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Cervical cancer remains one of the leading causes of cancer-related deaths worldwide. Here we report the extensive molecular characterization of 228 primary cervical cancers, one of the largest comprehensive genomic studies of cervical cancer to date. We observed notable APOBEC mutagenesis patterns and identified SHKBP1, ERBB3, CASP8, HLA-A and TGFBR2 as novel significantly mutated genes in cervical cancer. We also discovered amplifications in immune targets CD274 (also known as PD-L1) and PDCD1LG2 (also known as PD-L2), and the BCAR4 long non-coding RNA, which has been associated with response to lapatinib. Integration of human papilloma virus (HPV) was observed in all HPV18-related samples and 76% of HPV16-related samples, and was associated with structural aberrations and increased target-gene expression. We identified a unique set of endometrial-like cervical cancers, comprised predominantly of HPV-negative tumours with relatively high frequencies of KRAS, ARID1A and PTEN mutations. Integrative clustering of 178 samples identified keratin-low squamous, keratin-high squamous and adenocarcinoma-rich subgroups. These molecular analyses reveal new potential therapeutic targets for cervical cancers.

Background/aims: Pediatric patients with suspected gastroparesis often undergo antroduodenal manometry (ADM) and gastric emptying scintigraphy (GES) for diagnostic purposes. However, it is unknown if delayed gastric emptying (DGE) correlates with manometric findings. This study evaluates whether ADM parameters differ between normal and abnormal GES in pediatric patients., Methods: Data from pediatric patients undergoing ADM and GES at Nationwide Children's Hospital from 2011-2020 were retrospectively reviewed. Manometry parameters including motility index (Ln [sum of amplitudes × number of contractions + 1]), number of antral contractions, and direction of the phase III migrating motor complex (MMC) were compared to GES results from age-matched patients with DGE (n = 32) and normal gastric emptying (NGE) (n = 32) of similar sex, body mass index, and weight., Results: Children with DGE had a lower post-prandial antral motility index and antral contraction number than those with NGE (9.4 vs 11.2, P = 0.005; 21.8 vs 49.6, P < 0.001). The gastric emptying percentage at 4 hours was lower in patients with retrograde phase III (59.2% vs 83.9%, P = 0.022) and in those without an antral component in the fasting phase III of the migrating motor complex (70.3% vs 86.5%, P = 0.003). Post-prandial antral hypomotility occurred more frequently in the DGE group than in the NGE group (41% vs 9%, P = 0.008)., Conclusions: ADM findings differ between children with DGE and NGE. Children with DGE are more likely to have abnormal fasting phase III patterns and decreased post-prandial antral activity during ADM testing.

Purpose: It is not known whether temporal changes in childhood cancer therapy have reduced risk of subsequent malignant neoplasms (SMNs) of the central nervous system (CNS), a frequently fatal late effect of cancer therapy., Methods: Five-year survivors of primary childhood cancers diagnosed between 1970-1999 in the Childhood Cancer Survivor Study with a subsequent CNS SMN were identified. Cumulative incidence rates and standardized incidence ratios (SIR) were compared among survivors diagnosed between 1970-1979 (N = 6223), 1980-1989 (N = 9680), and 1990-1999 (N = 8999). Multivariable models assessed risk factors for CNS SMN., Results: 157 CNS SMNs (1970s, 52; 1980s, 63; 1990s, 42) were identified, excluding meningiomas, which were most often malignant gliomas. The proportion of survivors receiving any cranial radiotherapy (CRT) exposure was reduced over time (1970s 77.0%, 1980s 54.3%, 1990s 33.9%), while the proportion receiving >35Gy CRT showed a smaller reduction (11.4%, 10.8%, and 8.5%, respectively). Twenty-year cumulative incidence (95% CI) and SIR (95% CI) for CNS SMN by treatment decade were 0.32% (0.18-0.46%) and 6.6 (5.0-8.7); 0.55% (0.41-0.70%) and 8.3 (6.6-10.4); and 0.43% (0.31-0.55%) and 9.2 (7.0-12.0), respectively, with no statistically significant decreases between eras. Multivariable analyses showed increased risk for CRT dose levels >10Gy and for primary diagnoses of medulloblastoma/PNET (HR 18.7, 9.2-37.9) and astrocytoma (HR 10.1, 5.3-19.5). Three-year cumulative incidence of death after CNS SMN, by treatment decade, were 76%, 74%, and 73%, respectively., Conclusion: CNS SMN incidence has not decreased despite fewer survivors exposed to CNS-directed radiotherapy. CNS SMNs remain a substantial source of mortality for affected patients., (© The Author(s) 2025. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: There is need to identify evidence-based early childhood obesity prevention programs that are feasible and demonstrate cost-effectiveness for a broader health impact. This scale-out study leveraged community-engaged principles to compare the feasibility and cost-effectiveness of three delivery modes of a childhood obesity prevention family meals program (Simple Suppers) that demonstrated positive impacts on child and caregiver diet/nutritional health-related outcomes in a previous experimental trial tested among elementary-aged children. Methods: This three-arm (in-person, online, hybrid) pre-(T0) and post-(T1)-test study included families recruited from Head Start. Forty-five families (45 caregivers; 55 children) completed the study. The program was adapted to families with younger children (3-5 years). During the 8-week program, participants received weekly group education and meals through in-person, online, or hybrid format. Feasibility outcomes were attendance, acceptability (post-test survey; focus groups), fidelity, and cost (food; staff). Participant outcomes were related to diet/nutritional health. Kruskal-Wallis test was used to compare T0 to T1 differences in participant outcomes across delivery modes. Qualitative data were analyzed using thematic analysis. Cost-effectiveness was calculated as the net-cost of the program by changes in outcomes. Results: Overall attendance was 51.2%, and higher for in-person (72.0%) and hybrid (59.7%). Program satisfaction rate was highest for hybrid (93.0%), as well as program fidelity (96.7%). Focus group results revealed areas of program improvement, behavior change, and program approval. Cost was lowest for hybrid ($17.09/family). Children in the hybrid group had a reduced waist circumference ( p = 0.02) versus in-person and online groups. Conclusion: The hybrid mode of Simple Suppers demonstrated the greatest scaling potential for a broader public health impact.

Early gut microbiome development may impact brain and behavioral development. Using a nonhuman primate model ( Macaca mulatta ), we investigated the association between social environments and the gut microbiome on infant neurodevelopment and cognitive function. Infant rhesus monkeys ( n = 33) were either mother-peer-reared (MPR) or nursery-reared (NR). Neurodevelopmental outcomes, namely emotional responsivity, visual orientation, and motor maturity, were assessed with the Primate Neonatal Neurobehavioral Assessment (PNNA) at 14-30 days. Cognitive development was assessed through tasks evaluating infant reward association, cognitive flexibility, and impulsivity at 6-8 months. The fecal microbiome was quantified from rectal swabs via 16S rRNA sequencing. Factor analysis was used to identify "co-abundance factors" describing patterns of microbial composition. We used multiple linear regressions with AIC Model Selection and differential abundance analysis ( MaAsLin2 ) to evaluate relationships between co-abundance factors, microbiome diversity, and neuro-/cognitive development outcomes. At 30 days of age, a gut microbiome co-abundance factor, or pattern, with high Prevotella and Lactobacillus ( β = -0.88, p = 0.04, AIC Weight = 68%) and gut microbiome alpha diversity as measured by Shannon diversity ( β = -1.33, p = 0.02, AIC Weight = 80%) were both negatively associated with infant emotional responsivity. At 30 days of age, being NR was also associated with lower emotional responsivity (Factor 1 model: β = -3.13, p < 0.01; Shannon diversity model: β = -3.77, p < 0.01). The infant gut microbiome, along with early-rearing environments, may shape domains of neuro-/cognitive development related to temperament.

