搜索结果：Translational pediatrics

Most United States children with neurodevelopmental disorders have not received genetic testing aligned with current guidelines. Integration of genetic counselors into non-genetics departments is a potential strategy to improve uptake, but prevalence and details of integrated care models are unknown. To characterize availability, utilization, and perceived need for genetic counselors across non-genetics departments caring for patients with neurodevelopmental disorders. Cross-sectional observational department-level survey. Child neurology, adult neurology, developmental pediatrics, child psychiatry, and adult psychiatry departments at Intellectual and Developmental Disabilities Research Centers. The survey was distributed to 67 departments across 15 institutions. The departmental response rate was 52% (35/67), with at least one response from 87% (13/15) of institutions. Presence/absence of dedicated genetic counselor(s), where "dedicated" was defined as hired by the department. This was a descriptive study only, with no comparative statistical analyses due to the exploratory nature. One third of departments (34%; 12/35) reported having dedicated clinical genetic counselors. Prevalence was highest in child neurology (67%; 8/12), followed by adult neurology (40%; 2/5) and developmental pediatrics (22%; 2/9), with none in child psychiatry (0/7) or adult psychiatry (0/2). In almost all departments with genetic counselors (92%; 11/12), they directly billed for their services, which universally included pre-test counseling/consent and post-test counseling. In departments without genetic counselors, only 39% (9/23) reported providers ordered their own genetic testing. Among all departments, over half (57%) were interested in adding/increasing genetic counseling support, while 26% were unsure and 17% uninterested. Insufficient funding was the most cited barrier; only one department reported insufficient need. Though currently implemented in only one third of departments, our findings suggest those with dedicated genetic counselors directly pursue genetic testing (without referring to genetics) more than those without genetic counselors. Interest in increasing or adding genetic counseling support was high, and though funding was a reported barrier, feasible funding models were described. In the context of limited medical geneticists and expanding precision therapies, alternate delivery models for neurodevelopmental genetic testing including genetic counselor integration in non-genetics departments may help to scale and sustain uptake.

Community Engagement and Outreach (CEO) Cores are a key component of the IDeA Clinical and Translational Research (IDeA-CTR) Program, serving to develop and implement capacity-building initiatives that empower communities to engage and collaborate with investigators in community-engaged research. To strengthen collaboration and shared learning across sites, a CEO Special Interest Group was established. In 2022, the group conducted a landscape analysis to systematically characterize and categorize CEO Core activities across the IDeA-CTR network, with a focus on capacity-building efforts related to knowledge transfer, co-learning, and infrastructure development. The analysis revealed several common approaches to community engagement and capacity building across sites, as well as distinctive strategies tailored to the specific needs and communities served. Multiple innovative practices were identified and disseminated across the network, highlighting opportunities to enhance collective impact and inform future community-engaged efforts.

Pediatric pulmonary hypertension (PH) has high morbidity and mortality, with an estimated 5-year survival of 75% regardless of underlying cause. Pediatric PH most commonly affects infants born preterm who develop lung disease of prematurity as well as those with congenital heart disease. Current therapies have been adapted from the treatment of adult PH. One barrier to the study of pediatric PH is the lack of live tissue samples or primary cells for research. In this manuscript, we describe methods to obtain pulmonary endothelium from cardiac catheterization of pediatric patients with PH. We applied methods previously described in adult patients undergoing isolated right heart catheterization to obtain viable endothelium from pulmonary wedge catheters in pediatric patients. Primary cells were grown and passaged, and endothelial phenotype was confirmed by light microscopy, immunohistochemistry, flow cytometry, migration assay, and tube formation assay. To our knowledge, this is the first published account of endothelial culture from pulmonary wedge balloon catheters in pediatric patients. IMPACT: Validation of endothelial isolation from pulmonary wedge catheter to pediatric populations. Endothelium isolated from pulmonary wedge catheters are a valuable translational resource to study disease mechanism and develop therapeutics.

