Increasing confidence and changing behaviors in primary care providers engaged in genetic counselling.

BackgroundScreening and counseling for genetic conditions is an increasingly important part of primary care practice, particularly given the paucity of genetic counselors in the United States. However, primary care physicians (PCPs) often have an inadequate understanding of evidence-based screening; communication approaches that encourage shared decision-making; ethical, legal, and social implication (ELSI) issues related to screening for genetic mutations; and the basics of clinical genetics. This study explored whether an interactive, web-based genetics curriculum directed at PCPs in non-academic primary care settings was superior at changing practice knowledge, attitudes, and behaviors when compared to a traditional educational approach, particularly when discussing common genetic conditions.MethodsOne hundred twenty one PCPs in California and Pennsylvania physician practices were randomized to either an Intervention Group (IG) or Control Group (CG). IG physicians completed a 6 h interactive web-based curriculum covering communication skills, basics of genetic testing, risk assessment, ELSI issues and practice behaviors. CG physicians were provided with a traditional approach to Continuing Medical Education (CME) (clinical review articles) offering equivalent information.ResultsPCPs in the Intervention Group showed greater increases in knowledge compared to the Control Group. Intervention PCPs were also more satisfied with the educational materials, and more confident in their genetics knowledge and skills compared to those receiving traditional CME materials. Intervention PCPs felt that the web-based curriculum covered medical management, genetics, and ELSI issues significantly better than did the Control Group, and in comparison with traditional curricula. The Intervention Group felt the online tools offered several advantages, and engaged in better shared decision making with standardized patients, however, there was no difference in behavior change between groups with regard to increases in ELSI discussions between PCPs and patients.ConclusionWhile our intervention was deemed more enjoyable, demonstrated significant factual learning and retention, and increased shared decision making practices, there were few differences in behavior changes around ELSI discussions. Unfortunately, barriers to implementing behavior change in clinical genetics is not unique to our intervention. Perhaps the missing element is that busy physicians need systems-level support to engage in meaningful discussions around genetics issues. The next step in promoting active engagement between doctors and patients may be to put into place the tools needed for PCPs to easily access the materials they need at the point-of-care to engage in joint discussions around clinical genetics

Foot pressure distribution during walking in young and old adults

BACKGROUND: Measurement of foot pressure distribution (FPD) is clinically useful for evaluation of foot and gait pathologies. The effects of healthy aging on FPD during walking are not well known. This study evaluated FPD during normal walking in healthy young and elderly subjects. METHODS: We studied 9 young (30 ± 5.2 years), and 6 elderly subjects (68.7 ± 4.8 years). FPD was measured during normal walking speed using shoe insoles with 99 capacitive sensors. Measured parameters included gait phase characteristics, mean and maximum pressure and force, and relative load. Time-series measurements of each variable for all sensors were grouped into 9 anatomical masks. RESULTS: Elderly subjects had lower normalized maximum pressure for the medial and lateral calcaneal masks, and for all medial masks combined. In the medial calcaneus mask, the elderly group also had a lower absolute maximum and lower mean and normalized mean pressures and forces, compared to young subjects. Elderly subjects had lower maximum force and normalized maximum force and lower mean force and normalized mean forces in the medial masks as well. CONCLUSION: FPD differences between the young and elderly groups were confined to the calcaneus and hallux regions and to the medial side of the foot. In elderly subjects, weight bearing on the lateral side of the foot during heel touch and toe-off phases may affect stability during walking

Acquisition of pneumococci specific effector and regulatory Cd4+ T cells localising within human upper respiratory-tract mucosal lymphoid tissue

The upper respiratory tract mucosa is the location for commensal Streptococcus (S.) pneumoniae colonization and therefore represents a major site of contact between host and bacteria. The CD4(+) T cell response to pneumococcus is increasingly recognised as an important mediator of immunity that protects against invasive disease, with data suggesting a critical role for Th17 cells in mucosal clearance. By assessing CD4 T cell proliferative responses we demonstrate age-related sequestration of Th1 and Th17 CD4(+) T cells reactive to pneumococcal protein antigens within mucosal lymphoid tissue. CD25(hi) T cell depletion and utilisation of pneumococcal specific MHCII tetramers revealed the presence of antigen specific Tregs that utilised CTLA-4 and PDL-1 surface molecules to suppress these responses. The balance between mucosal effector and regulatory CD4(+) T cell immunity is likely to be critical to pneumococcal commensalism and the prevention of unwanted pathology associated with carriage. However, if dysregulated, such responses may render the host more susceptible to invasive pneumococcal infection and adversely affect the successful implementation of both polysaccharide-conjugate and novel protein-based pneumococcal vaccines

Short-term outcome of 1,465 computer-navigated primary total knee replacements 2005–2008: A report from the Norwegian Arthroplasty Register

