Tobacco pipes. pipemakers, and tobacconists in Newcastle and Gateshead until c1800: an archaeological study

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Analysis of 24-Hour Ambulatory Blood Pressure Monitoring Data using Orthonormal Polynomials in the Linear Mixed Model

The use of 24-hour ambulatory blood pressure monitoring (ABPM) in clinical practice and observational epidemiological studies has grown considerably in the past 25 years. ABPM is a very effective technique for assessing biological, environmental, and drug effects on blood pressure. In order to enhance the effectiveness of ABPM for clinical and observational research studies via analytical and graphical results, developing alternative data analysis approaches are important. The linear mixed model for the analysis of longitudinal data is particularly well-suited for the estimation of, inference about, and interpretation of both population and subject-specific trajectories for ABPM data. Subject-specific trajectories are of great importance in ABPM studies, especially in clinical research, but little emphasis has been placed on this dimension of the problem in the statistical analyses of the data. We propose using a linear mixed model with orthonormal polynomials across time in both the fixed and random effects to analyze ABPM data. Orthonormal polynomials in the linear mixed model may be used to develop model-based, subject-specific 24-hour ABPM correlates of cardiovascular disease outcomes. We demonstrate the proposed analysis technique using data from the Dietary Approaches to Stop Hypertension (DASH) study, a multicenter, randomized, parallel arm feeding study that tested the effects of dietary patterns on blood pressure

Avoiding bias in mixed model inference for fixed effects

Analysis of a large longitudinal study of children motivated our work. The results illustrate how accurate inference for fixed effects in a general linear mixed model depends on the covariance model selected for the data. Simulation studies have revealed biased inference for the fixed effects with an underspecified covariance structure, at least in small samples. One underspecification common for longitudinal data assumes a simple random intercept and conditional independence of the within-subject errors (i.e., compound symmetry). We prove that the underspecification creates bias in both small and large samples, indicating that recruiting more participants will not alleviate inflation of the Type I error rate associated with fixed effect inference. Enumerations and simulations help quantify the bias and evaluate strategies for avoiding it. When practical, backwards selection of the covariance model, starting with an unstructured pattern, provides the best protection. Tutorial papers can guide the reader in minimizing the chances of falling into the often spurious software trap of nonconvergence. In some cases, the logic of the study design and the scientific context may support a structured pattern, such as an autoregressive structure. The sandwich estimator provides a valid alternative in sufficiently large samples. Authors reporting mixed-model analyses should note possible biases in fixed effects inference because of the following: (i) the covariance model selection process; (ii) the specific covariance model chosen; or (iii) the test approximation

Choice of autogenous conduit for lower extremity vein graft revisions

AbstractBackground: Surgical revision to repair stenosis is necessary in about 20% of lower extremity vein grafts (LEVGs). Alternate conduit, especially arm vein, is often necessary to achieve a policy of all-autogenous revisions. Although basilic vein harvest necessitates deep exposure in proximity to major nerves, it typically uses a large vein unaffected by prior intravenous lines and as such appears ideally suited for revisions in which a segmental interposition conduit is needed for revision within the graft or for extension to a more proximal inflow or distal outflow site. In this report, we describe our experience with the use of the basilic vein for LEVG revisions compared with other sources of autogenous conduit. Methods: All patients who underwent LEVG were placed in a duplex scan surveillance program. LEVGs that developed a focal area of increased velocity or uniformly low velocities throughout the graft with appropriate lesions confirmed with angiography were candidates for revision. All patients who underwent graft revision with basilic vein segments from January 1, 1990, to September 1, 2001, were identified, and their courses were reviewed for subsequent adverse events (further revision or occlusion) and complications of harvest. These revisions were compared with revisions in which cephalic and saphenous vein were used. Results: One hundred thirty basilic veins were used to revise 122 LEVGs. The mean follow-up period after revision was 28 ± 27 months. Ninety-three grafts (71%) remained patent with no further revision, and 37 grafts (29%) either needed additional revisions (22 grafts) or were occluded (15 grafts). Only four of these adverse events (11%) were directly attributed to the basilic vein segment. Ten of 43 grafts revised with cephalic vein (23%) were either revised or occluded, of which three were related to the cephalic vein segment (P = not significant, compared with basilic vein). Twenty-four of 81 grafts revised with saphenous vein (30%) were either revised or occluded, of which 11 were attributed to the saphenous vein segment (P < .01, compared with basilic vein). Two patients (1.5%) had complications from basilic vein harvest (one hematoma, one arterial injury). No neurologic injuries resulted from basilic vein harvest. Conclusion: The basilic vein is a reliable and durable conduit when used to segmentally revise LEVGs. Stenoses rarely occur within interposed basilic vein segments, and excellent freedom from subsequent revision or occlusion is possible. We conclude the basilic vein can be safely harvested with minimal complications and is ideally suited for use as a short segment interposition graft for LEVG revision. (J Vasc Surg 2002;36:238-44.

