RESUMO
BACKGROUND: Exagamglogene autotemcel (exa-cel) is a nonviral cell therapy designed to reactivate fetal hemoglobin synthesis by means of ex vivo clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 gene editing of autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) at the erythroid-specific enhancer region of BCL11A. METHODS: We conducted a phase 3, single-group, open-label study of exa-cel in patients 12 to 35 years of age with sickle cell disease who had had at least two severe vaso-occlusive crises in each of the 2 years before screening. CD34+ HSPCs were edited with the use of CRISPR-Cas9. Before the exa-cel infusion, patients underwent myeloablative conditioning with pharmacokinetically dose-adjusted busulfan. The primary end point was freedom from severe vaso-occlusive crises for at least 12 consecutive months. A key secondary end point was freedom from inpatient hospitalization for severe vaso-occlusive crises for at least 12 consecutive months. The safety of exa-cel was also assessed. RESULTS: A total of 44 patients received exa-cel, and the median follow-up was 19.3 months (range, 0.8 to 48.1). Neutrophils and platelets engrafted in each patient. Of the 30 patients who had sufficient follow-up to be evaluated, 29 (97%; 95% confidence interval [CI], 83 to 100) were free from vaso-occlusive crises for at least 12 consecutive months, and all 30 (100%; 95% CI, 88 to 100) were free from hospitalizations for vaso-occlusive crises for at least 12 consecutive months (P<0.001 for both comparisons against the null hypothesis of a 50% response). The safety profile of exa-cel was generally consistent with that of myeloablative busulfan conditioning and autologous HSPC transplantation. No cancers occurred. CONCLUSIONS: Treatment with exa-cel eliminated vaso-occlusive crises in 97% of patients with sickle cell disease for a period of 12 months or more. (CLIMB SCD-121; ClinicalTrials.gov number, NCT03745287.).
Assuntos
Anemia Falciforme , Hemoglobina Fetal , Transplante de Células-Tronco Hematopoéticas , Adolescente , Adulto , Criança , Feminino , Humanos , Masculino , Adulto Jovem , Anemia Falciforme/complicações , Anemia Falciforme/genética , Anemia Falciforme/terapia , Antígenos CD34 , Bussulfano/uso terapêutico , Sistemas CRISPR-Cas , Hemoglobina Fetal/biossíntese , Hemoglobina Fetal/genética , Edição de Genes , Células-Tronco Hematopoéticas , Proteínas Repressoras , Condicionamento Pré-Transplante , Terapia Baseada em Transplante de Células e Tecidos/métodos , Agonistas Mieloablativos/uso terapêutico , Europa (Continente) , América do NorteRESUMO
BACKGROUND: Deoxygenated sickle hemoglobin (HbS) polymerization drives the pathophysiology of sickle cell disease. Therefore, direct inhibition of HbS polymerization has potential to favorably modify disease outcomes. Voxelotor is an HbS polymerization inhibitor. METHODS: In a multicenter, phase 3, double-blind, randomized, placebo-controlled trial, we compared the efficacy and safety of two dose levels of voxelotor (1500 mg and 900 mg, administered orally once daily) with placebo in persons with sickle cell disease. The primary end point was the percentage of participants who had a hemoglobin response, which was defined as an increase of more than 1.0 g per deciliter from baseline at week 24 in the intention-to-treat analysis. RESULTS: A total of 274 participants were randomly assigned in a 1:1:1 ratio to receive a once-daily oral dose of 1500 mg of voxelotor, 900 mg of voxelotor, or placebo. Most participants had sickle cell anemia (homozygous hemoglobin S or hemoglobin Sß0-thalassemia), and approximately two thirds were receiving hydroxyurea at baseline. In the intention-to-treat analysis, a significantly higher percentage of participants had a hemoglobin response in the 1500-mg voxelotor group (51%; 95% confidence interval [CI], 41 to 61) than in the placebo group (7%; 95% CI, 1 to 12). Anemia worsened between baseline and week 24 in fewer participants in each voxelotor dose group than in those receiving placebo. At week 24, the 1500-mg voxelotor group had significantly greater reductions from baseline in the indirect bilirubin level and percentage of reticulocytes than the placebo group. The percentage of participants with an adverse event that occurred or worsened during the treatment period was similar across the trial groups. Adverse events of at least grade 3 occurred in 26% of the participants in the 1500-mg voxelotor group, 23% in the 900-mg voxelotor group, and 26% in the placebo group. Most adverse events were not related to the trial drug or placebo, as determined by the investigators. CONCLUSIONS: In this phase 3 randomized, placebo-controlled trial involving participants with sickle cell disease, voxelotor significantly increased hemoglobin levels and reduced markers of hemolysis. These findings are consistent with inhibition of HbS polymerization and indicate a disease-modifying potential. (Funded by Global Blood Therapeutics; HOPE ClinicalTrials.gov number, NCT03036813.).
