Identification of Pathway-Specific Serum Biomarkers of Response to Glucocorticoid and Infliximab Treatment in Children with Inflammatory Bowel Disease

Objective: Serum biomarkers may serve to predict early response to therapy, identify relapse, and facilitate drug development in inflammatory bowel disease (IBD). Biomarkers are particularly important in children, in whom achieving early remission and minimizing procedures are especially beneficial. Methods: We profiled protein and micro RNA (miRNA) in serum from patients pre- and post-therapy, to identify molecular markers of pharmacodynamic effect. Serum was obtained from children with IBD before and after treatment with either corticosteroids (prednisone; n=12) or anti-tumor necrosis factor-α biologic (infliximab; n=7). Over 1,100 serum proteins were assayed using aptamer-based SOMAscan proteomics, and 22 miRNAs analyzed by quantitative real time PCR. Concordance of longitudinal changes between the groups was used to identify markers responsive to treatment. Bioinformatic analysis was used to build insight into mechanisms of changes in response to treatment. Results: We identified 18 proteins and three miRNAs responsive to both prednisone and infliximab. Eight markers that decreased are associated with inflammation and have gene promoters regulated by nuclear factor (NF)-κB. Several that increased are associated with resolving inflammation and tissue damage. We also identified six markers that appear to be steroid-specific, three of which have glucocorticoid receptor binding elements in their promoter region. Conclusions: Serum markers regulated by the inflammatory transcription factor NF-κB are potential candidates for pharmacodynamic biomarkers that, if correlated with later outcomes like endoscopic or histologic healing, could be used to monitor treatment, optimize dosing, and enhance drug development. The pharmacodynamic biomarkers identified here hold potential to improve both clinical care and drug development. Further studies are warranted to investigate these markers as early predictors of response, or possibly surrogate outcomes

Investigating the Role of Hypothalamic Tumor Involvement in Sleep and Cognitive Outcomes Among Children Treated for Craniopharyngioma

Objective: Despite excellent survival prognosis, children treated for craniopharyngioma experience significant morbidity. We examined the role of hypothalamic involvement (HI) in excessive daytime sleepiness (EDS) and attention regulation in children enrolled on a Phase II trial of limited surgery and proton therapy. Methods: Participants completed a sleep evaluation (N = 62) and a continuous performance test (CPT) during functional magnetic resonance imaging (fMRI; n = 29) prior to proton therapy. Results: EDS was identified in 76% of the patients and was significantly related to increased HI extent (p = .04). There was no relationship between CPT performance during fMRI and HI or EDS. Visual examination of group composite fMRI images revealed greater spatial extent of activation in frontal cortical regions in patients with EDS, consistent with a compensatory activation hypothesis. Conclusion: Routine screening for sleep problems during therapy is indicated for children with craniopharyngioma, to optimize the timing of interventions and reduce long-term morbidity

Comparison of three nudge interventions (priming, default option, and perceived variety) to promote vegetable consumption in a self-service buffet setting.

BACKGROUND: Dietary choices in out-of-home eating are key for individual as well as for public health. These dietary choices are caused by a wide array of determinants, one of which is automatic decision-making. Nudging is attracting considerable interest due to its understanding and application of heuristic biases among consumers. The aim of this study is to test and compare three nudges in promoting vegetable consumption among test persons in a food lab-based experiment. METHODS: The initial sample consisted of 88 participants recruited in Copenhagen, Denmark. Each study participant was randomly assigned to one of the three experiments: priming, default and perceived variety. The priming arm of the experiment consisted of creating a leafy environment with green plants and an odour of herbs. In the default arm of the experiment, the salad was pre-portioned into a bowl containing 200g of vegetables. The third experiment divided the pre-mixed salad into each of its components, to increase the visual variety of vegetables, yet not providing an actual increase in items. Each individual was partaking twice thus serving as her/his own control, randomly assigned to start with control or experimental setting. RESULTS: The default experiment successfully increased the energy intake from vegetables among the study participants (124 kcal vs. 90 kcal in control, p<0.01). Both the priming condition and perceived variety reduced the total energy intake among the study participants (169 kcal, p<0.01 and 124 kcal, p<0.01, respectively), mainly through a decrease in the meat-based meal component. CONCLUSIONS: Considerable progress has been made with regard to understanding the use of nudging in promoting a healthier meal composition, including increasing vegetable intake. This study suggests that the nature of a nudge-based intervention can have different effects, whether it is increasing intake of healthy components, or limiting intake of unhealthy meal components. This work has demonstrated that consumer behaviour can be influenced without restricting or providing incentives for behaviour change. The present findings have promising application to the foodservice sector

