Nationwide Children's Hospital

The study goal was to evaluate the outcomes associated with albumin use in children with sepsis and shock compared with those without shock, using causal inference analysis in a multicenter cohort. This was a secondary analysis of electronic health record data collected from 13 U.S. PICUs between 2012 and 2018, consisting of children younger than 18 years who met Phoenix sepsis criteria within the first 24 hours of PICU admission. Covariate-balancing propensity score weighting was applied to adjust for indication bias in the albumin use. Patients receiving at least 0.5 g/kg albumin within 24 hours of PICU admission were assigned to the albumin group; others to the control. Only 24-hour survivors were included to address immortal time bias. Overall, 17,307 children with sepsis survived at least 24 hours. Of these, 1,344 patients (7.8%) who received albumin within the first 24 hours, and 9,678 (55.9%) met the criteria for septic shock. A significant interaction between albumin use and shock status was observed (interaction: -0.353, p = 0.007), with albumin administration in pediatric septic shock patients associated with lower in-hospital mortality: odds ratio equals to 0.698 (95% CI, 0.629-0.774), risk ratio equals to 0.746 (95% CI, 0.625-0.891), and hazard ratio equals to 0.688 (95% CI, 0.558-0.848). In contrast, there was no difference in outcomes between the albumin and control groups in the non-shock group. Early albumin administration was associated with improved outcomes in children with septic shock, but not in those without shock. These results highlight the importance of considering clinical heterogeneity, such as the presence of shock, in identifying treatment-responsive subgroups and enabling more targeted interventions in pediatric sepsis. Further prospective validation is warranted.

Categorical variants, or sets of genomic alterations constrained by shared properties, are pervasive across clinical, regulatory, and research domains in the biomedical ecosystem, yet their inconsistent and non-computable representation hinders data interoperability and clinical interpretation. We surveyed genomic knowledgebases spanning regulatory approvals and the biomedical literature and found that categorical variants underpin a substantial proportion of clinical genomics knowledge, but are largely described using incompatible bespoke models. To address this, we developed the GA4GH Categorical Variation Representation Specification (Cat-VRS), a constraint-based framework that provides a unified computable representation for both precise and intentionally broad categories across molecular and systemic variant domains. Cat-VRS enables harmonization of genomic knowledgebases, computable category-based search, and automated matching between assayed variants and categorical entities in clinical and research contexts. By providing a principled, extensible model for categorical variation, Cat-VRS enables computable reasoning over genomic variant categories and establishes a foundation for the standardized representation and exchange of genomic knowledge.

A recurrent de novo germline variant in the MAX gene, p.(Arg60Gln), has recently been associated with polydactyly-macrocephaly syndrome in six unrelated individuals. Affected individuals presented with progressive macrocephaly, post-axial polydactyly, developmental delay, autistic features and a series of craniofacial, brain, cardiac, ocular, and renal anomalies. Here, we describe two unrelated female probands with the known recurrent MAX variant, c.179G>A p.(Arg60Gln), who presented with the emerging phenotypes of the MAX-associated syndrome. We also propose that genitourinary abnormalities, including Mayer-Rokitanski-Kuster-Hauser syndrome in one individual, may constitute an expansion of the known phenotype. These findings contribute to the current knowledge regarding the phenotypic spectrum of MAX-associated polydactyly-macrocephaly syndrome.

Background:In most clinical specialties, including plastic surgery, saying “no” to unnecessary, ill-timed, or simply frivolous referrals is discouraged and never taught. Carried forward into practice, this inability leads to overwhelming workloads, chaotic schedules, loss of professional autonomy, and exhaustion—well-known triggers for burnout. Providing communication tools to politely frame a refusal without jeopardizing professional relationships is essential.Methods:This narrative review provided a broad overview of existing literature on the topic across medical and nonmedical customer-service sectors, combined with the authors’ own experience. It established a context for a comprehensive summary and used the available material to create vignette-based training modules for residents and junior attendings.Results:Specifically, the traditional teaching is to always say yes to all clinical consults, no matter what they are or how overworked one already is. In contrast, publications on physician-burnout strongly recommend setting boundaries, none of which teach physicians how to do so. Although communication skills are taught during training, specific skills for politely refusing referrals, especially if inappropriate or ill-timed, are lacking.Conclusions:Using the reviewed material and our experience, a rich source of teaching materials, including clinical vignettes, was created that can be used by program leaders and younger faculty to say “no,” while maintaining honesty, professionalism, and positive referral relationships. Removing the stigma of self-guilt associated with saying “no” when appropriate, and doing so via clear and respectful communication, builds credibility, maintains professional autonomy, demonstrates integrity, and also ensures that patients receive the best possible care.

