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To better understand primary and recall T cell responses during coronavirus disease 2019 (COVID-19), it is important to examine unmanipulated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cells. By using peptide-human leukocyte antigen (HLA) tetramers for direct ex vivo analysis, we characterized CD8+ T cells specific for SARS-CoV-2 epitopes in COVID-19 patients and unexposed individuals. Unlike CD8+ T cells directed toward subdominant epitopes (B7/N257, A2/S269, and A24/S1,208) CD8+ T cells specific for the immunodominant B7/N105 epitope were detected at high frequencies in pre-pandemic samples and at increased frequencies during acute COVID-19 and convalescence. SARS-CoV-2-specific CD8+ T cells in pre-pandemic samples from children, adults, and elderly individuals predominantly displayed a naive phenotype, indicating a lack of previous cross-reactive exposures. T cell receptor (TCR) analyses revealed diverse TCRαß repertoires and promiscuous αß-TCR pairing within B7/N105+CD8+ T cells. Our study demonstrates high naive precursor frequency and TCRαß diversity within immunodominant B7/N105-specific CD8+ T cells and provides insight into SARS-CoV-2-specific T cell origins and subsequent responses.
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Linfócitos T CD8-Positivos/imunologia , COVID-19/imunologia , Proteínas do Nucleocapsídeo de Coronavírus/imunologia , Epitopos Imunodominantes/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , SARS-CoV-2/imunologia , Adulto , Idoso , Motivos de Aminoácidos , Linfócitos T CD4-Positivos , Criança , Convalescença , Proteínas do Nucleocapsídeo de Coronavírus/química , Epitopos de Linfócito T/química , Epitopos de Linfócito T/imunologia , Feminino , Humanos , Epitopos Imunodominantes/química , Masculino , Pessoa de Meia-Idade , Fenótipo , Fosfoproteínas/química , Fosfoproteínas/imunologia , Receptores de Antígenos de Linfócitos T/química , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T alfa-beta/química , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/imunologiaRESUMO
Maturation and migration to lymph nodes (LNs) constitutes a central paradigm in conventional dendritic cell (cDC) biology but remains poorly defined in humans. Using our organ donor tissue resource, we analyzed cDC subset distribution, maturation, and migration in mucosal tissues (lungs, intestines), associated lymph nodes (LNs), and other lymphoid sites from 78 individuals ranging from less than 1 year to 93 years of age. The distribution of cDC1 (CD141hiCD13hi) and cDC2 (Sirp-α+CD1c+) subsets was a function of tissue site and was conserved between donors. We identified cDC2 as the major mature (HLA-DRhi) subset in LNs with the highest frequency in lung-draining LNs. Mature cDC2 in mucosal-draining LNs expressed tissue-specific markers derived from the paired mucosal site, reflecting their tissue-migratory origin. These distribution and maturation patterns were largely maintained throughout life, with site-specific variations. Our findings provide evidence for localized DC tissue surveillance and reveal a lifelong division of labor between DC subsets, with cDC2 functioning as guardians of the mucosa.
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Células Dendríticas/citologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Citometria de Fluxo , Imunofluorescência , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Adulto JovemAssuntos
COVID-19 , Células T Matadoras Naturais , Citocinas , Citometria de Fluxo , Humanos , SARS-CoV-2RESUMO
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes severe coronavirus disease 2019 (COVID-19) in a small proportion of infected individuals. The immune system plays an important role in the defense against SARS-CoV-2, but our understanding of the cellular immune parameters that contribute to severe COVID-19 disease is incomplete. Here, we show that populations of effector γδ T cells are associated with COVID-19 in unvaccinated patients with acute disease. We found that circulating CD27neg CD45RA+ CX3CR1+ Vδ1effector cells expressing Granzymes (Gzms) were enriched in COVID-19 patients with acute disease. Moreover, higher frequencies of GzmB+ Vδ2+ T cells were observed in acute COVID-19 patients. SARS-CoV-2 infection did not alter the γδ T cell receptor repertoire of either Vδ1+ or Vδ2+ subsets. Our work demonstrates an association between effector populations of γδ T cells and acute COVID-19 in unvaccinated individuals.
