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Inflammatory processes are activated following ischemic stroke that lead to increased tissue damage for weeks following the ischemic insult, but there are no approved therapies that target this inflammation-induced secondary injury. Here, we report that SynB1-ELP-p50i, a novel protein inhibitor of the nuclear factor kappa B (NF-κB) inflammatory cascade bound to the drug carrier elastin-like polypeptide (ELP), decreases NF-κB induced inflammatory cytokine production in cultured macrophages, crosses the plasma membrane and accumulates in the cytoplasm of both neurons and microglia in vitro, and accumulates at the infarct site where the blood-brain barrier (BBB) is compromised following middle cerebral artery occlusion (MCAO) in rats. Additionally, SynB1-ELP-p50i treatment reduces infarct volume by 11.86% compared to saline-treated controls 24 h following MCAO. Longitudinally, SynB1-ELP-p50i treatment improves survival for 14 days following stroke with no effects of toxicity or peripheral organ dysfunction. These results show high potential for ELP-delivered biologics for therapy of ischemic stroke and other central nervous system disorders and further support targeting inflammation in ischemic stroke.
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Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Ratos , Animais , NF-kappa B/metabolismo , AVC Isquêmico/metabolismo , Elastina/metabolismo , Encéfalo/metabolismo , Peptídeos/farmacologia , Peptídeos/metabolismo , Acidente Vascular Cerebral/metabolismo , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/metabolismo , Infarto da Artéria Cerebral Média/metabolismo , Inflamação/metabolismo , Microglia/metabolismoRESUMO
Inflammatory processes are activated following ischemic strokes and lead to increased tissue damage for weeks following the ischemic insult, but there are no approved therapies that target this inflammation-induced secondary injury. Here, we report that SynB1-ELP-p50i, a novel protein inhibitor of the nuclear factor kappa B (NF-κB) inflammatory cascade bound to drug carrier elastin-like polypeptide (ELP), is able to enter both neurons and microglia, cross the blood-brain barrier, localize exclusively in the ischemic core and penumbra in Wistar-Kyoto and spontaneously hypertensive rats (SHRs), and reduce infarct volume in male SHRs. Additionally, in male SHRs, SynB1-ELP-p50i treatment improves survival for 14 days following stroke with no effects of toxicity or peripheral organ dysfunction. These results show high potential for ELP-delivered biologics for therapy of ischemic stroke and other central nervous system disorders and further support targeting inflammation in ischemic stroke.
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Premise: We developed a novel, cost-effective protocol that facilitates testing anoxia tolerance in plants without access to specialized equipment. Methods and Results: Arabidopsis thaliana and barley (Hordeum vulgare) seedlings were treated in airtight 2-L Kilner jars. An anoxic atmosphere was generated using Oxoid AnaeroGen 2.5-L sachets placed on in-house, custom-built wire stands. The performed experiments confirmed a higher sensitivity to low oxygen stress previously observed in anac017 A. thaliana mutants and the positive effect of exogenous sucrose on anoxia tolerance reported by previous studies in A. thaliana. Barley seedlings displayed typical responses to anoxia treatment, including shoot growth cessation and the induction of marker genes for anaerobic metabolism and ethylene biosynthesis in root tissue. Conclusions: The results validate the novel method as an inexpensive, simple alternative for testing anoxia tolerance in plants, where access to an anaerobic workstation is not possible. The novel protocol requires minimum investment and is easily adaptable.
