RESUMO
BACKGROUND: Cardiac valve disease is observed in 2.5% of the general population and 10% of the elderly people. Effective pharmacological treatments are currently not available, and patients with severe cardiac valve disease require surgery. PROX1 (prospero-related homeobox transcription factor 1) and FOXC2 (Forkhead box C2 transcription factor) are transcription factors that are required for the development of lymphatic and venous valves. We found that PROX1 and FOXC2 are expressed in a subset of valvular endothelial cells (VECs) that are located on the downstream (fibrosa) side of cardiac valves. Whether PROX1 and FOXC2 regulate cardiac valve development and disease is not known. METHODS: We used histology, electron microscopy, and echocardiography to investigate the structure and functioning of heart valves from Prox1ΔVEC mice in which Prox1 was conditionally deleted from VECs. Isolated valve endothelial cells and valve interstitial cells were used to identify the molecular mechanisms in vitro, which were tested in vivo by RNAScope, additional mouse models, and pharmacological approaches. The significance of our findings was tested by evaluation of human samples of mitral valve prolapse and aortic valve insufficiency. RESULTS: Histological analysis revealed that the aortic and mitral valves of Prox1ΔVEC mice become progressively thick and myxomatous. Echocardiography revealed that the aortic valves of Prox1ΔVEC mice are stenotic. FOXC2 was downregulated and PDGF-B (platelet-derived growth factor-B) was upregulated in the VECs of Prox1ΔVEC mice. Conditional knockdown of FOXC2 and conditional overexpression of PDGF-B in VECs recapitulated the phenotype of Prox1ΔVEC mice. PDGF-B was also increased in mice lacking FOXC2 and in human mitral valve prolapse and insufficient aortic valve samples. Pharmacological inhibition of PDGF-B signaling with imatinib partially ameliorated the valve defects of Prox1ΔVEC mice. CONCLUSIONS: PROX1 antagonizes PDGF-B signaling partially via FOXC2 to maintain the extracellular matrix composition and prevent myxomatous degeneration of cardiac valves.
Assuntos
Doenças das Valvas Cardíacas , Prolapso da Valva Mitral , Animais , Humanos , Camundongos , Células Endoteliais/metabolismo , Doenças das Valvas Cardíacas/genética , Doenças das Valvas Cardíacas/prevenção & controle , Doenças das Valvas Cardíacas/metabolismo , Valva Mitral/metabolismo , Prolapso da Valva Mitral/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Proto-Oncogênicas c-sis/metabolismoRESUMO
BACKGROUND: Specialized valve endothelial cell (VEC) populations are localized oriented to blood flow in developing aortic and mitral valves, but their roles in valve development and disease are unknown. In the aortic valve (AoV), a population of VECs on the fibrosa side expresses the transcription factor Prox1 together with genes found in lymphatic ECs. In this study, we examine Prox1's role in regulating a lymphatic-like gene network and promoting VEC diversity required for the development of the stratified trilaminar extracellular matrix (ECM) of murine AoV leaflets. METHODS: To determine whether disruption of Prox1 localization affects heart valve development, we generated mice (NFATc1enCre Prox1 gain-of-function) in which Prox1 is overexpressed on the ventricularis side of the AoV beginning in embryonic development. To identify potential targets of Prox1, we performed cleavage under targets and release using nuclease on wild-type and NFATc1enCre Prox1 gain-of-function AoVs with validation by colocalization in vivo using RNA in situ hybridization in NFATc1enCre Prox1 gain-of-function AoVs. Natural induction of Prox1 and target gene expression was evaluated in myxomatous AoVs in a mouse model of Marfan syndrome (Fbn1C1039G/+). RESULTS: The overexpression of Prox1 is sufficient to cause enlargement of AoVs by postnatal day (P)0, as well as a decrease in ventricularis-specific gene expression and disorganized interstitial ECM layers at P7. We identified potential targets of Prox1 known to play roles in lymphatic ECs including Flt1, Efnb2, Egfl7, and Cx37. Ectopic Prox1 colocalized with induced Flt1, Efnb2, and Cx37 expression in NFATc1enCre Prox1 gain-of-function AoVs. Moreover, in Marfan syndrome myxomatous AoVs, endogenous Prox1, and its identified targets, were ectopically induced in ventricularis side VECs. CONCLUSIONS: Our results support a role for Prox1 in localized lymphatic-like gene expression on the fibrosa side of the AoV. Furthermore, localized VEC specialization is required for development of the stratified trilaminar ECM critical for AoV function and is dysregulated in congenitally malformed valves.
