Stroke is a catastrophic complication of sickle cell anaemia (SCA) and is one of the leading causes of death in both adults and children with SCA. Evidence suggests that some genetic polymorphisms could be related to stroke development, but their association remains controversial. Here, we performed genotyping of five published single nucleotide polymorphisms, the α-thalassemia genotype, the G6PD A (-) variant deficiency, and the β(S) haplotype in a large series of SCA patients with well-defined stroke phenotypes. Of 261 unrelated SCA patients included in the study, 67 (9.5 %) presented a documented, primary stroke event. Markers of haemolysis (red blood cell (RBC) counts, p = 0.023; reticulocyte counts, p = 0.003; haemoglobin (Hb) levels, p < 0.001; indirect bilirubin levels, p = 0.006; lactate dehydrogenase (LDH) levels, p = 0.001) were associated with stroke susceptibility. Genetically, only the β(S) haplotype (odds ratio (OR) 2.9, 95 % confidence interval (CI) 1.56 to 4.31; p = 0.003) and the α(3.7kb)-thalassemia genotype (OR 0.31, 95 % CI 0.11 to 0. 83; p = 0.02) were associated with increased and decreased stroke risk, respectively. In multivariate analysis, the β(S) haplotype was independently associated with stroke development (OR 2.26, 95 % CI 1.16 to 4.4; p = 0.016). Our findings suggest that only the β(S) haplotypes and the α(3.7kb)-thalassemia genotype modulate the prevalence of stroke in our SCA population. Genetic heterogeneity among different populations may account for the irreproducibility amongst different studies.

Background: Direct-acting antivirals (DAA) have revolutionized hepatitis C treatment, with high sustained virological response (SVR) rates reported, even in historically difficultto-treat groups. SVR is associated with a decreased risk of hepatocellular carcinoma (HCC), need for transplantation, and overall and liver-related mortality. Data from real-life cohorts on the medium-to long-term outcomes of patients with advanced liver disease and DAA-induced SVR are still missing. Objectives: To report and analyze the long-term Seguimento a longo prazo da doença hepática avançada após cura do vírus C com antivíricos de ação direta: dados de uma coorte Portuguesa Palavras ChaveAgentes antivirais · Carcinoma hepatocelular · Cirrose hepática · Hepatite C · Resposta virológica sustentada Resumo Introdução: Os antivíricos de ação direta (AAD) revolucionaram o tratamento da hepatite C ao atingirem elevadas taxas de resposta virológica sustentada (RVS), mesmo em grupos historicamente difíceis de tratar. A RVS associa-se a uma diminuição do risco de carcinoma hepatocelular (CHC), necessidade de transplantação e mortalidade, global e de causa hepática. São ainda insuficientes de coortes reais na literatura dados que permitam avaliar a extensão dos benefícios clínicos a médio-longo prazo do atingimento de uma RVS com os AAD. Objetivos: Reportar e analisar o impacto a longo prazo da RVS numa coorte real de doentes com doença hepática avançada, tratados com AAD. Métodos: Estudo unicêntrico, retrospetivo, longitudinal com inclusão de doentes com hepatite C crónica com cirrose ou fibrose avançada, que iniciaram tratamento com AAD de fevereiro de 2015 a janeiro de 2017. Resultados: Foram incluídos 237 doentes. Verificou-se uma taxa de retenção no tratamento de 98.7% com uma taxa de RVS de 97.8% (intention to treat: 96.6%). Dos 229 doentes curados, 67.2% eram cirróticos (64.2% Child-Pugh A, 3.1% Child-Pugh B) e 32.8% F3, com um seguimento médio de 28 meses. A taxa de mortalidade global foi de 19/1,000 pessoas-ano e de mortalidade associada à doença hepática de 9.5/1,000 pessoasano. A incidência de eventos de descompensação hepática foi de 25/1,000 pessoas-ano e a de CHC foi de 11.6/1,000 pessoas-ano. Verificou-se um aumento sustentado dos valores séricos de plaquetas até 2 anos de seguimento. A história de eventos de descompensação hepática, concentração de plaquetas e albumina prétratamento encontrou-se significativamente associada a eventos adversos hepáticos durante o seguimento. Conclusões: A cura virológica após tratamento com AAD é sustentada no tempo, encontrando-se associada a um excelente prognóstico clínico em doentes com doença hepática avançada compensada, e a uma melhoria ou estabilização da doença em doentes descompensados. O atingimento de RVS associa-se a um baixo risco de CHC, não o eliminando, e de progressão da doença, sobretudo perante a presença de outros cofatores de agressão hepática, recomendando-se a manutenção do seguimento destes doentes.

