Johns Hopkins Children's Center

Identifying and preventing patient safety events is a goal for institutions that provide quality care; understanding and mitigating disparities in care is another. The mainstay of safety event detection, voluntary event reporting (VER), is prone to bias and under-reporting; previous research suggests this creates disparities in reported events. We aim to explore disparities in voluntary event reporting that may exist in a large, academic health system. We conducted a retrospective review of inpatient-associated safety events submitted to our health system's VER system from April 2021 to July 2022 and compared the cohort's demographics to those of all admitted patients during the same period. Pediatric patients, who are over-represented in the overall VER system (23% vs. 20%, P<0.001), are under-represented among most harmful events (P<0.001). Female patients, who are under-represented in the VER system (50.1% vs. 56.5%, P<0.001), remain so only in lower harm events. Other groups are over-represented in the VER system, including patients who are English-speaking (93.8% vs. 92.9%), non-Hispanic or Latino (88.9% vs. 82.4%), Black/African American (33.3% vs. 28.7%), and from areas of high neighborhood deprivation (23.5% vs. 18.9%) (all P<0.001). Disparities in VER were observed in a large academic health system. We conducted a broad analysis, including novel variables that have yet to be evaluated robustly in the literature, and we do find important disparities in these variables. Further research is needed to understand the mechanism for disparities to mitigate bias in reporting. Implementation of more objective methods of event detection may help reduce disparities.

The cerebrospinal fluid (CSF) provides a unique glimpse into the central nervous system (CNS) compartment and offers insights into immune processes associated with both healthy immune surveillance as well as inflammatory disorders of the CNS. The latter include demyelinating disorders, such as multiple sclerosis (MS) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), that warrant different therapeutic approaches yet are not always straightforward to distinguish on clinical and imaging grounds alone. Here, we establish a comprehensive phenotypic landscape of the pediatric CSF immune compartment across a range of non-inflammatory and inflammatory neurological disorders, with a focus on better elucidating CNS-associated immune mechanisms potentially involved in, and discriminating between, pediatric-onset MS (MS) and other pediatric-onset suspected neuroimmune disorders, including MOGAD. We find that CSF from pediatric patients with non-inflammatory neurological disorders is primarily composed of non-activated CD4+ T cells, with few if any B cells present. CSF from pediatric patients with acquired inflammatory demyelinating disorders is characterized by increased numbers of B cells compared to CSF of both patients with other inflammatory or non-inflammatory conditions. Certain features, including particular increased frequencies of antibody-secreting cells (ASCs) and decreased frequencies of CD14+ myeloid cells, distinguish MS from MOGAD and other acquired inflammatory demyelinating disorders.

Exertional chest pain in the setting of a structurally normal heart and no known arrhythmia are rarely thought to be related to cardiac etiology. Common non-cardiac etiologies of chest pain in the pediatric population include the following: lung infections, musculoskeletal, asthma, acid reflux, and anxiety. However, common cardiac etiologies that can cause exertional chest pain typically include the following: congenital heart disease, coronary anomalies, myocardial infections, left ventricular outflow obstruction, illicit drug use, and prothrombotic conditions. Rarely, pediatric patients present with an isolated finding of left main coronary artery ostial stenosis requiring intervention. Many of the published reports of left main ostial stenosis are in connection with other congenital heart disease, inflammation, or connective tissue disorders who have undergone percutaneous intervention. This report describes an 8-year-old patient with exertional chest pain for 5years found to have isolated left ostial stenosis requiring coronary artery bypass grafting at the age of 13.

Covered stent correction for a sinus venosus atrial septal defect (SVASD) was first performed in 2009. This innovative approach was initially viewed as experimental and was reserved for highly selected patients with unusual anatomic variants. In 2016, increasing numbers of procedures began to be performed, and in several centers, it is now offered as a standard of care option alongside surgical repair. However, covered stent correction for SVASD is not recognized by regulatory authorities, and in the minds of many pediatric and adult congenital cardiologists and surgeons, the condition is viewed as treatable only by cardiac surgery with cardiopulmonary bypass. In April 2023, all centers identified from international conferences, publications, and colleague networks to be undertaking covered stent correction for SVASD were invited to participate in a retrospective audit of their procedures. Data were received on 381 patients from 54 units over a 12-year period with 90% of procedures being performed over the past 5 years. Balloon-expandable stents (8 types) were used in the majority; self-expanding stents (4 types) were used in 4.5%. The commonest stent was the 10-zig covered Cheatham Platinum stent in 62% of cases. In 10 procedures, the stent embolized requiring surgical retrieval and repair of the defect, resulting in technically successful implantation in 371 of 381 (97.4%). Major complications (surgical drainage of tamponade, pacemaker implantation, surgery for pulmonary vein occlusion, and late stent removal) occurred in 5 patients (1.3%). Repeat catheterization to correct residual leaks was required in 7 patients (1.8%). Thus, 359 of 381 patients (94.2%) had successful correction without major complications or additional catheter interventions. This article details the exponential uptake of covered stent correction for SVASD during the past 5 years. Cardiopulmonary bypass was avoided in the majority of patients, and major complications were infrequent. Prospective registries with standardized definitions, inclusion criteria, and follow-up and comparative studies with surgery are now required to help support the extension of covered stent correction as an alternative standard-of-care option for patients with an SVASD.