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COVID-19 , Subpopulações de Linfócitos T , Humanos , Doença Aguda , Receptores de Antígenos de Linfócitos T gama-delta , SARS-CoV-2RESUMO
To demonstrate that point-of-care multimodal spectroscopy using Near-Infrared (NIR) and Raman Spectroscopy (RS) can be used to diagnose human heart tissue. We generated 105 spectroscopic scans, which comprised 4 NIR and 3 RS scans per sample to generate a "multimodal spectroscopic scan" (MSS) for each heart, done across 15 patients, 5 each from the dilated cardiomyopathy (DCM), Ischaemic Heart Disease (IHD) and Normal pathologies. Each of the MSS scans was undertaken in 3 s. Data were entered into machine learning (ML) algorithms to assess accuracy of MSS in diagnosing tissue type. The median age was 50 years (IQR 49-52) for IHD, 47 (IQR 45-50) for DCM and 36 (IQR 33-52) for healthy patients (p = 0.35), 60% of which were male. MSS identified key differences in IHD, DCM and normal heart samples in regions typically associated with fibrosis and collagen (NIR wavenumbers: 1433, 1509, 1581, 1689 and 1725 nm; RS wavelengths: 1658, 1450 and 1330 cm-1). In principal component (PC) analyses, these differences explained 99.2% of the variation in 4 PCs for NIR, 81.6% in 10 PCs for Raman, and 99.0% in 26 PCs for multimodal spectroscopic signatures. Using a stack machine learning algorithm with combined NIR and Raman data, our model had a precision of 96.9%, recall of 96.6%, specificity of 98.2% and Area Under Curve (AUC) of 0.989 (Table 1). NIR and Raman modalities alone had similar levels of precision at 94.4% and 89.8% respectively (Table 1). MSS combined with ML showed accuracy of 90% for detecting dilated cardiomyopathy, 100% for ischaemic heart disease and 100% for diagnosing healthy tissue. Multimodal spectroscopic signatures, based on NIR and Raman spectroscopy, could provide cardiac tissue scans in 3-s to aid accurate diagnoses of fibrosis in IHD, DCM and normal hearts. Table 1 Machine learning performance metrics for validation data sets of (a) Near-Infrared (NIR), (b) Raman and (c and d) multimodal data using logistic regression (LR), stochastic gradient descent (SGD) and support vector machines (SVM), with combined "stack" (LR + SGD + SVM) AUC Precision Recall Specificity (a) NIR model Logistic regression 0.980 0.944 0.933 0.967 SGD 0.550 0.281 0.400 0.700 SVM 0.840 0.806 0.800 0.900 Stack 0.933 0.794 0.800 0.900 (b) Raman model Logistic regression 0.985 0.940 0.929 0.960 SGD 0.892 0.869 0.857 0.932 SVM 0.992 0.940 0.929 0.960 Stack 0.954 0.869 0.857 0.932 (c) MSS: multimodal (NIR + Raman) to detect DCM vs. IHD vs. normal patients Logistic regression 0.975 0.841 0.828 0.917 SGD 0.847 0.803 0.793 0.899 SVM 0.971 0.853 0.828 0.917 Stack 0.961 0.853 0.828 0.917 (d) MSS: multimodal (NIR + Raman) to detect pathological vs. normal patients Logistic regression 0.961 0.969 0.966 0.984 SGD 0.944 0.967 0.966 0.923 SVM 1.000 1.000 1.000 1.000 Stack 1.000 0.944 0.931 0.969 Bold values indicate values obtained from the stack algorithm and used for analyses.