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OBJECTIVES: Successful lung cancer screening delivery requires sensitive, timely reporting of low-dose computed tomography (LDCT) scans, placing a demand on radiology resources. Trained non-radiologist readers and computer-assisted detection (CADe) software may offer strategies to optimise the use of radiology resources without loss of sensitivity. This report examines the accuracy of trained reporting radiographers using CADe support to report LDCT scans performed as part of the Lung Screen Uptake Trial (LSUT). METHODS: In this observational cohort study, two radiographers independently read all LDCT performed within LSUT and reported on the presence of clinically significant nodules and common incidental findings (IFs), including recommendations for management. Reports were compared against a 'reference standard' (RS) derived from nodules identified by study radiologists without CADe, plus consensus radiologist review of any additional nodules identified by the radiographers. RESULTS: A total of 716 scans were included, 158 of which had one or more clinically significant pulmonary nodules as per our RS. Radiographer sensitivity against the RS was 68-73.7%, with specificity of 92.1-92.7%. Sensitivity for detection of proven cancers diagnosed from the baseline scan was 83.3-100%. The spectrum of IFs exceeded what could reasonably be covered in radiographer training. CONCLUSION: Our findings highlight the complexity of LDCT reporting requirements, including the limitations of CADe and the breadth of IFs. We are unable to recommend CADe-supported radiographers as a sole reader of LDCT scans, but propose potential avenues for further research including initial triage of abnormal LDCT or reporting of follow-up surveillance scans. KEY POINTS: ⢠Successful roll-out of mass screening programmes for lung cancer depends on timely, accurate CT scan reporting, placing a demand on existing radiology resources. ⢠This observational cohort study examines the accuracy of trained radiographers using computer-assisted detection (CADe) software to report lung cancer screening CT scans, as a potential means of supporting reporting workflows in LCS programmes. ⢠CADe-supported radiographers were less sensitive than radiologists at identifying clinically significant pulmonary nodules, but had a low false-positive rate and good sensitivity for detection of confirmed cancers.
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Neoplasias Pulmonares , Nódulos Pulmonares Múltiplos , Computadores , Detecção Precoce de Câncer/métodos , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Nódulos Pulmonares Múltiplos/diagnóstico por imagem , Sensibilidade e Especificidade , Tomografia Computadorizada por Raios X/métodosRESUMO
BACKGROUND: Advanced colorectal neoplasms (ACNs), including colorectal cancers (CRC) and high-risk adenomas (HRA), are detected in less than 20% of persons aged 50 years or older who undergo colonoscopy. We sought to derive personalized predictive models of risk of harbouring ACNs to improve colonoscopy wait times for high-risk patients and allocation of colonoscopy resources. METHODS: We characterized colonoscopy indications, neoplasia risk factors and colonoscopy findings through chart review for consecutive individuals aged 50 years or older who underwent outpatient colonoscopy at The Ottawa Hospital (Ottawa, Canada) between April 1, 2008 and March 31, 2012 for non-life threatening indications. We linked patients to population-level health administrative datasets to ascertain additional historical predictor variables and derive multivariable logistic regression models for risk of harboring ACNs at colonoscopy. We assessed model discriminatory capacity and calibration and the ability of the models to improve colonoscopy specificity while maintaining excellent sensitivity for ACN capture. RESULTS: We modelled 17 candidate predictors in 11,724 individuals who met eligibility criteria. The final CRC model comprised 8 variables and had a c-statistic value of 0.957 and a goodness-of-fit p-value of 0.527. Application of the models to our cohort permitted 100% sensitivity for identifying persons with CRC and > 90% sensitivity for identifying persons with HRA, while improving colonoscopy specificity for ACNs by 23.8%. CONCLUSIONS: Our multivariable models show excellent discriminatory capacity for persons with ACNs and could significantly increase colonoscopy specificity without overly sacrificing sensitivity. If validated, these models could allow more efficient allocation of colonoscopy resources, potentially reducing wait times for those at higher risk while deferring unnecessary colonoscopies in low-risk individuals.
