The personalized advantage index: Translating research on prediction into individualized treatment recommendations. A demonstration

Background: Advances in personalized medicine require the identification of variables that predict differential response to treatments as well as the development and refinement of methods to transform predictive information into actionable recommendations. Objective: To illustrate and test a new method for integrating predictive information to aid in treatment selection, using data from a randomized treatment comparison. Method: Data from a trial of antidepressant medications (N = 104) versus cognitive behavioral therapy (N = 50) for Major Depressive Disorder were used to produce predictions of post-treatment scores on the Hamilton Rating Scale for Depression (HRSD) in each of the two treatments for each of the 154 patients. The patient's own data were not used in the models that yielded these predictions. Five pre-randomization variables that predicted differential response (marital status, employment status, life events, comorbid personality disorder, and prior medication trials) were included in regression models, permitting the calculation of each patient's Personalized Advantage Index (PAI), in HRSD units. Results: For 60% of the sample a clinically meaningful advantage (PAI≥3) was predicted for one of the treatments, relative to the other. When these patients were divided into those randomly assigned to their "Optimal" treatment versus those assigned to their "Non-optimal" treatment, outcomes in the former group were superior (d = 0.58, 95% CI .17-1.01). Conclusions: This approach to treatment selection, implemented in the context of two equally effective treatments, yielded effects that, if obtained prospectively, would rival those routinely observed in comparisons of active versus control treatments. © 2014 DeRubeis et al

Asymmetric Dimethylarginine, Endothelial Nitric Oxide Bioavailability and Mortality in Sepsis

Background: Plasma concentrations of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxidesynthase, are raised in patients with chronic vascular disease, causing increased cardiovascular risk and endothelialdysfunction, but the role of ADMA in acute inflammatory states is less well defined.Methods and Results: In a prospective longitudinal study in 67 patients with acute sepsis and 31 controls, digitalmicrovascular reactivity was measured by peripheral arterial tonometry and blood was collected at baseline and 2–4 dayslater. Plasma ADMA and L-arginine concentrations were determined by high performance liquid chromatography. Baselineplasma L-arginine: ADMA ratio was significantly lower in sepsis patients (median [IQR] 63 [45–103]) than in hospital controls(143 [123–166], p,0.0001) and correlated with microvascular reactivity (r = 0.34, R2 = 0.12, p = 0.02). Baseline plasma ADMAwas independently associated with 28-day mortality (Odds ratio [95% CI] for death in those in the highest quartile($0.66 mmol/L) = 20.8 [2.2–195.0], p = 0.008), and was independently correlated with severity of organ failure. Increase inADMA over time correlated with increase in organ failure and decrease in microvascular reactivity.Conclusions: Impaired endothelial and microvascular function due to decreased endothelial NO bioavailability is a potentialmechanism linking increased plasma ADMA with organ failure and death in sepsis

The Role of Self-Efficacy in Achieving Health Behavior Change

The concept of self-efficacy is receiving increasing recognition as a predictor of health behavior change and maintenance. The purpose of this article is to facilitate a clearer understanding of both the concept and its relevance for health education research and practice. Self-efficacy is first defined and distinguished from other related concepts. Next, studies of the self-efficacy concept as it relates to health practices are examined. This review focuses on cigarette smoking, weight control, contraception, alcohol abuse and exercise behaviors. The studies reviewed suggest strong relationships between self-efficacy and health behavior change and maintenance. Experimental manipulations of self-efficacy suggest that efficacy can be enhanced and that this enhancement is related to subsequent health behavior change. The findings from these studies also suggest methods for modifying health practices. These methods diverge from many of the current, traditional methods for changing health practices. Recommendations for incorporating the enhancement of self-efficacy into health behavior change programs are made in light of the reviewed findings.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68171/2/10.1177_109019818601300108.pd

Health status and its determinants in urban populations

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45779/1/11524_2006_Article_BF02345089.pd

Translating Clinical Findings into Knowledge in Drug Safety Evaluation - Drug Induced Liver Injury Prediction System (DILIps)

