The quality of subgroup analyses in chronic pain randomized controlled trials: a methodological review.

The quality of subgroup analyses (SGAs) in chronic non-cancer pain trials is uncertain. The purpose of this study was to address this issue. We conducted a comprehensive search in MEDLINE and EMBASE from January 2012 to September 2018 to identify eligible trials. Two pairs of reviewers assessed the quality of the SGAs and the credibility of subgroup claims using the 10 criteria developed by Sun et al. in 2012. The associations between the quality of the SGAs and the studies' characteristics including risk of bias, funding sources, sample size, and the latest impact factor, were assessed using multivariable logistic regression. Our search retrieved 3,401 articles of which 66 were eligible. The total number of SGAs was 177 of which 52 (29.4%) made a subgroup claim. Of these, only 15 (8.5%) were evaluated as being of high quality. Among the 30 SGAs that claimed subgroup effects using an appropriate method of performing interaction tests, the credibility of only 5 were assessed as high. None of the subgroup claims met all the credibility criteria. No significant association was found between the quality of SGAs and the studies' characteristics. The quality of the SGAs performed in chronic pain trials was poor. To enhance the quality of SGAs, scholars should consider the developed criteria when designing and conducting trials, particularly those which need to be specified a priori .

Impact of insulin on the intestinal microcirculation in a model of sepsis-related hyperglycemia.

BACKGROUND: Sepsis involves dysfunctional glucose metabolism. Among patients with sepsis, hyperglycemia is frequent and insulin administration has been evaluated for glycemic control to improve patient outcomes. Only few studies have examined the hyperglycemic microcirculation and the impact of insulin on the microvasculature in sepsis. OBJECTIVE: To study the functional capillary density (FCD) and leukocyte activation within the intestinal microcirculation in endotoxin-induced experimental sepsis. METHODS: In 50 male Lewis rats, endotoxemia was induced with lipopolysaccharide (LPS; 5 mg/kg). Low dose (LD) glucose was administered to avoid insulin-induced hypoglycemia. High dose (HD) glucose was administered to model sepsis-related hyperglycemia. Animals in LD and HD glucose groups received an insulin bolus (1.4 IU/kg). Two hours after LPS administration, intravital microscopy (IVM) of the terminal ileum was performed, and FCD and leukocyte adherence were measured in a blinded fashion. Blood glucose levels were measured every 30 min following the onset of endotoxemia. Plasma samples were collected 3 h after the onset of endotoxemia to measure IFN-γ, TNF-α, IL-1α, IL-4, GM-CSF and MCP-1 levels using multiplex bead immunoassay. RESULTS: Endotoxemia significantly reduced FCD and increased leukocyte adherence within the intestinal microvasculature. LD and HD glucose administration combined with insulin improved the FCD and decreased the adherence of leukocytes in endotoxemic animals as did HD glucose administration alone. Consistent with these results, IL-4, IL-1α, GM-CSF and IFN-γ levels were decreased following combined HD glucose and insulin administration in endotoxemic animals. CONCLUSIONS: Insulin administration, as well as an endogenous insulin response triggered by HD glucose administration, improved the FCD and decreased leukocyte activation in endotoxemic rats. The results of this study give insight into the immune and vaso-modulatory role of insulin administration during experimental endotoxemia, and may be extrapolated for clinical sepsis and other critical illnesses with marked microcirculatory dysfunction.

Iron chelation as novel treatment for lung inflammation in cystic fibrosis.

Cystic fibrosis (CF) is an autosomal recessive genetic disorder that results in defective cystic fibrosis transmembrane conductance regulator (CFTR) protein expression and function in various tissues. The leading cause of CF mortality and morbidity is the progressive destruction of the lungs due to recurrent infections and chronic inflammation. CFTR defect also affects immune cells, including neutrophils, resulting in ineffective, severe and persistent inflammatory response. Since unopposed recruitment of neutrophils significantly contributes to lung tissue damage through the generation of reactive oxygen species (ROS), we hypothesize that the administration of iron chelators could serve as a novel treatment to attenuate chronic inflammation in CF lungs since iron is significantly involved in ROS production by neutrophils. Ideally, the iron chelator should sequester host iron effectively, prevent bacterial access to chelator-bound iron and penetrates lung tissues efficiently, e.g. by inhalational route of administration.