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INTRODUCTION: Pectus excavatum repair by the Nuss procedure results in severe postoperative pain. Regional blocks and intercostal nerve cryoablation (INC) have emerged as potential strategies to manage analgesia. This study compares pain-related outcomes following these perioperative interventions. METHODS: We reviewed charts of patients <18 y who underwent the Nuss procedure at Duke Children's Hospital from July 2018 to June 2022. Patients were divided into three groups by analgesic strategy: no block, regional catheters, or INC, representing the chronologic change in our practice. The primary outcome was total and daily in-hospital opioid utilization measured by oral morphine equivalents (OMEs). Secondary outcomes included average daily pain scores, length of stay, opioid refills after discharge, and complications. RESULTS: Twenty-one patients were included and analyzed: no block (n = 6), regional catheters (n = 7), and INC (n = 8). INC-treated patients required significantly lower total postoperative, in-hospital OMEs (64 ± 47 [mean ± standard deviation]) than those with no block (270 ± 217, P = 0.04) or those with regional catheters (273 ± 176, P = 0.03). INC was associated with longer average operative times (161 ± 36 min) than no block (105 ± 21 min, P = 0.005) or regional catheters (90 ± 11 min, P < 0.001). INC-treated patients had shorter hospital length of stays (median 68 h) than those with regional catheters (median 74 h, P = 0.006). CONCLUSIONS: INC was associated with longer operative times but decreased in-hospital OMEs when compared to bilateral regional block catheters and multimodal analgesia alone.
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Analgesia Epidural , Tórax em Funil , Criança , Humanos , Analgésicos , Analgésicos Opioides/uso terapêutico , Tórax em Funil/cirurgia , Morfina , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/etiologia , Estudos RetrospectivosRESUMO
Given the limited information on the coagulation abnormalities of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in pediatric patients, we designed a systematic review to evaluate this topic. A comprehensive literature search was conducted for "SARS-CoV-2," "coagulopathy," and "pediatrics." Two authors independently screened the articles that the search returned for bleeding, thrombosis, anticoagulant and/or antiplatelet usage, and abnormal laboratory markers in pediatric patients with SARS-CoV-2, and the authors then extracted the relevant data. One hundred twenty-six publications were included. Thirty-four (27%) studies reported thrombotic complications in 504 patients. Thirty-one (25%) studies reported bleeding complications in 410 patients. Ninety-eight (78%) studies reported abnormal laboratory values in 6580 patients. Finally, 56 (44%) studies reported anticoagulant and/or antiplatelet usage in 3124 patients. The variety of laboratory abnormalities and coagulation complications associated with SARS-CoV-2 presented in this review highlights the complexity and variability of the disease presentation in infants and children.
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Transtornos da Coagulação Sanguínea , COVID-19 , Trombose , Anticoagulantes/uso terapêutico , Transtornos da Coagulação Sanguínea/etiologia , COVID-19/complicações , Criança , Humanos , Lactente , SARS-CoV-2 , Trombose/etiologiaRESUMO
Liver grafts from pediatric donors represent a small fraction of grafts transplanted into adult recipients, and their use in adults requires special consideration of donor size to prevent perioperative complications. In the past, graft weight or volume ratios have been adopted from the living donor liver transplant literature to guide clinicians; however, these metrics are not regularly available to surgeons accepting deceased donor organs. In this study, we evaluated all pediatric-to-adult liver transplants in the United Network for Organ Sharing Standard Transplant Analysis and Research database from 1987 to 2019, stratified by donor age and donor-recipient height mismatch ratio (HMR; defined as donor height/recipient height). On multivariable regression controlling for cold ischemia time, age, and transplantation era, the use of donors from ages 0 to 4 and 5 to 9 had increased risk of graft failure (hazard ratio [HR], 1.81 [P < 0.01] and HR, 1.16 [P < 0.01], respectively) compared with donors aged 15 to 17. On Kaplan-Meier survival analysis, a HMR < 0.8 was associated with inferior graft survival (mean, 11.8 versus 14.6 years; log-rank P < 0.001) and inferior patient survival (mean, 13.5 versus 14.9 years; log-rank P < 0.01) when compared with pairs with similar height (HMR, 0.95-1.05; ie, donors within 5% of recipient height). This study demonstrates that both young donor age and low HMR confer additional risk in adult recipients of pediatric liver grafts.