Assuntos
Valva Aórtica , Síndrome de Marfan , Camundongos , Animais , Valva Aórtica/metabolismo , Síndrome de Marfan/metabolismo , Matriz Extracelular/metabolismo , Fatores de Transcrição/metabolismo , Células Endoteliais/metabolismoRESUMO
The valves of the heart are crucial for ensuring that blood flows in one direction from the heart, through the lungs and back to the rest of the body. Heart valve development is regulated by complex interactions between different cardiac cell types and is subject to blood flow-driven forces. Recent work has begun to elucidate the important roles of developmental pathways, valve cell heterogeneity and hemodynamics in determining the structure and function of developing valves. Furthermore, this work has revealed that many key genetic pathways involved in cardiac valve development are also implicated in diseased valves. Here, we review recent discoveries that have furthered our understanding of the molecular, cellular and mechanosensitive mechanisms of valve development, and highlight new insights into congenital and acquired valve disease.
Assuntos
Doenças das Valvas Cardíacas/embriologia , Doenças das Valvas Cardíacas/patologia , Valvas Cardíacas/embriologia , Valvas Cardíacas/patologia , Animais , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Doenças das Valvas Cardíacas/metabolismo , Valvas Cardíacas/metabolismo , Hemodinâmica/fisiologia , HumanosRESUMO
Heart valve cells mediate extracellular matrix (ECM) remodeling during postnatal valve leaflet stratification, but phenotypic and transcriptional diversity of valve cells in development is largely unknown. Single cell analysis of mouse heart valve cells was used to evaluate cell heterogeneity during postnatal ECM remodeling and leaflet morphogenesis. The transcriptomic analysis of single cells from postnatal day (P)7 and P30 murine aortic (AoV) and mitral (MV) heart valves uncovered distinct subsets of melanocytes, immune and endothelial cells present at P7 and P30. By contrast, interstitial cell populations are different from P7 to P30. P7 valve leaflets exhibit two distinct collagen- and glycosaminoglycan-expressing interstitial cell clusters, and prevalent ECM gene expression. At P30, four interstitial cell clusters are apparent with leaflet specificity and differential expression of complement factors, ECM proteins and osteogenic genes. This initial transcriptomic analysis of postnatal heart valves at single cell resolution demonstrates that subpopulations of endothelial and immune cells are relatively constant throughout postnatal development, but interstitial cell subpopulations undergo changes in gene expression and cellular functions in primordial and mature valves.
Assuntos
Valva Aórtica/crescimento & desenvolvimento , Matriz Extracelular/química , Valva Mitral/crescimento & desenvolvimento , Animais , Valva Aórtica/fisiologia , Diferenciação Celular , Linhagem da Célula , Análise por Conglomerados , Colágeno/química , Células Endoteliais/citologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Marcadores Genéticos , Glicosaminoglicanos/química , Homeostase , Humanos , Imuno-Histoquímica , Masculino , Melanócitos/citologia , Camundongos , Valva Mitral/fisiologia , Fenótipo , Análise de Sequência de RNA , Análise de Célula Única/métodos , Suínos , Engenharia Tecidual/métodos , TranscriptomaAssuntos
Organogênese , Peixe-Zebra , Animais , Diferenciação Celular , Valvas Cardíacas , Fatores de TranscriçãoRESUMO
AIM: We assessed the management and outcomes of non-ST segment elevation myocardial infarction (NSTEMI) patients randomly assigned to fractional flow reserve (FFR)-guided management or angiography-guided standard care. METHODS AND RESULTS: We conducted a prospective, multicentre, parallel group, 1 : 1 randomized, controlled trial in 350 NSTEMI patients with ≥1 coronary stenosis ≥30% of the lumen diameter assessed visually (threshold for FFR measurement) (NCT01764334). Enrolment took place in six UK hospitals from October 2011 to May 2013. Fractional flow reserve was disclosed to the operator in the FFR-guided group (n = 176). Fractional flow reserve was measured but not disclosed in the angiography-guided group (n = 174). Fractional flow reserve ≤0.80 was an indication for revascularization by percutaneous coronary intervention (PCI) or coronary artery bypass surgery (CABG). The median (IQR) time from the index episode of myocardial ischaemia to angiography was 3 (2, 5) days. For the primary outcome, the proportion of patients treated initially by medical therapy was higher in the FFR-guided group than in the angiography-guided group [40 (22.7%) vs. 23 (13.2%), difference 95% (95% CI: 1.4%, 17.7%), P = 0.022]. Fractional flow reserve disclosure resulted in a change in treatment between medical therapy, PCI or CABG in 38 (21.6%) patients. At 12 months, revascularization remained lower in the FFR-guided group [79.0 vs. 86.8%, difference 7.8% (-0.2%, 15.8%), P = 0.054]. There were no statistically significant differences in health outcomes and quality of life between the groups. CONCLUSION: In NSTEMI patients, angiography-guided management was associated with higher rates of coronary revascularization compared with FFR-guided management. A larger trial is necessary to assess health outcomes and cost-effectiveness.
