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1.
Cell ; 184(5): 1281-1298.e26, 2021 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-33592174

RESUMO

T cells are critical effectors of cancer immunotherapies, but little is known about their gene expression programs in diffuse gliomas. Here, we leverage single-cell RNA sequencing (RNA-seq) to chart the gene expression and clonal landscape of tumor-infiltrating T cells across 31 patients with isocitrate dehydrogenase (IDH) wild-type glioblastoma and IDH mutant glioma. We identify potential effectors of anti-tumor immunity in subsets of T cells that co-express cytotoxic programs and several natural killer (NK) cell genes. Analysis of clonally expanded tumor-infiltrating T cells further identifies the NK gene KLRB1 (encoding CD161) as a candidate inhibitory receptor. Accordingly, genetic inactivation of KLRB1 or antibody-mediated CD161 blockade enhances T cell-mediated killing of glioma cells in vitro and their anti-tumor function in vivo. KLRB1 and its associated transcriptional program are also expressed by substantial T cell populations in other human cancers. Our work provides an atlas of T cells in gliomas and highlights CD161 and other NK cell receptors as immunotherapy targets.


Assuntos
Glioma/imunologia , Subfamília B de Receptores Semelhantes a Lectina de Células NK/genética , Linfócitos T/imunologia , Animais , Antígenos de Neoplasias , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Glioma/genética , Células Matadoras Naturais/imunologia , Lectinas Tipo C/genética , Linfócitos do Interstício Tumoral/imunologia , Camundongos , Receptores de Superfície Celular/genética , Análise de Célula Única , Subpopulações de Linfócitos T/imunologia , Linfócitos T/citologia , Evasão Tumoral
2.
New Phytol ; 243(3): 1172-1189, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38853429

RESUMO

IRE1, BI-1, and bZIP60 monitor compatible plant-potexvirus interactions though recognition of the viral TGB3 protein. This study was undertaken to elucidate the roles of three IRE1 isoforms, the bZIP60U and bZIP60S, and BI-1 roles in genetic reprogramming of cells during potexvirus infection. Experiments were performed using Arabidopsis thaliana knockout lines and Plantago asiatica mosaic virus infectious clone tagged with the green fluorescent protein gene (PlAMV-GFP). There were more PlAMV-GFP infection foci in ire1a/b, ire1c, bzip60, and bi-1 knockout than wild-type (WT) plants. Cell-to-cell movement and systemic RNA levels were greater bzip60 and bi-1 than in WT plants. Overall, these data indicate an increased susceptibility to virus infection. Transgenic overexpression of AtIRE1b or StbZIP60 in ire1a/b or bzip60 mutant background reduced virus infection foci, while StbZIP60 expression influences virus movement. Transgenic overexpression of StbZIP60 also confers endoplasmic reticulum (ER) stress resistance following tunicamycin treatment. We also show bZIP60U and TGB3 interact at the ER. This is the first demonstration of a potato bZIP transcription factor complementing genetic defects in Arabidopsis. Evidence indicates that the three IRE1 isoforms regulate the initial stages of virus replication and gene expression, while bZIP60 and BI-1 contribute separately to virus cell-to-cell and systemic movement.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Fatores de Transcrição de Zíper de Leucina Básica , Doenças das Plantas , Plantas Geneticamente Modificadas , Potexvirus , Arabidopsis/virologia , Arabidopsis/genética , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Fatores de Transcrição de Zíper de Leucina Básica/genética , Doenças das Plantas/virologia , Doenças das Plantas/genética , Proteínas de Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Potexvirus/fisiologia , Regulação da Expressão Gênica de Plantas , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático , Mutação/genética , Tunicamicina/farmacologia , Proteínas de Membrana , Proteínas Quinases
3.
J Immunol ; 208(3): 762-771, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-34987112

