Feedback GAP: pragmatic,cluster-randomized trial of goal setting and action plans to increase the effectiveness of audit and feedback interventions in primary care

Background

Audit and feedback to physicians is a commonly used quality improvement strategy, but its optimal design is unknown. This trial tested the effects of a theory-informed worksheet to facilitate goal setting and action planning, appended to feedback reports on chronic disease management, compared to feedback reports provided without these worksheets.

Methods

A two-arm pragmatic cluster randomized trial was conducted, with allocation at the level of primary care clinics. Participants were family physicians who contributed data from their electronic medical records. The ‘usual feedback’ arm received feedback every six months for two years regarding the proportion of their patients meeting quality targets for diabetes and/or ischemic heart disease. The intervention arm received these same reports plus a worksheet designed to facilitate goal setting and action plan development in response to the feedback reports. Blood pressure (BP) and low-density lipoprotein cholesterol (LDL) values were compared after two years as the primary outcomes. Process outcomes measured the proportion of guideline-recommended actions (e.g., testing and prescribing) conducted within the appropriate timeframe. Intention-to-treat analysis was performed.

Results

Outcomes were similar across groups at baseline. Final analysis included 20 physicians from seven clinics and 1,832 patients in the intervention arm (15% loss to follow up) and 29 physicians from seven clinics and 2,223 patients in the usual feedback arm (10% loss to follow up). Ten of 20 physicians completed the worksheet at least once during the study. Mean BP was 128/72 in the feedback plus worksheet arm and 128/73 in the feedback alone arm, while LDL was 2.1 and 2.0, respectively. Thus, no significant differences were observed across groups in the primary outcomes, but mean haemoglobin A1c was lower in the feedback plus worksheet arm (7.2% versus 7.4%, p<0.001). Improvements in both arms were noted over time for one-half of the process outcomes.

Discussion

Appending a theory-informed goal setting and action planning worksheet to an externally produced audit and feedback intervention did not lead to improvements in patient outcomes. The results may be explained in part by passive dissemination of the worksheet leading to inadequate engagement with the intervention.

Trial registration

ClinicalTrials.gov NCT00996645

     

Age and menopause affect the expression of specific cytokines/chemokines in plasma and cervical lavage samples from female sex workers in Nairobi,Kenya

Background

Aging of the immune system, known as immunosenescence, is associated with profound changes in both innate and adaptive immune responses, resulting in increased susceptibility to infection and a decreased ability to respond to vaccination. The purpose of this study was to investigate the effect of age and menopause on the expression of 22 different cytokines/chemokines in both plasma and cervical lavage samples from female sex-worker cohort from Nairobi, Kenya (age range 20–65).

Results

Cytokine/chemokine levels were measured using a Miliplex multiplex assay (Millipore). We found that age positively correlated with MCP-1 (p?=?0.0002) and IP-10 (p?=?0.03) systemic cytokine expression, and that women over 50 expressed the highest levels of these cytokines, but also had elevated expression of MIG (ANOVA p?=?0.0096) and MIP-3β(ANOVA p?=?0.0434). We also found that IL-8 (p?=?0.047) and sCD40L (p?=?0.01) systemic expression negatively correlated with age. Further, MIG (p?=?0.0081) and MCP-1 (p?=?0.0157) were present at higher levels in post-menopausal women suggesting a potential estrogen dependant systemic regulation of these cytokines. In cervical lavage samples, age did not directly correlate with the expression of any of the tested cytokines/chemokines, however sIL-2Rα (ANOVA p?=?0.0170) and IL-15 (ANOVA p?=?0.0251)were significantly higher in women over 50. Menopause was shown to have a more profound effect on cytokine expression in the cervical mucosa with MIG (p?=?0.0256), MIP-3α (p?=?0.0245), IL-1β (p?=?0.0261), IL-6 (p?=?0.0462), IL-8 (p?=?0.007), IP-10 (p?=?0.0357) and MCP-1 (p?=?0.0427) all significantly under-expressed in post-menopausal women.

Conclusions

This study demonstrates that aging and menopause-associated hormonal changes are associated with significant changes in systemic and mucosal cytokine/chemokine expression, which may have implications for the age-related decline in the ability to fight against infections.

     

Effects of Warm Ischemic Time on Gene Expression Profiling in Colorectal Cancer Tissues and Normal Mucosa

Background

Genome-wide gene expression analyses of tumors are a powerful tool to identify gene signatures associated with biologically and clinically relevant characteristics and for several tumor types are under clinical validation by prospective trials. However, handling and processing of clinical specimens may significantly affect the molecular data obtained from their analysis. We studied the effects of tissue handling time on gene expression in human normal and tumor colon tissues undergoing routine surgical procedures.

Methods

RNA extracted from specimens of 15 patients at four time points (for a total of 180 samples) after surgery was analyzed for gene expression on high-density oligonucleotide microarrays. A mixed-effects model was used to identify probes with different expression means across the four different time points. The p-values of the model were adjusted with the Bonferroni method.