Assuntos
Anemia Falciforme/tratamento farmacológico , Antidrepanocíticos/administração & dosagem , Benzaldeídos/administração & dosagem , Hemoglobina Falciforme/efeitos dos fármacos , Hemoglobinas/metabolismo , Pirazinas/administração & dosagem , Pirazóis/administração & dosagem , Adolescente , Adulto , Anemia Falciforme/sangue , Antidrepanocíticos/efeitos adversos , Antidrepanocíticos/uso terapêutico , Benzaldeídos/efeitos adversos , Biomarcadores/sangue , Criança , Relação Dose-Resposta a Droga , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Hemoglobina Falciforme/metabolismo , Hemólise/efeitos dos fármacos , Humanos , Hidroxiureia/uso terapêutico , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Polimerização/efeitos dos fármacos , Pirazinas/efeitos adversos , Pirazóis/efeitos adversos , Adulto JovemRESUMO
KEY MESSAGE: Assessing adaptation to abiotic stresses such as high temperature conditions across multiple environments presents opportunities for breeders to target selection for broad adaptation and specific adaptation. Adaptation of wheat to heat stress is an important component of adaptation in variable climates such as the cereal producing areas of Australia. However, in variable climates stress conditions may not be present in every season or are present to varying degrees, at different times during the season. Such conditions complicate plant breeders' ability to select for adaptation to abiotic stress. This study presents a framework for the assessment of the genetic basis of adaptation to heat stress conditions with improved relevance to breeders' selection objectives. The framework was applied here with the evaluation of 1225 doubled haploid lines from five populations across six environments (three environments selected for contrasting temperature stress conditions during anthesis and grain fill periods, over two consecutive seasons), using regionally best practice planting times to evaluate the role of heat stress conditions in genotype adaptation. Temperature co-variates were determined for each genotype, in each environment, for the anthesis and grain fill periods. Genome-wide QTL analysis identified performance QTL for stable effects across all environments, and QTL that illustrated responsiveness to heat stress conditions across the sampled environments. A total of 199 QTL were identified, including 60 performance QTL, and 139 responsiveness QTL. Of the identified QTL, 99 occurred independent of the 21 anthesis date QTL identified. Assessing adaptation to heat stress conditions as the combination of performance and responsiveness offers breeders opportunities to select for grain yield stability across a range of environments, as well as genotypes with higher relative yield in stress conditions.
Assuntos
Locos de Características Quantitativas , Triticum , Adaptação Fisiológica/genética , Grão Comestível/genética , Genótipo , Resposta ao Choque Térmico , Fenótipo , Triticum/genéticaRESUMO
New treatments directly targeting polymerization of sickle hemoglobin (HbS), the proximate event in the pathophysiology of sickle cell disease (SCD), are needed to address the severe morbidity and early mortality associated with the disease. Voxelotor (GBT440) is a first-in-class oral therapy specifically developed to treat SCD by modulating the affinity of hemoglobin (Hb) for oxygen, thus inhibiting HbS polymerization and downstream adverse effects of hemolytic anemia and vaso-occlusion. GBT440-001 was a phase 1/2 randomized, double-blind, placebo-controlled, single and multiple ascending dose study of voxelotor in adult healthy volunteers and patients with SCD, followed by a single-arm, open-label extension study. This report describes results of voxelotor (500-1000 mg per day) in patients with sickle cell anemia. The study evaluated the safety, tolerability, pharmacokinetic, and pharmacodynamic properties of voxelotor and established proof of concept by improving clinical measures of anemia, hemolysis, and sickling. Thirty-eight patients with SCD received 28 days of voxelotor 500, 700, or 1000 mg per day or placebo; 16 patients received 90 days of voxelotor 700 or 900 mg per day or placebo. Four patients from the 90-day cohort were subsequently enrolled in an extension study and treated with voxelotor 900 mg per day for 6 months. All patients who received multiple doses of voxelotor for ≥28 days experienced hematologic improvements including increased Hb and reduction in hemolysis and percentage of sickled red cells, supporting the potential of voxelotor to serve as a disease-modifying therapy for SCD. Voxelotor was well tolerated with no treatment-related serious adverse events and no evidence of tissue hypoxia. These trials were registered at www.clinicaltrials.gov as #NCT02285088 and #NCT03041909.
