Oral insulin immunotherapy in children at risk for type 1 diabetes in a randomised controlled trial

AIMS/HYPOTHESIS Oral administration of antigen can induce immunological tolerance. Insulin is a key autoantigen in childhood type 1 diabetes. Here, oral insulin was given as antigen-specific immunotherapy before the onset of autoimmunity in children from age 6~months to assess its safety and immune response actions on immunity and the gut microbiome. METHODS A phase I/II randomised controlled trial was performed in a single clinical study centre in Germany. Participants were 44 islet autoantibody-negative children aged 6~months to 2.99~years who had a first-degree relative with type 1 diabetes and a susceptible HLA DR4-DQ8-containing genotype. Children were randomised 1:1 to daily oral insulin (7.5~mg with dose escalation to 67.5~mg) or placebo for 12~months using a web-based computer system. The primary outcome was immune efficacy pre-specified as induction of antibody or T cell responses to insulin and measured in a central treatment-blinded laboratory. RESULTS Randomisation was performed in 44 children. One child in the placebo group was withdrawn after the first study visit and data from 22 insulin-treated and 21 placebo-treated children were analysed. Oral insulin was well tolerated with no changes in metabolic variables. Immune responses to insulin were observed in children who received both insulin (54.5%) and placebo (66.7%), and the trial did not demonstrate an effect on its primary outcome (p = 0.54). In exploratory analyses, there was preliminary evidence that the immune response and gut microbiome were modified by the INS genotype Among children with the type 1 diabetes-susceptible INS genotype (n = 22), antibody responses to insulin were more frequent in insulin-treated (72.7%) as compared with placebo-treated children (18.2%; p = 0.03). T cell responses to insulin were modified by treatment-independent inflammatory episodes. CONCLUSIONS/INTERPRETATION The study demonstrated that oral insulin immunotherapy in young genetically at-risk children was safe, but was not associated with an immune response as predefined in the trial primary outcome. Exploratory analyses suggested that antibody responses to oral insulin may occur in children with a susceptible INS genotype, and that inflammatory episodes may promote the activation of insulin-responsive T cells. TRIAL REGISTRATION Clinicaltrials.gov NCT02547519 FUNDING: The main funding source was the German Center for Diabetes Research (DZD e.V.)

Recruiting young pre-symptomatic children for a clinical trial in type 1 diabetes: insights from the Fr1da insulin intervention study

Background: Although detection of children at high risk of developing type 1 diabetes and diagnosis of early stages is possible, up to now there exists no approved therapy to delay or prevent type 1 diabetes. Thus it is vital to develop evidence-based interventions. For this a sufficient number of trial participants is crucial but difficult to obtain especially in asymptomatic children. Aim: Identifying family characteristics that lead to or impede trial participation and analyze reasons stated by families for non-participation. Methods: Participants for the Fr1da Insulin Intervention study are recruited from the Fr1da study, a population based screening for early stage type 1 diabetes in Bavaria. Families with eligible children were invited to enroll. We analyzed sex and age of the child, distance of the family to the study center in Munich and the existence of a first degree family member with type 1 as possible influential factors for study participation. We also analyzed reasons stated by families who declined study participation in a phone interview. Results: Of 146 eligible children 77 (53%) were enrolled into the trial. None of the tested family characteristics differed significantly between the enrolling and the families not participating, but in general enrolling families lived closer to the study site than families not participating. This is also reflected in the reasons given by non-participating families. The most frequent reason stated were time restrictions. The second most frequent reason was the venous blood draw. Conclusion: The factors for non-participation identified in this project need be taken into account for the design of future trials in young children to ensure proper recruitment and thus to generate valid results for medical treatment of children. More research on the reason of participation and non-participation in clinical trials is needed. Keywords: Type 1 diabetes, Trial recruitment, Trial enrollment, Infants, Children, Asymptomati

Executive Functions and Pain A Systematic Review

A growing body of literature suggests that chronic-pain patients suffer from problems in various neuropsychological domains, including executive functioning. In order to better understand which components of executive functioning (inhibition, shifting and/or updating) might be especially affected by pain and which mechanisms might underlie this association, we conducted a systematic review, including both chronic-pain studies as well as experimental-pain studies. The chronic-pain studies (N = 57) show that pain is associated with poorer executive functioning. The findings of experimental-pain studies (N = 28) suggest that this might be a bidirectional relationship: Pain can disrupt executive functioning, but poorer executive functioning might also be a risk factor for higher vulnerability to pain

