Comparative Effectiveness of Anti-TNF in Combination With Low-Dose Methotrexate vs Anti-TNF Monotherapy in Pediatric Crohn's Disease: A Pragmatic Randomized Trial.

BACKGROUND & AIMS: Tumor necrosis factor inhibitors, including infliximab and adalimumab, are a mainstay of pediatric Crohn's disease therapy; however, nonresponse and loss of response are common. As combination therapy with methotrexate may improve response, we performed a multicenter, randomized, double-blind, placebo-controlled pragmatic trial to compare tumor necrosis factor inhibitors with oral methotrexate to tumor necrosis factor inhibitor monotherapy. METHODS: Patients with pediatric Crohn's disease initiating infliximab or adalimumab were randomized in 1:1 allocation to methotrexate or placebo and followed for 12-36 months. The primary outcome was a composite indicator of treatment failure. Secondary outcomes included anti-drug antibodies and patient-reported outcomes of pain interference and fatigue. Adverse events (AEs) and serious AEs (SAEs) were collected. RESULTS: Of 297 participants (mean age, 13.9 years, 35% were female), 156 were assigned to methotrexate (110 infliximab initiators and 46 adalimumab initiators) and 141 to placebo (102 infliximab initiators and 39 adalimumab initiators). In the overall population, time to treatment failure did not differ by study arm (hazard ratio, 0.69; 95% CI, 0.45-1.05). Among infliximab initiators, there were no differences between combination and monotherapy (hazard ratio, 0.93; 95% CI, 0.55-1.56). Among adalimumab initiators, combination therapy was associated with longer time to treatment failure (hazard ratio, 0.40; 95% CI, 0.19-0.81). A trend toward lower anti-drug antibody development in the combination therapy arm was not significant (infliximab: odds ratio, 0.72; 95% CI, 0.49-1.07; adalimumab: odds ratio, 0.71; 95% CI, 0.24-2.07). No differences in patient-reported outcomes were observed. Combination therapy resulted in more AEs but fewer SAEs. CONCLUSIONS: Among adalimumab but not infliximab initiators, patients with pediatric Crohn's disease treated with methotrexate combination therapy experienced a 2-fold reduction in treatment failure with a tolerable safety profile. CLINICALTRIALS: gov, Number: NCT02772965.

High Body Mass Index and Response to Anti-Tumor Necrosis Factor Therapy in Pediatric Crohn's Disease.

INTRODUCTION: Obesity is common among patients with pediatric Crohn's disease (PCD). Some adult studies suggest obese patients respond less well to anti-tumor necrosis factor (TNF) treatment. This study sought compares anti-TNF response and anti-TNF levels between pediatric patients with normal and high body mass index (BMI). METHODS: The COMBINE trial compared anti-TNF monotherapy with combination therapy with methotrexate in patients with PCD. In this secondary analysis, a comparison of time-to-treatment failure among patients with normal BMI vs BMI Z -score >1, adjusting for prescribed anti-TNF (infliximab [IFX] or adalimumab [ADA]), trial treatment assignment (combination vs monotherapy), and relevant covariates. Median anti-TNF levels across BMI category was also examined. RESULTS: Of 224 participants (162 IFX initiators and 62 ADA initiators), 111 (81%) had a normal BMI and 43 (19%) had a high BMI. High BMI was associated with treatment failure among ADA initiators (7/10 [70%] vs 12/52 [23%], hazard ratio 0.29, P = 0.007) but not IFX initiators. In addition, ADA-treated patients with a high BMI had lower ADA levels compared with those with normal BMI (median 5.8 vs 12.8 µg/mL, P = 0.02). IFX trough levels did not differ between BMI groups. DISCUSSION: Overweight and obese patients with PCD are more likely to experience ADA treatment failure than those with normal BMI. Higher BMI was associated with lower drug trough levels. Standard ADA dosing may be insufficient for overweight children with PCD. Among IFX initiators, there was no observed difference in clinical outcomes or drug levels, perhaps due to weight-based dosing and/or greater use of proactive drug monitoring.

