Browsing by Author "Faustino, P"
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- Avaliação do Custo/Benefício do Diagnóstico Prénatal Efectuado num Centro de Referência numa População com Risco Genético ou MalformativoPublication . Tomé, T; Gaspar, G; Marques, A; Correia, J; Lacerda, A; Carreiro, H; Faustino, P; Ferreira, A; Rosa, D; Sing, CO diagnóstico prénatal (DPN) tem consequências assistenciais. psicológicas e económicas,sendo importante avaliar o custo beneficio para cada população. Com este objectivo foi feito um estudo prospectivo longitudinal e discriminativo na população referenciada à Maternidade Dr. Alfredo da Costa por risco genético subdividida em dois grupos, o grupo 1 em que foi feita técnica de DPN em tempo adequado e o grupo 2 em que não foi feito DPN ou foi feito em tempo inadequado. Foram estudadas as características gerais, indicações de referência e consequência do diagnóstico. Conclui-se que as indicações postas são adequadas permitindo o diagnóstico duma anomalia em 17% dos casos. O nível sócio económico e a multiparidade intervêm na adequabilidade da solicitação diagnóstica. Em relação às consequências diagnósticas houve um maior número de interrupções médicas de gravidez (IMG) no grupo 1 e um maior número de anomalias nos recém-nascidos do grupo 2.
- Biomarkers and Genetic Modulators of Cerebral Vasculopathy in Sub-Saharan Ancestry Children With Sickle Cell AnemiaPublication . Silva, M; Vargas, S; Coelho, A; Ferreira, E; Mendonça, J; Vieira, L; Maia, R; Dias, A; Ferreira, T; Morais, A; Soares, IM; Lavinha, J; Silva, R; Kjöllerström, P; Faustino, PWe investigated biomarkers and genetic modulators of the cerebral vasculopathy (CV) subphenotype in pediatric sickle cell anemia (SCA) patients of sub-Saharan African ancestry. We found that one VCAM1 promoter haplotype (haplotype 7) and VCAM1 single nucleotide variant rs1409419_T were associated with stroke events, stroke risk, as measured by time-averaged mean of maximum velocity in the middle cerebral artery, and with high serum levels of the hemolysis biomarker lactate dehydrogenase. Furthermore, VCAM-1 ligand coding gene ITGA4 variants rs113276800_A and rs3770138_T showed a positive association with stroke events. An additional positive relationship between a genetic variant and stroke risk was observed for ENPP1 rs1044498_A. Conversely, NOS3 variants were negatively associated with silent cerebral infarct events (VNTR 4b_allele and haplotype V) and CV globally (haplotype VII). The -alpha3.7kb-thal deletion did not show association with CV. However, it was associated with higher red blood cell and neutrophil counts, and lower mean corpuscular volume, mean corpuscular hemoglobin and red cell distribution width. Our results underline the importance of genetic modulators of the CV sub-phenotype and their potential as SCA therapeutic targets. We also propose that a biomarker panel comprising biochemical, hematological, imaging and genetic data would be instrumental for CV prediction, and prevention.
- Genetic Modulators of Fetal Hemoglobin Expression and Ischemic Stroke Occurrence in African Descendant Children With Sickle Cell AnemiaPublication . Nicolau, M; Vargas, S; Silva, M; Coelho, A; Ferreira, E; Mendonça, J; Vieira, L; Kjöllerström, P; Maia, R; Silva, R; Dias, A; Ferreira, T; Morais, A; Soares, IM; Lavinha, J; Faustino, PSickle cell anemia (SCA) is an autosomal recessive monogenic disease with significant clinical variability. Cerebrovascular disease, particularly ischemic stroke, is one of the most severe complications of SCA in children. This study aimed to investigate the influence of genetic variants on the levels of fetal hemoglobin (Hb F) and biochemical parameters related with chronic hemolysis, as well as on ischemic stroke risk, in ninety-one unrelated SCA patients, children of sub-Saharan progenitors. Our results show that a higher Hb F level has an inverse relationship with the occurrence of stroke, since the group of patients who suffered stroke presents a significantly lower mean Hb F level (5.34 ± 4.57% versus 9.36 ± 6.48%; p = 0.024). Furthermore, the co-inheritance of alpha-thalassemia improves the chronic hemolytic pattern, evidenced by a decreased reticulocyte count (8.61 ± 3.58% versus 12.85 ± 4.71%; p < 0.001). In addition, our findings have confirmed the importance of HBG2 and BCL11A loci in the regulation of Hb F expression in sub-Saharan African SCA patients, as rs7482144_A, rs11886868_C, and rs4671393_A alleles are significantly associated with a considerable increase in Hb F levels (p = 0.019, p = 0.026, and p = 0.028, respectively). Concerning KLF1, twelve different variants were identified, two of them novel. Seventy-three patients (80.2%) presented at least one variant in this gene. However, no correlation was observed between the presence of these variants and Hb F level, severity of hemolysis, or stroke occurrence, which is consistent with their in silico-predicted minor functional consequences. Thus, we conclude that the prevalence of functional KLF1 variants in a sub-Saharan African background does not seem to be relevant to SCA clinical modulation.
