RESUMO
Genome-wide association studies (GWASs) have focused primarily on populations of European descent, but it is essential that diverse populations become better represented. Increasing diversity among study participants will advance our understanding of genetic architecture in all populations and ensure that genetic research is broadly applicable. To facilitate and promote research in multi-ancestry and admixed cohorts, we outline key methodological considerations and highlight opportunities, challenges, solutions, and areas in need of development. Despite the perception that analyzing genetic data from diverse populations is difficult, it is scientifically and ethically imperative, and there is an expanding analytical toolbox to do it well.
Assuntos
Estudo de Associação Genômica Ampla/métodos , Técnicas de Genotipagem/métodos , Genética Humana/métodos , Confiabilidade dos Dados , Variação Genética , Genética Populacional/métodos , Genética Populacional/normas , Estudo de Associação Genômica Ampla/normas , Técnicas de Genotipagem/normas , Genética Humana/normas , Humanos , LinhagemRESUMO
Navigating the complex landscape of high-dimensional omics data with machine learning models presents a significant challenge. The integration of biological domain knowledge into these models has shown promise in creating more meaningful stratifications of predictor variables, leading to algorithms that are both more accurate and generalizable. However, the wider availability of machine learning tools capable of incorporating such biological knowledge remains limited. Addressing this gap, we introduce BioM2, a novel R package designed for biologically informed multistage machine learning. BioM2 uniquely leverages biological information to effectively stratify and aggregate high-dimensional biological data in the context of machine learning. Demonstrating its utility with genome-wide DNA methylation and transcriptome-wide gene expression data, BioM2 has shown to enhance predictive performance, surpassing traditional machine learning models that operate without the integration of biological knowledge. A key feature of BioM2 is its ability to rank predictor variables within biological categories, specifically Gene Ontology pathways. This functionality not only aids in the interpretability of the results but also enables a subsequent modular network analysis of these variables, shedding light on the intricate systems-level biology underpinning the predictive outcome. We have proposed a biologically informed multistage machine learning framework termed BioM2 for phenotype prediction based on omics data. BioM2 has been incorporated into the BioM2 CRAN package (https://cran.r-project.org/web/packages/BioM2/index.html).
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Aprendizado de Máquina , Fenótipo , Humanos , Metilação de DNA , Algoritmos , Biologia Computacional/métodos , Software , Transcriptoma , Genômica/métodosRESUMO
Applications of machine learning in the biomedical sciences are growing rapidly. This growth has been spurred by diverse cross-institutional and interdisciplinary collaborations, public availability of large datasets, an increase in the accessibility of analytic routines, and the availability of powerful computing resources. With this increased access and exposure to machine learning comes a responsibility for education and a deeper understanding of its bases and bounds, borne equally by data scientists seeking to ply their analytic wares in medical research and by biomedical scientists seeking to harness such methods to glean knowledge from data. This article provides an accessible and critical review of machine learning for a biomedically informed audience, as well as its applications in psychiatry. The review covers definitions and expositions of commonly used machine learning methods, and historical trends of their use in psychiatry. We also provide a set of standards, namely Guidelines for REporting Machine Learning Investigations in Neuropsychiatry (GREMLIN), for designing and reporting studies that use machine learning as a primary data-analysis approach. Lastly, we propose the establishment of the Machine Learning in Psychiatry (MLPsych) Consortium, enumerate its objectives, and identify areas of opportunity for future applications of machine learning in biological psychiatry. This review serves as a cautiously optimistic primer on machine learning for those on the precipice as they prepare to dive into the field, either as methodological practitioners or well-informed consumers.
