PURPOSE OF REVIEW:Behavioral and mental health challenges are important to understand in order to ensure that patients receive the anticipated benefits from organ transplantation. The present review centers on what we believe are the most important (and best researched) actionable challenges that may inform the care of transplant recipients - adherence to medical recommendations, transitions of care, and posttraumatic stress following transplantation. RECENT FINDINGS:Recent research has moved from identifying (and quantifying) the problem and is now trying to investigate how to best recognize - and address - behavioral and mental health challenges in this population. SUMMARY:While much remains unknown, it is increasingly becoming clear that early recognition is best done by increasing awareness amongst transplant team members, and objective surveillance methods. Subjective patient and parent reports should be considered if other methods are not available. It is becoming increasingly clear that psychosocial interventions are feasible and potentially effective. Transplant programs should try to be aware of such interventions, implement them when feasible, and create referral pathways that can be used when needed.

BACKGROUND:Patient-reported outcomes are increasingly recognized as essential complements to biological indices in chronic disease including pediatric liver transplantation. However, clinicians lack clear thresholds to determine when changes in patient-reported outcome measure (PROM) scores represent clinically meaningful change. Establishing minimal clinically important difference (MCID) values is critical to interpret longitudinal PROM data and guide action. The Starzl Network Patient Reported Outcomes (SPaRO) study provided a unique opportunity to derive MCID estimates of the Pediatric Liver Transplant Quality of Life (PeLTQL) questionnaire. METHODS:In SPaRO, English- or Spanish-speaking pediatric LT recipients aged 8-18 years and at least 1 year post-LT were recruited from 7 Starzl Network for Excellence in Pediatric Transplantation (SNEPT) sites. Participants and caregivers completed the PeLTQL (self- and proxy-report) questionnaire twice via a mobile application or web-based platform. MCIDs were estimated using anchor-based and distribution-based methods including predictive modeling. RESULTS:A total of 98 patients and 86 caregivers completed two PeLTQL assessments between March 2022 and October 2023. Triangulated MCID values for the total score (TS) were 6.4 (self-report) and 5.6 (proxy-report). Predictive modeling yielded estimates of 7.7 (self) and 6.8 (proxy). CONCLUSIONS:In this multicenter cohort, MCID thresholds for the PeLTQL TS were approximately 6-8 points (self-report) and 6-7 points (proxy-report), consistent with prior single-center estimates. Changes in the PeLTQL TS of greater than 6 points may help clinicians identify patients who warrant closer attention. Prospective validation using an independent anchor is underway. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT05241847.

Improving medication adherence in adolescents who had a liver transplant (iMALT), a prospective, block-randomized, single-blind, controlled multisite study in 13 pediatric transplant centers, used the medication level variability index (MLVI) to identify nonadherent adolescents. It compared a 2-year remote behavioral telemetric intervention (TI) that focused on adherence and addressed barriers to standard of care (SOC). The primary endpoint was the composite incidence of centrally determined (3 masked pathologists) rejection, death, retransplantation, or consent withdrawal. In 148 participants (TI group, n = 72 and the SOC group, n = 76), with a mean age 15.5 years, there were twice as many primary events in SOC (12; 15.8%) compared with TI (6; 8.3%) (relative risk, 0.57; 95% confidence interval, 0.24-1.35; P = .20). All secondary outcomes improved in the TI vs SOC groups. The study was underpowered because iMALT study sites used the MLVI score in clinical care, significantly reducing overall rejections compared with the previous MALT study cohort, where the MLVI score was not used (rejection was observed in 12/76 patients in the iMALT study, SOC vs 13/25 patients in the MALT study; P < .0001). The effect on the primary outcome, therefore, was not statistically significant; thus, the intervention is not evidence-based. MLVI score, an electronic health record-derived behavioral marker, can be used to target interventions to patients with clinically significant nonadherence. ClinicalTrials.Gov, NCT03691220.

