A serum-induced gene signature in hepatocytes is associated with pediatric nonalcoholic fatty liver disease.

OBJECTIVE: Pediatric nonalcoholic fatty liver disease (NAFLD) is a growing problem, but its underlying mechanisms are poorly understood. We used transcriptomic reporter cell assays to investigate differences in transcriptional signatures induced in hepatocyte reporter cells by the sera of children with and without NAFLD. METHODS: We studied serum samples from 45 children with NAFLD and 28 children without NAFLD. The sera were used to induce gene expression in cultured HepaRG cells and RNA-sequencing was used to determine gene expression. Computational techniques were used to compare gene expression patterns. RESULTS: Sera from children with NAFLD induced the expression of 195 genes that were significantly differentially expressed in hepatocytes compared to controls with obesity. NAFLD was associated with increased expression of genes promoting inflammation, collagen synthesis, and extracellular matrix remodeling. Additionally, there was lower expression of genes involved in endobiotic and xenobiotic metabolism, and downregulation of peroxisome function, oxidative phosphorylation, and xenobiotic, bile acid, and fatty acid metabolism. A 13-gene signature, including upregulation of TREM1 and MMP1 and downregulation of CYP2C9, was consistently associated with all diagnostic categories of pediatric NAFLD. CONCLUSION: The extracellular milieu of sera from children with NAFLD induced specific gene profiles distinguishable by a hepatocyte reporter system. Circulating factors may contribute to inflammation and extracellular matrix remodeling and impair xenobiotic and endobiotic metabolism in pediatric NAFLD.

A multicenter registry study on percutaneous electrical nerve field stimulation for pediatric disorders of gut-brain interaction.

OBJECTIVES: Percutaneous electrical nerve field stimulation (PENFS) has demonstrated promise in single-center trials for pediatric abdominal pain-related disorders of gut-brain interaction (DGBI). Our aim was to explore efficacy of PENFS as standard therapy for DGBI in a registry involving multiple pediatric gastroenterology referral centers. METHODS: This was a multicenter, prospective open-label registry of children (8-18 years) undergoing PENFS for DGBI at seven tertiary care gastroenterology clinics. DGBI subtypes were classified by Rome IV criteria. Parents and patients completed Abdominal Pain Index (API), Nausea Severity Scale (NSS), and Functional Disability Inventory (FDI) questionnaires before, during therapy and at follow-up visits up to 1 year later. RESULTS: A total of 292 subjects were included. Majority (74%) were female with median (interquartile range [IQR]) age 16.3 (14.0, 17.7) years. Most (68%) met criteria for functional dyspepsia and 61% had failed ≥4 pharmacologic therapies. API, NSS, and FDI scores showed significant declines within 3 weeks of therapy, persisting long-term in a subset. Baseline (n = 288) median (IQR) child-reported API scores decreased from 2.68 (1.84, 3.58) to 1.99 (1.13, 3.27) at 3 weeks (p < 0.001) and 1.81 (0.85, 3.20) at 3 months (n = 75; p < 0.001). NSS scores similarly improved from baseline, persisting at three (n = 74; p < 0.001) and 6 months later (n = 55; p < 0.001). FDI scores displayed similar reductions at 3 months (n = 76; p = 0.01) but not beyond. Parent-reported scores were consistent with child reports. CONCLUSIONS: This large, comprehensive, multicenter registry highlights efficacy of PENFS for gastrointestinal symptoms and functionality for pediatric DGBI.

Evaluating threshold for donor fraction cell-free DNA using clinically available assay for rejection in pediatric and adult heart transplantation.

BACKGROUND: The aims of the study were to assess the performance of a clinically available cell-free DNA (cfDNA) assay in a large cohort of pediatric and adult heart transplant recipients and to evaluate performance at specific cut points in detection of rejection. METHODS: Observational, non-interventional, prospective study enrolled pediatric and adult heart transplant recipients from seven centers. Biopsy-associated plasma samples were used for cfDNA measurements. Pre-determined cut points were tested for analytic performance. RESULTS: A total of 487 samples from 160 subjects were used for the analysis. There were significant differences for df-cfDNA values between rejection [0.21% (IQR 0.12-0.69)] and healthy samples [0.05% (IQR 0.01-0.14), p < .0001]. The pediatric rejection group had a median df-cfDNA value of 0.93% (IQR 0.28-2.84) compared to 0.09% (IQR 0.04-0.23) for healthy samples, p = .005. Overall negative predictive value was 0.94 while it was 0.99 for pediatric patients. Cut points of 0.13% and 0.15% were tested for various types of rejection profiles and were appropriate to rule out rejection. CONCLUSION: The study suggests that pediatric patients with rejection show higher levels of circulating df-cfDNA compared to adults and supports the specific cut points for clinical use in pediatric and adult patients with overall acceptable performance.