Humoral and cellular response to the COVID-19 vaccine in immunocompromised children.

BACKGROUND: A suboptimal response to the 2-dose COVID-19 vaccine series in the immunocompromised population prompted recommendations for a 3rd primary dose. We aimed to determine the humoral and cellular immune response to the 3rd COVID-19 vaccine in immunocompromised children. METHODS: Prospective cohort study of immunocompromised participants, 5-21 years old, who received 2 prior doses of an mRNA COVID-19 vaccine. Humoral and CD4/CD8 T-cell responses were measured to SARS-CoV-2 spike antigens prior to receiving the 3rd vaccine dose and 3-4 weeks after the 3rd dose was given. RESULTS: Of the 37 participants, approximately half were solid organ transplant recipients. The majority (86.5%) had a detectable humoral response after the 2nd and 3rd vaccine doses, with a significant increase in antibody levels after the 3rd dose. Positive T-cell responses increased from being present in 86.5% to 100% of the cohort after the 3rd dose. CONCLUSIONS: Most immunocompromised children mount a humoral and cellular immune response to the 2-dose COVID-19 vaccine series, which is significantly augmented after receiving the 3rd vaccine dose. This supports the utility of the 3rd vaccine dose and the rationale for ongoing emphasis for vaccination against COVID-19 in this population. IMPACT: Most immunocompromised children mount a humoral and cellular immune response to the 2-dose COVID-19 vaccine series, which is significantly augmented after receiving the 3rd vaccine dose. This is the first prospective cohort study to analyze both the humoral and T-cell immune response to the 3rd COVID-19 primary vaccine dose in children who are immunocompromised. The results of this study support the utility of the 3rd vaccine dose and the rationale for ongoing emphasis for vaccination against COVID-19 in the immunosuppressed pediatric population.

Use, Durability, and Risks for Discontinuation of Initial and Subsequent Biologics in a Large Pediatric-Onset IBD Cohort.

BACKGROUND: Biologic medications are recommended for treatment of moderately-to-severely active Crohn disease (CD) or ulcerative colitis (UC) in children. However, many patients require sequential biologic treatment because of nonresponse or loss of response to the initial biologic. METHODS: We analyzed pediatric inflammatory bowel disease (IBD) data from the ImproveCareNow Network registry between May 2006 and September 2016, including time to biologic initiation, choice of first subsequent biologics, biologic durability, and reasons for discontinuation. RESULTS: Of 17,649 patients with IBD [CD: 12,410 (70%); UC: 5239 (30%)], 7585 (43%) were treated with a biologic agent before age 18 (CD: 50%; UC: 25%). Biologic treatment was more likely for CD than UC (odds ratio, 3.0; 95% CI: 2.8-3.2; P < 0.0001). First biologic agents for all patients were anti-tumor necrosis factor agents (88% infliximab, 12% adalimumab). Probability of remaining on the first biologic was significantly higher in CD than UC ( P < 0.0001). First biologics were discontinued because of loss of response (39%), intolerance (23%), and nonresponse (19%). In univariate analysis, factors associated with discontinuation of first and/or second biologics in CD include colonic-only disease, corticosteroid use, upper gastrointestinal tract involvement, and clinical and biochemical markers of severe disease. Biologic durability improved with later induction date. CONCLUSIONS: Treatment with biologic medications is common in pediatric IBD. Patients with CD are more likely to receive biologics, receive biologics earlier in disease course, and remain on the first biologic longer than patients with UC. Multiple factors may predict biologic durability in children with IBD.

Activity Engagement after Cancer in Community-Based Survivors.

This paper discusses the activity engagement in a sample of cancer survivors (n = 25) seeking community-based support. A modified version of the Activity Card Sort (ACSm) was used to measure activity engagement after cancer. On average, participants reported a 27% reduction in activity engagement since their cancer diagnosis. Findings provide direction for continued study of the needs of survivors in community-based cancer care and generate ideas on occupational therapy's unique role in community-based survivorship.

Using a Mixed-method Approach to Develop a Transition Program for Young Adults With Inflammatory Bowel Disease.

