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- Genetic Modulators of Hemolytic Anemia in Angolan Children with Sickle Cell AnemiaPublication . Germano, Isabel; Santos, Brígida; Delgadinho, Mariana; Lopes, Pedro; Arez, Ana Paula; Brito, Miguel; Faustino, PaulaSickle Cell Anemia (SCA) is a recessive genetic disease caused by the c.20A>T variant in HBB gene. It is characterised by sickled erythrocytes, chronic hemolytic anemia and vaso-occlusive events. However, these manifestations are heterogeneous due to environmental and genetic modifying factors. The aim of this study was to investigate genetic modifiers of hemolytic anemia in pediatric SCA patients living in Africa, where the disease is a severe public health problem. The study was conducted on 200 Angolan SCA 3-12 year-old children. Thirteen polymorphic regions in genes previously associated with vascular cell adhesion (VCAM1 and CD36), vascular tonus (NOS3) or erythrocyte hemoglobinisation (HBA), were genotyped using PCR, RFLP, Gap-PCR and Sanger sequencing. Hematological and biochemical phenotypes were obtained at steady state and clinical adverse events were collected from patients’ medical records. Results revealed a high level (67.5%) of α-thalassemia co-inheritance (del. 3.7kb in HBA), which improve patients’ health by delaying the onset of the disease, decreasing anemia and the number of blood transfusions. Two SNPs in CD36 (rs1984112 and rs1413661) showed impact on anemia severity. Particularly, genotypes containing the rs1413661_allele C revealed to be risk factors for severe anemia, as they were associated with lower hemoglobin levels, increased number of hospitalizations and transfusions. This is the first report associating this SNP with SCA pathology. Moreover, the rs1041163_allele C in VCAM1 was associated with lower LDH levels, inversely the rs2070744_allele C in NOS3 was associated with higher LDH levels and a higher number of hospitalizations, being a possible risk factor for increased hemolytic rate. This study contributed to the understanding of SCA complex pathophysiology. It confirmed the positive role of α-thal., both in SCA related anemia and in its clinical manifestations. In addition, it reinforced the importance of vascular cell adhesion in hemolytic anemia variability. In this context, we propose the SNP rs1413661 in CD36 as an important novel genetic modulator of SCA in Africa.
- Impact of national lockdown in reducing SARS-CoV-2 transmission in Portuguese municipalitiesPublication . Garcia, Teresa; Kislaya, Irina; Matias-Dias, CarlosBackground: Rapid spread of the SARS-CoV-2 infections was responsible for the rupture of health services and forced drastic lockdown measures in many countries, driving millions into a socioeconomic crisis. Understanding the impact of non- pharmacological interventions on epidemic control in different socioeconomic contexts is important to inform decision-makers. We aimed to compare the effect of nationwide lockdown on SARS-Cov-2 incidence in different municipalities, grouped by socioeconomic features. Methods : Based on national surveillance data on a laboratory confirmed SARSCoV- 2 cases we developed an ecological interrupted time series analysis study in 277 Portuguese municipalities grouped by socioeconomic features using two- steps cluster analysis. Change in SARS-COV-2 daily incidence after lockdown introduction on March 18, 2020 was estimated in each cluster by negative binomial regression. Two municipality clusters were considered, with cluster A characterized by younger population with lower education and purchasing power and smaller population density. Results: Before lockdown, incidence rates increased by 24,7% and 19,0% daily, reaching 11,42 and 14,11 per 100.000 inhabitants in cluster A and B, respectively. With lockdown introduction, rates decreased by 4,0% and 4,2% daily, reaching 2,96 and 3,50 per 100.000, in cluster A and B 42 days after restrictions implementation. Overall, lockdown measures avoided 138.676,76 and 60.404,15 cases per 100.000, in cluster A and B, respectively. Conclusions: Before lockdown, higher SARS-CoV-2 transmission was observed in the municipalities with lower socioeconomic status, which was expected, considering these socioeconomic features are associated with higher transmission of the virus. Lockdown prevented more cases in these municipalities. Despite the socioeconomic impact, lockdown has demonstrated to be a crucial measure to control SARS-CoV-2 transmission, particularly in municipalities with lower socioeconomic status.
