Exploiting nonsystematic covariate monitoring to broaden the scope of evidence about the causal effects of adaptive treatment strategies

In studies based on electronic health records (EHR), the frequency of covariate monitoring can vary by covariate type, across patients, and over time, which can limit the generalizability of inferences about the effects of adaptive treatment strategies. In addition, monitoring is a health intervention in itself with costs and benefits, and stakeholders may be interested in the effect of monitoring when adopting adaptive treatment strategies. This paper demonstrates how to exploit nonsystematic covariate monitoring in EHR‐based studies to both improve the generalizability of causal inferences and to evaluate the health impact of monitoring when evaluating adaptive treatment strategies. Using a real world, EHR‐based, comparative effectiveness research (CER) study of patients with type II diabetes mellitus, we illustrate how the evaluation of joint dynamic treatment and static monitoring interventions can improve CER evidence and describe two alternate estimation approaches based on inverse probability weighting (IPW). First, we demonstrate the poor performance of the standard estimator of the effects of joint treatment‐monitoring interventions, due to a large decrease in data support and concerns over finite‐sample bias from near‐violations of the positivity assumption (PA) for the monitoring process. Second, we detail an alternate IPW estimator using a no direct effect assumption. We demonstrate that this estimator can improve efficiency but at the potential cost of increase in bias from violations of the PA for the treatment process.     

Impact of insurance and supply of health professionals on coverage of treatment for hypertension in Mexico: population based study

Objective To examine the independent and combined contributions of insurance status and supply of health professionals on coverage of antihypertensive treatment among adults in Mexico.Design Population based study.Setting Mexico.Participants 4032 hypertensive adults (2967 uninsured and 1065 insured): 1065 uninsured adults matched with 1065 adults insured through Seguro Popular, a programme to expand health insurance coverage to uninsured people in Mexico.Main outcome measures Coverage of antihypertensive treatment and coverage of antihypertensive treatment with control of blood pressure.Results Rates of treatment for hypertension varied by insurance status and supply of health professionals. Hypertensive adults insured through Seguro Popular had a significantly higher probability of receiving antihypertensive treatment (odds ratio 1.50, 95% confidence interval 1.27 to 1.78) and receiving antihypertensive treatment with control of blood pressure (1.35, 1.00 to 1.82). Greater supply of health professionals in areas with coverage through Seguro Popular was a significant predictor of antihypertensive treatment after adjusting for covariates (1.49, 1.00 to 2.20).Conclusions Expansion of healthcare coverage to uninsured people in Mexico was associated with greater use of antihypertensive treatment and blood pressure control, particularly in areas with a greater supply of health professionals.     

Realist synthesis: illustrating the method for implementation research

ABSTRACT: BACKGROUND: Realist synthesis is an increasingly popular approach to the review and synthesis of evidence, which focuses on understanding the mechanisms by which an intervention works (or not). There are few published examples of realist synthesis. This paper therefore fills a gap by describing, in detail, the process used for a realist review and synthesis to answer the question 'what interventions and strategies are effective in enabling evidence-informed healthcare?' The strengths and challenges of conducting realist review are also considered. METHODS: The realist approach involves identifying underlying causal mechanisms and exploring how they work under what conditions. The stages of this review included: defining the scope of the review (concept mining and framework formulation); searching for and scrutinising the evidence; extracting and synthesising the evidence; and developing the narrative, including hypotheses. RESULTS: Based on key terms and concepts related to various interventions to promote evidenceinformed healthcare, we developed an outcome-focused theoretical framework. Questions were tailored for each of four theory/intervention areas within the theoretical framework and were used to guide development of a review and data extraction process. The search for literature within our first theory area, change agency, was executed and the screening procedure resulted in inclusion of 52 papers. Using the questions relevant to this theory area, data were extracted by one reviewer and validated by a second reviewer. Synthesis involved organisation of extracted data into evidence tables, theming and formulation of chains of inference, linking between the chains of inference, and hypothesis formulation. The narrative was developed around the hypotheses generated within the change agency theory area. CONCLUSIONS: Realist synthesis lends itself to the review of complex interventions because it accounts for context as well as outcomes in the process of systematically and transparently synthesising relevant literature. While realist synthesis demands flexible thinking and the ability to deal with complexity, the rewards include the potential for more pragmatic conclusions than alternative approaches to systematic reviewing. A separate publication will report the findings of the review.     