The mechanisms governing PD-L1 expression in breast cancer are highly complex and context-dependent. This article proposes a novel "dual-track" regulatory model to resolve the conflicting roles of estrogen in tumor immunity. Genomic signaling through ER-α suppresses PD-L1 transcription, explaining lower PD-L1 levels in ER-α-positive tumors. Conversely, non-genomic signaling mediated by cell-surface integrin αvβ3 drives PD-L1 presentation by triggering downstream PI3K/Akt and MAPK/ERK 1/2 pathways. We synthesize emerging data on how post-translational modulators (RNF31, p66Shc) and metabolic regulators (SIRT1-NAD+ axis) fine-tune PD-L1 stability. This interplay reveals a therapeutic vulnerability: antiestrogen treatments can paradoxically increase surface PD-L1 expression. In triple-negative breast cancer (TNBC), the absence of ER-α combined with active integrin αvβ3 signaling accelerates PD-L1-mediated immune evasion. This comprehensive framework uncovers novel molecular targets to improve combined endocrine and immunotherapeutic regimens for breast cancer patients.

Neonatal global hypoxic-ischemic cerebral injury is a leading cause of infant mortality and lifelong disability. Current rodent models do not replicate neonatal global cerebral ischemia (nGCI) and reperfusion injury. Here, we developed and characterized a rodent model of cardiac arrest and cardiopulmonary reperfusion (CA/CPR) to induce nGCI, producing acute systemic ischemia, mild neuronal injury, white matter alterations, and motor and memory deficits. Rat pups underwent CA/CPR or sham procedure on postnatal day 9-11. CA/CPR in rat pups was performed under anesthesia while intubated. Asystole was induced with intravenous (IV) KCl and maintained for 10-14 min. Resuscitation included oxygen ventilation, chest compressions, and IV epinephrine. Twelve minutes of asystole provided an optimal balance between survival and systemic injury. Behavioral testing on postoperative day (POD) 7 revealed memory impairments. Despite the absence of overt neuronal death in the hippocampus or cerebellum, we observed evidence of glial activation and white matter alterations. This novel rodent model of nGCI addresses limitations in existing models while offering clinically relevant features to support future mechanistic and translational research. This study validates cardiac arrest and cardiopulmonary resuscitation (CA/CPR) as a novel model for neonatal global cerebral ischemia (nGCI), complementing existing rodent models of unilateral and permanent injury by enabling investigation of both global ischemia and reperfusion injury. nGCI results in memory impairment in the absence of overt neuronal cell death. Functional deficits are associated with neuroinflammatory responses in the hippocampus, white matter, and cerebellum. Neonatal CA/CPR induces global cerebral ischemia, which uniquely allows investigation of hindbrain structures, such as the cerebellum, which are typically spared in existing rodent models of neonatal hypoxia-ischemia.

Fragile X syndrome (FXS), the leading genetic cause of intellectual disability, arises from FMR1 gene silencing and the subsequent loss of the RNA-binding protein FMRP. N6-methyladenosine (m6A) is a prevalent mRNA modification essential for post-transcriptional regulation. FMRP binds and regulates the stability of m6A-containing transcripts. However, how FMRP deficiency impacts transcriptome-wide m6A modifications in FXS remains unknown. To address this, we generated cortical neurons from induced pluripotent stem cells (iPSCs) derived from healthy individuals and FXS patients. Electrophysiology recordings revealed synaptic and neuronal network defects in FXS iPSC-derived neurons. Transcriptome-wide analysis revealed striking m6A hypermethylation predominantly affecting synapse-associated transcripts. Mechanistically, we demonstrated that FMRP deficiency drives the aberrant translational upregulation of core m6A writers, a causal relationship definitively validated using CGG-corrected isogenic control lines. Targeted genetic knockdown of the m6A writer METTL3 successfully rescued synaptic phenotypes in FXS neurons, whereas its overexpression in control neurons phenocopied these synaptic defects, confirming the causal role of m6A dysregulation in FXS pathology. Notably, pharmacological intervention with the METTL3 inhibitor STM-2457 normalized methylation on synapse-associated transcripts and restored synaptic transmission in FXS neurons. Together, our findings uncover an FMRP-dependent epitranscriptomic mechanism contributing to FXS pathogenesis and suggest a promising avenue for m6A-targeted therapies.