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Cardiomiopatia Dilatada , Isquemia Miocárdica , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Cardiomiopatia Dilatada/diagnóstico , Sistemas Automatizados de Assistência Junto ao Leito , Algoritmos , FibroseRESUMO
(1) Liver regeneration following partial hepatectomy for colorectal liver metastasis (CRLM) has been linked to tumour recurrence. Inhibition of the renin−angiotensin system (RASi) attenuates CRLM growth in the non-regenerating liver. This study investigates whether RASi exerts an antitumour effect within the regenerating liver following partial hepatectomy for CRLM and examines RASi-induced changes in the tumour immune microenvironment; (2) CRLM in mice was induced via intrasplenic injection of mouse colorectal tumour cells, followed by splenectomy on Day 0. Mice were treated with RASi captopril (250 mg/kg/day), or saline (control) from Day 4 to Day 16 (endpoint) and underwent 70% partial hepatectomy on Day 7. Liver and tumour samples were characterised by flow cytometry and immunofluorescence; (3) captopril treatment reduced tumour burden in mice following partial hepatectomy (p < 0.01). Captopril treatment reduced populations of myeloid-derived suppressor cells (MDSCs) (CD11b+Ly6CHi p < 0.05, CD11b+Ly6CLo p < 0.01) and increased PD-1 expression on infiltrating hepatic tissue-resident memory (TRM)-like CD8+ (p < 0.001) and double-negative (CD4-CD8-; p < 0.001) T cells; (4) RASi reduced CRLM growth in the regenerating liver and altered immune cell composition by reducing populations of immunosuppressive MDSCs and boosting populations of PD-1+ hepatic TRMs. Thus, RASi should be explored as an adjunct therapy for patients undergoing partial hepatectomy for CRLM.
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Neoplasias Colorretais , Neoplasias Hepáticas , Animais , Anti-Hipertensivos/farmacologia , Captopril/metabolismo , Captopril/farmacologia , Captopril/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/cirurgia , Inibidores Enzimáticos/farmacologia , Hepatectomia , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/cirurgia , Camundongos , Recidiva Local de Neoplasia/cirurgia , Receptor de Morte Celular Programada 1/metabolismo , Sistema Renina-Angiotensina , Microambiente TumoralRESUMO
T cells coordinate rejection of transplanted allografts and are key targets for depletion, immunosuppression, and tolerance induction to promote long-term graft survival. Studies in mouse models and humans generally focus on circulating T cells or those from lymphoid sites; however, vast numbers of T cells reside in multiple peripheral tissue sites including lungs, intestines, liver, and skin as non-circulating, tissue-resident memory T cells (Trm cells). In this review, we define the basic properties of Trm cells, the emerging evidence of their importance for protective immunity, and the potential role of resident versus circulating T cells in transplant rejection and in providing protection to prevalent infections posttransplantation. We also discuss potential susceptibilities and/or resistance of protective Trm to immunosuppression therapies, and how consideration of Trm, their compartmentalization, and specificity can enable improved therapies for targeted inhibition of pathogenic and preservation of protective T-cell subsets.
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Transplante de Órgãos , Subpopulações de Linfócitos T/imunologia , Tolerância ao Transplante , Aloenxertos , Animais , Doenças Transmissíveis/imunologia , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto , Humanos , Memória Imunológica , Imunossupressores/uso terapêutico , Transplante de Órgãos/efeitos adversos , Subpopulações de Linfócitos T/efeitos dos fármacos , Tolerância ao Transplante/efeitos dos fármacos , Resultado do TratamentoRESUMO
Anthropometric data are essential for the design of military equipment including sizing of aircraft cockpits and personal gear. Currently, there are no anthropometric databases specific to Brazilian military personnel. The aim of this study was to create a Brazilian anthropometric database of Air Force pilots. The methods, protocols, descriptions, definitions, landmarks, tools and measurements procedures followed the instructions outlined in Measurer's Handbook: US Army and Marine Corps Anthropometric Surveys, 2010-2011 - NATICK/TR-11/017. The participants were measured countrywide, in all five Brazilian Geographical Regions. Thirty-nine anthropometric measurements related to cockpit design were selected. The results of 2133 males and 206 females aged 16-52 years constitute a set of basic data for cockpit design, space arrangement issues and adjustments, protective gear and equipment design, as well as for digital human modelling. Another important implication is that this study can be considered a starting point for reducing gender bias in women's career as pilots. Practitioner Summary: This paper describes the first large-scale anthropometric survey of the Brazilian Air Force pilots and the development of the related database. This study provides critical data for improving aircraft cockpit design for ergonomics and comprehensive pilot accommodation, protective gear and uniform design, as well as digital human modelling.