Assuntos
Reserva Fracionada de Fluxo Miocárdico/fisiologia , Infarto do Miocárdio/terapia , Angiografia Coronária/métodos , Estenose Coronária/diagnóstico por imagem , Estenose Coronária/fisiopatologia , Estenose Coronária/terapia , Custos e Análise de Custo , Eletrocardiografia , Feminino , Recursos em Saúde/economia , Recursos em Saúde/estatística & dados numéricos , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/fisiopatologia , Revascularização Miocárdica/métodos , Estudos Prospectivos , Qualidade de Vida , Radiografia Intervencionista/métodos , Resultado do TratamentoRESUMO
BACKGROUND: In the Fractional flow reserve (FFR) versus angiography in guiding management to optimise outcomes in non-ST elevation myocardial infarction (FAMOUS) clinical trial, FFR was shown to significantly reduce coronary revascularisation, compared to visual interpretation of standard coronary angiography without FFR. We estimated the cost-effectiveness from a UK National Health Service perspective, based on the results of FAMOUS. METHODS: A mixed trial- and model-based approach using decision and statistical modelling was used. Within-trial (1-year) costs and QALYs were assembled at the individual level and then modelled on subsequent management strategy [coronary artery bypass graft (CABG), percutaneous coronary intervention (PCI) or medical therapy (MT)] and major adverse coronary events (death, MI, stroke and revascularisation). One-year resource uses included: material, hospitalisation, medical, health professional service use and events. Utilities were derived from individual EQ5D responses. Unit costs were derived from the literature. Outcomes were extended to a lifetime on the basis of MACE during the 1st year. Costs and QALYs were modelled using generalized linear models whilst MACE was modelled using logistic regression. The analysis adopted a payer perspective. Costs and outcomes were discounted at 3.5 %. RESULTS: Costs were related to the subsequent management strategy and MACE whilst QALYs were not. FFR led to a modest cost increase, albeit an imprecise increase, over both the trial [£112 (-£129 to £357)] and lifetime horizons [£133 (-£199 to £499)]. FFR led to a small, albeit imprecise, increase in QALYs over both the trial [0.02 (-0.03 to 0.06)] and lifetime horizons [0.03 (-0.21 to 0.28)]. The mean ICER was £7516/QALY and £4290/QALY over the trial and lifetime horizons, respectively. Decision remained high; FFR had 64 and 59 % probability of cost-effectiveness over trial and lifetime horizons, respectively. CONCLUSIONS: FFR was cost-effective at the mean, albeit with considerable decision uncertainty. Uncertainty can be reduced with more information on long-term health events.
RESUMO
Valve remodeling is a process involving extracellular matrix organization and elongation of valve leaflets. Here, through single-cell RNA sequencing of human fetal valves, we identified an elastin-producing valve interstitial cell (VIC) subtype (apolipoprotein E (APOE)+, elastin-VICs) spatially located underneath valve endothelial cells (VECs) sensing unidirectional flow. APOE knockdown in fetal VICs resulted in profound elastogenesis defects. In valves with pulmonary stenosis (PS), we observed elastin fragmentation and decreased expression of APOE along with other genes regulating elastogenesis. Cell-cell interaction analysis revealed that jagged 1 (JAG1) from unidirectional VECs activates elastogenesis in elastin-VICs through NOTCH2. Similar observations were made in VICs cocultured with VECs under unidirectional flow. Notably, a drastic reduction of JAG1-NOTCH2 was also observed in PS valves. Lastly, we found that APOE controls JAG1-induced NOTCH activation and elastogenesis in VICs through the extracellular signal-regulated kinase pathway. Our study suggests important roles of both APOE and NOTCH in regulating elastogenesis during human valve remodeling.
