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BACKGROUND AND AIM OF THE STUDY: A major drawback of the transcatheter aortic valve replacement (TAVR) procedure using the self-expandable Medtronic CoreValve (MCV) prosthesis is the high incidence of conduction disturbances and the need for postprocedural permanent pacemaker (PPM) implantation. The depth of prosthesis implantation may be an important contributing factor. The study aim was to determine the relationship between angiographic measurements of the MCV prosthesis depth and the occurrence of new conduction disturbances and need for PPM after TAVR. METHODS: A retrospective analysis was conducted of 157 consecutive patients who had undergone TAVR procedures with the MCV between 2009 and 2013. Patients with pre-existing pacemakers (n = 27) were excluded. Prosthesis depth was defined as the angiographic distance from the lowest part of the prosthesis to the base of the non-coronary cusp (NCcD) and the base of the left coronary cusp (LCcD). RESULTS: A 26 mm MCV was implanted in 50% of patients, and a 29 mm MCV in 38%. The rate of new ≥2nd degree atrioventricular block (AVB) after TAVR was 5%, and the incidence of new left ventricular bundle branch block (LBBB) was 23%. PPMs were implanted in 13 patients (10%) within 30 days after the procedure. Freedom from new ≥2nd degree AVB, LBBB and the need for PPM after TAVR was significantly higher among patients with NCcD <6 mm or LCcD <8 mm (90% and 89%, respectively) compared to patients with NCcD ≥6 mm or LCcD ≥8 mm (53% and 54%, respectively) (p <0.0001). CONCLUSIONS: Prosthesis depth, measured relative to either the NCcD or LCcD, strongly predicted the occurrence of conduction disturbances and the need for PPM following TAVR with the MCV prosthesis.
Assuntos
Valva Aórtica/diagnóstico por imagem , Valva Aórtica/cirurgia , Próteses Valvulares Cardíacas/efeitos adversos , Complicações Pós-Operatórias/diagnóstico por imagem , Substituição da Valva Aórtica Transcateter/instrumentação , Idoso de 80 Anos ou mais , Angiografia , Estenose da Valva Aórtica/diagnóstico por imagem , Estenose da Valva Aórtica/cirurgia , Bloqueio Atrioventricular/etiologia , Bloqueio Atrioventricular/terapia , Bloqueio de Ramo/etiologia , Bloqueio de Ramo/terapia , Estimulação Cardíaca Artificial , Ecocardiografia , Eletrocardiografia , Feminino , Humanos , Masculino , Complicações Pós-Operatórias/cirurgia , Estudos Retrospectivos , Substituição da Valva Aórtica Transcateter/efeitos adversosRESUMO
PURPOSE OF REVIEW: To review the literature and create a concise evaluation and comment on the ways to provide financially efficient cataract surgery in a healthcare environment that produces significant challenges to providing care, while maintaining quality outcomes, safety, patient satisfaction, and employee satisfaction. RECENT FINDINGS: The recent reductions in reimbursement for cataract surgery have fueled an increased need to drive innovation in ways to be more financially efficient. At the same time, new technology in the field, especially as it relates to use of the femtosecond laser for portions of lens surgery, has increased the challenges in creating an efficient and cost-effective structure for providing care. SUMMARY: Cataract surgery is one of the most beneficial procedures for a patient's quality of life, and is one of the most common surgical procedures performed. At the same time, the current cost-effectiveness is quite high, and yet there are still ways to become more financially efficient in many centers providing cataract care.