- Contribution of HFE and HPSE genes and methaemoglobin reductase activity to heart failurePublication . Gaspar, Marcos A.; Aguiar, Laura; Ferreira, Joana; Faustino, Paula; Mascarenhas, Mário Rui; Menezes Falcão, Luiz; Bicho, Manuel; Inácio, ÂngelaIntroduction: Heart failure can be defined as a syndrome caused by a structural anomaly and/or by a committed cardiac function, which leads to an inadequate cardiac output unable to meet the metabolic necessities of the organism. We aim to understand if HFE and HPSE genes as well as methaemoglobin reductase activity, may influence the development of heart failure. Methodology: It was performed a case-control study, in which 252 DNA samples from Portuguese individuals were analysed, 143 derived from subjects with heart failure, and 109 from healthy controls. For HPSE genotyping (rs4693608), we performed endpoint PCR analysis. A multiplex ARMS (Amplification-Refractory Mutation System) assay was used for the simultaneous detection of two HFE polymorphisms (C282Y and H63D). Reductase methaemoglobin activity was determined by spectrophotometric methods. All statistical tests were performed with IBM® SPSS® Statistics 26.0 software. Statistical significance was defined as a p-value < 0.05. Results: Regarding the H63D polymorphism, results show the CG genotype as a risk factor [OR (95% CI) = 2.889 (1.041-8.018); p=0.042]. In what concerns HPSE gene, the GG genotype was found to have a protective effect [OR (95% CI) = 0.435 (0.193-0.982); p=0.045] while the presence of the A allele is a risk factor [OR (95% CI) = 2.297 (1.018-5.179); p=0.045. Considering methaemoglobin reductase, its activity was lower in patients than in healthy controls (p=0.019). Discussion: Intravenous iron supplementation is sometimes considered in heart failure treatment, emphasizing the results presented in the present study. Considering the high prevalence of heart failure in Portugal (400.000 individuals, according to Sociedade Portuguesa de Cardiologia), it is important to identify iron-related markers, since it may allow an earlier and more expert approach, which may provide better prevention and therapeutic strategies for this pathology.
- Modificadores Genéticos da Anemia de Células Falciformes em Crianças AngolanasPublication . Santos, Brígida; Delgadinho, Mariana; Ginete, Catarina; Ferreira, Joana; Arez, Ana Paula; Faustino, Paula; Brito, MiguelA anemia de células falciformes (ACF) é uma doença monogênica autossómica recessiva que afecta anualmente mais de 300.000 crianças em todo o mundo sendo particularmente prevalente na África subsariana. Em Angola a prevalência é de 2,4%. As manifestações clínicas são muito heterogénias com gravidade variável entre os pacientes, influenciada por factores ambientais e genéticos. O objectivo deste estudo foi investigar modificadores genéticos da ACF em Angola. Duzentas crianças com o diagnóstico de ACF foram seleccionadas para a caracterização clínica e foi obtida uma amostra de sangue para a quantificação da hemoglobina fetal, índices hematológicos, genotipagem da delecção alfa-talassémia de 3.7kb por GAP-PCR e determinação dos haplótipos no locus da beta-globina usando NGS. A delecção alfa-talassémia em homogozigotia foi de 12,5% e de 55 % em heterozigotia. O haplótipo CAR foi o mais comum, sendo CAR/CAR mais prevalente (92,15%). A hemoglobina fetal teve significância estatística entre os haplótipos. A presença da delecção da alfa-talassémia e a hemoglobina fetal tiveram influência na idade da primeira manifestação da doença, nos eventos clínicos, nos valores hematológicos e na taxa de hemólise observada pelo número reduzido na contagem de reticulócitos. Este estudo fornece uma contribuição relevante para o conhecimento genético dos pacientes com ACF em Angola importante para a prática clínica personalizada.
- Mental health during the COVID-19 pandemic in PortugalPublication . Santos, Osvaldo; Virgolino, Ana; Heitor, Maria João; Fialho, Mónica; Costa, Alexandra; Rasga, Célia; Martiniano, Hugo; Costa, Joana; Vicente, Astrid; Caldas de Almeida, TeresaMental health is being impacted by COVID-19, as a result of both the globalized perception of health risk and the massive social and economic measures, required to control the pandemic. A main goal of this study, the SM-COVID19, was to characterize the mental health of the general population and to identify vulnerable groups, during the first lockdown in Portugal.