RESUMO

Recent advancements in microfluidics and high-throughput sequencing technologies have enabled recovery of paired H and L chains of Igs and VDJ and VJ chains of TCRs from thousands of single cells simultaneously in humans and mice. Despite rhesus macaques being one of the most well-studied model organisms for the human adaptive immune response, high-throughput single-cell immune repertoire sequencing assays are not yet available due to the complexity of these polyclonal receptors. We used custom primers that capture all known rhesus macaque Ig and TCR isotypes and chains that are fully compatible with a commercial solution for single-cell immune repertoire profiling. Using these rhesus-specific assays, we sequenced Ig and TCR repertoires in >60,000 cells from cryopreserved rhesus PBMCs, splenocytes, and FACS-sorted B and T cells. We were able to recover every Ig isotype and TCR chain, measure clonal expansion in proliferating T cells, and pair Ig and TCR repertoires with gene expression profiles of the same single cells. Our results establish the ability to perform high-throughput immune repertoire analysis in rhesus macaques at the single-cell level.


Assuntos
Imunoglobulinas/genética , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T gama-delta/genética , Éxons VDJ/genética , Animais , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Macaca mulatta , Análise de Célula Única , Linfócitos T/imunologia , Transcriptoma/genética
4.
J Fish Biol ; 2024 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-39129462

RESUMO

There is some evidence that the river migration success of Atlantic salmon smolts, on their first migration to sea, varies both spatially and temporally. However, we have only a poor understanding of what may be driving this variation. In this study, we used acoustic telemetry to quantify the spatial and temporal variations in river migration success in Atlantic salmon smolts on their first migration to sea. In total 4120 Atlantic salmon smolts migrating through 22 rivers in Scotland, England, Ireland, and Northern Ireland over multiple years were included in the study. Individuals were defined as successful migrants if detected leaving the river to enter marine waters. The results show significant temporal (up to 4 years) and spatial (river) variations in migration success, with overall between-river migration success varying from 3.4% to 97.0% and between years from 3.4% and 61.0%. Temporal variation in migration success was river specific, with some rivers being more temporally stable (exhibiting little variation between years) than others. Across all rivers and years, individual migration success was predicted positively by body condition and negatively by tag burden. The rate of migration success for a population (migration success standardized to a common river distance [proportion km-1]) was predicted by a number of environmental factors. The proportion of river catchment that comprised wetland and woodland positively predicted migration success, whereas the proportion of grassland and peatland in a catchment negatively predicted the rate of migration success. Although the mechanisms through which these effects may be operating were not directly examined in this study, we discuss some potential routes through which they may occur.

5.
Ann Surg ; 277(2): 350-357, 2023 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33843792

RESUMO

OBJECTIVE: To define textbook outcome (TO) for lung transplantation (LTx) using a contemporary cohort from a high-volume institution. SUMMARY BACKGROUND DATA: TO is a standardized, composite quality measure based on multiple postoperative endpoints representing the ideal "textbook" hospitalization. METHODS: Adult patients who underwent LTx at our institution between 2016 and 2019 were included. TO was defined as freedom from intraoperative complication, postoperative reintervention, 30-day intensive care unit or hospital readmission, length of stay >75th percentile of LTx patients, 90 day mortality, 30-day acute rejection, grade 3 primary graft dysfunction at 48 or 72 hours, postoperative extracorporeal membrane oxygenation, tracheostomy within 7 days, inpatient dialysis, reintubation, and extubation >48 hours post-transplant. Recipient, operative, financial characteristics, and post-transplant outcomes were recorded from institutional data and compared between TO and non-TO groups. RESULTS: Of 401 LTx recipients, 97 (24.2%) achieved TO. The most common reason for TO failure was extubation >48 hours post-transplant (N = 119, 39.1%); the least common was mortality (N = 15, 4.9%). Patient and graft survival were improved among patients who achieved versus failed TO (patient survival: log-rank P < 0.01; graft survival: log-rank P < 0.01). Rejection-free and chronic lung allograft dysfunction-free survival were similar between TO and non-TO groups (rejection-free survival: log-rank P = 0.07; chronic lung allograft dysfunction-free survival: log-rank P = 0.3). On average, patients who achieved TO incurred approximately $638,000 less in total inpatient charges compared to those who failed TO. CONCLUSIONS: TO in LTx was associated with favorable post-transplant outcomes and significant cost-savings. TO may offer providers and patients new insight into transplant center quality of care and highlight areas for improvement.