Comparison and evaluation of biomechanical,electrical, and biological methods for assessment of damage to tissue collagen

In regard to evaluating tissue banking methods used to preserve or otherwise treat (process) soft allograft tissue, current tests may not be sufficiently sensitive to detect potential damage inflicted before, during, and after processing. Using controlled parameters, we aim to examine the sensitivity of specific biomechanical, electrical, and biological tests in detecting mild damage to collagen. Fresh porcine pulmonary heart valves were treated with an enzyme, collagenase, and incubated using various times. Controls received no incubation. All valves were cryopreserved and stored at ?135 °C until being rewarmed for evaluation using biomechanical, permeability, and cell viability tests. Statistically significant time dependent changes in leaflet ultimate stress, (p = 0.006), permeability (p = 0.01), and viability (p ≤ 0.02, four different days of culture) were found between heart valves subjected to 0–15 min of collagenase treatment (ANOVA). However, no statistical significance was found between the tensile modulus of treated and untreated valves (p = 0.07). Furthermore, the trends of decreasing and increasing ultimate stress and viability, respectively, were somewhat inconsistent across treatment times. These results suggest that permeability tests may offer a sensitive, quantitative assay to complement traditional biomechanical and viability tests in evaluating processing methods used for soft tissue allografts, or when making changes to current validated methods. Multiple test evaluation may also offer insight into the mechanism of potential tissue damage such as, as is the case here, reduced collagen content and increased tissue porosity.     

Functional characterization of cytochrome P450-derived epoxyeicosatrienoic acids in adipogenesis and obesity

Adipogenesis plays a critical role in the initiation and progression of obesity. Although cytochrome P450 (CYP)-derived epoxyeicosatrienoic acids (EETs) have emerged as a potential therapeutic target for cardiometabolic disease, the functional contribution of EETs to adipogenesis and the pathogenesis of obesity remain poorly understood. Our studies demonstrated that induction of adipogenesis in differentiated 3T3-L1 cells (in vitro) and obesity-associated adipose expansion in high-fat diet (HFD)-fed mice (in vivo) significantly dysregulate the CYP epoxygenase pathway and evoke a marked suppression of adipose-derived EET levels. Subsequent in vitro experiments demonstrated that exogenous EET analog administration elicits potent anti-adipogenic effects via inhibition of the early phase of adipogenesis. Furthermore, EET analog administration to mice significantly mitigated HFD-induced weight gain, adipose tissue expansion, pro-adipogenic gene expression, and glucose intolerance. Collectively, these findings suggest that suppression of EET bioavailability in adipose tissue is a key pathological consequence of obesity, and strategies that promote the protective effects of EETs in adipose tissue offer enormous therapeutic potential for obesity and its downstream pathological consequences.     

Trust in scientific experts on obesity: implications for awareness and behavior change

Objective: To explore the relationship between public trust in scientific experts on obesity and public attention to nutrition recommendations, to investigate trust as a predictor of weight‐related behaviors, and to identify the sociodemographic characteristics associated with high and low trust in scientific experts on obesity. Research Methods and Procedures: This analysis used survey data from two sources: 1) a 2005 Harvard School of Public Health Obesity Survey (N = 2033), and 2) the 2004 General Social Survey (N = 2812). Five outcome measures were used. Three were used to explore trust as a predictor of attention and weight‐related behaviors. Two were used to identify the sociodemographic predictors of trust. Logistic regression analysis was used to model the outcome variables. Results: Trust in scientific experts was the strongest predictor of public attention to nutritional recommendations from scientific experts, but it was not directly related to weight‐related behaviors. Public attention was significantly associated with two weight‐related behaviors: tracking fruit and vegetable intake and exercise. Women and more educated individuals had significantly higher odds of trusting scientific experts. Characteristics associated with distrust in scientific experts included Hispanic race and older age (over 50). Discussion: Public health experts should work toward building trust as an important step in stemming the obesity epidemic. Further, more research is necessary to better understand the factors driving trust in scientific experts on obesity. A deeper insight in this area will certainly be of great benefit to obesity‐related risk communication and potentially lead to positive behavior change.     

Institutionalizing evidence-based practice: an organizational case study using a model of strategic change

Background

There is a general expectation within healthcare that organizations should use evidence-based practice (EBP) as an approach to improving the quality of care. However, challenges exist regarding how to make EBP a reality, particularly at an organizational level and as a routine, sustained aspect of professional practice.

Methods

A mixed method explanatory case study was conducted to study context; i.e., in terms of the presence or absence of multiple, inter-related contextual elements and associated strategic approaches required for integrated, routine use of EBP ('institutionalization'). The Pettigrew et al. Content, Context, and Process model was used as the theoretical framework. Two sites in the US were purposively sampled to provide contrasting cases: i.e., a 'role model' site, widely recognized as demonstrating capacity to successfully implement and sustain EBP to a greater degree than others; and a 'beginner' site, self-perceived as early in the journey towards institutionalization.