Background and purpose: Improvement of positioning and alignment by the use of computer-assisted surgery (CAS) might improve longevity and function in total knee replacements, but there is little evidence. In this study, we evaluated the short-term results of computer-navigated knee replacements based on data from the Norwegian Arthroplasty Register. Patients and methods: Primary total knee replacements without patella resurfacing, reported to the Norwegian Arthroplasty Register during the years 2005–2008, were evaluated. The 5 most common implants and the 3 most common navigation systems were selected. Cemented, uncemented, and hybrid knees were included. With the risk of revision for any cause as the primary endpoint and intraoperative complications and operating time as secondary outcomes, 1,465 computer-navigated knee replacements (CAS) and 8,214 conventionally operated knee replacements (CON) were compared. Kaplan-Meier survival analysis and Cox regression analysis with adjustment for age, sex, prosthesis brand, fixation method, previous knee surgery, preoperative diagnosis, and ASA category were used. Results: Kaplan-Meier estimated survival at 2 years was 98% (95% CI: 97.5–98.3) in the CON group and 96% (95% CI: 95.0– 97.8) in the CAS group. The adjusted Cox regression analysis showed a higher risk of revision in the CAS group (RR = 1.7, 95% CI: 1.1–2.5; p = 0.02). The LCS Complete knee had a higher risk of revision with CAS than with CON (RR = 2.1, 95% CI: 1.3–3.4; p = 0.004)). The differences were not statistically significant for the other prosthesis brands. Mean operating time was 15 min longer in the CAS group. Interpretation: With the introduction of computer-navigated knee replacement surgery in Norway, the short-term risk of revision has increased for computer-navigated replacement with the LCS Complete. The mechanisms of failure of these implantations should be explored in greater depth, and in this study we have not been able to draw conclusions regarding causation

Altered thymic differentiation and modulation of arthritis by invariant NKT cells expressing mutant ZAP70

Various subsets of invariant natural killer T (iNKT) cells with different cytokine productions develop in the mouse thymus, but the factors driving their differentiation remain unclear. Here we show that hypomorphic alleles of Zap70 or chemical inhibition of Zap70 catalysis leads to an increase of IFN-gamma-producing iNKT cells (NKT1 cells), suggesting that NKT1 cells may require a lower TCR signal threshold. Zap70 mutant mice develop IL-17-dependent arthritis. In a mouse experimental arthritis model, NKT17 cells are increased as the disease progresses, while NKT1 numbers negatively correlates with disease severity, with this protective effect of NKT1 linked to their IFN-gamma expression. NKT1 cells are also present in the synovial fluid of arthritis patients. Our data therefore suggest that TCR signal strength during thymic differentiation may influence not only IFN-gamma production, but also the protective function of iNKT cells in arthritis

A heteroskedastic error covariance matrix estimator using a first-order conditional autoregressive Markov simulation for deriving asympotical efficient estimates from ecological sampled Anopheles arabiensis aquatic habitat covariates

<p>Abstract</p> <p>Background</p> <p>Autoregressive regression coefficients for <it>Anopheles arabiensis </it>aquatic habitat models are usually assessed using global error techniques and are reported as error covariance matrices. A global statistic, however, will summarize error estimates from multiple habitat locations. This makes it difficult to identify where there are clusters of <it>An. arabiensis </it>aquatic habitats of acceptable prediction. It is therefore useful to conduct some form of spatial error analysis to detect clusters of <it>An. arabiensis </it>aquatic habitats based on uncertainty residuals from individual sampled habitats. In this research, a method of error estimation for spatial simulation models was demonstrated using autocorrelation indices and eigenfunction spatial filters to distinguish among the effects of parameter uncertainty on a stochastic simulation of ecological sampled <it>Anopheles </it>aquatic habitat covariates. A test for diagnostic checking error residuals in an <it>An. arabiensis </it>aquatic habitat model may enable intervention efforts targeting productive habitats clusters, based on larval/pupal productivity, by using the asymptotic distribution of parameter estimates from a residual autocovariance matrix. The models considered in this research extends a normal regression analysis previously considered in the literature.</p> <p>Methods</p> <p>Field and remote-sampled data were collected during July 2006 to December 2007 in Karima rice-village complex in Mwea, Kenya. SAS 9.1.4^®was used to explore univariate statistics, correlations, distributions, and to generate global autocorrelation statistics from the ecological sampled datasets. A local autocorrelation index was also generated using spatial covariance parameters (i.e., Moran's Indices) in a SAS/GIS^®database. The Moran's statistic was decomposed into orthogonal and uncorrelated synthetic map pattern components using a Poisson model with a gamma-distributed mean (i.e. negative binomial regression). The eigenfunction values from the spatial configuration matrices were then used to define expectations for prior distributions using a Markov chain Monte Carlo (MCMC) algorithm. A set of posterior means were defined in WinBUGS 1.4.3^®. After the model had converged, samples from the conditional distributions were used to summarize the posterior distribution of the parameters. Thereafter, a spatial residual trend analyses was used to evaluate variance uncertainty propagation in the model using an autocovariance error matrix.</p> <p>Results</p> <p>By specifying coefficient estimates in a Bayesian framework, the covariate number of tillers was found to be a significant predictor, positively associated with <it>An. arabiensis </it>aquatic habitats. The spatial filter models accounted for approximately 19% redundant locational information in the ecological sampled <it>An. arabiensis </it>aquatic habitat data. In the residual error estimation model there was significant positive autocorrelation (i.e., clustering of habitats in geographic space) based on log-transformed larval/pupal data and the sampled covariate depth of habitat.</p> <p>Conclusion</p> <p>An autocorrelation error covariance matrix and a spatial filter analyses can prioritize mosquito control strategies by providing a computationally attractive and feasible description of variance uncertainty estimates for correctly identifying clusters of prolific <it>An. arabiensis </it>aquatic habitats based on larval/pupal productivity.</p