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Psiquiatria Biológica , Aprendizado de Máquina , Humanos , Psiquiatria Biológica/métodos , Psiquiatria/métodos , Pesquisa Biomédica/métodosRESUMO
Common variation in the gene encoding the neuron-specific RNA splicing factor RNA Binding Fox-1 Homolog 1 (RBFOX1) has been identified as a risk factor for several psychiatric conditions, and rare genetic variants have been found causal for autism spectrum disorder (ASD). Here, we explored the genetic landscape of RBFOX1 more deeply, integrating evidence from existing and new human studies as well as studies in Rbfox1 knockout mice. Mining existing data from large-scale studies of human common genetic variants, we confirmed gene-based and genome-wide association of RBFOX1 with risk tolerance, major depressive disorder and schizophrenia. Data on six mental disorders revealed copy number losses and gains to be more frequent in ASD cases than in controls. Consistently, RBFOX1 expression appeared decreased in post-mortem frontal and temporal cortices of individuals with ASD and prefrontal cortex of individuals with schizophrenia. Brain-functional MRI studies demonstrated that carriers of a common RBFOX1 variant, rs6500744, displayed increased neural reactivity to emotional stimuli, reduced prefrontal processing during cognitive control, and enhanced fear expression after fear conditioning, going along with increased avoidance behaviour. Investigating Rbfox1 neuron-specific knockout mice allowed us to further specify the role of this gene in behaviour. The model was characterised by pronounced hyperactivity, stereotyped behaviour, impairments in fear acquisition and extinction, reduced social interest, and lack of aggression; it provides excellent construct and face validity as an animal model of ASD. In conclusion, convergent translational evidence shows that common variants in RBFOX1 are associated with a broad spectrum of psychiatric traits and disorders, while rare genetic variation seems to expose to early-onset neurodevelopmental psychiatric disorders with and without developmental delay like ASD, in particular. Studying the pleiotropic nature of RBFOX1 can profoundly enhance our understanding of mental disorder vulnerability.
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Transtorno do Espectro Autista , Transtorno Depressivo Maior , Transtornos Mentais , Animais , Camundongos , Humanos , Transtorno do Espectro Autista/genética , Transtorno Depressivo Maior/genética , Estudo de Associação Genômica Ampla , Transtornos Mentais/genética , Camundongos Knockout , Fatores de Processamento de RNA/genéticaRESUMO
This study aimed to assess the efficacy and safety of different medications available at present for severe coronavirus disease 2019 (COVID-19) infection. We searched databases for randomized controlled trials (RCTs) published up to April 30, 2021, with Chinese or English language restriction, of medications recommended for patients (aged 18 years or older) with severe COVID-19 infection. We extracted data on trials and patient characteristics, and the following primary outcomes: all-cause mortality (ACM), and treatment-emergent adverse events (TEAEs). We identified 1855 abstracts and of these included 15 RCTs comprising 3073 participants through database searches and other sources. In terms of efficacy, compared with the standard of care (SOC) group, no significant decrease in ACM was found in α-lipoic acid, convalescent plasma (CP), azithromycin, tocilizumab, methylprednisolone, interferon beta, CP/SOC, high dosage sarilumab, low dosage sarilumab, remdesivir, lopinavir-ritonavir, auxora, and placebo group. Compared with placebo, we found that a significant decrease in ACM was only found in methylprednisolone (odds ratio [OR]: 0.16, 95% confidence interval [CI]: 0.03-0.75]. With respect to TEAEs, the CP group showed lower TEAEs than placebo (OR: 0.07, 95% CI: 0.01-0.58) or SOC (OR: 0.05, 95% CI: 0.01-0.42) group for the therapy of severe COVID-19 patients. This study only demonstrated that methylprednisolone was superior to placebo in treating patients with severe COVID-19 infection. Meanwhile, this further confirmed that the safety of other treatment interventions might be inferior to CP for the therapy of severe COVID-19 patients.
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COVID-19/terapia , Metanálise em Rede , COVID-19/mortalidade , Humanos , SARS-CoV-2 , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
Copy number variations (CNV) involving multiple genes are ideal models to study polygenic neuropsychiatric disorders. Since 22q11.2 deletion is regarded as the most important single genetic risk factor for developing schizophrenia, characterizing the effects of this CNV on neural networks offers a unique avenue towards delineating polygenic interactions conferring risk for the disorder. We used a Df(h22q11)/+ mouse model of human 22q11.2 deletion to dissect gene expression patterns that would spatially overlap with differential resting-state functional connectivity (FC) patterns in this model (N = 12 Df(h22q11)/+ mice, N = 10 littermate controls). To confirm the translational relevance of our findings, we analyzed tissue samples from schizophrenia patients and healthy controls using machine learning to explore whether identified genes were co-expressed in humans. Additionally, we employed the STRING protein-protein interaction database to identify potential interactions between genes spatially associated with hypo- or hyper-FC. We found significant associations between differential resting-state connectivity and spatial gene expression patterns for both hypo- and hyper-FC. Two genes, Comt and Trmt2a, were consistently over-expressed across all networks. An analysis of human datasets pointed to a disrupted co-expression of these two genes in the brain in schizophrenia patients, but not in healthy controls. Our findings suggest that COMT and TRMT2A form a core genetic component implicated in differential resting-state connectivity patterns in the 22q11.2 deletion. A disruption of their co-expression in schizophrenia patients points out a prospective cause for the aberrance of brain networks communication in 22q11.2 deletion syndrome on a molecular level.
