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1.
J Biopharm Stat ; : 1-13, 2024 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-38549503

RESUMO

The generalized estimating equations method (GEE) is commonly applied to analyze data obtained from family studies. GEE is well known for its robustness on misspecification of correlation structure. However, the unbalanced distribution of family sizes and complicated genetic relatedness structure within each family may challenge GEE performance. We focused our research on binary outcomes. To evaluate the performance of GEE, we conducted a series of simulations, on data generated adopting the kinship matrix (correlation structure within each family) from the Strong Heart Family Study (SHFS). We performed a fivefold cross-validation to further evaluate the GEE predictive power on data from the SHFS. A Bayesian modeling approach, with direct integration of the kinship matrix, was also included to contrast with GEE. Our simulation studies revealed that GEE performs well on a binary outcome from families having a relatively simple kinship structure. However, data with a binary outcome generated from families with complex kinship structures, especially with a large genetic variance, can challenge the performance of GEE.

2.
Biophys J ; 122(18): 3570-3576, 2023 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-37041746

RESUMO

Cell migration is a complex phenomenon. Not only do different cells migrate in different default modes, but the same cell can also change its migration mode to adapt to different terrains. This complexity has riddled cell biologists and biophysicists for decades in that, despite the development of many powerful tools over the past 30 years, how cells move is still being actively investigated. This is because we have yet to fully understand the mystery of cell migration plasticity, particularly the reciprocal relation between force generation and migration mode transition. Herein we explore the future directions, in terms of measurement platforms and imaging-based techniques, to facilitate the undertaking of elucidating the relation between force generation machinery and migration mode transition. By briefly reviewing the evolution of the platforms and techniques developed in the past, we propose the desirable features to be added to achieve high measurement accuracy and improved temporal and spatial resolution, permitting us to unveil the mystery of cell migration plasticity.


Assuntos
Fenômenos Mecânicos , Movimento Celular
3.
Biophys J ; 122(6): 1033-1042, 2023 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-36566351

RESUMO

High-resolution x-ray data are reported for the ordered phases of long-chain di-monounsaturated C22:1 phosphocholine lipid bilayers. Similar to PC lipids that have saturated chains, diC22:1PC has a subgel phase and a gel phase, but dissimilarly, we find no ripple phase. Our quantitative focus is on the structure of the gel phase. We have recorded 17 lamellar orders, indicating a very well-ordered structure. Fitting to a model provides the phases of the orders. The Fourier construction of the electron density profile has two well-defined headgroup peaks and a very sharp and deep methyl trough. The wide-angle scattering exhibits two Bragg rods that provide the area per molecule. They have an intensity pattern quite different than that of lipids with saturated chains. Models of chain packing indicate that ground state chain configurations are tilted primarily toward next nearest neighbors with an angle that is also consistent with the modeling of the electron density profile. Wide-angle modeling also indicates broken mirror symmetry between the monolayers. Our wide-angle results and our electron density profile together leads to the hypothesis that the sn-1 and sn-2 chains have equivalent penetration depths in contrast to the gel phase structure of lipids with saturated hydrocarbon chains.


Assuntos
Bicamadas Lipídicas , Fosfatidilcolinas , Bicamadas Lipídicas/química , Difração de Raios X , Fenômenos Químicos , Fosfatidilcolinas/química
4.
AIDS Care ; 35(2): 306-315, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36200405

RESUMO

In 2014, UNAIDS outlined the 90-90-90 treatment targets. The "fourth 90" reflects the need to focus on optimising quality of life (HRQoL) in people living with HIV. Using a sample of non-heterosexual males in Melbourne, Australia, we aimed to assess HRQoL differences between HIV-positive and HIV-negative individuals, and identify factors that predict HRQoL both at baseline and after three years of follow up. Clinical information and patient-reported outcomes incorporating the Assessing Quality of Life-6D scale were collected at baseline and at three years. Sixty-two HIV-positive cases (antiretroviral therapy naïve at baseline) and 48 controls were enrolled. Results were compared between cases and controls at baseline, three-year follow-up, and between timepoints. HRQoL was significantly lower in cases compared to controls (83.5 (IQR 77.2-88.6) vs 87.3 (IQR 82.1-91.8), p = 0.022) at baseline, with increased depression and anxiety associated with reduced HRQoL in multivariate analysis. Mental health in cases improved between timepoints (75.0 (IQR 56.3-81.3) to 81.3 (IQR 62.5-81.3), p = 0.0428). No differences between the HRQoL of cases and controls were observed at three years. Increased mental health support may be required at commencement of antiretroviral therapy to enable similar levels of HRQoL between HIV-positive and HIV-negative individuals to be achieved.