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Adenoma , Neoplasias Colorretais , Adenoma/diagnóstico , Colonoscopia , Neoplasias Colorretais/diagnóstico , Humanos , Modelos Logísticos , Fatores de RiscoRESUMO
Vascular Endothelial Growth Factor (VEGF), a key mediator of angiogenesis and vascular repair, is reduced in chronic ischemic renal diseases, leading to microvascular rarefaction and deterioration of renal function. We developed a chimeric fusion of human VEGF-A121 with the carrier protein Elastin-like Polypeptide (ELP-VEGF) to induce therapeutic angiogenesis via targeted renal VEGF therapy. We previously showed that ELP-VEGF improves renal vascular density, renal fibrosis, and renal function in swine models of chronic renal diseases. However, VEGF is a potent cytokine that induces angiogenesis and increases vascular permeability, which could cause undesired off-target effects or be deleterious in a patient with a solid tumor. Therefore, the current study aims to define the toxicological profile of ELP-VEGF and assess its risk for exacerbating tumor progression and vascularity using rodent models. A dose escalating toxicology assessment of ELP-VEGF was performed by administering a bolus intravenous injection at doses ranging from 0.1 to 200 mg/kg in Sprague Dawley (SD) rats. Blood pressure, body weight, and glomerular filtration rate (GFR) were quantified longitudinally, and terminal blood sampling and renal vascular density measurements were made 14 days after treatment. Additionally, the effects of a single administration of ELP-VEGF (0.1-10 mg/kg) on tumor growth rate, mass, and vascular density were examined in a mouse model of breast cancer. At doses up to 200 mg/kg, ELP-VEGF had no effect on body weight, caused no changes in plasma or urinary markers of renal injury, and did not induce renal fibrosis or other histopathological findings in SD rats. At the highest doses (100-200 mg/kg), ELP-VEGF caused an acute, transient hypotension (30 min), increased GFR, and reduced renal microvascular density 14 days after injection. In a mouse tumor model, ELP-VEGF did not affect tumor growth rate or tumor mass, but analysis of tumor vascular density by micro-computed tomography (µCT) revealed significant, dose dependent increases in tumor vascularity after ELP-VEGF administration. ELP-VEGF did not induce toxicity in the therapeutic dosing range, and doses one hundred times higher than the expected maximum therapeutic dose were needed to observe any adverse signs in rats. In breast tumor-bearing mice, ELP-VEGF therapy induced a dose-dependent increase in tumor vascularity, demanding caution for potential use in a patient suffering from kidney disease but with known or suspected malignancy.
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Produtos Biológicos/farmacologia , Neoplasias da Mama/irrigação sanguínea , Elastina/genética , Neovascularização Patológica/induzido quimicamente , Proteínas Recombinantes de Fusão/farmacologia , Insuficiência Renal Crônica/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/genética , Animais , Produtos Biológicos/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/patologia , Permeabilidade Capilar/efeitos dos fármacos , Modelos Animais de Doenças , Elastina/metabolismo , Feminino , Expressão Gênica , Taxa de Filtração Glomerular/efeitos dos fármacos , Xenoenxertos , Humanos , Hipotensão/induzido quimicamente , Hipotensão/diagnóstico por imagem , Hipotensão/fisiopatologia , Camundongos , Mimetismo Molecular , Neovascularização Patológica/diagnóstico por imagem , Neovascularização Patológica/patologia , Neovascularização Fisiológica/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Insuficiência Renal Crônica/diagnóstico por imagem , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/fisiopatologia , Suínos , Testes de Toxicidade Crônica , Fator A de Crescimento do Endotélio Vascular/metabolismo , Microtomografia por Raio-XRESUMO
The Lung Screen Uptake Trial tested a novel invitation strategy to improve uptake and reduce socioeconomic and smoking-related inequalities in lung cancer screening (LCS) participation. It provides one of the first UK-based 'real-world' LCS cohorts. Of 2012 invited, 1058 (52.6%) attended a 'lung health check'. 768/996 (77.1%) in the present analysis underwent a low-dose CT scan. 92 (11.9%) and 33 (4.3%) participants had indeterminate pulmonary nodules requiring 3-month and 12-month surveillance, respectively; 36 lung cancers (4.7%) were diagnosed (median follow-up: 1044 days). 72.2% of lung cancers were stage I/II and 79.4% of non-small cell lung cancer had curative-intent treatment.