Background: Engagement of clinicians who understand clinical workflows and technology constraints can accelerate the development and implementation of better electronic health record (EHR) designs that improve quality and reduce burnout. Provider builder programs can accelerate clinical informatics education for a broader coalition of clinical specialties., Objective: In this State of the Art / Best Practice paper, we aim to (1) propose a provider builder maturity model informed by the experience of three institutions using a single EHR vendor (Epic Systems©) and (2) describe the program elements and relationships necessary to advance along this model to yield organizational benefits., Methods: We used a modified version of the Glaser State-of-the-Art approach, gathering consensus among a small group of experts at institutions with successful provider builder programs. The model was updated through meetings with a larger group of experts and then feedback from presentation at national conferences and the American Medical Informatics Association's Maturity Model Working Group., Results: The final maturity model describes the characteristics and suggested next steps beginning from Planting the Seed (Stage 0) and progressing through Lone Wolves (Stage 1), a Community of Builders (Stage 2), Organizational Structure (Stage 3), a Council of Builders (Stage 4), and Informatics in the Room Where it Happens (Stage 5). We also describe the journeys of 3 organizations through these stages., Conclusions: A provider builder maturity model can help guide organizations on their journey engaging clinicians in collaborative EHR design to promote quality and safety and reduce burnout., Competing Interests: EWO is a co-founder and has equity in Phrase Health, a clinical decision support analytics company. He receives no direct revenue. All other authors disclose no conflicts of interest., (Thieme. All rights reserved.)

Abstract: Kinesiophobia (KP) is the fear of movement or physical activity (PA) that is related to a medical condition. In adolescents, KP is associated with depression, anxiety, and impaired quality of life (QoL). Adolescents with heart disease (HD) often avoid PA. Factors that may moderate PA avoidance, such as KP, have not been adequately studied in this population. Purpose: To assess the validity and reliability of a newly adapted Tampa Scale for KP for adolescents with HD (TSK-Heart-A). Methods: The TSK-Heart-A survey consists of 17 Likert scale items, producing a summary score (SS) ranging from 17 (low KP) to 68 (high KP). Following content and face validity, adolescents (age 12-18 years) with arrhythmia disorders or Fontan palliation were recruited. The PROMIS pediatric anxiety and depression short forms, PedsQL generic core and cardiac module, and a PA questionnaire for adolescents (PAQ-A) were used for criterion validity. The TSK-Heart-A was completed twice (20.4 ± 6.3 days apart) for assessment of internal and test-retest reliability. Pearson correlations and Cronbach's alpha determined validity and reliability, respectively. Results: Adolescents (n = 63) were 15.5 ± 1.8 years-old, 50.8% female, and 69.8% had arrhythmia disorder. Mean TSK-Heart-A SS was 33.8 ± 7.8 (range: 20 to 56). The TSK-Heart-A SS correlated significantly with PROMIS T-scores (anxiety: 49.7 ± 12.2, r = 0.48; depression: 46.9 ± 12.7, r = 0.41), PedsQL score (generic QoL: 75.2 ± 18.9, r = -0.61; cardiac QoL: 74.7 ± 17.5, r = -0.56), and PAQ-A (score: 2.0 ± 0.7, r = -0.35). Test-retest and internal reliability had a total score of r = 0.77 (p = 0.89). Conclusions: The new TSK-Heart-A survey is valid and reliable and suggests KP is present in some adolescents with HD., Competing Interests: Conflict of Interest and Funding Source: This study was funded by the Center for Children’s Healthy Lifestyles & Nutrition Pilot Research Grant through Children’s Mercy Kansas City and Kansas University Medical Center. Dr. White receives salary support from the NIH through a K23 Career Development Award (HL159325) from the National Heart, Lung, and Blood Institute and the Additional Ventures Single Ventricle Foundation. Dr. Black receives salary support from the NIH through a K23 Career Development Award (AR078337) through the National Institute of Arthritis and Musculoskeletal and Skin Diseases. The authors have no professional relationships with companies or manufacturers who could benefit from the results of this study., (Copyright © 2025 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American College of Sports Medicine.)

De novo variants in CSNK2A1 cause autosomal dominant Okur-Chung neurodevelopmental syndrome (OCNDS). OCNDS has an evolving clinical phenotype predominantly characterized by intellectual disability, global delays, dysmorphic features, and immunological manifestations. Microcephaly, defined as a small head circumference, is not widely recognized as a classical clinical presentation. Here, we describe four individuals from three unrelated families who shared several clinical features characteristic of an underlying syndromic neurodevelopmental condition. Trio clinical exome and research genome sequencing revealed that all affected individuals had heterozygous pathogenic missense variants in CSNK2A1. Two variants (c.468T>A p.Asp156Glu and c.149A>G p.Tyr50Cys) were de novo and previously reported, but the third variant (c.137G>T p.Gly46Val) is novel and segregated in two affected individuals in a family. This adds to growing evidence of inherited disease-causing variants in CSNK2A1, an observation reported only twice previously. A detailed phenotypic analysis of our cohort together with those individuals reported in the literature revealed that OCNDS individuals, on average, have a smaller head circumference with one-third presenting with microcephaly. We also show that the incidence of microcephaly is significantly correlated with the location of the variant in the encoded protein. Our findings suggest that small head circumference is a common but under-recognized feature of OCNDS, which may not be apparent at birth., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: While clinical practice guidelines (CPGs) for pediatric oncology infection prophylaxis and management exist, few data describe actual management occurring at pediatric oncology centers., Methods: An electronic survey querying infection management practices in nontransplant pediatric oncology patients was iteratively created by the Children's Oncology Group (COG) Cancer Control and Supportive Care Infectious Diseases Subcommittee and sent to leaders at all COG institutions, limiting each site to one response to represent their institution., Results: The response rate was 57% (129/227 institutions). Many sites reported utilizing COG-endorsed CPGs for antibacterial (76%) and antifungal prophylaxis (74%), and fever and neutropenia (FN, 64%). Most institutions reported using antimicrobial prophylaxis for patients with acute myeloid leukemia (88% antibacterial, 100% antifungal) and relapsed acute lymphoblastic leukemia (82% antibacterial, 95% antifungal). Definitions of fever, phagocyte recovery, and antibiotic duration in febrile patients varied. Most institutions administer empiric broad-spectrum antibiotics for nonneutropenic fever, although 14% reported withholding antibiotics based on initial clinical status or risk stratification tools. Most respondents reported (70%) admitting FN patients for at least 48 h, however 15% have low-risk FN protocols allowing outpatient management. FN patients remain admitted on antibiotics through count recovery in 50% of institutions, whereas the others employed various early discharge/early antibiotic discontinuation strategies., Conclusions: There is often consistency but also substantial variability in reported antimicrobial prophylaxis strategies and management of patients with fever and represents an opportunity for implementation studies to standardize application of CPG recommendations and randomized trials to advance evidence where knowledge gaps exist., (© 2025 The Author(s). Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Asymptomatic chronic carriers occur in approximately 5% of humans infected with Salmonella enterica serovar Typhi ( S . Typhi) and represent a critical reservoir for bacterial dissemination. While chronic carriage primarily occurs in the gallbladder (GB) through biofilms on gallstones, additional anatomic sites have been suggested that could also harbor Salmonella. S . Typhimurium, orally infected 129 × 1/SvJ mice were pre-treated with a cholesterol-rich diet as a gallstone model for chronic carriage. We observed S . Typhimurium in feces and the cecum during early and persistent infection. Furthermore, bacterial biofilm-like aggregates were associated with the cecum epithelium at 7 and 21 days post-infection (DPI) in mice on a lithogenic diet (Ld) and correlated with an increase in cecal cholesterol at 21 DPI. Salmonella 's extracellular matrix (ECM) was demonstrated as important in colonizing the cecum, as survival and aggregate formation significantly decreased when mice were infected with a quadruple ECM mutant strain. Gallbladder Salmonella counts were low at 36 DPI while cecal Salmonella were high, suggesting that gallbladder colonization was likely not responsible for the high cecal burden. All cecum phenotypes were significantly diminished in mice fed a normal diet (Nd). Finally, we examined the capability of S . Typhi to colonize the cecum and showed S . Typhi in feces and in aggregates in the cecum up to 7 DPI, with slightly higher counts in mice fed a Ld compared to Nd. Our findings suggest that the cecum, particularly under cholesterol-rich conditions, serves as an adaptative niche for Salmonella spp. aggregates/biofilms and is a putative site for long-term infection.IMPORTANCETyphoid fever is a systemic infectious disease triggered by the gastrointestinal dissemination of Salmonella Typhi and Paratyphi in humans. Three to five percent of infected individuals become chronic carriers, a state in which gallstone biofilm formation facilitates spread of the bacteria in feces. Notably, surgical removal of the gallbladder (GB) in some chronic carriers (22%) does not guarantee the elimination of the bacteria, and the rationale for this remains poorly understood. This study is significant as it explores other tissues associated with the chronic carrier state. It highlights not only a cholesterol-rich diet as an important etiological factor for Salmonella colonization but also identifies the cecum as a crucial tissue promoting fecal shedding. Additionally, we determined that biofilm matrix components of Salmonella are key factors contributing to these effects. A greater understanding of these mechanisms will allow the formulation of new therapeutic strategies specifically targeted at preventing typhoid fever dissemination from chronic carriers., Competing Interests: The authors declare no conflict of interest.

