Exome Analysis of Rare and Common Variants within the NOD Signaling Pathway.

Pediatric inflammatory bowel disease (pIBD) is a chronic heterogeneous disorder. This study looks at the burden of common and rare coding mutations within 41 genes comprising the NOD signaling pathway in pIBD patients. 136 pIBD and 106 control samples underwent whole-exome sequencing. We compared the burden of common, rare and private mutation between these two groups using the SKAT-O test. An independent replication cohort of 33 cases and 111 controls was used to validate significant findings. We observed variation in 40 of 41 genes comprising the NOD signaling pathway. Four genes were significantly associated with disease in the discovery cohort (BIRC2 p = 0.004, NFKB1 p = 0.005, NOD2 p = 0.029 and SUGT1 p = 0.047). Statistical significance was replicated for BIRC2 (p = 0.041) and NOD2 (p = 0.045) in an independent validation cohort. A gene based test on the combined discovery and replication cohort confirmed association for BIRC2 (p = 0.030). We successfully applied burden of mutation testing that jointly assesses common and rare variants, identifying two previously implicated genes (NFKB1 and NOD2) and confirmed a possible role in disease risk in a previously unreported gene (BIRC2). The identification of this novel gene provides a wider role for the inhibitor of apoptosis gene family in IBD pathogenesis.

Molecular diagnosis of infantile onset inflammatory bowel disease by exome sequencing.

Pediatric-onset inflammatory bowel disease (IBD) is known to be associated with severe disease, poor response to therapy, and increased morbidity and mortality. We conducted exome sequencing of two brothers from a non-consanguineous relationship who presented before the age of one with severe infantile-onset IBD, failure to thrive, skin rash, and perirectal abscesses refractory to medical management. We examined the variants discovered in all known IBD-associated and primary immunodeficiency genes in both siblings. The siblings were identified to harbor compound heterozygous mutations in IL10RA (c.784C>T, p.Arg262Cys; c.349C>T, p.Arg117Cys). Upon molecular diagnosis, the proband underwent successful hematopoietic stem cell transplantation and demonstrated marked clinical improvement of all IBD-associated clinical symptoms. Exome sequencing can be an effective tool to aid in the molecular diagnosis of pediatric-onset IBD. We provide additional evidence of the safety and benefit of HSCT for patients with IBD due to mutations in the IL10RA gene.

Games for Cystic Fibrosis: Creating the Will to Get Better.

Adolescent cystic fibrosis has significant impacts on the physical, psychological, and social development of the kids who suffer from it. Physical therapies can be effective, but compliance in the age group is a challenge that has gotten the attention of doctors, nurses, and game developers. The following roundtable discussion illustrates some of the work being done in this important field.

Can a Simulation Game Change Cystic Fibrosis Patients' Attitudes Toward Treatment Adherence?

OBJECTIVE: The authors hypothesized that playing a simulation game designed according to Multiple Identification Theory (MIT) would improve attitudes toward treatment adherence among adolescent cystic fibrosis (CF) patients. SUBJECTS AND METHODS: Study participants (n=16) were recruited from a large Midwestern children's hospital. As part of a within-group pilot study, they played "My Life with CF," an MIT simulation game. Their attitudes toward treatment adherence and general decision-making were assessed prior to playing the game. They were measured again immediately post-play and 1 month afterward. RESULTS: Statistically significant differences (P<0.05) were found immediately post-treatment on questionnaires concerning participants' holding present versus future-centered orientations and their attitudes toward adherence. One month post-treatment, significant differences were found regarding participants' attitudes toward adherence and whether luck or effort determines what happens to them in life. Effect sizes for all these differences ranged from large (r(2)=0.31) to very large (r(2)=0.94). CONCLUSION: The MIT-based "My Life with CF" game was effective at changing adolescent CF patients' attitudes toward adherence.

Volitional and accidental nonadherence to pediatric inflammatory bowel disease treatment plans: initial investigation of associations with quality of life and disease activity.

OBJECTIVE: To examine rates of volitional and accidental nonadherence, and explore potential differential associations of each with disease activity and quality of life (QOL), in pediatric patients with inflammatory bowel disease (IBD). METHODS: One hundred families (100 parents, 78 adolescents) recruited from a large Midwestern children's hospital reported on the child's medication nonadherence and QOL. Healthcare providers supplied disease activity ratings. RESULTS: Most adolescents (73.1%) and parents (70.1%) reported engaging in accidental nonadherence, whereas a smaller group (35 and 30%, respectively) reported engaging in volitional nonadherence to the child's prescribed medication regimen. Frequency of accidental nonadherence was unrelated to disease activity or any specific QOL area examined, whereas greater frequency of volitional nonadherence was associated with greater disease activity and poorer parent reported psychosocial QOL. CONCLUSIONS: Nonadherence and the relationship with disease severity and QOL may be more complex for children with IBD than understood through previous work.

Including the perspective of the adolescent in palliative care preferences.

Improving communication with an adolescent with a life-limiting or life-threatening disease is key to providing comprehensive care and support. A pediatric hospital in the Midwest uses a communication tool (CCCT) to facilitate conversations about the adolescent's wishes, beliefs, values, preferences and goals. Information gathered in a CCCT conversation becomes a key intervention to providing compassionate, appropriate care that is directed toward quality of life consistent with the adolescent's and family's goals.

Implementation of a palliative care team in a pediatric hospital.

Recommendations for best practice from the American Academy of Pediatrics include the availability of palliative care for children with life-threatening or life-limiting health care conditions. The uniqueness of the both the pediatric population and a pediatric health care setting requires changing the culture that previously has provided only curative or hospice care to these individuals. Methods to provide palliative care alongside of treatment and coordination of these efforts must be multidisciplinary and include family members.

Development of a pediatric palliative care team.

The American Academy of Pediatrics has provided clinical recommendations for palliative care needs of children. This article outlines the steps involved in implementing a pediatric palliative care program in a Midwest pediatric magnet health care facility. The development of a Pediatric Advanced Comfort Care Team was supported by hospital administration and funded through grants. Challenges included the development of collaborative relationships with health care professionals from specialty areas. Pediatric Advanced Comfort Care Team services, available from the time of diagnosis, are provided by a multidisciplinary team of health care professionals and individualized on the basis of needs expressed by each child and his or her family.

Safety of infliximab treatment in pediatric patients with inflammatory bowel disease.

BACKGROUND: Infliximab appears to be efficacious in the treatment of pediatric Crohn disease (CD). There are few large-scale pediatric studies on the complications of infliximab therapy. METHODS: A retrospective review of all infliximab infusions administered to IBD patients at a tertiary children's hospital was undertaken. Data was obtained from an infliximab infusion database maintained in the section of Pediatric Gastroenterology, pharmacy records and patient charts. RESULTS: 594 infusions were administered to 111 IBD patients (88 CD and 23 UC; 55 male and 56 female; ages 4 to 20 years; mean age, 13.4 years). The number of infusions ranged from 1 to 24 with a mean of 5.4/patient. Infusion reactions occurred in 8.1% of patients (seven early and two delayed) and in 1.5% of all infusions. Reactions occurred more frequently in female patients (14% versus 2%; P = 0.03). All reactions were mild and responded rapidly to treatment. Four patients had infections deemed unusual, including three cutaneous tinea infections and one case of shingles. CONCLUSION: Infliximab is safe in pediatric IBD patients with a low incidence of generally mild reactions that respond rapidly to intervention. Infusion reactions are more common in female patients. Our patients had no serious infectious complications, although cutaneous tinea infection may represent a newly reported associated complication.