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Carcinoma/diagnóstico , Detecção Precoce de Câncer , Neoplasias Pulmonares/diagnóstico , Aceitação pelo Paciente de Cuidados de Saúde , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Doses de Radiação , Fatores Socioeconômicos , Reino UnidoRESUMO
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified as the etiologic agent associated with coronavirus disease, which emerged in late 2019. In response, we developed a diagnostic panel consisting of 3 real-time reverse transcription PCR assays targeting the nucleocapsid gene and evaluated use of these assays for detecting SARS-CoV-2 infection. All assays demonstrated a linear dynamic range of 8 orders of magnitude and an analytical limit of detection of 5 copies/reaction of quantified RNA transcripts and 1 x 10-1.5 50% tissue culture infectious dose/mL of cell-cultured SARS-CoV-2. All assays performed comparably with nasopharyngeal and oropharyngeal secretions, serum, and fecal specimens spiked with cultured virus. We obtained no false-positive amplifications with other human coronaviruses or common respiratory pathogens. Results from all 3 assays were highly correlated during clinical specimen testing. On February 4, 2020, the Food and Drug Administration issued an Emergency Use Authorization to enable emergency use of this panel.
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Betacoronavirus/genética , Infecções por Coronavirus/diagnóstico , Proteínas do Nucleocapsídeo/genética , Pneumonia Viral/diagnóstico , RNA Viral/genética , Reação em Cadeia da Polimerase em Tempo Real/métodos , Biomarcadores/análise , COVID-19 , Centers for Disease Control and Prevention, U.S. , Infecções por Coronavirus/virologia , Proteínas do Nucleocapsídeo de Coronavírus , Primers do DNA/síntese química , Primers do DNA/genética , Fezes/virologia , Fluoresceínas/química , Corantes Fluorescentes/química , Humanos , Limite de Detecção , Nasofaringe/virologia , Pandemias , Fosfoproteínas , Pneumonia Viral/virologia , Reação em Cadeia da Polimerase em Tempo Real/normas , Reprodutibilidade dos Testes , SARS-CoV-2 , Escarro/virologia , Estados UnidosRESUMO
Rationale: Individuals eligible for lung cancer screening (LCS) by low-dose computed tomography (LDCT) are also at risk of chronic obstructive pulmonary disease (COPD) due to age and smoking exposure. Whether the LCS episode is useful for early detection of COPD is not well established.Objectives: To explore associations between symptoms, comorbidities, spirometry, and emphysema in participants enrolled in the Lung Screen Uptake Trial.Methods: This cross-sectional study was a prespecified analysis nested within Lung Screen Uptake Trial, which was a randomized study testing the impact of differing invitation materials on attendance of 60- to 75-year-old smokers and ex-smokers to a "lung health check" between November 2015 and July 2017. Participants with a smoking history ≥30 pack-years and who quit ≤15 years ago, or meeting a lung cancer risk of ≥1.51% via the Prostate Lung Colorectal Ovarian model or ≥2.5% via the Liverpool Lung Project model, were offered LDCT. COPD was defined and classified according to the GOLD (Global Initiative for Obstructive Lung Disease) criteria using prebronchodilator spirometry. Analyses included the use of descriptive statistics, chi-square tests to examine group differences, and univariable and multivariable logistic regression to explore associations between symptom prevalence, airflow limitation, and visually graded emphysema.Results: A total of 560 of 986 individuals included in the analysis (57%) had prebronchodilator spirometry consistent with COPD; 67% did not have a prior history of COPD and were termed "undiagnosed." Emphysema prevalence in those with known and "undiagnosed" COPD was 73% and 68%, respectively. A total of 32% of those with "undiagnosed COPD" had no emphysema on LDCT. Inhaler use and symptoms were more common in the "known" than the "undiagnosed" COPD group (63% vs. 33% with persistent cough [P < 0.001]; 73% vs. 33% with dyspnea [P < 0.001]). Comorbidities were common in all groups. Adjusted odds ratio (aOR) of respiratory symptoms were more significant for airflow obstruction (aOR GOLD 1 and 2, 1.57; confidence interval [CI], 1.14-2.17; aOR GOLD 3 and 4, 4.6; CI, 2.17-9.77) than emphysema (aOR mild, 1.12; CI, 0.81-1.55; aOR moderate, 1.33; CI, 0.85-2.09; aOR severe, 4.00; CI, 1.57-10.2).Conclusions: There is high burden of "undiagnosed COPD" and emphysema in LCS participants. Adding spirometry findings to the LDCT enhances identification of individuals with COPD.Clinical trial registered with www.clinicaltrials.gov (NCT02558101).