Historically considered to be nonenveloped, hepatitis E virus (HEV), an important zoonotic pathogen, has recently been discovered to egress from infected cells as quasi-enveloped virions. These quasi-enveloped virions circulating in the blood are resistant to neutralizing antibodies, thereby facilitating the stealthy spread of infection. Despite abundant evidence of the essential role of the HEV-encoded ORF3 protein in quasi-enveloped virus formation, the underlying mechanism remains unclear. Here, we demonstrate that the HEV ORF3 protein possesses an inherent capacity for self-secretion and that palmitoylation at two cysteine residues within the ORF3 N-terminal region is essential for its secretion and quasi-enveloped virus formation. We further found that only palmitoylated ORF3 proteins hijacked Annexin II for transport to the cytoskeleton and are then directed into multivesicular bodies through the nSMase-endosomal sorting complexes required for transport-III pathway for secretion. Finally, we show that infection of gerbils with HEV mutants harboring mutations at palmitoylation sites within ORF3 showed no fecal viral shedding but competent replication in the liver. Our study fills a gap in the understanding of the assembly and release of quasi-enveloped virions mediated by ORF3 and offers the potential for designing therapeutic strategies to control HEV infection., Competing Interests: Competing interests statement:The authors declare no competing interest.

Pediatric asthma exacerbations represent a significant cause of emergency department use and hospitalizations. Despite available treatment options, many children's exacerbations are refractory to standard therapies and require adjunct treatments. The Intravenous Magnesium: Prompt use for Asthma in Children Treated in the Emergency Department study investigated the pharmacology of intravenous magnesium sulfate (IVMg) in treating pediatric asthma exacerbations. Specifically, the objectives of the study included (1) externally validating a previously published population pharmacokinetic model and (2) linking serum magnesium concentrations with outcomes including asthma severity score (efficacy) and hypotension (safety). Data were obtained from 49 children prospectively treated with IVMg (placebo, 50 or 75 mg/kg) after presenting to the pediatric emergency department with an acute asthma exacerbation. Reductions in Pediatric Respiratory Assessment Measure scores were associated with both total and ionized serum magnesium area under the concentration-time curve (AUC 0-2 h ). Despite frequent study-specific blood pressure monitoring, hypotension was uncommon in IVMg-treated participants (n = 2/31), and no concentration dependence was observed. The findings signal that IVMg may be an efficacious and safe option for treating moderate-severe pediatric acute asthma exacerbations in the ED. Importantly, this study is the first to suggest a serum exposure target (total serum magnesium AUC 0-2 h >63.1 mg h/L) reflective of effective IVMg dosing in pediatric acute asthma. While further study in a larger clinical trial is needed to refine and validate this exposure target, these findings support the continued study of IVMg therapy as an adjunct therapeutic option in the setting of pediatric asthma exacerbations., (© 2025 The Author(s). The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Introduction: We sought to understand the impact of locum tenens surgeons on pediatric surgical care delivery., Methods: We conducted a cross-sectional survey of Children's Hospital Association pediatric surgical practices. Anonymous electronic surveys were used to investigate locum tenens utilization, primary reason for use, limitations on clinical activities, and variations in practice standards or quality. Bivariate analysis and multivariable logistic regression were performed to evaluate for associations between practice characteristics and locum tenens use., Results: Of 172 practices, 71% (n = 122) completed the survey. Median hospital size was 203 beds (interquartile range = 130-350). Median number of surgeons per practice was 5 (interquartile range = 3-8). Thirty-seven practices (30%) employed locum tenens at primary (n = 27) or satellite (n = 12) sites. Locum tenens utilization was higher in suburban (odds ratio [OR] = 3.78, P = 0.006) and rural (OR = 4.96, P = 0.041) locations and lower at sites with a level 4 neonatal intensive care unit (OR = 0.35, P = 0.035). Most (51%) used locum tenens ≥ 1 time monthly but < 1 time weekly and for ongoing or interim coverage (87%). In total, 14% of practices reported clinical restrictions for locum tenens surgeons, including limitations on extracorporeal membrane oxygenation, neonatal index cases, and operative trauma. Most (76%) practices using locum tenens reported variations in practice standards or quality; all were perceived as negative (57%) or neutral (43%)., Conclusions: Locum tenens providers are utilized most commonly in suburban and rural sites and hospitals without the highest level of neonatal intensive care. While locum tenens surgeons may help maintain access to pediatric surgical care where gaps exist, there may be a need to improve the quality and reliability of care rendered., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Interleukin-12 (IL-12) is a potent NK cell-stimulating cytokine, but the presence of immunosuppressive myeloid cells such as myeloid-derived suppressor cells (MDSC) can inhibit IL 12-induced NK-cell cytotoxicity. Thus, we hypothesized that trabectedin, a myeloid cell-depleting agent, would improve the efficacy of IL-12 in triple-negative breast cancer (TNBC). In vitro treatment of healthy donor NK cells with trabectedin increased expression of the activation marker CD69 and mRNA expression of T BET (Tbx21), the cytotoxic ligands TRAIL (TNFSF10) and Fas ligand (FASLG) and the dendritic cell (DC)-recruiting chemokine lymphotactin (XCL1). The combination of IL-12 and trabectedin increased NK-cell cytotoxicity, activation and production of IFN-γ, TNF-α and granzyme B in the presence of human TNBC cells. Treatment of 4T1 and EMT6 tumor-bearing mice with IL-12 and trabectedin led to a significant reduction in tumor burden compared to single-agent controls, and the highest levels of plasma IFN-γ, intratumoral CD8+ T cells and conventional type 1 DC. MDSC and M2-like macrophages were significantly decreased with combination therapy. NK-cell depletion abrogated the effects of combination therapy, as did elimination of CD8+ T cells. NK-cell depletion led to lower levels of the NK cell-derived chemokine CCL5 and the DC-derived chemokine CXCL10, higher tumor burden, and decreased intratumoral CD8+ T cells. IL 12 and trabectedin also significantly enhanced the response of TNBC to anti-PD-L1 therapy. These data suggest that MDSC depletion augments the ability of IL-12-activated NK cells to drive the infiltration of DC and CD8+ T cells into TNBC for an antitumor effect.

