Multimodal profiling of peripheral blood identifies proliferating circulating effector CD4+ T cells as predictors for response to integrin α4ß7-blocking therapy in inflammatory bowel disease.

BACKGROUND AND AIMS: Despite the success of biological therapies in treating inflammatory bowel disease (IBD), managing patients remains challenging due to the absence of reliable predictors of therapy response. METHODS: In this study, we prospectively sampled two cohorts of IBD patients receiving the anti-integrin α4ß7 antibody vedolizumab. Samples were subjected to mass cytometry, single-cell RNA sequencing, single-cell V(D)J sequencing, serum proteomics, and multidimensional flow cytometry to comprehensively assess vedolizumab-induced immunological changes in the peripheral blood and their potential associations with treatment response. RESULTS: Vedolizumab treatment led to substantial alterations in the abundance of circulating immune cell lineages and modified the T cell receptor diversity of gut-homing CD4+ memory T cells. Through integration of multimodal parameters and machine learning, we identified a significant increase in proliferating CD4+ memory T cells among non-responders prior to treatment compared with responders. This predictive T cell signature demonstrated an activated Th1/Th17 phenotype and exhibited elevated levels of integrin α4ß1, potentially making these cells less susceptible to direct targeting by vedolizumab. CONCLUSION: These findings provide a reliable predictive classifier with significant implications for personalized IBD management.

Comparison of EULAR/PRINTO/PReS Ankara 2008 and 2022 ACR/EULAR classification criteria for granulomatosis with polyangiitis in children.

OBJECTIVE: Granulomatosis with polyangiitis (GPA) is an ANCA-associated vasculitis. The 2022 ACR/EULAR-endorsed classification criteria for GPA was derived using data only from adult patients. We aimed to assess the performance of the ACR/EULAR classification criteria for GPA in paediatric patients and compare it with the EULAR/Pediatric Rheumatology International Trials Organization (PRINTO)/Pediatric Rheumatology European Society (PReS)-endorsed Ankara 2008 criteria for GPA. METHODS: Retrospective data of paediatric patients with GPA in 20 centres from 9 countries were evaluated. The diagnosis of GPA was made according to the expert opinion. The sensitivity, specificity, positive predictive value, and negative predictive value of the criteria sets were evaluated. RESULTS: The study included 77 patients with GPA and 108 controls [IgA vasculitis (n = 44), Takayasu's arteritis (n = 20), microscopic polyangiitis (n = 16), polyarteritis nodosa (n = 14), Behçet's disease (n = 12), eosinophilic granulomatosis with polyangiitis (n = 1) and Cogan's syndrome (n = 1)] with a median age of 17.8 and 15.2 years, respectively. Among patients with GPA, constitutional symptoms (85.7%) and ENT involvement (79.2%) were the most common presentations. In the GPA group, 73 patients fulfilled the Ankara 2008 criteria and 69 the ACR/EULAR classification criteria. Sensitivities of the Ankara 2008 criteria and the ACR/EULAR classification criteria were 94.8% and 89.6%, while specificities were 95.3% and 96.3%, respectively. No significant difference was found between sensitivities and specificities of both classification criteria (P = 0.229 and P = 0.733, respectively). CONCLUSION: In children, both the ACR/EULAR and EULAR/PRINTO/PReS Ankara 2008 classification criteria for GPA perform well and similarly.

Association between high-density mapping of atypical atrial flutter, clinical outcomes and healthcare utilization.