Diagnostic test evaluation requires a reference standard. We describe an approach for creating a reference standard for acute infection using unrestricted adjudication and apply it to compare biomarker tools. Adults and children with suspected acute infection enrolled in three prospective studies at emergency departments and urgent cares were included. Adjudicators, blinded to C-reactive protein, procalcitonin, and MeMed BV (MMBV), labeled each case (bacterial/viral/non-infectious/indeterminate). Initial adjudication involved 3 adjudicators. Reference standard cohorts were defined: Microbiologically confirmed (3/3 adjudicators concur with high confidence and a concordant microbiological finding), unanimous (3/3 adjudicators concur with high confidence), suspected (3/3 adjudicators concur with high/moderate confidence or 2/3 adjudicators concur with high confidence), and all-inclusive (remaining unlabeled cases were reviewed by up to 7 additional adjudicators until reaching a leading label). Among 1016 patients, 156 difficult-to-diagnose cases required over 3 adjudicators. The area under the receiver operating characteristic curve in the microbiologically confirmed (n = 427), unanimous (n = 565), suspected (n = 860), and all-inclusive (n = 1016) cohorts for MMBV were 0.98 (95% confidence interval .94-1.00), 0.98 (.95-1.00), 0.95 (.92-.98) and 0.90 (.87-.93), respectively, and for procalcitonin were 0.69 (.57-.81), 0.77 (.68-.86), 0.74 (.68-.80) and 0.70 (.65-.75), respectively. A delta in performance between MMBV and procalcitonin was maintained across the different cohorts. Creating a reference standard that includes difficult-to-diagnose cases demands an approach to addressing diagnostic uncertainty in acute infections. Tool performance depends on the reference standard applied and decreases as the difficulty to diagnose increases, highlighting the importance of using the same reference standard when comparing tools.

The search for target sites on chromatin by eukaryotic sequence-specific transcription factors (TFs) is integral to the regulation of gene expression but the mechanism of nuclear exploration has remained obscure. Here we use multicolor single-molecule fluorescence resonance energy transfer and single-particle imaging to track the diffusion of purified Drosophila GAGA factor (GAF) on DNA and nucleosomes. Monomeric GAF DNA-binding domain (DBD) bearing one zinc finger finds its cognate site through one-dimensional (1D) or three-dimensional (3D) diffusion on bare DNA and rapidly slides back and forth between naturally clustered motifs for seconds before dissociation. Multimeric, full-length GAF also finds clustered motifs on DNA through 1D–3D diffusion but remains locked on target for longer periods. Nucleosome architecture effectively blocks GAF-DBD 1D sliding into the histone core but favors retention of GAF-DBD once it has bound to a solvent-exposed motif through 3D diffusion. Despite the occlusive nature of nucleosomes, 1D–3D facilitated diffusion enables GAF to effectively search for clustered cognate motifs in chromatin, providing a mechanism for navigation to nucleosomal and nucleosome-free sites by a member of the zinc finger TF family.

Advancements in early diagnosis and novel treatments for children with complex and chronic needs have improved their chances of survival. But many survive with complex medical needs and ongoing medical management in the setting of prognostic uncertainty. Their medical care relies more and more on preference-sensitive decisions, requiring medical team and family engagement in ethically challenging situations. Many families are unprepared as they face these ethical challenges and struggle to access relevant ethical resources. In this paper, Timmy's narrative, situated in the context of what is known about ethical challenges in the care of children with chronic critical illness (CCI), serves as a case study of the gap in available ethical resources to guide families in their approach to difficult decision making for children with significant medical complexity and CCI. Our author group, inclusive of parents of children with complex medical needs and medical professionals, identifies domains of ethical challenges facing families of children with CCI and we highlight the development of family/caregiver-oriented ethics resources as an essential expansion of pediatric bioethics.