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Aeronaves , Tamanho Corporal , Militares/estatística & dados numéricos , Pilotos , Adolescente , Adulto , Medicina Aeroespacial , Antropometria , Brasil , Bases de Dados como Assunto , Desenho de Equipamento , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Equipamentos de Proteção , Adulto JovemRESUMO
Infants and young children are disproportionately susceptible to severe complications from respiratory viruses, although the underlying mechanisms remain unknown. Recent studies show that the T cell response in the lung is important for protective responses to respiratory infections, although details on the infant/pediatric respiratory immune response remain sparse. The objectives of the present study were to characterize the local versus systemic immune response in infants and young children with respiratory failure from viral respiratory tract infections and its association to disease severity. Daily airway secretions were sampled from infants and children 4 years of age and younger receiving mechanical ventilation owing to respiratory failure from viral infection or noninfectious causes. Samples were examined for immune cell composition and markers of T cell activation. These parameters were then correlated with clinical disease severity. Innate immune cells and total CD3(+) T cells were present in similar proportions in airway aspirates derived from infected and uninfected groups; however, the CD8:CD4 T cell ratio was markedly increased in the airways of patients with viral infection compared with uninfected patients, and specifically in infected infants with acute lung injury. T cells in the airways were phenotypically and functionally distinct from those in blood with activated/memory phenotypes and increased cytotoxic capacity. We identified a significant increase in airway cytotoxic CD8(+) T cells in infants with lung injury from viral respiratory tract infection that was distinct from the T cell profile in circulation and associated with increasing disease severity. Airway sampling could therefore be diagnostically informative for assessing immune responses and lung damage.
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Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/virologia , Linfócitos T CD8-Positivos/imunologia , Infecções Respiratórias/imunologia , Infecções Respiratórias/virologia , Lesão Pulmonar Aguda/complicações , Lesão Pulmonar Aguda/patologia , Fatores Etários , Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular , Demografia , Feminino , Humanos , Imunofenotipagem , Lactente , Interleucina-6/metabolismo , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Contagem de Linfócitos , Subpopulações de Linfócitos/imunologia , Masculino , Modelos Estatísticos , Infecções Respiratórias/complicações , Infecções Respiratórias/patologiaRESUMO
BACKGROUND: In vitro laboratory and animal studies demonstrate a synergistic role for the combination of vancomycin and antistaphylococcal ß-lactams for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. Prospective clinical data are lacking. METHODS: In this open-label, multicenter, clinical trial, adults with MRSA bacteremia received vancomycin 1.5 g intravenously twice daily and were randomly assigned (1:1) to receive intravenous flucloxacillin 2 g every 6 hours for 7 days (combination group) or no additional therapy (standard therapy group). Participants were stratified by hospital and randomized in permuted blocks of variable size. Randomization codes were kept in sealed, sequentially numbered, opaque envelopes. The primary outcome was the duration of MRSA bacteremia in days. RESULTS: We randomly assigned 60 patients to receive vancomycin (n = 29), or vancomycin plus flucloxacillin (n = 31). The mean duration of bacteremia was 3.00 days in the standard therapy group and 1.94 days in the combination group. According to a negative binomial model, the mean time to resolution of bacteremia in the combination group was 65% (95% confidence interval, 41%-102%; P = .06) that in the standard therapy group. There was no difference in the secondary end points of 28- and 90-day mortality, metastatic infection, nephrotoxicity, or hepatotoxicity. CONCLUSIONS: Combining an antistaphylococcal ß-lactam with vancomycin may shorten the duration of MRSA bacteremia. Further trials with a larger sample size and objective clinically relevant end points are warranted. Australian New Zealand Clinical Trials Registry: ACTRN12610000940077 (www.anzctr.org.au).