Many regions of heterochromatin associate with the nuclear periphery and are known as Lamin-associated domains (LADs). Histone acetyltransferase 1 (Hat1) is a highly conserved enzyme which acetylates newly synthesized histones H4 on lysines 5 and 12 prior to their deposition on chromatin. Hat1 is required to preserve chromatin accessibility within a subset of LADs called Hat1-dependent accessibility domains (HADs). Here we profile a diverse set of histone modifications in Hat1 KO and WT immortalized mouse embryonic fibroblasts (iMEFs) and find that Hat1 regulates diverse aspects of the structure of HADs and non-HAD LADs (nhLADS). In HADs, these changes include the conversion of H3K9me2 to H3K9me3. Analysis of H3K9-specific histone methyltransferases (HMTs) shows that that Suv39h1 and Suv39h2 have distinct localization patterns, where only Suv39h2 localizes to LADs. G9a only localizes to LADs in regions enriched for H3K9me2. We find that Hat1 loss results in a redistribution of these HMTs in both HADs and nh LADs. There is a decrease in the levels of G9a with a concomitant increase in Suv39h2. These results suggest Hat1 functions to restrain the formation of a more strongly heterochromatic state and highlight a role for Hat1 as an essential regulator of heterochromatin inheritance.

Congenital lung abnormalitiesare commonly encountered in the recent era of multi-modality fetal imaging. Congenital lung abnormalities encompass a diverse range of developmental disorders affecting the lung parenchyma, airways, and vascular structures. The anomalies, such as congenital pulmonary airway malformations (CPAM), bronchopulmonary sequestration, and congenital lobar overinflation (CLO), can present with varying degrees of severity, from asymptomatic cases to life-threatening respiratory distress. Ultrasound (US) plays a crucial role in the prenatal detection of these abnormalities, providing real-time imaging and facilitating early diagnosis and management planning. Magnetic resonance imaging (MRI), on the other hand, provides detailed morphological insights, particularly for complex cases. Its ability to visualize soft tissue structures and vascular anomalies without ionizing radiation makes it an indispensable tool in fetal and pediatric imaging. The combined use of US and MRI enhances diagnostic accuracy for fetuses with congenital lung abnormalities. These modalities continue to evolve, offering promising advancements in the understanding and management of these conditions. In this review article, we present a spectrum of common and uncommon congenital lung abnormalities, along with their typical imaging findings in US and MRI, and an approach to diagnosis.

Objective To examine the utility of implementing a neurorehabilitation intervention in pediatric psychology and neuropsychology training programs for building clinical competencies in neurorehabilitation. Method Using a convergent mixed methods approach, we surveyed neuropsychological and pediatric psychology trainees who completed training for the Teen Online Problem-Solving program (TOPS). The survey asked about training and competency on a 5-point Likert scale. Open-ended responses to “How has completing TOPS training changed how you practice as a psychologist?” were used for inductive thematic analyses. We surveyed site leaders and supervising psychologists at three hospitals (two in the United States and one in Canada) that integrated TOPS into their psychology training programs to provide case studies. Results 30 trainees completed the survey. Quantitatively, they indicated the TOPS program was a valuable part of training and improved understanding of neurological sequelae. Trainees endorsed that TOPS increased confidence and comfort working with adolescents and families and enhanced competency in delivering evidence-based interventions for neurodevelopmental disorders. Qualitative analyses yielded five themes: (1) enhanced clinical skills, (2) better tailoring to patients’ needs, (3) greater confidence delivering and adapting interventions, (4) equipping families with a helpful tool, and (5) informed feedback and recommendations for families. Conclusion Our mixed-methods analysis suggests that integrating evidence-based neurorehabilitation programs, such as TOPS, into neuropsychology and pediatric psychology training can build competencies, confidence, and interdisciplinary collaboration in neurorehabilitation.

Clinical laboratory tests in the United States have been subject to dichotomous regulatory oversight, encompassing both laboratory-developed tests (LDTs) and US Food and Drug Administration (FDA)-approved or FDA-cleared in vitro diagnostic products (IVDs). To assess the factors and preferences that are important for the selection of tests by clinical laboratories. A questionnaire was sent to laboratories participating in College of American Pathologists proficiency testing programs for 5 molecular analytes across molecular oncology, infectious disease, and germline genetics. The questionnaire asked about the factors that influenced the decision to implement an LDT or an FDA IVD. For all laboratories providing analyte responses, including those using LDTs and FDA IVDs, the factors most rated as very important were assay coverage of specific variants and/or positions of interest (95.1%; 656 of 690) and assay performance (eg, analytical sensitivity and specificity) (92.8%; 666 of 718). Laboratories using LDTs preferentially rated flexibility to modify the assay and already possessing the testing platform/equipment as very important. Laboratories using FDA IVDs preferentially rated the reputation of the assay manufacturer and support and customer service as very important. This study highlights the primacy of performance for laboratories' selection of assays. The variability of laboratory preferences for LDTs and FDA IVDs illustrates the need for a regulatory approach that minimizes burdens and is flexible, so that laboratories can best adapt to their unique clinical environments. These preferences should be considered to reduce impact on laboratories and on patient care as the FDA and other agencies assess regulatory oversight.