BACKGROUND: Although transition guidelines have been specified in pediatric inflammatory bowel disease (IBD), few IBD centers implement these into standard care. We describe a mixed qualitative and quantitative process of developing a needs-based transition program for adolescents and young adults with IBD. METHODS: We enrolled 29 adolescents with IBD, 8 young adults with IBD in adult care, 14 pediatric gastroenterologists, and 58 adult gastroenterologists to provide input into barriers to successful transition, essential patient competencies, and key targets of clinical intervention. RESULTS: The availability and expertise of adult gastroenterologists in childhood-onset IBD were identified by pediatric providers as primary barriers to health care transfer. A medical summary containing pertinent health information was identified by adult providers as instrumental to assume patient care post transfer. Young adults with IBD identified self-advocacy, education on insurance basics, and peer mentoring as essential targets of transition support and preparation in pediatric care. Findings were used to develop educational materials, a portable medical summary, a referral database of adult gastroenterologists, and a young adult clinic geared towards transition planning. CONCLUSION: Involving key patient and provider stakeholders in the development of a transition program is aimed at ensuring that the individual needs of patients and their families are met. Collaboration between pediatric and adult providers is also intended to facilitate a seamless continuum from pediatric to adult health care services. Efforts to evaluate the impact of such programming on self-management in adult care are needed.

Health-Related Quality of Life Predicts Psychology Referral in Youth with Inflammatory Bowel Disease.

PURPOSE: The current study sought to explore psychosocial data gathered from routine screening within an interdisciplinary IBD program, with two-fold aims: 1) to examine parent-child agreement across health-related quality of life domains and 2) to evaluate the differential predictive value of child and parent ratings of health-related quality of life domains on referrals for psychological services. DESIGN AND METHODS: A convenience sample of 92 youth (ages 8-18) and their parents completed the Pediatric Quality of Life Inventory. RESULTS: Children and parents showed moderate to good agreement across health-related quality of life domains. Additionally, regression analyses revealed that child and parent-proxy reports of emotional difficulties, parent report of school difficulties, and child report of physical symptoms were significantly predictive of psychology referral status. CONCLUSIONS: Study findings suggest moderate to good agreement among child and parent-proxy reporters and support the shared value of both child and parent ratings of health-related quality of life in predicting psychology referrals in youth with IBD. PRACTICE IMPLICATIONS: Routine psychosocial screening among youth with IBD can promote the early identification of emotional and behavioral needs, and family receipt of appropriate, evidence-based intervention.

Investigation of potential early Histologic markers of pediatric inflammatory bowel disease.

BACKGROUND: Early manifestations of pediatric inflammatory bowel disease (IBD) can be relatively nonspecific. Initial mucosal biopsies may not be conclusive, delaying the diagnosis until subsequent biopsies demonstrate typical histologic features of IBD. We hypothesized that certain inflammatory cell types may be utilized as early histologic indicators of IBD in children. METHODS: A retrospective analysis compared histologic findings from initially inconclusive or negative endoscopic studies in 22 patients who were subsequently diagnosed with IBD (after diagnostic endoscopy) to those of 20 comparison patients with functional abdominal pain matched for age, gender, and study type. A pediatric pathologist, blinded to study group, reviewed biopsies for histologic abnormalities. Eosinophil densities were obtained from the stomach, duodenum, and rectosigmoid areas. Immunohistochemistry (IHC) staining for tumor necrosis factor-α (TNF-α) and matrix metalloproteinase-9 (MMP-9) was performed on the stomach and rectosigmoid areas. RESULTS: Gastritis and colonic crypt distortion were present in the IBD group at a greater rate (61 % vs. 22 %, p = 0.020; 34 % vs. 4 %, p = 0.008, respectively). Peak and mean eosinophil densities in the rectosigmoid area were greater in the IBD group (17.0/hpf vs. 5.0/hpf, p = 0.0063; 12.3/hpf vs. 4.2/hpf, p = 0.0106, respectively). TNF-α and MMP-9 staining did not reveal any significant differences. CONCLUSIONS: Our data suggests that significantly greater inflammation in the stomach, crypt distortion in the colon, and eosinophilia in the rectosigmoid distinguished the IBD group from the comparison group at the time of the initial endoscopic evaluation.