Drug-induced liver injury (DILI) is a significant concern in drug development due to the poor concordance between preclinical and clinical findings of liver toxicity. We hypothesized that the DILI types (hepatotoxic side effects) seen in the clinic can be translated into the development of predictive in silico models for use in the drug discovery phase. We identified 13 hepatotoxic side effects with high accuracy for classifying marketed drugs for their DILI potential. We then developed in silico predictive models for each of these 13 side effects, which were further combined to construct a DILI prediction system (DILIps). The DILIps yielded 60–70% prediction accuracy for three independent validation sets. To enhance the confidence for identification of drugs that cause severe DILI in humans, the “Rule of Three” was developed in DILIps by using a consensus strategy based on 13 models. This gave high positive predictive value (91%) when applied to an external dataset containing 206 drugs from three independent literature datasets. Using the DILIps, we screened all the drugs in DrugBank and investigated their DILI potential in terms of protein targets and therapeutic categories through network modeling. We demonstrated that two therapeutic categories, anti-infectives for systemic use and musculoskeletal system drugs, were enriched for DILI, which is consistent with current knowledge. We also identified protein targets and pathways that are related to drugs that cause DILI by using pathway analysis and co-occurrence text mining. While marketed drugs were the focus of this study, the DILIps has a potential as an evaluation tool to screen and prioritize new drug candidates or chemicals, such as environmental chemicals, to avoid those that might cause liver toxicity. We expect that the methodology can be also applied to other drug safety endpoints, such as renal or cardiovascular toxicity

Role of Visible Light-Activated Photocatalyst on the Reduction of Anthrax Spore-Induced Mortality in Mice

BACKGROUND: Photocatalysis of titanium dioxide (TiO(2)) substrates is primarily induced by ultraviolet light irradiation. Anion-doped TiO(2) substrates were shown to exhibit photocatalytic activities under visible-light illumination, relative environmentally-friendly materials. Their anti-spore activity against Bacillus anthracis, however, remains to be investigated. We evaluated these visible-light activated photocatalysts on the reduction of anthrax spore-induced pathogenesis. METHODOLOGY/PRINCIPAL FINDINGS: Standard plating method was used to determine the inactivation of anthrax spore by visible light-induced photocatalysis. Mouse models were further employed to investigate the suppressive effects of the photocatalysis on anthrax toxin- and spore-mediated mortality. We found that anti-spore activities of visible light illuminated nitrogen- or carbon-doped titania thin films significantly reduced viability of anthrax spores. Even though the spore-killing efficiency is only approximately 25%, our data indicate that spores from photocatalyzed groups but not untreated groups have a less survival rate after macrophage clearance. In addition, the photocatalysis could directly inactivate lethal toxin, the major virulence factor of B. anthracis. In agreement with these results, we found that the photocatalyzed spores have tenfold less potency to induce mortality in mice. These data suggest that the photocatalysis might injury the spores through inactivating spore components. CONCLUSION/SIGNIFICANCE: Photocatalysis induced injuries of the spores might be more important than direct killing of spores to reduce pathogenicity in the host

Th17 cytokines and arthritis

Th17 cells are implicated in human autoimmune diseases, such as rheumatoid arthritis (RA), although it has not been established whether this persistent destructive arthritis is driven by Th1 and/or Th17 cells. Interleukin-17A (IL-17A) contributes to the pathogenesis of arthritis as has been shown in several experimental arthritis models. Importantly, recent data from first clinical trials with anti-IL-17A antibody treatment in psoriatic arthritis patients and RA patients looks promising. This review summarizes the findings about the role of Th17 cells in arthritis and discusses the impact of the different Th17 cytokines in the pathogenesis of this disease. However, further studies are needed to unravel the interplay between IL-17A and other Th17 cytokines such as IL-17F, IL-22, and IL-21 in the pathoimmunological process of this crippling disease, in particular, whether regulating Th17 cell activity or specific combinations of Th17 cytokines will have additional value compared to neutralizing IL-17A activity alone. Moreover, tumor necrosis factor-positive Th17 cells are discussed as potential dangerous cells in driving persistent arthritis in human early RA

Phenotypic characterisation of regulatory T cells in dogs reveals signature transcripts conserved in humans and mice

Regulatory T cells (Tregs) are a double-edged regulator of the immune system. Aberrations of Tregs correlate with pathogenesis of inflammatory, autoimmune and neoplastic disorders. Phenotypically and functionally distinct subsets of Tregs have been identified in humans and mice on the basis of their extensive portfolios of monoclonal antibodies (mAb) against Treg surface antigens. As an important veterinary species, dogs are increasingly recognised as an excellent model for many human diseases. However, insightful study of canine Tregs has been restrained by the limited availability of mAb. We therefore set out to characterise CD4+CD25high T cells isolated ex vivo from healthy dogs and showed that they possess a regulatory phenotype, function, and transcriptomic signature that resembles those of human and murine Tregs. By launching a cross-species comparison, we unveiled a conserved transcriptomic signature of Tregs and identified that transcript hip1 may have implications in Treg function