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ObjectiveThis report describes our experience in electronic health record (EHR) note modification and creation of an external dashboard to create a local learning health system that contributes to quality improvement and patient care within our pediatric rheumatology clinic.MethodsWe applied quality improvement methodology to develop a more reliable and accurate system to identify patients with juvenile idiopathic arthritis and track important measures that aide in improving patient care and performance outcomes. From 2019 to 2021, we iteratively modified our outpatient clinic EHR note to include structured data elements to improve longitudinal monitoring. We then validated data transferred to an electronic dashboard external to the EHR and demonstrated utility for identifying an accurate patient population and tracking quality improvement initiatives.ResultsCreation of the structured data elements improved the identification of patients with JIA with >99% accuracy and without requiring manual review of the chart. Using the dashboard to monitor performance, we improved documentation of critical disease activity measures that resulted in improvement in those scores across the local population of patients with JIA. The structured data elements also enabled us to automate electronic data transfer to a multicenter learning network registry.ConclusionThe structured data element modifications made to our outpatient EHR note populate a local dashboard that allows real time access to critical information for patient care, population management, and improvement in quality metrics. The collection and monitoring of structured data can be scaled to other quality improvement initiatives in our clinic and shared with other centers.

ObjectivesTo examine the feasibility of a social phone call program to address social isolation and loneliness in stroke survivors.Materials and methodsWe paired 14 lonely community-living stroke survivors with 14 health professional students for 6-weekly unstructured social phone calls. Feasibility data and measures of social isolation, loneliness and other psychosocial metrics were collected pre- and post-intervention. Students journaled following each unstructured call to capture the informal conversation and their sentiments.ResultsSixty-two percent of the targeted sample was interested. Fourteen eligible and interested participants were enrolled. The 13 (93%) participants completing all calls and surveys were an average of 57 years old, 85% female, and 77% non-Hispanic white. At baseline, participants were highly lonely and moderately depressed. Participants disclosed physical and emotional challenges, previous valued employment, and enjoyment from the calls. Students reported enjoying the connections, learning about the struggles of aging-in-place after stroke, and valuing compassionate care for the stroke population.ConclusionsKnowledge gaps remain regarding effective social support interventions to provide continuity of care directed at managing social disconnection after stroke. A health professional student-delivered social phone call intervention with stroke survivors appears to be a feasible, in part, and encouraging approach for addressing social isolation and loneliness. Future trials require re-evaluation of eligibility criteria and strategies to boost enrollment before efficacy testing is conducted in a larger trial.

Abstract Background Vaccinations are a vital part of routine childhood and adolescent preventive care. We sought to identify current oncology provider practices, barriers, and attitudes towards vaccinating childhood and adolescent cancer patients and survivors. Methods We conducted a one-time online survey distributed from March-October 2018 to pediatric oncologists at nine institutions across the United States (N = 111, 68.8% participation rate). The survey included 32 items about vaccination practices, barriers to post-treatment vaccination, availability of vaccinations in oncology clinic, familiarity with vaccine guidelines, and attitudes toward vaccination responsibilities. Descriptive statistics were calculated in STATA 14.2. Results Participants were 54.0% female and 82.9% white, with 12.6% specializing in Bone Marrow Transplants. Influenza was the most commonly resumed vaccine after treatment (7030%). About 50%-60% were familiar with vaccine guidelines for immunocompromised patients. More than half (62.7%) recommended that patients restart most immunizations 6 months to 1 year after chemotherapy. Common barriers to providers recommending vaccinations included not having previous vaccine records for patients (56.8%) or lacking time to ascertain which vaccines are needed (32.4%). Of participants, 66.7% stated that vaccination should be managed by primary care providers, but with guidance from oncologists. Conclusions Many pediatric oncologists report being unfamiliar with vaccine guidelines for immunocompromised patients and almost all report barriers in supporting patients regarding vaccines after cancer treatment. Our findings show that further research and interventions are needed to help bridge oncology care and primary care regarding immunizations after treatment.