Impact of Underweight, Overweight, and Obesity on Health-Related Quality of Life in Children with Tetralogy of Fallot Variants.

Traditional cardiovascular risk factors put patients with congenital heart disease (CHD) at increased risk for cardiovascular morbidity and mortality. The aim of this study was to evaluate whether body mass index (BMI) is associated with health-related quality of life (HRQoL) in patients with variants of Tetralogy of Fallot (TOF). Patients and parents of children with variants of TOF-CHD were asked to fill out the PedsQL 4.0 questionnaire and provide weight and length. Patients were categorized into low, normal, and high BMI percentiles. Other demographic data were obtained from the Swedish national registry for congenital heart disease (SWEDCON). Statistical analyses included non-parametric Mann-Whitney U test, Fisher exact, and Chi-square tests. Eighty-five patients were included. Twelve were overweight or obese, 57 had a normal BMI, and 16 were underweight. There was a significant difference in age and gender between the groups. Comparing overweight/obese children to those with normal BMI, physical and social functioning were impaired, while emotional and school function were comparable between the groups. This applied to both child and parental assessment. When comparing underweight to normal weight children, school functioning assessed by the parent was the only domain significantly different from patients with a normal BMI. Children with variants of TOF and overweight/obesity have lower HRQoL, particularly in physical and social functioning, while underweight children may have impaired school functioning. We suggest that preventive measures aimed at maintaining a normal weight should be taken early in life to reduce long-term cardiovascular risk in the CHD population.

Natural History of Pediatric Cyclic Vomiting Syndrome: Progression to Dysautonomia.

BACKGROUND: The clinical features of pediatric cyclic vomiting syndrome (CVS) often evolve over time. Many patients develop a constellation of chronic symptoms that suggest autonomic nervous system (ANS) dysfunction during adolescence. We aimed to determine the proportion of children with CVS who develop chronic rather than episodic symptoms consistent with ANS dysfunction. METHODS: Retrospective chart review of children ages 0-18 years followed in an outpatient tertiary care CVS center. Patients completed standardized questionnaires at intake and follow-up visits, documenting clinical symptom pattern. Continuous variables are summarized as median [interquartile range (IQR)]. A Mann-Whitney test was used for group comparisons. RESULTS: One hundred subjects were included. A total of 40% developed symptoms of ANS dysfunction (ANS+); 20% were confirmed by comprehensive ANS testing, 11% by orthostatic vital sign abnormalities, and 9% by clinical symptoms. The median (IQR) age at onset of chronic symptoms was 14 (10.02, 15) years. The presence of another disorder of gut-brain interaction ( P = 0.018) and a greater number of comorbidities ( P = 0.031) were more common in the ANS+ group. ANS+ subjects missed more school days ( P = 0.047) and were seen less frequently in the emergency department ( P = 0.023). CONCLUSIONS: Many children with CVS (40%) develop symptoms consistent with clinical dysautonomia in adolescence. These patients experience more comorbid conditions and a greater impact on school attendance, possibly representing a worsened quality of life as their disease course transitions to daily symptoms. When symptoms of CVS change over time, therapeutic interventions may need to be adjusted and targeted accordingly.

Percutaneous Electrical Nerve Field Stimulation for Drug-Refractory Pediatric Cyclic Vomiting Syndrome.