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Antibacterianos/farmacologia , Bacteriemia/tratamento farmacológico , Floxacilina/farmacologia , Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , Infecções Estafilocócicas/tratamento farmacológico , Vancomicina/farmacologia , Administração Intravenosa , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Bacteriemia/microbiologia , Quimioterapia Combinada/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nova Zelândia , Estudos Prospectivos , Infecções Estafilocócicas/microbiologia , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
INTRODUCTION: A common bottleneck during ontology evaluation is knowledge acquisition from domain experts for gold standard creation. This paper contributes a novel semi-automated method for evaluating the concept coverage and accuracy of biomedical ontologies by complementing expert knowledge with knowledge automatically extracted from clinical practice guidelines and electronic health records, which minimizes reliance on expensive domain expertise for gold standards generation. METHODS: We developed a bacterial clinical infectious diseases ontology (BCIDO) to assist clinical infectious disease treatment decision support. Using a semi-automated method we integrated diverse knowledge sources, including publically available infectious disease guidelines from international repositories, electronic health records, and expert-generated infectious disease case scenarios, to generate a compendium of infectious disease knowledge and use it to evaluate the accuracy and coverage of BCIDO. RESULTS: BCIDO has three classes (i.e., infectious disease, antibiotic, bacteria) containing 593 distinct concepts and 2345 distinct concept relationships. Our semi-automated method generated an ID knowledge compendium consisting of 637 concepts and 1554 concept relationships. Overall, BCIDO covered 79% (504/637) of the concepts and 89% (1378/1554) of the concept relationships in the ID compendium. BCIDO coverage of ID compendium concepts was 92% (121/131) for antibiotic, 80% (205/257) for infectious disease, and 72% (178/249) for bacteria. The low coverage of bacterial concepts in BCIDO was due to a difference in concept granularity between BCIDO and infectious disease guidelines. Guidelines and expert generated scenarios were the richest source of ID concepts and relationships while patient records provided relatively fewer concepts and relationships. CONCLUSIONS: Our semi-automated method was cost-effective for generating a useful knowledge compendium with minimal reliance on domain experts. This method can be useful for continued development and evaluation of biomedical ontologies for better accuracy and coverage.
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Ontologias Biológicas , Registros Eletrônicos de Saúde , Armazenamento e Recuperação da Informação , Conhecimento , Infecções Bacterianas , Sistemas de Apoio a Decisões Clínicas , HumanosRESUMO
We designed and administered an online survey experiment to 444 educators in a large social sciences university in the United Kingdom to evaluate their perceptions on the effectiveness of online teaching methods. We find that a nudge, designed to inform educators about the benefits of online teaching, does not improve the personal evaluations of educators in our sample (ntreat = 142, ncontrol = 142) about this new mode of teaching. Overall, most respondents in our sample report being comfortable with online teaching methods and think this form of teaching can continue to have some positive impact. Nonetheless, they do not favour any further online transition away from traditional modes of teaching. Online teaching is largely perceived by a majority of these educators to negatively affect student well-being and their overall university experience. We call for more experimental research in higher educational settings to evaluate the role of edunudges in improving the uptake of online teaching tools.
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Disorders of bone integrity carry a high global disease burden, frequently requiring intervention, but there is a paucity of methods capable of noninvasive real-time assessment. Here we show that miniaturized handheld near-infrared spectroscopy (NIRS) scans, operated via a smartphone, can assess structural human bone properties in under three seconds. A hand-held NIR spectrometer was used to scan bone samples from 20 patients and predict: bone volume fraction (BV/TV); and trabecular (Tb) and cortical (Ct) thickness (Th), porosity (Po), and spacing (Sp). NIRS scans on both the inner (trabecular) surface or outer (cortical) surface accurately identified variations in bone collagen, water, mineral, and fat content, which then accurately predicted bone volume fraction (BV/TV, inner R2 = 0.91, outer R2 = 0.83), thickness (Tb.Th, inner R2 = 0.9, outer R2 = 0.79), and cortical thickness (Ct.Th, inner and outer both R2 = 0.90). NIRS scans also had 100% classification accuracy in grading the quartile of bone thickness and quality. We believe this is a fundamental step forward in creating an instrument capable of intraoperative real-time use.