Assuntos
Anemia Falciforme/tratamento farmacológico , Benzaldeídos/uso terapêutico , Fármacos Hematológicos/uso terapêutico , Pirazinas/uso terapêutico , Pirazóis/uso terapêutico , Adolescente , Adulto , Benzaldeídos/farmacocinética , Estudos de Casos e Controles , Estudos de Coortes , Método Duplo-Cego , Feminino , Seguimentos , Fármacos Hematológicos/farmacocinética , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Prognóstico , Pirazinas/farmacocinética , Pirazóis/farmacocinética , Distribuição Tecidual , Adulto JovemRESUMO
Initiation of regular transfusion in transfusion-dependent thalassemia (TDT) is based on the assessment of clinical phenotype. Pathogenic HBB variants causing ß-thalassemia are important determinants of phenotype and could be used to aid decision making. We investigated the association of HBB genotype with survival in a cohort study in the four thalassemia centres in Cyprus. HBB genotype was classified as severe (ß0/ß0 or ß+/ß0), moderate (ß+/ß+), or mild (ß0/ß++ or ß+/ß++). Risk factors for mortality were evaluated using multivariate Cox proportional-hazards regression. 537 subjects were followed for a total of 20,963 person years. 80.4% (95% CI 76.4-84.7) of individuals survived to 50 years of age with increasing rates of liver, infection and malignancy-related deaths observed during recent follow-up. We evaluated non-modifiable risk factors and found worse outcomes associated with male sex (Hazard ratio 1.9, 95% CI 1.1-3.0, p=0.01) and milder genotype (Hazard ratio 1.6, 95% CI 1.1-2.3, p=0.02). The effect of genotype was confirmed in a second model, which included treatment effects. Patients with a milder genotype initiated transfusion significantly later and had reduced blood requirements compared to those with moderate or severe genotypes, although pre-transfusion hemoglobin levels did not differ between genotypes. Our results suggest that early treatment decisions to delay transfusion and different long-term treatment strategies in milder genotypes have led to adverse long-term effects of under-treated thalassemia and worse survival. We propose that HBB genotype determination and use of this information to aid in decision making can improve long-term outcomes of thalassaemia patients.
Assuntos
Talassemia beta , Estudos de Coortes , Chipre/epidemiologia , Genótipo , Humanos , Masculino , Mutação , Fenótipo , Globinas beta/genética , Talassemia beta/epidemiologia , Talassemia beta/genética , Talassemia beta/terapiaRESUMO
KEY MESSAGE: Adaptation to abiotic stresses such as high-temperature conditions should be considered as its independent components of total performance and responsiveness. Understanding and identifying improved adaptation to abiotic stresses such as heat stress has been the focus of a number of studies in recent decades. However, confusing and potentially misleading terminology has made progress difficult and hard to apply within breeding programs selecting for improved adaption to heat stress conditions. This study proposes that adaption to heat stress (and other abiotic stresses) be considered as the combination of total performance and responsiveness to heat stress. In this study, 1413 doubled haploid lines from seven populations were screened through a controlled environment assay, subjecting plants to three consecutive eight hour days of an air temperature of 36 °C and a wind speed of 40 km h-1, 10 days after the end of anthesis. QTL mapping identified a total of 96 QTL for grain yield determining traits and anthesis date with nine correlating to responsiveness, 72 for total performance and 15 for anthesis date. Responsiveness QTL were found both collocated with other performance QTL as well as independently. A sound understanding of genomic regions associated with total performance and responsiveness will be important for breeders. Genomic regions of total performance, those that show higher performance that is stable under both stressed and non-stressed conditions, potentially offer significant opportunities to breeders. We propose this as a definition and selection target that has not previously been defined for heat stress adaptation.