Assuntos
Transplante de Pulmão , Indicadores de Qualidade em Assistência à Saúde , Adulto , Humanos , Estudos Retrospectivos , Pulmão , Transplante Homólogo
6.
J Immunol ; 206(7): 1668-1676, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33597150

RESUMO

Costimulation blockade (CoB)-based immunosuppression offers the promise of improved transplantation outcomes with reduced drug toxicity. However, it is hampered by early acute rejections, mediated at least in part by differentiated, CoB-resistant T cells, such as CD57+PD1- CD4 T cells. In this study, we characterize these cells pretransplant, determine their fate posttransplant, and examine their proliferative capacity in vitro in humans. Our studies show that CD57+PD1- CD4 T cells are correlated with increasing age and CMV infection pretransplant, and persist for up to 1 y posttransplant. These cells are replication incompetent alone but proliferated in the presence of unsorted PBMCs in a contact-independent manner. When stimulated, cells sorted by CD57/PD1 status upregulate markers of activation with proliferation. Up to 85% of CD57+PD1- cells change expression of CD57/PD1 with stimulation, typically, upregulating PD1 and downregulating CD57. PD1 upregulation is accentuated in the presence of rapamycin but prevented by tacrolimus. These data support a general theory of CoB-resistant cells as Ag-experienced, costimulation-independent cells and suggest a mechanism for the synergy of belatacept and rapamycin, with increased expression of the activation marker PD1 potentiating exhaustion of CoB-resistant cells.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Infecções por Citomegalovirus/imunologia , Citomegalovirus/fisiologia , Rejeição de Enxerto/imunologia , Falência Renal Crônica/cirurgia , Transplante de Rim , Receptor de Morte Celular Programada 1/metabolismo , Abatacepte/uso terapêutico , Adulto , Antígenos CD57/metabolismo , Plasticidade Celular , Infecções por Citomegalovirus/tratamento farmacológico , Sinergismo Farmacológico , Feminino , Regulação da Expressão Gênica , Rejeição de Enxerto/tratamento farmacológico , Humanos , Terapia de Imunossupressão , Imunossupressores , Falência Renal Crônica/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Fenótipo , Receptor de Morte Celular Programada 1/genética , Sirolimo/uso terapêutico , Tacrolimo/uso terapêutico
7.
J Pediatr Orthop ; 43(3): 181-186, 2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-36649473

RESUMO

ABSTRACT: The authors describe their 11-year experience with 1 model for providing short-term (about 1 wk/y in country) pediatric orthopaedic surgical care in a limited resource environment. This paper provides a detailed narrative of 1 team's pediatric orthopaedic work at the Moore Pediatric Surgery Center in Guatemala City, how it has evolved over these 11 years, financial aspects of the model, and examines patient follow-up data for a consecutive 8-year period. The authors have reviewed financial records, case lists, patient charts from 2014 to 2022, and patient photographic records from The Moore Center and as provided via internet by a local contracted Guatemalan pediatric orthopaedic fellowship-trained surgeon to present a complete picture of how the service functions. Specific follow-up data included: last follow-up date, date discharged from follow-up, and major complications including infection, surgical wound dehiscence, return for unplanned surgery, major nerve injury, and recurrent hip dislocation for cases of closed or open reduction of developmental hip dislocation. A total of 297 consecutive pediatric orthopaedic surgical patients were identified from 2014 to 2022. Of these, charts were found for 235 patients (135 female, 110 male), of which 43% were from the urban Guatemala City region. Two hundred sixteen (72%) had at least 1 follow-up clinic visit, and 87 (37%) had at least 1-year follow-up or were discharged. All complications identified by this retrospective chart review included 4 recurrent hip dislocations (3 after closed reduction), 1 femur fracture after implant removal, 1 superficial infection requiring antibiotics, 1 partial dehiscence treated only with dressings, 1 thumb subluxation, and 1 failed graft with internal fixation for congenital pseudoarthrosis of tibia. CONCLUSIONS: The Moore Pediatric Surgery Center is a financially viable, sustainable, safe, and effective model for delivering short-term surgical care for many pediatric orthopaedic conditions in a limited resource environment. LEVEL OF EVIDENCE: None (descriptive).