Positive parenting behaviors and children's internalizing problems (Int. Probs) are bidirectionally associated during late childhood and early adolescence. These bidirectional associations likely emerge earlier and may be stronger when children are prone to reactive negative emotions, making parents' support especially critical in children's regulation of negative emotions. The purpose of this study was to test (a) bidirectional associations between parents' positive responsivity and children's internalizing problems from very early through middle childhood and (b) the moderating role of children's negative emotionality in these bidirectional associations ( N = 4,898). Small bidirectional associations between internalizing problems and responsivity were found from ages 3 to 5. Internalizing problems at 3 years were negatively associated with responsive parenting at 5 years. Parent responsivity at 3 and 5 years was negatively associated with later internalizing problems at ages 5 and 9 years, respectively. Negative emotionality only moderated the parent-driven association between responsivity at 3 years and internalizing problems at 5 years, with higher responsivity associated with lower internalizing problems only for children with moderate to high negative emotionality. Parents' positive responsivity to children's behavior and children's internalizing problems were only bidirectionally associated in early childhood (ages 3-5). Across ages 3-5 and 5-9, greater parent responsivity to children's behavior was associated with fewer internalizing problems and may be especially beneficial for children with higher negative emotionality. Results further suggest that young children experiencing internalizing problems may be more likely to receive less responsive parenting later, regardless of children's negative emotionality. (PsycInfo Database Record (c) 2025 APA, all rights reserved).

As qualitative data analysis becomes more frequently applied within the fields of medicine and surgery, it is beneficial to expand our knowledge of the utility, methodology, and interpretation of these techniques. While qualitative research serves a distinct purpose and differs from quantitative research, both can be approached with diligence, with careful techniques that are similarly maintained and respected. In advance of this installment in the Evidence-Based Medicine in Otolaryngology series, we presented a comparison between qualitative and quantitative methods. To provide additional understanding of the specifics of qualitative research, this article presents further insights into qualitative research applications, theories, data collection methods, sources of and approaches to bias, and methods which support rigorous results., (© 2025 American Academy of Otolaryngology–Head and Neck Surgery Foundation.)

Lennox-Gastaut syndrome (LGS) is a severe developmental and epileptic encephalopathy characterized by multiple drug-resistant seizure types, cognitive impairment, and distinctive electroencephalographic patterns. Neuromodulation techniques, including vagus nerve stimulation (VNS), deep brain stimulation (DBS), and responsive neurostimulation (RNS), have emerged as important treatment options for patients with LGS who do not respond adequately to antiseizure medications. This review, developed with input from the Pediatric Epilepsy Research Consortium (PERC) LGS Special Interest Group, provides practical guidance for clinicians on the use of these neuromodulation approaches in patients with LGS. We discuss patient selection criteria, expected seizure and non-seizure outcomes, potential complications, and device management considerations for each technique. The review also covers initiation and titration strategies, ongoing care requirements, and emerging data on combining multiple neuromodulation modalities. While all three approaches can reduce seizure frequency in patients with LGS, with commonly reported responder rates ranging from 50 % to 60 %, their impacts on cognition, behavior and quality of life are more variable. Careful patient selection, individualized programming, and long-term follow-up are essential to optimize outcomes with neuromodulation in this challenging patient population. Further research is needed to identify optimal candidates, determine the ideal timing during patients' clinical course to consider neuromodulation, develop standardized outcome measures, and evaluate the comparative effectiveness and cost-effectiveness of different neuromodulation techniques for LGS., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Objective: Hematopoietic stem cell transplant is a life-saving procedure that treats patients with various conditions by transplanting hematopoietic stem cells from bone marrow. Mobile health apps could be useful in closing the digital divide and improving health equity among Spanish-speaking caregivers of children who undergo pediatric hematopoietic stem cell transplant. This study aims to transcreate the BMT4me adherence app originally designed for English-speaking caregivers for Spanish-speaking caregivers and evaluate the feasibility and usability., Methods: This study consists of two phases. Phase 1 transcreates the existing BMT4me app for Spanish-speaking populations. App feedback is collected from three community advisory board focus groups ( n  = 10; each meeting will include the same 10 community advisory board members). Groups consist of members connected to the local Spanish-speaking population and participating in the Community Engagement Program at The Ohio State University Center for Clinical and Translation Science. Phase 2 tests the feasibility and usability of the Spanish BMT4me app with child-caregiver dyads ( n  = 30; 15 at site 1, n  = 15 at site 2) whose primary language is Spanish. This phase is mixed methods and incorporates both a qualitative approach (caregiver interviews) and quantitative measures (system usability scale). It is expected that app users in phase 2 will report above average system usability scale scores (>68%). It is also expected that >75% of families approached in phase 2 will enroll and complete the surveys in our study., Conclusion: This protocol paper details the transcreation process of the BMT4me app into a Spanish version. The findings of the study will demonstrate the level of acceptability of the Spanish BMT4me app with participants whose primary language is Spanish. As a digital health intervention for an underrepresented population that is increasingly online yet historically underserved, this app can overcome health barriers and disparities and improve overall health equity., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2025.)

Introduction: Child Opportunity Index (COI) is associated with complicated appendicitis (CA) in children. Value-based care through an accountable care organization (ACO) may modify this association. We aimed to determine if enrollment in our state's ACO, Partners For Kids (PFK), modified the association between COI and CA., Methods: Using a single-institution, retrospective review of children with public insurance undergoing appendectomy for acute appendicitis, COI and clinical confounders were compared by simple versus CA. Multivariable logistic regression models using COI, insurance, and age were fit with and without interaction terms to determine if PFK enrollment modified the association between COI and CA., Results: Among 1337 children, 31.0% had CA. Most (78.6%) were enrolled in PFK; this was not different between simple and CA. CA was associated with younger median age (7.0 y versus 8.0 y, P < 0.001). As overall COI quintile decreased (lower opportunity), the percentage of children with CA increased (P = 0.01). On multivariable regression controlling for age, PFK, and COI, only Very Low COI and age remained significantly associated with CA. The association between COI and CA was not modified by PFK enrollment. COI and PFK enrollment were not associated with postoperative complications, except children with PFK had fewer 30-d readmissions (4.2% versus 14.6%, P < 0.001) compared to those with other public insurance., Conclusions: Low COI was associated with higher CA, and this association was not modified by enrollment in an ACO, suggesting that ACO enrollment alone may not be sufficient in addressing social determinants of health among children with CA., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: Fatal and nonfatal pediatric opioid poisonings have increased in recent years. Emergency medical services (EMS) clinicians are often the first to respond to an opioid poisoning and administer opioid reversal therapy. Currently, the epidemiology of prehospital naloxone use among children and adolescents is incompletely characterized. Thus, our study objective was to describe naloxone administrations reported by EMS clinicians during pediatric activations in the United States., Methods: We performed a cross-sectional study using the National Emergency Medical Services Information System (NEMSIS). Within NEMSIS, we identified emergency responses where children 1 day through 17 years old were documented by EMS to have received ≥1 dose of naloxone in 2022. We analyzed demographic and EMS characteristics and age-specific prevalence rates of activations where naloxone was reported., Results: In 2022, 6,215 activations involved naloxone administration to children. Most activations involved males (55.4%, 3,435 of 6,201) and occurred in urban settings (85.7%, 5,214 of 6,083). Naloxone administration prevalence per 10,000 activations was highest among the 13-17 year age group (57.5), followed by 1 day to <1 year (17.9) age group. A dispatch complaint of an overdose or poisoning was documented in 28.9% (1,797 of 6,215) of activations and was more common among activations involving adolescents aged 13-17 years (31.5%, 1,555 of 4,937) than infants 1 day to <1 year (12.8%, 48 of 375). The first naloxone dose was documented to improve clinical status in 54.1% (3,136 of 5,793) of activations. Naloxone was documented to worsen clinical status in only 0.2% (11 of 5,793) of activations., Conclusions: In pediatric activations involving naloxone, less than one-third were dispatched as an overdose or poisoning but over half were documented to clinically improve after the first dose of naloxone. Naloxone was rarely documented to worsen clinical status. Our findings highlight the safety of prehospital naloxone use, as well as the importance of a high index of suspicion for opioid poisoning in the pediatric population. Opportunities exist to leverage linked data sources to develop interventions to improve prehospital opioid poisoning recognition and management.