- Hypophosphatemia As a Possible Biomarker for Epileptic Seizures at the Emergency DepartmentPublication . Coutinho, M; Faustino, P; Ladeira, F; Leitão, LIntroduction: Hypophosphatemia seems to be temporally associated with seizures, despite not being considered a trigger. We aimed to evaluate hypophosphatemia as a biomarker for seizures. Methods: Retrospective study, including all consecutive patients admitted at our central hospital's emergency department from 01/01-31/03/2021, screened as "altered consciousness/syncope" or "seizures", with available phosphate levels. Results: 277 patients included, mostly male (61.7%), mean age 64.3 years. Final diagnosis was "seizure" in 34.7% and "other diagnosis" in 65.3%. Patients with seizures were younger (p<0.001), had more frequent epilepsy (p<0.001) and alcoholism (p=0.01). Patients with other diagnosis had more often renal failure (p<0.001) and statin (p=0.02) or diuretic (p=0.003) therapy. Time to blood collection (from the event and from admission) was similar between groups. Patients with seizures had lower mean phosphate levels and more frequent hypophosphatemia (<2.4mg/dL) (p<0.001). Mean CK levels were similar in both groups (p=0.25). HyperCK (>200U/L) was more frequent in the seizure group (p=0.04). Odds ratio (OR) of hypophosphatemia for seizures was 4.330 (CI 95% 2.170-8.640, p<0.001), persisting after correction for confounders. OR of hyperCK was 1.890 (CI 95% 1.060-3.371, p=0.03), losing significance when adjusted. Sensitivity was low for both. Hypophosphatemia was more specific (91.2% vs 79.9%). Conclusions: Our findings support hypophosphatemia as a seizure biomarker. More studies are needed.
- Next-Generation Sequencing of Hereditary Hemochromatosis-Related Genes: Novel Likely Pathogenic Variants Found in the Portuguese PopulationPublication . Faria, R; Silva, B; Silva, C; Loureiro, P; Queiroz, A; Fraga, S; Esteves, J; Mendes, D; Fleming, R; Vieira, L; Gonçalves, J; Faustino, PHereditary hemochromatosis (HH) is an autosomal recessive disorder characterized by excessive iron absorption resulting in pathologically increased body iron stores. It is typically associated with common HFE gene mutation (p.Cys282Tyr and p.His63Asp). However, in Southern European populations up to one third of HH patients do not carry the risk genotypes. This study aimed to explore the use of next-generation sequencing (NGS) technology to analyse a panel of iron metabolism-related genes (HFE, TFR2, HJV, HAMP, SLC40A1, and FTL) in 87 non-classic HH Portuguese patients. A total of 1241 genetic alterations were detected corresponding to 53 different variants, 13 of which were not described in the available public databases. Among them, five were predicted to be potentially pathogenic: three novel mutations in TFR2 [two missense (p.Leu750Pro and p.Ala777Val) and one intronic splicing mutation (c.967-1G>C)], one missense mutation in HFE (p.Tyr230Cys), and one mutation in the 5'-UTR of HAMP gene (c.-25G>A). The results reported here illustrate the usefulness of NGS for targeted iron metabolism-related gene panels, as a likely cost-effective approach for molecular genetics diagnosis of non-classic HH patients. Simultaneously, it has contributed to the knowledge of the pathophysiology of those rare iron metabolism-related disorders.