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Extração de Catarata/economia , Catarata/economia , Eficiência Organizacional/economia , Reembolso de Seguro de Saúde/economia , Procedimentos Cirúrgicos Ambulatórios , Análise Custo-Benefício , Atenção à Saúde/economia , HumanosRESUMO
Muscle and its connective tissue are intimately linked in the embryo and in the adult, suggesting that interactions between these tissues are crucial for their development. However, the study of muscle connective tissue has been hindered by the lack of molecular markers and genetic reagents to label connective tissue fibroblasts. Here, we show that the transcription factor Tcf4 (transcription factor 7-like 2; Tcf7l2) is strongly expressed in connective tissue fibroblasts and that Tcf4(GFPCre) mice allow genetic manipulation of these fibroblasts. Using this new reagent, we find that connective tissue fibroblasts critically regulate two aspects of myogenesis: muscle fiber type development and maturation. Fibroblasts promote (via Tcf4-dependent signals) slow myogenesis by stimulating the expression of slow myosin heavy chain. Also, fibroblasts promote the switch from fetal to adult muscle by repressing (via Tcf4-dependent signals) the expression of developmental embryonic myosin and promoting (via a Tcf4-independent mechanism) the formation of large multinucleate myofibers. In addition, our analysis of Tcf4 function unexpectedly reveals a novel mechanism of intrinsic regulation of muscle fiber type development. Unlike other intrinsic regulators of fiber type, low levels of Tcf4 in myogenic cells promote both slow and fast myogenesis, thereby promoting overall maturation of muscle fiber type. Thus, we have identified novel extrinsic and intrinsic mechanisms regulating myogenesis. Most significantly, our data demonstrate for the first time that connective tissue is important not only for adult muscle structure and function, but is a vital component of the niche within which muscle progenitors reside and is a critical regulator of myogenesis.
Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/fisiologia , Tecido Conjuntivo/fisiologia , Desenvolvimento Muscular/fisiologia , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/deficiência , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Feminino , Fibroblastos/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Fluorescência Verde/metabolismo , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Desenvolvimento Muscular/genética , Fibras Musculares de Contração Rápida/metabolismo , Fibras Musculares de Contração Lenta/metabolismo , Músculo Esquelético/embriologia , Músculo Esquelético/crescimento & desenvolvimento , Músculo Esquelético/metabolismo , Gravidez , Transdução de Sinais , Fator de Transcrição 4 , beta Catenina/metabolismoRESUMO
The extraordinary phenotypic diversity of dog breeds has been sculpted by a unique population history accompanied by selection for novel and desirable traits. Here we perform a comprehensive analysis using multiple test statistics to identify regions under selection in 509 dogs from 46 diverse breeds using a newly developed high-density genotyping array consisting of >170,000 evenly spaced SNPs. We first identify 44 genomic regions exhibiting extreme differentiation across multiple breeds. Genetic variation in these regions correlates with variation in several phenotypic traits that vary between breeds, and we identify novel associations with both morphological and behavioral traits. We next scan the genome for signatures of selective sweeps in single breeds, characterized by long regions of reduced heterozygosity and fixation of extended haplotypes. These scans identify hundreds of regions, including 22 blocks of homozygosity longer than one megabase in certain breeds. Candidate selection loci are strongly enriched for developmental genes. We chose one highly differentiated region, associated with body size and ear morphology, and characterized it using high-throughput sequencing to provide a list of variants that may directly affect these traits. This study provides a catalogue of genomic regions showing extreme reduction in genetic variation or population differentiation in dogs, including many linked to phenotypic variation. The many blocks of reduced haplotype diversity observed across the genome in dog breeds are the result of both selection and genetic drift, but extended blocks of homozygosity on a megabase scale appear to be best explained by selection. Further elucidation of the variants under selection will help to uncover the genetic basis of complex traits and disease.
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Comportamento Animal , Cruzamento , Cães/genética , Variação Genética/genética , Seleção Genética , Animais , Tamanho Corporal/genética , Cães/anatomia & histologia , Orelha/anatomia & histologia , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Haplótipos , Heterozigoto , Homozigoto , Fenótipo , Filogenia , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Primary cutaneous signet-ring cell carcinoma (PCSRCC) is a rare but aggressive tumor. Our case highlights a 60-year-old man who presented with eyelid ptosis, for which he underwent multiple surgical procedures over a 3-year period prior to referral to our clinic. These procedures were complicated by scarring, delayed healing, and poor cosmetic outcome. In addition, the patient was noted to develop progressive enophthalmos. These concerning signs led to a CT scan and subsequent eyelid biopsy, which revealed a diagnosis of PCSRCC. Further management has involved an MRI and orbitotomy with biopsy revealing widespread extension of the carcinoma. Exenteration was performed to reduce the likelihood of metastasis. There are few documented case reports of PCSRCC of the eyelid in the literature. Of the 33 published cases of PCSRCC, 27 cases involve the eyelids and the other 6 cases involve the axilla. The unique clinical features of this case will be discussed, in particular the presentation as ptosis, an otherwise commonplace complaint in the oculoplastics clinic. The surgical course and histopathologic findings will be presented. The literature regarding PCSRCC will be reviewed including demographics, management, and prognosis. Although rare, PCSRCC follows an aggressive course with characteristically delayed diagnosis. Early identification and treatment likely offer a better prognosis. Thus, description of the clinical presentation of this rare tumor may aid in recognition and earlier treatment.