Background: Nusinersen and risdiplam are U.S. Food and Drug Administration (FDA)-approved treatments for spinal muscular atrophy (SMA). No head-to-head clinical trials to assess efficacy exist. Observational studies are needed to determine if transitioning to risdiplam is safe and efficacious., Methods: This retrospective study at Nationwide Children's Hospital included individuals with SMA treated with nusinersen who switched to risdiplam. Motor, pulmonary and bulbar function were assessed before and 2 years after nusinersen and risdiplam initiation., Results: Forty-four individuals were included: 11 with SMA type 1, 25 with SMA type 2 and 8 with SMA type 3. Motor function improved after initiation of nusinersen treatment with the most significant improvements seen in the first year. After transition to risdiplam, motor function remained largely stable. Need for noninvasive ventilation (NIV) overnight occurred in both groups. Cough peak flow significantly improved in the risdiplam group. Hospitalizations were the same in both groups. One individual in the nusinersen group gained the ability to take some food by mouth; two individuals in the risdiplam group achieved some oral feeding and two became exclusively orally fed., Conclusions: As expected, motor function was most improved in treatment naïve individuals in the first year after nusinersen initiation. Over half of our study population had posterior spinal fusion surgery (57%) which significantly impacted motor and respiratory outcomes, though slightly less so in the risdiplam group. Overall, our data demonstrates that transitioning from nusinersen to risdiplam is associated with a favorable safety profile and stable motor outcomes., (© 2025 The Author(s). Muscle & Nerve published by Wiley Periodicals LLC.)

Purpose: Caregivers in pediatric oncology need accurate and understandable information about their child's condition, treatment, and side effects. This study assesses the performance of publicly accessible large language model (LLM)-supported tools in providing valuable and reliable information to caregivers of children with cancer., Methods: In this cross-sectional study, we evaluated the performance of the four LLM-supported tools-ChatGPT (GPT-4), Google Bard (Gemini Pro), Microsoft Bing Chat, and Google SGE-against a set of frequently asked questions (FAQs) derived from the Children's Oncology Group Family Handbook and expert input (In total, 26 FAQs and 104 generated responses). Five pediatric oncology experts assessed the generated LLM responses using measures including accuracy, clarity, inclusivity, completeness, clinical utility, and overall rating. Additionally, the content quality was evaluated including readability, AI disclosure, source credibility, resource matching, and content originality. We used descriptive analysis and statistical tests including Shapiro-Wilk, Levene's, Kruskal-Wallis H-tests, and Dunn's post hoc tests for pairwise comparisons., Results: ChatGPT shows high overall performance when evaluated by the experts. Bard also performed well, especially in accuracy and clarity of the responses, whereas Bing Chat and Google SGE had lower overall scores. Regarding the disclosure of responses being generated by AI, it was observed less frequently in ChatGPT responses, which may have affected the clarity of responses, whereas Bard maintained a balance between AI disclosure and response clarity. Google SGE generated the most readable responses whereas ChatGPT answered with the most complexity. LLM tools varied significantly (p < 0.001) across all expert evaluations except inclusivity. Through our thematic analysis of expert free-text comments, emotional tone and empathy emerged as a unique theme with mixed feedback on expectations from AI to be empathetic., Conclusion: LLM-supported tools can enhance caregivers' knowledge of pediatric oncology. Each model has unique strengths and areas for improvement, indicating the need for careful selection based on specific clinical contexts. Further research is required to explore their application in other medical specialties and patient demographics, assessing broader applicability and long-term impacts., (© 2025 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Pain is a prevalent, frequent, and often persistent symptom among children with acute lymphoblastic leukemia (ALL). Despite its high prevalence, pain has remained understudied, and no evidence-based recommendations exist for how best to assess and treat pain in this population. Without proper assessment, clinical efforts to improve pain management in pediatric ALL will be ineffective., Aims: Therefore, the purpose of this systematic review is to describe and identify gaps in measurement approaches that have been used to assess pain in pediatric ALL, evaluate the psychometric properties of available pediatric pain measures, and provide recommendations for clinical research and practice., Methods: Literature searches were performed following Cochrane and PRISMA guidelines for systematic reviews. Domains of pain assessed, measures used to assess pain, measure format, respondent, and timing of pain assessment were extracted from studies that met inclusion criteria. The psychometric properties of included measures were then evaluated. A total of 238 full-text articles were screened and 123 met inclusion criteria., Results: Most studies assessed pain using generic health-related quality of life instruments rather than pain-specific measures. A total of 39 measures were used across the 123 included studies, and the psychometric properties of the measures varied considerably., Conclusions: Recommendations include a selection of well-validated pain assessment measures that are currently available and can be used to facilitate best practices in ALL pain assessment. Clinicians and investigators are encouraged to utilize a multidimensional pain assessment approach to inform and enhance pain care in pediatric ALL., (© 2025 John Wiley & Sons Ltd.)

Background: Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is a developmental epileptic encephalopathy historically characterized by seizures that are resistant to antiseizure medications. Treatment with pyridoxine and lysine reduction therapies are associated with seizure control and improved developmental outcomes. In rare circumstances, patients have died prior to diagnosis and treatment with pyridoxine, and many patients are diagnosed after six months of age when lysine reduction therapies have limited efficacy. Recently two new metabolites were identified (2S,6S-/2S,6R-oxopropylpiperidine-2-carboxylic acid, 2-OPP and 6-oxo-pipecolate, 6-oxo-pip), and we evaluated these metabolites as potential newborn screening biomarkers., Methods: We recruited participants with a confirmed diagnosis of PDE-ALDH7A1 and retrieved their residual dried blood spots from state-sponsored newborn screening programs. We evaluated the dried blood spots for 2-OPP using commercially available newborn screening kits and equipment, and developed a second-tier test for 6-oxo-pip using LC-MS/MS., Results: We received eight residual dried blood spots collected before the onset of seizures and the diagnosis of PDE-ALDH7A1. In our newborn screening experiments, 2-OPP was elevated in 7 of 8 samples from affected participants with a mean of 3.08 μmol/L (95 % CI 2.17-3.99) compared to a mean of 0.09 μmol/L (95 % CI 0.09-0.10) in controls (p < 0.001). Second tier testing demonstrated elevated 6-oxo-pip in all samples from affected participants with a mean of 5.66 μmol/L (95 % CI 1.51-9.81) and was undetectable in controls (p < 0.001)., Conclusion: Patients with PDE-ALDH7A1 can be identified using neonatal dried blood spots prior to the onset of symptoms. The use of commercially available newborn screening approaches demonstrates the feasibility of newborn screening for this treatable condition., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Tianeptine is an atypical tricyclic antidepressant not approved for medical use in the US but is found in dietary supplements. This study investigates single-substance tianeptine exposures reported to US poison centers., Methods: We analyzed cases involving tianeptine reported to the National Poison Data System from 2015 to 2023., Results: There were 892 single-substance tianeptine exposures reported to US poison centers from 2015 to 2023, and the rate of exposures increased 1,400% from 2015 to 2023, including a 525% increase from 2018 to 2023. Most exposures were associated with moderate (51.5%) or major (12.0%) effects, and 40.1% required medical admission, including 22.9% to a critical care unit. Individuals 50 years and older were more likely to experience major effects (RR: 1.70, 95% CI: 1.13-2.56) or require medical admission (RR: 1.43, 95% CI: 1.20-1.72) than younger individuals. Tianeptine abuse accounted for 40.1% of exposures and was more likely to be associated with moderate or major effects (RR: 1.18, 95% CI: 1.06-1.31) than exposures not attributed to abuse. Withdrawal accounted for 22.5% of tianeptine exposures. Tianeptine exposure rates were highest in the US South. Alabama enacted legislation to regulate tianeptine as a controlled substance in 2021. Alabama's tianeptine exposure rate increased by 1,413.7% from 2018 to 2021, followed by a 74.6% decrease from 2021 to 2023, while the rate in other southern states continued to increase., Conclusions: This study demonstrates the toxicity and rapid increase of tianeptine exposures reported to US poison centers. Uniform regulation of tianeptine across all states may offer an important strategy to help mitigate this public health problem., Competing Interests: Declarations. Conflict of Interest: The authors declare that they have no conflicts of interest nor financial disclosures relevant to this study. Previous Presentation of Data: Not applicable., (© 2024. American College of Medical Toxicology.)