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Catecol O-Metiltransferase/genética , Síndrome de DiGeorge/genética , Expressão Gênica , tRNA Metiltransferases/genética , Animais , Deleção Cromossômica , Variações do Número de Cópias de DNA , Modelos Animais de Doenças , Humanos , Imageamento por Ressonância Magnética , Masculino , Camundongos , Esquizofrenia/genéticaRESUMO
Alterations in the structural connectome of schizophrenia patients have been widely characterized, but the mechanisms remain largely unknown. Generative network models have recently been introduced as a tool to test the biological underpinnings of altered brain network formation. We evaluated different generative network models in healthy controls (n=152), schizophrenia patients (n=66), and their unaffected first-degree relatives (n=32), and we identified spatial and topological factors contributing to network formation. We further investigated how these factors relate to cognition and to polygenic risk for schizophrenia. Our data show that among the four tested classes of generative network models, structural brain networks were optimally accounted for by a two-factor model combining spatial constraints and topological neighborhood structure. The same wiring model explained brain network formation across study groups. However, relatives and schizophrenia patients exhibited significantly lower spatial constraints and lower topological facilitation compared to healthy controls. Further exploratory analyses point to potential associations of the model parameter reflecting spatial constraints with the polygenic risk for schizophrenia and cognitive performance. Our results identify spatial constraints and local topological structure as two interrelated mechanisms contributing to regular brain network formation as well as altered connectomes in schizophrenia and healthy individuals at familial risk for schizophrenia. On an exploratory level, our data further point to the potential relevance of spatial constraints for the genetic risk for schizophrenia and general cognitive functioning, thereby encouraging future studies in following up on these observations to gain further insights into the biological basis and behavioral relevance of model parameters.
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Encéfalo/diagnóstico por imagem , Família , Esquizofrenia/diagnóstico por imagem , Adulto , Encéfalo/fisiopatologia , Estudos de Casos e Controles , Conectoma , Imagem de Tensor de Difusão , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Vias Neurais/diagnóstico por imagem , Vias Neurais/fisiopatologia , Testes Neuropsicológicos , Análise de Componente Principal , Esquizofrenia/genética , Esquizofrenia/fisiopatologia , Adulto JovemRESUMO
BACKGROUND: Malaria causes major public health problems globally and drug resistance hinders its control and elimination. Molecular markers associated with drug resistance are considered as a beneficial tool to monitor the disease trends, evolution and distribution so as to help improve drug policy. METHODS: We collected 148 Plasmodium falciparum and 20 Plasmodium vivax isolates imported into Hangzhou city, China between 2014 and 2019. k13 gene of P. falciparum and k12 of P. vivax were sequenced. Polymorphisms and prevalence of k13 and k12 were analyzed. RESULTS: Most (98.65%, 146/148) P. falciparum infections were imported from Africa, and half P. vivax cases came from Africa and the other half from Asia. Nucleotide mutation prevalence was 2.03% (3/148) and the proportion of amino acid mutations was 0.68% (1/148). The amino acid mutation, A676S, was observed in an isolate from Nigeria. No mutation of k12 was observed from the parasites from African and Asian countries. CONCLUSIONS: Limited polymorphism in k13 gene of P. falciparum isolates imported from African countries, but no evidence for the polymorphism of k12 in P. vivax samples from African and Asian countries was found. These results provide information for drug policy update in study region.
