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1.
AMA J Ethics ; 24(8): E788-794, 2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-35976937

RESUMO

Clinicians cannot always directly or effectively engage patients experiencing mental health crises. This article considers the common practice of relying upon law enforcement personnel to facilitate mental health checks and considers its implications for Black patients. An antiracist approach to decriminalizing acute exacerbations of mental illness requires clinicians' engagement in educating, training, and policymaking. This article recommends strategies for effective real-time communication before, during, and after a 911 call involving a person experiencing a mental health crisis.


Assuntos
Transtornos Mentais , Serviços de Saúde Mental , Intervenção em Crise/educação , Humanos , Transtornos Mentais/psicologia , Transtornos Mentais/terapia , Saúde Mental
2.
Curr Opin Neurobiol ; 76: 102590, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35753108

RESUMO

The ventral hippocampus (vHPC) has long been thought of as the "emotional" hippocampus. Over the past several years, the complexity of vHPC has come to light, highlighting the diversity of cell types, inputs, and outputs that coordinate a constellation of positively and negatively motivated behaviors. Here, we review recent work on how vCA1 contributes to a network that associates external stimuli with internal motivational drive states to promote the selection of adaptive behavioral responses. We propose a model of vHPC function that emphasizes its role in the integration and transformation of internal and external cues to guide behavioral selection when faced with multiple potential outcomes.


Assuntos
Hipocampo , Hipocampo/fisiologia
3.
J Sch Health ; 92(2): 177-184, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34841533

RESUMO

BACKGROUND: Studies show that food insecurity is associated with adverse health behaviors for children and adults. However, published data among adolescents are limited. The objective of this study was to examine the association between food insecurity and substance use behaviors among US high school students. METHODS: Data from the 2017 Youth Risk Behavior Survey in 10 states were combined to examine the association between household food insecurity and adolescent use of alcohol, marijuana, prescription opioid misuse, and illicit drugs using logistic regression. RESULTS: Among surveyed respondents, 12.3% of high school students reported experiencing food insecurity. In unadjusted analyses, the prevalence of substance use was higher among students with food insecurity compared to food secure students: current binge drinking (16.2% vs 11.5%), current marijuana use (24.0% vs 16.2%), lifetime prescription opioid misuse (21.3% vs 12.6%), and lifetime use of illicit drugs (12.3% vs 5.0%) (all p < .05). In adjusted models, food insecurity was associated with lifetime prescription opioid misuse and lifetime use of illicit drugs (aPR 1.38 and 1.70, respectively). CONCLUSION: Students with food insecurity are a potential group at a higher rise of substance misuse and may benefit from prevention programs designed to address their needs.


Assuntos
Uso da Maconha , Transtornos Relacionados ao Uso de Opioides , Transtornos Relacionados ao Uso de Substâncias , Adolescente , Adulto , Criança , Insegurança Alimentar , Humanos , Uso da Maconha/epidemiologia , Assunção de Riscos , Estudantes , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Estados Unidos/epidemiologia
5.
Nat Neurosci ; 23(11): 1444-1452, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32929245

RESUMO

The ventral hippocampus (vHPC) is a critical hub in networks that process emotional information. While recent studies have indicated that ventral CA1 (vCA1) projection neurons are functionally dissociable, the basic principles of how the inputs and outputs of vCA1 are organized remain unclear. Here, we used viral and sequencing approaches to define the logic of the extended vCA1 circuit. Using high-throughput sequencing of genetically barcoded neurons (MAPseq) to map the axonal projections of thousands of vCA1 neurons, we identify a population of neurons that simultaneously broadcast information to multiple areas known to regulate the stress axis and approach-avoidance behavior. Through molecular profiling and viral input-output tracing of vCA1 projection neurons, we show how neurons with distinct projection targets may differ in their inputs and transcriptional signatures. These studies reveal new organizational principles of vCA1 that may underlie its functional heterogeneity.