BACKGROUND: Success of atypical atrial flutter (AAFL) ablation has historically been limited by difficulty mapping the complex re-entrant circuits involved. While high-density (HD) mapping has become commonplace in clinical practice, there are limited data on outcomes of HD versus non-HD mapping for AAFL ablation. OBJECTIVE: To compare clinical outcomes and healthcare utilization using HD mapping versus non-HD mapping for AAFL ablation. METHODS: Retrospective analysis of all AAFL procedures between 2005 and 2022 at an academic medical center was conducted. Procedures utilizing a 16-electrode HD Grid catheter and Precision mapping system were compared to procedures using prior generation 10-20 electrode spiral catheters and the Velocity system (Abbott, IL). Cox regression models and Poisson regression models were utilized to examine procedural and healthcare utilization outcomes. Models were adjusted for left ventricular ejection fraction, CHA2DS2-VASc, and history of prior ablation. RESULTS: There were 108 patients (62% HD mapping) included in the analysis. Baseline clinical characteristics were similar between groups. Use of HD mapping was associated with a higher rate of AAFL circuit delineation (92.5% vs. 76%; p = .014) and a greater adjusted procedure success rate, defined as non-inducibility at procedure end, (aRR (95% CI) 1.26 (1.02-1.55) p = .035) than non-HD mapping. HD mapping was also associated with a lower rate of ED visits (aIRR (95% CI) 0.32 (0.14-0.71); p = .007) and hospitalizations (aIRR (95% CI) 0.32 (0.14-0.68); p = .004) for AF/AFL/HF through 1 year. While there was a lower rate of recurrent AFL through 1 year among HD mapping cases (aHR (95% CI) 0.60 (0.31-1.16) p = .13), statistical significance was not met likely due to the low sample size and higher rate of ambulatory rhythm monitoring in the HD group (61% vs. 39%, p = .025). CONCLUSION: Compared to non-HD mapping, AAFL ablation with HD mapping is associated with improvements in the ability to define the AAFL circuit, greater procedural success, and a reduction in the number of ED visits and hospitalization for AF/AFL/HF.

Which parents provide zero-alcohol beverages to adolescents? A survey of Australian parents' practices and intentions.

OBJECTIVE: Zero-alcohol beverages (<0.5% alcohol by volume) appear and taste similar to alcoholic beverages but are regulated similarly to soft drinks in many countries, blurring the distinction between alcoholic and non-alcoholic beverages. How parents view provision of zero-alcohol beverages to adolescents is likely a key determinant of adolescent consumption. We investigated factors associated with parents' provision of zero-alcohol beverages to adolescents, including attitudes toward zero-alcohol beverages and demographic, knowledge, and behavioural factors known to be associated with provision of alcoholic beverages. METHODS: We conducted an online cross-sectional survey of N = 1197 Australian parents of adolescents aged 12-17 years in April-May 2022. We examined associations with zero-alcohol beverage provision using binomial logistic regression, and with future provision intentions using multinomial logistic regression analyses. RESULTS: Factors significantly associated (p < .001) with parents' provision and future intentions to provide zero-alcohol beverages to their adolescent included beliefs that zero-alcohol beverages had benefits for adolescents (Adjusted Odds Ratio [AOR] 2.69 (provision); 3.72 (intentions)), provision of alcoholic beverages (AOR 2.67 (provision); 3.72 (intentions)), and an incorrect understanding of alcohol guidelines for adolescents (AOR 2.38 (provision); 1.95 (intentions)). CONCLUSIONS: Parents' provision and intentions to provide zero-alcohol beverages were associated with beliefs about zero-alcohol beverages as well as some factors associated with provision of alcoholic beverages. Precautionary advice to parents that the provision of zero-alcohol beverages may serve to normalise alcohol consumption may be warranted.

Mental health in paediatric and adult myositis-related diseases: current state of research, interventions, and future steps from the MIHRA Psychological Impact Scientific Working Group.

Psychological and emotional well-being are critical aspects of overall health for individuals with chronic rheumatologic conditions. Mental health-related literature, however, predominantly focuses on systemic lupus erythematosus or rheumatoid arthritis, with limited emphasis on idiopathic inflammatory myopathies (IIMs). High proportions of those with juvenile myositis report psychological distress at levels warranting mental health referral. Adults with dermatomyositis diagnosed with depression or anxiety do not receive adequate mental health care. Mental health symptoms in those with IIMs are associated with worse health-related quality of life, medication adherence, and disease outcomes. Despite demonstrated high rates of mental health burden, access to mental health care remains severely lacking.Data related to mental health burden is limited by small sample size, limited generalisability, variable methods of assessment, and inconsistent diagnosis codes to define mental health conditions. Additional research is needed to validate current screening tools in myositis populations. Other relevant measurable factors include disease severity, non-health- and health-related trauma exposure, loneliness, isolation, loss of control, sleep difficulties, fatigue, pain, self-esteem, body image, sexual health, and health inequities. Studiesare needed investigating the efficacy of therapeutic and pharmacologic interventions among patients with myositis who experience depression and anxiety. Currently, knowledge and resources are limited around mental health burden and potential intervention for those living with IIMs. The Myositis International Health & Research Collaborative Alliance (MIHRA) Psychological Impact Scientific Working Group offers a preliminary road map to characterise and prioritise the work ahead to understand baseline mental health burden and compare avenues for intervention.