BACKGROUND AND AIM:Optimizing health and quality of life for pediatric recipients of liver transplant (LT) requires balancing the protection of the liver graft with the overall burden of treatments on the child. Since the American Association for the Study of Liver Diseases (AASLD)'s 2013 guidelines, strategies for achieving this balance have evolved, with a particular focus on mitigating long-term complications. Advances include operative and intensive care strategies for reducing complications, minimizing exposure to immunosuppression and its long-term adverse effects on other organs, infection prevention with prophylaxis and vaccination, optimizing support of early nutrition and development, and improving support around transition from pediatric to adult care. This document aims to provide an evidence-based guideline for the comprehensive care of pediatric recipients of LT, starting at transplant and continuing as they advance to adulthood. METHODS:A multidisciplinary writing group of pediatric LT experts and a medical librarian was convened by AASLD, with guidance by its Practice Guidelines Development Policy, and in collaboration with the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) and the American Society of Transplantation (AST). We conducted a systematic global literature review, formulated key clinical questions, and developed recommendations. Each recommendation was graded using the Oxford Centre for Evidence-Based Medicine framework and categorized by strength through a consensus voting process. CONCLUSION:All recommendations are based on the best available evidence and reflect expert consensus. Most of the evidence base remains retrospective or observational data, or extrapolation from related populations. To continue improving long-term outcomes after pediatric LT, multidisciplinary, multicenter collaboration to strengthen the evidence will be essential.

OBJECTIVE:To evaluate the relationship between patient outcomes and a discrepancy score, a new way to quantify caretaker vs child discrepancies on patient-reported outcome measures (PROMs). STUDY DESIGN:Children aged between 8 and 18 years, at least 1 year from a primary liver transplantation, and their primary adult caretaker were recruited in a prospective, hypothesis-driven cohort study conducted in 7 centers (USA, Canada) from the Starzl Network for Excellence in Pediatric Transplantation. A novel electronic application computed a "discrepancy score": the absolute cumulative value of each year's difference in scores between child and caretaker responses on a Health-Related Quality of Life (HRQoL) questionnaire. Liver and HRQoL outcomes were also evaluated. RESULTS:Of 200 enrolled, 160 patients/140 dyads answered the questionnaire at least once; 101 patients/85 dyads answered twice. Median age was 13 years, and 60.6% were females. HRQoL was not associated with liver outcomes but was associated with discrepancy scores in both the first and second administration: Pearson correlation -0.469 (95% confidence interval: -0.588, -0.328, P < .01) and -0.347 (95% confidence interval: -0.520, -0.143, P < .01), respectively. CONCLUSIONS:Quantifying differences between child and caretaker PROMs in a "discrepancy score" is a novel way to interpret PROM results. Decreasing discrepancies could be a reasonable clinical target.

Increased variability in systolic blood pressure, expressed as the coefficient of variation (BPCoV), is associated with poor cardiovascular outcomes. Variability could be due to episodic non-adherence to medical recommendations in some patients. Reports of targeted attempts to mitigate such variation are lacking. A behavioral intervention targeted at patients with initially high BPCoV may decrease variability. In this single-site, single arm prospective proof-of-concept trial, an electronic health record review identified patients with excessive variability (BPCov>10%). Enrolled patients received a blood pressure monitor and a remotely delivered behavioral intervention for 3 months. The primary outcome was mean blood pressure variability before versus after the intervention. Of 551 initially screened patients, 107 (19.4%) met the BPCoV criteria, and 25 consented (6 females and 19 males, mean age 64.24 years). Average BPCoV for the 6 months pre-enrollment was 12.96 (SD=2.11) compared to 7.02 (SD=3.54) during intervention (p<0.001). Other variability metrics also improved. Sensitivity analyses (different timeframes, using measurements obtained in the clinic vs. home monitor) all showed significant improvement. This proof-of-concept trial suggests that patients with high systolic blood pressure variability can successfully engage in a remotely delivered behavioral intervention, and that such an intervention can reduce such variability. Trial Registration: NCT05814562, ClinicalTrials.gov.