Assuntos
Luxações Articulares , Ortopedia , Procedimentos de Cirurgia Plástica , Humanos , Masculino , Criança , Feminino , Estudos Retrospectivos , Fixação Interna de Fraturas , Redução Aberta
8.
Am J Transplant ; 22(6): 1578-1592, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35322536

RESUMO

Mitochondria released from injured cells activate endothelial cells (ECs), fostering inflammatory processes, including allograft rejection. The stimulator of interferon genes (STING) senses endogenous mitochondrial DNA, triggering innate immune activation via NF-κB signaling. Here, we show that exogenous mitochondria exposure induces EC STING-NF-κB activation, promoting EC/effector memory T cell adhesion, which is abrogated by NF-κB and STING inhibitors. STING activation in mitochondrion-activated ECs is independent of canonical cGMP-AMP synthetase sensing/signaling, but rather is mediated by interferon gamma-inducible factor 16 (IFI16) and can be inhibited by IFI16 inhibition. Internalized mitochondria undergo mitofusion and STING-dependent mitophagy, leading to selective sequestration of internalized mitochondria. The exposure of donor hearts to exogenous mitochondria activates murine heart ECs in vivo. Collectively, our results suggest that IFI16-STING-NF-κB signaling regulates exogenous mitochondrion-induced EC activation and mitophagy, and exogenous mitochondria foster T cell-mediated CoBRR. These data suggest a novel, donor-directed, therapeutic approach toward mitigating perioperative allograft immunogenicity.


Assuntos
Transplante de Coração , NF-kappa B , Animais , Células Endoteliais/metabolismo , Transplante de Coração/efeitos adversos , Humanos , Camundongos , Mitocôndrias/metabolismo , NF-kappa B/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fosfoproteínas , Doadores de Tecidos
9.
Fungal Genet Biol ; 163: 103747, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36309094

RESUMO

Colletotrichum graminicola is an economically significant fungal pathogen of maize. The primary infective conidia of the fungus, falcate conidia, are splash-dispersed during rain events. The adhesion of the falcate conidia triggers germination and is required for the development of infection structures. Falcate conidia are capable of immediate adhesion upon encountering the substrate. We report that rapid adhesion in C. graminicola is polarized, with a single-sided strip of adhesive material running the length of a single side (or face) of the conidium between the tips. This strip of adhesive is co-localized with dynamic transverse actin cables, and both the adhesive strip and actin cables are formed after liberation of the conidium from its conidiogenous cell but prior to adhesion to the infection court. Orientation of conidia upon contact with substrate determines whether they will rapidly adhere, and those which do not initially adhere can be induced to do so by applying force to reorient or "flip" the conidia. We propose that C. graminicola possesses an adhesive mechanism resulting in an adhesion efficiency of approximately 50% upon initial contact with substrata, and that an increase in adhesion efficiency can be induced by disturbance.


Assuntos
Adesivos , Colletotrichum , Esporos Fúngicos/genética , Adesivos/análise , Adesivos/metabolismo , Actinas/metabolismo , Colletotrichum/genética
10.
Clin Transplant ; 36(5): e14619, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35175664

RESUMO

There are no established regulations governing patient selection for simultaneous heart-kidney (SHK) transplantation, creating the potential for significant center-level variations in clinical practice. METHODS: Using the United Network for Organ Sharing (UNOS) Standard Transplant Analysis and Research (STAR) file, we examined practice trends and variations in patient selection for SHK at the center level between January 1, 2004 and March 31, 2019. RESULTS: Overall, SHK is becoming more common with most centers performing heart transplants also performing SHK. Among patients who underwent heart transplant who were receiving dialysis, the rate of SHK varied from 22% to 86% at the center level. Among patients not on dialysis, the median estimated glomerular filtration rate (eGFR) of patients receiving SHK varied between 19 and 59 mL/min/1.73 m2 . When adjusting for other factors, the odds of SHK varied 57-fold between the highest and lowest SHK performing centers. CONCLUSION: Variation in SHK at the center level suggests the need for national guidelines around the selection of patients for SHK.


