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Sickle cell disease (SCD) is associated with multiple known complications and increased mortality. This study aims to further understand the profile of intensive care unit (ICU) admissions of SCD patients. In this single-center retrospective cohort (approval number 0926-11), we evaluated SCD-related ICU admissions at our hospital in São Paulo, Brazil. Admissions were clustered using clinical data and organ dysfunction at ICU admission. A hierarchical clustering method was used to distinguish phenotypes. From 140 admissions obtained, 125 were included. The mean age was 30 years, 48% were male, and SS genotype was predominant (71.2%). Non-surgical causes of admissions accounted for 85.6% (n = 107). The mean Sequential Organ Failure Assessment score (SOFA) was 4 (IQR 2-7). Vasopressors were required by 12% and mechanical ventilation by 17.6%. After analysis of the average silhouette width, the optimal number of clusters was 3: cluster 1 (n = 69), cluster 2 (n = 25), cluster 3 (n = 31). Cluster 1 had a mean age of 29 years, 87% of SS genotype, and mean SOFA of 4. Cluster 2 had a mean age of 37 years, 80% of SS genotype, and mean SOFA of 8. Cluster 3 had a mean age of 26 years, 29% of SS genotype, and mean SOFA of 3. The need for mechanical ventilation was 11.6%, 44%, and 9.7%, respectively. Mortality was significantly higher in cluster 2 (44%, p = 0.012). This cohort of critical SCD admissions suggested the presence of three different profiles. This can be informative in the ICU setting to identify SCD patients at higher risk of worse outcomes., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Sickle cell disease (SCD), the most common monogenic disease worldwide, is marked by a phenotypic variability that is, to date, only partially understood. Because inflammation plays a major role in SCD pathophysiology, we hypothesized that single nucleotide polymorphisms (SNP) in genes encoding functionally important inflammatory proteins might modulate the occurrence of SCD complications. We assessed the association between 20 SNPs in genes encoding Toll-like receptors (TLR), NK cell receptors (NKG), histocompatibility leukocyte antigens (HLA), major histocompatibility complex class I polypeptide-related sequence A (MICA) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), and the occurrence of six SCD clinical complications (stroke, acute chest syndrome (ACS), leg ulcers, cholelithiasis, osteonecrosis, or retinopathy). This study was performed in a cohort of 500 patients. We found that the TLR2 rs 4696480 TA, TLR2 rs 3804099 CC , and HLA-G, rs 9380142 AA genotypes were more frequent in patients who had fewer complications. Also, in logistic regression, the HLA-G rs 9380142 G allele increased the risk of cholelithiasis ( AG vs. AA , OR 1.57, 95%CI 1.16-2.15; GG vs. AA , OR 2.47, 95%CI 1.34-4.64; P = 0.02). For SNPs located in the NKG2D loci, in logistic regression, the A allele in three SNPs was associated with a lower frequency of retinopathy, namely, rs 2246809 ( AA vs. GG : OR 0.22, 95%CI 0.09-0.50; AG vs. GG : OR 0.47, 95%CI 0.31-0.71; P = 0.004, for patients of same origin), rs 2617160 ( AT vs. TT : OR 0.67, 95%CI 0.48-0.92; AA vs. TT : OR 0.45, 95%CI 0.23-0.84; P = 0.04), and rs 2617169 ( AA vs. TT : OR 0.33, 95%CI 0.13-0.82; AT vs. TT : OR 0.58, 95%CI 0.36-0.91, P = 0.049, in patients of same SCD genotype). These results, by uncovering susceptibility to, or protection against SCD complications, might contribute to a better understanding of the inflammatory pathways involved in SCD manifestations and to pave the way for the discovery of biomarkers that predict disease severity, which would improve SCD management., (Copyright © 2020 Tozatto-Maio, Girot, Ly, Silva Pinto, Rocha, Fernandes, Diagne, Benzerara, Dinardo, Soler, Kashima, Araujo, Kenzey, Fonseca, Rodrigues, Volt, Jarduli, Ruggeri, Mariaselvam, Gualandro, Rafii, Cappelli, Nogueira, Scigliuolo, Guerino-Cunha, Malmegrim, Simões, Gluckman and Tamouza.)