BACKGROUND:Medication non-adherence is a major reason for poor outcomes across chronic diseases. Specifically, it is the most common cause for organ rejection in pediatric liver transplant recipients. Therefore, understanding how to improve adherence through behavior change interventions could lead to substantial health benefits. The Improving Medication Adherence in Adolescents who had a Liver Transplant (iMALT) study is a longitudinal, multisite, randomized controlled trial that uses a biomarker of adherence (the Medication Level Variability Index, calculated from electronic health record information) to identify non-adherent patients. The fully remote intervention uses repeat measurements of the biomarker to determine intervention intensity over time. This paper describes the iMALT intervention with an emphasis on innovative elements, including the use of a biomarker to guide the intervention as it unfolds, the theoretical framework, and delivery methods. METHODS:We use the Template for Intervention Description and Replication (TIDieR) guidelines to describe the iMALT intervention. We review design elements that help to improve engagement (in a particularly hard-to-engage cohort) and reduce attrition, discuss the tailoring paradigm that uses biomarker readings to modify aspects of the manual-driven protocol, and present considerations for designing remote interventions that engage patients across state lines. CONCLUSIONS:Our intervention introduces a novel concept in behavioral intervention design-the use of a biomarker to identify risk and inform intervention intensity while the intervention is ongoing. The remote approach, which allows for intervention dissemination from one "hub" of trained individuals and decreased patient burden, may also inform future intervention designs.

Background: It has recently been shown that excessive fluctuation in blood pressure readings for an individual over time is closely associated with poor outcomes, including increased risk of cardiovascular mortality, coronary heart disease and stroke. Fluctuations may be associated with inconsistent adherence to medical recommendations. This new marker of risk has not yet been incorporated into a monitoring and intervention strategy that seeks to reduce cardiovascular risk by identifying patients through an algorithm tied to their electronic health record (EHR). Methods: We describe the methods used in an innovative "proof of concept" trial using CP&R (Cardiovascular Precision Medicine and Remote Intervention). A blood pressure variability index is calculated for clinic patients via an EHR review. Consenting patients with excessive variability are offered a remote intervention aimed at improving adherence to medical recommendations. The outcomes include the ability to identify and engage the identified patients and the effects of the intervention on blood pressure variability using a pre-post comparison design without parallel controls. Conclusions: Our innovative approach uses a recently identified marker based on reviewing and manipulating EHR data tied to a remote intervention. This design reduces patient burden and supports equitable and targeted resource allocation, utilizing an objective criterion for behavioral risk. This study is registered under ClinicalTrials.gov Identifier: NCT05814562.

Behavioral or mental health disorders are common in children, adolescents, and young adults. Medication use is increasingly common, with few data describing drug-drug combinations in ambulatory settings. The objectives of this study were to describe the pharmaco-epidemiology of behavioral and mental health (BMH) medications among children, adolescents, and young adults in New York Medicaid and assess the prevalence of contraindicated drug pairs within this population. This observational cross-sectional study evaluated New York State Medicaid managed care and fee-for-service enrollees under 21 years of age dispensed BMH medications in 2014. Main outcomes included number of members with prescriptions filled; number filling > 1 medication prescription concurrently for ≥ 30 days (polypharmacy), and number and nature of potentially contraindicated drug pairs. Of 2,430,434 children, adolescents, and young adults, 422,486 (17.4

Food allergy is a vulnerability that is typically managed—and usually managed well—by avoidance of an allergen. But like any vulnerability, it can be exploited in bullying behavior. The present article is intended as a primer and a review of extant literature. Basic concepts related to bullying in general are presented (e.g., definition) and then extant literature about bullying related to food allergy is reviewed. Bullying related to food allergy is quite prevalent and may lead to serious physical and mental health consequences. It should be handled by creating an opportunity for a child to be forthcoming about it (and asking about it directly in clinical encounters), adopting a zero tolerance for threats, and adult intervention. Unfortunately, the literature about intervention and prevention efforts in the bullying literature in general does not support any specific strategy. For example, education about the risk, an approach that is frequently advocated as a way to mitigate bullying, was not conclusively shown to be helpful. In the absence of specific scientifically proven guidance, common-sense approaches are reviewed and recommended, alongside a strong recommendation to study prevention methods more rigorously.