Abstract Objective Pediatric rheumatology faces a looming supply-demand crisis. While strategies have been proposed to address the supply shortfall, investigation into the increased demand for pediatric rheumatic care has been limited. Herein, we analyze new patient visits to a large tertiary care pediatric rheumatology center to identify emerging trends in referrals and areas for potential intervention to meet this increased demand. Methods All patients referred to and seen by the University of Alabama at Birmingham Pediatric Rheumatology Division between January 2019 and December 2021 for a new patient evaluation were identified. Patient data was retrospectively abstracted, de-identified, and analyzed to develop trends in referrals and frequency of rheumatic disease, non-rheumatic disease, and specific diagnoses. Results During the study period, 2638 patients were referred to and seen in by the pediatric rheumatology division. Six hundred and ten patients (23.1%) were diagnosed with rheumatic disease. The most common rheumatic disease was juvenile idiopathic arthritis (JIA) at 45.6%, followed by primary Raynaud phenomenon (7.4%), recurrent fever syndromes (6.9%), vasculitides (6.7%), and inflammatory eye disease (6.2%). Of the 2028 patients (76.9%) diagnosed with a non-rheumatic condition, benign musculoskeletal pain was the most common (61.8%), followed by a combination of somatic conditions (11.6%), and non-inflammatory rash (7.7%). Conclusion In this analysis of new patient referrals to a large pediatric rheumatology center, the majority of patients were diagnosed with a non-rheumatic condition. As a worsening supply-demand gap threatens the field of pediatric rheumatology, increased emphasis should be placed on reducing non-rheumatic disease referrals.

Abstract Background Childhood-onset Systemic Lupus Erythematosus (cSLE) is an autoimmune disease associated with fatigue, mood symptoms, and pain. Fortunately, these symptoms are potentially modifiable with psychological intervention such as cognitive-behavioral therapy (CBT). The Treatment and Education Approach for Childhood-onset Lupus (TEACH) program is a CBT intervention developed to target these symptoms for adolescents and young adults with cSLE. This pilot randomized controlled trial (RCT) aims to determine the feasibility and effect of TEACH for youth with cSLE. Adjustments to the study protocol following the COVID-19 pandemic are also described. Methods This two-arm multisite RCT will explore the feasibility (primary outcome) and effect (secondary outcome) of a remotely delivered TEACH protocol. Participants will be randomized to a six-week remotely delivered TEACH program plus medical treatment as usual (TAU) or TAU alone. We will include patients ages 12–22 years presenting to rheumatology clinics from six sites. Validated measures of fatigue, depressive symptoms, and pain will be obtained at baseline and approximately eight and 20 weeks later. Protocol adjustments were also made due to the COVID-19 pandemic, in collaboration with the investigative team, which included patients and caregivers. Conclusions Findings from this multi-site RCT aim to document the feasibility of TEACH and provide an estimate of effect of a remotely delivered TEACH protocol on fatigue, depression, and pain symptoms in youth with cSLE as compared to standard medical treatment alone. This findings may positively impact clinical care for patients with cSLE. Clinical trials.gov registration: NCT04335643.

Abstract Background Young adult cancer survivors experience early aging‐related morbidities and mortality. Biological aging biomarkers may identify at‐risk survivors and increase our understanding of mechanisms underlying this accelerated aging. Methods Using an observational study design, we cross‐sectionally measured DNA methylation‐based epigenetic age in young adult cancer survivors at a tertiary, academic state cancer hospital. Participants were a convenience sample of consecutively enrolled survivors of childhood, adolescent, and young adult cancers treated with either an anthracycline or alkylating agent, and who were at least 3 months post‐treatment. Similarly aged healthy comparators were consecutively enrolled. Cancer treatment and treatment intensity were compared to DNA methylation‐based epigenetic age and pace of aging. Results Sixty survivors (58 completing assessments, mean age 20.5 years, range 18–29) and 27 comparators (mean age 20 years, range 17–29) underwent DNA methylation measurement. Survivors were predominantly female (62%) and white (60%) and averaged nearly 6 years post‐treatment (range 0.2–25 years). Both epigenetic age (AgeAccelGrim: 1.5 vs. −2.4, p