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Antimaláricos , Malária Falciparum , Antimaláricos/uso terapêutico , Ásia , China/epidemiologia , Resistência a Medicamentos , Humanos , Malária Falciparum/tratamento farmacológico , Malária Falciparum/epidemiologia , Nigéria , Plasmodium falciparum/genética , Plasmodium vivax/genética , Proteínas de Protozoários/genéticaRESUMO
MOTIVATION: Genotype imputation is essential for genome-wide association studies (GWAS) to retrieve information of untyped variants and facilitate comparability across studies. However, there is a lack of automated pipelines that perform all required processing steps prior to and following imputation. RESULTS: Based on widely used and freely available tools, we have developed Gimpute, an automated processing and imputation pipeline for genome-wide association data. Gimpute includes processing steps for genotype liftOver, quality control, population outlier detection, haplotype pre-phasing, imputation, post imputation, data management and the extension to other existing pipeline. AVAILABILITY AND IMPLEMENTATION: The Gimpute package is an open source R package and is freely available at https://github.com/transbioZI/Gimpute. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Estudo de Associação Genômica Ampla , Software , Genoma , Genótipo , HaplótiposRESUMO
PURPOSE OF REVIEW: This study aims to review the history of the human immunodeficiency virus (HIV) infection epidemic in China. RECENT FINDINGS: The HIV infection epidemic in China has evolved significantly over the past 35 years, from initially exclusively within people who inject drugs (PWID), to outbreaks due to plasma collection contamination in the mid-1990s, to now almost exclusive transmission via sexual contact. The number of newly-diagnosed cases and the number HIV-related deaths have increased each year since 2004, coinciding with a massive scale-up of both HIV testing and antiretroviral therapy initiation. The proportion of cases diagnosed later in their disease progression has remained constant. The initial outbreaks of HIV across China were identified quickly and the overall trends have been monitored. While the HIV epidemic among PWID has been well managed, the growing HIV epidemic via sexual contact has grown more complex and even more difficult to control.
Assuntos
Infecções por HIV/epidemiologia , Homossexualidade Feminina/estatística & dados numéricos , Homossexualidade Masculina/estatística & dados numéricos , Abuso de Substâncias por Via Intravenosa/epidemiologia , Adulto , Antirretrovirais/uso terapêutico , China/epidemiologia , Surtos de Doenças , Epidemias , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Masculino , Prevalência , Comportamento SexualRESUMO
We studied adults with acute myeloid leukemia (AML) after haploidentical (n = 192) and 8/8 HLA-matched unrelated donor (n = 1982) transplantation. Haploidentical recipients received calcineurin inhibitor (CNI), mycophenolate, and posttransplant cyclophosphamide for graft-versus-host disease (GVHD) prophylaxis; 104 patients received myeloablative and 88 received reduced intensity conditioning regimens. Matched unrelated donor transplant recipients received CNI with mycophenolate or methotrexate for GVHD prophylaxis; 1245 patients received myeloablative and 737 received reduced intensity conditioning regimens. In the myeloablative setting, day 30 neutrophil recovery was lower after haploidentical compared with matched unrelated donor transplants (90% vs 97%, P = .02). Corresponding rates after reduced intensity conditioning transplants were 93% and 96% (P = .25). In the myeloablative setting, 3-month acute grade 2-4 (16% vs 33%, P < .0001) and 3-year chronic GVHD (30% vs 53%, P < .0001) were lower after haploidentical compared with matched unrelated donor transplants. Similar differences were observed after reduced intensity conditioning transplants, 19% vs 28% (P = .05) and 34% vs 52% (P = .002). Among patients receiving myeloablative regimens, 3-year probabilities of overall survival were 45% (95% CI, 36-54) and 50% (95% CI, 47-53) after haploidentical and matched unrelated donor transplants (P = .38). Corresponding rates after reduced intensity conditioning transplants were 46% (95% CI, 35-56) and 44% (95% CI, 0.40-47) (P = .71). Although statistical power is limited, these data suggests that survival for patients with AML after haploidentical transplantation with posttransplant cyclophosphamide is comparable with matched unrelated donor transplantation.
Assuntos
Ciclofosfamida/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Imunossupressores/uso terapêutico , Leucemia Mieloide Aguda/cirurgia , Doadores de Tecidos , Adulto , Idoso , Feminino , Doença Enxerto-Hospedeiro/prevenção & controle , Antígenos HLA/genética , Teste de Histocompatibilidade , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Condicionamento Pré-Transplante/métodos , Adulto JovemRESUMO
As substantial efforts are being made to identify biological markers of psychiatric illnesses, it is becoming clear that clinically useful accuracy will require larger sets of readouts that potentially span different technological platforms. For discovery of proteomic biomarkers, simultaneous measurement of analytes in small sample quantities has developed into a widely used technology of similar quality as the respective single-plex assays. Multiplex assay systems therefore hold promise for biomarker discovery and development in many complex disease areas including psychiatry. However, analysis of the derived data is subject to substantial challenges that may impede the possibility of obtaining meaningful findings. This chapter discusses potential applications of multiplexed assay technologies during biomarker development and highlights potential challenges for machine learning analysis of derived data.
