Assessment of fluorinated steroids to avert progression and mortality in anti-SSA/Ro-associated cardiac injury limited to the fetal conduction system.

OBJECTIVES: Extension of disease beyond the atrioventricular (AV) node is associated with increased mortality in cardiac neonatal lupus (NL). Treatment of isolated heart block with fluorinated steroids to prevent disease progression has been considered but published data are limited and discordant regarding efficacy. This study evaluated whether fluorinated steroids given to manage isolated advanced block prevented development of disease beyond the AV node and conferred a survival benefit. METHODS: In this retrospective study of cases enrolled in the Research Registry for NL, inclusion was restricted to anti-SSA/Ro-exposed cases presenting with isolated advanced heart block in utero who either received fluorinated steroids within 1 week of detection (N=71) or no treatment (N=85). Outcomes evaluated were: development of endocardial fibroelastosis, dilated cardiomyopathy and/or hydrops fetalis; mortality and pacemaker implantation. RESULTS: In Cox proportional hazards regression analyses, fluorinated steroids did not significantly prevent development of disease beyond the AV node (adjusted HR=0.90; 95% CI 0.43 to 1.85; p=0.77), reduce mortality (HR=1.63; 95% CI 0.43 to 6.14; p=0.47) or forestall/prevent pacemaker implantation (HR=0.87; 95% CI 0.57 to 1.33; p=0.53). No risk factors for development of disease beyond the AV node were identified. CONCLUSIONS: These data do not provide evidence to support the use of fluorinated steroids to prevent disease progression or death in cases presenting with isolated heart block.

Development of a Model System to Evaluate Local Recurrence in Osteosarcoma and Assessment of the Effects of Bone Morphogenetic Protein-2.

PURPOSE: It is increasingly relevant to better define what constitutes an adequate surgical margin in an effort to improve reconstructive longevity and functional outcomes following osteosarcoma surgery. In addition, nonunion remains a challenging problem in some patients following allograft reconstruction. Bone morphogenetic protein-2 (BMP-2) could enhance osseous union, but has been historically avoided due to concerns that it may promote tumor recurrence. EXPERIMENTAL DESIGN: An orthotopic xenograft murine model was utilized to describe the natural temporal course of osteosarcoma growth. Tumors were treated either with surgery alone, surgery and single-agent chemotherapy, or surgery and dual-agent chemotherapy to assess the relationship between surgical margin and local recurrence. The effect of BMP-2 on local recurrence was similarly assessed. RESULTS: Osteosarcoma tumor growth was categorized into reproducible phases. Margins greater than 997 µm resulted in local control following surgery alone. Margins greater than 36 µm resulted in local control following surgery and single-agent chemotherapy. Margins greater than 12 µm resulted in local control following surgery and dual-agent chemotherapy. The application of exogenous BMP-2 does not confer an increased risk of local recurrence. CONCLUSIONS: This model reliably reproduces the clinical, radiographic, and surgical conditions encountered in human osteosarcoma. It successfully incorporates relevant chemotherapy, further paralleling the human experience. Surgical margins required to achieve local control in osteosarcoma can be reduced using single-agent chemotherapy and further decreased using dual-agent chemotherapy. The application of BMP-2 does not increase local recurrence in this model.

Implicit bias and its relation to health disparities: a teaching program and survey of medical students.

BACKGROUND: The varying treatment of different patients by the same physician are referred to as within provider disparities. These differences can contribute to health disparities and are thought to be the result of implicit bias due to unintentional, unconscious assumptions. PURPOSES: The purpose is to describe an educational intervention addressing both health disparities and physician implicit bias and the results of a subsequent survey exploring medical students' attitudes and beliefs toward subconscious bias and health disparities. METHODS: A single session within a larger required course was devoted to health disparities and the physician's potential to contribute to health disparities through implicit bias. Following the session the students were anonymously surveyed on their Implicit Association Test (IAT) results, their attitudes and experiences regarding the fairness of the health care system, and the potential impact of their own implicit bias. The students were categorized based on whether they disagreed ("deniers") or agreed ("accepters") with the statement "Unconscious bias might affect some of my clinical decisions or behaviors." Data analysis focused specifically on factors associated with this perspective. RESULTS: The survey response rate was at least 69%. Of the responders, 22% were "deniers" and 77% were "accepters." Demographics between the two groups were not significantly different. Deniers were significantly more likely than accepters to report IAT results with implicit preferences toward self, to believe the IAT is invalid, and to believe that doctors and the health system provide equal care to all and were less likely to report having directly observed inequitable care. CONCLUSIONS: The recognition of bias cannot be taught in a single session. Our experience supports the value of teaching medical students to recognize their own implicit biases and develop skills to overcome them in each patient encounter, and in making this instruction part of the compulsory, longitudinal undergraduate medical curriculum.