Assuntos
Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Animais , Encéfalo/citologia , Encéfalo/metabolismo , Feminino , Perfilação da Expressão Gênica , Masculino , Camundongos Endogâmicos C57BL , Vias Neurais/citologia , Vias Neurais/metabolismo
6.
Palliat Med ; 34(6): 708-730, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32286157

RESUMO

BACKGROUND: Despite being a terminal neurodegenerative disease, the role of palliative care is less recognised for motor neurone disease than for other life-limiting conditions. Understanding the experiences of, and need for, palliative care for patients and carers is key to configuring optimal policy and healthcare services. AIM: To explore the experiences of, and need for, palliative care of people with motor neurone disease and their informal carers across the disease trajectory. DESIGN: A systematic review of qualitative research conducted using Thematic Synthesis - PROSPERO registration CRD42017075311. DATA SOURCES: Four electronic databases were searched (MEDLINE, CINAHL, PsycINFO, Social Science Citation Index) using terms for motor neurone disease, amyotrophic lateral sclerosis, palliative care, and qualitative research, from inception to November 2018. Included papers were data extracted and assessed for quality. RESULTS: A total of 41 papers were included, representing the experiences of 358 people with motor neurone disease and 369 caregivers. Analytical themes were developed detailing patients' and carers' experiences of living with motor neurone disease and of palliative care through its trajectory including response to diagnosis, maintaining control, decision-making during deterioration, engaging with professionals, planning for end-of-life care, bereavement. CONCLUSION: The review identified a considerable literature exploring the care needs of people with motor neurone disease and their carers; however, descriptions of palliative care were associated with the last days of life. Across the disease trajectory, clear points were identified where palliative care input could enhance patient and carer experience of the disease, particularly at times of significant physical change.


Assuntos
Cuidadores , Doença dos Neurônios Motores , Cuidados Paliativos , Cuidadores/estatística & dados numéricos , Cuidados Paliativos na Terminalidade da Vida/estatística & dados numéricos , Humanos , Doença dos Neurônios Motores/terapia , Cuidados Paliativos/estatística & dados numéricos , Pesquisa Qualitativa
7.
Thorax ; 75(4): 306-312, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32139611

RESUMO

BACKGROUND: Estimation of the risk of malignancy in pulmonary nodules detected by CT is central in clinical management. The use of artificial intelligence (AI) offers an opportunity to improve risk prediction. Here we compare the performance of an AI algorithm, the lung cancer prediction convolutional neural network (LCP-CNN), with that of the Brock University model, recommended in UK guidelines. METHODS: A dataset of incidentally detected pulmonary nodules measuring 5-15 mm was collected retrospectively from three UK hospitals for use in a validation study. Ground truth diagnosis for each nodule was based on histology (required for any cancer), resolution, stability or (for pulmonary lymph nodes only) expert opinion. There were 1397 nodules in 1187 patients, of which 234 nodules in 229 (19.3%) patients were cancer. Model discrimination and performance statistics at predefined score thresholds were compared between the Brock model and the LCP-CNN. RESULTS: The area under the curve for LCP-CNN was 89.6% (95% CI 87.6 to 91.5), compared with 86.8% (95% CI 84.3 to 89.1) for the Brock model (p≤0.005). Using the LCP-CNN, we found that 24.5% of nodules scored below the lowest cancer nodule score, compared with 10.9% using the Brock score. Using the predefined thresholds, we found that the LCP-CNN gave one false negative (0.4% of cancers), whereas the Brock model gave six (2.5%), while specificity statistics were similar between the two models. CONCLUSION: The LCP-CNN score has better discrimination and allows a larger proportion of benign nodules to be identified without missing cancers than the Brock model. This has the potential to substantially reduce the proportion of surveillance CT scans required and thus save significant resources.


Assuntos
Inteligência Artificial , Transformação Celular Neoplásica/patologia , Neoplasias Pulmonares/patologia , Nódulos Pulmonares Múltiplos/patologia , Redes Neurais de Computação , Adulto , Idoso , Algoritmos , Área Sob a Curva , Estudos de Coortes , Bases de Dados Factuais , Detecção Precoce de Câncer/métodos , Feminino , Humanos , Incidência , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/fisiopatologia , Masculino , Pessoa de Meia-Idade , Nódulos Pulmonares Múltiplos/epidemiologia , Nódulos Pulmonares Múltiplos/fisiopatologia , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Prognóstico , Curva ROC , Estudos Retrospectivos , Medição de Risco
8.
Eur Respir J ; 54(4)2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31537697