Assuntos
Transplante de Coração , Transplante de Rim , Taxa de Filtração Glomerular , Humanos , Rim , Seleção de Pacientes
11.
Pediatr Transplant ; 26(8): e14371, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35938682

RESUMO

BACKGROUND: Malnutrition, including obesity and undernutrition, among children is increasing in prevalence and is common among children on renal replacement therapy. The effect of malnutrition on the pre-transplant immune system and how the pediatric immune system responds to the insult of both immunosuppression and allotransplantation is unknown. We examined the relationship of nutritional status with post-transplant outcomes and characterized the peripheral immune cell phenotypes of children from the Immune Development of Pediatric Transplant (IMPACT) study. METHODS: Ninety-eight patients from the IMPACT study were classified as having obesity, undernutrition, or normal nutrition-based pre-transplant measurements. Incidence of infectious and alloimmune outcomes at 1-year post-transplantation was compared between nutritional groups using Gray's test and Fine-Gray subdistribution hazards model. Event-free survival was estimated by Kaplan-Meier method and compared between groups. Differences in immune cell subsets between nutritional groups over time were determined using generalized estimating equations accounting for the correlation between repeated measurements. RESULTS: We did not observe that nutritional status was associated with infectious or alloimmune events or event-free survival post-transplant. We demonstrated that children with obesity had distinct T-and B-cell signatures relative to those with undernutrition and normal nutrition, even when controlling for immunosuppression. Children with obesity had a lower frequency of CD8 Tnaive cells 9-month post-transplant (p < .001), a higher frequency of CD4 CD57 + PD1- T cells, and lower frequencies of CD57-PD1+ CD8 and CD57-PD1- CD8 T cells at 12-month transplant (p < .05 for all). CONCLUSIONS: Children with obesity have distinct immunophenotypes that may influence the tailoring of immunosuppression.


Assuntos
Transplante de Rim , Desnutrição , Humanos , Terapia de Imunossupressão , Linfócitos T CD8-Positivos , Desnutrição/complicações , Obesidade
12.
Am J Transplant ; 21(9): 3163-3174, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33942491

RESUMO

Thymic output and homeostatic mature cell proliferation both influence T cell repopulation following depletional induction, though the relative contribution of each and their association with recipient age have not been well studied. We investigated the repopulating T cell kinetics in kidney transplant recipients who underwent alemtuzumab induction followed by belatacept/rapamycin-based immunosuppression over 36-month posttransplantation. We focused specifically on the correlation between repopulating T cell subsets and the age of patients. Substantial homeostatic Ki67-expressing T cell proliferation was seen posttransplantation. A repertoire enriched for naïve T (TNaïve ) cells emerged posttransplantation. Analysis by generalized estimating equation linear models revealed a strong negative linear association between reconstituting TNaïve cells and advancing age. A relationship between age and persistence of effector memory cells was shown. We assessed thymic output and found an increase in the frequency of recent thymic emigrants (RTEs, CD4+ CD31+ ) at 12-month posttransplantation. Patients under 30 years of age showed significantly higher levels of CD4+ CD31+ cells than patients over 55 years of age pre- and posttransplantation. IL-7 and autologous mature dendritic cells (mDCs) induced CD57- cell proliferation. In contrast, mDCs, but not IL-7, induced CD57+ cell proliferation. This study establishes the relationship between age and thymic output during T cell homeostatic repopulation after alemtuzumab induction. Trial Registration: ClinicalTrials.gov - NCT00565773.


Assuntos
Transplante de Rim , Abatacepte , Proliferação de Células , Humanos , Terapia de Imunossupressão , Pessoa de Meia-Idade , Transplantados
13.
Am J Transplant ; 21(7): 2468-2478, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33350052

