Certainty of genuine treatment increases drug responses among intellectually disabled patients.

OBJECTIVE: To determine the placebo component of treatment responses in patients with intellectual disability (ID). METHODS: A statistical meta-analysis comparing bias-corrected effect sizes (Hedges g) of drug responses in open-label vs placebo-controlled clinical trials was performed, as these trial types represent different certainty of receiving genuine treatment (100% vs 50%). Studies in fragile X, Down, Prader-Willi, and Williams syndrome published before June 2015 were considered. RESULTS: Seventeen open-label trials (n = 261, 65% male; mean age 23.6 years; mean trial duration 38 weeks) and 22 placebo-controlled trials (n = 721, 62% male; mean age 17.1 years; mean trial duration 35 weeks) were included. The overall effect size from pre to post treatment in open-label studies was g = 0.602 (p = 0.001). The effect of trial type was statistically significant (p = 0.001), and revealed higher effect sizes in studies with 100% likelihood of getting active drug, compared to both the drug and placebo arm of placebo-controlled trials. We thus provide evidence for genuine placebo effects, not explainable by natural history or regression toward the mean, among patients with ID. CONCLUSIONS: Our data suggest that clinical trials in patients with severe cognitive deficits are influenced by the certainty of receiving genuine medication, and open-label design should thus not be used to evaluate the effect of pharmacologic treatments in ID, as the results will be biased by an enhanced placebo component.

Placebo Responses in Genetically Determined Intellectual Disability: A Meta-Analysis.

BACKGROUND: Genetically determined Intellectual Disability (ID) is an intractable condition that involves severe impairment of mental abilities such as learning, reasoning and predicting the future. As of today, little is known about the placebo response in patients with ID. OBJECTIVE: To determine if placebo response exists in patients with genetically determined ID. DATA SOURCES AND STUDY SELECTION: We searched Medline/PubMed, EMBASE, CENTRAL and PsycINFO to find all placebo-controlled double-blind randomized clinical trials (RCTs) in patients with genetically determined ID, published up to April 2013, focusing on core ID symptoms. DATA EXTRACTION AND SYNTHESIS: Two investigators extracted outcome data independently. MAIN OUTCOMES AND MEASURES: Bias-corrected standardized mean difference (Hedge's g) was computed for each outcome measure, using the Comprehensive Meta-Analysis software. A priori defined patient sub-groups were analyzed using a mixed-effect model. The relationship between pre-defined continuous variable moderators (age, IQ, year of publication and trial duration) and effect size was analyzed using meta-regression. RESULTS: Twenty-two placebo-controlled double-blind RCTs met the inclusion criteria (n = 721, mean age = 17.1 years, 62% men, mean trial duration = 35 weeks). There was a significant overall placebo response from pre- to post-treatment in patients with ID (g = 0.468, p = 0.002), both for "subjective outcomes" (a third-person's evaluation of the patient) (g = 0.563, p = 0.022) and "objective outcomes" (direct evaluation of the patient's abilities) (g = 0.434, p = 0.036). Individuals with higher IQ had higher response to placebo (p = 0.02) and no placebo response was observed in ID patients with comorbid dementia. A significant effect of age (p = 0.02) was found, indicating higher placebo responses in treatment of younger patients. CONCLUSIONS AND RELEVANCE: Results suggest that patients with genetically determined ID improve in the placebo arm of RCTs. Several mechanisms may contribute to placebo effects in ID, including expectancy, implicit learning and "placebo-by-proxy" induced by clinicians/family members. As the condition is refractory, there is little risk that improvements are explained by spontaneous remission. While new avenues for treatment of genetically determined ID are emerging, our results demonstrate how contextual factors can affect clinical outcomes and emphasize the importance of being vigilant on the role of placebos when testing novel treatments in ID.

Risk factors and risk adjustment for surgical site infections in pediatric cardiothoracic surgery patients.

BACKGROUND: The complexity of congenital cardiac defects and the aggressive medical management required to support patients through their recovery place children at high risk for surgical site infection (SSI). METHODS: We conducted a retrospective review of children undergoing cardiothoracic surgery at a tertiary care referral center between January 1, 2000, and June 30, 2001. Preoperative, intraoperative, and postoperative data were assessed by multivariate analysis. RESULTS: Of 726 surgical procedures performed in 626 patients, SSIs occurred after 46 procedures performed in 46 patients (6.3%). Infections were superficial (n = 22; 47.8%), deep tissue (n = 7; 15.2%), or organ space (n = 17; 37.0%), including 5 episodes of mediastinitis. Median time to SSI was 10 days; 36% of the infections were identified after discharge. On multivariate analysis, children with SSIs were more likely to have been <30 days old (odds ratio [OR], 2.9; 95% confidence interval [CI], 1.2-70), to have a perioperative medical device, and to use parenteral nutrition (OR, 3.3; 95% CI, 1.4-7.9). Multiple severity of illness scores, the Risk Adjustment for Congenital Heart Surgery (RACHS-1) category, and longer duration of postoperative antimicrobials were not associated with SSI. CONCLUSION: The use of perioperative medical interventions increases the risk of SSI in young children after cardiac surgery. Prolonged postoperative courses of antimicrobials should be avoided in the absence of documented infection.

Tricarbocyanine cholesteryl laurates labeled LDL: new near infrared fluorescent probes (NIRFs) for monitoring tumors and gene therapy of familial hypercholesterolemia.

For monitoring low-density lipoprotein receptors (LDLr) in tumors and in livers of patients with familial hypercholesterolemia (FH) treated with gene therapy, a series of tricarbocyanine cholesteryl laurates were synthesized with the cholesteryl laurate moiety serving as the lipid-chelating anchor for low-density lipoprotein (LDL). One of these conjugates, TCL17, was successfully used to label LDL to give a new NIRF, TCL17-LDL. Ex vivo biological studies on an LDLr overexpressing tumor model, human hepatoblastoma G(2) (HepG(2)), confirmed that this NIRF were internalized selectively by the tumor and detected with high sensitivity by a low-temperature 3-D redox scanner.