Assuntos
Adaptação Fisiológica , Cromossomos de Plantas/genética , Genoma de Planta , Resposta ao Choque Térmico , Locos de Características Quantitativas , Triticum/genética , Mapeamento Cromossômico/métodos , Epistasia Genética , Ligação Genética , Genética Populacional , Fenótipo , Melhoramento Vegetal , Triticum/crescimento & desenvolvimento , Triticum/metabolismoRESUMO
A retrospective cohort analysis to explore 10-year mortality and prevalence of transfusion-dependent ß-thalassaemia (TDT)-associated co-morbidities in patients with TDT was undertaken using Hospital Episode Statistics (HES) data from the National Health Service (NHS) in England. A 10-year forward-looking cohort analysis for the period 2009-2018 was completed using HES admitted patient care (APC), outpatient data, and linked HES/Office of National Statistics mortality data for patients with ß-thalassaemia (ICD-10 diagnosis code D56.1). TDT-associated co-morbidity rates were high in the 612 patients with TDT, with 76% having at least one co-morbidity, 54% suffering from two of more, and 37% three or more. The three most common TDT-associated co-morbidities, occurring in more than one third of patients were: endocrine disorders (excluding diabetes) 40%, osteoporosis 40%, and diabetes 34%. Cardiac disease was observed in 18% of patients overall, with atrial fibrillation and heart failure being the most common with a prevalence of 11% and 9%, respectively. The crude 10-year mortality rate in the TDT cohort was 6·2% (38/612), significantly greater than the 1·2% age/sex-adjusted mortality rate of the general population (P < 0·001). These data support the notion that the unmet need in TDT remains significant, with high rates of co-morbidity and mortality.
Assuntos
Diabetes Mellitus/mortalidade , Cardiopatias/mortalidade , Osteoporose/mortalidade , Talassemia beta/mortalidade , Adolescente , Adulto , Transfusão de Sangue , Criança , Comorbidade , Diabetes Mellitus/terapia , Inglaterra , Feminino , Seguimentos , Cardiopatias/terapia , Humanos , Masculino , Osteoporose/terapia , Estudos Retrospectivos , Talassemia beta/terapiaRESUMO
With the developing COVID-19 pandemic, patients with inherited anaemias require specific advice regarding isolation and changes to usual treatment schedules. The National Haemoglobinopathy Panel (NHP) has issued guidance on the care of patients with sickle cell disease, thalassaemia, Diamond Blackfan anaemia (DBA), congenital dyserythropoietic anaemia (CDA), sideroblastic anaemia, pyruvate kinase deficiency and other red cell enzyme and membrane disorders. Cascading of accurate information for clinicians and patients is paramount to preventing adverse outcomes, such as patients who are at increased risk of fulminant bacterial infection due to their condition or its treatment erroneously self-isolating if their fever is mistakenly attributed to a viral cause, delaying potentially life-saving antibiotic therapy. Outpatient visits should be minimised for most patients, however some, such as first transcranial dopplers for children with sickle cell anaemia should not be delayed as known risk of stroke will outweigh the unknown risk from COVID-19 infection. Blood transfusion programmes should be continued, but specific changes to usual clinical pathways can be instituted to reduce risk of patient exposure to COVID-19, as well as contingency planning for possible reductions in blood available for transfusions. Bone marrow transplants for these disorders should be postponed until further notice. With the current lack of evidence on the risk and complications of COVID-19 infection in these patients, national data collection is ongoing to record outcomes and eventually to identify predictors of disease severity, particularly important if further waves of infection travel through the population.
Assuntos
Anemia/complicações , Anemia/terapia , Betacoronavirus , Infecções por Coronavirus/complicações , Infecções por Coronavirus/prevenção & controle , Pandemias/prevenção & controle , Pneumonia Viral/complicações , Pneumonia Viral/prevenção & controle , Transfusão de Sangue , Transplante de Medula Óssea , COVID-19 , Infecção Hospitalar/prevenção & controle , Humanos , SARS-CoV-2RESUMO
A brief measure of patient satisfaction with treatment for pain is needed to help improve the treatment of painful episodes caused by sickle cell disease (SCD), especially during and after the transition from paediatric to adult care. Focus groups of 28 adolescent and adult patients were consulted about the content, clarity and relevance of 30 potential items, resulting in an 18-item version. This was validated by analysing questionnaire responses from 120 patients aged 12-53 years. Confirmatory factor analysis and item analysis indicated five subscales with high internal reliability: 'Communication and Involvement' (6 items, α = 0·87); 'Respect and Dignity' (3 items, α = 0·82); 'Pain Control' (3 items, α = 0·91); 'Staff Attitudes and Behaviour' (4 items, α = 0·88); and 'Overall Satisfaction' (2 items, α = 0·85) plus a Total Satisfaction score (18 items, α = 0·96). High negative correlations with the Picker Patient Experience Questionnaire, a measure of problem experiences, indicated good convergent validity. Lower satisfaction scores among patients aged over 18 years, those admitted via the emergency department, those treated by non-specialist hospital staff, and those reporting more breakthrough pain indicated good concurrent validity. The questionnaire provides a convenient brief measure that can be used to inform and evaluate improvements in healthcare for adolescent and adult patients with SCD, and could potentially be adapted for other painful conditions.