RESUMO

BACKGROUND: Low-dose computed tomography (LDCT) screening detects early-stage lung cancer and reduces mortality. We proposed a sequential approach targeted to a high-risk group as a potentially efficient screening strategy. METHODS: LungSEARCH was a national multicentre randomised trial. Current/ex-smokers with mild/moderate chronic obstructive pulmonary disease (COPD) were allocated (1:1) to have 5 years surveillance or not. Screened participants provided annual sputum samples for cytology and cytometry, and if abnormal were offered annual LDCT and autofluorescence bronchoscopy (AFB). Those with normal sputum provided annual samples. The primary end-point was the percentage of lung cancers diagnosed at stage I/II (nonsmall cell) or limited disease (small cell). RESULTS: 1568 participants were randomised during 2007-2011 from 10 UK centres. 85.2% of those screened provided an adequate baseline sputum sample. There were 42 lung cancers among 785 screened individuals and 36 lung cancers among 783 controls. 54.8% (23 out of 42) of screened individuals versus 45.2% (14 out of 31) of controls with known staging were diagnosed with early-stage disease (one-sided p=0.24). Relative risk was 1.21 (95% CI 0.75-1.95) or 0.82 (95% CI 0.52-1.31) for early-stage or advanced cancers, respectively. Overall sensitivity for sputum (in those randomised to surveillance) was low (40.5%) with a cumulative false-positive rate (FPR) of 32.8%. 55% of cancers had normal sputum results throughout. Among sputum-positive individuals who had AFB, sensitivity was 45.5% and cumulative FPR was 39.5%; the corresponding measures for those who had LDCT were 100% and 16.1%, respectively. CONCLUSIONS: Our sequential strategy, using sputum cytology/cytometry to select high-risk individuals for AFB and LDCT, did not lead to a clear stage shift and did not improve the efficiency of lung cancer screening.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Pequenas/patologia , Detecção Precoce de Câncer/métodos , Neoplasias Pulmonares/patologia , Escarro/citologia , Adenocarcinoma de Pulmão/complicações , Adenocarcinoma de Pulmão/diagnóstico por imagem , Adenocarcinoma de Pulmão/patologia , Broncoscopia , Carcinoma de Células Grandes/complicações , Carcinoma de Células Grandes/diagnóstico por imagem , Carcinoma de Células Grandes/patologia , Carcinoma Pulmonar de Células não Pequenas/complicações , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma de Células Pequenas/complicações , Carcinoma de Células Pequenas/diagnóstico por imagem , Carcinoma de Células Escamosas/complicações , Carcinoma de Células Escamosas/diagnóstico por imagem , Carcinoma de Células Escamosas/patologia , Técnicas Citológicas , Feminino , Humanos , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Imagem Óptica , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Medição de Risco , Sensibilidade e Especificidade , Tomografia Computadorizada por Raios X , Reino Unido
9.
Diabetes Res Clin Pract ; 154: 52-65, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31202865

RESUMO

BACKGROUND: A multi-layered association between tobacco use and type 2 diabetes mellitus (T2DM) is well established. However, global epidemiological patterns of tobacco use among T2DM patients are not well documented; this review thus aims to estimate the overall global burden of tobacco use in T2DM. METHODS: A systematic review of studies published from Jan 1, 1990 to October 5, 2017 was undertaken, comprising: a comprehensive literature search on multiple electronic databases; quality assessment of studies; data extraction for the primary (prevalence of tobacco use in T2DM patients) and secondary outcomes (patterns of tobacco use in T2DM patients); and a meta-analysis. The review was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines. A protocol for this review is available on PROSPERO (CRD42016038793). FINDINGS: 74 studies were included in the review, reporting data from 3.2 million participants across 33 countries. Global mean prevalence of tobacco use in T2DM was 20·81% (95% CI 18·93-22·76), and was higher in the WHO East Asia and Pacific and South Asia regions, compared to the Americas, Middle East and North Africa, Europe and Central Asia. In studies which compared prevalence of tobacco use in patients to non-patients, patients with T2DM were 26% less likely to use tobacco (pooled OR = 0·74 (CI 0·61-0·88). INTERPRETATION: Tobacco is used by one in five T2DM patients globally, but usage is less likely in patients than in non-patients. Global patterns of use demonstrated by this review have implications for both prevention and The understanding of diabetes burden, and the success of tobacco cessation strategies.