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We aimed to facilitate the donation of tissue samples for research by establishing a centralized system integrated in the organ donation program for collection, storage, and distribution of samples (the Australian Donation and Transplantation Biobank [ADTB]). Methods: Feasibility of a research biobank integrated within the deceased organ and tissue donation program was assessed. DonateLife Victoria sought consent for ADTB donation after consent was received for organ donation for transplantation from the donor's senior available next of kin. ADTB samples were collected during donation surgery and distributed fresh to researchers or stored for future research. The main outcome measures were ADTB donation rates, ADTB sample collection, ADTB sample use, and to identify ethical considerations. Results: Over 2 y, samples were collected for the ADTB from 69 donors (28% of 249 donors). Samples were obtained from the spleen (n = 59, 86%), colon (n = 57, 83%), ileum (n = 56, 82%), duodenum (n = 55, 80%), blood (n = 55, 80%), bone marrow (n = 55, 80%), skin (n = 54, 78%), mesenteric lymph nodes (n = 56, 81%), liver (n = 21, 30%), lung (n = 29, 42%), and lung-draining lymph node (n = 29, 42%). Heart (n = 20), breast (n = 1), and lower urinary tract (n = 1) samples were obtained in the second year. Five hundred fifty-six samples were used in 19 ethics-approved research projects spanning the fields of immunology, microbiology, oncology, anatomy, physiology, and surgery. Conclusions: The integration of routine deceased donation and transplantation activities with a coordinated system for retrieval and allocation of donor samples for use in a range of research projects is feasible and valuable.
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OBJECTIVE: Remodeling of the coronary arteries is a common feature in severe cases of Kawasaki disease (KD). This pathology is driven by the dysregulated proliferation of vascular fibroblasts, which can lead to coronary artery aneurysms, stenosis, and myocardial ischemia. We undertook this study to investigate whether inhibiting fibroblast proliferation might be an effective therapeutic strategy to prevent coronary artery remodeling in KD. METHOD: We used a murine model of KD (induced by the injection of the Candida albicans water-soluble complex [CAWS]) and analyzed patient samples to evaluate potential antifibrotic therapies for KD. RESULTS: We identified the mechanistic target of rapamycin (mTOR) pathway as a potential therapeutic target in KD. The mTOR inhibitor rapamycin potently inhibited cardiac fibroblast proliferation in vitro, and vascular fibroblasts up-regulated mTOR kinase signaling in vivo in the CAWS mouse model of KD. We evaluated the in vivo efficacy of mTOR inhibition and found that the therapeutic administration of rapamycin reduced vascular fibrosis and intimal hyperplasia of the coronary arteries in CAWS-injected mice. Furthermore, the analysis of cardiac tissue from KD fatalities revealed that vascular fibroblasts localizing with inflamed coronary arteries up-regulate mTOR signaling, confirming that the mTOR pathway is active in human KD. CONCLUSION: Our findings demonstrate that mTOR signaling contributes to coronary artery remodeling in KD, and that targeting this pathway offers a potential therapeutic strategy to prevent or restrict this pathology in high-risk KD patients.
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Doença da Artéria Coronariana , Síndrome de Linfonodos Mucocutâneos , Humanos , Animais , Camundongos , Síndrome de Linfonodos Mucocutâneos/tratamento farmacológico , Vasos Coronários/patologia , Sirolimo/farmacologia , Modelos Animais de Doenças , Serina-Treonina Quinases TORRESUMO
Introduction: Visual assessment and imaging of the donor liver are inaccurate in predicting fibrosis and remain surrogates for histopathology. We demonstrate that 3-s scans using a handheld near-infrared-spectroscopy (NIRS) instrument can identify and quantify fibrosis in fresh human liver samples. Methods: We undertook NIRS scans on 107 samples from 27 patients, 88 from 23 patients with liver disease, and 19 from four organ donors. Results: Liver disease patients had a median immature fibrosis of 40% (interquartile range [IQR] 20-60) and mature fibrosis of 30% (10%-50%) on histopathology. The organ donor livers had a median fibrosis (both mature and immature) of 10% (IQR 5%-15%). Using machine learning, this study detected presence of cirrhosis and METAVIR grade of fibrosis with a classification accuracy of 96.3% and 97.2%, precision of 96.3% and 97.0%, recall of 96.3% and 97.2%, specificity of 95.4% and 98.0% and area under receiver operator curve of 0.977 and 0.999, respectively. Using partial-least square regression machine learning, this study predicted the percentage of both immature (R 2 = 0.842) and mature (R 2 = 0.837) with a low margin of error (root mean square of error of 9.76% and 7.96%, respectively). Conclusion: This study demonstrates that a point-of-care NIRS instrument can accurately detect, quantify and classify liver fibrosis using machine learning.