The International Organization for the Study of Inflammatory Bowel Disease (IOIBD) is an international scientific organization that has shaped the framework for inflammatory bowel disease (IBD) research, clinical management strategy, therapeutic development, and clinical trial methodology for more than four decades. Formally constituted in April 1981 in Lyon, France, IOIBD was created to address fundamental barriers to scientific and clinical progress in IBD, including inconsistent definitions of disease activity and outcomes across studies and countries. Since the establishment of the IOIBD Foundation for Research and Education in 1997, IOIBD has combined a highly engaged global membership of experts with structured governance, continuously active thematic clusters, and an annual rotating international meeting to deliver consensus frameworks and collaborative initiatives that translate directly to clinical practice and regulatory and translational science. Key outputs include studies of global epidemiology of IBD, the Selecting Therapeutic Targets in IBD (Selecting Therapeutic Targets in Inflammatory Bowel Disease, STRIDE) treat-to-target programs; the SPIRIT consensus initiative addressing long-term disease impact and endpoints for disease-modification trials; validated approaches to capturing disability and patient-reported outcomes; consensus guidance on nutrition and diet as modifiable and potentially disease-modifying factors; recommendations to optimize IBD clinical trial design and endpoints; reclassification of IBD initiative; rapid international guidance during the COVID-19 pandemic; and educational initiatives including topic-focused satellite symposia, the Helmsley-IOIBD Clinical Experience Exchange Program, and the Empowering Women in IBD Leadership Program (EMPOWHER). This manuscript reviews IOIBD's history, operational model, selected scientific contributions, educational mission, and evolving strategy as the field moves toward precision medicine, globalization of care, and data-intensive approaches, including artificial intelligence. International organization for the study of inflammatory bowel diseases (IOIBD) Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, faces ongoing challenges. Although treatment has improved, many patients still face delayed diagnosis, ongoing inflammation, complications, surgery, and reduced quality of life. These challenges have also made it hard for researchers and clinicians worldwide to compare studies and agree on the best ways to measure improvement. This article reviews the work of International Organization for the Study of Inflammatory Bowel Disease (IOIBD), an international network of experts founded in 1981 to help solve these problems through collaboration and shared standards. IOIBD brings together clinicians and scientists from many countries and disciplines, works year-round in focused topic groups, and meets annually to develop practical guidance and shared definitions that can be used in research studies, clinical trials, and everyday care.

Snyder-Robinson syndrome (SRS), a rare X-linked disorder caused by pathogenic variants in spermine synthase (SMS), results in spermine deficiency and excessive spermidine accumulation. Previously reported mouse models exhibited reduced birthrate and survival of affected males, greatly limiting their experimental utility. Here we describe a new mouse model carrying the clinically relevant Sms p.Gly56Ser (SmsG56S) allele in which viable males are recovered at Mendelian ratios, enabling generation of adequately powered cohorts. Hemizygous males produce markedly reduced SMS protein across tissues, recreating the biochemical hallmark of SRS, an elevated spermidine:spermine ratio. SmsG56S/Y males exhibit reduced body size, altered body composition, decreased locomotor and exploratory behaviors, and reduced seizure threshold, aligning with clinical features reported in SRS patients. Serum LDL, HDL, and cholesterol levels were reduced, while brain histology revealed modest region-specific astrocytic changes. Comprehensive polyamine profiling revealed tissue-specific biochemical disturbances, highlighting putrescine elevation in the brain and informing development of translational strategies and windows for intervention. Overall, this improved model reproduces multiple key aspects of the human SRS phenotype and provides a robust platform for mechanistic studies and preclinical evaluation of therapies.