Assuntos
Diabetes Mellitus Tipo 2/fisiopatologia , Uso de Tabaco/epidemiologia , Saúde Global , Humanos , Prevalência
10.
Palliat Med ; 33(6): 607-617, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30848703

RESUMO

BACKGROUND: Existing quantitative evidence suggests that at a population level, socioeconomic factors affect access to preferred place of death. However, the influence of individual and contextual socioeconomic factors on preferred place of death are less well understood. AIM: To systematically synthesise the existing qualitative evidence for socioeconomic factors affecting access to preferred place of death in the United Kingdom. DESIGN: A thematic synthesis of qualitative research. DATA SOURCES: Cochrane Library, MEDLINE, Embase, CINAHL, ASSIA, Scopus and PsycINFO databases were searched from inception to May 2018. RESULTS: A total of 13 articles, reporting on 12 studies, were included in the synthesis. Two overarching themes were identified: 'Human factors' representing support networks, interactions between people and decision-making and 'Environmental factors', which included issues around locations and resources. Few studies directly referenced socioeconomic deprivation. The main factor affecting access to preferred place of death was social support; people with fewer informal carers were less likely to die in their preferred location. Other key findings included fluidity around the concept of home and variability in preferred place of death itself, particularly in response to crises. CONCLUSION: There is limited UK-based qualitative research on socioeconomic factors affecting preferred place of death. Further qualitative research is needed to explore the barriers and facilitators of access to preferred place of death in socioeconomically deprived UK communities. In practice, there needs to be more widespread discussion and documentation of preferred place of death while also recognising these preferences may change as death nears or in times of crisis.


Assuntos
Atitude Frente a Morte , Preferência do Paciente/psicologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Tomada de Decisões , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pesquisa Qualitativa , Fatores Socioeconômicos , Reino Unido
11.
Thorax ; 73(12): 1128-1136, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29950525

RESUMO

BACKGROUND: Lung cancer outcomes in the UK are worse than in many other developed nations. Symptom awareness campaigns aim to diagnose patients at an earlier stage to improve cancer outcomes. METHODS: An early diagnosis campaign for lung cancer commenced in Leeds, UK in 2011 comprising public and primary-care facing components. Rates of community referral for chest X-ray and lung cancer stage (TNM seventh edition) at presentation were collected from 2008 to 2015. Linear trends were assessed by χ2 test for trend in proportions. Headline figures are presented for the 3 years pre-campaign (2008-2010) and the three most recent years for which data are available during the campaign (2013-2015). FINDINGS: Community-ordered chest X-ray rates per year increased from 18 909 in 2008-2010 to 34 194 in 2013-2015 (80.8% increase). A significant stage shift towards earlier stage lung cancer was seen (χ2(1)=32.2, p<0.0001). There was an 8.8 percentage point increase in the proportion of patients diagnosed with stage I/II lung cancer (26.5% pre-campaign vs 35.3% during campaign) and a 9.3% reduction in the absolute number of patients diagnosed with stage III/IV disease (1254 pre-campaign vs 1137 during campaign). INTERPRETATION: This is the largest described lung cancer stage-shift in association with a symptom awareness campaign. A causal link between the campaign and stage-shift cannot be proven but appears plausible. Limitations of the analysis include a lack of contemporary control population.


Assuntos
Detecção Precoce de Câncer/tendências , Medicina Geral/educação , Educação em Saúde , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Neoplasias Abdominais , Idoso , Idoso de 80 Anos ou mais , Autoavaliação Diagnóstica , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Atenção Primária à Saúde , Radiografia Torácica/tendências , Avaliação de Sintomas , Reino Unido
12.
Sci Rep ; 5: 11098, 2015 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-26067905

RESUMO

Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). To identify recipient risk factors, a genome-wide study was performed including 481,820 single-nucleotide polymorphisms (SNPs). Two GVHD susceptibility loci (rs17114803 and rs17114808) within the SUFU gene were identified in the discovery cohort (p = 2.85 × 10(-5)). The incidence of acute GVHD among patients homozygous for CC at SUFU rs17114808 was 69%, which was significantly higher than the 8% rate observed in CT heterozygous patients (p = 0.0002). In an independent validation cohort of 100 patients, 50% of the patients with the CC genotype developed GVHD compared to 8% of the patients with either CT or TT genotype (p = 0.01). In comparison to CC dendritic cells, those from CT expressed higher levels of SUFU mRNA and protein, had lower levels of surface HLA-DR, and induced less allogeneic mixed leukocyte response (MLR). Ectopic expression of SUFU in THP-1 derived DCs reduced HLA-DR expression and suppressed MLR, whereas silencing of SUFU enhanced HLA-DR expression and increased MLR. Thus our findings provide novel evidence that recipient SUFU germline polymorphism is associated with acute GVHD and is a novel molecular target for GVHD prevention and treatment.