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Transplante de Fígado , Obtenção de Tecidos e Órgãos , Adolescente , Adulto , Criança , Sobrevivência de Enxerto , Humanos , Estimativa de Kaplan-Meier , Transplante de Fígado/efeitos adversos , Doadores Vivos , Estudos Retrospectivos , Doadores de Tecidos , Transplantados , Resultado do TratamentoRESUMO
BACKGROUND: Most studies examining the relationship between neonatal abstinence syndrome (NAS) and health insurance status in the United States (USA) have used administrative insurance claims data, which is subject to myriad limitations. We examined the association between NAS and health insurance status in a large geographically defined rural population in the United States, using non-claims data. METHODS: We utilized data from a population-based cohort of all newborns born in 2017-2019 in the rural state of West Virginia (WV) and restricted analyses to WV residents' births (n = 46 213). NAS was defined as neonatal withdrawal from many substances, including opiates and not limited to those cases that require pharmacological treatment. RESULTS: Medicaid covered more than half (52.6%) of all infants' births in the state of WV. The incidence of NAS was 85.8 and 12.7 per 1000 livebirths in the Medicaid and privately insured groups, respectively. Among all infants diagnosed with NAS, 86.1% were enrolled in the state's Medicaid programme. The risk of NAS in the Medicaid-insured newborns was higher than privately insured newborns in the unadjusted analysis (risk ratio (RR) 6.76, 95% confidence interval (CI) 5.95, 7.68) and the adjusted analysis RR 3.00, 95% CI 2.01, 4.49); adjusted risk difference 20.3 (95% CI 17.5, 23.1 cases per 1000 livebirths). CONCLUSIONS: NAS is an important indicator of the immediate effect of the opioid crisis. This study shows the disparity in NAS by health insurance status for a large rural population in the United States, and its burden on the state's Medicaid programme. Providing timely and accurate estimates of NAS is important for public health policies and decision making.
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Síndrome de Abstinência Neonatal , Analgésicos Opioides , Pré-Escolar , Humanos , Incidência , Lactente , Recém-Nascido , Seguro Saúde , Medicaid , Síndrome de Abstinência Neonatal/epidemiologia , Estados Unidos/epidemiologiaRESUMO
B*38:01 and B*39:06 are present with phenotypic frequencies <2% in the general population, but are of interest as B*39:06 is the B allele most associated with type 1 diabetes susceptibility and 38:01 is most protective. A previous study derived putative main anchor motifs for both alleles based on peptide elution data. The present study has utilized panels of single amino acid substitution peptide libraries to derive detailed quantitative motifs accounting for both primary and secondary influences on peptide binding. From these analyses, both alleles were confirmed to utilize the canonical position 2/C-terminus main anchor spacing. B*38:01 preferentially bound peptides with the positively charged or polar residues H, R, and Q in position 2 and the large hydrophobic residues I, F, L, W, and M at the C-terminus. B*39:06 had a similar preference for R in position 2, but also well-tolerated M, Q, and K. A more dramatic contrast between the two alleles was noted at the C-terminus, where the specificity of B*39:06 was clearly for small residues, with A as most preferred, followed by G, V, S, T, and I. Detailed position-by-position and residue-by-residue coefficient values were generated from the panels to provide detailed quantitative B*38:01 and B*39:06 motifs. It is hoped that these detailed motifs will facilitate the identification of T cell epitopes recognized in the context of two class I alleles associated with dramatically different dispositions towards type 1 diabetes, offering potential avenues for the investigation of the role of CD8 T cells in this disease.