Assuntos
Infecções por HIV , Qualidade de Vida , Masculino , Humanos , Qualidade de Vida/psicologia , Infecções por HIV/psicologia , Ansiedade/psicologia , Saúde Mental , Austrália/epidemiologia
5.
Pharm Stat ; 21(5): 1090-1108, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35322520

RESUMO

In this paper, we consider randomized controlled clinical trials comparing two treatments in efficacy assessment using a time to event outcome. We assume a relatively small number of candidate biomarkers available in the beginning of the trial, which may help define an efficacy subgroup which shows differential treatment effect. The efficacy subgroup is to be defined by one or two biomarkers and cut-offs that are unknown to the investigator and must be learned from the data. We propose a two-stage adaptive design with a pre-planned interim analysis and a final analysis. At the interim, several subgroup-finding algorithms are evaluated to search for a subgroup with enhanced survival for treated versus placebo. Conditional powers computed based on the subgroup and the overall population are used to make decision at the interim to terminate the study for futility, continue the study as planned, or conduct sample size recalculation for the subgroup or the overall population. At the final analysis, combination tests together with closed testing procedures are used to determine efficacy in the subgroup or the overall population. We conducted simulation studies to compare our proposed procedures with several subgroup-identification methods in terms of a novel utility function and several other measures. This research demonstrated the benefit of incorporating data-driven subgroup selection into adaptive clinical trial designs.


Assuntos
Futilidade Médica , Projetos de Pesquisa , Biomarcadores/análise , Ensaios Clínicos como Assunto , Humanos , Tamanho da Amostra
6.
Am J Epidemiol ; 190(4): 588-599, 2021 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-32997130

RESUMO

Administrative health databases have been used to monitor trends in infective endocarditis hospitalization related to nonprescription injection drug use (IDU) using International Classification of Diseases (ICD) code algorithms. Because no ICD code for IDU exists, drug dependence and hepatitis C virus (HCV) have been used as surrogate measures for IDU, making misclassification error (ME) a threat to the accuracy of existing estimates. In a serial cross-sectional analysis, we compared the unadjusted and ME-adjusted prevalences of IDU among 70,899 unweighted endocarditis hospitalizations in the 2007-2016 National Inpatient Sample. The unadjusted prevalence of IDU was estimated with a drug algorithm, an HCV algorithm, and a combination algorithm (drug and HCV). Bayesian latent class models were used to estimate the median IDU prevalence and 95% Bayesian credible intervals and ICD algorithm sensitivity and specificity. Sex- and age group-stratified IDU prevalences were also estimated. Compared with the misclassification-adjusted prevalence, unadjusted estimates were lower using the drug algorithm and higher using the combination algorithm. The median ME-adjusted IDU prevalence increased from 9.7% (95% Bayesian credible interval (BCI): 6.3, 14.8) in 2008 to 32.5% (95% BCI: 26.5, 38.2) in 2016. Among persons aged 18-34 years, IDU prevalence was higher in females than in males. ME adjustment in ICD-based studies of injection-related endocarditis is recommended.


Assuntos
Algoritmos , Endocardite/epidemiologia , Hospitalização/estatística & dados numéricos , Pacientes Internados , Sistema de Registros , Abuso de Substâncias por Via Intravenosa/complicações , Adolescente , Adulto , Estudos Transversais , Endocardite/etiologia , Endocardite/terapia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos , Abuso de Substâncias por Via Intravenosa/epidemiologia , Estados Unidos/epidemiologia , Adulto Jovem
7.
Sensors (Basel) ; 21(24)2021 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-34960371

RESUMO

This study is motivated by the fact that there are currently no widely used applications available to quantitatively measure a power wheelchair user's mobility, which is an important indicator of quality of life. To address this issue, we propose an approach that allows power wheelchair users to use their own mobile devices, e.g., a smartphone or smartwatch, to non-intrusively collect mobility data in their daily life. However, the convenience of data collection brings substantial challenges in data analysis because the data patterns associated with wheelchair maneuvers are not as strong as other activities, e.g., walking, running, etc. In addition, the built-in sensors in different mobile devices create significant heterogeneity in terms of sensitivity, noise patterns, sampling settings, etc. To address the aforementioned challenges, we developed a novel approach composed of algorithms that work collaboratively to reduce noise, identify patterns intrinsic to wheelchair maneuvers, and finalize mobility analysis by removing spikes and dips caused by abrupt maneuver changes. We conducted a series of experiments to evaluate the proposed approach. Experimental results showed that our approach could accurately determine wheelchair maneuvers regardless of the models and placements of the mobile devices.