Investigating severity of symptoms associated with Posterior Fossa Syndrome as predictors of long-term cognitive and functional outcomes: A case series

Purpose: Patients may experience Posterior Fossa Syndrome (PFS) also often referred to as Cerebellar Mutism Syndrome (CMS) following medulloblastoma resection. PFS/CMS is associated with delayed onset speech/language changes, motor impairments, and emotional lability. While initially considered a temporary condition, PFS/CMS symptoms impacting patients’ quality of life persist. Existing literature is limited by largely retrospective studies, with short follow-up, and exclusion of cognitive assessment during acute recovery. The current study reviews the history of patients with PFS/CMS acutely and throughout treatment who were matched on variables associated with poorer long-term cognitive functioning. Procedures: The Cognitive and Linguistic Scale (CALS) was used to evaluate two participants with PFS/CMS across the course of cancer-directed treatment. In addition, gold-standard measures of cognitive, academic, motor, language, and adaptive functioning were utilized following completion of treatment. Findings: Mutism duration varied between the two patients (Patient 1 = 88 days, Patient 2 = 28 days). The longer period of mutism was associated with lower CALS scores before radiation therapy, which persisted through pre-chemotherapy and end of treatment. The longer period of mutism and lower initial CALS score were associated with greater reading and math difficulties at the 1- and 2-years post-diagnosis evaluations, and were associated with significantly lower processing speed, visuomotor integration, and adaptive functioning at the 2-years post-diagnosis evaluation. Conclusions: Medulloblastoma survivors are at risk for cognitive late effects. Early assessment of cognitive skills during initial recovery from PFS/CMS (i.e., before mutism resolves) is feasible and may predict severity of PFS/CMS and long-term outcomes, thus providing earlier opportunity to guide caregiver education and advocate for support services

In pediatric patients with brain tumors treated with radiation therapy

Background. Pediatric patients with brain tumors who are treated with radiation therapy (RT) are at risk for neurocognitive and psychosocial late effects. Research to date has primarily examined these outcomes at a group level and in isolation. Advanced statistical techniques allow for person-centered analyses, as well as examination of relationships between domain-specific trajectories. Methods. Patients with brain tumors (craniopharyngioma, ependymoma, low-grade astrocytoma, high-grade astrocytoma) were enrolled on a phase II clinical trial of RT.Three hundred and fifty patients completed serial neurocognitive assessments as part of their treatment monitoring, including pre-RT baseline, 6 months post-RT, and then yearly for 5 years.This secondary analysis focused on outcomes of cognition (estimated IQ, parent-reported attention problems) and psychosocial effects (parent-reported socialization and social problems) post-RT. Results. Latent growth curve modeling indicated that estimated IQ and socialization were best served by quadratic models, while attention and social problems were best served by linear models. Growth mixture modeling indicated 3-class models were the best fit for IQ and socialization, and 2-class models for attention and social problems. Baseline IQ and socialization scores were associated, but there was no association over time.Young age at diagnosis and pre-RT treatments (surgery, chemotherapy) were associated with class membership. Conclusions. Person-centered statistical analyses provide rich information regarding the variability in neurocognitive and psychosocial functioning following RT for pediatric brain tumor. While many patients do well over time, a subset are exhibiting significant cognitive and/or psychosocial deficits. Class membership was associated with some medical factors (eg, pre-radiation surgery/chemotherapy, age at diagnosis, shunted hydrocephalus)

Executive function late effects in survivors of pediatric brain tumors and acute lymphoblastic leukemia

BACKGROUND: Survivors of pediatric brain tumors (BT) and acute lymphoblastic leukemia (ALL) are at risk for neurocognitive late effects related to executive function. PROCEDURE: Survivors of BT (48) and ALL (50) completed neurocognitive assessment. Executive function was compared to estimated IQ and population norms by diagnostic group. RESULTS: Both BT and ALL demonstrated relative executive function weaknesses. As a group, BT survivors demonstrated weaker executive functioning than expected for age. Those BT survivors with deficits exhibited a profile suggestive of global executive dysfunction, while affected ALL survivors tended to demonstrate specific rapid naming deficits. CONCLUSION: Findings suggest that pediatric BT and ALL survivors may exhibit different profiles of executive function late effects, which may necessitate distinct intervention plans