BACKGROUND: Cyclic vomiting syndrome (CVS) is a disabling condition frequently refractory to pharmacologic therapy. The aim of this study was to evaluate the effects of noninvasive, auricular percutaneous electrical nerve field stimulation (PENFS) as prophylactic therapy for pediatric CVS. METHODS: Children 8-18 years with drug-refractory CVS were prospectively enrolled from a tertiary care CVS clinic. Subjects received 6 consecutive weeks of PENFS. CVS severity was quantified by episode frequency and duration score (range 0-25) at baseline and at extended follow-up (4-6 months after end of therapy). Response was classified as ≥50% improvement in either frequency or duration of attacks at extended follow-up. Subjects also completed validated surveys of nausea, disability, and global response. RESULTS: Thirty subjects completed the study. Median (interquartile range, IQR) age was 10.5 (8.5-15.5) years; 60% were female. At follow-up, 80% met criteria for treatment response with a median (IQR) response duration of 113 (61-182) days. The frequency-duration score improved from baseline median (IQR) 12.0 (9.0-16.0) to 3.0 (1.0-6.0) at follow-up, P < 0.0001. Median (IQR) nausea and disability scores decreased from baseline to week 6: 2.1 (1.3-2.7) to 0.9 (0-1.6), P = 0.003 and 47.5 (41.0-53.0) to 38.0 (16.0-51.0), P = 0.001, respectively. At end of therapy, 66% and 55% patients reported global response of at least "moderately better" and "a good deal better," respectively. There were no serious side effects. CONCLUSIONS: This study suggests long-term benefits of PENFS for children with CVS. PENFS improves several disabling aspects of CVS, including episode frequency, duration, and functional disability.

Safety and Efficacy of Direct Oral Anticoagulants for Treatment of Venous Thromboembolism in Pediatric Oncology Patients.

BACKGROUND/OBJECTIVES: Children with cancer have an increased risk for developing a venous thromboembolism (VTE) during their treatment course. Direct oral anticoagulants (DOACs) represent a relatively new class of oral medications to treat VTE; however, data are limited to support use in this patient group. Given the safety and efficacy data from numerous perspective adult studies, providers now consider off-label use in select children. METHODS: We performed a single-center, retrospective review of children 0 to 20 years of age from 2012 to 2020 with malignancy and confirmed VTE, with the objective to evaluate the hypothesis that the safety and the efficacy of DOACs are noninferior to enoxaparin in this population. The primary composite efficacy outcome comprises symptomatic recurrent VTE, death due to VTE, and thrombus progression. The principal safety outcome is a combination of major and clinically relevant nonmajor bleeding. RESULTS: The safety and efficacy outcomes collected revealed that DOAC use was equivalent when compared with the enoxaparin group for treatment of VTE. One patient in the DOAC group had clinically relevant, nonmajor bleeding compared with 2 patients in the enoxaparin group. No treatment failures were observed. CONCLUSIONS: This single-center study suggests that DOACs are both safe and efficacious for the treatment of VTE in children with cancer. It also highlights the need for larger studies to address this clinical question.

Dexmedetomidine for sedation during hematopoietic stem cell harvest apheresis and leukapheresis in the PICU: Guideline development.

BACKGROUND: Hematopoietic stem cell (HSC) harvest apheresis and leukapheresis are performed in the pediatric intensive care unit (PICU) for high-risk pediatric patients who require procedural sedation. Patients need central access either with their own central lines, ports or require apheresis catheter (CVL) placement. Previously, patients were either awake or emerging from sedation on PICU admission. Uncertainty regarding procedural sedation plans caused delays initiating sedation and apheresis. A guideline was developed to standardize Dexmedetomidine (DEX) for procedural sedation. We investigated if guideline implementation would improve efficiency during PICU admission as demonstrated by shorter time intervals for initiation of sedation, apheresis, PICU length of stay and less alternative sedating medication. METHODS: Data was collected retrospectively from electronic health records of preguideline and post-guideline patients who were admitted to the PICU for sedated apheresis. We compared demographic and clinical characteristics, time intervals for sedation, apheresis, PICU length of stay, and sedation agents between the two groups using Fisher Exact tests and Mann-Whitney tests, as appropriate. RESULTS: The groups did not differ in age or weight at the time of apheresis. All intervals of time compared were shorter post-guideline. Time intervals from admission to start of sedation, admission to start of apheresis, and admission to end of apheresis were statistically significantly different. The type and number of alternative sedating medications administered did not differ between the two groups. CONCLUSION: This guideline implementation improved efficiency during PICU admission. This study might have been too small to demonstrate statistically significant differences in other time intervals studied.

Creating a data dictionary for pediatric autonomic disorders.