Assuntos
Pessoas com Deficiência , Cadeiras de Rodas , Algoritmos , Qualidade de Vida , Smartphone
8.
J Nanobiotechnology ; 14(1): 47, 2016 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-27328938

RESUMO

BACKGROUND: Human antigen R (HuR) is an RNA binding protein that is overexpressed in many human cancers, including lung cancer, and has been shown to regulate the expression of several oncoproteins. Further, HuR overexpression in cancer cells has been associated with poor-prognosis and therapy resistance. Therefore, we hypothesized that targeted inhibition of HuR in cancer cells should suppress several HuR-regulated oncoproteins resulting in an effective anticancer efficacy. To test our hypothesis, in the present study we investigated the efficacy of folate receptor-α (FRA)-targeted DOTAP:Cholesterol lipid nanoparticles carrying HuR siRNA (HuR-FNP) against human lung cancer cells. RESULTS: The therapeutic efficacy of HuR-FNP was tested in FRA overexpressing human H1299 lung cancer cell line and compared to normal lung fibroblast (CCD16) cells that had low to no FRA expression. Physico-chemical characterization studies showed HuR-FNP particle size was 303.3 nm in diameter and had a positive surface charge (+4.3 mV). Gel retardation and serum stability assays showed that the FNPs were efficiently protected siRNA from rapid degradation. FNP uptake was significantly higher in H1299 cells compared to CCD16 cells indicating a receptor-dose effect. The results of competitive inhibition studies in H1299 cells demonstrated that HuR-FNPs were efficiently internalized via FRA-mediated endocytosis. Biologic studies demonstrated HuR-FNP but not C-FNP (control siRNA) induced G1 phase cell-cycle arrest and apoptosis in H1299 cells resulting in significant growth inhibition. Further, HuR-FNP exhibited significantly higher cytotoxicity against H1299 cells than it did against CCD16 cells. The reduction in H1299 cell viability was correlated with a marked decrease in HuR mRNA and protein expression. Further, reduced expression of HuR-regulated oncoproteins (cyclin D1, cyclin E, and Bcl-2) and increased p27 tumor suppressor protein were observed in HuR-FNP-treated H1299 cells but not in C-FNP-treated cells. Finally, cell migration was significantly inhibited in HuR-FNP-treated H1299 cells compared to C-FNP. CONCLUSIONS: Our results demonstrate that HuR is a molecular target for lung cancer therapy and its suppression using HuR-FNP produced significant therapeutic efficacy in vitro.


Assuntos
Proteína Semelhante a ELAV 1/genética , Receptor 1 de Folato/metabolismo , Neoplasias Pulmonares/terapia , RNA Interferente Pequeno/uso terapêutico , Terapêutica com RNAi , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Colesterol/química , Colesterol/metabolismo , Sistemas de Liberação de Medicamentos , Receptor 1 de Folato/genética , Ácido Fólico/química , Ácido Fólico/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Pulmão/metabolismo , Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Nanopartículas/química , Nanopartículas/metabolismo , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética
9.
Toxicol Appl Pharmacol ; 287(1): 86-92, 2015 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-26048585

RESUMO

The medical applications of aptamers have recently emerged. We developed an antagonistic thioaptamer (ESTA) against E-selectin. Previously, we showed that a single injection of ESTA at a dose of 100µg inhibits breast cancer metastasis in mice through the functional blockade of E-selectin. In the present study, we evaluated the safety of different doses of intravenously administered ESTA in single-dose acute and repeat-dose subacute studies in ICR mice. Our data indicated that intravenous administration of up to 500µg ESTA did not result in hematologic abnormality in either study. Additionally, intravenous injection of ESTA did not affect the levels of plasma cytokines (IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-10, GM-CSF, IFN-γ, and TNF-α) or complement split products (C3a and C5a) in either study. However, repeated injections of ESTA slightly increased plasma ALT and AST activities, in accordance with the appearance of small necrotic areas in the liver. In conclusion, our data demonstrated that intravenous administration of ESTA does not cause overt hematologic, organs, and immunologic responses under the experimental conditions.