Objective The study objective was to compare leukocyte telomere length (LTL) among patients with systemic lupus erythematosus (SLE) diagnosed in childhood versus adulthood. Methods Data are from the Black Women's Experiences Living with Lupus (BeWELL) study. Multivariable linear regression analyses that examined childhood diagnosis of SLE (diagnosed before 18 years of age), age, and their interaction in relationship to LTL were conducted, adjusting for a range of demographic, socioeconomic, and health‐related covariates. Results The total analytic sample size was 415. Forty participants (9.6%) were diagnosed in childhood. There was no main effect of childhood diagnosis on LTL (b = 0.007; 95% confidence interval [CI]: −0.089 to 0.103). However, the interaction between age and childhood diagnosis was significant (b = −0.008; 95% CI: −0.016 to −0.001), indicating a steeper inverse association between age and LTL among those diagnosed in childhood compared with those diagnosed in adulthood. This interaction remained statistically significant (P = 0.024) after controlling for disease duration measured dichotomously (less than 10 years vs. 10 years or more); it was marginally significant (P = 0.083) when controlling for disease duration measured continuously. Conclusion This cross‐sectional analysis suggests that Black women with childhood‐onset SLE may undergo accelerated LTL shortening compared with their adult‐onset counterparts. This relationship persisted even after controlling for differences in SLE damage and disease duration. These findings inform research on immunosenescence mechanisms of SLE.

Abstract The translation of research findings into clinical practice is challenging, especially fields like in pediatric rheumatology, where the evidence base is limited, there are few clinical trials, and the conditions are rare and heterogeneous. Implementation science methodologies have been shown to reduce the research- to- practice gap in other clinical settings may have similar utility in pediatric rheumatology. This paper describes the key discussion points from the inaugural Childhood Arthritis and Rheumatology Research Alliance Implementation Science retreat held in February 2020. The aim of this report is to synthesize those findings into an Implementation Science Roadmap for pediatric rheumatology research. This roadmap is based on three foundational principles: fostering curiosity and ensuring discovery, integration of research and quality improvement, and patient-centeredness. We include six key steps anchored in the principles of implementation science. Applying this roadmap will enable researchers to evaluate the full range of research activities, from the initial clinical design and evidence acquisition to the application of those findings in pediatric rheumatology clinics and direct patient care.

Objective Determine the pharmacokinetics (PK) and exposure–response of hydroxychloroquine (HCQ) and desethylhydroxychloroquine (DHCQ) in paediatric SLE (pSLE).Methods We conducted an exploratory phase 2, direct-to-family trial. Children enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry with a diagnosis of pSLE were eligible if they were receiving HCQ as standard of care for ≥3 months. Biological samples were collected at up to four visits over a 6-month period. At each visit, plasma was obtained to measure the concentrations of HCQ and DHCQ, as well as cytokines. HCQ and DHCQ plasma PK data were analysed using a population PK modelling approach.Results Twenty-five subjects provided a total of 88 plasma concentrations for PK analysis. There was a poor linear fit between HCQ concentrations and total body weight (R2=0.03). There was a decline in both interferon (IFN)-alpha and IFN-gamma with higher concentrations of HCQ and DHCQ. Volume of distribution for HCQ in plasma was higher in children compared with published values in adults (73 000 L vs 44 000 L), but clearance values in children were similar to adults.Conclusions We report the first population PK model for HCQ and DHCQ in children using data from a novel direct-to-family clinical trial. We observed high interindividual variability in HCQ PK and found that weight-based dosing for HCQ is poorly correlated with drug concentrations, suggesting the need to use therapeutic drug monitoring to individualise dosing. Furthermore, our results suggest that the current weight-based dosing paradigm for HCQ may result in suboptimal drug exposures, particularly for children with obesity. Accordingly, additional studies of HCQ are needed in pSLE to determine the optimal drug concentration and dosing to reduce disease activity and improve outcomes.Trial registration number NCT04358302.