PURPOSE: Whether evaluating patients clinically, documenting care in the electronic health record, performing research, or communicating with administrative agencies, the use of a common set of terms and definitions is vital to ensure appropriate use of language. At a 2017 meeting of the Pediatric Section of the American Autonomic Society, it was determined that an autonomic data dictionary comprising aspects of evaluation and management of pediatric patients with autonomic disorders would be an important resource for multiple stakeholders. METHODS: Our group created the list of terms for the dictionary. Definitions were prioritized to be obtained from established sources with which to harmonize. Some definitions needed mild modification from original sources. The next tier of sources included published consensus statements, followed by Internet sources. In the absence of appropriate sources, we created a definition. RESULTS: A total of 589 terms were listed and defined in the dictionary. Terms were organized by Signs/Symptoms, Triggers, Co-morbid Disorders, Family History, Medications, Medical Devices, Physical Examination Findings, Testing, and Diagnoses. CONCLUSION: Creation of this data dictionary becomes the foundation of future clinical care and investigative research in pediatric autonomic disorders, and can be used as a building block for a subsequent adult autonomic data dictionary.

Assessment of comorbid symptoms in pediatric autonomic dysfunction.

PURPOSE: Pediatric patients with autonomic dysfunction and orthostatic intolerance (OI) often present with co-existing symptoms and signs that might or might not directly relate to the autonomic nervous system. Our objective was to identify validated screening instruments to characterize these comorbidities and their impact on youth functioning. METHODS: The Pediatric Assembly of the American Autonomic Society reviewed the current state of practice for identifying symptom comorbidities in youth with OI. The assembly includes physicians, physician-scientists, scientists, advanced practice providers, psychologists, and a statistician with expertise in pediatric disorders of OI. A total of 26 representatives from the various specialties engaged in iterative meetings to: (1) identify and then develop consensus on the symptoms to be assessed, (2) establish committees to review the literature for screening measures by member expertise, and (3) delineate the specific criteria for systematically evaluating the measures and for making measure recommendations by symptom domains. RESULTS: We review the measures evaluated and recommend one measure per system/concern so that assessment results from unrelated clinical centers are comparable. We have created a repository to apprise investigators of validated, vetted assessment tools to enhance comparisons across cohorts of youth with autonomic dysfunction and OI. CONCLUSION: This effort can facilitate collaboration among clinical settings to advance the science and clinical treatment of these youth. This effort is essential to improving management of these vulnerable patients as well as to comparing research findings from different centers.

Does High-Intensity Exercise Cause Acute Liver Injury in Patients with Fontan Circulation? A Prospective Pilot Study.

The Fontan procedure results in chronic hepatic congestion and Fontan-associated liver disease (FALD) characterized by progressive liver fibrosis and cirrhosis. Exercise is recommended in this population, but may accelerate the progression of FALD from abrupt elevations in central venous pressure. The aim of this study was to assess if acute liver injury occurs after high-intensity exercise in patients with Fontan physiology. Ten patients were enrolled. Nine had normal systolic ventricular function and one had an ejection fraction < 40%. During cardiopulmonary exercise testing, patients had near-infrared spectroscopy (NIRS) to measure oxygen saturation of multiple organs, including the liver, and underwent pre- and post-exercise testing with liver elastography, laboratory markers, and cytokines to assess liver injury. The hepatic and renal NIRS showed a statistically significant decrease in oxygenation during exercise, and the hepatic NIRS had the slowest recovery compared to renal, cerebral, and peripheral muscle NIRS. A clinically significant increase in shear wave velocity occurred after exercise testing only in the one patient with systolic dysfunction. There was a statistically significant, albeit trivial, increase in ALT and GGT after exercise. Fibrogenic cytokines traditionally associated with FALD did not increase significantly in our cohort; however, pro-inflammatory cytokines that predispose to fibrogenesis did significantly rise during exercise. Although patients with Fontan circulation demonstrated a significant reduction in hepatic tissue oxygenation based on NIRS saturations during exercise, there was no clinical evidence of acute increase in liver congestion or acute liver injury following high-intensity exercise.

Stress Numerical Rating Scale-11: Validation in Pediatric Inpatient and Outpatient Pain Settings.

