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2.
Pediatr Blood Cancer ; 66(10): e27919, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31298495

RESUMO

OBJECTIVE: To examine the association between perioperative red blood cell (RBC) transfusion and postoperative venous thromboembolism (VTE) in pediatric surgical patients. METHODS: Retrospective cohort study using the National Surgical Quality Improvement Project Pediatric, a validated registry of 118 United States children's hospitals. Patients under 19 years of age undergoing a surgical procedure between 2012 and 2017 were included, with the main exposure being RBC transfusion in the perioperative period (48 hours prior to operation to 72 hours after operation). The primary 30-day outcome of interest was a postoperative VTE requiring therapy. Risk-adjusted odds ratios (aOR) were calculated using multiple logistic regression. Subgroup analyses were performed across multiple surgical specialties. Sensitivity analyses were performed after (a) imputation for missing variables and (b) propensity score matching. RESULTS: During the study years, 482 867 pediatric patients (56.7% male; median age, 6 years [interquartile range, 1-12 years]) underwent an operation. Of these, 30 879 (6.4%) received at least one perioperative RBC transfusion. Postoperative VTE requiring therapy occurred in 618 patients (0.13%). After adjustment for multiple risk factors, perioperative RBC transfusion was associated with an increased risk of VTE (aOR 2.4; 95% CI, 1.9-3.0). The increased VTE risk persisted after imputation of missing demographic and clinical data as well as after 1:1 propensity score matching (29 811 matched pairs, aOR 2.2; 95% CI, 1.7-2.8). CONCLUSIONS: Perioperative RBC transfusion is associated with an increased, albeit still very low, risk of postoperative VTE in pediatric patients. Patients receiving blood in the perioperative period may benefit from additional monitoring or VTE prophylaxis.


Assuntos
Transfusão de Eritrócitos/efeitos adversos , Tromboembolia Venosa/etiologia , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Masculino , Pontuação de Propensão , Estudos Retrospectivos , Fatores de Risco , Tromboembolia Venosa/epidemiologia
3.
Pediatr Blood Cancer ; 66(8): e27807, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31094093

RESUMO

BACKGROUND: The Uganda Sickle Surveillance Study provided evidence for a large sickle burden among HIV-exposed infants in Uganda. To date, however, no large scale screening program has been developed for Central or East Africa. METHODS: A 3-year targeted sickle cell screening project in Uganda was designed by the Ministry of Health to (1) determine sickle cell trait and disease prevalence within high-burden districts, (2) document the prevalence among HIV-exposed and nonexposed children, (3) confirm previously suggested HIV comorbidity, and (4) estimate the co-inheritance of known genetic modifiers of sickle cell disease. RESULTS: A total of 163 334 dried blood spot samples collected between April 2015 and March 2018 were analyzed, including 112 352 samples within the HIV Early Infant Diagnosis program. A high burden with >1% sickle cell disease was found within targeted East Central and Mid-Northern districts, in both HIV-exposed and nonexposed children. Based on crude birth-rate data, 236 905 sickle cell trait births and 16 695 sickle cell disease births will occur annually in Uganda. Compared to sickle cell disease without HIV, the odds ratio of having sickle cell disease plus HIV was 0.50 (95% confidence interval = 0.40-0.64, P < .0001). Alpha-thalassemia trait and G6PD deficiency were common with sickle cell disease, but with different geospatial distribution. CONCLUSIONS: High sickle cell burden and potential HIV comorbidity are confirmed in Uganda. Genetic modifiers are common and likely influence laboratory and clinical phenotypes. These prospective data document that targeted sickle cell screening is feasible and effective in Uganda, and support development of district-level comprehensive care programs.


Assuntos
Anemia Falciforme/diagnóstico , Genes Modificadores , Deficiência de Glucosefosfato Desidrogenase/diagnóstico , Infecções por HIV/diagnóstico , Programas de Rastreamento/métodos , Talassemia alfa/diagnóstico , Anemia Falciforme/complicações , Anemia Falciforme/epidemiologia , Anemia Falciforme/genética , Pré-Escolar , Comorbidade , Feminino , Seguimentos , Deficiência de Glucosefosfato Desidrogenase/complicações , Deficiência de Glucosefosfato Desidrogenase/epidemiologia , Deficiência de Glucosefosfato Desidrogenase/genética , HIV/genética , HIV/isolamento & purificação , Infecções por HIV/complicações , Infecções por HIV/epidemiologia , Infecções por HIV/genética , Humanos , Lactente , Recém-Nascido , Masculino , Prevalência , Prognóstico , Estudos Prospectivos , Talassemia alfa/complicações , Talassemia alfa/epidemiologia , Talassemia alfa/genética
4.
PLoS Genet ; 14(6): e1007368, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29879116