Assuntos
Antineoplásicos/administração & dosagem , Aptâmeros de Nucleotídeos/administração & dosagem , Selectina E/efeitos dos fármacos , Alanina Transaminase/sangue , Animais , Antineoplásicos/química , Antineoplásicos/toxicidade , Aptâmeros de Nucleotídeos/química , Aptâmeros de Nucleotídeos/toxicidade , Aspartato Aminotransferases/sangue , Biomarcadores/sangue , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Complemento C3a/metabolismo , Complemento C5a/metabolismo , Citocinas/sangue , Relação Dose-Resposta a Droga , Esquema de Medicação , Selectina E/metabolismo , Feminino , Injeções Intravenosas , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Camundongos Endogâmicos ICR , Necrose , Medição de Risco
10.
Proc Natl Acad Sci U S A ; 108(33): 13728-33, 2011 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-21795608

RESUMO

In the majority of cases, advanced prostate cancer responds initially to androgen deprivation therapy by depletion of gonadal testosterone. The response is usually transient, and metastatic tumors almost invariably eventually progress as castration-resistant prostate cancer (CRPC). The development of CRPC is dependent upon the intratumoral generation of the potent androgen, dihydrotestosterone (DHT), from adrenal precursor steroids. Progression to CRPC is accompanied by increased expression of steroid-5α-reductase isoenzyme-1 (SRD5A1) over SRD5A2, which is otherwise the dominant isoenzyme expressed in the prostate. DHT synthesis in CRPC is widely assumed to require 5α-reduction of testosterone as the obligate precursor, and the increased expression of SRD5A1 is thought to reflect its role in converting testosterone to DHT. Here, we show that the dominant route of DHT synthesis in CRPC bypasses testosterone, and instead requires 5α-reduction of androstenedione by SRD5A1 to 5α-androstanedione, which is then converted to DHT. This alternative pathway is operational and dominant in both human CRPC cell lines and fresh tissue obtained from human tumor metastases. Moreover, CRPC growth in mouse xenograft models is dependent upon this pathway, as well as expression of SRD5A1. These findings reframe the fundamental metabolic pathway that drives CRPC progression, and shed light on the development of new therapeutic strategies.


Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/metabolismo , Di-Hidrotestosterona/metabolismo , Proteínas de Membrana/metabolismo , Neoplasias da Próstata/metabolismo , Animais , Castração , Progressão da Doença , Humanos , Masculino , Redes e Vias Metabólicas , Camundongos , Testosterona , Transplante Heterólogo
11.
Neurol Clin Pract ; 13(2): e200126, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37064579

RESUMO

Background and Objectives: Patients with cervical spondylotic myelopathy (CSM) have motor impairments, including weakness, imbalance, and loss of dexterity. The reliable assessment of these symptoms is critical for treatment decisions. This study aimed to determine, for the first time, the use of the NIH Toolbox motor battery (NIHTBm) in the objective assessment of motor deficits in patients with CSM. Methods: Patients with symptoms and MRI evidence of CSM and age-matched healthy controls (HC), with no evidence of spinal disorder or surgery were included in this case-control study based on our inclusion and exclusion criteria. We performed motor tests, dexterity, gait speed, grip strength, and balance tests, using the NIHTBm in patients with CSM and HCs. Motor impairment rates were determined in patients with CSM based on the NIHTBm scores. We determined the association between NIHTBm scores and patient-reported outcome scores; patient-reported outcome measures (the modified Japanese Orthopedic Association [mJOA] and Nurick grade) to determine the association. One-way analysis of variance was used to analyze group differences and the Spearman rank correlation to determine the relationship between assessment scores. Results: We enrolled 24 patients with CSM with a mean age (SD) of 57.96 (10.61) years and 24 age-matched HCs with a mean age (SD) of 53.17 (6.04) years in this study. Overall, we observed a significant decrease in the motor function T-scores mean (SD): dexterity 31.54 (14.82) vs 51.54 (9.72), grip strength 32.00 (17.47) vs 56.79 (8.46), balance 27.58 (16.65) vs 40.21 (6.35), and gait speed 0.64 (0.18) vs 0.99 (0.17) m/s, in patients with CSM compared with that in HCs. The lower extremity dysfunction scores on the NIHTBm, balance (ρ = -0.67) and gait speed (ρ = -0.62), were associated with higher Nurick grades. We observed a similar but weaker association with the Nurick grades and NIHTBm tests: dexterity (ρ = -0.49) and grip strength (ρ = -0.31) scores. The total motor mJOA showed a positive but weak association with NIHTBm scores, gait speed (ρ = 0.38), balance (ρ = 0.49), grip strength (ρ = 0.41), and dexterity (ρ = 0.45). Discussion: Patients with CSM had significantly lower NIHTBm scores compared with HCs. The results from the NIHTBm are consistent with the clinical presentation of CSM showing patients have motor impairments in both upper and lower extremities. As a neurologic-specific scale, NIHTBm should be used in the evaluation and clinical management of patients with CSM.