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Neoplasias Pulmonares/diagnóstico por imagem , Programas de Rastreamento/métodos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Fumar/efeitos adversos , Idoso , Tosse/etiologia , Estudos Transversais , Detecção Precoce de Câncer , Enfisema/diagnóstico por imagem , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prevalência , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Espirometria , Tomografia Computadorizada por Raios X , Reino Unido/epidemiologiaRESUMO
INTRODUCTION: Lung cancer screening (LCS) by low-dose computed tomography (LDCT) offers an opportunity to impact both lung cancer and coronary heart disease mortality through detection of coronary artery calcification (CAC). Here, we explore the value of CAC and cardiovascular disease (CVD) risk assessment in LCS participants in the Lung Screen Uptake Trial (LSUT). METHODS: In this cross-sectional study, current and ex-smokers aged 60-75 were invited to a 'lung health check'. Data collection included a CVD risk assessment enabling estimation of 10 year CVD risk using the QRISK2 score. Participants meeting the required lung cancer risk underwent an ungated, non-contrast LDCT. Descriptive data, bivariate associations and a multivariate analysis of predictors of statin use are presented. RESULTS: Of 1005 individuals enrolled, 680 were included in the final analysis. 421 (61.9%) had CAC present and in 49 (7.2%), this was heavy. 668 (98%) of participants had a QRISK2≥10% and QRISK2 was positively associated with increasing CAC grade (OR 4.29 (CI 0.93 to 19.88) for QRISK2=10%-20% and 12.29 (CI 2.68 to 56.1) for QRISK2≥20% respectively). Of those who qualified for statin primary prevention (QRISK2≥10%), 56.8% did not report a history of statin use. In the multivariate analysis statin use was associated with age, body mass index and history of hypertension and diabetes. CONCLUSIONS: LCS offers an important opportunity for instituting CVD risk assessment in all LCS participants irrespective of the presence of LDCT-detected CAC. Further studies are needed to determine whether CAC could enhance uptake and adherence to primary preventative strategies.
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Doenças Cardiovasculares/prevenção & controle , Detecção Precoce de Câncer/métodos , Neoplasias Pulmonares/diagnóstico por imagem , Idoso , Doenças Cardiovasculares/complicações , Estudos de Coortes , Doença das Coronárias/complicações , Doença das Coronárias/diagnóstico por imagem , Estudos Transversais , Uso de Medicamentos/estatística & dados numéricos , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Neoplasias Pulmonares/complicações , Masculino , Programas de Rastreamento/métodos , Pessoa de Meia-Idade , Prevenção Primária/métodos , Estudos Prospectivos , Doses de Radiação , Medição de Risco/métodos , Tomografia Computadorizada por Raios X/métodos , Calcificação Vascular/complicações , Calcificação Vascular/diagnóstico por imagemRESUMO
RATIONALE AND OBJECTIVES: Chest X-rays (CXR) are one of the most frequently requested imaging examinations and are fundamental to many patient pathways. The aim of this study was to investigate the diagnostic accuracy of CXR interpretation by reporting radiographers (technologists). METHODS: A cohort of consultant radiologists (n = 10) and reporting radiographers (technologists; n = 11) interpreted a bank (n = 106) of adult CXRs that contained a range of pathologies. Jack-knife alternate free-response receiver operating characteristic (JAFROC) methodology was used to determine the performance of the observers (JAFROC v4.2). A noninferiority approach was used, with a predefined margin of clinical insignificance of 10% of average consultant radiologist diagnostic accuracy. RESULTS: The diagnostic accuracy of the reporting radiographers (figure of merit = 0.828, 95% confidence interval 0.808-0.847) was noninferior to the consultant radiologists (figure of merit = 0.788, 95% confidence interval 0.766-0.811), P < .0001. CONCLUSIONS: With appropriate postgraduate education, reporting radiographers are able to interpret CXRs at a level comparable to consultant radiologists.