Donor Characteristics and Outcomes of Pediatric Heart Transplantation in South Korea.

BACKGROUND: Heart transplantation is often limited by the availability of transplantable donor heart and understanding of donor aspects that would influence transplant outcomes becomes important. In this study, donor characteristics and their impact on the outcomes of pediatric heart transplantations performed in South Korea were investigated. METHODS: We reviewed the medical records of patients less than 18 years old who received heart transplantation between 2002 and 2022 in three tertiary hospitals located in South Korea. RESULTS: A total of 139 cases were enrolled. One-year mortality was 10.4% and total mortality was 33.8%. Forty-nine recipients (35.3%) showed biopsy-proven rejections and 20 (14.4%) showed cardiac allograft vasculopathy during mean follow-up of 6.4 ± 4.9 years. Six recipients (4.5%) showed left ventricle ejection fraction of less than 55% post-transplantation. The mean age of the donors was 23.0 ± 15.4 years. The most common cause of death of the donors was unspecified illness (46.4%). Donors with a history of diabetes, hypertension, smoking, and alcohol consumption were 0%, 3.1%, 32.1%, and 34.4%, respectively. Mean total ischemic time was 191.6 ± 72.7 min, while total ischemic time was over 4 h in 37 patients (26.6%). There were no significant relationship between donor factors and survival. However, donor's history of drinking or cardiopulmonary resuscitation was significantly associated with acute rejection and donor's age with cardiac allograft vasculopathy. CONCLUSION: Donor factors did not show significant impact on post-transplant survival but some factors were predictive of post-transplant rejection and cardiac allograft vasculopathy.

Exacerbation-prone pediatric asthma is associated with arginine, lysine, and methionine pathway alterations.

BACKGROUND: The asthma of some children remains poorly controlled, with recurrent exacerbations despite treatment with inhaled corticosteroids. Aside from prior exacerbations, there are currently no reliable predictors of exacerbation-prone asthma in these children and only a limited understanding of the potential underlying mechanisms. OBJECTIVE: We sought to quantify small molecules in the plasma of children with exacerbation-prone asthma through mass spectrometry-based metabolomics. We hypothesized that the plasma metabolome of these children would differ from that of children with non-exacerbation-prone asthma. METHODS: Plasma metabolites were extracted from 4 pediatric asthma cohorts (215 total subjects, with 41 having exacerbation-prone asthma) and detected with a mass spectrometer. High-confidence annotations were retained for univariate analysis and were confirmed by a sensitivity analysis in subjects receiving high-dose inhaled corticosteroids. Metabolites that varied by cohort were excluded. MetaboAnalyst software was used to identify pathways of interest. Concentrations were calculated by reference standardization. RESULTS: We identified 32 unique, cohort-independent metabolites that differed in children with exacerbation-prone asthma compared to children with non-exacerbation-prone asthma. Comparison of metabolite concentrations to literature-reported values for healthy children revealed that most metabolites were decreased in both asthma groups, but more so in exacerbation-prone asthma. Pathway analysis identified arginine, lysine, and methionine pathways as most impacted. CONCLUSIONS: Several plasma metabolites are perturbed in children with exacerbation-prone asthma and are largely related to arginine, lysine, and methionine pathways. While validation is needed, plasma metabolites may be potential biomarkers for exacerbation-prone asthma in children.

Cardiovascular Characteristics and Progressions of Hypertrophic Cardiomyopathy and Pulmonary Stenosis in RASopathy Syndrome in the Genomic Era.