Assuntos
Estudo de Associação Genômica Ampla , Doença Enxerto-Hospedeiro/genética , Transplante de Células-Tronco Hematopoéticas , Homozigoto , Polimorfismo de Nucleotídeo Único , Proteínas Repressoras/genética , Doença Aguda , Aloenxertos , Linhagem Celular Tumoral , Feminino , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/metabolismo , Antígenos HLA-DR/genética , Antígenos HLA-DR/metabolismo , Humanos , Incidência , Masculino , Proteínas Repressoras/metabolismo
13.
Blood ; 124(8): 1266-76, 2014 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-24970932

RESUMO

Asparaginase is a therapeutic enzyme used to treat leukemia and lymphoma, with immune responses resulting in suboptimal drug exposure and a greater risk of relapse. To elucidate whether there is a genetic component to the mechanism of asparaginase-induced immune responses, we imputed human leukocyte antigen (HLA) alleles in patients of European ancestry enrolled on leukemia trials at St. Jude Children's Research Hospital (n = 541) and the Children's Oncology Group (n = 1329). We identified a higher incidence of hypersensitivity and anti-asparaginase antibodies in patients with HLA-DRB1*07:01 alleles (P = 7.5 × 10(-5), odds ratio [OR] = 1.64; P = 1.4 × 10(-5), OR = 2.92, respectively). Structural analysis revealed that high-risk amino acids were located within the binding pocket of the HLA protein, possibly affecting the interaction between asparaginase epitopes and the HLA-DRB1 protein. Using a sequence-based consensus approach, we predicted the binding affinity of HLA-DRB1 alleles for asparaginase epitopes, and patients whose HLA genetics predicted high-affinity binding had more allergy (P = 3.3 × 10(-4), OR = 1.38). Our results suggest a mechanism of allergy whereby HLA-DRB1 alleles that confer high-affinity binding to asparaginase epitopes lead to a higher frequency of reactions. These trials were registered at www.clinicaltrials.gov as NCT00137111, NCT00549848, NCT00005603, and NCT00075725.


Assuntos
Alelos , Anticorpos , Antineoplásicos/efeitos adversos , Asparaginase/efeitos adversos , Hipersensibilidade a Drogas , Cadeias HLA-DRB1 , Leucemia/tratamento farmacológico , Adolescente , Adulto , Anticorpos/sangue , Anticorpos/imunologia , Antineoplásicos/administração & dosagem , Asparaginase/administração & dosagem , Criança , Pré-Escolar , Hipersensibilidade a Drogas/sangue , Hipersensibilidade a Drogas/genética , Hipersensibilidade a Drogas/imunologia , Epitopos/sangue , Epitopos/genética , Epitopos/imunologia , Feminino , Cadeias HLA-DRB1/genética , Cadeias HLA-DRB1/imunologia , Humanos , Lactente , Leucemia/genética , Leucemia/imunologia , Leucemia/patologia , Masculino , Fatores de Risco
14.
J Clin Oncol ; 31(30): 3782-90, 2013 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-24043749