Genetic and functional characterization of putative Ras/Raf interaction inhibitors in C. elegans and mammalian cells

Abstract Background Activation of the mammalian Ras-Raf-MEK-ERK MAPK signaling cascade promotes cellular proliferation, and activating Ras mutations are implicated in cancer onset and maintenance. This pathway, a therapeutic target of interest, is highly conserved and required for vulval development in C. elegans. Gain-of-function mutations in the Ras ortholog lead to constitutive pathway signaling and a multivulva (Muv) phenotype. MCP compounds were identified in a yeast two-hybrid screen for their ability to disrupt Ras-Raf interactions. However, this had not been confirmed in another system, and conflicting results were reported regarding selective MCP-mediated blockade of Ras- and Raf-mediated biological activities in mammalian cells. Here we used the easily-scored Muv phenotype as an in vivo readout to characterize the selectivity of MCP110 and its analogs, and performed biochemical studies in mammalian cells to determine whether MCP treatment results in impaired interaction between Ras and its effector Raf. Results Our genetic analyses showed significant dose-dependent MCP-mediated reduction of Muv in C. elegans strains with activating mutations in orthologs of Ras (LET-60) or Raf (LIN-45), but not MAP kinases or an Ets-like transcription factor. Thus, these inhibitors selectively impair pathway function downstream of Ras and upstream of or at the level of Raf, consistent with disruption of the Ras/Raf interaction. Our biochemical analyses of MCP110-mediated disruption of Ras-Raf interactions in mammalian cells showed that MCP110 dose-dependently reduced Raf-RBD pulldown of Ras, displaced a fluorescently-tagged Raf-RBD probe from plasma membrane locations of active Ras to the cytosol and other compartments, and decreased active, phosphorylated ERK1/2. Conclusions We have effectively utilized C. elegans as an in vivo genetic system to evaluate the activity and selectivity of inhibitors intended to target the Ras-Raf-MAPK pathway. We demonstrated the ability of MCP110 to disrupt, at the level of Ras/Raf, the Muv phenotype induced by chronic activation of this pathway in C. elegans. In mammalian cells, we not only demonstrated MCP-mediated blockade of the physical interaction between Ras and Raf, but also narrowed the site of interaction on Raf to the RBD, and showed consequent functional impairment of the Ras-Raf-MEK-ERK pathway in both in vivo and cell-based systems

Early-Life Soy Exposure and Gender-Role Play Behavior in Children

Background: Soy-based infant formula contains high levels of isoflavones. These estrogen-like compounds have been shown to induce changes in sexually dimorphic behaviors in animals exposed in early development

Kronecker Product Linear Exponent AR(1) Correlation Structures for Multivariate Repeated Measures

Longitudinal imaging studies have moved to the forefront of medical research due to their ability to characterize spatio-temporal features of biological structures across the lifespan. Credible models of the correlations in longitudinal imaging require two or more pattern components. Valid inference requires enough flexibility of the correlation model to allow reasonable fidelity to the true pattern. On the other hand, the existence of computable estimates demands a parsimonious parameterization of the correlation structure. For many one-dimensional spatial or temporal arrays, the linear exponent autoregressive (LEAR) correlation structure meets these two opposing goals in one model. The LEAR structure is a flexible two-parameter correlation model that applies to situations in which the within-subject correlation decreases exponentially in time or space. It allows for an attenuation or acceleration of the exponential decay rate imposed by the commonly used continuous-time AR(1) structure. We propose the Kronecker product LEAR correlation structure for multivariate repeated measures data in which the correlation between measurements for a given subject is induced by two factors (e.g., spatial and temporal dependence). Excellent analytic and numerical properties make the Kronecker product LEAR model a valuable addition to the suite of parsimonious correlation structures for multivariate repeated measures data. Longitudinal medical imaging data of caudate morphology in schizophrenia illustrates the appeal of the Kronecker product LEAR correlation structure