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Biomarcadores/análise , Transtornos Mentais/metabolismo , Proteômica/métodos , Fatores de Confusão Epidemiológicos , Interpretação Estatística de Dados , Humanos , Aprendizado de Máquina , Transtornos Mentais/diagnóstico , Proteínas do Tecido Nervoso/análise , Projetos de PesquisaRESUMO
We investigated whether and how recipient-donor sex affects transplantation outcomes of 11,797 patients transplanted between 2008 and 2010. Thirty-seven percent were male recipients with male donors, 21% male recipients with female donors, 25% female recipients with male donors, and 17% female recipients with female donors. In multivariable analyses, male recipients had inferior overall survival and progression-free survival compared to females regardless of donor sex, with an 11% relative increase in the hazard of death (P<0.0001) and a 10% relative increase in the hazard of death or relapse (P<0.0001). The detrimental effect of male recipients varied by donor sex. For male recipients with male donors, there was a 12% relative increase in the subdistribution hazard of relapse compared with female recipients with male donors (P=0.0036) and male recipients with female donors (P=0.0037). For male recipients with female donors, there was a 19% relative increase in the subdistribution hazard of non-relapse mortality compared with male recipients with male donors (P<0.0001) and a 22% relative increase compared with female recipients with male donors (P=0.0003). In addition, male recipients with female donors showed a 21% relative increase in the subdistribution hazard of chronic graft-versus-host disease (P<0.0001) compared with female recipients with male donors. Donor sex had no effect on outcomes for female recipients. Transplantation of grafts from male and female donors was associated with inferior overall survival and progression-free survival in male recipients with differing patterns of failure. Recipient sex is an important prognostic factor independent of donor sex.
Assuntos
Fatores Sexuais , Transplante de Células-Tronco/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Transplante de Células-Tronco/efeitos adversos , Análise de Sobrevida , Transplante Homólogo , Adulto JovemRESUMO
We sought to determine whether differences in chronic graft-versus-host disease (GVHD) rates would lead to survival differences by comparing 2463 peripheral blood (PB) and 1713 bone marrow (BM) hematopoietic cell transplant recipients. Patients had acute leukemia, chronic myeloid leukemia (CML), or myelodysplastic syndrome, and they received myeloablative conditioning regimens and calcineurin-inhibitor GVHD prophylaxis. There were no significant differences in long-term survival after transplantation of PB and BM, except for patients in first chronic phase CML. For these patients, the 5-year rate of survival was lower after transplantation of PB compared with transplantation of BM (35% versus 56%, P = .001). Although mortality risks were higher in patients with chronic GVHD after both PB (hazard ratio [HR], 1.58; P < .001) and BM (HR 1.73; P < .001) transplantations, its effect on mortality did not differ by graft type (P = .42). BM is the preferred graft for first chronic phase CML, whereas as either graft is suitable for other leukemias.
Assuntos
Transplante de Medula Óssea , Doença Enxerto-Hospedeiro/mortalidade , Leucemia Aguda Bifenotípica/mortalidade , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Síndromes Mielodisplásicas/mortalidade , Transplante de Células-Tronco de Sangue Periférico , Condicionamento Pré-Transplante , Adolescente , Adulto , Idoso , Inibidores de Calcineurina/uso terapêutico , Doença Crônica , Feminino , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/patologia , Doença Enxerto-Hospedeiro/terapia , Humanos , Leucemia Aguda Bifenotípica/imunologia , Leucemia Aguda Bifenotípica/patologia , Leucemia Aguda Bifenotípica/terapia , Leucemia Mielogênica Crônica BCR-ABL Positiva/imunologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Masculino , Pessoa de Meia-Idade , Agonistas Mieloablativos/uso terapêutico , Síndromes Mielodisplásicas/imunologia , Síndromes Mielodisplásicas/patologia , Síndromes Mielodisplásicas/terapia , Análise de Sobrevida , Fatores de Tempo , Transplante Homólogo , Doadores não RelacionadosRESUMO
The inclusion of antithymocyte globulin (ATG) in cord blood transplantation is controversial. We evaluated outcomes according to ATG inclusion in 297 children and adolescents with acute lymphoblastic leukemia (ALL) who received myeloablative total body irradiation-based conditioning and either single-unit (74%) or double-unit (26%) grafts. Ninety-two patients (31%) received ATG and 205 (69%) did not. ATG recipients were more likely to be cytomegalovirus seronegative. The incidences of day 100 grades II to IV acute graft-versus-host disease (GVHD; 30% versus 54%, P = .0002) and chronic GVHD (22% versus 43%, P = .0008) were lower with ATG compared with non-ATG regimens. However, day 100 grades III to IV acute GVHD was comparable (11% versus 17%, P = .15). The 3-year incidences of transplant-related mortality (16% versus 17%, P = .98), relapse (17% versus 27%, P = .12), and leukemia-free survival (66% versus 55%, P = .23) in ATG and non-ATG recipients were similar. There were no differences in viral reactivation between treatment groups (60% versus 58%, P = .83). Therefore, the data suggest that incorporation of ATG with myeloablative conditioning regimens may be useful in reducing the risk of acute and chronic GVHD without any deleterious effect on transplant-related mortality, relapse, or leukemia-free survival in children and adolescents with ALL.