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Pessoal Técnico de Saúde/normas , Cardiopatias/diagnóstico por imagem , Pneumopatias/diagnóstico por imagem , Radiologistas/normas , Erros de Diagnóstico , Humanos , Variações Dependentes do Observador , Estudos Prospectivos , Curva ROC , Radiografia TorácicaRESUMO
INTRODUCTION: Diagnostic capacity and time to diagnosis are frequently identified as a barrier to improving cancer patient outcomes. Maximising the contribution of the medical imaging workforce, including reporting radiographers, is one way to improve service delivery. METHODS: An efficient and effective centralised model of workplace training support was designed for a cohort of trainee chest X-ray (CXR) reporting radiographers. A comprehensive schedule of tutorials was planned and aligned with the curriculum of a post-graduate certificate in CXR reporting. Trainees were supported via a hub and spoke model (centralised training model), with the majority of education provided by a core group of experienced CXR reporting radiographers. Trainee and departmental feedback on the model was obtained using an online survey. RESULTS: Fourteen trainees were recruited from eight National Health Service Trusts across London. Significant efficiencies of scale were possible with centralised support (48 h) compared to traditional workplace support (348 h). Trainee and manager feedback overall was positive. Trainees and managers both reported good trainee support, translation of learning to practice and increased confidence. Logistics, including trainee travel and release, were identified as areas for improvement. CONCLUSION: Centralised workplace training support is an effective and efficient method to create sustainable diagnostic capacity and support improvements in the lung cancer pathway.
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Capacitação em Serviço/métodos , Neoplasias Pulmonares/diagnóstico por imagem , Radiografia Torácica/normas , Radiologistas/educação , Adulto , Inglaterra , Feminino , Humanos , Capacitação em Serviço/normas , Masculino , Radiologistas/normas , Materiais de EnsinoRESUMO
In 2010, the Centers for Disease Control and Prevention began to develop an Influenza Risk Assessment Tool (IRAT) to methodically capture and assess information relating to influenza A viruses not currently circulating among humans. The IRAT uses a multiattribute, additive model to generate a summary risk score for each virus. Although the IRAT is not intended to predict the next pandemic influenza A virus, it has provided input into prepandemic preparedness decisions.
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Vírus da Influenza A , Influenza Humana/epidemiologia , Influenza Humana/virologia , Animais , China/epidemiologia , Genótipo , Humanos , Vírus da Influenza A/classificação , Vírus da Influenza A/genética , Infecções por Orthomyxoviridae/epidemiologia , Infecções por Orthomyxoviridae/virologia , Vigilância da População , Medição de RiscoRESUMO
PURPOSE AND HYPOTHESIS: The principal purpose of this paper was to identify whether femoral notch morphology was different in females without anterior cruciate ligament (ACL) injury from those with ACL injury. Magnetic resonance imaging (MRI) was used to assess the femoral notch type, notch width index and 'α angle' in female patients and measure these differences. METHODS: This is a retrospective case control study of 119 female patients, 58 with ACL injury and 61 patients without ACL injury who underwent knee MRI between March 2014 and April 2016. The morphometric measurements were taken by two independent observers. The femoral notch width index was calculated as the ratio between the central notch width and transcondylar or intercondylar width; values >0.27 were considered normal. The femoral notch shape was classified as Type A, Type U or Type W, with Type A describing a stenotic notch, Type U a notch with a wider contour and Type W a wider Type U with two apices apparent. The angle between the longitudinal femoral axis and the Blumensaat line was identified as the 'α angle'. The statistical analysis was performed with t tests, simple and multivariable logistic regression analysis to evaluate the strength of these specific femoral notch morphometric values as predictive factors to ACL rupture. RESULTS: Stenotic femoral notch Type A was identified as a high risk factor to ACL injury (odds ratio [OR] = 2.8; p = 0.03). There was no significant difference between the two groups for the notch width index (OR = 0.7; p = n.s.) and the 'α angle' (OR 1.02; p = n.s.). Significant association between NWI and stenotic notch was found (p < 0.01). CONCLUSIONS: This study showed that Type A stenotic femoral notch can be considered as a valuable predictive factor for ACL injury. Notch width index and 'α angle' are weak indicators in ACL injury prognosis. Ligament impingement may be inferred as an important mechanism in female ACL rupture. Injury prevention strategies, such as prehabilitation programmes, could be introduced in the benefit of young females with stenotic notch. LEVEL OF EVIDENCE: III.