RESUMO

Selection pressure due to exposure to infectious pathogens endemic to Africa may explain distinct genetic variations in immune response genes. However, the impact of those genetic variations on human immunity remains understudied, especially within the context of modern lifestyles and living environments, which are drastically different from early humans in sub Saharan Africa. There are few data on population differences in constitutional immune environment, where genetic ancestry and environment are likely two primary sources of variation. In a study integrating genetic, molecular and epidemiologic data, we examined population differences in plasma levels of 14 cytokines involved in innate and adaptive immunity, including those implicated in chronic inflammation, and possible contributing factors to such differences, in 914 AA and 855 EA women. We observed significant differences in 7 cytokines, including higher plasma levels of CCL2, CCL11, IL4 and IL10 in EAs and higher levels of IL1RA and IFNα2 in AAs. Analyses of a wide range of demographic and lifestyle factors showed significant impact, with age, education level, obesity, smoking, and alcohol intake, accounting for some, but not all, observed population differences for the cytokines examined. Levels of two pro-inflammatory chemokines, CCL2 and CCL11, were strongly associated with percent of African ancestry among AAs. Through admixture mapping, the signal was pinpointed to local ancestry at 1q23, with fine-mapping analysis refined to the Duffy-null allele of rs2814778. In AA women, this variant was a major determinant of systemic levels of CCL2 (p = 1.1e-58) and CCL11 (p = 2.2e-110), accounting for 19% and 40% of the phenotypic variance, respectively. Our data reveal strong ancestral footprints in inflammatory chemokine regulation. The Duffy-null allele may indicate a loss of the buffering function for chemokine levels. The substantial immune differences by ancestry may have broad implications to health disparities between AA and EA populations.


Assuntos
Adaptação Biológica/genética , Citocinas/genética , Regulação da Expressão Gênica , Variação Genética , Seleção Genética , Imunidade Adaptativa/genética , Adulto , Grupo com Ancestrais do Continente Africano/genética , Alelos , Evolução Biológica , Citocinas/sangue , Sistema do Grupo Sanguíneo Duffy/genética , Meio Ambiente , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Frequência do Gene , Disparidades nos Níveis de Saúde , Voluntários Saudáveis , Humanos , Imunidade Inata/genética , Pessoa de Meia-Idade
5.
J Pediatr Surg ; 53(10): 1996-2002, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29370891

RESUMO

BACKGROUND: Venous thromboembolism (VTE) in pediatric surgical patients is a rare event. The risk factors for VTE in pediatric general surgery patients undergoing abdominopelvic procedures are unknown. STUDY DESIGN: The American College of Surgeon's National Surgical Quality Improvement Program-Pediatric (NSQIP-P) database (2012-2015) was queried for patients with VTE after abdominopelvic general surgery procedures. Patient and operative variables were assessed to identify risk factors associated with VTE and develop a pediatric risk score. RESULTS: From 2012-2015, 68 of 34,813 (0.20%) patients who underwent abdominopelvic general surgery procedures were diagnosed with VTE. On multivariate analysis, there was no increased risk of VTE based on concomitant malignancy, chemotherapy, inflammatory bowel disease, or laparoscopic surgical approach, while a higher rate of VTE was identified among female patients. The odds of experiencing VTE were increased on stepwise regression for patients older than 15 years and those with preexisting renal failure or a diagnosis of septic shock, patients with American Society of Anesthesia (ASA) classification ≥ 2, and for anesthesia time longer than 2 h. The combination of age > 15 years, ASA classification ≥ 2, anesthesia time > 2 h, renal failure, and septic shock was included in a model for predicting risk of VTE (AUC = 0.907, sensitivity 84.4%, specificity 88.2%). CONCLUSION: VTE is rare in pediatric patients, but prediction modeling may help identify those patients at heightened risk. Additional studies are needed to validate the factors identified in this study in a risk assessment model as well as to assess the efficacy and cost-effectiveness of prophylaxis methods. LEVEL OF EVIDENCE: Level III, retrospective comparative study.


Assuntos
Complicações Pós-Operatórias/epidemiologia , Tromboembolia Venosa/epidemiologia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Razão de Chances , Medição de Risco , Fatores de Risco , Procedimentos Cirúrgicos Operatórios/efeitos adversos
6.
Pediatr Transplant ; 21(4)2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28322484

RESUMO

Pediatric RCC is a rare pediatric neoplasm and is distinctly different compared to adult RCC, often demonstrating translocation morphology evidenced by unique histopathological features and TFE3 or TFEB nuclear expression. We report three cases of pediatric TFE3 positive RCC (TFE3-RCC) occurring in the setting of chronic kidney disease and long-term pharmacological immunosuppression, including two cases that developed in the native kidney following kidney transplantation. Together, these cases suggest that the kidney microenvironment in combination with immune dysregulation is likely contributing factors in the pathogenesis of some pediatric RCC, warranting further study. Long-term post-transplant surveillance may warrant screening for RCC.


Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/diagnóstico , Falência Renal Crônica/cirurgia , Neoplasias Renais/diagnóstico , Transplante de Rim , Complicações Pós-Operatórias/diagnóstico , Carcinoma de Células Renais/etiologia , Carcinoma de Células Renais/metabolismo , Criança , Evolução Fatal , Feminino , Humanos , Imunossupressores/efeitos adversos , Lactente , Neoplasias Renais/etiologia , Neoplasias Renais/metabolismo , Masculino , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/metabolismo , Microambiente Tumoral
7.
Pediatr Blood Cancer ; 64(2): 284-286, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27701822

RESUMO

Kaposiform hemangioendothelioma (KHE) is a rare aggressive vascular tumor of skin and deep soft tissues that typically presents in infancy and may be associated with a potentially life-threatening coagulopathy known as Kasabach-Merrit phenomenon (KMP). Recent advances in medical therapy have successfully treated many patients. However, our knowledge regarding the natural history of these lesions and optimum surveillance strategies remains rudimentary. We report two young women who had KHE with KMP treated in infancy and presented in adolescence with comorbidities related to their KHE tumor. This presentation supports the need for long-term surveillance in these patients.


Assuntos
Hemangioendotelioma/mortalidade , Hemangioendotelioma/terapia , Síndrome de Kasabach-Merritt/mortalidade , Síndrome de Kasabach-Merritt/terapia , Sarcoma de Kaposi/mortalidade , Sarcoma de Kaposi/terapia , Terapia Combinada , Feminino , Hemangioendotelioma/patologia , Humanos , Lactente , Síndrome de Kasabach-Merritt/patologia , Prognóstico , Sarcoma de Kaposi/patologia , Taxa de Sobrevida
8.
Br J Haematol ; 176(4): 515-526, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27982424

RESUMO

Although haemoglobin SC (HbSC) accounts for 30% of sickle cell disease (SCD) in the United States and United Kingdom, evidence-based guidelines for genotype specific management are lacking. The unique pathology of HbSC disease is complex, characterized by erythrocyte dehydration, intracellular sickling and increased blood viscosity. The evaluation and treatment of patients with HbSC is largely inferred from studies of SCD consisting mostly of haemoglobin SS (HbSS) patients. These studies are underpowered to allow definitive conclusions about HbSC. We review the pathophysiology of HbSC disease, including known and potential differences between HbSS and HbSC, and highlight knowledge gaps in HbSC disease management. Clinical and translational research is needed to develop targeted treatments and to validate management recommendations for efficacy, safety and impact on quality of life for people with HbSC.


Assuntos
Doença da Hemoglobina SC/terapia , Gerenciamento Clínico , Eritrócitos Anormais/patologia , Genótipo , Doença da Hemoglobina SC/diagnóstico , Humanos , Qualidade de Vida
9.
PLoS One ; 11(10): e0164364, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27711207

RESUMO

Discovery and validation of genetic variants that influence disease severity in children with sickle cell anemia (SCA) could lead to early identification of high-risk patients, better screening strategies, and intervention with targeted and preventive therapy. We hypothesized that newly identified genetic risk factors for the general African American population could also impact laboratory biomarkers known to contribute to the clinical disease expression of SCA, including variants influencing the white blood cell count and the development of albuminuria and abnormal glomerular filtration rate. We first investigated candidate genetic polymorphisms in well-characterized SCA pediatric cohorts from three prospective NHLBI-supported clinical trials: HUSTLE, SWiTCH, and TWiTCH. We also performed whole exome sequencing to identify novel genetic variants, using both a discovery and a validation cohort. Among candidate genes, DARC rs2814778 polymorphism regulating Duffy antigen expression had a clear influence with significantly increased WBC and neutrophil counts, but did not affect the maximum tolerated dose of hydroxyurea therapy. The APOL1 G1 polymorphism, an identified risk factor for non-diabetic renal disease, was associated with albuminuria. Whole exome sequencing discovered several novel variants that maintained significance in the validation cohorts, including ZFHX4 polymorphisms affecting both the leukocyte and neutrophil counts, as well as AGGF1, CYP4B1, CUBN, TOR2A, PKD1L2, and CD163 variants affecting the glomerular filtration rate. The identification of robust, reliable, and reproducible genetic markers for disease severity in SCA remains elusive, but new genetic variants provide avenues for further validation and investigation.