Assuntos
Blefaroptose/etiologia , Carcinoma de Células em Anel de Sinete/diagnóstico , Neoplasias Palpebrais/diagnóstico , Biomarcadores Tumorais/análise , Blefaroptose/cirurgia , Carcinoma de Células em Anel de Sinete/química , Carcinoma de Células em Anel de Sinete/complicações , Carcinoma de Células em Anel de Sinete/patologia , Carcinoma de Células em Anel de Sinete/radioterapia , Carcinoma de Células em Anel de Sinete/cirurgia , Terapia Combinada , Diagnóstico Tardio , Enoftalmia/etiologia , Estética , Enucleação Ocular , Neoplasias Palpebrais/química , Neoplasias Palpebrais/complicações , Neoplasias Palpebrais/patologia , Neoplasias Palpebrais/radioterapia , Neoplasias Palpebrais/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Radioterapia Adjuvante , Indução de RemissãoRESUMO
PURPOSE: To evaluate the ex vivo safety and efficacy of using paired peripheral incisions to achieve a triple scroll conformation that facilitates unscrolling in Descemet membrane endothelial keratoplasty (DMEK). METHODS: The safety of adding paired peripheral incisions to DMEK grafts was evaluated by assessing endothelial cell loss (ECL) and risk of tearing. ECL was measured using calcein-AM staining after incisions. The risk of tearing was evaluated by comparing incision lengths before and after simulated DMEK surgery using cadaveric eyes. Efficacy was evaluated by comparing the scrolling pattern and the width of grafts with different incision lengths (0.0 mm, 0.5 mm, and 1.0 mm). Surgical unscrolling times in simulated DMEK surgery by a novice DMEK surgeon were evaluated to determine whether incisions facilitate unscrolling in DMEK surgery. RESULTS: The mean ECL after adding incisions was 0.78% ± 0.23%. There was no significant change in incision length after simulated DMEK surgery (P = 0.6). In donor grafts aged less than or equal to 65 years, 60% (6/10) achieved a stable triple scroll with 0.5 mm incisions and 80% (8/10) achieved a stable triple scroll with 1.0 mm incisions. In donor grafts aged greater than 65 years, 0% (0/4) achieved a stable triple scroll. Mean graft width increased significantly after forming a triple scroll (5575 µm ± 1128 µm) compared with baseline (1563 µm ± 428 µm) (P < 0.001). In the hands of a novice DMEK surgeon, the mean unscrolling time was significantly shorter with incisions (2.61 min ± 1.41 min) versus without incisions (5.44 min ± 3.17 min) (P = 0.02). CONCLUSIONS: Paired peripheral incisions are safe and effective for inducing a triple scroll in DMEK grafts with donor age less than or equal to 65 years. Adding incisions may facilitate unscrolling for inexperienced DMEK surgeons.
Assuntos
Lâmina Limitante Posterior/cirurgia , Ceratoplastia Endotelial com Remoção da Lâmina Limitante Posterior/métodos , Distrofia Endotelial de Fuchs/cirurgia , Adulto , Idoso , Perda de Células Endoteliais da Córnea/diagnóstico , Perda de Células Endoteliais da Córnea/cirurgia , Feminino , Sobrevivência de Enxerto , Humanos , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia , Doadores de Tecidos , Coleta de Tecidos e Órgãos , Resultado do Tratamento , Acuidade VisualRESUMO
Bioluminescent reporter genes are sensitive in situ tools for following disease progression in preclinical models, albeit they are subject to scattering and absorption in deep tissues. We have generated a bicistronic Cre/LoxP reporter mouse line that pairs the expression of firefly luciferase with quantifiable expression of a human placental alkaline phosphatase that is secreted into the serum (SeAP). With the use of this dual-modality bioreporter with a novel, inducible Pax7-CreER line for tracking muscle satellite cells, we demonstrate the longitudinal kinetics of muscle stem cell turnover, accounting for a doubling of the signal from satellite cell and progeny every 3.93 wk in the transition from adolescence to early adulthood. We also show that this dual-modality bioreporter can be incorporated in preclinical cancer models, whereby SeAP activity is reflective of tumor burden. Thus, this dual bioreporter permits both spatial localization and accurate quantification of biological processes in vivo even when the tissue of interest is deep within the animal.