RESUMO

The incidence of simultaneous heart-kidney transplant (SHK) has increased markedly in the last 15 years. There are no universally agreed upon indications for SHK vs. heart alone (HA) transplant, and center evaluation processes vary widely. We utilized Scientific Registry of Transplant Recipients data from 2003 to 2017 to quantify changes in the practice of SHK, examine the survival of SHK vs. HA, and identify patients with marginal benefit from SHK. We used Kaplan-Meier curves and Cox proportional hazards to assess differences in survival. The incidence of SHK increased more than fourfold between 2003 and 2017 from 1.6% to 6.6% of total hearts transplanted, while the proportion of dialysis-dependent patients undergoing SHK has remained constant. SHK was associated with increased survival in dialysis-dependent patients (Median Survival SHK: 12.6 vs. HA: 7.1 years p < .0001) but not with nondialysis-dependent patients (Median Survival SHK: 12.5 vs. HA 12.3, p = .24). The marginal effect of SHK in decreasing the hazard of death diminished with increasing eGFR. Delayed graft function occurred in 26% of SHK recipients. Posttransplant chronic dialysis was similar for both operations (6.4% of HA and 6.0% of SHK). Further study is needed to define patients who benefit from SHK.


Assuntos
Transplante de Rim , Obtenção de Tecidos e Órgãos , Taxa de Filtração Glomerular , Sobrevivência de Enxerto , Humanos , Rim , Estudos Retrospectivos , Fatores de Risco , Doadores de Tecidos
14.
Am J Transplant ; 21(2): 766-775, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33480466

RESUMO

Depletional induction using antithymocyte globulin (ATG) reduces rates of acute rejection in adult kidney transplant recipients, yet little is known about its effects in children. Using a longitudinal cohort of 103 patients in the Immune Development in Pediatric Transplant (IMPACT) study, we compared T cell phenotypes after ATG or non-ATG induction. We examined the effects of ATG on the early clinical outcomes of alloimmune events (development of de novo donor specific antibody and/or biopsy proven rejection) and infection events (viremia/viral infections). Long-term patient and graft outcomes were examined using the Scientific Registry of Transplant Recipients. After ATG induction, although absolute counts of CD4 and CD8 T cells were lower, patients had higher percentages of CD4 and CD8 memory T cells with a concomitant decrease in frequency of naïve T cells compared to non-ATG induction. In adjusted and unadjusted models, ATG induction was associated with increased early event-free survival, with no difference in long-term patient or allograft survival. Decreased CD4+ naïve and increased CD4+ effector memory T cell frequencies were associated with improved clinical outcomes. Though immunologic parameters are drastically altered with ATG induction, long-term clinical benefits remain unclear in pediatric patients.


Assuntos
Soro Antilinfocitário , Transplante de Rim , Adulto , Soro Antilinfocitário/uso terapêutico , Criança , Rejeição de Enxerto/etiologia , Sobrevivência de Enxerto , Humanos , Imunossupressores , Transplante de Rim/efeitos adversos , Fenótipo
15.
Liver Transpl ; 27(8): 1106-1115, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33733560

RESUMO

Historically in the United States, kidneys for simultaneous liver-kidney transplantation (SLKT) candidates were allocated with livers, prioritizing SLKT recipients over much of the kidney waiting list. A 2017 change in policy delineated renal function criteria for SLKT and implemented a safety net for kidney-after-liver transplantation. We compared the use and outcomes of SLKT and kidney-after-liver transplant with the 2017 policy. United Network for Organ Sharing Standard Transplant Analysis and Research files were used to identify adults who received liver transplantations (LT) from August 10, 2007 to August 10, 2012; from August 11, 2012 to August 10, 2017; and from August 11, 2017 to June 12, 2019. LT recipients with end-stage renal disease (ESRD) were defined by dialysis requirement or estimated glomerular filtration rate <25. We evaluated outcomes and center-level, regional, and national practice before and after the policy change. Nonparametric cumulative incidence of kidney-after-liver listing and transplant were modeled by era. A total of 6332 patients received SLKTs during the study period; fewer patients with glomerular filtration rate (GFR) ≥50 mL/min underwent SLKT over time (5.8%, 4.8%, 3.0%; P = 0.01 ). There was also less variability in GFR at transplant after policy implementation on center and regional levels. We then evaluated LT-alone (LTA) recipients with ESRD (n = 5408 from 2012-2017; n = 2321 after the policy). Listing for a kidney within a year of LT increased from 2.9% before the policy change to 8.8% after the policy change, and the rate of kidney transplantation within 1 year increased from 0.7% to 4% (P < 0.001). After the policy change, there was no difference in patient survival rates between SLKT and LTA among patients with ESRD. Implementation of the 2017 SLKT policy change resulted in reduced variability in SLKT recipient kidney function and increased access to deceased donor kidney transplantation for LTA recipients with kidney disease without negatively affecting outcomes.