- Outcomes in Guillain-Barré Syndrome Following a Second Therapeutic Cycle – A Single-Centre Retrospective Observational StudyPublication . Faustino, P; Coutinho, M; Brum, M; Medeiros, L; Ladeira, FIntroduction: The treatment of Guillain-Barré Syndrome (GBS) with intravenous immunoglobulin (IVIg) or plasma exchange (PE) reduces time to clinical recovery. Although sometimes used in clinical practice, the benefit of a second treatment cycle is of unproven benefit. Aims: Our aim was to compare GBS prognosis in patients treated with one or two cycles of IVIg or PE. Methods: We selected patients with electrophysiological studies compatible with acute inflammatory demyelinating polyneuropathy or acute motor-sensory axonal neuropathy, from January 2018 to December 2020 in our hospital. Our primary outcome was any improvement in the Guillain-Barré Syndrome Disability Score (GBS-DS) at a mean of twelve weeks. We compared patients treated with one or two treatment cycles with a binary regression. Results: We included twenty-six patients, 65.4% with the classical presentation and 30.8% were treated with two cycles. Patients treated with two cycles presented a higher basal GBS-DS (median 4; IQR 1-5) compared with the group of patients treated with one cycle (median 3; IQR 1-5), p = 0.01. The remaining basal characteristics were similar between groups. The two-cycle treatment regimen did not associate with an improvement in GBS-DS (OR 0.28, 95% CI 0.03-2.35, p = 0.24). Likewise there was no benefit in the need for intensive care unit (OR 2.0, 95% CI 0.37-10.92, p = 0.42) or mechanical invasive ventilation (OR 10.2, 95% CI 0.86-120.96, p = 0.66). Discussion: Our analysis reinforces the recent literature data regarding the absence of benefit of two treatment cycles in patients with GBS.
- Population Genetics of IFITM3 in Portugal and Central Africa Reveals a Potential Modifier of Influenza SeverityPublication . David, S; Correia, V; Antunes, L; Faria, R; Ferrão, J; Faustino, P; Nunes, B; Maltez, F; Lavinha, J; Rebelo de Andrade, HInfluenza epidemics are a serious global public health and economic problem. The IFITM3 allele (rs12252-C) was suggested as a population-based genetic risk factor for severe influenza virus infection by A(H1N1)pdm09. We analyzed the population genetics of IFITM3 variants in the Portuguese general population (n = 200) and Central Africans (largely Angolan) (n = 148) as well as its association to influenza severity in Portuguese patients (n = 41). Seven SNPs, within the 352 bp IFITM3 amplicon around rs12252, were identified. SNP distributions in the Portuguese appeared at an intermediate level between the Africans and other Europeans. According to HapMap, rs34481144 belongs to the same linkage disequilibrium (LD) block as rs12252 and is in strong LD with rs6421983. A negative association with severe relative to mild disease was observed for allele rs34481144-A, indicating a protective effect under the dominant model. Moreover, haplotype Hap4 with rs34481144-A, not including rs12252-C, was significantly associated to mild influenza. Conversely, although with borderline significance, haplotype Hap1 with rs34481144-G, not including rs12252-C, was associated to severe disease. Moreover, in comparison to the general Portuguese population, statistical significant differences in the frequencies of the protective allele rs34481144-A in the severe disease group, the deleterious Hap1 in the mild disease group, and the protective Hap4 in the severe disease group were observed. The population attributable risk (PAR) for the targeted rs34481144 allele or genotype was of 55.91 and 64.44% in the general population and the mildly infected individuals, respectively. Implication of these variants in disease phenotype needs further validation, namely through functional analysis as is discussed.