Results

Thirty-two probe sets associated with tissue handling time in the tumor specimens, and thirty-one in the normal tissues, were identified. Most genes exhibited moderate changes in expression over the time points analyzed; however four of them were oncogenes, and two confirmed the effect of tissue handling by independent validation.

Conclusions

Our results suggest that a critical time point for tissue handling in colon seems to be 60 minutes at room temperature. Although the number of time-dependent genes we identified was low, the three genes that already showed changes at this time point in tumor samples were all oncogenes, hence recommending standardization of tissue-handling protocols and effort to reduce the time from specimen removal to snap freezing accounting for warm ischemia in this tumor type.     

Excess Cardiovascular Risk Burden in Jamaican Women Does Not Influence Predicted 10-Year CVD Risk Profiles of Jamaica Adults: An Analysis of the 2007/08 Jamaica Health and Lifestyle Survey

Background

Black Caribbean women have a higher burden of cardiovascular disease (CVD) risk factors than their male counterparts. Whether this results in a difference in incident cardiovascular events is unknown. The aim of this study was to estimate the 10 year World Health Organization/International Society for Hypertension (WHO/ISH) CVD risk score for Jamaica and explore the effect of sex as well as obesity, physical activity and socioeconomic status on these estimates.

Methods and Findings

Data from 40–74 year old participants in the 2007/08 Jamaica Health and Lifestyle Survey were used. Trained interviewers administered questionnaires and measured anthropometrics, blood pressure, fasting glucose and cholesterol. Education and occupation were used to assess socioeconomic status. The Americas B tables were used to estimate the WHO/ISH 10 year CVD risk scores for the population. Weighted prevalence estimates were calculated. Data from 1,432 (450 men, 982 women) participants were analysed, after excluding those with self-reported heart attack and stroke. The women had a higher prevalence of diabetes (19%W;12%M), hypertension (49%W;47%M), hypercholesterolemia (25%W;11%M), obesity (46%W;15%M) and physical inactivity (59%W;29%M). More men smoked (6%W;31%M). There was good agreement between the 10-year cardiovascular risk estimates whether or not cholesterol measurements were utilized for calculation (kappa –0.61). While 90% had a 10 year WHO/ISH CVD risk of less than 10%, approximately 2% of the population or 14,000 persons had a 10 year WHO/ISH CVD risk of ≥30%. As expected CVD risk increased with age but there was no sex difference in CVD risk distribution despite women having a greater risk factor burden. Women with low socioeconomic status had the most adverse CVD risk profile.

Conclusion

Despite women having a higher prevalence of CVD risk factors there was no sex difference in 10-year WHO/ISH CVD risk in Jamaican adults.     

Combining ethidium monoazide treatment with real-time PCR selectively quantifies viable Batrachochytrium dendrobatidis cells

Detection of the lethal amphibian fungus Batrachochytrium dendrobatidis relies on PCR-based techniques. Although highly accurate and sensitive, these methods fail to distinguish between viable and dead cells. In this study a novel approach combining the DNA intercalating dye ethidium monoazide (EMA) and real-time PCR is presented that allows quantification of viable B. dendrobatidis cells without the need for culturing. The developed method is able to suppress real-time PCR signals of heat-killed B. dendrobatidis zoospores by 99.9 % and is able to discriminate viable from heat-killed B. dendrobatidis zoospores in mixed samples. Furthermore, the novel approach was applied to assess the antifungal activity of the veterinary antiseptic F10^® Antiseptic Solution. This disinfectant killed B. dendrobatidis zoospores effectively within 1 min at concentrations as low as 1:6400.     

Mutation of the LXCXE Binding Cleft of pRb Facilitates Transformation by ras In Vitro but Does Not Promote Tumorigenesis In Vivo

Background

The Retinoblastoma protein (pRB) is a key tumor suppressor that is functionally inactivated in most cancers. pRB regulates the cell division cycle and cell cycle exit through protein–protein interactions mediated by its multiple binding interfaces. The LXCXE binding cleft region of pRB mediates interactions with cellular proteins that have chromatin regulatory functions. Chromatin regulation mediated by pRB is required for a stress responsive cell cycle arrest, including oncogene induced senescence. The in vivo role of chromatin regulation by pRB during senescence, and its relevance to cancer is not clear.

Methodology/Principal Findings

Using gene-targeted mice, uniquely defective for pRB mediated chromatin regulation, we investigated its role during transformation and tumor progression in response to activation of oncogenic ras. We report that the pRB^∆L mutation confers susceptibility to escape from HrasV12 induced senescence and allows transformation in vitro, although these cells possess high levels of DNA damage. Intriguingly, LSL-Kras, Rb1 ^∆L/∆L mice show delayed lung tumor formation compared to controls. This is likely due to the increased apoptosis seen in the early hyperplastic lesions shortly following ras activation that inhibits tumor progression. Furthermore, DMBA treatment to induce sporadic ras mutations in other tissues also failed to reveal greater susceptibility to cancer in Rb1 ^∆L/∆L mice.