Assuntos
Transplante de Fígado , Adulto , Humanos , Rim/fisiologia , Rim/cirurgia , Fígado , Políticas , Diálise Renal , Estudos Retrospectivos , Estados Unidos/epidemiologia
16.
Xenotransplantation ; 28(6): e12713, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34951057

RESUMO

Porcine islet xenotransplantation is a viable strategy to treat diabetes. Its translation has been limited by the pre-clinical development of a clinically available immunosuppressive regimen. We tested two clinically relevant induction agents in a non-human primate (NHP) islet xenotransplantation model to compare depletional versus nondepletional induction immunosuppression. Neonatal porcine islets were isolated from GKO or hCD46/GKO transgenic piglets and transplanted via portal vein infusion in diabetic rhesus macaques. Induction therapy consisted of either basiliximab (n = 6) or rhesus-specific anti-thymocyte globulin (rhATG, n = 6), combined with a maintenance regimen using B7 costimulation blockade, tacrolimus with a delayed transition to sirolimus, and mycophenolate mofetil. Xenografts were monitored by blood glucose levels and porcine C-peptide measurements. Of the six receiving basiliximab induction, engraftment was achieved in 4 with median graft survival of 14 days. All six receiving rhATG induction engrafted with significantly longer xenograft survival at 40.5 days (P = 0.03). These data suggest that depletional induction provides superior xenograft survival to nondepletional induction, in the setting of a costimulation blockade-based maintenance regimen.


Assuntos
Soro Antilinfocitário , Transplante das Ilhotas Pancreáticas , Animais , Soro Antilinfocitário/farmacologia , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto , Humanos , Imunossupressores/farmacologia , Macaca mulatta , Suínos , Transplante Heterólogo
17.
Clin Transplant ; 35(8): e14369, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34021521

RESUMO

Rabbit antithymocyte globulin (RATG) preparations are widely used in transplantation. They are developed in vivo against thymocytes and contain polyclonal antibodies specific for myriad cellular targets. The rhesus monkey is commonly used as a preclinical transplant model, but the fidelity of commercially available human-specific RATGs to anticipate the effects of RATGs in rhesus has not been established. We therefore developed two rhesus-specific ATGs (rhATG) and compared them to human-specific RATG (huATG, Thymoglobulin® ) in rhesus monkeys, assessing the magnitude and phenotype of depletion peripherally and in lymph nodes. Four primates were assigned to each group and received 20 mg/kg of drug. Depletion, repopulation, and changes in lymphocyte subsets were evaluated in peripheral blood and lymph nodes by flow cytometry over four months. We observed similar qualitative changes in lymphocyte subsets, but a generally more profound depletion with huATG compared to either rhATG. Peripheral homeostatic proliferation rather than thymic output was the major mechanism for repopulation with all RATGs. Repopulation was slower but qualitatively similar when examining RATGs in additional animals receiving concomitant chronic immunosuppression. Depletional induction is similar to human- and rhesus-specific RATGs in rhesus macaques. Both rhesus- and human-specific agents appear appropriate for preclinical modeling of clinical RATG use.


Assuntos
Soro Antilinfocitário , Animais , Citometria de Fluxo , Humanos , Macaca mulatta
18.
World J Surg ; 45(5): 1504-1513, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33486584