Critical congenital heart disease (CCHD) screening was added to the US Recommended Uniform Screening Panel in 2011 and adopted by all US states and territories by 2018. In addition to reviewing key developments in CCHD screening since the initial American Academy of Pediatrics (AAP) endorsement in 2011, this clinical report provides 3 updated recommendations. First, a new AAP algorithm has been endorsed for use in CCHD screening. Compared with the original AAP algorithm from 2011, this new algorithm a) has a passing oxygen saturation threshold of ≥95% in both pre- and post-ductal measurements; and b) has only 1 retest instead of 2 for infants who did not pass the first screen. Second, to continue to improve screening, state newborn screening programs should collect a recommended minimum uniform dataset to aid in surveillance and monitoring of the program. Finally, stakeholders should be educated on the limitations of screening, the significance of non-CCHD conditions, and the importance of protocol adherence. Future directions of CCHD screening include improving overall sensitivity and implementing methods to reduce health inequities. It will remain critical that the AAP and its chapters and members work with health departments and hospitals to achieve awareness and implementation of these recommendations., (Copyright © 2024 by the American Academy of Pediatrics.)

Liver masses in children with underlying systemic disease or a predisposing syndrome can be benign or malignant, ranging from focal fat to hepatocellular carcinoma (HCC). Knowledge of the underlying condition, the pathophysiologic effect on the liver, and the development of liver disease and specific liver lesions allows radiologists to guide imaging with regard to modality and frequency and give recommendations for biopsy when appropriate. In some predisposition disorders, such as Beckwith Wiedemann spectrum, familial adenomatous polyposis syndrome, and tuberous sclerosis complex, established guidelines for imaging screening exist. In many of the syndromes discussed, masses may occur outside of the liver and the liver may not be the primary focus of screening. For other entities, no consensus recommendations exist. Screening recommendations may be based on the risk of development of chronic liver disease. Once cirrhosis occurs, the risk of developing HCC is elevated. The authors summarize the spectrum of liver lesions that may be encountered in children with predisposing syndromes and systemic diseases, the imaging appearance of the lesions with various modalities, and screening guidelines where published. © RSNA, 2024 See the invited commentary by Rutten and Chavan in this issue.

Background: Artificial intelligence-based language model chatbots are being increasingly used as a quick reference for healthcare related information. In pediatric orthopaedics, studies have shown that a significant percentage of parents use online search engines to find out more about the health condition of their children. Several studies have investigated the accuracy of the responses generated from these chatbots. The accuracy of responses with these programs in limb lengthening and reconstruction surgery has not previously been determined. Our goal was to assess the response accuracy of 3 different chatbots (ChatGPT, Google Bard, and Microsoft Copilot) to questions related to limb reconstruction surgery., Methods: A list of 23 common questions related to limb reconstruction surgery was generated and posed to the 3 chatbots on 3 separate occasions. Responses were randomized and platform-blinded before rating by 3 orthopaedic surgeons. The 4-point rating system reported by Mika et al was used to grade all responses., Results: We found that ChatGPT had the best response accuracy score of all 3 chatbots while Microsoft Copilot had the worst score, and this finding was consistent among all 3 raters., Conclusions: Using the Response Accuracy Score, the responses from ChatGPT were determined to be satisfactory, requiring minimal clarification, while responses from Microsoft Copilot required moderate clarification., Level of Evidence: Level IV-diagnostic., Competing Interests: C.A.I. is a consultant for Nuvasive, Orthofix Medical, Inc, New Standard Device LLC (Metalogix). The other authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: J.A.P.: projects completed while at The Ohio State University Wexner Medical Center, Columbus, OH; The Ohio State University Nisonger Center, Columbus, OH; Riverside Methodist Hospital, Columbus, OH; and University of Pittsburgh Medical Center, Department of Physical Medicine & Rehabilitation. S.S.: Projects completed while at Lincoln Memorial University-DeBusk College of Osteopathic Medicine, Harrogate, TN and University of Louisville School of Medicine, Department of Neurological Surgery and PM&R, Louisville, KY. The remaining authors declare no conflict of interest.

Competing Interests: Dr. Alexander’s institution received funding from the National Institutes of Health and the U.S. Department of Defense (DoD); she received funding from the DoD Clinical Trial Award for Trial of Indication-based Transfusion of RBCs in Extracorporeal Membrane Oxygenation (TITRE) trial; and she disclosed that she is President-Elect of the Extracorporeal Life Support Organization (ELSO) and immediate past-President of Pediatric Extracorporeal Membrane Oxygenation, the research collaborative between the Pediatric Acute Lung Injury and Sepsis Investigators and ELSO. Dr. Muszynski has disclosed that she does not have any potential conflicts of interest.

Purpose: To replace an existing clinical practice guideline for the diagnosis and management of phenylalanine hydroxylase (PAH) deficiency., Methods: The PAH Deficiency Guideline Workgroup used the Grading of Recommendations Assessment, Development, and Evaluation evidence-to-decision framework to develop evidence summaries and practice recommendations based on the recent American College of Medical Genetics and Genomics systematic review., Results: Many recommendations from the 2014 PAH practice guideline are recognized as standard of care in this evidence-based guideline. Key recommendations from the previous guideline that were not supported by strong evidence are now strongly supported; (1) treatment for PAH deficiency should be lifelong for individuals with untreated phenylalanine (Phe) levels >360 μmol/L, (2) individuals with lifelong Phe levels ≤360 μmol/L have better intellectual outcomes than those who do not, (3) achieving Phe levels ≤360 μmol/L before conception is strongly recommended to prevent pregnancy complications and negative outcomes for the offspring, and (4) genetic testing for PAH variants is recommended at birth to confirm diagnosis and guide therapy., Conclusion: We strongly recommend lifelong maintenance of Phe ≤360 μmol/L (using plasma or whole blood) for optimal intellectual outcomes and for reduced teratogenicity, utilizing all available and necessary dietary, pharmaceutical, and patient-educational modalities., Competing Interests: Conflict of Interest The funding and support listed here did not support development of this document unless included in the acknowledgments section. Susan A. Berry is a member of the Board of Directors of the National PKU Alliance. Barbara K. Burton has received consulting fees and honoraria for speaking engagements from BioMarin Pharmaceutical, consulting fees from PTC Therapeutics and Jnana Therapeutics and funding for conducting clinical trials in PAH deficiency from BioMarin, Jnana Therapeutics, Homology Medicines, and Synlogic. Kim L. McBride has received research funding from BioMarin Pharmaceutical, Homology Medicines, and Ultragenyx, received speaker fees from Ultragenyx, and serves on a data monitoring board for Sanofi. Jerry Vockley has received research funding from BioMarin Pharmaceutical, Jnana Therapeutics, Homology Medicines, and PTC Therapeutics for participation in clinical trials on PAH deficiency. All other authors report no conflicts of interest., (Copyright © 2024 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Anaplastic large cell lymphoma (ALCL) is a mature T-cell lymphoma that accounts for 10-15% of childhood lymphomas. Despite the observation that more than 90% of pediatric cases harbor the anaplastic lymphoma kinase (ALK) rearrangement resulting in aberrant ALK kinase expression, there is significant clinical, morphologic, and biological heterogeneity. To gain insights into the genomic aberrations and molecular heterogeneity within ALK-positive ALCL (ALK+ ALCL), we analyzed 46 pediatric ALK+ ALCLs by whole-exome sequencing, RNA sequencing, and DNA methylation profiling. Whole-exome sequencing found on average 25 SNV/Indel events per sample with recurring genetic events in regulators of DNA damage (TP53, MDM4), transcription (JUNB), and epigenetic regulators (TET1, KMT2B, KMT2A, KMT2C, KMT2E). Gene expression and methylation profiling consistently subclassified ALK+ ALCLs into two groups characterized by differential ALK expression levels. The ALK-low group showed enrichment of pathways associated with immune response, cytokine signaling, and a hypermethylated predominant pattern compared to the ALK-high group, which had more frequent copy number changes and was enriched with pathways associated with cell growth, proliferation, and metabolism. Altogether, these findings suggest that there is molecular heterogeneity within pediatric ALK+ ALCL, predicting distinct biological mechanisms that may provide novel insights into disease pathogenesis and represent prognostic markers., Competing Interests: Competing interests: TIS reports a patent for EBD CAR pending. CGM reports personal fees from Illumina during the conduct of the study, as well as grants from Pfizer and AbbVie, and other support from Amgen outside the submitted work. No disclosures were reported by the other authors. Ethics approval and consent to participate: This study was conducted in accordance with the International Ethical Guidelines for Biomedical Research Involving Human Subjects. Informed written consent was obtained from all patients and/or their legal guardians before enrollment in the study. The St. Jude Children’s Research Hospital Institutional Review Board approved the use of excess diagnostic material and data for this study (XPD14-018). All methods were performed in accordance with the relevant guidelines and regulations., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