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Antígeno HLA-B38/genética , Antígeno HLA-B38/metabolismo , Antígeno HLA-B39/genética , Antígeno HLA-B39/metabolismo , Peptídeos/metabolismo , Sequência de Aminoácidos , Antígeno HLA-B38/imunologia , Antígeno HLA-B39/imunologia , Humanos , Peptídeos/química , Peptídeos/imunologia , Ligação ProteicaRESUMO
Analyses investigating low frequency variants have the potential for explaining additional genetic heritability of many complex human traits. However, the natural frequencies of rare variation between human populations strongly confound genetic analyses. We have applied a novel collapsing method to identify biological features with low frequency variant burden differences in thirteen populations sequenced by the 1000 Genomes Project. Our flexible collapsing tool utilizes expert biological knowledge from multiple publicly available database sources to direct feature selection. Variants were collapsed according to genetically driven features, such as evolutionary conserved regions, regulatory regions genes, and pathways. We have conducted an extensive comparison of low frequency variant burden differences (MAF<0.03) between populations from 1000 Genomes Project Phase I data. We found that on average 26.87% of gene bins, 35.47% of intergenic bins, 42.85% of pathway bins, 14.86% of ORegAnno regulatory bins, and 5.97% of evolutionary conserved regions show statistically significant differences in low frequency variant burden across populations from the 1000 Genomes Project. The proportion of bins with significant differences in low frequency burden depends on the ancestral similarity of the two populations compared and types of features tested. Even closely related populations had notable differences in low frequency burden, but fewer differences than populations from different continents. Furthermore, conserved or functionally relevant regions had fewer significant differences in low frequency burden than regions under less evolutionary constraint. This degree of low frequency variant differentiation across diverse populations and feature elements highlights the critical importance of considering population stratification in the new era of DNA sequencing and low frequency variant genomic analyses.
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Variação Genética , Genética Populacional , Genoma Humano , Sequência de Bases , Bases de Dados Genéticas , Estudo de Associação Genômica Ampla , Projeto Genoma Humano , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único , Sequências Reguladoras de Ácido Nucleico/genéticaRESUMO
Here we describe a detailed quantitative peptide-binding motif for the common equine leukocyte antigen (ELA) class I allele Eqca-1*00101, present in roughly 25 % of Thoroughbred horses. We determined a preliminary binding motif by sequencing endogenously bound ligands. Subsequently, a positional scanning combinatorial library (PSCL) was used to further characterize binding specificity and derive a quantitative motif involving aspartic acid in position 2 and hydrophobic residues at the C-terminus. Using this motif, we selected and tested 9- and 10-mer peptides derived from the equine herpesvirus type 1 (EHV-1) proteome for their capacity to bind Eqca-1*00101. PSCL predictions were very efficient, with an receiver operating characteristic (ROC) curve performance of 0.877, and 87 peptides derived from 40 different EHV-1 proteins were identified with affinities of 500 nM or higher. Quantitative analysis revealed that Eqca-1*00101 has a narrow peptide-binding repertoire, in comparison to those of most human, non-human primate, and mouse class I alleles. Peripheral blood mononuclear cells from six EHV-1-infected, or vaccinated but uninfected, Eqca-1*00101-positive horses were used in IFN-γ enzyme-linked immunospot (ELISPOT) assays. When we screened the 87 Eqca-1*00101-binding peptides for T cell reactivity, only one Eqca-1*00101 epitope, derived from the intermediate-early protein ICP4, was identified. Thus, despite its common occurrence in several horse breeds, Eqca-1*00101 is associated with a narrow binding repertoire and a similarly narrow T cell response to an important equine viral pathogen. Intriguingly, these features are shared with other human and macaque major histocompatibility complex (MHC) molecules with a similar specificity for D in position 2 or 3 in their main anchor motif.