12.
J Am Board Fam Med ; 35(2): 329-340, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35379720

RESUMO

CONTEXT: Coordination between oncology and primary care practices in cancer survivorship is lacking. OBJECTIVE: To identify cancer care coordination perceptions, knowledge, and practices in a sample of Oklahoma oncology care providers (ONCs) and primary care providers (PCPs) regarding post-treatment care of adult cancer survivors. DESIGN: Cross-sectional, statewide survey by mail/web link in 2014/5. SETTING: PCPs identified through a primary care research network, primary care organization membership lists; ONCs identified through www.Healthgrades.com. PARTICIPANTS: Contacts who were clinically active and seeing cancer patients were eligible. The final sample size included 101 ONCs and 58 PCPs who reported actively seeing cancer patients. MEASURES: Responses to predominately Likert scale or ranked-order questions derived from the Survey of Physician Attitudes Regarding the Care of Cancer Survivors. ANALYSES: Chi square and t tests were performed to test bivariate associations between provider type and survey measures. RESULTS: Statistically significant differences (P < .05) between ONC and PCP perceptions were observed for several questions on communication between the 2 provider types, ONC perceptions of PCP ability to address survivorship care, and responsibilities for post-treatment care. CONCLUSIONS: Highly discrepant perspectives between ONCs and PCPs regarding communications and responsibilities for survivorship care may lead to adverse health outcomes. Interventions aimed at improving care coordination for cancer survivors should define each provider group's responsibilities in survivorship care, and create structures and processes that foster clear channels of communication between ONC and PCP practices.


Assuntos
Sobreviventes de Câncer , Neoplasias , Adulto , Estudos Transversais , Humanos , Neoplasias/terapia , Atenção Primária à Saúde , Sobrevivência
13.
Am J Cardiol ; 178: 72-79, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-35773043

RESUMO

The 6-minute walk distance (6MWD) carries prognostic value in patients with heart failure with reduced ejection fraction (HFrEF). We performed this systematic review and meta-analysis to evaluate the effect of heart failure therapies on improvement in 6MWD. A systematic search of MEDLINE and Embase was conducted for randomized controlled trials measuring 6MWD at baseline and at follow-up in at least 50 patients with HFrEF across both arms. The primary outcome was improvement in 6MWD at follow-up. Meta-analysis was stratified in groups on the basis of medical therapy, device-based therapy, autonomic modulation, and exercise. Mean differences (MDs) with 95% confidence interval (CI) were reported across multiple studies that were included in the meta-analysis. A total of 44 studies met the inclusion criteria for systematic review; 17 of which were included for meta-analysis. Statistical analysis showed a statistically significant improvement in 6MWD in meters (m) at follow-up for device-based therapy (MD 20.01 m, 95% CI 18.71 to 21.31), autonomic modulation (MD 76.64 m, 95% CI 54.10 to 99.19), and exercise group (MD 39.52 m, 95% CI 19.68 to 59.35). Pooled analysis of medical therapy did not show statistically significant improvement in 6MWD at follow-up (MD 31.69 m, 95% CI -6.52 to 69.91). Device-based therapy (cardiac resynchronization therapy and cardiac contractility modulation), autonomic modulation, and exercise training programs are associated with improvement in 6MWD in patients with HFrEF. 6MWD is a useful test to gauge improvement in functional capacity among patients with HFrEF, especially those with severe symptomatic heart failure.