Stress is a commonly reported issue in pediatric populations of chronic and acute pain. Both outpatient and inpatient settings impose time constraints, which decreases opportunities to measure and address patient stress. The aim of these studies was to evaluate the validity of the Stress Numeric Rating Scale-11 (SNRS-11) in both inpatient and outpatient settings. The SNRS-11 is a single item stress measure ranging from 0 to 10 with endpoint anchors: 0 = "No stress" and 10 = "Highest stress possible". Results showed discriminative validity in the inpatient sample and convergent and discriminant validity in both outpatient and inpatient samples. Additionally, approximately 40% to 50% of the sample reported moderate-severe stress on all post-operative days. The SNRS-11 shows promise as a quick, easy, and free stress measure to be used in both inpatient and outpatient settings.

Caregiver Reports of Infant Distress and Injury in Abused Infants.

OBJECTIVES: To determine whether in infants evaluated for physical abuse, medical encounters for infant distress are correlated with physical abuse or a history of sentinel injuries. STUDY DESIGN: This retrospective, case-control analysis of infants aged <12 months evaluated for physical abuse identified demographic characteristics, prior injuries, and medical encounters for infant distress. Variables were compared between abused infants and nonabused infants with and without sentinel injuries. A nonparametric recursive classification tree analysis assessed interactions between variables. RESULTS: Infant distress was associated with abuse (67.9% vs 44.7%; P = .008; OR, 2.6; 95% CI, 1.3-5.2). Infants with sentinel injuries had higher rates of infant distress (74.1% vs 42.4%; P ≤ .001) and crying (81.5% vs 62.7%; P = .012). Previous falls (32.6% vs 18.1%; P = .03) and nonsentinel injuries (18.2% vs 5.4%; P = .002) also were associated with abuse, although sentinel injuries were the most important predictor of abuse, followed by infant distress. CONCLUSIONS: Infants with medical encounters for distress and injury may be at higher risk for abuse and may benefit from intensive educational and support services for their caregivers. Additional research evaluating the most effective interventions for caregivers of fussy infants is needed.

Interaction of chronic pain, obesity and time of day on cortisol in female human adolescents.

Adolescent obesity augments and impedes the treatment of chronic pain. This is associated with increased systemic inflammation and is more prominent in females. In addition, pain and obesity each independently affect the hypothalamic-pituitary-adrenal (HPA) axis. However, the interaction of pain and obesity on the HPA axis and the potential for sexual dimorphism in this phenomenon is not established. We hypothesized that dysregulation of the HPA axis occurs in female human adolescents with chronic pain, obesity, or the combination of the two and is associated with gonadal steroids. We measured serum cortisol, estradiol, and testosterone in 13-17-year-old adolescent females (N = 79) from venous blood drawn during the daytime (0830-1730 h) and analyzed the data in toto and partitioned by morning vs. afternoon sampling time. Subjects were categorized as healthy weight/no pain (controls; BMI = 56th percentile [37-71]), healthy weight with chronic pain, obese without pain (BMI = 97th percentile [95-99]), or the combination of obesity and chronic pain. Serum cortisol was lower with chronic pain and/or obesity compared to healthy controls and was lower with chronic pain and obesity compared to chronic pain alone (healthy weight). The lower serum cortisol in the pain alone group was more prominent in the morning compared to the afternoon. There was no relationship between serum estradiol and testosterone and study group. The decrease in the anti-inflammatory and other pain-ameliorating effects of cortisol may contribute to chronic pain and its resistance to treatment with concurrent obesity in female adolescents.

Increase in nuclear cell-free DNA is associated with major adverse events in adult and pediatric heart transplant recipients.

BACKGROUND: Cell-free DNA is an emerging biomarker. While donor fraction may detect graft events in heart transplant recipients, the prognostic value of total nuclear cell-free DNA (ncfDNA) itself is largely unexplored. OBJECTIVE: Explore the relationship between ncfDNA and clinical events in heart transplant recipients. METHODS: We conducted a multi-center prospective study to investigate the value of cell-free DNA in non-invasive monitoring following heart transplantation. Over 4000 blood samples were collected from 388 heart transplant patients. Total ncfDNA and donor fraction were quantified. Generalized linear models with maximum likelihood estimation for repeated measures with subjects as clusters were used to explore the relationship of ncfDNA and major adverse events. Receiver operating characteristic curves were used to help choose cutpoints. RESULTS: A ncfDNA threshold (50 ng/ml) was identified that was associated with increased risk of major adverse events. NcfDNA was elevated in patients who suffered cardiac arrest, required mechanical circulatory support or died post heart transplantation as well as in patients undergoing treatment for infection. CONCLUSIONS: Elevated ncfDNA correlates with risk for major adverse events in adult and pediatric heart transplant recipients and may indicate a need for enhanced surveillance after transplant.