INTRODUCTION: To investigate cardiovascular characteristics and progressions of hypertrophic cardiomyopathy (HCM) and pulmonary stenosis (PS) and determine whether any genotype-phenotype correlations exist in patients with gene-confirmed RASopathy syndrome. STUDY DESIGN: Eighty patients (male, 55%) confirmed as having RASopathy syndrome by genetic testing at a single tertiary center were enrolled. Subjects' medical and echocardiography records were reviewed and the changes in the z scores of left ventricular wall thickness (LVWT) and the degree of PS over time were examined during follow-up of 5.7 ± 3.1 and 7.5 ± 5.2 years, respectively. RESULTS: The most common RASopathy gene identified was PTPN11 (56%), followed by RAF1 (10%). Eighty-five percent of patients had cardiovascular diseases, wherein 42% had HCM, and 38% PS. Mean maximal LVWT z score on the initial echocardiography (mean age 5.0 ± 6.0 years) was 3.4 ± 1.3 (median 2.8, range 2.1-6.6) in the HCM group. Overall, the maximal LVWT increased with time, especially in the HCM group (z = 3.4 ± 1.3 to 3.7 ± 1.6, P = .008) and RAF1-variant group (z = 3.7 ± 1.7 to 4.6 ± 1.8, P = .031). Five patients newly developed HCM during the study period. Genotype-phenotype correlation was significant for HCM (P = .002); 31% of patients with PTPN11 and 88% with RAF1 variants had HCM. PS did not progress in this study cohort. CONCLUSIONS: In this study, progression of ventricular hypertrophy was seen in a significant number of patients with genotype correlation. Thus, long-term follow up of cardiovascular problems in patients with RASopathy is necessary.

Implementation of an intravenous sotalol initiation protocol: Implications for feasibility, safety, and length of stay.

INTRODUCTION: Oral sotalol initiation requires a multiple-day, inpatient admission to monitor for QT prolongation during loading. A 1-day intravenous (IV) sotalol loading protocol was approved by the United States Food and Drug Administration in March 2020, but limited data on clinical use and administration currently exists. This study describes implementation of an IV sotalol protocol within an integrated health system, provides initial efficacy and safety outcomes, and examines length of stay (LOS) compared with oral sotalol initiation. METHODS: IV sotalol was administered according to a prespecified initiation protocol to adult patients with refractory atrial or ventricular arrhythmias. Baseline characteristics, safety and feasibility outcomes, and LOS were compared with patients receiving oral sotalol over a similar time period. RESULTS: From January 2021 to June 2022, a total of 29 patients (average age 66.0 ± 8.6 years, 27.6% women) underwent IV sotalol load and 20 patients (average age 60.4 ± 13.9 years, 65.0% women) underwent oral sotalol load. The load was successfully completed in 22/29 (75.9%) patients receiving IV sotalol and 20/20 (100%) of patients receiving oral sotalol, although 7/20 of the oral sotalol patients (35.0%) required dose reduction. Adverse events interrupting IV sotalol infusion included bradycardia (seven patients, 24.1%) and QT prolongation (three patients, 10.3%). No patients receiving IV or oral sotalol developed sustained ventricular arrhythmias before discharge. LOS for patients completing IV load was 2.6 days shorter (mean 1.0 vs. 3.6, p < .001) compared with LOS with oral load. CONCLUSION: IV sotalol loading has a safety profile that is similar to oral sotalol. It significantly shortens hospital LOS, potentially leading to large cost savings.

Methotrexate for inflammatory skin disease in pediatric patients: Consensus treatment guidelines.

Methotrexate (MTX) is a readily accessible drug, first used in 1948 and employed for a wide variety of indications since then. However, despite widespread off-label use, FDA labeling does not include approved indications for the use of MTX for many inflammatory skin diseases in pediatric patients, including morphea, psoriasis, atopic dermatitis, and alopecia areata, among others. Without published treatment guidelines, some clinicians may be hesitant to use MTX off-label, or uncomfortable prescribing MTX in this population. To address this unmet need, an expert consensus committee was convened to develop evidence- and consensus-based guidelines for use of MTX to treat pediatric inflammatory skin disease. Clinicians with experience and expertise in clinical research, drug development, and treating inflammatory skin disease in pediatric patients with MTX were recruited. Five committees were created based on major topic areas: (1) indications and contraindications, (2) dosing, (3) interactions with immunizations and medications, (4) adverse effects (potential for and management of), and (5) monitoring needs. Pertinent questions were generated and addressed by the relevant committee. The entire group participated in a modified Delphi process to establish agreement on recommendations for each question. The committee developed 46 evidence- and consensus-based recommendations, each with >70% agreement among members, across all five topics. These are presented in tables and text, along with a discussion of supporting literature, and level of evidence. These evidence- and consensus-based recommendations will support safe and effective use of MTX for the underserved population of pediatric patients who may benefit from this valuable, time-honored medication.