Assuntos
Albuminúria/diagnóstico , Anemia Falciforme/diagnóstico , Adolescente , Albuminúria/complicações , Anemia Falciforme/complicações , Anemia Falciforme/tratamento farmacológico , Anemia Falciforme/genética , Apolipoproteína L1 , Apolipoproteínas/genética , Criança , Sistema do Grupo Sanguíneo Duffy/genética , Sistema do Grupo Sanguíneo Duffy/metabolismo , Feminino , Variação Genética , Genótipo , Taxa de Filtração Glomerular , Proteínas de Homeodomínio/genética , Humanos , Hidroxiureia/uso terapêutico , Contagem de Leucócitos , Leucócitos/citologia , Lipoproteínas HDL/genética , Masculino , Neutrófilos/citologia , Fenótipo , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Fatores de Risco , Análise de Sequência de DNA , Fatores de Transcrição/genética
10.
Blood Adv ; 1(1): 93-100, 2016 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-29296698

RESUMO

The Uganda Sickle Surveillance Study analyzed dried blood spots that were collected from almost 100 000 infants and young children from all 10 regions and 112 districts in the Republic of Uganda, with the primary objective of determining the prevalence of sickle cell trait and disease. An overall prevalence of 13.3% sickle cell trait and 0.7% sickle cell disease was recently reported. The isoelectric focusing electrophoresis technique coincidentally revealed numerous hemoglobin (Hb) variants (defined as an electrophoresis band that was not Hb A, Hb F, Hb S, or Hb C) with an overall country-wide prevalence of 0.5%, but with considerable geographic variability, being highest in the northwest regions and districts. To elucidate these Hb variants, the original isoelectric focusing (IEF) gels were reviewed to identify and locate the variant samples; corresponding dried blood spots were retrieved for further testing. Subsequent DNA-based investigation of 5 predominant isoelectric focusing patterns identified 2 α-globin variants (Hb Stanleyville II, Asn78Lys; Hb G-Pest, Asp74Asn), 1 ß-globin variant (Hb O-Arab, Glu121Lys), and 2 fusion globin variants (Hb P-Nilotic, ß31-δ50; Hb Kenya, Aγ81Leu-ß86Ala). Compound heterozygotes containing an Hb variant plus Hb S were also identified, including both Hb S/O-Arab and HbS/Kenya. Regional differences in the types and prevalence of these hemoglobin variants likely reflect tribal ancestries and migration patterns. Algorithms are proposed to characterize these Hb variants, which will be helpful for emerging neonatal hemoglobinopathy screening programs that are under way in sub-Saharan Africa.

11.
Am J Hematol ; 91(2): 205-10, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26537622

RESUMO

Sickle cell disease (SCD) is a common and life-threatening hematological disorder, affecting approximately 400,000 newborns annually worldwide. Most SCD births occur in low-resource countries, particularly in sub-Saharan Africa, where limited access to accurate diagnostics results in early mortality. We evaluated a prototype immunoassay as a novel, rapid, and low-cost point-of-care (POC) diagnostic device (Sickle SCAN) designed to identify HbA, HbS, and HbC. A total of 139 blood samples were scored by three masked observers and compared to results using capillary zone electrophoresis. The sensitivity (98.3-100%) and specificity (92.5-100%) to detect the presence of HbA, HbS, and HbS were excellent. The test demonstrated 98.4% sensitivity and 98.6% specificity for the diagnosis of HbSS disease and 100% sensitivity and specificity for the diagnosis of HbSC disease. Most variant hemoglobins, including samples with high concentrations of HbF, did not interfere with the ability to detect HbS or HbC. Additionally, HbS and HbC were accurately detected at concentrations as low as 1-2%. Dried blood spot samples yielded clear positive bands, without loss of sensitivity or specificity, and devices stored at 37°C gave reliable results. These analyses indicate that the Sickle SCAN POC device is simple, rapid, and robust with high sensitivity and specificity for the detection of HbA, HbS, and HbC. The ability to obtain rapid and accurate results with both liquid blood and dried blood spots, including those with newborn high-HbF phenotypes, suggests that this POC device is suitable for large-scale screening and potentially for accurate diagnosis of SCD in limited resource settings.


Assuntos
Anemia Falciforme/sangue , Hemoglobina A/análise , Hemoglobina C/análise , Hemoglobina Falciforme/análise , Sistemas Automatizados de Assistência Junto ao Leito , Eletroforese Capilar , Humanos , Imunoensaio/economia , Imunoensaio/métodos , Projetos Piloto , Sistemas Automatizados de Assistência Junto ao Leito/economia , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Fatores de Tempo
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