Estimation and inference on correlations between biomarkers with repeated measures and left-censoring due to minimum detection levels.

Statistical approaches for estimating and drawing inference on the correlation between two biomarkers that are repeatedly assessed over time and subject to left-censoring because minimum detection levels are lacking. We propose a linear mixed-effects model and estimate the parameters with the Monte Carlo expectation maximization (MCEM) method. Inferences regarding the model parameters and the correlation between the biomarkers are performed by applying Louis's method and the delta method. Simulation studies were conducted to compare the proposed MCEM method with existing methods including the maximum likelihood estimation method, the multiple imputation method, and two widely used ad hoc approaches: replacing the censored values with the detection limit or with half of the detection limit. The results show that the performance of the MCEM with respect to relative bias and coverage probability for the 95% confidence interval is superior to the detection limit and half of the detection limit approaches and exceeds that of the multiple imputation method at medium to high levels of censoring, and the standard error estimates from the MCEM method are close to ideal. The maximum likelihood estimation method can estimate the parameters accurately; however, a nonpositive definite information matrix can occur so that the variances are not estimable. These five methods are illustrated with data from a longitudinal human immunodeficiency virus study to estimate and draw inference on the correlation between human immunodeficiency virus RNA levels measured in plasma and in cervical secretions at multiple time points.

Cox regression analysis in presence of collinearity: an application to assessment of health risks associated with occupational radiation exposure.

This paper considers the analysis of time to event data in the presence of collinearity between covariates. In linear and logistic regression models, the ridge regression estimator has been applied as an alternative to the maximum likelihood estimator in the presence of collinearity. The advantage of the ridge regression estimator over the usual maximum likelihood estimator is that the former often has a smaller total mean square error and is thus more precise. In this paper, we generalized this approach for addressing collinearity to the Cox proportional hazards model. Simulation studies were conducted to evaluate the performance of the ridge regression estimator. Our approach was motivated by an occupational radiation study conducted at Oak Ridge National Laboratory to evaluate health risks associated with occupational radiation exposure in which the exposure tends to be correlated with possible confounders such as years of exposure and attained age. We applied the proposed methods to this study to evaluate the association of radiation exposure with all-cause mortality.

Assessment of the proliferative status of epithelial cell types in the endometrium of young and menopausal transition women.

BACKGROUND: We determined protein and mRNA expressions of markers of normal human endometrial proliferation and hypothesized that dysregulation of the endometrial response to estradiol (E(2)) and progesterone would be observed in the older menopausal transition (MT) women compared with mid-reproductive age (MRA) controls. METHODS: Endometrial biopsies were prospectively obtained from MRA and MT non-randomized healthy volunteers during proliferative (+/- exogenous E(2)) and secretory (MRA only) menstrual cycle phases. mRNA and/or nuclear protein expressions of proliferative markers (MKI67, PCNA and MCM2), cell-cycle regulators (cyclins A1, E1 and D1 and cyclin dependent kinase Inhibitor B; CCNA1, CCNE1, CCND1 and CDKN1B) and sex-steroid receptors [estrogen receptor (ER) and progesterone receptor (PR)] were assessed in endometrial lumen, gland and stroma. RESULTS: MRA women had significantly higher proliferative than secretory expression of MKI67, PCNA, MCM2, CCNA1, CCNE1, ESR1 and PGR in lumen and gland (minimal stromal changes), whereas CDKN1B protein expression was higher during the secretory phase. E(2)-treatment of MT women led to relatively less MKI67 glandular protein expression compared with MRA women; no other age-related differences were observed. CONCLUSION: Although the MT does not appear to alter the proliferative cell phenotype of endometrial epithelium and stroma, the data suggest that prior to the MT, age is associated with a decrease in some proliferative markers and steroid receptor expression status within different endometrial cell types.