Assuntos
Células-Tronco Adultas/metabolismo , Genes Reporter , Sarcoma Experimental/genética , Sarcoma Experimental/metabolismo , Células Satélites de Músculo Esquelético/metabolismo , Fosfatase Alcalina/genética , Animais , Sequência de Bases , Primers do DNA/genética , Proteínas Ligadas por GPI , Humanos , Isoenzimas/genética , Luciferases de Vaga-Lume/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fator de Transcrição PAX7/genéticaRESUMO
BACKGROUND: Tumor initiation has been attributed to haploinsufficiency at a single locus for a large number of cancers. Patched1 (Ptc1) was one of the first such loci, and Ptc1 haploinsufficiency has been asserted to lead to medulloblastoma and rhabdomyosarcoma in mice. PROCEDURE: To study the role of Ptc1 in cerebellar tumor development and to create a preclinical therapeutic platform, we have generated a conditional Ptc1 haploinsufficiency model of medulloblastoma by inactivating Ptc1 in Pax7-expressing cells of the cerebellum. RESULTS: These mice developed exclusively medulloblastoma. We show that despite the presence of transcription of Ptc1, Ptc1 protein is nearly undetectable or absent in tumors. Our results suggest that Ptc1 loss of function is complete, but achieved at the protein level rather than by the classic genetic two-hit mechanism or a strict half-dosage genetic haploinsufficiency mechanism. Furthermore, we found that bortezomib, a 26S proteasome inhibitor, had a significant anti-tumor activity in vitro and in vivo, which was accompanied by restoration of Ptc1 protein and downregulation of the hedgehog signaling pathway. The same effect was seen for both human and mouse medulloblastoma tumor cell growth. CONCLUSIONS: These results suggest that proteasome inhibition is a potential new therapeutic approach in medulloblastoma.
Assuntos
Antineoplásicos/farmacologia , Ácidos Borônicos/farmacologia , Neoplasias Cerebelares/genética , Meduloblastoma/genética , Processamento de Proteína Pós-Traducional/fisiologia , Pirazinas/farmacologia , Receptores de Superfície Celular/efeitos dos fármacos , Animais , Bortezomib , Linhagem Celular Tumoral , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Modelos Animais de Doenças , Técnicas de Introdução de Genes , Proteínas Hedgehog/efeitos dos fármacos , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Humanos , Immunoblotting , Imunoprecipitação , Perda de Heterozigosidade/efeitos dos fármacos , Perda de Heterozigosidade/genética , Camundongos , Camundongos Knockout , Fator de Transcrição PAX7 , Receptores Patched , Receptor Patched-1 , Complexo de Endopeptidases do Proteassoma/metabolismo , Isoformas de Proteínas , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismoRESUMO
A bold new effort to disrupt every gene in the mouse genome necessitates systematic, interdisciplinary approaches to analyzing patterning defects in the mouse embryo. We present a novel, rapid, and inexpensive method for obtaining high-resolution virtual histology for phenotypic assessment of mouse embryos. Using osmium tetroxide to differentially stain tissues followed by volumetric X-ray computed tomography to image whole embryos, isometric resolutions of 27 mum or 8 mum were achieved with scan times of 2 h or 12 h, respectively, using mid-gestation E9.5-E12.5 embryos. The datasets generated by this method are immediately amenable to state-of-the-art computational methods of organ patterning analysis. This technique to assess embryo anatomy represents a significant improvement in resolution, time, and expense for the quantitative, three-dimensional analysis of developmental patterning defects attributed to genetically engineered mutations and chemically induced embryotoxicity.