Assuntos
Insuficiência Cardíaca , Terapia por Exercício , Tolerância ao Exercício , Insuficiência Cardíaca/terapia , Humanos , Qualidade de Vida , Volume Sistólico
14.
Ecol Evol ; 11(20): 13875-13883, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34707824

RESUMO

Colorful displays have evolved in multiple plant and animal species as signals to mutualists, antagonists, competitors, mates, and other potential receivers. Studies of color have long relied on subjective classifications of color by human observers. However, humans have a limited ability to perceive color compared to other animals, and human biological, cultural, and environmental variables can influence color perception. Here, we test the consistency of human color classification using fruit color as a model system. We used reflectance data of 67 tropical fruits and surveyed 786 participants to assess the degree to which (a) participants of different cultural and linguistic backgrounds agree on color classification of fruits; and (b) human classification to a discrete set of commonly used colors (e.g., red, blue, green) corresponds to natural clusters based on light reflectance measures processed through visual systems of other animals. We find that individual humans tend to agree on the colors they attribute to fruits across language groups. However, these colors do not correspond to clearly discernible clusters in di- or tetrachromatic visual systems. These results indicate that subjective color categorizations tend to be consistent among observers and can be used for large synthetic studies, but also that they do not fully reflect natural categories that are relevant to animal observers.

15.
Acta Biomater ; 135: 425-440, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34481053

RESUMO

The leaflets of the atrioventricular heart valves (AHVs) regulate the one-directional flow of blood through a coordination of the extracellular matrix components, including the collagen fibers, elastin, and glycosaminoglycans. Dysfunction of the AHVs, such as those caused by unfavorable microstructural remodeling, lead to valvular heart diseases and improper blood flow, which can ultimately cause heart failure. In order to better understand the mechanics and remodeling of the AHV leaflets and how therapeutics can inadvertently cause adverse microstructural changes, a systematic characterization of the role of each constituent in the biomechanical properties is appropriate. Previous studies have quantified the contributions of the individual microstructural components to tissue-level behavior for the semilunar valve cusps, but not for the AHV leaflets. In this study, for the first time, we quantify the relationships between microstructure and mechanics of the AHV leaflet using a three-step experimental procedure: (i) biaxial tension and stress relaxation testing of control (untreated) porcine AHV anterior leaflet specimens; (ii) enzyme treatment to remove a portion of either the collagen or elastin constituent; and (iii) biaxial tensile and stress relaxation testing of the constituent-removed (treated) specimens. We have observed that the removal of ∼100% elastin resulted in a ∼10% decrease in the tissue extensibility with biaxial tension and a ∼10% increase in the overall stress reduction with stress relaxation. In contrast, removal of 46% of the collagen content insignificantly affected tissue extensibility with biaxial tension and significantly increased stress decay (10%) with stress relaxation. These findings provide an insight into the microstructure-mechanics relationship of the AHVs and will be beneficial for future developments and refinements of microstructurally informed constitutive models for the simulation of diseased and surgically intervened AHV function. STATEMENT OF SIGNIFICANCE: This study presents, for the first time, a thorough mechanical characterization of the atrioventricular heart valve leaflets before and after enzymatic removal of elastin and collagen. We found that the biaxial tensile properties of elastin-deficient tissues and collagen-deficient are stiffer. The fact of elastin supporting low-stress valve function and collagen as the main load-bearing component was evident in a decrease in the low-tension modulus for elastin-deficient tissues and in the high-tension modulus for collagen-deficient tissues. Our quantification and experimental technique could be useful in predicting the disease-related changes in heart valve mechanics. The information obtained from this work is valuable for refining the constitutive models that describe the essential microstructure-mechanics relationship.


Assuntos
Valva Aórtica , Elastina , Animais , Fenômenos Biomecânicos , Colágeno , Estresse Mecânico , Suínos , Suporte de Carga
16.
JAMA Netw Open ; 3(7): e209411, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32721028