Assuntos
Dor Aguda/etiologia , Dor Aguda/terapia , Anemia Falciforme/complicações , Manejo da Dor/normas , Satisfação do Paciente , Adolescente , Adulto , Anemia Falciforme/terapia , Criança , Inglaterra , Feminino , Grupos Focais , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Manejo da Dor/psicologia , Psicometria , Reprodutibilidade dos Testes , Inquéritos e Questionários/normas , Transição para Assistência do Adulto , Adulto JovemRESUMO
Barley (Hordeum vulgare L.) is a major cereal grain widely used for livestock feed, brewing malts and human food. Grain yield is the most important breeding target for genetic improvement and largely depends on optimal timing of flowering. Little is known about the allelic diversity of genes that underlie flowering time in domesticated barley, the genetic changes that have occurred during breeding, and their impact on yield and adaptation. Here, we report a comprehensive genomic assessment of a worldwide collection of 895 barley accessions based on the targeted resequencing of phenology genes. A versatile target-capture method was used to detect genome-wide polymorphisms in a panel of 174 flowering time-related genes, chosen based on prior knowledge from barley, rice and Arabidopsis thaliana. Association studies identified novel polymorphisms that accounted for observed phenotypic variation in phenology and grain yield, and explained improvements in adaptation as a result of historical breeding of Australian barley cultivars. We found that 50% of genetic variants associated with grain yield, and 67% of the plant height variation was also associated with phenology. The precise identification of favourable alleles provides a genomic basis to improve barley yield traits and to enhance adaptation for specific production areas.
Assuntos
Produção Agrícola , Genes de Plantas/genética , Hordeum/genética , Flores/genética , Flores/crescimento & desenvolvimento , Genes de Plantas/fisiologia , Variação Genética/genética , Estudo de Associação Genômica Ampla , Sequenciamento de Nucleotídeos em Larga Escala , Hordeum/crescimento & desenvolvimento , Melhoramento Vegetal , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Característica Quantitativa HerdávelRESUMO
Single-marker genome-wide association studies (GWAS) have successfully detected associations between single nucleotide polymorphisms (SNPs) and agronomic traits such as flowering time and grain yield in barley. However, the analysis of individual SNPs can only account for a small proportion of genetic variation, and can only provide limited knowledge on gene network interactions. Gene-based GWAS approaches provide enormous opportunity both to combine genetic information and to examine interactions among genetic variants. Here, we revisited a previously published phenotypic and genotypic data set of 895 barley varieties grown in two years at four different field locations in Australia. We employed statistical models to examine gene-phenotype associations, as well as two-way epistasis analyses to increase the capability to find novel genes that have significant roles in controlling flowering time in barley. Genetic associations were tested between flowering time and corresponding genotypes of 174 putative flowering time-related genes. Gene-phenotype association analysis detected 113 genes associated with flowering time in barley, demonstrating the unprecedented power of gene-based analysis. Subsequent two-way epistasis analysis revealed 19 pairs of gene×gene interactions involved in controlling flowering time. Our study demonstrates that gene-based association approaches can provide higher capacity for future crop improvement to increase crop performance and adaptation to different environments.
Assuntos
Epistasia Genética/genética , Flores , Estudo de Associação Genômica Ampla/métodos , Hordeum/genética , Mapeamento Cromossômico , Redes Reguladoras de Genes/genética , Genótipo , Desequilíbrio de Ligação/genética , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genéticaRESUMO
BACKGROUND: The Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-Me) has been shown to be a reliable and valid questionnaire measuring health-related quality of life (HRQoL) in the US sickle cell disease (SCD) population. The study objective was to test the validity and reliability of the ASCQ-Me for use in the UK. METHODS: The US ASCQ-Me, Hospital Anxiety and Depression Scale (HADS), self-reported symptoms, and Medical Outcome Survey Short Form 36 (SF-36) were administered to 173 patients with SCD. Clinical severity was assessed by the number of painful episodes indicated by hospital admissions. RESULTS: The results showed that the item banks of the UK ASCQ-Me had good internal consistency. Anxiety and depression were strongly correlated with the emotional, and social item banks of the UK ASCQ-Me, with moderate correlations between the UK ASCQ-Me item banks and SF-36 components suggesting convergent validity. A confirmatory factor analysis confirmed the conceptual framework of the scale as being the same as the US ASCQ-Me, indicating construct validity. Known groups validity was found, with the ASCQ-Me being able to differentiate by SCD severity groups. CONCLUSION: The analysis of the sample shows evidence of both validity and reliability of the ASCQ-Me for use in the UK SCD population.