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Camundongos Transgênicos/genética , Animais , Anormalidades Congênitas/diagnóstico por imagem , Anormalidades Congênitas/embriologia , Embrião de Mamíferos/citologia , Embrião de Mamíferos/diagnóstico por imagem , Desenvolvimento Embrionário , Proteína Forkhead Box O1 , Fatores de Transcrição Forkhead/genética , Testes Genéticos/métodos , Humanos , Camundongos , Camundongos Transgênicos/embriologia , Dados de Sequência Molecular , Fator de Transcrição PAX3 , Fatores de Transcrição Box Pareados/genética , Fenótipo , Tomografia Computadorizada por Raios X , Interface Usuário-ComputadorRESUMO
INTRODUCTION: Accurate prediction of embolic events in infective endocarditis could inform critical clinical decisions, such as the timing of cardiac surgical intervention. However, many embolic events occur before hospital admission and echocardiography and are thus non-modifiable. We aimed to identify time-sensitive variables that predict embolic events in infective endocarditis, focusing on those that occur after diagnosis. METHODS: Clinical, microbiological, and echocardiographic characteristics were collected from 116 patients with definite or probable left-sided infective endocarditis admitted to Sunnybrook Health Sciences Centre (Toronto, Canada) between October 2013 and July 2016; associations between these characteristics and embolic events were identified using simple logistic regression. RESULTS: The mean (SD) age was 66 (17) years; 82 patients (71%) were men. The most frequent microorganisms were Staphylococcus aureus (23%) and viridans group streptococci (21%). Seventy-nine (68%) patients had left-sided vegetations, with involvement of the aortic valve in 34 (43%) patients, mitral valve in 37 (47%) patients, and both in 8 (10%) patients. The mean (SD) vegetation size was 10 (7) mm. Forty-three unique patients (37%) had 50 embolic events, with most (34/43; 79%) having a first embolic event (38/50; 76%) before or on the day of echocardiography. There were no significant predictors of the 11 patients with an embolic event after echocardiography; significant predictors of an embolic event at any time were single valve vegetation vs. no vegetation (OR, 4.75; 95% confidence interval [CI], 1.76-12.78) and, among patients with a vegetation, mitral vs. aortic valve location (OR, 4.43; 95%CI, 1.63-12.04). CONCLUSIONS: Associations between patient and echocardiographic characteristics and embolism in patients with infective endocarditis may be time-sensitive, as few embolic events occurred after clinical and echocardiographic assessment.
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Embolia/complicações , Endocardite/complicações , Idoso , Estudos de Coortes , Ecocardiografia , Embolia/diagnóstico por imagem , Endocardite/diagnóstico por imagem , Endocardite/microbiologia , Feminino , Humanos , Masculino , Valva Mitral/diagnóstico por imagem , Fatores de TempoRESUMO
BACKGROUND: A multidisciplinary approach has been recommended for the management of patients with infective endocarditis. We evaluated the impact of multidisciplinary case conferences on morbidity, mortality, and quality of care for these patients. METHODS: We conducted a quasi-experimental study of consecutive patients admitted for infective endocarditis before (2013/10/1-2015/10/12, n = 97) and after (2015/10/13-2017/11/30, n = 80) implementation of case conferences to discuss medical and surgical management. These occurred as face-to-face discussions or electronically (for non-complex patients), and included physicians from cardiac surgery, cardiology, critical care, infectious diseases and neurology. We assessed process-of-care and clinical outcomes, with the primary outcome being complications up to 90 days after hospital discharge. RESULTS: A case conference was held for 80/80 (100%) of patients in the post-intervention group. After the intervention, more patients received inpatient cardiology assessment (81.3% [post-intervention] vs. 63.9% [pre-intervention], p = 0.01), and more patients with definite infective endocarditis underwent cardiac surgery treatment (44.6% vs. 21.7%, p = 0.007). All pre-intervention and post-intervention patients received guideline-concordant antimicrobial therapy. There was no difference in rates of complications (40.0% vs. 51.5%, p = 0.13) or mortality up to 90 days after hospital discharge (26.3% vs. 17.5%, p = 0.20). In multivariable analyses, the intervention was not associated with differences in mortality (odds ratio 1.87, 95% confidence interval 0.88-3.99) or a composite measure of complications and mortality (odds ratio 0.86, 95% confidence interval 0.46-1.58). CONCLUSION: We successfully implemented a standardized multidisciplinary case conference protocol for patients with infective endocarditis. This intervention had no detectable effect on complications or mortality.