Relationship between donor fraction cell-free DNA and clinical rejection in heart transplantation.

BACKGROUND: Clinical rejection (CR) defined as decision to treat clinically suspected rejection with change in immunotherapy based on clinical presentation with or without diagnostic biopsy findings is an important part of care in heart transplantation. We sought to assess the utility of donor fraction cell-free DNA (DF cfDNA) in CR and the utility of serial DF cfDNA in CR patients in predicting outcomes of clinical interest. METHODS: Patients with heart transplantation were enrolled in two sequential, multi-center, prospective observational studies. Blood samples were collected for surveillance or clinical events. Clinicians were blinded to the results of DF cfDNA. RESULTS: A total of 835 samples from 269 subjects (57% pediatric) were included for this analysis, including 28 samples associated with CR were analyzed. Median DF cfDNA was 0.43 (IQR 0.15, 1.36)% for CR and 0.10 (IQR 0.07, 0.16)% for healthy controls (p < .0001). At cutoff value of 0.13%, the area under curve (AUC) was 0.82, sensitivity of 0.86, specificity of 0.67, and negative predictive value of 0.99. There was serial decline in DF cfDNA post-therapy, however, those with cardiovascular events (cardiac arrest, need for mechanical support or death) showed significantly higher levels of DF cfDNA on Day 0 (2.11 vs 0.31%) and Day 14 (0.51 vs 0.22%) compared to those who did not have such an event (p < .0001). CONCLUSION: DF cfDNA has excellent agreement with clinical rejection and, importantly, serial measurement of DF cfDNA predict clinically significant outcomes post treatment for rejection in these patients.

Detection of changes of functioning over time after asthma exacerbation in children with the use of PROMIS domains.

OBJECTIVES: Patient reported outcome measures, such as the Patient Reported Outcomes Measurement Information System (PROMIS) may be utilized to understand experiences of patients. The purpose of this study was to determine the ability of PROMIS domains to detect changes in pain, physical functioning, and asthma impact over time for children experiencing asthma exacerbation. METHODS: Our prospective cohort study included children presenting to the emergency department (ED) for asthma exacerbation. Children completed PROMIS surveys in the ED, 7-10 days, and 1-3 months post-discharge. We used linear mixed models adjusted for age, gender, acute care utilization, and child global health to determine changes in PROMIS T-scores. We used self-reported child health response (Much better now versus a little better now or worse) at discharge as an anchor to determine if change in PROMIS scores corresponded with changes in health. A change was statistically significant if the 95% CI did not include 0. RESULTS: Our study included 63 children who presented to the ED for acute asthma exacerbation. We identified that children improved significantly in all domains over time. There was improvement over time following discharge from ED for all pain and physical functioning domains, and asthma impact. Using the clinical anchor, those with considerable improvement in asthma symptoms had improved T scores from 4-17. CONCLUSIONS: PROMIS domains of pain, physical functioning, depression, fatigue, peer relationships, and asthma impact are responsive to changes in health states over time. These domains may be used to measure clinically significant change in children experiencing asthma exacerbation.

Predictors of behavioural and emotional outcomes in toddlers with congenital heart disease.

OBJECTIVES: Children with congenital heart disease (CHD) are at risk for psychological challenges, including internalising (e.g., depression, anxiety) and externalising (e.g., aggression, inattention) problems. The present study aimed to investigate the development of psychological concerns in early childhood by identifying predictors of behavioural and emotional problems in toddlers with CHD. METHODS: Children with CHD who were seen for neurodevelopmental (ND) evaluation at 12 ± 3 months of age, who completed the Bayley Scales of Infant Development-III (BSID-III) and whose parents completed the Child Behavior Checklist (CBCL), a standardised measure of emotional/behavioural problems at age 24-36 months, were included in the study (n = 144). CBCL scores were compared to test norms and classified as normal or abnormal. A classification tree was used to assess the association between CBCL scores and demographic and clinical variables. RESULTS: Multi-variable tree analyses revealed lower BSID-III language composite scores at age 9-15 months predicted clinical CBCL internalising (p < 0.001), externalising (p = 0.004) and total scores (p < 0.001) at age 24-36 months. Lower maternal education levels also predicted clinical CBCL internalising (p < 0.0001), externalising (p < 0.001) and total scores (p < 0.0001). CONCLUSIONS: Lower language abilities and lower maternal education predict increased behavioural and emotional problems in toddlers with CHD. These risk factors should be considered during routine ND evaluations to allow for earlier identification of children with CHD and their families who may benefit from psychological support.