Preparing Patients for Transfer of Care: Practices of Primary Care Pediatricians.

Comprehensive transition planning by pediatric providers is essential for successful transition into adulthood and transfer to adult medical health care settings. Yet, little is known about the level and type of transition planning and preparation provided by pediatric primary care providers. This study examined the range of transition services provided in primary care pediatric centers. Primary care pediatricians across two states in the Midwest were mailed an anonymous survey designed to examine the transition practices of community pediatricians. A response rate of 38.4% was obtained. Most endorsed transferring patients to adult care at age 18 or older, and using patient chronological age, health status, and patient relationship with pediatric provider as criteria to gauge transfer time. About 60% of responders provide preparation to patients before transition, usually by providing a list of adult providers or by transferring medical records. Few responders provide additional type of transition or transfer planning. Many primary care pediatricians provide transition planning, yet there is high variability in the degree of transition planning provided and 40% of pediatricians provide no such support to their patients. Transition planning is also largely limited to providing referrals and transferring medical records. Study findings support the need for outreach efforts so that all youth receive the needed education and resources to successfully transition and transfer to adult health care.

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.

Application of the Person-Environment-Occupation-Performance Model: A Scoping Review.

The Person-Environment-Occupation-Performance (PEOP) Model is one of several occupation-based models in occupational therapy. The model describes the transactional nature of person, environment, and occupation factors that support performance (doing), participation (engagement), and well-being (health and quality of life). The purpose of this study was to explore the extent and nature of evidence on the PEOP Model. We used a scoping review to identify and analyze journal articles that used the PEOP Model as a framework for study. The PRISMA extension for scoping reviews (PRISMA-ScR) criteria were used to develop the research methods. We found 109 articles that adopted the PEOP Model as an organizing framework. The studies reviewed represent the breadth of occupational therapy practice and the transactional nature of person, environment, occupation, and performance in the PEOP Model. The PEOP Model is a useful international framework for research and practice across populations, conditions, life circumstances, settings, and areas of practice.

METHOD: We searched five databases to identify published articles that used the PEOP Model. Then, we analyzed our findings from peer-reviewed journals and peer-reviewed practice publications using a recommended process called a scoping review. We summarized how often the PEOP Model was used and the way in which it was used. FINDINGS: We found the PEOP Model was used in more than 100 published articles. The PEOP Model has been used to study everyday living for different populations, life circumstances, countries, and communities. Authors found the PEOP Model was helpful for identifying what was important to individuals and determining things that were helpful and barriers to everyday living. CONCLUSION: Authors described the PEOP Model as a useful tool in their research methods and analyses. Occupational therapy professionals may find the PEOP Model helpful in current and innovative areas of practice to help people achieve their goals related to everyday living.

The Person­Environment­Occupation­Performance (PEOP) Model: Summary of Current Research on an Occupational Therapy Lens for Everyday LivingBackground and Purpose: The Person­Environment­Occupation­Performance (PEOP) Model was developed to guide occupational therapy practice. The PEOP Model summarizes all the factors that support or limit our involvement in everyday living. By everyday living, we mean all the things we do to take care of ourselves, maintain our health and home, connect with friends and family, engage in meaningful activities, and support ourselves and our community through work and volunteering. The purpose of this study was to summarize the reasons why and the extent to which the PEOP Model was used in research and practice.

Life balance and perceived stress: predictors and demographic profile.

This article explored differences in life balance scores between demographic groups and whether life balance predicted perceived stress. This research used secondary analysis of 1,048 subjects from a database for the Life Balance Inventory (LBI). Analysis of variance showed that the profile of people with the highest total life balance scores was: white, 61 years or older, earned a master's degree, had incomes between $81,000 and $100,000, lived in the suburbs, had two children (but the children were not at home), were not working (if working, they were self-employed), owned a home, and lived in the United States. Other demographic groups differed in their LBI subscale scores. Regression analysis showed that life balance scores predicted lower perceived stress scores. This research provides additional construct validity evidence for the LBI and its associated Life Balance Model. [OTJR: Occupation, Participation & Health 2013;33(3):146-158.].