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Epitopos de Linfócito T/imunologia , Epitopos de Linfócito T/metabolismo , Herpesvirus Equídeo 1/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/metabolismo , Linfócitos T Citotóxicos/imunologia , Alelos , Animais , Infecções por Herpesviridae/genética , Infecções por Herpesviridae/imunologia , Infecções por Herpesviridae/veterinária , Infecções por Herpesviridae/virologia , Herpesvirus Equídeo 1/genética , Antígenos de Histocompatibilidade Classe I/metabolismo , Doenças dos Cavalos/genética , Doenças dos Cavalos/imunologia , Doenças dos Cavalos/virologia , Cavalos , Humanos , Leucócitos Mononucleares , Camundongos , Ligação Proteica , Proteoma/imunologia , Linfócitos T Citotóxicos/metabolismo , Espectrometria de Massas em TandemRESUMO
Ecosystems subject to mantle degassing are of particular interest for understanding global biogeochemistry, as their microbiomes are shaped by prolonged exposure to high CO2 and have recently been suggested to be highly active. While the genetic diversity of bacteria and archaea in these deep biosphere systems have been studied extensively, little is known about how viruses impact these microbial communities. Here, we show that the viral community in a high-CO2 cold-water geyser (Wallender Born, Germany) undergoes substantial fluctuations over a period of 12 days, although the corresponding prokaryotic community remains stable, indicating a newly observed "infect to keep in check" strategy that maintains prokaryotic community structure. We characterized the viral community using metagenomics and metaproteomics, revealing 8 654 viral operational taxonomic units (vOTUs). CRISPR spacer-to-protospacer matching linked 278 vOTUs to 32 hosts, with many vOTUs sharing hosts from different families. High levels of viral structural proteins present in the metaproteome (several structurally annotated based on AlphaFold models) indicate active virion production at the time of sampling. Viral genomes expressed many proteins involved in DNA metabolism and manipulation, and encoded for auxiliary metabolic genes, which likely bolster phosphate and sulfur metabolism of their hosts. The active viral community encodes genes to facilitate acquisition and transformation of host nutrients, and appears to consist of many nutrient-demanding members, based on abundant virion proteins. These findings indicate viruses are inextricably linked to the biogeochemical cycling in this high-CO2 environment and substantially contribute to prokaryotic community stability in the deep biosphere hotspots.
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Rhesus and pigtail macaques have proven to be valuable animal models for several important human diseases, including HIV, where they exhibit similar pathology and disease progression. Because rhesus macaques have been extensively characterized in terms of their major histocompatibility complex (MHC) class I alleles, their demand has soared, making them increasingly difficult to obtain for research purposes. This problem has been exacerbated by a continued export ban in place since 1978. Pigtail macaques represent a potential alternative animal model. However, because their MHC class I alleles have not been characterized in detail, their use has been hindered. To address this, in the present study, we have characterized the peptide binding specificity of the pigtail macaque class I allele Mane-A1*082:01 (formerly known as Mane A*0301), representative of the second most common MHC class I antigen detected across several cohorts. The motif was defined on the basis of binding studies utilizing purified MHC protein and panels of single amino acid substitution analog peptides, as well as sequences of peptide ligands eluted from Mane-A1*082:01. Based on these analyses, Mane-A1*082:01 was found to recognize a motif with H in position 2 and the aromatic residues F and Y, or the hydrophobic/aliphatic residue M, at the C-terminus. Finally, analysis of the binding of a combinatorial peptide library allowed the generation of a detailed quantitative motif that proved effective in the prediction of a set of high-affinity binders derived from chimeric SIV/HIV, an important model virus for studying HIV infection in humans.
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Antígenos de Histocompatibilidade Classe I/imunologia , Macaca nemestrina/imunologia , Peptídeos/metabolismo , Motivos de Aminoácidos , Animais , Sítios de Ligação , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Vírus da Imunodeficiência Símia/imunologiaRESUMO
The SIV-infected rhesus macaque (Macaca mulatta) is the most established model of AIDS disease systems, providing insight into pathogenesis and a model system for testing novel vaccines. The understanding of cellular immune responses based on the identification and study of Major Histocompatibility Complex (MHC) molecules, including their MHC:peptide-binding motif, provides valuable information to decipher outcomes of infection and vaccine efficacy. Detailed characterization of Mamu-B*039:01, a common allele expressed in Chinese rhesus macaques, revealed a unique MHC:peptide-binding preference consisting of glycine at the second position. Peptides containing a glycine at the second position were shown to be antigenic from animals positive for Mamu-B*039:01. A similar motif was previously described for the D(d) mouse MHC allele, but for none of the human HLA molecules for which a motif is known. Further investigation showed that one additional macaque allele, present in Indian rhesus macaques, Mamu-B*052:01, shares this same motif. These "G2" alleles were associated with the presence of specific residues in their B pocket. This pocket structure was found in 6% of macaque sequences but none of 950 human HLA class I alleles. Evolutionary studies using the "G2" alleles points to common ancestry for the macaque sequences, while convergent evolution is suggested when murine and macaque sequences are considered. This is the first detailed characterization of the pocket residues yielding this specific motif in nonhuman primates and mice, revealing a new supertype motif not present in humans.