Rituximab and antimetabolite treatment of granulomatous and lymphocytic interstitial lung disease in common variable immunodeficiency.

BACKGROUND: Granulomatous and lymphocytic interstitial lung disease (GLILD) is a life-threatening complication in patients with common variable immunodeficiency (CVID), but the optimal treatment is unknown. OBJECTIVE: Our aim was to determine whether rituximab with azathioprine or mycophenolate mofetil improves the high-resolution computed tomography (HRCT) chest scans and/or pulmonary function test results in patients with CVID and GLILD. METHODS: A retrospective chart review of clinical and laboratory data on 39 patients with CVID and GLILD who completed immunosuppressive therapy was performed. Chest HRCT scans, performed before therapy and after the conclusion of therapy, were blinded, randomized, and scored independently by 2 radiologists. Differences between pretreatment and posttreatment HRCT scan scores, pulmonary function test results, and lymphocyte subsets were analyzed. Whole exome sequencing was performed on all patients. RESULTS: Immunosuppressive therapy improved patients' HRCT scan scores (P < .0001), forced vital capacity (P = .0017), FEV1 (P = .037), and total lung capacity (P = .013) but not their lung carbon monoxide diffusion capacity (P = .12). Nine patients relapsed and 6 completed retreatment, with 5 of 6 of these patients (83%) having improved HRCT scan scores (P = .063). Relapse was associated with an increased number of B cells (P = .016) and activated CD4 T cells (P = .016). Four patients (10%) had pneumonia while undergoing active treatment, and 2 patients (5%) died after completion of therapy. Eight patients (21%) had a damaging mutation in a gene known to predispose (TNFRSF13B [n = 3]) or cause a CVID-like primary immunodeficiency (CTLA4 [n = 2], KMT2D [n = 2], or BIRC4 [n = 1]). Immunosuppression improved the HRCT scan scores in patients with (P = .0078) and without (P < .0001) a damaging mutation. CONCLUSIONS: Immunosuppressive therapy improved the radiographic abnormalities and pulmonary function of patients with GLILD. A majority of patients had sustained remissions.

Human leukocyte antigen (HLA)-incompatible mean fluorescence intensity-selected platelet products have corrected count increments similar to HLA antigen-matched platelets.

BACKGROUND: Donor specific antibody sum mean fluorescence intensity (MFI) values have been successfully used in transplant medicine to assess risk for organ rejection. However, little is known regarding whether MFI values could be similarly used to aid in platelet product selection. We have developed a novel protocol where MFI values are used to offer human leukocyte antigen (HLA)-incompatible platelet products when HLA antigen-matched products are not available. We aimed to evaluate the efficacy of this protocol. METHODS: We performed a 4-year retrospective chart review for all patients who received at least one MFI-selected platelet product. A corrected count increment (CCI) was calculated for each transfusion event. A mixed effects model was used to investigate the association between CCIs for MFI-selected, HLA antigen matched, and random donor platelet transfusions. A random effects expectation-maximization regression tree was used to define the extent to which other patient variables, such as age, sex, and diagnosis impacted the CCI for each platelet transfusion. RESULTS: Twenty highly HLA alloimmunized patients received a total of 591 platelets. MFI-selected platelet (low MFI) transfusions had a significantly higher median CCI 0-6 hour post-transfusion (13,559, interquartile range [IQR]: 8275-18,736) compared to random donor platelets (2121, IQR: 0-10,368, p < 0.0001). There was no significant difference in median CCI between HLA antigen matched and MFI selected platelet transfusions (p = 0.2). Mixed effects and regression modeling revealed that MFI-selected platelet products had a significantly higher CCI than non-matched platelets, even when accounting for other significant patient variables. CONCLUSION: MFI-selected HLA-incompatible platelet products could provide a comparable alternative to traditional HLA antigen-matched platelet products.