Assuntos
Anemia Falciforme/psicologia , Medidas de Resultados Relatados pelo Paciente , Qualidade de Vida , Adulto , Ansiedade/psicologia , Depressão/psicologia , Análise Fatorial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Psicometria , Reprodutibilidade dos Testes , Índice de Gravidade de Doença , Reino UnidoRESUMO
BACKGROUND: Young people's experiences of healthcare as they move into adult services can have a major impact on their health, and the transition period for young people with sickle cell disease (SCD) needs improvement. In this study, we explore how young people with SCD experience healthcare during this period of transition. METHODS: We conducted a co-produced longitudinal qualitative study, including 80 interviews in 2016-2017 with young people with SCD aged 13-21 (mean age 16.6) across two cities in England. We recruited 48 participants (30 female, 18 male): 27 interviews were one-off, and 53 were repeated 2-3 times over approximately 18 months. We used an inductive analytical approach, combining elements of Grounded Theory and thematic analysis. RESULTS: Participants reported significant problems with the care they received in A&E during painful episodes, and in hospital wards as inpatients during unplanned healthcare. They experienced delays in being given pain relief and their basic care needs were not always met. Participants said that non-specialist healthcare staff did not seem to know enough about SCD and when they tried to work with staff to improve care, staff often seemed not prepared to listen to them or act on what they said. Participants said they felt out of place in adult wards and uncomfortable with the differences in adult compared with paediatric wards. Because of their experiences, they tried to avoid being admitted to hospital, attempting to manage their painful episodes at home and accessing unplanned hospital care only as a last resort. By contrast, they did not report having problems within SCD specialist services during planned, routine care. CONCLUSIONS: Our study underscores the need for improvements to make services youth-friendly and youth-responsive, including training staff in SCD-specific care, compassionate care and communication skills that will help them elicit and act on young people's voices to ensure they are involved in shaping their own healthcare. If young people are prevented from using transition skills (self-management, self-advocacy), or treated by staff who they worry do not have enough medical competency in their condition, they may well lose their trust in services, potentially compromising their own health.
Assuntos
Anemia Falciforme/terapia , Serviços Médicos de Emergência/normas , Manejo da Dor/normas , Qualidade da Assistência à Saúde , Transição para Assistência do Adulto , Adolescente , Anemia Falciforme/complicações , Empatia , Inglaterra , Feminino , Hospitalização , Humanos , Entrevistas como Assunto , Estudos Longitudinais , Masculino , Dor/etiologia , Relações Profissional-Paciente , Pesquisa Qualitativa , Transição para Assistência do Adulto/normas , Adulto JovemRESUMO
Sickle Cell Disease (SCD) is an increasing global health problem and presents significant challenges to European health care systems. Newborn screening (NBS) for SCD enables early initiation of preventive measures and has contributed to a reduction in childhood mortality from SCD. Policies and methodologies for NBS vary in different countries, and this might have consequences for the quality of care and clinical outcomes for SCD across Europe. A two-day Pan-European consensus conference was held in Berlin in April 2017 in order to appraise the current status of NBS for SCD and to develop consensus-based statements on indications and methodology for NBS for SCD in Europe. More than 50 SCD experts from 13 European countries participated in the conference. This paper aims to summarise the discussions and present consensus recommendations which can be used to support the development of NBS programmes in European countries where they do not yet exist, and to review existing programmes.