Results

The two sites were clearly different in terms of their organizational context, level of EBP activity, and degree of institutionalization. For example, the role model site had a pervasive, integrated presence of EBP versus a sporadic, isolated presence in the beginner site. Within the inner context of the role model site, there was also a combination of the Pettigrew and colleagues' receptive elements that, together, appeared to enhance its ability to effectively implement EBP-related change at multiple levels. In contrast, the beginner site, which had been involved for a few years in EBP-related efforts, had primarily non-receptive conditions in several contextual elements and a fairly low overall level of EBP receptivity. The beginner site thus appeared, at the time of data collection, to lack an integrated context to either support or facilitate the institutionalization of EBP.

Conclusion

Our findings provide evidence of some of the key contextual elements that may require attention if institutionalization of EBP is to be realized. They also suggest the need for an integrated set of receptive contextual elements to achieve EBP institutionalization; and they further support the importance of specific interactions among these elements, including ways in which leadership affects other contextual elements positively or negatively.     

Pulmonary cytochrome P-450 2J4 is reduced in a rat model of acute Pseudomonas pneumonia

We previously reported that the levels of epoxyeicosatrienoic acids (EETs) and 20-hydroxyeicosatetraenoic acid (20-HETE) are depressed in microsomes prepared from lungs of rats with acute Pseudomonas pneumonia. We also showed a potential role for cytochrome P-450 (CYP) metabolites of arachidonic acid (AA) in contractile responses of both normal pulmonary arteries and pulmonary arteries from rats with pneumonia. The CYP2J subfamily enzymes (endogenous source of EETs and HETEs) are constitutively expressed in human and rat lungs where they are localized in vascular smooth muscle and endothelium. The purpose of this study was to determine if CYP2J proteins are modified in pneumonia. Pseudomonas organisms were injected via a tracheostomy in the lungs of rats. Later (44 h), lungs were frozen, and microsomes were prepared from pneumonia and control rat lung homogenates. Lung microsomal proteins were then immunoblotted with anti-CYP2B1/2B2, anti-CYP4A, anti-CYP2J9pep2 (which reacts with rat CYP2J3), anti-CYP2J6pep1 (which reacts with rat CYP2J4), anti-CYP2J2pep4, or anti-CYP2J2pep3 (both of which react with all known CYP2J isozymes). Western blotting revealed a prominent 55-kDa band with anti-CYP2J2pep3, anti-CYP2J2pep4, and anti-CYP2J6pep1 (but not anti-CYP2J9pep2) that was reduced in pneumonia compared with control lung microsomes. The CYP2B bands (51-52 kDa) were less prominent and not different between pneumonia and control lungs. CYP4A proteins (20-HETE sources) were not detected in rat lung microsomes. Therefore, rat lung contains a protein with immunological characteristics similar to CYP2J4, and this CYP is reduced after pneumonia. We speculate that CYP2J (but not CYP2B) enzymes and their AA metabolic products (EETs) are involved in the modulation of pulmonary vascular tone in pneumonia in rats.     

Modeling yeast spoilage in cold-filled ready-to-drink beverages with Saccharomyces cerevisiae, Zygosaccharomyces bailii, and Candida lipolytica

Mathematical models were developed to predict the probability of yeast spoilage of cold-filled ready-to-drink beverages as a function of beverage formulation. A Box-Behnken experimental design included five variables, each at three levels: pH (2.8, 3.3, and 3.8), titratable acidity (0.20, 0.40, and 0.60%), sugar content (8.0, 12.0, and 16.0 degrees Brix), sodium benzoate concentration (100, 225, and 350 ppm), and potassium sorbate concentration (100, 225, and 350 ppm). Duplicate samples were inoculated with a yeast cocktail (100 microl/50 ml) consisting of equal proportions of Saccharomyces cerevisiae, Zygosaccharomyces bailii, and Candida lipolytica (approximately 5.0 x 10(4) CFU/ml each). The inoculated samples were plated on malt extract agar after 0, 1, 2, 4, 6, and 8 weeks. Logistic regression was used to create the predictive models. The pH and sodium benzoate and potassium sorbate concentrations were found to be significant factors controlling the probability of yeast growth. Interaction terms for pH and each preservative were also significant in the predictive model. Neither the titratable acidity nor the sugar content of the model beverages was a significant predictor of yeast growth in the ranges tested.