RESUMO

PURPOSE: Killer-cell immunoglobulin-like receptors (KIRs) that regulate natural-killer cells are highly polymorphic. Some KIR2DL1 alleles encode receptors that have stronger signaling function than others. We tested the hypothesis that the clinical outcomes of allogeneic hematopoietic stem-cell transplantation (HSCT) could be affected by donor KIR2DL1 polymorphism. PATIENTS AND METHODS: All 313 pediatric patients received allogeneic HSCT at a single institution. Donor KIR2DL1 functional allele typing was retrospectively performed using single nucleotide polymorphism assay. RESULTS: Patients who received a donor graft containing the functionally stronger KIR2DL1 allele with arginine at amino acid position 245 (KIR2DL1-R(245)) had better survival (P = .0004) and lower cumulative incidence of disease progression (P = .001) than those patients who received a donor graft that contained only the functionally weaker KIR2DL1 allele with cysteine at the same position (KIR2DL1-C(245)). The effect of KIR2DL1 allelic polymorphism was similar in patients with acute myeloid leukemia or acute lymphoblastic leukemia among all allele groups (P ≥ .71). Patients who received a KIR2DL1-R(245)-positive graft with HLA-C receptor-ligand mismatch had the best survival (P = .00003) and lowest risk of leukemia progression (P = .0005) compared with those who received a KIR2DL1-C(245) homozygous graft. CONCLUSION: Donor KIR2DL1 allelic polymorphism affects recipient outcomes after allogeneic HSCT. These findings have substantial implications for prognostication and donor selection.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/cirurgia , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras/cirurgia , Receptores KIR2DL1/genética , Adolescente , Alelos , Análise de Variância , Arginina , Criança , Pré-Escolar , Cisteína , Progressão da Doença , Intervalo Livre de Doença , Feminino , Antígenos HLA-C , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/genética , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Transplante Homólogo
15.
Blood ; 121(23): 4800-6, 2013 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-23637130

RESUMO

The impact of HLA homozygosity at mismatched (MM) loci on the outcome of 2687 myeloablative unrelated donor hematopoietic cell transplantations performed for malignant disease was evaluated among 4 groups: 7/8 bidirectional MM transplants (donor and recipient heterozygous MM, n = 1393), 7/8 host-versus-graft (HVG) vector MM (recipient homozygous, n = 112), 7/8 graft-versus-host (GVH) vector MM (donor homozygous, n = 119), and 8/8 matches (n = 1063). Multivariate analyses found 7/8 GVH (P = .001) and bidirectional MM groups (P < .0001) had significantly worse transplant-related mortality and overall and disease-free survival than the 8/8 match group, a difference not observed with the 7/8 HVG MM group (P > .01). The 3 7/8 groups differed only for grades III-IV acute GVH disease (GVHD), where HVG MM had less GVHD than the 7/8 bidirectional MM (hazard ratio [HR] 0.52, P = .0016) and GVH MM (HR 0.43, P = .0009) groups but not the 8/8 group (HR 0.83, P = .39). There were no differences between the 7/8 groups for relapse, chronic GVHD, neutrophil engraftment, or graft failure. GVH MM have the same risk as 7/8 bidirectional MM. 7/8 HVG MM confer a reduced risk of acute GVHD without an increased risk of disease relapse or graft failure compared with a 7/8 bidirectional MM.


Assuntos
Doença Enxerto-Hospedeiro/mortalidade , Antígenos HLA/metabolismo , Neoplasias Hematológicas/mortalidade , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Condicionamento Pré-Transplante , Doadores não Relacionados/estatística & dados numéricos , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/etiologia , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/terapia , Histocompatibilidade , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Agonistas Mieloablativos/uso terapêutico , Prognóstico , Fatores de Risco , Taxa de Sobrevida , Adulto Jovem
16.
Pediatr Blood Cancer ; 59(5): 895-901, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22238059

RESUMO

BACKGROUND: The Chilean population is ethnically diverse, and more than 50% of children referred for hematopoietic stem cell transplantation (HSCT) lack a suitable donor. PROCEDURE: To expand the donor pool, we assessed the feasibility, tolerance, and efficacy of using a haploidentical (HI) donor and a reduced-intensity conditioning regimen for high-risk pediatric leukemia. This study was facilitated by technology transfer from St. Jude Children's Research Hospital over the 2 preceding years. RESULTS: Between March 2006 and April 2009, 10 patients (median age, 9.8 years) received T cell-depleted grafts at Calvo Mackenna Hospital in Santiago. Median cell doses were CD34+: 7.45 × 10(6)/kg (range, 4.00-20.20 × 10(6)/kg); CD3+: 0.88 × 10(5)/kg (0.11-1.35 × 10(5)/kg); and CD56+: 71.30 × 10(6)/kg (31.50-131.80 × 10(6)/kg). Nine patients experienced complete engraftment; six of the nine remain alive and clinically well 13-50 months post-HSCT. Three patients died after bone marrow relapse, while only one died of transplant-related causes. Virus reactivation was the main post-transplant complication: 5/10 had positive CMV PCR but none had CMV disease. One patient developed acute GvHD > grade II and only one had chronic GvHD. CONCLUSIONS: HI-HSCT is feasible in our setting, offers a rational treatment option, and expands the donor pool significantly for children with high-risk leukemia in a developing country. This information is especially relevant to other ethnically diverse populations that are poorly represented in international donor registries.