Assuntos
Apolipoproteínas E , Elastina , Células Endoteliais , Proteína Jagged-1 , Transdução de Sinais , Humanos , Proteína Jagged-1/metabolismo , Proteína Jagged-1/genética , Elastina/metabolismo , Elastina/genética , Células Endoteliais/metabolismo , Apolipoproteínas E/metabolismo , Apolipoproteínas E/genética , Receptor Notch2/metabolismo , Receptor Notch2/genética , Células Cultivadas , Valva Pulmonar/metabolismo , Técnicas de Cocultura , Comunicação Celular/fisiologia , Valvas Cardíacas/embriologia , Valvas Cardíacas/metabolismoRESUMO
Little is known about extracellular matrix (ECM) contributions to formation of the earliest cell lineages in the embryo. Here, we show that the proteoglycan versican and glycosaminoglycan hyaluronan are associated with emerging Flk1+ hematoendothelial progenitors at gastrulation. The mouse versican mutant Vcanhdf lacks yolk sac vasculature, with attenuated yolk sac hematopoiesis. CRISPR/Cas9-mediated Vcan inactivation in mouse embryonic stem cells reduced vascular endothelial and hematopoietic differentiation within embryoid bodies, which generated fewer blood colonies, and had an impaired angiogenic response to VEGF165. Hyaluronan was severely depleted in Vcanhdf embryos, with corresponding upregulation of the hyaluronan-depolymerase TMEM2. Conversely, hyaluronan-deficient mouse embryos also had vasculogenic suppression but with increased versican proteolysis. VEGF165 and Indian hedgehog, crucial vasculogenic factors, utilized the versican-hyaluronan matrix, specifically versican chondroitin sulfate chains, for binding. Versican-hyaluronan ECM is thus an obligate requirement for vasculogenesis and primitive hematopoiesis, providing a vasculogenic factor-enriching microniche for Flk1+ progenitors from their origin at gastrulation.
Assuntos
Matriz Extracelular/metabolismo , Ácido Hialurônico/metabolismo , Células-Tronco Embrionárias Murinas/citologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Versicanas/genética , Animais , Sistemas CRISPR-Cas , Diferenciação Celular , Células Cultivadas , Proteínas Hedgehog/metabolismo , Hematopoese , Proteínas de Membrana/metabolismo , Camundongos , Células-Tronco Embrionárias Murinas/metabolismo , Nicho de Células-Tronco , Regulação para Cima , Versicanas/metabolismoRESUMO
A quasi-experimental study performed in a pediatric hematology-oncology unit demonstrated that whole-room ultraviolet-C disinfection was associated with a significant reduction in hospital-onset Clostridioides difficile infection (P< .01, trend and level), but not healthcare-associated viral respiratory infections (P= .06 for trend, P= .36 for level) or central line-associated bloodstream infections (P> 0.75, trend and level).
Assuntos
Clostridioides difficile , Infecção Hospitalar , Criança , Infecção Hospitalar/prevenção & controle , Desinfecção , Hospitais , Humanos , Raios UltravioletaRESUMO
Asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) carriage among hospitalized children and risk of transmission to healthcare workers (HCWs) was evaluated by point prevalence survey. We estimated 1-2% prevalence of SARS-CoV-2 among children without coronavirus disease 2019 symptoms. There was no secondary transmission among HCWs exposed to these patients.