Infliximab Rescue Therapy in Pediatric Severe Colitis.

INTRODUCTION: Clinical remission has been achieved with infliximab in patients with refractory ulcerative colitis (UC). However, there is conflicting data regarding its effectiveness as rescue therapy in adult acute severe colitis. Furthermore, pediatric inflammatory bowel disease (IBD) is associated with more severe disease that may be less amenable to attempted rescue. We reviewed our experience and outcomes with pediatric severe colitis after attempted inpatient rescue with infliximab. METHODS: A single-institution, retrospective review was conducted of pediatric patients with UC or indeterminate colitis who received inpatient rescue infliximab therapy from 1/2000 to 1/2019. Rescue infliximab therapy was considered if a child failed non-biologic therapy or progressed to fulminant or toxic colitis. Primary outcome was failed therapy resulting in colectomy. A p-value of <0.05 determined significance. RESULTS: Thirty patients met inclusion criteria. The median age at administration of rescue infliximab treatment was 14 years [IQR 13,17]. Rescue therapy with infliximab was successful in 33% (n = 10), while 67% (n = 20) underwent colectomy. Children on maintenance steroids were less likely to be successfully rescued with infliximab and require colectomy (p = 0.03). Children requiring colectomy had a longer hospital stay (p = 0.03), more abdominal radiographs (p = 0.01), and were on a longer duration of antibiotics (p = <0.01) compared to children who were successfully rescued with infliximab. There was no difference in baseline vital signs or laboratory abnormalities between the two groups. CONCLUSION: In severe acute ulcerative or indeterminate colitis cases where infliximab has not been previously used, rescue infliximab can be used to avoid colectomy but has a high failure rate. LEVEL OF EVIDENCE: IV. TYPE OF STUDY: Retrospective study.

Occurrence of Crohn's disease in children after total colectomy for ulcerative colitis.

BACKGROUND: Colectomy is the definitive treatment for ulcerative colitis (UC) to remove the inflammatory burden. Crohn's disease, however, can affect any portion of the bowel with a propensity to involve the terminal ileum. In some patients with fulminant colitis, distinction between the two is imperfect. Manifestations of Crohn's after colectomy can be devastating because the ileum is needed for restoration of continuity. There is currently little information in the pediatric literature addressing this concern. Therefore, we reviewed all of our patients who underwent colectomy for inflammatory bowel disease to evaluate the risk of subsequent Crohn's manifestations and to document the outcomes. METHODS: A two-center retrospective review of children who underwent colectomy for IBD from January 2000 to July 2010 was performed. Demographic, diagnostic, management, and outcome variables were recorded. RESULTS: We identified 70 patients who underwent colectomy for UC. The mean age at diagnosis was 12 y ± 7 y, and 59% were female. Clinical diagnosis prior to colectomy was UC in 90%, and indeterminate colitis in 10%. There was discordance between clinical and pathologic diagnosis in five patients, two patients were clinically diagnosed with UC but had an indeterminate biopsy, and three patients were clinically diagnosed as indeterminate colitis with a biopsy confirming UC. Indications for colectomy were refractory bleeding in 63%, failure of medical treatment in 28%, toxic megacolon in 6%, and perforation in 3%. A restorative pouch was created after colectomy in 46% using a two-stage approach while, 53% were managed with an initial colectomy and three-stage approach. In one patient, Crohn's was intraoperatively diagnosed from the operative colectomy specimen. This patient had a clinical diagnosis of UC with concordant biopsy prior to surgery. After total abdominal colectomy, 68 patients went on to ileal pouch anal anastomosis by either a two-stage or three-stage approach. In these patients, nine (13%) had a change in their diagnosis to Crohn's after reconstruction. Crohn's complications requiring an operation consisted of two patients with anastomotic dilations, four patients with fistulotomies, and one patient with perianal abscess drainage procedures. CONCLUSIONS: In the children studied, 13% had a diagnostic change to Crohn's disease, and 13% were diagnosed with Crohn's after ileal pouch-anal anastomosis (IPAA). In patients with IPAA and Crohn's, there were more operative interventions for perianal disease.