RESUMO

Importance: Cardiovascular disease is the leading cause of death in the United States. To improve cardiovascular outcomes, primary care must have valid methods of assessing performance on cardiovascular clinical quality measures, including aspirin use (aspirin measure), blood pressure control (BP measure), and smoking cessation counseling and intervention (smoking measure). Objective: To compare observed performance scores measured using 2 imperfect reference standard data sources (medical record abstraction [MRA] and electronic health record [EHR]-generated reports) with misclassification-adjusted performance scores obtained using bayesian latent class analysis. Design, Setting, and Participants: This cross-sectional study used a subset of the 2016 aspirin, BP, and smoking performance data from the Healthy Hearts for Oklahoma Project. Each clinical quality measure was calculated for a subset of a practice's patient population who can benefit from recommended care (ie, the eligible population). A random sample of 380 eligible patients were included for the aspirin measure; 126, for the BP measure; and 115, for the smoking measure. Data were collected from 21 primary care practices belonging to a single large health care system from January 1 to December 31, 2018, and analyzed from February 21 to April 17, 2019. Main Outcomes and Measures: The main outcomes include performance scores for the aspirin, BP, and smoking measures using imperfect MRA and EHRs and estimated through bayesian latent class models. Results: A total of 621 eligible patients were included in the analysis. Based on MRA and EHR data, observed aspirin performance scores were 76.0% (95% bayesian credible interval [BCI], 71.5%-80.1%) and 74.9% (95% BCI, 70.4%-79.1%), respectively; observed BP performance scores, 80.6% (95% BCI, 73.2%-86.9%) and 75.1% (95% BCI, 67.2%-82.1%), respectively; and observed smoking performance scores, 85.7% (95% BCI, 78.6%-91.2%) and 75.4% (95% BCI, 67.0%-82.6%), respectively. Misclassification-adjusted estimates were 74.9% (95% BCI, 70.5%-79.1%) for the aspirin performance score, 75.0% (95% BCI, 66.6%-82.5%) for the BP performance score, and 83.0% (95% BCI, 74.4%-89.8%) for the smoking performance score. Conclusions and Relevance: Ensuring valid performance measurement is critical for value-based payment models and quality improvement activities in primary care. This study found that extracting information for the same individuals using different data sources generated different performance score estimates. Further research is required to identify the sources of these differences.


Assuntos
Aspirina/uso terapêutico , Determinação da Pressão Arterial/estatística & dados numéricos , Doenças Cardiovasculares , Registros Eletrônicos de Saúde/normas , Atenção Primária à Saúde/métodos , Medição de Risco , Fumar/epidemiologia , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/uso terapêutico , Melhoria de Qualidade , Indicadores de Qualidade em Assistência à Saúde , Padrões de Referência , Reprodutibilidade dos Testes , Medição de Risco/métodos , Medição de Risco/normas , Medição de Risco/estatística & dados numéricos , Estados Unidos/epidemiologia
17.
Cancers (Basel) ; 12(5)2020 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-32429557

RESUMO

Cervical cancer is caused by high-risk human papillomavirus (HPV) types and treated with conventional chemotherapy with surgery and/or radiation. HPV E6 and E7 proteins increase phosphorylation of retinoblastoma (Rb) by cyclin D1/cyclin dependent kinase (CDK)4/6 complexes. We hypothesized that cyclin D1 degradation by the SHetA2 drug in combination with palbociclib inhibition of CDK4/6 activity synergistically reduces phosphorylated Rb (phospho-Rb) and inhibits cervical cancer growth. The effects of these drugs, alone, and in combination, were evaluated in SiHa and CaSki HPV-positive and C33A HPV-negative cervical cancer cell lines using cell culture, western blots and ELISA, and in a SiHa xenograft model. Endpoints were compared by isobolograms, ANOVA, and Chi-Square. In all cell lines, combination indexes documented synergistic interaction of SHetA2 and palbociclib in association SHetA2 reduction of cyclin D1 and phospho-Rb, palbociclib reduction of phospho-Rb, and enhanced phospho-Rb reduction upon drug combination. Both drugs significantly reduced phospho-Rb and growth of SiHa xenograft tumors as single agents and acted additively when combined, with no evidence of toxicity. Dilated CD31-negative blood vessels adjacent to, or within, areas of necrosis and apoptosis were observed in all drug-treated tumors. These results justify development of the SHetA2 and palbociclib combination for targeting phospho-Rb in cervical cancer treatment.