Assuntos
Infecções Assintomáticas/epidemiologia , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/epidemiologia , Transmissão de Doença Infecciosa do Paciente para o Profissional/estatística & dados numéricos , Recursos Humanos em Hospital , Pneumonia Viral/epidemiologia , COVID-19 , Criança , Criança Hospitalizada , Pré-Escolar , Infecções por Coronavirus/transmissão , Feminino , Hospitais Pediátricos , Humanos , Lactente , Tempo de Internação , Masculino , Pandemias , Pneumonia Viral/transmissão , Prevalência , SARS-CoV-2RESUMO
The umbilical artery lumen closes rapidly at birth, preventing neonatal blood loss, whereas the umbilical vein remains patent longer. Here, analysis of umbilical cords from humans and other mammals identified differential arterial-venous proteoglycan dynamics as a determinant of these contrasting vascular responses. The umbilical artery, but not the vein, has an inner layer enriched in the hydrated proteoglycan aggrecan, external to which lie contraction-primed smooth muscle cells (SMC). At birth, SMC contraction drives inner layer buckling and centripetal displacement to occlude the arterial lumen, a mechanism revealed by biomechanical observations and confirmed by computational analyses. This vascular dimorphism arises from spatially regulated proteoglycan expression and breakdown. Mice lacking aggrecan or the metalloprotease ADAMTS1, which degrades proteoglycans, demonstrate their opposing roles in umbilical vascular dimorphism, including effects on SMC differentiation. Umbilical vessel dimorphism is conserved in mammals, suggesting that differential proteoglycan dynamics and inner layer buckling were positively selected during evolution.
Assuntos
Agrecanas/metabolismo , Miócitos de Músculo Liso , Artérias Umbilicais , Proteína ADAMTS1/metabolismo , Animais , Diferenciação Celular/fisiologia , Feminino , Humanos , Camundongos Transgênicos , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/fisiologia , Parto/fisiologia , Gravidez , Artérias Umbilicais/citologia , Artérias Umbilicais/metabolismo , Artérias Umbilicais/fisiologiaRESUMO
Although hundreds of cytosolic or transmembrane molecules form the primary cilium, few secreted molecules are known to contribute to ciliogenesis. Here, homologous secreted metalloproteases ADAMTS9 and ADAMTS20 are identified as ciliogenesis regulators that act intracellularly. Secreted and furin-processed ADAMTS9 bound heparan sulfate and was internalized by LRP1, LRP2 and clathrin-mediated endocytosis to be gathered in Rab11 vesicles with a unique periciliary localization defined by super-resolution microscopy. CRISPR-Cas9 inactivation of ADAMTS9 impaired ciliogenesis in RPE-1 cells, which was restored by catalytically active ADAMTS9 or ADAMTS20 acting in trans, but not by their proteolytically inactive mutants. Their mutagenesis in mice impaired neural and yolk sac ciliogenesis, leading to morphogenetic anomalies resulting from impaired hedgehog signaling, which is transduced by primary cilia. In addition to their cognate extracellular proteolytic activity, ADAMTS9 and ADAMTS20 thus have an additional proteolytic role intracellularly, revealing an unexpected regulatory dimension in ciliogenesis.
Assuntos
Proteínas ADAMTS/metabolismo , Proteína ADAMTS9/metabolismo , Cílios/metabolismo , Cílios/ultraestrutura , Proteínas ADAMTS/deficiência , Proteínas ADAMTS/genética , Proteína ADAMTS9/deficiência , Proteína ADAMTS9/genética , Animais , Linhagem Celular , Endocitose , Técnicas de Inativação de Genes , Humanos , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Microscopia Eletrônica de Varredura , Modelos Biológicos , Mutação , Defeitos do Tubo Neural/embriologia , Defeitos do Tubo Neural/genética , Defeitos do Tubo Neural/metabolismo , Proteólise , Transdução de Sinais , Versicanas/genética , Versicanas/metabolismo , Saco Vitelino/embriologia , Saco Vitelino/metabolismoRESUMO
BACKGROUND.: Although Clostridium difficile infections (CDIs) are increasingly diagnosed in children, many children diagnosed with CDI lack classic risk factors. Frequent use of highly sensitive tcdB polymerase chain reaction (PCR) testing in low-risk patients leads to CDI misdiagnosis and unnecessary CDI antibiotic use in children with C difficile carriage. METHODS.: For this quasi-experimental study, we developed and implemented an educational intervention (EI) to inform healthcare providers (HCPs) about tcdB PCR test limitations. We provided HCP didactic education and built an electronic notification into the tcdB PCR test order that describes scenarios in which carriage is more likely than CDI. Segmented regression analysis assessed changes in level (ie, overall rates) and trend of C difficile testing rate ([TR] number of tests performed per 1000 patient encounters) and test positivity rate ([PR] number of positive tests per 1000 patient encounters) between the pre- (August 2009-August 2013) and postintervention (February 2014-July 2015) periods. RESULTS.: Hospital-wide, absolute TR reduction was 0.71 (P[level] = .0067; P[trend] = .0042) and absolute PR reduction was 0.14 (P[level] = .22; P[trend] = .018). In the outpatient setting, absolute TR reduction was 0.30 (P[level] = .0015; P[trend] < .001) and absolute PR reduction was 0.09 (P[level] = .0069; P[trend] = .046). The incidence density of healthcare facility-associated CDI did not significantly change after the EI. The EI was associated with avoidance of 574 tests and 113 positive tests (and subsequent antibiotic courses) during the postintervention period, which saved approximately $250 000 in patient charges related to CDI testing and treatment. CONCLUSIONS.: Healthcare provider education can cost-effectively reduce the frequency of C difficile testing and CDI misdiagnosis by improving test utilization among low-risk children.