Assuntos
Anemia Falciforme/diagnóstico por imagem , Anemia Falciforme/genética , Anemia Falciforme/epidemiologia , Conferências de Consenso como Assunto , Europa (Continente)/epidemiologia , Feminino , Humanos , Recém-Nascido , Masculino , Triagem Neonatal , Guias de Prática Clínica como AssuntoRESUMO
OBJECTIVES: Children with sickle cell anemia (SCA) are commonly reported to experience executive dysfunction. However, the development of executive function (EF) in preschool-age children without stroke in this patient population has not been investigated so it is unclear when and how these deficits emerge. METHODS: This case-control study examines the feasibility of assessing the early development of executive functioning in 22 preschool children years with SCA in the domains of processing speed, working memory, attention, inhibitory control, and cognitive flexibility, as well as everyday function, in comparison to matched control children. RESULTS: A pattern of potential deficits in early emerging executive skills was observed in the domains of inhibitory control and cognitive flexibility. Parents reported no differences for everyday EF and no significant differences were observed for working memory and processing speed. CONCLUSIONS: Results suggest that deficits in everyday executive difficulties, working memory, and processing speed, as commonly reported for older children with SCA, may not yet have emerged at this early developmental stage, despite specific deficits in cognitive flexibility and inhibitory control on behavioral measures. The feasibility of using available executive measures with preschool age children to characterize the development of early EF skills is discussed. (JINS, 2018, 24, 949-954).
Assuntos
Anemia Falciforme/psicologia , Função Executiva , Atenção , Estudos de Casos e Controles , Pré-Escolar , Cognição , Estudos de Viabilidade , Feminino , Humanos , Inibição Psicológica , Masculino , Memória de Curto Prazo , Testes Neuropsicológicos , Pais , Desempenho PsicomotorRESUMO
Objective: Sickle cell disease (SCD) is a genetic red blood cell disorder that often leads to stroke and executive dysfunction in school-age children and adults. This study aimed to characterize the development of the neural correlates of selective attention, an early component of executive function, in preschool children with SCD. Methods: Auditory event-related potentials (ERPs) were recorded while children attended to a story stream in one ear and ignored a second story in the other ear interchangeably. In total, 12 patients (mean age = 5.5, 7 males) and 22 typically developing children (mean age = 4.4, 10 males) were included in the final analyses. Results: By 100 ms, more positive ERP amplitudes were observed for attended relative to unattended stimuli in typically developing children but not those with SCD, suggesting deficits in the ability to focus attention. Reduced attention effects were associated with lower performance intellectual quotient. Conclusion: There are deficits in early attention modulation in young children with SCD.
Assuntos
Anemia Falciforme/fisiopatologia , Atenção/fisiologia , Percepção Auditiva/fisiologia , Potenciais Evocados Auditivos/fisiologia , Estimulação Acústica/métodos , Pré-Escolar , Eletroencefalografia , Feminino , Humanos , MasculinoRESUMO
BACKGROUND: Silent cerebral infarcts are the most common neurologic injury in children with sickle cell anemia and are associated with the recurrence of an infarct (stroke or silent cerebral infarct). We tested the hypothesis that the incidence of the recurrence of an infarct would be lower among children who underwent regular blood-transfusion therapy than among those who received standard care. METHODS: In this randomized, single-blind clinical trial, we randomly assigned children with sickle cell anemia to receive regular blood transfusions (transfusion group) or standard care (observation group). Participants were between 5 and 15 years of age, with no history of stroke and with one or more silent cerebral infarcts on magnetic resonance imaging and a neurologic examination showing no abnormalities corresponding to these lesions. The primary end point was the recurrence of an infarct, defined as a stroke or a new or enlarged silent cerebral infarct. RESULTS: A total of 196 children (mean age, 10 years) were randomly assigned to the observation or transfusion group and were followed for a median of 3 years. In the transfusion group, 6 of 99 children (6%) had an end-point event (1 had a stroke, and 5 had new or enlarged silent cerebral infarcts). In the observation group, 14 of 97 children (14%) had an end-point event (7 had strokes, and 7 had new or enlarged silent cerebral infarcts). The incidence of the primary end point in the transfusion and observation groups was 2.0 and 4.8 events, respectively, per 100 years at risk, corresponding to an incidence rate ratio of 0.41 (95% confidence interval, 0.12 to 0.99; P=0.04). CONCLUSIONS: Regular blood-transfusion therapy significantly reduced the incidence of the recurrence of cerebral infarct in children with sickle cell anemia. (Funded by the National Institute of Neurological Disorders and Stroke and others; Silent Cerebral Infarct Multi-Center Clinical Trial ClinicalTrials.gov number, NCT00072761, and Current Controlled Trials number, ISRCTN52713285.).