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Lesões do Ligamento Cruzado Anterior/etiologia , Constrição Patológica/diagnóstico por imagem , Fêmur/diagnóstico por imagem , Adulto , Lesões do Ligamento Cruzado Anterior/diagnóstico por imagem , Lesões do Ligamento Cruzado Anterior/cirurgia , Estudos de Casos e Controles , Constrição Patológica/complicações , Feminino , Fêmur/anatomia & histologia , Humanos , Imageamento por Ressonância Magnética/métodos , Estudos Retrospectivos , Fatores de Risco , Adulto JovemRESUMO
TNF-related apoptosis-inducing ligand (TRAIL) was initially described to induce apoptosis of tumor cells and/or virally infected cells, although sparing normal cells, and has been implicated in the pathogenesis of HIV disease. We previously identified TRAILshort, a TRAIL splice variant, in HIV-infected patients and characterized it as being a dominant negative ligand to subvert TRAIL-mediated killing. Herein, using single-cell genomics we demonstrate that TRAILshort is produced by HIV-infected cells, as well as by uninfected bystander cells, and that the dominant stimulus which induces TRAILshort production are type I IFNs and TLR7, TLR8, and TLR9 agonists. TRAILshort has a short t1/2 by virtue of containing a PEST domain, which targets the protein toward the ubiquitin proteasome pathway for degradation. Further we show that TRAILshort binds preferentially to TRAIL receptors 1 and 2 with significantly reduced interaction with the decoy TRAIL receptors 3 and 4. Recombinant TRAILshort is sufficient to protect cells against TRAIL-induced killing, whereas immunodepletion of TRAILshort with a specific Ab restores TRAIL sensitivity. Importantly we show that TRAILshort is shed in microvesicles into the cellular microenvironment and therefore confers TRAIL resistance not only on the cell which produces it, but also upon neighboring bystander cells. These results establish a novel paradigm for understanding and overcoming TRAIL resistance, in particular how HIV-infected cells escape immune elimination by the TRAIL:TRAILshort receptor axis.
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Linfócitos T CD4-Positivos/imunologia , Microambiente Celular/imunologia , Infecções por HIV/imunologia , Isoformas de Proteínas/genética , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/genética , Processamento Alternativo/genética , Apoptose , Efeito Espectador/imunologia , Linfócitos T CD4-Positivos/virologia , Linhagem Celular Tumoral , Membrana Celular/imunologia , Células HEK293 , Infecções por HIV/patologia , Infecções por HIV/virologia , Células HeLa , Humanos , Células Jurkat , Isoformas de Proteínas/biossíntese , Ligante Indutor de Apoptose Relacionado a TNF/biossínteseRESUMO
In this study, a multicenter evaluation of the Life Technologies TaqMan(®) Array Card (TAC) with 21 custom viral and bacterial respiratory assays was performed on the Applied Biosystems ViiA™ 7 Real-Time PCR System. The goal of the study was to demonstrate the analytical performance of this platform when compared to identical individual pathogen specific laboratory developed tests (LDTs) designed at the Centers for Disease Control and Prevention (CDC), equivalent LDTs provided by state public health laboratories, or to three different commercial multi-respiratory panels. CDC and Association of Public Health Laboratories (APHL) LDTs had similar analytical sensitivities for viral pathogens, while several of the bacterial pathogen APHL LDTs demonstrated sensitivities one log higher than the corresponding CDC LDT. When compared to CDC LDTs, TAC assays were generally one to two logs less sensitive depending on the site performing the analysis. Finally, TAC assays were generally more sensitive than their counterparts in three different commercial multi-respiratory panels. TAC technology allows users to spot customized assays and design TAC layout, simplify assay setup, conserve specimen, dramatically reduce contamination potential, and as demonstrated in this study, analyze multiple samples in parallel with good reproducibility between instruments and operators.