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Evolução Molecular , Antígenos de Histocompatibilidade/química , Macaca mulatta/imunologia , Camundongos/imunologia , Motivos de Aminoácidos , Animais , Linhagem Celular , Antígenos H-2/química , Antígeno de Histocompatibilidade H-2D , Antígenos de Histocompatibilidade Classe I/química , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Alinhamento de SequênciaRESUMO
Knowledge of the binding repertoires and specificities of HLA-DQ molecules is somewhat limited and contradictory, partly because of the scarcity of reports addressing some of the most common molecules and possibly because of the diversity of the techniques used. In this paper, we report the development of high-throughput binding assays for the six most common DQ molecules in the general worldwide population. Using comprehensive panels of single substitution analogs of specific ligands, we derived detailed binding motifs for DQA1*0501/DQB1*0301, DQA1*0401/DQB1*0402, and DQA1*0101/DQB1*0501 and more detailed motifs for DQA1*0501/DQB1*0201, DQA1*0301/DQB1*0302, and DQA1*0102/DQB1*0602, previously characterized on the basis of sets of eluted ligands and/or limited sets of substituted peptides. In contrast to what has previously been observed for DR and DP molecules, DQ motifs were generally less clearly defined in terms of chemical specificity and, strikingly, had little overlap with each other. However, testing a panel of peptides spanning a set of Phleum pratense Ags, and panels of known DQ epitopes, revealed a surprisingly significant and substantial overlap in the repertoire of peptides bound by these DQ molecules. Although the mechanism underlying these apparently contradictory findings is not clear, it likely reflects the peculiar mode of interaction between DQ (and not DR or DP) molecules and their peptide ligands. Because the DQ molecules studied are found in >85% of the general human population, these findings have important implications for epitope identification studies and monitoring of DQ-restricted immune responses.
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Antígenos HLA-DQ/genética , Polimorfismo Genético , Motivos de Aminoácidos , Humanos , Grupos Populacionais/genéticaRESUMO
Compared with DR and DQ, knowledge of the binding repertoires and specificities of HLA-DP alleles is somewhat limited. However, a growing body of literature has indicated the importance of DP-restricted responses in the context of cancer, allergy, and infectious disease. In the current study, we developed high-throughput binding assays for the five most common HLA-DPB1 alleles in the general worldwide population. Using these assays on a comprehensive panel of single-substitution analogs and large peptide libraries, we derived novel detailed binding motifs for DPB1*0101 and DPB1*0501. We also derived more detailed quantitative motifs for DPB1*0201, DPB1*0401, and DPB1*0402, which were previously characterized on the basis of sets of eluted ligands and/or limited sets of substituted peptides. Unexpectedly, all five DP molecules, originally selected only on the basis of their frequency in human populations, were found to share largely overlapping peptide motifs. Testing panels of known DP epitopes and a panel of peptides spanning a set of Phleum pratense Ags revealed that these molecules also share largely overlapping peptide-binding repertoires. This demonstrates that a previously hypothesized DP supertype extends far beyond what was originally envisioned and includes at least three additional very common DP specificities. Taken together, these DP supertype molecules are found in >90% of the human population. Thus, these findings have important implications for epitope-identification studies and monitoring of human class II-restricted immune responses.