- Enhanced surveillance of COVID-19 in secondary care in Europe: a tale of two wavesPublication . Mokogwu, Damilola; Hamilton, Mark; Harvey, Ciaran; Elgohari, Suzanne; Burgui, Cristina; Mazagatos, Clara; Galtier, Florence; Seyler, Lucie; Machado, Ausenda; Jonikaite, Indre; Lazar, Mihaela; Rath, Barbara; Mutch, Heather; McMahon, James; Ladbury, Georgia; Akinnawo, Ayodele; Martínez-Baz, Iván; Larrauri, Amparo; Laine, Fabrice; Fico, Albana; Demuyser, Thomas; Kislaya, Irina; Gefenaite, Giedre; Cherciu, Carmen; Harrabi, Myriam; MC Rose, Angela; I-MOVE study groupBackground: The I-MOVE-COVID-19 Consortium was established to conduct surveillance of hospitalised COVID-19 cases in nine European countries, aiming to describe the clinical and epidemiological characteristics of severe COVID-19 in order to inform public health response. Methods: Data are pooled from 11 participating sites; two (England and Scotland) submitting national data, with the remainder being from a selection of hospitals. Descriptive analysis is performed on the pooled dataset overall and comparing data on patients admitted from week 5 to 28 of 2020 (“first wave”) vs those admitted later (“second wave”). Results: Data on 84,297 hospitalised patients were submitted for 01 February 2020 - 31 January 2021. Fifty-six percent of cases (46,907/84,193) were male and median age was 69 years. Where information was available, 44% (25,344 /57,769) patients were recorded as having at least one chronic condition. Ninety-five percent (7,868/8,270 and 90% (5,606/6,231) were reported with respiratory and febrile presentations respectively. Twenty-four percent (18,795/78,955) were admitted to intensive care units (ICU) and 26% (19,805/76,764) died in hospital (all sites); 12% (3,305/28,262) and 20% (5,454/27,066) respectively for all sites except England (where ICU reporting is mandated, biasing the dataset towards more severe outcomes as this site represents >50% of all cases). As a percentage of all hospital admissions, both ICU admissions and deaths decreased significantly between the first and second waves in both sexes and across all age- groups, apart from the over 75s. Conclusions: Results from this multicentre European surveillance system suggest that about one in 10 hospitalised COVID-19 patients are admitted to ICU and one in five have fatal outcomes. Fatality and ICU admission were lower in the second wave compared with the first.
- Meta-analysis of the clinical performance of commercial SARS-CoV-2 nucleic acid and antibody tests up to 22 August 2020Publication . Walle, I.V.; Leitmeyer, K.; Broberg, E.K.; The European Covid-19 microbiological laboratories groupBackground: Reliable testing for SARS-CoV-2 is key for the management of the COVID-19 pandemic. Aim: We estimate diagnostic accuracy for nucleic acid and antibody tests 5 months into the COVID-19 pandemic, and compare with manufacturer-reported accuracy. Methods: We reviewed the clinical performance of SARS-CoV-2 nucleic acid and antibody tests based on 93,757 test results from 151 published studies and 20,205 new test results from 12 countries in the European Union and European Economic Area (EU/ EEA). Results: Pooling the results and considering only results with 95% confidence interval width≤5%, we found four nucleic acid tests, including one pointof-care test and three antibody tests, with a clinical sensitivity ≥95% for at least one target population (hospitalised, mild or asymptomatic, or unknown). Nine nucleic acid tests and 25 antibody tests, 12 of them point-of-care tests, had a clinical specificity of ≥98%. Three antibody tests achieved both thresholds. Evidence for nucleic acid point-of-care tests remains scarce at present, and sensitivity varied substantially. Study heterogeneity was low for eight of 14 sensitivity and 68 of 84 specificity results with confidence interval width≤5%, and lower for nucleic acid tests than antibody tests. Manufacturer-reported clinical performance was significantly higher than independently assessed in 11 of 32 and four of 34 cases, respectively, for sensitivity and specificity, indicating a need for improvement in this area. Conclusion: Continuous monitoring of clinical performance within more clearly defined target populations is needed.
- Familial Hypercholesterolemia Monogenic Polygenic or BothPublication . Medeiros, A.M.; Alves, A.C.; Chora, J.R.; Bourbon, M.The present work aims to determine the genetic cause (monogenic or polygenic) of hypercholesterolemia in clinical FH patients.