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Análise de Sequência com Séries de Oligonucleotídeos/normas , Reação em Cadeia da Polimerase em Tempo Real/métodos , Reação em Cadeia da Polimerase em Tempo Real/normas , Bactérias/genética , Bactérias/isolamento & purificação , Centers for Disease Control and Prevention, U.S. , Humanos , Microfluídica/métodos , Microfluídica/normas , Reação em Cadeia da Polimerase em Tempo Real/instrumentação , Reprodutibilidade dos Testes , Infecções Respiratórias/diagnóstico , Infecções Respiratórias/microbiologia , Infecções Respiratórias/virologia , Sensibilidade e Especificidade , Estados Unidos , Vírus/genética , Vírus/isolamento & purificaçãoRESUMO
A system for actively changing the stiffness of a long, thin, flexible robotic manipulator has been designed for cardiologists to use in a range of diagnosis and treatment procedures. Low-stiffness manipulators, such as catheters, are ideal for steering through vasculature with low risk of tissue injury. However, such instruments are not well-suited for applying force to tissue. The proposed system solves this problem by using a series of bead-shaped vertebrae containing pull wires to actively change the stiffness of the catheter, similar to gooseneck surgical retractors. Individual wires steer the catheter to a desired location. All wires are then tensioned to create friction between each vertebra and prevent sliding, therefore resisting motion. While this design concept has been implemented manually in various settings for decades, fine robotic control of the friction and stiffness of the system relies on a thorough understanding of the friction properties between vertebral segments. We have developed an analytical model to understand the interactions between vertebrae and determine the relationships between system parameters and the overall stiffness of the catheter. Experiments validated the calculations from the model and the functionality of the system by applying known loads to the tip of the catheter and measuring the catheter displacement. The catheter stiffness was measured to range from 100 N/m to 800 N/m, which is sufficient for performing many surgical tasks on tissue. This system can be useful in minimally invasive procedures involving direct instrument contact with tissue by improving accuracy, safety, and work flow.
RESUMO
Although predicting which influenza virus subtype will cause the next pandemic is not yet possible, public health authorities must continually assess the pandemic risk associated with animal influenza viruses, particularly those that have caused infections in humans, and determine what resources should be dedicated to mitigating that risk. To accomplish this goal, a risk assessment framework was created in collaboration with an international group of influenza experts. Compared with the previously used approach, this framework, named the Influenza Risk Assessment Tool, provides a systematic and transparent approach for assessing and comparing threats posed primarily by avian and swine influenza viruses. This tool will be useful to the international influenza community and will remain flexible and responsive to changing information.
Assuntos
Influenza Humana/epidemiologia , Pandemias/estatística & dados numéricos , Saúde Pública/métodos , Medição de Risco/métodos , Humanos , Influenza Humana/imunologia , Influenza Humana/mortalidade , Saúde Pública/instrumentaçãoRESUMO
The social determinants of health represent the societal and economic influences responsible for most health inequities. Advocacy to eliminate health inequities for homeless children oftentimes involves the use of community-based approaches. This article details the Floating Hospital's (TFH) community-based participatory research (CBPR) project that resulted in an advocacy brief. Within the project, the community practice concepts of a strengths perspective, empowerment, capacity building, and advocacy are embedded. The brief enhances TFH's capacity to advocate for the needs of homeless children. This example serves as a guide for social work and public health professionals to use CBPR to address health inequities within their communities.