Severe Mycoplasma pneumoniae pneumonia (SMPP) presents a major clinical challenge, increasingly complicated by macrolide-resistant strains (MRMP) and viral co-infections. The progression of SMPP is fundamentally driven by intricate immune-mediated mechanisms rather than direct pathogen-induced injury. Key drivers include innate immune hyperactivation, such as NLRP3 inflammasome-mediated pyroptosis, and adaptive immune dysregulation, characterized by the hyperactivation of pathogenic Th17 cells. Furthermore, systemic azithromycin administration can disrupt the gut-lung axis by depleting short-chain fatty acid (SCFA)-producing commensals, impairing regulatory T cell (Treg) generation, and exacerbating lung injury. Traditional diagnostics often struggle to predict severe disease; however, integrating multi-omics data and clinical biomarkers into machine-learning nomograms offers a more precise approach for identifying high-risk patients early. This precision risk stratification guides the deployment of targeted host-directed therapies (HDTs), including corticosteroids, small molecule inhibitors, anticoagulants, and early bronchoalveolar lavage. These interventions aim to dampen excessive inflammation, counteract hypercoagulability, and restore airway patency. This review summarizes the current understanding of SMPP and proposes a translational framework combining advanced diagnostics with targeted interventions to optimize clinical outcomes.

Limited guidance on the use and interpretation of cardiac troponin (cTn) testing in pediatric populations has restricted its broader adoption, despite the significant burden of congenital and acquired cardiac conditions in children. This survey aimed to evaluate global availability, utilization patterns, and key challenges associated with cTn testing in laboratories and among clinicians serving pediatric patients. The International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Committee on Emerging Technologies in Pediatric Laboratory Medicine (C-ETPLM) conducted an electronic survey in 2025. Distributed to IFCC members and their networks over one month, the survey included 19 questions targeting both laboratory professionals and clinicians involved in pediatric care. A total of 439 responses were collected from 48 countries spanning all continents, with 330 meeting eligibility criteria. Most respondents were laboratory specialists; clinicians represented 5.8 %. Among the 58.4 % who reported offering in-house cTn testing, 65.5 % lacked pediatric-specific reference intervals. Among those providing intervals, considerable variability existed in derivation, numerical limits, and sex-specific stratification. High-sensitivity cTn assays were widely available, and at least 71 % reported turnaround times under 2 hours. Clinicians indicated a broad range of indications for cTn testing in pediatric patients. Both clinicians and laboratory professionals consistently highlighted the lack of validated pediatric reference intervals, clear clinical guidelines, and standardized testing indications as major limitations. The absence of robust, outcome-based pediatric reference intervals, alongside limited clinical guidance and interpretive frameworks, remains a critical barrier to the effective and appropriate use of cardiac troponin testing in pediatric practice worldwide. - Pediatric cardiac troponin interpretation lacks standardization, with no universally accepted clinical guidelines, decision thresholds, or harmonized reference intervals supported by robust outcome-based evidence. - Most pediatric reference intervals are extrapolated from adult data or secondary sources, including manufacturer package inserts, despite clear biological and analytical justification for age- and sex-specific pediatric limits. - The clinical application of troponin in children differs from adults: whereas troponin is central to acute myocardial infarction diagnosis in adults, AMI is rare in children. In pediatrics, troponin is more frequently used to evaluate inflammatory and non-ischemic cardiac conditions, such as myocarditis. - There is an urgent need for pediatric-specific validation studies to establish appropriate interpretive frameworks, clinical decision limits, and outcome-driven guidance for cardiac troponin testing in children.

Oxidative stress and genotoxic damage activate NF-κB signaling through intracellular pathways distinct from those initiated by membrane receptors. DNA damage selectively induces post-translational modifications at lysine residues 277 and 309 of the human ubiquitin-binding protein NEMO to promote NF-κB signaling, but the physiological importance of these modifications in vivo remains unclear. Here, we show that a newly developed mouse model (NEMODK) carrying germline arginine substitutions of the corresponding NEMO lysine residues exhibits B-cell-intrinsic defects in germinal center formation and anti-viral humoral responses. Mechanistically, we identify in NEMODK B-cells a CD40-specific NF-κB signaling defect that is not linked to the well-characterized canonical or noncanonical NF-κB pathways. These B-cells fail to secure sustained NEMO monoubiquitination following CD40-induced ROS generation, which specifically reduces downstream RelA (p65) signaling required for the transcriptomic and epigenetic remodeling underlying homotypic B-cell aggregation, cell proliferation, class-switch recombination, and antibody-secreting cell generation. Our results establish a physiological role of murine NEMO K270 and K302 in linking CD40 engagement to B-cell responses through enabling sustained NEMO modification and RelA transcriptional activity.