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Clostridioides difficile , Educação Médica Continuada , Enterocolite Pseudomembranosa/diagnóstico , Reação em Cadeia da Polimerase , Chicago , Criança , Erros de Diagnóstico/prevenção & controle , Educação Médica Continuada/métodos , Hospitais Pediátricos , Humanos , Procedimentos Desnecessários/estatística & dados numéricosRESUMO
BACKGROUND: Patients with recent non-ST-segment elevation myocardial infarction commonly have heterogeneous characteristics that may be challenging to assess clinically. METHODS AND RESULTS: We prospectively studied the diagnostic accuracy of 2 novel (T1, T2 mapping) and 1 established (T2-weighted short tau inversion recovery [T2W-STIR]) magnetic resonance imaging methods for imaging the ischemic area at risk and myocardial salvage in 73 patients with non-ST-segment elevation myocardial infarction (mean age 57±10 years, 78% male) at 3.0-T magnetic resonance imaging within 6.5±3.5 days of invasive management. The infarct-related territory was identified independently using a combination of angiographic, ECG, and clinical findings. The presence and extent of infarction was assessed with late gadolinium enhancement imaging (gadobutrol, 0.1 mmol/kg). The extent of acutely injured myocardium was independently assessed with native T1, T2, and T2W-STIR methods. The mean infarct size was 5.9±8.0% of left ventricular mass. The infarct zone T1 and T2 times were 1323±68 and 57±5 ms, respectively. The diagnostic accuracies of T1 and T2 mapping for identification of the infarct-related artery were similar (P=0.125), and both were superior to T2W-STIR (P<0.001). The extent of myocardial injury (percentage of left ventricular volume) estimated with T1 (15.8±10.6%) and T2 maps (16.0±11.8%) was similar (P=0.838) and moderately well correlated (r=0.82, P<0.001). Mean extent of acute injury estimated with T2W-STIR (7.8±11.6%) was lower than that estimated with T1 (P<0.001) or T2 maps (P<0.001). CONCLUSIONS: In patients with non-ST-segment elevation myocardial infarction, T1 and T2 magnetic resonance imaging mapping have higher diagnostic performance than T2W-STIR for identifying the infarct-related artery. Compared with conventional STIR, T1 and T2 maps have superior value to inform diagnosis and revascularization planning in non-ST-segment elevation myocardial infarction. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02073422.
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Doença da Artéria Coronariana/diagnóstico por imagem , Vasos Coronários/diagnóstico por imagem , Interpretação de Imagem Assistida por Computador/métodos , Imagem Cinética por Ressonância Magnética/métodos , Infarto do Miocárdio sem Supradesnível do Segmento ST/diagnóstico por imagem , Idoso , Artefatos , Meios de Contraste/administração & dosagem , Angiografia Coronária , Eletrocardiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Miocárdio/patologia , Compostos Organometálicos/administração & dosagem , Valor Preditivo dos Testes , Estudos Prospectivos , Reprodutibilidade dos TestesRESUMO
PURPOSE: To improve the stability of pectin-oligochitosan hydrogel microcapsules under physiological conditions. METHODS: Two different approaches were examined: change of the cross-linker length and treatment of the hydrogel microcapsules with 150 Mm CaCl2. Replacement of pectin with alginate was also studied. RESULTS AND CONCLUSIONS: It was observed that the molecular weight of the cross-linker oligochiotsan had no significant improvement on microcapsule stability. On the other hand, the treatment of pectin-oligochitosan microcapsules with Ca2+ increased the microcapsule stability significantly. Different types of alginate were used; however, no red-blood-cell-shaped microcapsules could be produced, which is likely due to the charge-density difference between deprotonated pectin and alginate polymers.