Introduction Direct-to-family clinical trials efficiently provide data while reducing the participation burden for children and their families. Although these trials can offer significant advantages over traditional clinical trials, the process of designing and implementing direct-to-family studies is poorly defined, especially in children with rheumatic disease. This paper provides lessons learnt from the design and implementation of a self-controlled, direct-to-family pilot trial aimed to evaluate the effects of a medication management device on adherence to hydroxychloroquine in paediatric SLE.Methods Several design features accommodate a direct-to-family approach. Participants meeting eligibility criteria from across the USA were identified a priori through a disease registry, and all outcome data are collected remotely. The primary outcome (medication adherence) is evaluated using electronic medication event-monitoring, plasma drug levels, patient questionnaires and pill counts. Secondary and exploratory endpoints include (1) lupus disease activity measured by a remote SLE Disease Activity Index examination and the Systemic Lupus Activity Questionnaire; and (2) hydroxychloroquine pharmacokinetics and pharmacodynamics. Recruitment of the initial target of 20 participants was achieved within 10 days. Due to initial recruitment success, enrolment was increased to 26 participants. Additional participants who were interested were placed on a waiting list in case of dropouts during the study.Discussion and dissemination Direct-to-family trials offer several advantages but present unique challenges. Lessons learnt from the protocol development, design, and implementation of this trial will inform future direct-to-family trials for children and adults with rheumatic diseases. Additionally, the data collected remotely in this trial will provide critical information regarding the accuracy of teleresearch in lupus, the impact of adherence to hydroxychloroquine on disease activity and a pharmacokinetic analysis to inform paediatric-specific dosing of hydroxychloroquine.Trial registration number ClinicalTrials.gov Registry (NCT04358302).

Tissue-resident and infiltrating immune cells are continuously exposed to molecules derived from the local cells that often come in form of secreted factors, such as cytokines. These factors are known to impact the immune cells' biology. However, very little is known about whether the tissue resident immune cells in return also affect the local environment. In this study, with the help of RNA-sequencing, we show for the first time that long-term absence of epidermal resident Langerhans cells led to significant gene expression changes in the local keratinocytes and resident dendritic epidermal T cells. Thus, immune cells might play an active role in maintaining tissue homeostasis, which should be taken in consideration at data interpretation.

Background: Primary (familial) hemophagocytic lymphohistiocytosis (pHLH) is a potentially lethal syndrome of infancy, caused by genetic defects in natural killer (NK) cell and CD8 T cell cytotoxicity, leading to hyperinflammation, elevated cytokine levels, and a disorganized immune response resulting in multi-organ system failure and frequently death. Secondary HLH (sHLH) can be triggered in the setting of malignances, diseases of chronic immune system activation, or by infectious etiologies. While pHLH is usually a result of homozygous gene mutations, monoallelic hypomorphic and dominant-negative mutations in pHLH genes have been implicated in sHLH. Coronavirus disease 2019 (COVID-19) has been an omnipresent viral infection since its arrival, and severe cases can present with cytokine storm and have clinical features and laboratory findings consistent with sHLH. Herein, we report an adolescent with severe COVID-19, decreased NK cell function, and features of sHLH. Her genetic evaluation identified a monoallelic missense mutation in the pHLH gene STXBP2, and NK cell assays of her blood showed decreased cytolysis and degranulation ex vivo. Methods: Patient data was extracted through an electronic medical record review. Using a lentiviral approach, the patient’s STXBP2 mutation and wild-type (WT) STXBP2 were separately transduced into the NK-92 human NK cell line. The WT and mutant STXBP2 transduced NK-92 cells were stimulated with NK-sensitive K562 erythroleukemia target cells in vitro, and NK cell degranulation and cytolysis were measured via CD107a expression and Live/Dead near-IR dye, respectively. Results: Compared to WT STXBP2, the patient’s STXBP2 mutation caused significantly decreased NK cell cytolysis and associated degranulation in vitro. Conclusion: These findings add weight to the hypothesis that some severe cases of COVID-19 may be accompanied by sHLH and hyperinflammation, especially in the setting of heterozygous pHLH genetic mutations. This has implications both diagnostically and therapeutically for severe COVID-19.