Breastfeeding reduces the risk of severe lower respiratory infections (sLRIs), a leading cause of infant mortality; however, the protective mechanisms remain elusive. Here, we demonstrated that the absence of milk-derived osteopontin (OPN), highly expressed in colostrum, predisposes neonatal mice to viral and bacterial sLRI, consequent to disrupted dendritic cell (DC) hematopoiesis in the developing liver and lung. Amelioration of disease severity by oral OPN supplementation was associated with increased enteric abundance of Lactobacillaceae and elevated levels of serum 3-phenyllactic acid (PLA), a peroxisome proliferator-activated receptor gamma (PPARγ) agonist. Supplementation with PLA or the PPARγ agonist rosiglitazone restored lung DC hematopoiesis via airway epithelium-derived chemokine ligand 25 (CCL25)-mediated recruitment of lymphoid-myeloid primed progenitors and induction of a supportive lung niche. PLA-induced DC hematopoiesis and disease tolerance were attenuated by plasmacytoid DC depletion, immunoneutralization of stem cell factor, or genetic deletion of airway epithelial Flt3L. Our findings elucidate a microbiome-host interaction by which milk OPN confers protection against sLRI.

The Jagged1 (JAG1) gene is essential for cardiac development, yet its tissue-specific transcriptional regulation remains poorly understood. In this study we used an integrative screening approach to identify 19 candidate enhancers within the ±100 kb region flanking the JAG1 locus, among which R7 exhibited the highest activity in dual-luciferase assays. CRISPR/Cas9-mediated deletion of R7 in AC16 cells significantly reduced JAG1 expression, decreased proliferative and migratory capacities, and increased apoptosis. Mechanistically, R7 deletion altered local chromatin contacts and reduced accessibility at CTCF-bound regions near the JAG1 promoter, accompanied by decreased H3K27ac, H3K4me3, RNA polymerase II, and SRF occupancy. These findings identify R7 as a cardiac-associated promoter-proximal regulatory element with enhancer-like activity that contributes to local chromatin organization and transcriptional activity at the JAG1 locus.

In patients with repaired congenital heart disease (CHD) and pulmonary regurgitation (PR), a common metric for guiding the timing of pulmonary valve replacement (PVR) is right ventricular (RV) end-diastolic volume (EDV). The standard practices of indexing RV EDV to body surface area and calculating RV EDV Z-scores are imperfect, and guidelines for PVR based on threshold values for indexed volumes may be insensitive to individual patient circumstances. Indexing RV EDV to left ventricular EDV is an alternative method of normalizing RV volume in patients with PR. We reviewed clinically obtained cardiac magnetic resonance (CMR) studies in patients with a PR fraction ≥ 15% to determine relationships between the RV EDV index (EDVi), RV: LV EDV ratio, and PR fraction, as well as demographic and diagnostic factors mitigating these relationships. The PR fraction correlated better with the RV: LV EDV ratio than with RV EDVi. The correlation between RV: LV EDV ratio and RV EDVi was similar to that between PR fraction and the RV: LV EDV ratio. Factors associated with greater variation in the RV: LV EDV ratio - RV EDVi relationship included a native/patched RV outflow tract vs. a conduit, age at CMR, BSA, weight, height, and significant aortic regurgitation. In patients with repaired CHD and PR, relationships between RV EDVi, the RV: LV EDV ratio, and PR fraction are variable and influenced by a number of demographic, anthropometric, anatomic, and physiologic factors. The RV: LV EDV ratio correlated better with PR fraction than did RV EDVi, and accordingly, it may better reflect the response of the RV to PR.