RESUMO
BACKGROUND: The use of fractional flow reserve (FFR) in acute coronary syndromes is controversial. The British Heart Foundation Fractional Flow Reserve Versus Angiography in Guiding Management to Optimize Outcomes in Non-ST-Elevation Myocardial Infarction (FAMOUS-NSTEMI) study (NCT01764334) has recently demonstrated the safety and feasibility of FFR measurement in patients with non-ST-segment-elevation myocardial infarction. We report the findings of the cardiac magnetic resonance (CMR) substudy to assess the diagnostic accuracy of FFR compared with 3.0-T stress CMR perfusion. METHODS AND RESULTS: One hundred six patients with non-ST-segment-elevation myocardial infarction who had been referred for early invasive management were included from 2 centers. FFR was measured in all major patent epicardial coronary arteries with a visual stenosis estimated at ≥30%, and if percutaneous coronary intervention was performed, an FFR assessment was repeated. Myocardial perfusion was assessed with stress perfusion CMR at 3 T. The mean age was 56.7±9.8 years; 82.6% were men. Mean time from FFR evaluation to CMR was 6.1±3.1 days. The mean±SD left ventricular ejection fraction was 58.2±9.1%. Mean infarct size was 5.4±7.1%, and mean troponin concentration was 5.2±9.2 µg/L. There were 34 fixed and 160 inducible perfusion defects. There was a negative correlation between the number of segments with a perfusion abnormality and FFR (r=-0.77; P<0.0001). The overall sensitivity, specificity, positive predictive value, and negative predictive value for an FFR of ≤0.8 were 91.4%, 92.2%, 76%, and 97%, respectively. Diagnostic accuracy was 92%. The positive and negative predictive values of FFR for flow-limiting coronary artery disease (FFR≤0.8) in patients with non-ST-segment-elevation myocardial infarction (n=21) who underwent perfusion CMR before invasive angiography were 92% and 93%, respectively. Receiver operating characteristic analysis indicated that the optimal cutoff value of FFR for demonstrating reversible ischemia on CMR was ≤0.805 (area under the receiver operating characteristic curve, 0.94 [0.9-0.99]; P<0.0001). CONCLUSIONS: FFR in patients with recent non-ST-segment-elevation myocardial infarction showed high concordance with myocardial perfusion in matched territories as revealed by 3.0-T stress perfusion CMR. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02073422.
Assuntos
Reserva Fracionada de Fluxo Miocárdico/fisiologia , Imageamento por Ressonância Magnética/métodos , Infarto do Miocárdio/fisiopatologia , Imagem de Perfusão do Miocárdio/métodos , Idoso , Eletrocardiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/terapia , Revascularização Miocárdica/métodos , Resultado do TratamentoRESUMO
INTRODUCTION: Interventions to reduce preventable complications such as catheter-related bloodstream infections (CRBSI) can also decrease hospital costs. However, little is known about the cost-effectiveness of simulation-based education. The aim of this study was to estimate hospital cost savings related to a reduction in CRBSI after simulation training for residents. METHODS: This was an intervention evaluation study estimating cost savings related to a simulation-based intervention in central venous catheter (CVC) insertion in the Medical Intensive Care Unit (MICU) at an urban teaching hospital. After residents completed a simulation-based mastery learning program in CVC insertion, CRBSI rates declined sharply. Case-control and regression analysis methods were used to estimate savings by comparing CRBSI rates in the year before and after the intervention. Annual savings from reduced CRBSIs were compared with the annual cost of simulation training. RESULTS: Approximately 9.95 CRBSIs were prevented among MICU patients with CVCs in the year after the intervention. Incremental costs attributed to each CRBSI were approximately $82,000 in 2008 dollars and 14 additional hospital days (including 12 MICU days). The annual cost of the simulation-based education was approximately $112,000. Net annual savings were thus greater than $700,000, a 7 to 1 rate of return on the simulation training intervention. CONCLUSIONS: A simulation-based educational intervention in CVC insertion was highly cost-effective. These results suggest that investment in simulation training can produce significant medical care cost savings.