<b><i>Background and Aims:</i></b> The impact of SARS-CoV-2 infection on the liver and the possibility of chronic liver disease (CLD) as a risk factor for COVID-19 severity is not fully understood. Our goal was to describe clinical outcomes of COVID-19 inpatients regarding the presence of abnormal liver tests and CLD. <b><i>Methods:</i></b> A retrospective analysis of patients with SARS-CoV-2 infection, hospitalized in a tertiary center in Portugal, was performed. Studied outcomes were disease and hospitalization length, COVID-19 severity, admission to intensive care unit (ICU) and mortality, analyzed by the presence of abnormal liver tests and CLD. <b><i>Results:</i></b> We included 317 inpatients with a mean age of 70.4 years, 50.5% males. COVID-19 severity was moderate to severe in 57.4% and critical in 12.9%. The mean disease length was 37.8 days, the median hospitalization duration 10.0 days and overall mortality 22.8%. At admission, 50.3% showed abnormal liver tests, and 41.5% showed elevated aminotransferase levels, from which 75.4% were mild. Elevated aminotransferase levels at admission were associated with COVID-19 severity (78.7 vs. 63.3%, <i>p</i> = 0.01), ICU admission (13.1 vs. 5.92%, <i>p</i> = 0.034) and increased mortality (25.8 vs. 13.3%, <i>p</i> = 0.007). However, in a subgroup analysis, only aspartate transaminase (AST) was associated with these worse outcomes. Alkaline phosphatase was elevated in 11.4% of the patients and was associated with critical COVID-19 (21.1 vs. 9.92%, <i>p</i> = 0.044) and mortality (20.4 vs. 9.52%, <i>p</i> = 0.025), while 24.6% of the patients showed elevated γ-glutamyl transferase, which was associated with ICU admission (42.3 vs. 22.8%, <i>p</i> = 0.028). Fourteen patients had baseline CLD (4.42%), 3 with liver cirrhosis. Alcohol (<i>n</i> = 6) and nonalcoholic fatty liver disease (<i>n</i> = 6) were the most frequent etiologies. CLD patients had critical COVID-19 in 21.4% (<i>p</i> = 0.237), mean disease length of 36.6 days (<i>p</i> = 0.291), median hospitalization duration of 11.5 days (<i>p</i> = 0.447) and a mortality rate of 28.6% (<i>p</i> = 0.595), which increased to 66.7% among cirrhotic patients (<i>p</i> = 0.176). <b><i>Conclusions:</i></b> Liver test abnormalities in COVID-19 patients were frequent but most commonly mild. AST, but not alanine transaminase, was associated with worse clinical outcomes, such as COVID-19 severity and mortality, probably indicating these outcomes were independent of liver injury. A low prevalence of CLD was seen, and a clear impact on COVID-19 outcomes was not seen.

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Although sickle cell anemia results from homozygosity for a single mutation at position 7 of the β-globin chain, the clinical aspects of this condition are very heterogeneous. Complications include leg ulcers, which have a negative impact on patients’ quality of life and are related to the severity of the disease. Nevertheless, the complex pathogenesis of this complication has yet to be elucidated. To identify novel genes associated with leg ulcers in sickle cell anemia, we performed whole-exome sequencing of extreme phenotypes in a sample of Brazilian sickle cell anemia patients and validated our findings in another sample. Our discovery cohort consisted of 40 unrelated sickle cell anemia patients selected based on extreme phenotypes: 20 patients without leg ulcers, aged from 40 to 61 years, and 20 with chronic leg ulcers. DNA was extracted from peripheral blood leukocytes and used for whole-exome sequencing. After the bioinformatics analysis, eight variants were selected for validation by Sanger sequencing and TaqMan® genotyping in 293 sickle cell anemia patients (153 without leg ulcers) from two different locations in Brazil. After the validation, Fisher’s exact test revealed a statistically significant difference in a stop codon variant (rs12568784 G/T) in the FLG2 gene between the GT and GG genotypes ( P = 0.035). We highlight the importance of rs12568784 in leg ulcer development as this variant of the FLG2 gene results in impairment of the skin barrier, predisposing the individual to inflammation and infection. Additionally, we suggest that the remaining seven variants and the genes in which they occur could be strong candidates for leg ulcers in sickle cell anemia. Impact statement To our knowledge, the present study is the first to use whole-exome sequencing based on extreme phenotypes to identify new candidate genes associated with leg ulcers in sickle cell anemia patients. There are few studies about this complication; the pathogenesis remains complex and has yet to be fully elucidated. We identified interesting associations in genes never related with this complication to our knowledge, especially the variant in the FLG2 gene. The knowledge of variants related with leg ulcer in sickle cell anemia may lead to a better comprehension of the disease’s etiology, allowing prevention and early treatment options in risk genotypes while improving quality of life for these patients.