Assuntos
Endocardite/terapia , Melhoria de Qualidade , Idoso , Estudos de Coortes , Gerenciamento Clínico , Endocardite/mortalidade , Feminino , Humanos , Masculino , Equipe de Assistência ao Paciente , Resultado do TratamentoRESUMO
Acute aortic syndrome (AAS) comprises acute aortic dissection, intramural hematoma, and penetrating ulcer of the aorta. The importance of accurate, rapid diagnosis and intervention for AAS is underscored by its clinical and epidemiologic overlap with acute coronary syndrome and by the risks of inappropriate treatment with antithrombotic agents. To explore these concerns, the recognition, management, and outcomes of AAS in the contemporary experience of a tertiary referral center were reviewed. Sixty-six consecutive patients with AAS admitted from January 2000 to December 2004 were identified, and their records reviewed. Misdiagnosis occurred in 39% (n = 26) and was associated with longer time to correct diagnosis (mean +/- SEM 51 +/- 12 vs 15 +/- 5 hours, p = 0.003). Acute coronary syndrome was the most common misdiagnosis, resulting in inappropriate treatment with acetylsalicylic acid in 26 (100%), clopidogrel in 1 (4%), heparin in 22 (85%), and fibrinolytic agents in 3 (12%). Exposure to antithrombotic agents was associated with higher rates of major bleeding (38% vs 13%) and a trend toward greater in-hospital mortality (27% vs 13%) (p = 0.02 for combined end point). Antithrombotic agent administration was also associated with increased hemorrhagic pericardial fluid (50% vs 25%), hemorrhagic pleural effusion (15% vs 3%), and hemodynamic instability (30% vs 13%) (p = 0.02 for combined end point). In conclusion, AAS is frequently confused with acute coronary syndrome, leading to delayed diagnosis and clinically significant bleeding as a consequence of inappropriate treatment with antithrombotic agents.
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Aneurisma Aórtico/diagnóstico , Aneurisma Aórtico/terapia , Dissecção Aórtica/diagnóstico , Dissecção Aórtica/terapia , Erros de Diagnóstico , Tratamento de Emergência , Doença Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Dissecção Aórtica/patologia , Aneurisma Aórtico/patologia , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Erros de Medicação , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/patologia , Infarto do Miocárdio/terapia , Ontário , Estudos Prospectivos , Encaminhamento e Consulta , Terapia Trombolítica/efeitos adversosRESUMO
BACKGROUND: Appropriate use criteria (AUC) have defined transthoracic echocardiogram (TTE) indications for which there is a clear lack of benefit as rarely appropriate (rA). OBJECTIVES: This study sought to investigate the impact of an AUC-based educational intervention on outpatient TTE ordering by cardiologists and primary care providers. METHODS: The authors conducted a prospective, investigator-blinded, multicenter, randomized controlled trial of an AUC-based educational intervention aimed at reducing rA outpatient TTEs. The study was conducted at 8 hospitals across 2 countries. The authors randomized cardiologists and primary care providers to receive either intervention or control (no intervention). The primary outcome measure was the proportion of rA TTEs. RESULTS: One hundred and ninety-six physicians were randomized, and 179 were included in the analysis. From December 2014 to April 2016, the authors assessed 14,697 TTEs for appropriateness, of which 99% were classifiable using the 2011 AUC. The mean proportion of rA TTEs was significantly lower in the intervention versus the control group (8.8% vs. 10.1%; odds ratio [OR]: 0.75; 95% confidence interval [CI]: 0.57 to 0.99; p = 0.039). In physicians who ordered, on average, at least 1 TTE per month, there was a significantly lower proportion of rA TTEs in the intervention versus the control group (8.6% vs. 11.1%; OR: 0.76; 95% CI: 0.57 to 0.99; p = 0.047). There was no difference in the TTE ordering volume between the intervention and control groups (mean 77.7 ± 89.3 vs. 85.4 ± 111.4; p = 0.83). CONCLUSIONS: An educational intervention reduced the number of rA TTEs ordered by attending physicians in a variety of ambulatory care environments. This may prove to be an effective strategy to improve the use of imaging. (A Multi-Centered Feedback and Education Intervention Designed to Reduce Inappropriate Transthoracic Echocardiograms [Echo WISELY]; NCT02038101).