Simulator sickness in a helicopter flight training school.

INTRODUCTION: Simulator sickness (SS) is a common problem during flight training and can affect both instructor pilots (IP) and student pilots (SP). This study was conducted in response to complaints about a high incidence of SS associated with use of new simulators for rotary-wing aircraft. METHODS: The problem was evaluated using the Simulator Sickness Questionnaire (SSQ) to collect data on 73 IP and 129 SP who used the new simulators. Based on analysis of these data, operator comments, and a search of the literature, we recommended limiting simulator flights to 2 h, removing unusual or unnatural maneuvers, turning off the sidescreens to reduce the field-of-view, avoiding use of improperly calibrated simulators until repaired, and stressing proper rest and health discipline among the pilots. The success of these measures was evaluated 1 yr later by collecting SSQ data on 25 IP and 50 SP. RESULTS: There was a main effect of time, in that after the recommendations were implemented, there was a significant reduction in nausea, oculomotor, and total SSQ scores from the pre-study to the post-study. There was also a main effect of experience, as IP reported significantly greater SS than SP for the same scores. DISCUSSION: Implementation of the recommendations reduced SS in the new simulators at the cost of limiting session duration and shutting down some simulator features. Although the optimal solution to the SS problem lies in addressing SS during a simulator's design stage, these recommendations can be used as interim solutions to reduce SS.

Implementing a Novel Quality Improvement-Based Approach to Data Quality Monitoring and Enhancement in a Multipurpose Clinical Registry.

OBJECTIVE: To implement a quality improvement based system to measure and improve data quality in an observational clinical registry to support a Learning Healthcare System. DATA SOURCE: ImproveCareNow Network registry, which as of September 2019 contained data from 314,250 visits of 43,305 pediatric Inflammatory Bowel Disease (IBD) patients at 109 participating care centers. STUDY DESIGN: The impact of data quality improvement support to care centers was evaluated using statistical process control methodology. Data quality measures were defined, performance feedback of those measures using statistical process control charts was implemented, and reports that identified data items not following data quality checks were developed to enable centers to monitor and improve the quality of their data. PRINCIPAL FINDINGS: There was a pattern of improvement across measures of data quality. The proportion of visits with complete critical data increased from 72 percent to 82 percent. The percent of registered patients improved from 59 percent to 83 percent. Of three additional measures of data consistency and timeliness, one improved performance from 42 percent to 63 percent. Performance declined on one measure due to changes in network documentation practices and maturation. There was variation among care centers in data quality. CONCLUSIONS: A quality improvement based approach to data quality monitoring and improvement is feasible and effective.

Practice survey: adherence monitoring and intervention in pediatric gastroenterology and hepatology.

PURPOSE: Despite significant medication nonadherence rates among youth with pediatric gastroenterology and hepatology disorders, little is known about current adherence practices in pediatric gastroenterology care. This study summarizes current practices surrounding adherence monitoring and intervention in pediatric gastrointestinal (GI) and hepatologic care in the USA. PARTICIPANTS AND METHODS: One hundred and fifty-four pediatric GI providers completed an online survey designed to examine current practices surrounding adherence monitoring and intervention, specific strategies used to monitor and treat poor adherence, and the barriers currently experienced in relation to adherence monitoring and intervention. RESULTS: Practices varied greatly in terms of when and how patient adherence is monitored and by whom; however, physicians and nursing professionals take primary responsibility for adherence monitoring. Approximately 25% utilize screeners to assess adherence, and most participants use patient and caregiver reports as a primary measure of adherence. Most participants rated their level of adherence monitoring and intervention as fair to poor. While most participants perceive adherence monitoring to be very important in clinical practice, only 20.8% perceive being able to significantly modify patient adherence. CONCLUSION: There exists great variability in adherence monitoring and intervention practices across pediatric GI providers. Greater understanding of current adherence practices can inform future clinical efforts.