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Alelos , Genética Populacional , Antígenos HLA-DP/genética , Motivos de Aminoácidos/genética , Sítios de Ligação/genética , Ligação Competitiva , Epitopos/genética , Frequência do Gene , Antígenos HLA-DP/metabolismo , Cadeias beta de HLA-DP , Humanos , Biblioteca de Peptídeos , Polimorfismo Genético , Ligação ProteicaRESUMO
BACKGROUND: Colorectal liver metastases (CRLM) are the most common cause of disease-specific mortality in patients with colorectal cancer. Hepatic artery infusion (HAI) combined with systemic chemotherapy improves survival for these patients. The safety of colorectal resection at the time of HAI pump placement has not been well established. METHODS: Patients with CRLM who underwent combined HAI pump placement and colorectal (primary) resection or HAI pump placement alone were evaluated for perioperative outcomes, pump-specific complications, infectious complications, and time to treatment initiation. These outcomes were compared using comparative statistics. RESULTS: Patients who underwent combined HAI pump placement and primary resection (n = 19) vs HAI pump placement alone (n = 13) had similar demographics and rates of combined hepatectomy. Combined HAI pump placement and primary resection group had similar operative time and blood loss (both p = NS), but longer length of stay (6 vs 4 days, p = 0.02) compared to pump placement alone. Overall postoperative complications (21% vs 8%) and pump-specific complications (16% vs 31%) were similar (both p = NS). Infection rates were not different between groups, nor was time to initiation of HAI therapy (19 vs 16 days p = NS), or systemic therapy (34 vs 35 days p = NS). CONCLUSION: Combining colorectal resection with HAI pump implantation is a safe surgical approach for management of unresectable CRLM. Postoperative complications, specifically infectious complications, were not increased, nor was there a delay to initiation of HAI or systemic chemotherapy. Investigation of long-term oncologic outcomes for HAI pump placement and primary tumor resection in patients with unresectable CRLM is ongoing.
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Neoplasias Colorretais , Neoplasias Hepáticas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/patologia , Fluoruracila/uso terapêutico , Artéria Hepática/patologia , Humanos , Bombas de Infusão , Infusões Intra-Arteriais , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/cirurgia , Complicações Pós-Operatórias/tratamento farmacológico , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologiaRESUMO
BACKGROUND: Depression in patients with cancer negatively influences physical symptoms, treatment success, coping, and quality of life (QOL), and is associated with increased mortality. OBJECTIVES: This study investigated the prevalence of depression and explored fatigue, QOL, and pain that is associated with depression in patients on first admission to a hematologic oncology unit. METHODS: This descriptive study measured depression, QOL, and fatigue with the Patient Health Questionnaire-9, the Functional Assessment of Cancer Therapy (FACT)-General, and the FACT-Anemia scale, respectively. Pain levels were examined with a numeric rating scale. FINDINGS: 58 patients participated; 17 reported moderate to severe depression, which highly correlated with fatigue, QOL, and pain. Among all factors, multivariate analysis showed that fatigue, particularly the physical domain of fatigue, has the strongest reverse correlation with depression.
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Testes Hematológicos , Hospitalização , Pacientes Internados/psicologia , Neoplasias/psicologia , Adaptação Psicológica , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Qualidade de Vida , Adulto JovemRESUMO
BACKGROUND: Donor brain death duration (BDD) may impact posttransplant graft function and survival in lung transplant. METHODS: We queried the 2007 to 2018 United Network for Organ Sharing Registry for adult recipients undergoing first-time isolated lung transplant. Cox proportional hazard modeling with splines enabled identification of 3 donor brain death intervals for subsequent analysis: short (<24 hours), reference (24-60 hours), and long (>60 hours). The primary outcome was posttransplant survival. RESULTS: In total, 19,721 donors and recipients met inclusion criteria. Median time from donor brain death until cross-clamp was 36.6 hours (interquartile range, 19.5). Unadjusted overall survival between cohorts was equivalent (log-rank P = .42); however, longer BDD was associated with improved bronchiolitis obliterans syndrome (BOS)-free survival (log-rank P < .001). On multivariable Cox proportional hazards regression, BDD was not associated with recipient survival (P > .05). Similarly, logistic regression did not identify an independent association between BDD and primary graft dysfunction (P > .05). Increased BDD was, however, associated with a decreased risk of acute rejection (long vs reference; adjusted odds ratio, 0.78; 95% confidence interval, 0.64-0.94) and improved BOS-free survival (long vs reference; adjusted hazard ratio, 0.88; 95% confidence interval, 0.81-0.96). CONCLUSIONS: Donor BDD is not associated with posttransplant survival or primary graft dysfunction. Long donor BDD, however, is associated with a decreased risk for acute rejection and improved BOS-free survival. Therefore, lung allografts from donors with a prolonged length of time from brain death until explant should not be viewed less favorably by donor selection centers.