Background: A wealth of research has investigated the impact of early life trauma exposure on functional brain activation during facial emotion processing and has often demonstrated amygdala hyperactivity and weakened connectivity between amygdala and medial PFC (mPFC). There have been notably limited investigations linking these previous node-specific findings into larger-scale network models of brain organization. Method: To address these gaps, we applied graph theoretical analyses to fMRI data collected during a facial emotion processing task among 88 adolescent girls (n=59 exposed to direct physical or sexual assault; n=29 healthy controls), aged 11–17, during fMRI. Large-scale organization indices of modularity, assortativity, and global efficiency were calculated for stimulus-specific functional connectivity using an 883 region-of-interest parcellation. Results: Among the entire sample, more severe early life trauma was associated with more modular and assortative, but less globally efficient, network organization across all stimulus categories. Among the assaulted girls, severity of early life trauma and PTSD diagnoses were both simultaneously related to increased modular brain organization. We also found that more modularized network organization was related both to amygdala hyperactivation and weakened connectivity between amygdala and medial PFC. Conclusions: These results demonstrate that early life trauma is associated with enhanced brain organization during facial emotion processing and that this pattern of brain organization might explain the commonly observed association between childhood trauma and amygdala hyperactivity and weakened connectivity with mPFC. Implications of these results for neurocircuitry models are discussed.

The purpose of this study was to use meta-analytic thinking to evaluate the results of a three-week professional development on mathematics teachers’ technological pedagogical content knowledge (TPACK). The study aims to elucidate the necessity of technology professional development activities to support mathematics teaching and learning in urban schools. This study utilizes mean difference confidence intervals as measures of the effectiveness of a professional development intervention in an urban school district in the U.S. This article presents a practical application of meta-analytic thinking to better contextualize the results through direct comparisons to similar studies. The results of this study suggest that the professional development increased mathematics teachers’ perceptions of their pedagogical knowledge, technological knowledge, pedagogical content knowledge, and technological content knowledge. The study results indicate that despite smaller overall effect sizes the results observed in this urban intervention were not statistically significantly different from most prior research in this area. Because of the chosen research approach, the research results have practical as well as empirical implications for the development and delivery of professional development in urban schools. This article contributes to the literature by providing a contextualized assessment of PD effects and by placing these effects in a broader scholarly context.

Background: The phyllosphere hosts a variety of microorganisms, including bacteria, which can play a positive role in the success of the host plant. Bacterial communities in the phylloplane are influenced by both biotic and abiotic factors, including host plant surface topography and chemistry, which change in concert with microbial communities as the plant leaves develop and age. Methods: We examined how the Zea mays L. leaf microbial community structure changed with plant age. Ribosomal spacer length and scanning electron microscopic imaging strategies were used to assess microbial community composition across maize plant ages, using a novel staggered experimental design. Results: Significant changes in community composition were observed for both molecular and imaging analyses, and the two analysis methods provided complementary information about bacterial community structure within each leaf developmental stage. Conclusions: Both taxonomic and cell-size trait patterns provided evidence for niche-based contributions to microbial community development on leaves.

Numerous data demonstrate that distracting emotional stimuli cause behavioral slowing (i.e. emotional conflict) and that behavior dynamically adapts to such distractors. However, the cognitive and neural mechanisms that mediate these behavioral findings are poorly understood. Several theoretical models have been developed that attempt to explain these phenomena, but these models have not been directly tested on human behavior nor compared. A potential tool to overcome this limitation is Hidden Markov Modeling (HMM), which is a computational approach to modeling indirectly observed systems. Here, we administered an emotional Stroop task to a sample of healthy adolescent girls (N = 24) during fMRI and used HMM to implement theoretical behavioral models. We then compared the model fits and tested for neural representations of the hidden states of the most supported model. We found that a modified variant of the model posited by Mathews et al. (1998) was most concordant with observed behavior and that brain activity was related to the model-based hidden states. Particularly, while the valences of the stimuli themselves were encoded primarily in the ventral visual cortex, the model-based detection of threatening targets was associated with increased activity in the bilateral anterior insula, while task effort (i.e. adaptation) was associated with reduction in the activity of these areas. These findings suggest that emotional target detection and adaptation are accomplished partly through increases and decreases, respectively, in the perceived immediate relevance of threatening cues and also demonstrate the efficacy of using HMM to apply theoretical models to human behavior.