RESUMO

BACKGROUND: "Textbook outcome" (TO) is a novel composite quality measure that encompasses multiple postoperative endpoints, representing the ideal "textbook" hospitalization for complex surgical procedures. We defined TO for kidney transplantation using a cohort from a high-volume institution. METHODS: Adult patients who underwent isolated kidney transplantation at our institution between 2016 and 2019 were included. TO was defined by clinician consensus at our institution to include freedom from intraoperative complication, postoperative reintervention, 30-day intensive care unit or hospital readmission, length of stay > 75th percentile of kidney transplant patients, 90-day mortality, 30-day acute rejection, delayed graft function, and discharge with a Foley catheter. Recipient, operative, financial characteristics, and post-transplant patient, graft, and rejection-free survival were compared between patients who achieved and failed to achieve TO. RESULTS: A total of 557 kidney transplant patients were included. Of those, 245 (44%) achieved TO. The most common reasons for TO failure were delayed graft function (N = 157, 50%) and hospital readmission within 30 days (N = 155, 50%); the least common was mortality within 90 days (N = 6, 2%). Patient, graft, and rejection-free survival were significantly improved among patients who achieved TO. On average, patients who achieved TO incurred approximately $50,000 less in total inpatient charges compared to those who failed TO. CONCLUSIONS: TO in kidney transplantation was associated with favorable post-transplant outcomes and significant cost-savings. TO may offer transplant centers a detailed performance breakdown to identify aspects of perioperative care in need of process improvement.


Assuntos
Transplante de Rim , Adulto , Rejeição de Enxerto , Sobrevivência de Enxerto , Humanos , Readmissão do Paciente , Assistência Perioperatória , Indicadores de Qualidade em Assistência à Saúde , Estudos Retrospectivos
19.
Radiol Med ; 126(1): 40-46, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33006087

RESUMO

The long-term sequelae of coronavirus disease 2019 (COVID-19) are still unknown. Lessons from past viral epidemics reveal that, after recovery, patients with viral pulmonary infections can suffer from irreversible pulmonary dysfunction and demonstrate residual imaging or functional abnormalities. Residual ground glass opacities, consolidations, reticular and linear opacities, residual crazy paving pattern, melted sugar sign, and parenchymal fibrotic bands are several features found in the late or remission stages of COVID-19. These radiologic findings have been observed weeks after symptom onset, even after hospital discharge, and they may or may not correlate with clinical manifestations. High-resolution CT may be indicated to establish new baselines and track changes in residual impairments. In our previous review, we observed significant pulmonary sequelae in some COVID-19 survivors at follow-up. In this update, we review the current literature on the clinical and radiologic manifestations of post-recovery COVID-19 toward the end of hospital admission and after discharge.


Assuntos
COVID-19/diagnóstico por imagem , COVID-19/fisiopatologia , Pneumonia Viral/diagnóstico por imagem , Pneumonia Viral/fisiopatologia , Convalescença , Progressão da Doença , Humanos , Pandemias , Pneumonia Viral/virologia , Testes de Função Respiratória , SARS-CoV-2 , Fatores de Tempo
20.
HPB (Oxford) ; 23(12): 1830-1836, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-33980477

RESUMO

BACKGROUND: Liver transplantation is definitive therapy for end stage liver disease in pediatric patients. Living donor liver transplantation (LDLT) with the left lateral segment (LLS) is often a feasible option. However, the size of LLS is an important factor in donor suitability - particularly when the recipient weighs less than 10 kg. In the present study, we sought to define a formula for estimating left lateral segment volume (LLSV) in potential LLS donors. METHODS: We obtained demographic and anthropometric measurements on 50 patients with Computed Tomography (CT) scans to determine whole liver volume (WLV), right liver volume (RLV), and LLSV. We performed univariable and multivariable linear regression with backwards stepwise variable selection (p < 0.10) to determine final models. RESULTS: Our study found that previously reported anthropometric and demographics variables correlated with volume were significantly associated with WLV and RLV. On univariable analysis, no demographic or anthropometric measures were correlated with LLSV. On multivariable analysis, LLSV was poorly predicted by the final model (R2 = 0.10, Coefficient of Variation [CV] = 42.2) relative to WLV (R2 = 0.33, CV = 18.8) and RLV (R2 = 0.41, CV = 15.8). CONCLUSION: Potential LLS living donors should not be excluded based on anthropometric data: all potential donors should be evaluated regardless of their size.


Assuntos
Doença Hepática Terminal , Transplante de Fígado , Criança , Humanos , Fígado/diagnóstico por imagem , Fígado/cirurgia , Transplante de Fígado/efeitos adversos , Doadores Vivos
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