Conditioned Pain Modulation (CPM) Effects Captured in Facial Expressions

Purpose: Conditioned pain modulation (CPM) is most often assessed using self-report of pain. However, self-report of pain is not always available (eg in individuals with cognitive impairment) and is susceptible to report bias. In comparison, the facial expression of pain is more reflex-like and represents one of the most sensitive and specific non-verbal signals of pain. The aim of the present study was to investigate whether the facial expression of pain is sensitive enough to capture endogenous pain inhibition as elicited during CPM paradigms. Patients and Methods: In total, 26 female participants took part in this study. Facial and verbal responses to phasic heat pain were assessed once while participants immersed their hand in a hot water bath and once without additional stimulation. Facial responses were analyzed using the Facial Action Coding System (FACS). Verbal responses were assessed using a Numerical Rating Scale (NRS). Results: Pain-relevant facial responses as well as pain ratings to phasic heat pain were significantly reduced when participants simultaneously immersed their hand in a hot water bath compared to baseline. Thus, CPM effects could be demonstrated both on subjective as well as on facial responses. Moreover, CPM-induced changes in pain-relevant facial responses and in NRS ratings were significantly correlated. Conclusion: The present study shows that facial expressions of pain are sensitive enough to capture CPM effects. Given the proven clinical usefulness of assessing CPM, the parallel assessment of verbal and facial CPM effects might be a promising approach with wider scope of applications. Further research in other demographic healthy participant and clinical cohorts is warranted

Does EEG activity during painful stimulation mirror more closely the noxious stimulus intensity or the subjective pain sensation?

Background: Many researchers have tried to investigate pain by studying brain responses. One method used to investigate pain-related brain responses is continuous electroencephalography (EEG). The objective of the current study is to add on to our understanding of EEG responses during pain, by differentiation between EEG patterns indicative of (i) the noxious stimulus intensity and (ii) the subjective pain sensation. Methods: EEG was recorded during the administration of tonic experimental pain, consisting of six minutes of contact heat applied to the leg via a thermode. Two stimuli above pain threshold, one at pain threshold and two non-painful stimuli were administered. Thirty-six healthy participants provided a subjective pain rating during thermal stimulation. Relative EEG power was calculated for the frequency bands alpha1, alpha2, beta1, beta2, delta, and theta. Results: Whereas EEG activity could not be predicted by stimulus intensity (except in one frequency band), subjective pain sensation could significantly predict differences in EEG activity in several frequency bands. An increase in the subjective pain sensation was associated with a decrease in alpha2, beta1, beta2 as well as in theta activity across the midline electrodes. Conclusion: The subjective experience of pain seems to capture unique variance in EEG activity above and beyond what is captured by noxious stimulus intensity

Internalization and Coreceptor Expression Are Critical for TLR2-Mediated Recognition of Lipoteichoic Acid in Human Peripheral Blood

Lipoteichoic acid (LTA), a ubiquitous cell wall component of Gram-positive bacteria, represents a potent immunostimulatory molecule. Because LTA of a mutant Staphylococcus aureus strain lacking lipoproteins (Δlgt-LTA) has been described to be immunobiologically inactive despite a lack of ascertained structural differences to wild-type LTA (wt-LTA), we investigated the functional requirements for the recognition of Δlgt-LTA by human peripheral blood cells. In this study, we demonstrate that Δlgt-LTA–induced immune activation critically depends on the immobilization of LTA and the presence of human serum components, which, to a lesser degree, was also observed for wt-LTA. Under experimental conditions allowing LTA-mediated stimulation, we found no differences between the immunostimulatory capacity of Δlgt-LTA and wt-LTA in human blood cells, arguing for a limited contribution of possible lipoprotein contaminants to wt-LTA–mediated immune activation. In contrast to human blood cells, TLR2-transfected human embryonic kidney 293 cells could be activated only by wt-LTA, whereas activation of these cells by Δlgt-LTA required the additional expression of TLR6 and CD14, suggesting that activation of human embryonic kidney 293 cells expressing solely TLR2 is probably mediated by residual lipoproteins in wt-LTA. Notably, in human peripheral blood, LTA-specific IgG Abs are essential for Δlgt-LTA–mediated immune activation and appear to induce the phagocytic uptake of Δlgt-LTA via engagement of FcγRII. In this study, we have elucidated a novel mechanism of LTA-induced cytokine induction in human peripheral blood cells that involves uptake of LTA and subsequent intracellular recognition driven by TLR2, TLR6, and CD14