Assuntos
Serviço Hospitalar de Cardiologia/estatística & dados numéricos , Doenças Cardiovasculares/diagnóstico por imagem , Ecocardiografia/normas , Fidelidade a Diretrizes , Padrões de Prática Médica , Ecocardiografia/estatística & dados numéricos , Feminino , Seguimentos , Humanos , Masculino , Estudos Prospectivos , Método Simples-CegoRESUMO
BACKGROUND: Cardiac troponin I (cTnI) has been validated as a sensitive and specific marker of myocyte damage, and is elevated in some patients with congestive heart failure. OBJECTIVE: To assess the relationship between elevated levels of cTnI and survival in stable patients with congestive heart failure. PATIENTS AND METHODS: It was assessed whether detectable serial levels of cTnI were associated with mortality in 211 patients with stable, severe heart failure at entry and one month into the Prospective Randomized Flosequinan Longevity Evaluation (PROFILE) study. Of these patients, 66 also had measurements taken at 12 months. RESULTS: Patients were New York Heart Association (NYHA) class III (n=197) or IV (n=14), with a baseline left ventricular ejection fraction of 22+/-7% (range 8% to 35%). Patients with a detectable level of cTnI at one month had an increased mortality (OR 2.608 [95% CI 1.061 to 6.409]; P=0.037). The association between mortality and detectable cTnI levels at baseline or 12 months did not reach statistical significance. Patients with a cTnI level that rose or remained elevated between baseline and one month had a higher mortality rate (50%) than those in whom the cTnI level fell (9%) between baseline and one month (P=0.025). In a multivariate model of survival that included sex, treatment, age, left ventricular ejection fraction, NYHA class and creatinine, only detectable levels of cTnI at one month were associated with survival (P=0.037). CONCLUSIONS: cTnI is released in stable, chronic heart failure and is associated with a poor prognosis, independent of other important risk factors. The risk is particularly elevated when detectable cTnI levels rise or remain elevated over time.
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Causas de Morte , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/mortalidade , Troponina I/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Estudos de Coortes , Feminino , Insuficiência Cardíaca/sangue , Testes de Função Cardíaca , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Valor Preditivo dos Testes , Prognóstico , Medição de Risco , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Análise de SobrevidaRESUMO
The myocardial contractile protein myosin light chain 1 isoform (MLC-1) is released into the circulation during myocyte necrosis and could thus be a marker of low-grade myocardial damage and of poor prognosis in patients with heart failure. Two hundred eighteen patients with stable heart failure (ejection fraction [EF] <35%) and in New York Heart Association (NYHA) class III to IV had MLC-1 measured at baseline and 1 month after being randomized to the direct vasodilator flosequinan or placebo. Patients were followed a mean of 302 +/- 142 days. The prognostic value of an increase in MLC-1 above the 98th percentile of normal controls was compared with that of conventional prognostic variables in heart failure. MLC-1 was increased in over half of patients at baseline and 1 month, and this was associated with increased age, NYHA class IV, and renal insufficiency. By Kaplan-Meier survival analysis, patients with a baseline increase in MLC-1 had a greater mortality (26%) than those without an increase (15%) (p = 0.043). A significant interaction among MLC-1, survival, and treatment was found (p = 0.043). In the placebo group, MLC-1 was associated with increased mortality (29% vs 12%, p = 0.025), whereas there was no significant difference among patients receiving flosequinan. In a multivariate logistic regression model including age, treatment, and left ventricular (LV) ejection fraction, the MLC-1 chain was most predictive of mortality (p = 0.049). Thus, circulating MLC-1 is elevated in over half of patients with stable severe heart failure, and this increase is associated with a poor prognosis. Flosequinan treatment eliminates this association, highlighting the complexity of the relation between cardiac myocyte damage, drug treatment, and mortality.