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Morte Encefálica , Transplante de Pulmão , Obtenção de Tecidos e Órgãos/estatística & dados numéricos , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Estudos Retrospectivos , Taxa de Sobrevida , Fatores de Tempo , Resultado do TratamentoRESUMO
OBJECTIVE: The objective of this project was to assess the best measure for postoperative outcomes by comparing 30-day and 90-day mortality rates after surgery for non-small cell lung cancer using the National Cancer Database. Secondarily, hospital performance was examined at multiple postoperative intervals to assess changes in ranking based on mortality up to 1 year after surgery. METHODS: Patients who had undergone surgery for non-small cell lung cancer between 2004 and 2013 were identified in the National Cancer Database. Mortality rates at 30 days and 90 days were compared after adjusting for several patient characteristics, tumor variables, and hospital procedural volume using generalized logistic mixed models. Subsequently, mixed model logistic regression models were employed to evaluate hospital performance based on calculated mortality at prespecified time points. RESULTS: A total of 303,579 patients with non-small cell lung cancer were included for analysis. The 90-day mortality was almost double the 30-day mortality (3.0% vs 5.7%). Several patient characteristics, tumor features, and hospital volume were significantly associated with mortality at both 30 days and 90 days. Hospital rankings fluctuate appreciably between early mortality time points, which is additional evidence that quality metrics need to be based on later mortality time points. CONCLUSIONS: Thirty-day mortality is the commonly accepted quality measure for thoracic surgeons; however, hospital rankings may be inaccurate if based on this variable alone. Mortality after 90 days appears to be a threshold after which there is less variability in hospital ranking and should be considered as an alternative quality metric in lung cancer surgery.
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Carcinoma Pulmonar de Células não Pequenas/mortalidade , Neoplasias Pulmonares/mortalidade , Indicadores de Qualidade em Assistência à Saúde , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Bases de Dados como Assunto , Feminino , Humanos , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Pneumonectomia/mortalidade , Pneumonectomia/normas , Qualidade da Assistência à Saúde/normas , Adulto JovemRESUMO
BACKGROUND: The genetic etiology of human lipid quantitative traits is not fully elucidated, and interactions between variants may play a role. We performed a gene-centric interaction study for four different lipid traits: low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglycerides (TG). RESULTS: Our analysis consisted of a discovery phase using a merged dataset of five different cohorts (n = 12,853 to n = 16,849 depending on lipid phenotype) and a replication phase with ten independent cohorts totaling up to 36,938 additional samples. Filters are often applied before interaction testing to correct for the burden of testing all pairwise interactions. We used two different filters: 1. A filter that tested only single nucleotide polymorphisms (SNPs) with a main effect of p < 0.001 in a previous association study. 2. A filter that only tested interactions identified by Biofilter 2.0. Pairwise models that reached an interaction significance level of p < 0.001 in the discovery dataset were tested for replication. We identified thirteen SNP-SNP models that were significant in more than one replication cohort after accounting for multiple testing. CONCLUSIONS: These results may reveal novel insights into the genetic etiology of lipid levels. Furthermore, we developed a pipeline to perform a computationally efficient interaction analysis with multi-cohort replication.