Assuntos
Soro Antilinfocitário/uso terapêutico , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Depleção Linfocítica , Agonistas Mieloablativos/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Condicionamento Pré-Transplante/métodos , Irradiação Corporal Total , Doença Aguda , Adolescente , Criança , Pré-Escolar , Feminino , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/patologia , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Imunossupressores/uso terapêutico , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Recidiva , Indução de Remissão , Estudos Retrospectivos , Análise de Sobrevida , Transplante Homólogo , Resultado do Tratamento , Adulto JovemRESUMO
The effects of substrate temperature on the plasma active species were investigated by plasma optical emission spectroscopy. With increasing substrate temperature, the characteristic spectroscopy intensity of the first positive series of N2* (B(3)Πg-->A(3)Σu(+)), the second positive N2* (C(3)Πu-->B(3)Πg), the first negative series N2(+)* (B(2)Σu(+)-->X(2)Σg(+)) and Zn* are increased. Due to the substrate temperature, each ion kinetic energy is increased and the collision ionization intensified in the chamber. That leading to plasma ion density increase. These phenomenons's show that the substrate temperature raises in a certain range was conducive to zinc nitride thin films growth. Zn3N2 thin films were prepared on Al films using ion sources-assisted magnetron sputtering deposition method. The degree of crystalline of the films was examined with X-ray diffraction (XRD). The results show that has a dominant peak located at 34.359° in room temperature, which was corresponding to the (321) plane of cubic anti-bixbyite zinc nitride structure (JCPDS Card No35-0762). When the substrate temperature was 100 °C, in addition to the (321) reflection, more diffraction peaks appeared corresponding to the (222), (400) and (600) planes, which were located at 31.756°, 36.620° and 56.612° respectively. When the substrate temperature was 200 °C, in addition to the (321), (222), (400) and (600) reflection, more new diffraction peaks also appeared corresponding to the (411), (332), (431) and (622) planes, which were located at 39.070, 43.179°, 47.004° and 62.561° respectively. These results show the film crystalline increased gradually with raise the substrate temperature. XP-1 profilometer were used to analyze the thickness of the Zn3N2 films. The Zn3N2 films deposited on Al films in mixture gas plasma had a deposition rate of 2.0, 2.2, and 2.7 nm · min(-1). These results indicate that the deposition rate was gradually enhanced as substrate temperature increased. Field emission scanning electron microscope (SEM) images revealed that the particles of zinc nitride thin films became smaller but more uniform and density with increase the substrate temperature. The Zn3N2 thin films were strongly bound on the Al films. The experiments of films properties analysis results about the substrate temperature were consistent with the results of the plasma optical emission spectroscopy. The results would help improving the preparation of magnetron sputtering technique and getting better Zn3N2 thin films. On the other hand, the results were reflected that the plasma emission spectrum was fast and effective method to analyze the intrinsic characteristics of plasma.