Estimation of health risks associated with occupational radiation exposure: addressing measurement error and minimum detectable exposure level.

Occupational exposures are subject to several types of measurement errors. This paper considers two of the most common types of measurement error associated with occupational exposures: the error due to below minimum detection level and doses due to random measurement error. Doses are often recorded as zero when the exposure is below the minimum detection level. Values that are below the minimum detection level and are entered as zero lead to underestimation of the true exposure and can result in either an overestimate or underestimate of risk associated with the exposure. Random measurement error leads to an inefficient and attenuated estimate of risk associated with exposure. However, the levels of bias and inefficiency that can result from the simultaneous presence of both types of measurement error have not previously been studied. In addition, the impact of these measurement errors on the type I error and type II error for an exposure-response effect is unclear. Since the magnitude of the random error associated with cumulative exposure may vary with individuals and across time within an individual, traditional methods to correct for random measurement errors are not applicable here. Further, correcting errors for minimum detectable levels and random errors simultaneously is too complex for analytical solutions. Therefore, this paper uses simulation studies to quantitatively evaluate the magnitude of the bias, inefficiency, and type I and type II errors associated with them. The simulation results are applied to a sample of historical occupational radiation exposure data from the Oak Ridge National Laboratory. We conclude that after taking into consideration random measurement error and missed doses due to falling below the minimum detection level, radiation exposure is not significantly associated with all-cause mortality in that cohort.

Health disparities between island and mainland Puerto Ricans.

OBJECTIVE: To detect health disparities among three populations--Puerto Ricans living in Puerto Rico as well as Puerto Ricans and non-Hispanic whites living on the United States (U.S.) mainland. METHODS: Data from two similarly designed surveys conducted in 1999-2000 were analyzed. The Behavioral Risk Factor Surveillance System (BRFSS) provided data on Puerto Ricans living on the island and on non-Hispanic whites in the U.S. Another survey of Puerto Ricans living in New York City provided data on mainland Puerto Ricans. The age- and sex-standardized weighted prevalences of various health parameters (e.g., obesity, diabetes, smoking, and physical illness) and indicators of access to health care (e.g., frequencies of routine checkups and diabetes care) were compared between populations by means of standardized rate ratios (SRR). RESULTS: Puerto Ricans living on the mainland and those living on the island had a similar prevalence of obesity (21% to 22%). Compared with islanders, mainland Puerto Ricans had a higher prevalence of diabetes (SRR = 1.4; 95% confidence interval [95% CI] = 1.01 to 2.0); those with diabetes also showed higher prevalences of smoking (SRR = 4.2; 95% CI = 2.3 to 7.7) and physical illness (SRR = 1.5; 95% CI = 1.1 to 2.0) than Puerto Ricans living on the island. While mainland Puerto Ricans were similar to non-Hispanic whites in terms of their utilization of primary prevention and diabetes care, island Puerto Ricans trailed behind significantly. CONCLUSIONS: Puerto Ricans living on the U.S. mainland and those living in Puerto Rico both need to target lowering their prevalence of obesity and diabetes. For island Puerto Ricans, improved education about the significance of primary prevention and diabetes care is needed. For mainland Puerto Ricans, the accessibility of the primary health care system renders it a potentially effective venue for interventions, particularly for smoking cessation. More studies are warranted to identify factors associated with the poor health status observed in mainland Puerto Ricans.