Assuntos
Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/tratamento farmacológico , Cadeias Leves de Miosina/sangue , Cadeias Leves de Miosina/efeitos dos fármacos , Quinolinas/uso terapêutico , Vasodilatadores/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Método Duplo-Cego , Feminino , Seguimentos , Insuficiência Cardíaca/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , América do Norte , Valor Preditivo dos Testes , Estudos Prospectivos , Países Escandinavos e Nórdicos , Índice de Gravidade de Doença , Volume Sistólico/efeitos dos fármacos , Volume Sistólico/fisiologia , Análise de Sobrevida , Resultado do TratamentoRESUMO
PURPOSE: To assess the effects of Rho-associated kinase (ROCK) inhibition on the intraocular penetration of timolol maleate. METHODS: Ex vivo porcine corneal penetration of timolol maleate, sotalol hydrochloride, or brinzolamide incubated with or without Y-27632 was determined in vertical Franz diffusion cells. The effect of ROCK inhibition on the vasodilation of porcine conjunctival vasculature was assessed by scanning electron microscopy (SEM) and immunohistochemical staining with subsequent laser-scanning confocal microscopy (LSCM). Experiments were conducted in New Zealand White (NZW) rabbits to assess the effect of ROCK inhibition on the intraocular distribution of timolol maleate. RESULTS: ROCK inhibition resulted in minimal alteration of ex vivo porcine corneal drug penetration of timolol, sotalol, or brinzolamide. SEM and LSCM experiments conducted with conjunctiva and sclera tissue in Franz diffusion cells suggested vasodilation in the conjunctival vasculature in the presence of Y-27632. Pretreatment of the eyes of NZW rabbits with Y-27632 resulted in aggregate fold reductions (1 hour, 0.25-fold; 4 hours, 0.45-fold) of timolol maleate drug concentrations in intraocular tissues (aqueous humor, lens, and iris) versus eyes not receiving Y-27632 pretreatment. Pretreatment with a vasoconstrictor, phenylephrine, resulted in a reversal of the effect of Y-27632 on diminished timolol maleate intraocular penetration in NZW rabbits. CONCLUSIONS: ROCK inhibition reduced the intraocular penetration of administered timolol maleate presumably due to increased systemic elimination through the conjunctival vasculature. It is anticipated that care in order and timing of ROCK inhibitor administration will be warranted for those patients who may be on a multiple topical drug regimen for primary open-angle glaucoma.
Assuntos
Antagonistas Adrenérgicos beta/farmacocinética , Córnea/metabolismo , Timolol/farmacocinética , Quinases Associadas a rho/antagonistas & inibidores , Amidas/farmacologia , Animais , Humor Aquoso/metabolismo , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Túnica Conjuntiva/irrigação sanguínea , Cultura em Câmaras de Difusão , Inibidores Enzimáticos/farmacologia , Iris/metabolismo , Cristalino/metabolismo , Masculino , Microscopia Confocal , Microscopia Eletrônica de Varredura , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Piridinas/farmacologia , Coelhos , Sotalol/farmacocinética , Sulfonamidas/farmacocinética , Suínos , Espectrometria de Massas em Tandem , Tiazinas/farmacocinética , Distribuição TecidualRESUMO
BACKGROUND: The dissection of complex traits of economic importance to the pig industry requires the availability of a significant number of genetic markers, such as single nucleotide polymorphisms (SNPs). This study was conducted to discover several hundreds of thousands of porcine SNPs using next generation sequencing technologies and use these SNPs, as well as others from different public sources, to design a high-density SNP genotyping assay. METHODOLOGY/PRINCIPAL FINDINGS: A total of 19 reduced representation libraries derived from four swine breeds (Duroc, Landrace, Large White, Pietrain) and a Wild Boar population and three restriction enzymes (AluI, HaeIII and MspI) were sequenced using Illumina's Genome Analyzer (GA). The SNP discovery effort resulted in the de novo identification of over 372K SNPs. More than 549K SNPs were used to design the Illumina Porcine 60K+SNP iSelect Beadchip, now commercially available as the PorcineSNP60. A total of 64,232 SNPs were included on the Beadchip. Results from genotyping the 158 individuals used for sequencing showed a high overall SNP call rate (97.5%). Of the 62,621 loci that could be reliably scored, 58,994 were polymorphic yielding a SNP conversion success rate of 94%. The average minor allele frequency (MAF) for all scorable SNPs was 0.274. CONCLUSIONS/SIGNIFICANCE: Overall, the results of this study indicate the utility of using next generation sequencing technologies to identify large numbers of reliable SNPs. In addition, the validation of the PorcineSNP60 Beadchip demonstrated that the assay is an excellent tool that will likely be used in a variety of future studies in pigs.
Assuntos
Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA/métodos , Suínos/genética , Animais , Genótipo , Especificidade da EspécieRESUMO
Forward and reverse genetics now allow researchers to understand embryonic and postnatal gene function in a broad range of species. Although some genetic mutations cause obvious morphological change, other mutations can be more subtle and, without adequate observation and quantification, might be overlooked. For the increasing number of genetic model organisms examined by the growing field of phenomics, standardized but sensitive methods for quantitative analysis need to be incorporated into routine practice to effectively acquire and analyze ever-increasing quantities of phenotypic data. In this study, we present platform-independent parameters for the use of microscopic x-ray computed tomography (microCT) for phenotyping species-specific skeletal morphology of a variety of different genetic model organisms. We show that microCT is suitable for phenotypic characterization for prenatal and postnatal specimens across multiple species.