Computational Modelling of Genome-Side Transcription Assembly Networks Using a Fluidics Analogy

Understanding how a myriad of transcription regulators work to modulate mRNA output at thousands of genes remains a fundamental challenge in molecular biology. Here we develop a computational tool to aid in assessing the plausibility of gene regulatory models derived from genome-wide expression profiling of cells mutant for transcription regulators. mRNA output is modelled as fluid flow in a pipe lattice, with assembly of the transcription machinery represented by the effect of valves. Transcriptional regulators are represented as external pressure heads that determine flow rate. Modelling mutations in regulatory proteins is achieved by adjusting valves' on/off settings. The topology of the lattice is designed by the experimentalist to resemble the expected interconnection between the modelled agents and their influence on mRNA expression. Users can compare multiple lattice configurations so as to find the one that minimizes the error with experimental data. This computational model provides a means to test the plausibility of transcription regulation models derived from large genomic data sets

Peptide-MHC Cellular Microarray with Innovative Data Analysis System for Simultaneously Detecting Multiple CD4 T-Cell Responses

Peptide:MHC cellular microarrays have been proposed to simultaneously characterize multiple Ag-specific populations of T cells. The practice of studying immune responses to complicated pathogens with this tool demands extensive knowledge of T cell epitopes and the availability of peptide:MHC complexes for array fabrication as well as a specialized data analysis approach for result interpretation. T cell cultures. A novel statistical methodology was also developed to facilitate batch processing of raw array-like data into standardized endpoint scores, which linearly correlated with total Ag-specific T cell inputs. Applying these methods to analyze Influenza A viral antigen-specific T cell responses, we not only revealed the most prominent viral epitopes, but also demonstrated the heterogeneity of anti-viral cellular responses in healthy individuals. Applying these methods to examine the insulin producing beta-cell autoantigen specific T cell responses, we observed little difference between autoimmune diabetic patients and healthy individuals, suggesting a more subtle association between diabetes status and peripheral autoreactive T cells.The data analysis system is reliable for T cell specificity and functional testing. Peptide:MHC cellular microarrays can be used to obtain multi-parametric results using limited blood samples in a variety of translational settings

Anopheles larval abundance and diversity in three rice agro-village complexes Mwea irrigation scheme, central Kenya

<p>Abstract</p> <p>Background</p> <p>The diversity and abundance of <it>Anopheles </it>larvae has significant influence on the resulting adult mosquito population and hence the dynamics of malaria transmission. Studies were conducted to examine larval habitat dynamics and ecological factors affecting survivorship of aquatic stages of malaria vectors in three agro-ecological settings in Mwea, Kenya.</p> <p>Methods</p> <p>Three villages were selected based on rice husbandry and water management practices. Aquatic habitats in the 3 villages representing planned rice cultivation (Mbui Njeru), unplanned rice cultivation (Kiamachiri) and non-irrigated (Murinduko) agro-ecosystems were sampled every 2 weeks to generate stage-specific estimates of mosquito larval densities, relative abundance and diversity. Records of distance to the nearest homestead, vegetation coverage, surface debris, turbidity, habitat stability, habitat type, rice growth stage, number of rice tillers and percent <it>Azolla </it>cover were taken for each habitat.</p> <p>Results</p> <p>Captures of early, late instars and pupae accounted for 78.2%, 10.9% and 10.8% of the total <it>Anopheles </it>immatures sampled (n = 29,252), respectively. There were significant differences in larval abundance between 3 agro-ecosystems. The village with 'planned' rice cultivation had relatively lower <it>Anopheles </it>larval densities compared to the villages where 'unplanned' or non-irrigated. Similarly, species composition and richness was higher in the two villages with either 'unplanned' or limited rice cultivation, an indication of the importance of land use patterns on diversity of larval habitat types. Rice fields and associated canals were the most productive habitat types while water pools and puddles were important for short periods during the rainy season. Multiple logistic regression analysis showed that presence of other invertebrates, percentage <it>Azolla </it>cover, distance to nearest homestead, depth and water turbidity were the best predictors for <it>Anopheles </it>mosquito larval abundance.</p> <p>Conclusion</p> <p>These results suggest that agricultural practices have significant influence on mosquito species diversity and abundance and that certain habitat characteristics favor production of malaria vectors. These factors should be considered when implementing larval control strategies which should be targeted based on habitat productivity and water management.</p