18.
Drug Alcohol Depend ; 209: 107906, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32145659

RESUMO

BACKGROUND: International Classification of Diseases (ICD) code algorithms are routinely used to estimate the frequency of illicit injection drug use (IDU)-associated hospitalizations in administrative health datasets despite a lack of evidence regarding their validity. We aimed to measure the sensitivity and specificity of ICD code algorithms used to estimate the prevalence of current/recent IDU among infective endocarditis (IE) hospitalizations without a reference standard. METHODS: We reviewed medical records of 321 patients aged 18-64 years old from an urban academic hospital with an IE diagnosis between 2007 and 2017. Diagnostic tests for IDU included self-reported IDU in medical records; a drug use, abuse and dependence (UAD) ICD algorithm; a Hepatitis C Virus (HCV) ICD algorithm; and a combination drug UAD/HCV ICD algorithm. Sensitivity, specificity and the misclassification error (ME)-adjusted IDU prevalence were estimated using Bayesian latent class models. RESULTS: The combination algorithm had the highest sensitivity and lowest specificity. Sensitivity increased for the drug UAD algorithm in the ICD-10 period compared to the ICD-9 period. The ME-adjusted current/recent IDU prevalence estimated using the drug UAD and HCV algorithms was 23 % (95 % Bayesian credible interval: 16 %, 31 %). The unadjusted prevalence estimate from the drug UAD algorithm underestimated the ME-adjusted prevalence, while the combination algorithm overestimated it. CONCLUSION: The validity of ICD code algorithms for IDU among IE hospitalizations is imperfect and differs between ICD-9 and ICD-10. Commonly used ICD-based algorithms could lead to substantially biased prevalence estimates in IDU-associated hospitalizations when using administrative health data.


Assuntos
Algoritmos , Endocardite/epidemiologia , Hospitalização/tendências , Classificação Internacional de Doenças/normas , Abuso de Substâncias por Via Intravenosa/epidemiologia , Adolescente , Adulto , Teorema de Bayes , Estudos Transversais , Endocardite/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Padrões de Referência , Reprodutibilidade dos Testes , Estudos Retrospectivos , Abuso de Substâncias por Via Intravenosa/diagnóstico , Adulto Jovem
19.
Drug Alcohol Depend ; 208: 107825, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31982637

RESUMO

BACKGROUND: The twenty-first century opioid crisis has spurred interest in using International Classification of Diseases (ICD) code algorithms to identify patients using illicit drugs from administrative healthcare data. We conducted a systematic review of studies that validated ICD code algorithms for illicit drug use against a reference standard of medical record data. METHODS: Systematic searches of MEDLINE, EMBASE, PsycINFO, and Web of Science were conducted for studies published between 1980 and 2018 in English, French, Italian, or Spanish. We included validation studies of ICD-9 or ICD-10 code algorithms for an illicit drug use target condition (e.g., illicit drug use, abuse, or dependence (UAD), illicit drug use-related complications) given the sensitivity or specificity was reported or could be calculated. Bias was assessed with the Quality Assessment of Diagnostic Accuracy Studies Version 2 (QUADAS-2) tool. RESULTS: Six of the 1210 articles identified met the inclusion criteria. For validation studies of broad UAD (n = 4), the specificity was nearly perfect, but the sensitivity ranged from 47% to 83%, with higher sensitivities tending to occur in higher prevalence populations. For validation studies of injection drug use (IDU)-associated infective endocarditis (n = 2), sensitivity and specificity were poor due to the lack of an ICD code for IDU. For all six studies, the risk of bias for the QUADAS-2 "reference standard" and "flow/timing domains" was scored as "unclear" due to insufficient reporting. CONCLUSIONS: Few studies have validated ICD code algorithms for illicit drug use target conditions, and available evidence is challenging to interpret due to inadequate reporting. PROSPERO Registration: CRD42019118401.


Assuntos
Bases de Dados Factuais/normas , Drogas Ilícitas , Classificação Internacional de Doenças/normas , Prontuários Médicos/normas , Transtornos Relacionados ao Uso de Substâncias/diagnóstico , Algoritmos , Confiabilidade dos Dados , Humanos , Padrões de Referência , Reprodutibilidade dos Testes , Transtornos Relacionados ao Uso de Substâncias/epidemiologia
20.
J Surv Stat Methodol ; 7(2): 157-174, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31098386

RESUMO

For complex survey data, the parameters in a quantile regression can be estimated by minimizing an objective function with units weighted by the original design weights. However, when the complex survey sampling design is informative (i.e., when the design weights are correlated with the study variable even after conditioning on other covariates), the efficiency of this design-weighted estimator may be improved. In this article, we propose several weight-smoothing estimators for quantile regression analysis of complex survey data collected with an informative sampling design. Our new estimators incorporate nonparametric methods for modeling the weight functions and pseudo-population bootstrap methods for variance estimation. A simulation study compares, our proposed methods with the original design-based method in terms of bias, standard error, mean squared error, and confidence coverage. Our proposed estimators have smaller bias and mean squared error than does the design-based estimator. We further illustrate and compare estimators for the 1988 US National Maternal and Infant Health Survey.

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