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BACKGROUND: BioBin is a bioinformatics software package developed to automate the process of binning rare variants into groups for statistical association analysis using a biological knowledge-driven framework. BioBin collapses variants into biological features such as genes, pathways, evolutionary conserved regions (ECRs), protein families, regulatory regions, and others based on user-designated parameters. BioBin provides the infrastructure to create complex and interesting hypotheses in an automated fashion thereby circumventing the necessity for advanced and time consuming scripting. PURPOSE OF THE STUDY: In this manuscript, we describe the software package for BioBin, along with type I error and power simulations to demonstrate the strengths and various customizable features and analysis options of this variant binning tool. RESULTS: Simulation testing highlights the utility of BioBin as a fast, comprehensive and expandable tool for the biologically-inspired binning and analysis of low-frequency variants in sequence data. CONCLUSIONS AND POTENTIAL IMPLICATIONS: The BioBin software package has the capability to transform and streamline the analysis pipelines for researchers analyzing rare variants. This automated bioinformatics tool minimizes the manual effort of creating genomic regions for binning such that time can be spent on the much more interesting task of statistical analyses. This software package is open source and freely available from http://ritchielab.com/software/biobin-download.
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Background. Phenome-Wide Association Studies (PheWAS) identify genetic associations across multiple phenotypes. Clinical trials offer opportunities for PheWAS to identify pharmacogenomic associations. We describe the first PheWAS to use genome-wide genotypic data and to utilize human immunodeficiency virus (HIV) clinical trials data. As proof-of-concept, we focused on baseline laboratory phenotypes from antiretroviral therapy-naive individuals. Methods. Data from 4 AIDS Clinical Trials Group (ACTG) studies were split into 2 datasets: Dataset I (1181 individuals from protocol A5202) and Dataset II (1366 from protocols A5095, ACTG 384, and A5142). Final analyses involved 2547 individuals and 5 954 294 imputed polymorphisms. We calculated comprehensive associations between these polymorphisms and 27 baseline laboratory phenotypes. Results. A total of 10 584 (0.17%) polymorphisms had associations with P < .01 in both datasets and with the same direction of association. Twenty polymorphisms replicated associations with identical or related phenotypes reported in the Catalog of Published Genome-Wide Association Studies, including several not previously reported in HIV-positive cohorts. We also identified several possibly novel associations. Conclusions. These analyses define PheWAS properties and principles with baseline laboratory data from HIV clinical trials. This approach may be useful for evaluating on-treatment HIV clinical trials data for associations with various clinical phenotypes.
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Investigating the association between biobank derived genomic data and the information of linked electronic health records (EHRs) is an emerging area of research for dissecting the architecture of complex human traits, where cases and controls for study are defined through the use of electronic phenotyping algorithms deployed in large EHR systems. For our study, cataract cases and controls were identified within the Marshfield Personalized Medicine Research Project (PMRP) biobank and linked EHR, which is a member of the NHGRI-funded electronic Medical Records and Genomics (eMERGE) Network. Our goal was to explore potential gene-gene and gene-environment interactions within these data for 527,953 and 527,936 single nucleotide polymorphisms (SNPs) for gene-gene and gene-environment analyses, respectively, with minor allele frequency > 1%, in order to explore higher level associations with cataract risk beyond investigations of single SNP-phenotype associations. To build our SNP-SNP interaction models we utilized a prior-knowledge driven filtering method called Biofilter to minimize the multiple testing burden of exploring the vast array of interaction models possible from our extensive number of SNPs. Using Biofilter, we developed 57,376 prior-knowledge directed SNP-SNP models to test for association with cataract status. We selected models that required 6 sources of external domain knowledge. We identified 13 statistically significant SNP-SNP models with an interaction with p-value < 1 × 10(-4), as well as an overall model with p-value < 0.01 associated with cataract status. We also conducted gene-environment interaction analyses for all GWAS SNPs and a set of environmental factors from the PhenX Toolkit: smoking, UV exposure, and alcohol use;these environmental factors have been previously associated with the formation of cataracts. We found a total of 782 gene-environment models that exhibit an interaction with a p-value < 1 × 10(-4) associatedwith cataract status. Our results show these approaches enable advanced searches for epistasis and gene-environment interactions beyond GWAS, and that the EHR based approach provides an additional source of data for seeking these advanced explanatory models of the etiology of complex disease/outcome such as cataracts.