- Assessing the potential of RNA-based therapeutics for a group of Lysosomal Storage Diseases with neurological involvementPublication . Santos, Juliana Inês; Gonçalves, Mariana; Matos, Liliana; Gaspar, Paulo; Pires, Maria João; Oliveira, Paula; Prata, Maria JoãoDuring the first two decades of the 21st century, remarkable progresses have been achieved in the field of RNA-based therapeutics. From antisense RNA to RNA modification, the therapeutic potential of RNA-based technologies has nothing but increased. In our lab, we have been addressing the potential of different RNA-based drugs to either correct or ameliorate the sub-cellular phenotype of a number of severe, life-threatening diseases: the so-called Lysosomal Storage Disorders (LSDs). Among them, we are focusing our efforts on those which present with a predominant neurological phenotype, since there are virtually no approved treatments for any of them. Briefly, two major research lines are being pursued: the first relies on the design of mutation-specific approaches to correct abnormal splicing processes in LSD-related genes, whenever they underlie pathology. The second depends upon selective downregulation of genes involved in the biosynthethic cascades that give origin to the substrates that accumulate in each pathology. Here we present an overview on our results with both approaches on Sanfilippo syndrome, a sub-group of severe neurodegenerative LSDs. For the mutation-specific, splicing correction approach, we are using U1snRNA vectors to restore the splicing defect caused by the HGSNAT mutation c.234+1G>A, that leads to Sanfilippo C disease. We started by demonstrating in vitro that a modified U1snRNA vector designed to improve the definition of HGSNAT exon 2 could partially restore its normal splicing process. Now, we are evaluating its therapeutic potential in vivo, in mice expressing the human splicing defect. For the substrate reduction approach, we are using siRNAs. By acting over a specific biosynthethic cascade, siRNAs promote an overall decrease of the accumulating substrate. So far, we have already tested this approach in patients’ fibroblasts and observed a high inhibition of the target mRNAs and a decrease in storage. Overall, there are substantial differences between these two approaches but they also face common challenges and show equally promising results.
- Establishing a novel European hospital surveillance platform in response to a newly emerging infection lessons from the I-MOVE-COVID-19 hospital networkPublication . Ladbury, Georgia; Hamilton, Mark; Harvey, Ciaran; Mutch, Heather; McMahon, James; Mokogwu, Damilola; Sadiq, Fatima; Young, Johanna; Wallace, Lesley; Murray, Josie; Lopez‑Bernal, Jamie; Andrews, Nick; Castilla, Jesús; Casado, Itziar; Larrauri, Amparo; Mazagatos, Clara; Duval, Xavier; Bino, Silvia; Demuyser, Thomas; Machado, Ausenda; Mickiene, Aukse; Lazar, Mihaela; Stavaru, Crina; Rath, Barbara; Harrabi, Myriam; Rekacewicz, Claire; Kapisyszi, Perlat; Seyler, Lucie; Gómez, Verónica; Jancoriene, Ligita; Rose, AngelaBackground: The first signal of a new infection is often severe cases presenting at hospital. Enhanced surveillance of these cases is critical to learning more about disease epidemiology and patient outcomes, but nationallevel surveillance can lack power to draw conclusions. In response to the emergence of SARS-CoV-2, the Influenza-Monitoring Vaccine Effectiveness (I-MOVE) network, founded in 2007, expanded to establish the I-MOVE-COVID-19 Consortium in February 2020. The Consortium’s surveillance objectives included using pooled data to describe clinical and epidemiological characteristics of hospitalised COVID-19 patients across Europe, in order to contribute to the knowledge base, guide patient management, and inform public health response. Methods: Eleven study sites participated in the surveillance, including 23 hospitals across six EU Member States and Albania, and hospitals nationally in England and Scotland. A standardised protocol and dataset for collection was agreed by April 2020. In England and Scotland, data were generated by linkage of routine datasets; other sites used bespoke paper or electronic questionnaires. Data were submitted, pooled and analysed quarterly. Results: Data were received regarding 84,297 COVID-19 patients hospitalised between 1 February 2020 and 31 January 2021. Three surveillance bulletins were published between September 2020 and March 2021, providing key insights into severe COVID-19 at European level. However, the unexpected, overwhelming workload at participating sites, and difficulties securing data protection and ethics permissions, delayed data submissions and presented challenges for timely analysis. Conclusions: Building on an existing network facilitated a novel European multicentre hospital surveillance system to be implemented during a pandemic; however, timeliness was nonetheless problematic. In future, processes could be streamlined e.g. by developing pre-approved template protocols with information governance and ethical approvals in place during the inter- pandemic period.