Assuntos
Sobrevivência de Enxerto , Leucemia/terapia , Doadores Vivos , Sistema de Registros , Transplante de Células-Tronco , Adolescente , Criança , Pré-Escolar , Chile , Infecções por Citomegalovirus/etiologia , Infecções por Citomegalovirus/mortalidade , Infecções por Citomegalovirus/terapia , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/terapia , Humanos , Leucemia/mortalidade , Masculino , Fatores de Risco , Transplante Homólogo
17.
Clin Immunol ; 138(3): 274-81, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21239231

RESUMO

Killer cell immunoglobulin-like receptors (KIRs) regulate NK cell function. KIRs and their HLA ligands are highly polymorphic in nature with substantial allelic polymorphism. At present, there is a lack of an expedient method for KIR and HLA allele typing with relevant functional information. Here, we developed a single-nucleotide polymorphism (SNP) assay to type various allele groups of KIR2DL1 with distinct functional properties based on polymorphism at position 245. We also established a SNP assay to type different KIR ligands based on polymorphism at position 77 in HLA-C and position 83 in HLA-B and -A. Our SNP assays for KIR and KIR ligand typing are much cheaper and faster than existing high-resolution typing. Importantly, our high-throughput methods provide readouts that are informative in predicting NK cell activity in health, disease, and transplantation.


Assuntos
Polimorfismo de Nucleotídeo Único , Receptores KIR2DL1/genética , Receptores KIR2DL1/imunologia , Análise de Sequência de DNA/métodos , Alelos , Linhagem Celular , Antígenos HLA-A/genética , Antígenos HLA-A/imunologia , Antígenos HLA-B/genética , Antígenos HLA-B/imunologia , Antígenos HLA-C/genética , Antígenos HLA-C/imunologia , Humanos , Ligantes
18.
Exp Hematol ; 35(5): 831-41, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17577931

RESUMO

OBJECTIVE: Analysis of T-cell population diversity is important to hematopoietic stem cell transplantation (HSCT). The millions of specificities in T-cell receptor (TCR) hypervariable complementarity- determining region 3 (CDR3) precludes detection of all T-cell populations by antibody-based flow cytometry. An alternative method, the TCR CDR3 spectratyping assay, involves multiple polymerase chain reaction (PCR) analyses and is interpreted only qualitatively. In this study, we designed the first TCRbeeta-based oligonucleotide microarray and investigated its specificity, clonality discrimination, sensitivity of detection, and feasibility for monitoring T-cell population diversity in HSCT. MATERIALS AND METHODS: The array contains 27 TCR Vbeta probes and 13 Jbeta probes. TCRbeta repertoire diversity was detected with single PCR, microarray hybridization system, and Spotfire analysis software. RESULTS: TCRO-based microarray provides specific sequence-based information and can distinguish T-cell monoclonal expansion within a polyclonal population. We successfully used this microarray to quantitatively and qualitatively analyze T-cell population diversity in recipients of hematopoietic stem cell transplants. CONCLUSION: This success suggests broad potential applications of the microarray for use in many other areas, including anti-tumor immunity, vaccination, autoimmunity, infectious diseases, and leukemia. By providing a single PCR-based assay to quantify multiple T-cell populations in parallel, this device will allow clinicians and researchers to rapidly perform high-throughput surveys.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Linfócitos T/imunologia , Adolescente , Adulto , Criança , Pré-Escolar , Células Clonais , Citometria de Fluxo , Sobrevivência de Enxerto/genética , Sobrevivência de Enxerto/imunologia , Humanos , Lactente , Recém-Nascido , Reação em Cadeia da Polimerase/métodos , Sensibilidade e Especificidade , Subpopulações de Linfócitos T/imunologia , Linfócitos T/citologia
19.
Br J Haematol ; 135(4): 524-32, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17010105