We analyzed four cases from the CASP15 experiment with low prediction accuracy and compared AlphaFold2, SPINE-X, and Seder on these cases. We find that overall, AlphaFold2 performs better than SPINE-X in predicting secondary structure (SS) and solvent accessible surface area (ASA). For some cases, SPINE-X better predicts sheet and coil regions. We also find that AlphaFold2 is better than Seder in selecting the best matching tertiary structure model for one case and is worse in another case. For two cases Alphafold2 and Seder selected the same models. From the cases presented here, it appears that AlphaFold2 predicts more compact structures than the native one. We find that while, as widely reported, AlphaFold2 significantly improved protein tertiary structure prediction, there are cases, such as the four presented here, for which the tertiary structure prediction could still be significantly enhanced. The source code, license, and documentation for SPINE-X and Seder are available from Research and Information Systems, LLC at http://mamiris.com ., (© 2025. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

An appealing strategy for the treatment of several diseases is the therapeutic targeting of noncoding RNAs (ncRNAs), such as microRNAs (miRNAs) and long noncoding RNAs (lncRNAs). Many antisense oligonucleotides and small interfering RNAs have been tested in clinical studies over the past 10 years, and several of these have received FDA approval. However, trial results have thus far been mixed, with some studies reporting strong effects and others showing low effectiveness or side effects, including toxicity. Clinical trials for alternative entities like antimiRNAs are underway, and interest in lncRNA-based therapies is constantly growing. From this perspective, we discuss the basic overview of ncRNAs, their significant role as therapeutic biomarkers against different diseases, and the role of secondary structure in noncoding RNAs., (© 2025. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Protein and peptide aggregation has recently become one of the most studied biomedical problems due to its central role in several neurodegenerative disorders and of biotechnological importance. Multiple in silico methods, databases, tools, and algorithms have been developed to predict aggregation of proteins and peptides to better understand fundamental mechanisms of various aggregation diseases. Here, we attempt to provide a brief overview of bioinformatic methods and tools to better understand molecular mechanisms of aggregation disorders. Furthermore, through a better understanding of protein aggregation mechanisms, it might be possible to design novel therapeutic agents to treat and hopefully prevent protein aggregation diseases., (© 2025. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Musculoskeletal ultrasound (MSUS) is increasingly used to evaluate pediatric inflammatory arthritis. This study aimed to explore the relationship between MSUS findings with medication modifications in patients with juvenile idiopathic arthritis (JIA) and clinical disease activity measurements (clinical Juvenile Arthritis Disease Activity Score [cJADAS-10], active joint count [AJC], patient/parent global assessment [PPGA], and physician global assessment [PGA])., Methods: Data from patients with JIA who underwent a 12-joint (bilateral second and third metacarpophalangeal, wrist, elbow, knee, and ankle) MSUS examination during a 57-month period were collected. Patients were categorized into 2 groups: a medication change group and a control group (patients without medication change). A pediatric-specific MSUS scoring system was used to assess MSUS findings. The association between clinical and MSUS findings was examined for the study groups., Results: A total of 38 patients, 23 in the medication change group and 15 in the control group were included. The medication change group had higher AJC, PGA, and cJADAS-10. These patients also had a statistically significant presence of abnormal knee MSUS findings. For other joints, the frequency of abnormal MSUS findings was slightly higher in patients with a medication change, but the difference was not statistically significant. No strong correlation was observed between MSUS findings and clinical disease activity measurements., Conclusions: Abnormal MSUS findings were not observed to be higher in patients with a change in medication except for the involvement of the knee joint. Further longitudinal studies are needed to understand the role of MSUS in the medical decision-making process in JIA., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Metabolic and bariatric surgery is a safe and effective treatment strategy for severe childhood obesity, affecting 10% of US adolescents., Objectives: This prospective observational study addresses knowledge gaps related to changes in weight, cardiometabolic risk, and weight-related quality of life (WRQOL) in adolescents 10 years after laparoscopic adjustable gastric band (LAGB) insertion., Setting: Five Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) US centers., Methods: Anthropometric, micronutrient, cardiometabolic risk, and WRQOL data were collected on 274 adolescents undergoing metabolic and bariatric surgery, of which 14 participants underwent LAGB insertion (2008-2011). Descriptive analyses compared outcomes from baseline to 10 years., Results: Participants were mostly female (86%), White (71%), with a median age of 18.5 years and preoperative median BMI of 49. Baseline prevalence of type 2 diabetes, hypertension, and dyslipidemia were 1 of 14 (7%), 8 of 14 (57%), and 8 of 13 (62%), respectively, versus 10-year prevalence of 1 of 8 (13%), 4 of 10 (40%), and 3 of 9 (33%), respectively. Two participants underwent LAGB removal (years 2 and 3), whereas two converted from LAGB to Roux-en-Y gastric bypass (years 2 and 6). Following initial BMI reduction (-10%) at year 1, 10-year median BMI in the LAGB retention group was 51, representing a 9.2% increase versus baseline. Micronutrient abnormalities and WRQOL remained similar between baseline and 10 years. One participant (1 of 14) withdrew from the study at year 7., Conclusions: Long-term follow-up of this cohort reveals that LAGB had minimal impact on BMI, cardiometabolic risk factors, and WRQOL among adolescents. These results confirm the limited efficacy of LAGB in the pediatric population., Competing Interests: Disclosures Dr. Michalsky has received educational honoraria from Intuitive Surgical, Inc., unrelated to this project. Dr. Courcoulas has a grant from Allurion Technologies, outside the scope of this work. Dr. Inge has received consulting fees from Standard Bariatrics, Teleflex, Medtronic, Mediflix, Independent Medical Expert Consulting Services, and royalties from Wolters Kluwer (UpToDate) all unrelated to this project. Funding for Teen-LABS was provided by the National Institutes of Health (NIH) U01DK072493, UM1DK072493, and UM1DK095710., (Copyright © 2025 American Society for Metabolic and Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