Conclusions/Significance

Our data suggests that chromatin regulation by pRB can function to limit proliferation, but its loss fails to contribute to cancer susceptibility in ras driven tumor models because of elevated levels of DNA damage and apoptosis.     

Real Time Assays for Quantifying Cytotoxicity with Single Cell Resolution

A new live cell-based assay platform has been developed for the determination of complement dependent cytotoxicity (CDC), antibody dependent cellular cytotoxicity (ADCC), and overall cytotoxicity in human whole blood. In these assays, the targeted tumor cell populations are first labeled with fluorescent Cell Tracker dyes and immobilized using a DNA-based adhesion technique. This allows the facile generation of live cell arrays that are arranged arbitrarily or in ordered rectilinear patterns. Following the addition of antibodies in combination with serum, PBMCs, or whole blood, cell death within the targeted population can be assessed by the addition of propidium iodide (PI) as a viability probe. The array is then analyzed with an automated microscopic imager. The extent of cytotoxicity can be quantified accurately by comparing the number of surviving target cells to the number of dead cells labeled with both Cell Tracker and PI. Excellent batch-to-batch reproducibility has been achieved using this method. In addition to allowing cytotoxicity analysis to be conducted in real time on a single cell basis, this new assay overcomes the need for hazardous radiochemicals. Fluorescently-labeled antibodies can be used to identify individual cells that bear the targeted receptors, but yet resist the CDC and ADCC mechanisms. This new approach also allows the use of whole blood in cytotoxicity assays, providing an assessment of antibody efficacy in a highly relevant biological mixture. Given the rapid development of new antibody-based therapeutic agents, this convenient assay platform is well-poised to streamline the drug discovery process significantly.     

Relative Biological Effectiveness of HZE Particles for Chromosomal Exchanges and Other Surrogate Cancer Risk Endpoints

The biological effects of high charge and energy (HZE) particle exposures are of interest in space radiation protection of astronauts and cosmonauts, and estimating secondary cancer risks for patients undergoing Hadron therapy for primary cancers. The large number of particles types and energies that makeup primary or secondary radiation in HZE particle exposures precludes tumor induction studies in animal models for all but a few particle types and energies, thus leading to the use of surrogate endpoints to investigate the details of the radiation quality dependence of relative biological effectiveness (RBE) factors. In this report we make detailed RBE predictions of the charge number and energy dependence of RBE’s using a parametric track structure model to represent experimental results for the low dose response for chromosomal exchanges in normal human lymphocyte and fibroblast cells with comparison to published data for neoplastic transformation and gene mutation. RBE’s are evaluated against acute doses of γ-rays for doses near 1 Gy. Models that assume linear or non-targeted effects at low dose are considered. Modest values of RBE (<10) are found for simple exchanges using a linear dose response model, however in the non-targeted effects model for fibroblast cells large RBE values (>10) are predicted at low doses <0.1 Gy. The radiation quality dependence of RBE’s against the effects of acute doses γ-rays found for neoplastic transformation and gene mutation studies are similar to those found for simple exchanges if a linear response is assumed at low HZE particle doses. Comparisons of the resulting model parameters to those used in the NASA radiation quality factor function are discussed.     

Aqueous Angiography: Real-Time and Physiologic Aqueous Humor Outflow Imaging

Purpose

Trabecular meshwork (TM) bypass surgeries attempt to enhance aqueous humor outflow (AHO) to lower intraocular pressure (IOP). While TM bypass results are promising, inconsistent success is seen. One hypothesis for this variability rests upon segmental (non-360 degrees uniform) AHO. We describe aqueous angiography as a real-time and physiologic AHO imaging technique in model eyes as a way to simulate live AHO imaging.

Methods

Pig (n = 46) and human (n = 6) enucleated eyes were obtained, orientated based upon inferior oblique insertion, and pre-perfused with balanced salt solution via a Lewicky AC maintainer through a 1mm side-port. Fluorescein (2.5%) was introduced intracamerally at 10 or 30 mm Hg. With an angiographer, infrared and fluorescent (486 nm) images were acquired. Image processing allowed for collection of pixel information based on intensity or location for statistical analyses. Concurrent OCT was performed, and fixable fluorescent dextrans were introduced into the eye for histological analysis of angiographically active areas.

Results

Aqueous angiography yielded high quality images with segmental patterns (p<0.0001; Kruskal-Wallis test). No single quadrant was consistently identified as the primary quadrant of angiographic signal (p = 0.06–0.86; Kruskal-Wallis test). Regions of high proximal signal did not necessarily correlate with regions of high distal signal. Angiographically positive but not negative areas demonstrated intrascleral lumens on OCT images. Aqueous angiography with fluorescent dextrans led to their trapping in AHO pathways.

Conclusions

Aqueous angiography is a real-time and physiologic AHO imaging technique in model eyes.