10G (G16 to G29) and 3 alleles in IL10R (R13 to R15) were defined. The short G20 allele of IL10G was more frequent in Ab(neg) patients (8.2%) than in Ab(pos) (2.9%) and HIT patients (3%). It thereby appeared to protect against developing Abs to PF4/heparin (OR 0.29; 95% CI [0.12-0.70], p=0.006). Combined haplotypes cH1/cH8 comprising the short G20 + R13 alleles were less frequent in HIT (OR 0.33; 95% CI [0.11-0.97], p=0.036), and levels of Abs to PF4 in Ab(pos) patients were lower in cH1/cH8 subjects (p=0.019). CONCLUSION: These results suggest that IL10 promoter microsatellite polymorphisms might influence the immune response against PF4/heparin and the risk of HIT.
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Heparina/efeitos adversos , Imunidade Inata/efeitos dos fármacos , Interleucina-10/genética , Polimorfismo Genético , Regiões Promotoras Genéticas/genética , Trombocitopenia/induzido quimicamente , Trombocitopenia/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , França/epidemiologia , Heparina/uso terapêutico , Humanos , Imunidade Inata/genética , Imunidade Inata/imunologia , Interleucina-10/imunologia , Masculino , Repetições de Microssatélites/genética , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Prevalência , Medição de Risco , Fatores de Risco , Trombocitopenia/epidemiologia , Trombocitopenia/genéticaRESUMO
The diagnosis of heparin-induced thrombocytopenia (HIT) is based on clinical criteria and biological assays. Most immunoassays detect antibodies (either IgG alone or additionally IgA and IgM) against PF4 immobilised in wells of microtiter plates with stoichiometric concentrations of polyanion (heparin or polyvinylsulfonate). We studied whether diagnostic sensitivity and/or specificity for HIT could be improved using a novel assay in which unfractionated heparin is immobilised alone to the microwells, with PF4 (and, potentially, other heparin-dependent antigen proteins) provided by adding platelet lysate during the procedure. Samples from 101 patients with suspected HIT and from 101 controls (including 50 with antiphospholipid antibodies) were tested. The global assay (Zymutest HIA IgG/A/M, Hyphen BioMed) was positive for 39 of 40 patients with definite HIT (positive PF4-specific ELISA and positive serotonin release assay). It was positive in only two of the 101 control patients studied and also in 14 of the 61 patients with suspected HIT for whom the disease was excluded (specificity (sp): 77%). On the other hand, Zymutest HIA IgG, an IgG-specific assay, was positive in only six patients without HIT (Sp: 90%). Heparin-dependent IgG antibodies were present at higher levels in patients with definite HIT than in those for whom the diagnosis of HIT was ruled out. A single ELISA that detects IgG antibodies is more effective for the diagnosis of HIT in clinical practice. These results also support the hypothesis that heparin-dependent antibodies of IgG class have a major role in the pathogenesis of HIT.