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OBJECTIVES: To analyse the adherence and impact of quality-of-care indicators (QCIs) in the management of Staphylococcus aureus bloodstream infection in a prospective and multicentre cohort. METHODS: Analysis of the prospective, multicentre international S. Aureus Collaboration cohort of S. Aureus bloodstream infection cases observed between January 2013 and April 2015. Multivariable analysis was performed to evaluate the impact of adherence to QCIs on 90-day mortality. RESULTS: A total of 1784 cases were included. Overall, 90-day mortality was 29.9% and mean follow-up period was 118 days. Adherence was 67% (n = 1180/1762) for follow-up blood cultures, 31% (n = 416/1342) for early focus control, 77.6% (n = 546/704) for performance of echocardiography, 75.5% (n = 1348/1784) for adequacy of targeted antimicrobial therapy, 88.6% (n = 851/960) for adequacy of treatment duration in non-complicated bloodstream infections and 61.2% (n = 366/598) in complicated bloodstream infections. Full bundle adherence was 18.4% (n = 328/1784). After controlling for immortal time bias and potential confounders, focus control (adjusted hazard ratio = 0.76; 95% CI, 0.59-0.99; p 0.038) and adequate targeted antimicrobial therapy (adjusted hazard ratio = 0.75; 95% CI, 0.61-0.91; p 0.004) were associated with low 90-day mortality. DISCUSSION: Adherence to QCIs in S. Aureus bloodstream infection did not reach expected rates. Apart from the benefits of application as a bundle, focus control and adequate targeted therapy were independently associated with low mortality.
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Bacteriemia , Sepse , Infecções Estafilocócicas , Humanos , Staphylococcus aureus , Estudos Prospectivos , Antibacterianos/uso terapêutico , Bacteriemia/diagnóstico , Bacteriemia/tratamento farmacológico , Bacteriemia/microbiologia , Infecções Estafilocócicas/diagnóstico , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Sepse/tratamento farmacológico , PrognósticoRESUMO
Tissue-resident memory T (TRM) cells provide immune defense against local infection and can inhibit cancer progression. However, it is unclear to what extent chronic inflammation impacts TRM activation and whether TRM cells existing in tissues before tumor onset influence cancer evolution in humans. We performed deep profiling of healthy lungs and lung cancers in never-smokers (NSs) and ever-smokers (ESs), finding evidence of enhanced immunosurveillance by cells with a TRM-like phenotype in ES lungs. In preclinical models, tumor-specific or bystander TRM-like cells present prior to tumor onset boosted immune cell recruitment, causing tumor immune evasion through loss of MHC class I protein expression and resistance to immune checkpoint inhibitors. In humans, only tumors arising in ES patients underwent clonal immune evasion, unrelated to tobacco-associated mutagenic signatures or oncogenic drivers. These data demonstrate that enhanced TRM-like activity prior to tumor development shapes the evolution of tumor immunogenicity and can impact immunotherapy outcomes.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Células T de Memória , Memória Imunológica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Pulmão , Linfócitos T CD8-PositivosRESUMO
Pregnancy poses a greater risk for severe COVID-19; however, underlying immunological changes associated with SARS-CoV-2 during pregnancy are poorly understood. We defined immune responses to SARS-CoV-2 in unvaccinated pregnant and nonpregnant women with acute and convalescent COVID-19, quantifying 217 immunological parameters. Humoral responses to SARS-CoV-2 were similar in pregnant and nonpregnant women, although our systems serology approach revealed distinct antibody and FcγR profiles between pregnant and nonpregnant women. Cellular analyses demonstrated marked differences in NK cell and unconventional T cell activation dynamics in pregnant women. Healthy pregnant women displayed preactivated NK cells and γδ T cells when compared with healthy nonpregnant women, which remained unchanged during acute and convalescent COVID-19. Conversely, nonpregnant women had prototypical activation of NK and γδ T cells. Activation of CD4+ and CD8+ T cells and T follicular helper cells was similar in SARS-CoV-2-infected pregnant and nonpregnant women, while antibody-secreting B cells were increased in pregnant women during acute COVID-19. Elevated levels of IL-8, IL-10, and IL-18 were found in pregnant women in their healthy state, and these cytokine levels remained elevated during acute and convalescent COVID-19. Collectively, we demonstrate perturbations in NK cell and γδ T cell activation in unvaccinated pregnant women with COVID-19, which may impact disease progression and severity during pregnancy.