- Seroconversion Rate Following HBV Vaccination in Clinical Practice: The Role of Age and DMT TreatmentPublication . Faustino, P; Coutinho, M; Leitão, L; Capela, C; Brum, M; Parra, J; Sequeira, J; Barros, A; Araújo, C; Sousa, A; Ladeira, FHBV screening and immunization is recommended in all MS patients and is mandatory before the start of some DMT. However, studies evaluating the immune response to HBV vaccine in MS patients are scarce. We aimed to evaluate the seroprotection rate following HBV immunization in MS patients and to assess if older age and DMT-treatment influenced seroprotection. We conducted a cohort study between 2016 and 2020 and compared the immune response to HBV vaccine in MS patients under different DMTs and in patients 50 years old or younger and older than 50. We found that patients under non-injectable DMT presented lower rates of seroprotection comparing to patients under injectable DMT's or without treatment. In patients older than 50, although the seroprotection rate was similar to the remaining patients, the antibody anti-HBV surface antigen titers following HBV immunization were lower and patients were more likely to require a 4th dose of the vaccine to achieve seroprotection. Our findings highlight to need to consider HBV immunization in MS patients early in the disease course, in order to ensure a proper immune response to the vaccine.
- Sickle cell anemia - Nitric oxide related genetic modifiers of hematological and biochemical parametersPublication . Aguiar, L; Matos, A; Gil, A; Afonso, C; Almeida, S; Braga, L; Lavinha, J; Kjollerstrom, P; Faustino, P; Bicho, M; Inácio, ASickle cell anemia (SCA) is an inherited blood disorder. SCA patients present clinical and hematologic variability that cannot be only explained by the single mutation in the beta-globin gene. Others genetic modifiers and environmental effects are important for the clinical phenotype. SCA patients present arginine deficiency that contributes to a lower nitric oxide (NO) bioactivity.
- Variantes Genéticas Pró-Trombóticas como (Improváveis?) Factores de Risco para as Grandes Crises Vaso-Oclusivas na DrepanocitosePublication . Moreira, I; Faustino, P; Picanço, I; Martins, R; Morais, A; Dias, A; Soares, I; Rolão, C; Ducla-Soares, JL; Braga, L; David, D; Lavinha, JCONTEXTO: A drepanocitose é uma anemia hemolítica hereditária com características pró-adesivas, pró-inflamatórias e pró-coagulantes, incluindo alterações na hemostase e activação da cascata da coagulação. PLANO DO ESTUDO: Neste estudo analisaram-se, em 140 drepanocíticos africanos e 126 indivíduos sem hemoglobina S também de origem africana, variantes genéticas polimórficas em quatro loci envolvidos na coagulação (F2 20210G>A e F5 R506Q), na fibrinólise (PAI-1 5G>4G), ou no metabolismo da homocisteína (MTHFR 677C>T). Estratificaram-se os pacientes em dois grupos de acordo com a ocorrência ou não de, pelo menos, uma complicação vaso-oclusiva (CVO) grave até à data da sua participação no estudo. RESULTADOS: Não se observou uma associação estatisticamente significativa entre a ocorrência de uma CVO grave e a herança do alelo predisponente à trombose, 4G no locus PAI-1 ou 677T no locus MTHFR. Nenhum drepanocítico apresentava os alelos F2 20210A ou F5 506Q (factor V Leiden). Visando excluir a possibilidade de que genuínas diferenças inter-grupos fossem mascaradas pela presença de indivíduos mais jovens no grupo sem-CVO, dividiu-se este num sub-grupo de pacientes mais novos e num sub-grupo de pacientes cuja idade não diferia significativamente do grupo com-CVO grave. Mesmo assim, não foi encontrada associação significativa. No entanto, pode observar-se, no grupo de doentes com o alelo PAI-1 4G (cuja expressão resulta numa diminuição da actividade fibrinolítica), uma tendência (OR=1,6) para um risco acrescido de CVO. Esta tendência era ligeiramente maior (OR=2,1) se se considerasse apenas a CVO síndrome torácica aguda. CONCLUSÕES: O alelo 4G no promotor do PAI-1 poderá ser um factor de risco para CVO na drepanocitose, uma hipótese a testar numa série maior de doentes, idealmente oriunda de uma população homogénea e com alta prevalência de drepanocitose.