The therapeutic milieu has long been considered an essential mechanism of recovery for youth requiring inpatient psychiatric admissions. However, with increasing demand for crisis services, shrinking length of stay, rising patient acuity, and critical workforce shortages, innovation is necessary to maintain the goals of the therapeutic milieu (and equip the workforce to meet this challenge). This review surveys the evolution of the goals of milieu therapy over time, evidence for increasing challenges, and initial evidence for possible solutions. The study concludes with a case example detailing efforts to improve milieu therapy and empower frontline staff at a Midwestern pediatric hospital., Competing Interests: Disclosure The authors have no conflicts to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

An inpatient psychiatric stay for youth should go beyond acute containment of risk and pharmacologic changes and, instead, offer tailored evidence-based treatments in a manner that is individualized for the patient and caregivers. A unique, transdiagnostic guidebook can be utilized within the inpatient hospitalization structure in a way that adds value to the treatment but does not burden the clinical floor staff. This study describes the process of creating a patient-centered youth guidebook, implementation, and recommendations for others wanting to consider the use of a similar modality., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Rhabdomyosarcoma is the most common pediatric soft tissue sarcoma, and 5-year overall survival exceeds 70%. With more long-term survivors, it is critical to understand the frequency of late events, including recurrence, second malignant neoplasm, and death, occurring 5 years after diagnosis, and the variables associated with these events. We report late events in patients enrolled on Intergroup Rhabdomyosarcoma Study Group and Children's Oncology Group trials from 1997 to 2013 including D9602, D9803, D9802, ARST0331, ARST0431, ARST0531, and ARST08P1. A late event occurred in 2.9% of 5-year event-free survivors supporting guidelines to limit surveillance for these events to 5 years from diagnosis., (© 2024 Wiley Periodicals LLC.)

Objectives: Pediatric granulomatosis with polyangiitis (GPA) is associated with several pulmonary manifestations. This study aims to describe these manifestations at time of diagnosis and longitudinally at a tertiary-care pediatric hospital., Methods: We performed a retrospective chart review of patients with GPA treated at our facility between 1 January 2010 through 31 December 2021. We collected baseline demographics, reported symptoms, imaging findings, pulmonary function tests (PFTs), and laboratory data at time of diagnosis. Data were collected using 6-month observation intervals to follow recurrence of respiratory manifestations, testing during recurrence, and resultant treatment modifications., Results: Of 13 patients treated for GPA during the study period, 12 developed respiratory tract involvement. A total of 87 6-month observation periods were analyzed. At time of diagnosis, 83% (10/12) of subjects reported respiratory symptoms, 92% (11/12) had abnormal chest computed tomography (CT) imaging, and 42% (5/12) had abnormal PFTs. Fewer than half of the patients were seen by pulmonology within 6 months of diagnosis. Eight subjects (75%) had respiratory manifestations during subsequent observation periods. Chest CT or PFTs were obtained in 23/44 (52%) of observations periods with respiratory symptoms, with pulmonary consultation in only 9/44 (20%)., Conclusions: This is the first US study to describe respiratory manifestations in pediatric GPA patients longitudinally, finding they are common and frequently recurrent. Our cohort had almost universally abnormal imaging at diagnosis regardless of respiratory symptoms. Early collaboration with pediatric pulmonology in the care of GPA patients may allow rheumatology teams to efficiently evaluate recurrent symptoms and address concomitant lung disease., (© 2024 The Author(s). Pediatric Pulmonology published by Wiley Periodicals LLC.)

The vitreous humor undergoes liquefaction with age, resulting in complications that may require a vitrectomy, or surgical removal of the vitreous from the eye. Silicone oil, a common vitreous substitute, lacks properties similar to the natural vitreous. In particular, it lacks antioxidants that may be necessary to reduce oxidative stress in the eye. The purpose of this study was to evaluate antioxidant-loaded hydrogel vitreous substitutes in a pilot in vivo study. Ascorbic acid and glutathione were loaded into synthesized PEGDA hydrogels. Following vitrectomy, experimental antioxidant hydrogels or silicone oil were injected into one eye of rabbits, while the other eye served as untreated or sham control. Ophthalmic assessments, including electroretinography, were performed. Levels of glutathione and ascorbic acid were higher in the eyes treated with the antioxidant-loaded hydrogel vitreous substitute, although this was not found to be significant after 28 days. There were no statistically significant differences between groups with respect to clinical examination, and ocular health scores, electroretinograms, and histology were normal. These results indicate minimal concerns for the hydrogel formulation or high levels of antioxidants. Future research will assess the capability of vitreous substitutes to prolong antioxidant release, with the goal of minimizing cataract after vitrectomy., (© 2024 The Author(s). Journal of Biomedical Materials Research Part A published by Wiley Periodicals LLC.)

Background: Although the risk of pregnancy-related morbidity and mortality in people with sickle cell disease (SCD) is well established, limitations in data sources and heterogeneity in outcome reporting hinder the ability to make meaningful comparisons between historical and contemporary populations. This study used a national administrative claims database to compare pregnancy outcomes in people with SCD between 2006-2011 and 2012-2018. Materials and Methods: Pregnant females aged 16-44 years with SCD were identified from the Centers for Medicare and Medicaid Service Analytic eXtract, along with a control cohort of pregnant people. People were followed from first identified pregnancy until one year postpartum. Outcomes of interest were identified with ICD-9 or 10 codes. Results: We included 6,388 people with SCD and 17,278 controls in analyses. Preeclampsia/eclampsia, hypertension, thrombosis, poor fetal growth, preterm delivery, and postpartum hemorrhage were all more common in people with SCD compared with controls. Maternal death occurred in 0.5% of people with SCD versus <0.1% in those without SCD ( p < 0.001). When comparing infant deliveries in 2006-2011 to those occurring in 2012-2018, all pregnancy-related complications except preterm delivery, including maternal death, occurred at similar or higher frequencies in more recent years. Conclusions: Between 2006 and 2018, maternal death occurred in approximately 1 out of every 200 publicly insured people with SCD in the year following infant delivery. Our work confirms, on a national-level, that pregnancy-related outcomes in people with SCD in the United States have not improved with time, and that some complications have in fact increased in frequency.

Objective: To examine the association between caregiver-report of their child's inadequate sleep and exposure to interpersonal racism within racially minoritized subpopulations., Study Design: We conducted cross-sectional analysis among racially minoritized 21 924 school-aged children and 27 142 adolescents using a National Survey of Children's Health sample from 2016 through 2021. Multivariable logistic regression models were fit to estimate predicted probabilities for the adjusted associations between caregiver-report of their child's inadequate sleep and prior exposure to interpersonal racism., Results: In bivariate models, caregiver report of child exposure to interpersonal racism was significantly associated with a higher probability of inadequate sleep within non-Hispanic Asian American/Pacific Islander school-aged children, Hispanic adolescents, and non-Hispanic multiracial adolescents. After adjusting for covariates, only the association within Hispanic youth remained significant though attenuated. Unexpectedly, non-Hispanic Black school-age children exposed to racism had a lower probability of inadequate sleep than non-Hispanic Black children without exposure to racism after adjusting for covariates., Conclusions: Nationally representative pooled data that showed caregiver-report of Hispanic adolescents' inadequate sleep was associated with their exposure to interpersonal racism, although an association with inadequate sleep was not found in other racially minoritized subpopulations. Examining within-race associations helps to assess more accurately risk and target efforts that seek to address racism-related stress among racially minoritized subpopulations., Competing Interests: Declaration of Competing Interest At the time of this study, M.A.D.’s time was funded by the National Heart, Lung, Blood Institute (NHLBI) award number: 1K01HL169493-01.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this manuscript., (Copyright © 2024 Elsevier Inc. All rights reserved.)