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Reduced-intensity conditioning/nonmyeloablative conditioning regimens are increasingly used in allogeneic hematopoietic cell transplantation (HCT). Reports have shown CD34(+) dose to be important for transplantation outcome using myeloablative conditioning. The role of CD34(+) dose of peripheral blood progenitor cells (PBPC) has not been previously analyzed in a large population undergoing reduced-intensity conditioning/nonmyeloablative HCT. We studied 1054 patients, ages 45 to 75 years, with acute myeloid leukemia or myelodysplastic syndrome who underwent transplantation between 2002 and 2011. Results of multivariate analysis showed that PBPC from HLA-matched siblings containing <4 × 10(6) CD34(+)/kg was associated with higher nonrelapse mortality (hazard ratio [HR], 2.03; P = .001), overall mortality (HR, 1.48; P = .008), and lower neutrophil (odds ratio [OR], .76; P = .03) and platelet (OR, .76; P = .03) recovery. PBPC from unrelated donors with CD34(+) dose < 6 × 10(6) CD34(+)/kg was also associated with higher nonrelapse (HR, 1.38; P = .02) and overall mortality (HR, 1.20; P = .05). In contrast to reports after myeloablative HCT, CD34(+) dose did not affect relapse or graft-versus-host disease with either donor type. An upper cell dose limit was not associated with adverse outcomes. These data suggest that PBPC CD34(+) doses >4 × 10(6) CD34(+)/kg and >6 × 10(6) CD34(+)/kg are optimal for HLA-matched sibling and unrelated donor HCT, respectively.
Assuntos
Antígenos CD34/imunologia , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicas/terapia , Condicionamento Pré-Transplante/métodos , Transplante Homólogo/métodos , Idoso , Feminino , Humanos , Leucemia Mieloide Aguda/imunologia , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Resultado do TratamentoRESUMO
The number of newly reported HIV-1 infections among older individuals (aged ≥50 years) has increased rapidly in Hangzhou, a central city in the Yangtze River Delta region of China. To provide a scientific basis for prevention and intervention strategies targeted at older individuals in Hangzhou, an epidemiological survey combined with molecular transmission network analysis was conducted. A total of 2899 individuals with newly confirmed HIV-1 infections, including 635 older individuals and 2264 younger individuals (aged <50 years), were enrolled in this study. Among older individuals, heterosexual contact was the predominant mode of HIV-1 transmission. Additionally, it was observed that older individuals with lower levels of education exhibited a higher susceptibility to HIV-1 infection. The analysis of transmission network which was inferred using HIV-TRACE algorithm revealed that the newly diagnosed HIV-1 infections among older individuals in Hangzhou exhibited a pattern of scattered transmission, with key clusters primarily located in non-main urban areas. The predominant mode of transmission in these areas was non-marital and non-commercial or non-marital and commercial heterosexual transmission. Notably, the study highlighted a significant proportion of older individuals (73.3%, 11/15) within B subtype. Multivariate logistic regression analysis further revealed that the subtype B was a significant factor associated with older individuals having ≥3 node degrees in the network, occurring 5.55 times more frequent than subtype CRF07_BC (95% CI = 1.17-26.22, p = 0.031). Furthermore, the lower CD4 levels observed among older individuals underscored the challenge of late diagnosis in Hangzhou. Taken together, it is imperative to test and intervene for high-risk older individuals. To tackle this issue effectively, it is essential to enhance the detection of the B subtype and implement targeted interventions in key clusters within non-main urban areas. Additionally, proactive measures should be implemented to address the challenge of late diagnosis in Hangzhou by promoting widespread testing among the older individuals, particularly in priority areas.
RESUMO
BACKGROUND: Understanding the biological processes that underlie individual differences in emotion regulation and stress responsivity is a key challenge for translational neuroscience. The gene FKBP5 is a core regulator in molecular stress signaling that is implicated in the development of psychiatric disorders. However, it remains unclear how FKBP5 DNA methylation in peripheral blood is related to individual differences in measures of neural structure and function and their relevance to daily-life stress responsivity. METHODS: Here, we characterized multimodal correlates of FKBP5 DNA methylation by combining epigenetic data with neuroimaging and ambulatory assessment in a sample of 395 healthy individuals. RESULTS: First, we showed that FKBP5 demethylation as a psychiatric risk factor was related to an anxiety-associated reduction of gray matter volume in the ventromedial prefrontal cortex, a brain area that is involved in emotion regulation and mental health risk and resilience. This effect of epigenetic upregulation of FKBP5 on neuronal structure is more pronounced where FKBP5 is epigenetically downregulated at baseline. Leveraging 208 functional magnetic resonance imaging scans during a well-established emotion-processing task, we found that FKBP5 DNA methylation in peripheral blood was associated with functional differences in prefrontal-limbic circuits that modulate affective responsivity to daily stressors, which we measured using ecological momentary assessment in daily life. CONCLUSIONS: Overall, we demonstrated how FKBP5 contributes to interindividual differences in neural and real-life affect regulation via structural and functional changes in prefrontal-limbic brain circuits.