Assuntos
Anemia Falciforme/terapia , Transfusão de Sangue , Infarto Cerebral/prevenção & controle , Adolescente , Anemia Falciforme/complicações , Infarto Cerebral/etiologia , Criança , Pré-Escolar , Feminino , Ferritinas/sangue , Hemoglobina Falciforme/análise , Humanos , Inteligência , Análise de Intenção de Tratamento , Masculino , Prevenção Secundária , Método Simples-Cego , Reação TransfusionalRESUMO
Sickle cell disease is an increasing global health burden. This inherited disease is characterized by a remarkable phenotypic heterogeneity, which can only partly be explained by genetic factors. Environmental factors are likely to play an important role but studies of their impact on disease severity are limited and their results are often inconsistent. This study investigated associations between a range of environmental factors and hospital admissions of young patients with sickle cell disease in London and in Paris between 2008 and 2012. Specific analyses were conducted for subgroups of patients with different genotypes and for the main reasons for admissions. Generalized additive models and distributed lag non-linear models were used to assess the magnitude of the associations and to calculate relative risks. Some environmental factors significantly influence the numbers of hospital admissions of children with sickle cell disease, although the associations identified are complicated. Our study suggests that meteorological factors are more likely to be associated with hospital admissions for sickle cell disease than air pollutants. It confirms previous reports of risks associated with wind speed (risk ratio: 1.06/standard deviation; 95% confidence interval: 1.00-1.12) and also with rainfall (1.06/standard deviation; 95% confidence interval: 1.01-1.12). Maximum atmospheric pressure was found to be a protective factor (0.93/standard deviation; 95% confidence interval: 0.88-0.99). Weak or no associations were found with temperature. Divergent associations were identified for different genotypes or reasons for admissions, which could partly explain the lack of consistency in earlier studies. Advice to patients with sickle cell disease usually includes avoiding a range of environmental conditions that are believed to trigger acute complications, including extreme temperatures and high altitudes. Scientific evidence to support such advice is limited and sometimes confusing. This study shows that environmental factors do explain some of the variations in rates of admission to hospital with acute symptoms in sickle cell disease, but the associations are complex, and likely to be specific to different environments and the individual's exposure to them. Furthermore, this study highlights the need for prospective studies with large numbers of patients and standardized protocols across Europe.
Assuntos
Anemia Falciforme/epidemiologia , Meio Ambiente , Exposição Ambiental , Hospitalização , Vigilância em Saúde Pública , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Progressão da Doença , Exposição Ambiental/efeitos adversos , Humanos , Londres/epidemiologia , Pessoa de Meia-Idade , Razão de Chances , Paris/epidemiologia , Fatores de Risco , Adulto JovemRESUMO
KEY MESSAGE: Genomic prediction accuracy within a large panel was found to be substantially higher than that previously observed in smaller populations, and also higher than QTL-based prediction. In recent years, genomic selection for wheat breeding has been widely studied, but this has typically been restricted to population sizes under 1000 individuals. To assess its efficacy in germplasm representative of commercial breeding programmes, we used a panel of 10,375 Australian wheat breeding lines to investigate the accuracy of genomic prediction for grain yield, physical grain quality and other physiological traits. To achieve this, the complete panel was phenotyped in a dedicated field trial and genotyped using a custom AxiomTM Affymetrix SNP array. A high-quality consensus map was also constructed, allowing the linkage disequilibrium present in the germplasm to be investigated. Using the complete SNP array, genomic prediction accuracies were found to be substantially higher than those previously observed in smaller populations and also more accurate compared to prediction approaches using a finite number of selected quantitative trait loci. Multi-trait genetic correlations were also assessed at an additive and residual genetic level, identifying a negative genetic correlation between grain yield and protein as well as a positive genetic correlation between grain size and test weight.
Assuntos
Genômica , Melhoramento Vegetal , Triticum/genética , Austrália , Mapeamento Cromossômico , Genótipo , Modelos Lineares , Desequilíbrio de Ligação , Modelos Genéticos , Fenótipo , Polimorfismo de Nucleotídeo Único , Locos de Características QuantitativasRESUMO
Snoring and poor sleep may affect cognition, particularly in young children with chronic conditions. Parents of London preschoolers with sickle cell anemia (SCA; n = 22), matched controls (n = 24), and unselected typically developing (n = 142) preschoolers completed sleep questionnaires. Preschoolers with SCA had significantly more sleep problems when compared to matched controls and the larger population. Snoring occurred at least one to two nights a week for 79% of the SCA group. This is compared with 25% of matched controls and 33% of larger population. Randomized controlled trials to improve sleep in young children with SCA already at-risk for cognitive dysfunction should be considered.