Hereditary Xerocytosis (HX) is an autosomal dominantly inherited congenital hemolytic anemia associated with erythrocyte dehydration due to decreased intracellular potassium content resulting in increased mean corpuscular hemoglobin concentration. The affected members of HX families show compensated anemia with splenomegaly, hemosiderosis, and perinatal edema but are in large part transfusion independent. Functional studies show a link between mutations in mechanosensitive ion channel, encoded by PIEZO1 gene and the HX. We identified new PIEZO1 variants that are likely pathogenic in three phenotypically characterized multi-generational HX Brazilian families. Interestingly, one missense variant of the PIEZO1 gene identified, p.E2494V was associated in trans with the previously reported most frequent pathogenic duplication p.E2496ELE. The three-dimensional structure of the human protein modeled using structural coordinates of the mouse Piezo1 solved by cryo-electron microscopy (Cryo-ME) showed that the two identified variants, p.M2007L and p.T2014I, are localized to an important mechanosensitive transmembrane domain suggesting a conformational mechanism for altered channel's gating. The p.E2496ELE variant identified alters the extension of helix α1 bringing it much closer to the beam affecting the position of it structure at the end of the pore., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Despite adequate immunization and penicillin prophylaxis, bacterial infections remain a leading cause of morbidity and mortality in patients with sickle cell disease (SCD). Besides hyposplenism, inflammatory and genetic factors might modulate their susceptibility to bacterial infections. We performed a candidate gene association of single nucleotide polymorphisms (SNPs) located in Toll-like receptor (TLR) genes, encoding prominent molecules for innate immune responses, with the occurrence of bacterial infections in patients with SCD. A cohort followed in centres in Brazil, France and Senegal (n = 430) was divided in two groups: patients who presented at least one episode of bacterial infection (n = 235) and patients who never had bacterial infections (n = 195). There were no differences in gender or age distribution among the groups. The frequency of the TLR2 rs4696480 TA genotype was significantly lower in the infected group (50% vs. 67%, odds ratio [OR] = 0·50, 95% confidence interval [CI] 0·34-0·75, P < 0·001), and the TT genotype was significantly higher in the infected group (15% vs. 5%, OR = 3·18, 95% CI 1·53-6·61, P < 0·001). Previous reports demonstrated higher secretion of inflammatory factors in cells from AA individuals, lower occurrence and severity of immune diseases in T carriers. The rs4696480 TA genotype might stand between deleterious effects of over inflammatory response (AA genotype) and inefficient responses (TT genotype) to infectious agents in SCD settings., (© 2019 British Society for Haematology and John Wiley & Sons Ltd.)

Background: Hereditary hemochromatosis (HH) encompasses a group of autosomal recessive disorders mainly characterized by enhanced intestinal absorption of iron and its accumulation in parenchymal organs. HH diagnosis is based on iron biochemical and magnetic resonance imaging (MRI) assessment, and genetic testing. Questionnaires, such as SF-36 (short form health survey), have been increasingly used to assess the impact of diseases on the patient's quality of life (QL). In addition, different genotypes are identified as results of genetic tests in patients with suspected primary iron overload. In the present study, our aim was to evaluate whether domains of QL are different according to genotypic groups in patients suspected of HH., Methods: Seventy-nine patients with primary iron overload were included and two genotypic groups were formed (group 1: homozygous genotype for the HFE p.Cys282Tyr mutation; group 2: other genotypes)., Results: Group 1 had higher means of plasma transferrin saturation (86 ± 19%) and serum ferritin (1669 ± 1209 ng/mL) compared to group 2 (71 ± 12%, 1252 ± 750 ng/mL, respectively; p = 0.001). Four domains were significantly different among groups 1 and 2: physical functioning (p = 0.03), bodily pain (p = 0.03), vitality (p = 0.02) and social functioning (p = 0.01)., Conclusions: Our main finding was that patients with p.Cys282Tyr homozygosity had a worse QL scenario assessed by SF-36, compared with patients with iron overload without the same genotype. Being aware of this relationship between genotypes and QL might be helpful in the overall management of patients suspected of hereditary hemochromatosis.