The underlying pathophysiological mechanisms of complex regional pain syndrome (CRPS) have been under debate in recent years. Previous studies identified mechanistic CRPS subtypes, which were characterised as 'cold' and 'warm' or peripheral and central phenotypes. Our aim was to examine CRPS patients through comprehensive somatosensory testing and identify potential subgroups using unbiased statistics. Thus, our approach differs fundamentally from previous top-down approaches which stratified along predefined pathophysiological mechanisms. In total, 604 patients (age: 51.9 [SD 13.4] yr, female: 436, disease duration: 1.6 [SD 2.9] yr) with CRPS (type I: n=520; type II: n=84) underwent Quantitative Sensory Testing according to the DFNS protocol (German Research Network on Neuropathic Pain). We assessed 13 parameters, including thermal and mechanical detection and pain thresholds, indicating one distinct sensory profile for each participant. We conducted a hypothesis-free cluster analysis in a training set (A, n=380), which was re-evaluated in a validation set (B, n=224) to account for possible overfitting of the data and a comparison towards human pain surrogate models. We identified three sensory phenotypes in the training set, which were confirmed in the validation set. The largest group showed pronounced hypersensitivity towards cold and heat pain (n=382), a second group showed loss of thermal and mechanical sensation (n=200), and a third, small, but consistent, group exhibited strong allodynia and mechanical hyperalgesia (n=22). A novel bottom-up approach can stratify CRPS based on sensory phenotypes, adding to a mechanistic understanding through a comparative analysis of human pain surrogate models.

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Pontocerebellar hypoplasia type 6 (PCH6) is caused by biallelic pathogenic variants in RARS2, encoding mitochondrial arginyl-tRNA synthetase. Although mitochondrial dysfunction is a recognised feature, how RARS2 deficiency disrupts neural lineage development remains unclear. We generated rars2-deficient zebrafish using the clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) system and performed single-cell RNA sequencing (scRNA-seq) at 48 hours postfertilisation, complemented by immunofluorescence, in situ hybridisation, behavioural assays and ultrastructural analyses. Neural lineage composition, developmental trajectories, intercellular communication and transcriptional programmes were systematically examined. rars2 -/- zebrafish displayed impaired survival, locomotor deficits, early mitochondrial ultrastructural damage and marked disruption of neurogenesis. scRNA-seq revealed reduced neuronal populations and expansion of neural progenitor and glial-like cells. Key neurogenic regulators (neurod4, her6 and pou3f1) were downregulated, whereas glial and stress-associated markers (hmgb1a, fabp7a and foxp1b) were upregulated. Developmental pathways including Notch and non-canonical Wnt were attenuated while extracellular matrix (ECM), adhesion and inflammatory programmes were activated. Additional trajectory-based analyses supported dysregulated lineage progression characterised by glial programme activation and impaired maintenance of neurogenic differentiation. RARS2 deficiency disrupts mitochondrial integrity and reprograms neural lineage development through coordinated suppression of neurogenic transcriptional networks and activation of glial/ECM programmes. These findings provide mechanistic insight into loss-of-function RARS2 deficiency and highlight candidate molecular pathways for future therapeutic investigation.

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The use of anticoagulation in reproductive-aged females increases the risk of heavy menstrual bleeding (HMB). Excessive blood loss from HMB can lead to iron deficiency (ID), without or with anemia (IDA). We investigated the frequency with which reproductive-aged female patients on anticoagulants undergo screening for and receive a diagnosis of ID/IDA. We conducted a retrospective cohort study using the TriNetX global dataset of females aged 18-55 without a diagnosis of cancer who started anticoagulation therapy. The cohort was divided into sub-groups based upon ferritin testing within 90&#xa0;days of starting anticoagulation and descriptive statistics were calculated. The initial cohort included 1,463,349 unique female patients across 93 healthcare organizations. Exclusion of those with cancer and those without laboratory values resulted in a final cohort of 783,196. Out of the final cohort, 9.2% had a ferritin level checked within 90&#xa0;days of starting anticoagulation. Of those, 36.6% had a ferritin level&#xa0;&#x2264;&#xa0;50&#xa0;ng/mL while 25.8% had ferritin levels &#x2264;30&#xa0;ng/mL. Among individuals with ferritin &#x2264;30&#xa0;ng/mL, 19.7% (n&#xa0;=&#xa0;3655) had a hemoglobin &#x2265;12 and 44.0% (n&#xa0;=&#xa0;8170) had MCV&#xa0;<&#xa0;80&#xa0;fL. These findings highlight a significant gap in the evaluation of ID for reproductive-aged females taking anticoagulation and emphasize the importance of using ferritin for the diagnosis of ID with or without anemia. Future studies and interventions are indicated to increase screening and expedite treatment of ID/IDA in reproductive-aged female patients starting anticoagulation.