Health disparities between island and mainland Puerto Ricans / Disparidades de salud entre puertorriqueños que viven en la isla de Puerto Rico y en tierra firme estadounidense

Objective. To detect health disparities among three populations­Puerto Ricans living in Puerto Rico as well as Puerto Ricans and non-Hispanic whites living on the United States (U.S.) mainland. Methods. Data from two similarly designed surveys conducted in 1999­2000 were analyzed. The Behavioral Risk Factor Surveillance System (BRFSS) provided data on Puerto Ricans living on the island and on non-Hispanic whites in the U.S. Another survey of Puerto Ricans living in New York City provided data on mainland Puerto Ricans. The age- and sexstandardized weighted prevalences of various health parameters (e.g., obesity, diabetes, smoking, and physical illness) and indicators of access to health care (e.g., frequencies of routine checkups and diabetes care) were compared between populations by means of standardized rate ratios (SRR). Results. Puerto Ricans living on the mainland and those living on the island had a similar prevalence of obesity (21% to 22%). Compared with islanders, mainland Puerto Ricans had a higher prevalence of diabetes (SRR = 1.4; 95% confidence interval [95% CI] = 1.01 to 2.0); those with diabetes also showed higher prevalences of smoking (SRR = 4.2; 95% CI = 2.3 to 7.7) and physical illness (SRR = 1.5; 95% CI = 1.1 to 2.0) than Puerto Ricans living on the island. While mainland Puerto Ricans were similar to non-Hispanic whites in terms of their utilization of primary prevention and diabetes care, island Puerto Ricans trailed behind significantly. Conclusions. Puerto Ricans living on the U.S. mainland and those living in Puerto Rico both need to target lowering their prevalence of obesity and diabetes. For island Puerto Ricans, improved education about the significance of primary prevention and diabetes care is needed. For mainland Puerto Ricans, the accessibility of the primary health care system renders it a potentially effective venue for interventions, particularly for smoking cessation. More studies are warranted to identify factors associated with the poor health status observed in mainland Puerto Ricans.

OBJETIVO: Detectar disparidades de salud entre tres poblaciones: puertorriqueños que viven en Puerto Rico, así como puertorriqueños y personas no hispanas de raza blanca que viven en tierra firme estadounidense. MÉTODOS: Se analizaron los datos obtenidos mediante dos encuestas de similar diseño que se realizaron en 1999–2000. El Sistema de Vigilancia de Factores de Riesgo Conductuales proporcionó datos acerca de los puertorriqueños radicados en la isla y de residentes de Estados Unidos de raza blanca que no son hispanos. Otra encuesta de puertorriqueños radicados en la Ciudad de Nueva York aportó datos acerca de los puertorriqueños que residían en tierra firme estadounidense. Se usaron las razones de las tasas estandarizadas (standardized rate ratios, SRR) para hacer las comparaciones interpoblacionales de las prevalencias ponderadas, estandarizadas por edad y sexo, de varios parámetros (obesidad, diabetes, tabaquismo y dolencias físicas) y de indicadores de acceso a la atención sanitaria (frecuencia de los exámenes de rutina y de la atención de la diabetes). RESULTADOS: Los puertorriqueños que vivían en tierra firme estadounidense y los que vivían en la isla tuvieron una prevalencia de obesidad parecida (21% a 22%). Comparados con los habitantes de la isla, los puertorriqueños radicados en tierra firme tuvieron una prevalencia de diabetes más alta (SRR = 1,4; intervalo de confianza de 95% [IC95%]: 1,01 a 2,0); los que tenían diabetes también mostraron una mayor prevalencia de tabaquismo (SRR = 4,2; IC 95%: 2,3 a 7,7) y de dolencias físicas (SRR = 1,5%; IC95%: 1,1 a 2,0) que los puertorriqueños que vivían en la isla. Mientras que los puertorriqueños en tierra firme se asemejaron a los blancos que no eran hispanos en cuanto a la utilización de servicios de prevención primaria y de atención de la diabetes, los puertorriqueños en la isla tenían cifras de utilización mucho más bajas. Conclusiones. Tanto los puertorriqueños radicados en tierra firme estadounidense como los que viven en Puerto Rico tienen que ponerse como meta reducir su prevalencia de obesidad y diabetes. En el caso de los puertorriqueños en la isla, hace falta una mejor educación en torno a la importancia de la prevención primaria y de la atención de la diabetes. En el caso de los puertorriqueños en tierra firme, la accesibilidad del sistema de atención primaria hace que este sea idóneo para llevar a cabo diversas intervenciones, particularmente contra el hábito de fumar. Se necesitan más estudios para determinar qué factores se asocian con el mal estado de salud observado en puertorriqueños radicados en tierra firme.