BACKGROUND/AIMS:Medication non-adherence is a leading cause of transplant rejection, organ loss, and death; yet no rigorous controlled study to date has shown compelling clinical benefits from an adherence-improving intervention. Non-adherent patients are less likely to participate in trials, and therefore, most studies enroll a majority of adherent patients who do not stand to benefit from the intervention, as they do not have the condition (non-adherence) under investigation. The improving Medication Adherence in adolescent Liver Transplant recipients trial specifically targets non-adherent patients to investigate whether a remote intervention to improve adherence results in reduced incidence of biopsy-confirmed rejection. METHODS:Improving Medication Adherence in adolescent Liver Transplant is a randomized single-blind controlled multisite, multinational National Institutes of Health-funded trial involving 13 pediatric transplant centers in the United States and Canada. An innovative, objective adherence biomarker-the Medication Level Variability Index, which is the standard deviation of a series of medication blood levels for each patient, is used to identify non-adherent patients at risk for rejection. The index is computed using electronic health record information for all potentially eligible patients based on repeated reviews of the entire clinic's roster. Identified patients, after consent, are randomized to intervention versus control (treatment as usual) arms. The remote intervention is delivered for 2 years by trained interventionists who reside in various locations in the United States. The primary outcome is the incidence of biopsy-confirmed acute cellular rejection, as confirmed by a majority vote of three pathologists who are masked to the study allocation and clinical information. DISCUSSION:Improving Medication Adherence in adolescent Liver Transplant includes several innovative design elements. The use of a validated, objective adherence index to survey a large cohort of transplant recipients allows the teams to avoid bias inherent in both convenience sampling and referral-based recruitment and enroll only patients whose computed index indicates substantially increased risk of rejection. The remote intervention paradigm helps to engage patients who are by definition hard to engage. The use of an objective, masked medical (rather than behavioral) outcome measure reduces the likelihood of biases related to clinical information and ensures broad acceptance by the field. Finally, monitoring for potential adverse events related to increased medication exposure due to the adherence intervention acknowledges that a successful intervention (increasing adherence) could have detrimental side effects via increased exposure to and potential toxicity of the medication. Such monitoring is almost never attempted in clinical trials evaluating adherence interventions.

Background Patient-reported outcome measures (PROMs) are not routinely used in clinical care by pediatric liver transplant (LT) teams. The Starzl Network for Excellence in Pediatric Transplantation (SNEPT) assessed feasibility of using a disease-specific Quality of Life (QoL) questionnaire in the ambulatory setting at 10 SNEPT sites. Methods A mixed methods feasibility project assessing administration processes, barriers, and user experiences with the Pediatric Liver Transplant Quality of Life (PeLTQL) tool. Iterative processes sought stakeholder feedback across four phases (Pilot, Extended Pilot, Development of a Mobile App PeLTQL version, and Pilot App use). Results A total of 149 patient-parent dyads completed the PeLTQL during LT clinic follow-up. Clinicians, parents, and patients evaluated and reported on feasibility of operationalization. Only two of 10 SNEPT sites continued PeLTQL administration after the initial two pilot phases. Reasons include limited clinical time and available personnel aggravated by the COVID-19 pandemic. In response, a mobile application version of the PeLTQL was initiated. Providing PeLTQL responses electronically was "very easy" or "easy" as reported by 96% (22/23) parents. Conclusions Administration of a PROM into post-pediatric LT clinical care was feasible, but ongoing utilization stalled. Use of a mobile app towards facilitating completion of the PeLTQL outside of clinic hours may address the time and work-flow barriers identified.

Since the start of the COVID‐19 pandemic and consequent lockdowns, the use of telehealth interventions has rapidly increased both in the general population and among transplant recipients. Among pediatric transplant recipients, this most frequently takes the form of interventions on mobile devices, or mHealth, such as remote visits via video chat or phone, phone‐based monitoring, and mobile apps. Telehealth interventions may offer the opportunity to provide care that minimizes many of the barriers of in‐person care.

This chapter addresses the problem of medication adherence and substance abuse among adolescents with liver disease. Adherence is defined as the degree to which a person’s behavior is consistent with agreed upon recommendations from a healthcare provider (World Health Organization, Adherence to long-term therapies: evidence for action. World Health Organization, 2003). This chapter first provides an overview of nonadherence in adolescents with liver disease and ways to assess for it. Next, it explores which interventions for promoting adherence show the most promise. Lastly, it addresses the growing problem of substance use as it relates to nonadherence and, more generally, among adolescents with liver disease. Most of the research in this area has focused on liver transplant recipients; however, research on nonadherence in other liver diseases has been incorporated whenever possible.