RESUMO

The main obstacles to successful haploidentical haematopoietic stem cell transplantation from a mismatched family member donor are delayed immune reconstitution, vulnerability to infections and severe graft-versus-host disease (GvHD). We designed a reduced-intensity conditioning regimen that excluded total body irradiation and anti-thymocyte globulin in order to expedite immune reconstitution after a CD3-depleted haploidentical stem cell transplant. This protocol was used to treat 22 paediatric patients with refractory haematological malignancies. After transplantation, 91% of the patients achieved full donor chimaerism. They also showed rapid recovery of CD3(+) T-cells, T-cell receptor (TCR) excision circle counts, TCRbeta repertoire diversity and natural killer (NK)-cells during the first 4 months post-transplantation, compared with those results from a group of patients treated with a myeloablative conditioning regimen. The incidence and extent of viremia were limited and no lethal infection was seen. Only 9% of patients had grade 3 acute GvHD, while 27% patients had grade 1 and another 27% had grade 2 acute GvHD. This well-tolerated regimen appears to accelerate immune recovery and shorten the duration of early post-transplant immunodeficiency, thereby reducing susceptibility to viral infections. Rapid T-cell reconstitution, retention of NK-cells in the graft and induction of low grade GvHD may also enhance the potential anti-cancer immune effect.


Assuntos
Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Depleção Linfocítica , Condicionamento Pré-Transplante/métodos , Adolescente , Linfócitos B/imunologia , Complexo CD3/sangue , Criança , Pré-Escolar , Feminino , Citometria de Fluxo , Sobrevivência de Enxerto/imunologia , Doença Enxerto-Hospedeiro/imunologia , Neoplasias Hematológicas/imunologia , Humanos , Células Matadoras Naturais/imunologia , Contagem de Linfócitos , Masculino , Infecções Oportunistas/imunologia , Infecções Oportunistas/prevenção & controle , Receptores de Antígenos de Linfócitos T alfa-beta/análise , Subpopulações de Linfócitos T/imunologia , Quimeras de Transplante/imunologia , Carga Viral , Viremia/imunologia , Viremia/prevenção & controle
20.
J Immunol ; 174(10): 6540-5, 2005 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-15879158

RESUMO

The repertoire of killer Ig-like receptors (KIRs) can be determined at the level of DNA, RNA, or surface protein expression for selection of blood stem cell donors. We compared genotyping and phenotyping of the four inhibitory KIRs that are important in transplantation for leukemia in 73 unrelated persons. In 5 (7%) of the 68 individuals in whom the KIR2DL1 gene was present and in 10 (15%) of the 67 in whom KIR3DL1 was present, the corresponding receptor was not expressed by NK cells, as determined by flow cytometry analysis. In contrast, one or both allelic forms of KIR2DL2/KIR2DL3 were expressed by a high proportion of NK cells in all 73 individuals. However if both KIR2DL2 and KIR2DL3 genes were present, KIR2DL3 was preferentially expressed, as transcripts of KIR2DL2 was not detectable by RT-PCR in 42% of these individuals. In total, repertoire assessment for the four KIRs by genotyping vs phenotyping was not in complete agreement in 18 (25%) of the 73 individuals. Furthermore, among the samples that tested positive for the expression of a certain KIR gene, the levels of transcripts and surface expression varied considerably as measured by both real-time quantitative PCR and flow cytometry analysis. Extension of this comparative analysis to include all 12 KIR family members showed that KIR2DL3 and KIR3DL2 were the only genes whose transcripts were consistently detectable. These results caution the use of genotyping alone for donor selection or leukemia-relapse prognostication because some KIRs may be expressed at a very low level.


Assuntos
Seleção do Doador , Transplante de Células-Tronco Hematopoéticas , Imunofenotipagem , Células Matadoras Naturais/imunologia , Receptores Imunológicos/genética , Testes Imunológicos de Citotoxicidade , Metilação de DNA , Seleção do Doador/métodos , Genótipo , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Polimorfismo Genético/imunologia , Estudos Prospectivos , Receptores Imunológicos/biossíntese , Receptores KIR , Receptores KIR2DL1 , Receptores KIR2DL2 , Receptores KIR2DL3 , Receptores KIR3DL1 , Receptores KIR3DL2 , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos
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