Mathematics teachers frequently provide concrete manipulatives to students during instruction; however, the rationale for using certain manipulatives in conjunction with concepts may not be explored. This article focuses on area models that are currently used in classrooms to provide concrete examples of integer and binomial multiplication. The innovation of combining the representations for negative numbers with both algebra tiles and Algeblocks is provided, with a mathematical justification for its development. Teachers’ effective integration of tools such as these in mathematics instruction can help students develop conceptual understanding and procedural fluency.

Mathematics teachers frequently provide concrete manipulatives to students during instruction; however, the rationale for using certain manipulatives in conjunction with concepts may not be explored. This article focuses on area models that are currently used in classrooms to provide concrete examples of integer and binomial multiplication. The innovation of combining the representations for negative numbers with both algebra tiles and Algeblocks is provided, with a mathematical justification for its development. Teachers’ effective integration of tools such as these in mathematics instruction can help students develop conceptual understanding and procedural fluency.

Posttraumatic stress disorder (PTSD) is often chronic and disabling across the lifespan. The gold standard treatment for adolescent PTSD is Trauma-Focused Cognitive-Behavioral Therapy (TF-CBT), though treatment response is variable and mediating neural mechanisms are not well understood. Here, we test whether PTSD symptom reduction during TF-CBT is associated with individual differences in large-scale brain network organization during emotion processing. Twenty adolescent girls, aged 11-16, with PTSD related to assaultive violence completed a 12-session protocol of TF-CBT. Participants completed an emotion processing task, in which neutral and fearful facial expressions were presented either overtly or covertly during 3T fMRI, before and after treatment. Analyses focused on characterizing network properties of modularity, assortativity, and global efficiency within an 824 region-of-interest brain parcellation separately during each of the task blocks using weighted functional connectivity matrices. We similarly analyzed an existing dataset of healthy adolescent girls undergoing an identical emotion processing task to characterize normative network organization. Pre-treatment individual differences in modularity, assortativity, and global efficiency during covert fear vs neutral blocks predicted PTSD symptom reduction. Patients who responded better to treatment had greater network modularity and assortativity but lesser efficiency, a pattern that closely resembled the control participants. At a group level, greater symptom reduction was associated with greater pre-to-post-treatment increases in network assortativity and modularity, but this was more pronounced among participants with less symptom improvement. The results support the hypothesis that modularized and resilient brain organization during emotion processing operate as mechanisms enabling symptom reduction during TF-CBT.

Posttraumatic Stress Disorder (PTSD) is characterized by intrusive recall of the traumatic memory. While numerous studies have investigated the neural processing mechanisms engaged during trauma memory recall in PTSD, these analyses have only focused on group-level contrasts that reveal little about the predictive validity of the identified brain regions. By contrast, a multivariate pattern analysis (MVPA) approach towards identifying the neural mechanisms engaged during trauma memory recall would entail testing whether a multivariate set of brain regions is reliably predictive of (i.e., discriminates) whether an individual is engaging in trauma or non-trauma memory recall. Here, we use a MVPA approach to test 1) whether trauma memory vs neutral memory recall can be predicted reliably using a multivariate set of brain regions among women with PTSD related to assaultive violence exposure (N=16), 2) the methodological parameters (e.g., spatial smoothing, number of memory recall repetitions, etc.) that optimize classification accuracy and reproducibility of the feature weight spatial maps, and 3) the correspondence between brain regions that discriminate trauma memory recall and the brain regions predicted by neurocircuitry models of PTSD. Cross-validation classification accuracy was significantly above chance for all methodological permutations tested; mean accuracy across participants was 76% for the methodological parameters selected as optimal for both efficiency and accuracy. Classification accuracy was significantly better for a voxel-wise approach relative to voxels within restricted regions-of-interest (ROIs); classification accuracy did not differ when using PTSD-related ROIs compared to randomly generated ROIs. ROI-based analyses suggested the reliable involvement of the left hippocampus in discriminating memory recall across participants and that the contribution of the left amygdala to the decision function was dependent upon PTSD symptom severity. These results have methodological implications for real-time fMRI neurofeedback of the trauma memory in PTSD and conceptual implications for neurocircuitry models of PTSD that attempt to explain core neural processing mechanisms mediating PTSD.