Competing risk and heterogeneity of treatment effect in clinical trials

It has been demonstrated that patients enrolled in clinical trials frequently have a large degree of variation in their baseline risk for the outcome of interest. Thus, some have suggested that clinical trial results should routinely be stratified by outcome risk using risk models, since the summary results may otherwise be misleading. However, variation in competing risk is another dimension of risk heterogeneity that may also underlie treatment effect heterogeneity. Understanding the effects of competing risk heterogeneity may be especially important for pragmatic comparative effectiveness trials, which seek to include traditionally excluded patients, such as the elderly or complex patients with multiple comorbidities. Indeed, the observed effect of an intervention is dependent on the ratio of outcome risk to competing risk, and these risks – which may or may not be correlated – may vary considerably in patients enrolled in a trial. Further, the effects of competing risk on treatment effect heterogeneity can be amplified by even a small degree of treatment related harm. Stratification of trial results along both the competing and the outcome risk dimensions may be necessary if pragmatic comparative effectiveness trials are to provide the clinically useful information their advocates intend

Modulation of Neutrophil Function by a Secreted Mucinase of Escherichia coli O157∶H7

Escherichia coli O157∶H7 is a human enteric pathogen that causes hemorrhagic colitis which can progress to hemolytic uremic syndrome, a severe kidney disease with immune involvement. During infection, E. coli O157∶H7 secretes StcE, a metalloprotease that promotes the formation of attaching and effacing lesions and inhibits the complement cascade via cleavage of mucin-type glycoproteins. We found that StcE cleaved the mucin-like, immune cell-restricted glycoproteins CD43 and CD45 on the neutrophil surface and altered neutrophil function. Treatment of human neutrophils with StcE led to increased respiratory burst production and increased cell adhesion. StcE-treated neutrophils exhibited an elongated morphology with defective rear detachment and impaired migration, suggesting that removal of the anti-adhesive capability of CD43 by StcE impairs rear release. Use of zebrafish embryos to model neutrophil migration revealed that StcE induced neutrophil retention in the fin after tissue wounding, suggesting that StcE modulates neutrophil-mediated inflammation in vivo. Neutrophils are crucial innate effectors of the antibacterial immune response and can contribute to severe complications caused by infection with E. coli O157∶H7. Our data suggest that the StcE mucinase can play an immunomodulatory role by directly altering neutrophil function during infection. StcE may contribute to inflammation and tissue destruction by mediating inappropriate neutrophil adhesion and activation

A Novel Tool for the Assessment of Pain: Validation in Low Back Pain

Joachim Scholz and colleagues develop and validate an assessment tool that distinguishes between radicular and axial low back pain

Problem drinking as a risk factor for tuberculosis: a propensity score matched analysis of a national survey

BACKGROUND:Epidemiological and other evidence strongly supports the hypothesis that problem drinking is causally related to the incidence of active tuberculosis and the worsening of the disease course. The presence of a large number of potential confounders, however, complicates the assessment of the actual size of this causal effect, leaving room for a substantial amount of bias. This study aims to contribute to the understanding of the role of confounding in the observed association between problem drinking and tuberculosis, assessing the effect of the adjustment for a relatively large number of potential confounders on the estimated prevalence odds ratio of tuberculosis among problem drinkers vs. moderate drinkers/abstainers in a cross-sectional, nationally representative sample of the South African adult population. METHODS: A propensity score approach was used to match each problem drinker in the sample with a subset of moderate drinkers/abstainers with similar characteristics in respect to a set of potential confounders. The prevalence odds ratio of tuberculosis between the matched groups was then calculated using conditional logistic regression. Sensitivity analyses were conducted to assess the robustness of the results in respect to misspecification of the model. RESULTS: The prevalence odds ratio of tuberculosis between problem drinkers and moderate drinkers/abstainers was 1.97 (95% CI: 1.40 to 2.77), and the result was robust with respect to the matching procedure as well as to incorrect adjustment for potential mediators and to the possible presence of unmeasured confounders. Sub-population analysis did not provide noteworthy evidence for the presence of interaction between problem drinking and the observed confounders. CONCLUSION: In a cross-sectional national survey of the adult population of a middle income country with high tuberculosis burden, problem drinking was associated with a two fold increase in the odds of past TB diagnosis after controlling for a large number of socio-economic and biological confounders. Within the limitations of a cross-sectional study design with self-reported tuberculosis status, these results adds to previous evidence of a causal link between problem drinking and tuberculosis, and suggest that the observed higher prevalence of tuberculosis among problem drinkers commonly found in population studies cannot be attributed to the confounding effect of the uneven distribution of other risk factors

The low level laser therapy (LLLT) operating in 660 nm reduce gene expression of inflammatory mediators in the experimental model of collagenase-induced rat tendinitis

International audienceTendinopathy is a common disease with a variety of treatments and therapies. Laser therapy appears as an alternative treatment. Here, we investigate the effects of laser irradiation in an experimental model of tendinitis induced by collagenase injection on rats' Achilles tendon, verifying its action in important inflammatory markers. Male Wistar rats were used and divided into five groups: control saline (C), non-treated tendinitis (NT) and tendinitis treated with sodium diclofenac (D) or laser (1 J) and (3 J). The tendinitis was induced by collagenase (100 μg/tendon) on the Achilles tendon, which was removed for further analyses. The gene expression for COX-2; TNF-α; IL-6; and IL-10 (RT-PCR) was measured. The laser irradiation (660 nm, 100 mW, 3 J) used in the treatment of the tendinitis induced by collagenase in Achilles tendon in rats was effective in the reduction of important pro-inflammatory markers such as IL-6 and TNF-α, becoming a promising tool for the treatment of tendon diseases