Type-I-interferon-responsive microglia shape cortical development and behavior.

Microglia are brain-resident macrophages that shape neural circuit development and are implicated in neurodevelopmental diseases. Multiple microglial transcriptional states have been defined, but their functional significance is unclear. Here, we identify a type I interferon (IFN-I)-responsive microglial state in the developing somatosensory cortex (postnatal day 5) that is actively engulfing whole neurons. This population expands during cortical remodeling induced by partial whisker deprivation. Global or microglial-specific loss of the IFN-I receptor resulted in microglia with phagolysosomal dysfunction and an accumulation of neurons with nuclear DNA damage. IFN-I gain of function increased neuronal engulfment by microglia in both mouse and zebrafish and restricted the accumulation of DNA-damaged neurons. Finally, IFN-I deficiency resulted in excess cortical excitatory neurons and tactile hypersensitivity. These data define a role for neuron-engulfing microglia during a critical window of brain development and reveal homeostatic functions of a canonical antiviral signaling pathway in the brain.

p53 protein expression patterns associated with TP53 mutations in breast carcinoma.

PURPOSE: The importance of a TP53 mutation has been demonstrated in several tumor types, including breast cancer (BC). However, the accuracy of p53 protein expression as a predictor of gene mutation has not been well studied in BC. Therefore, we evaluated p53 protein expression associated with TP53 mutations in breast cancers from 64 patients. METHODS: TP53 mutation was examined using next-generation sequencing (NGS). p53 protein expression was examined using immunohistochemistry (IHC). RESULTS: Among the 64 BCs, 55% demonstrated abnormal expression patterns including 27% overexpression, 22% null, 6% equivocal with 45% having a wild-type pattern. A TP53 mutation was present in 53% (34/64) of tumors including 30% (19/64) demonstrating a missense mutation, 11% (7/64) with a frameshift mutation, 11% (7/64) with a nonsense mutation, and 3% (1/64) with a splice site mutation. Abnormal expression of p53 protein was present in 33 of 34 (97%) tumors carrying a TP53 mutation; conversely, a wild-type pattern was present in 28 of 30 (93%) tumors without a detectable mutation (p < 0.0001). The majority of BCs with a p53 IHC overexpression pattern (15/17, 88%) contained a missense TP53 mutation; while the majority of BCs with a null pattern (12/14, 86%) contained a truncating mutation (p < 0.0001). The BCs with a null pattern are associated with a high Nottingham histological grade and a triple-negative phenotype when compared to those demonstrating overexpression (p < 0.05). CONCLUSION: These findings suggest that p53 IHC can be a potential surrogate for TP53 mutations in BC. Different p53 expression patterns may correlate with specific TP53 genetic mutations in BC.

Immunosuppression-Free Life after Pediatric Liver Transplant: A Case-Control Study from the Society of Pediatric Liver Transplant (SPLIT) Registry.

OBJECTIVE: To compare long-term outcomes of pediatric liver transplant (LT) recipients off immunosuppression (IS) with matched controls on IS using data from the Society of Pediatric Liver Transplant (SPLIT) registry. STUDY DESIGN: This was a retrospective case-control study. SPLIT participants <18 years of age, ≥4 years after isolated LT, and off IS for ≥1 year (cases) were age- and sex-matched 1:2 to patients with the same primary diagnosis and post-LT follow-up duration (controls). Primary outcomes included retransplantation, allograft rejection, IS comorbidities, and prevalence of SPLIT-derived composite ideal outcome (c-IO) achieved at the end of the follow-up period. Differences were compared using multiple linear regression for continuous outcomes and logistic regression for dichotomous data. RESULTS: The study cohort was composed of 33 cases (42.4% male, 60.6% biliary atresia, median age at LT of 0.7 [P25, P75, 0.5, 1.6] years, median IS withdrawal time of 9 [P25, P75, 6, 12] years after LT) and 66 age- and sex-matched controls. No cases required retransplantation. Cases and controls had similar growth parameters, laboratory values, calculated glomerular filtration rates, rates of post-transplant lymphoproliferative disease, graft rejection, and attainment of c-IO. CONCLUSIONS: No differences in allograft rejection rates, IS complications, or c-IO prevalence were seen between SPLIT patients off IS and age- and sex-matched controls remaining on IS. Discontinuation of IS most commonly occurred in the context of rigorously designed IS withdrawal trials. The available sample size was small, affecting generalizability to the broader pediatric LT population.

Paediatric emergency front-of-neck airway: issues of ethics, law, and philosophy.

Practitioners can face significant challenges when managing the airways of infants and neonates because of their unique anatomical and physiological features. The requirement for emergency airway management in this age group is rare. Details of emergency airway techniques in paediatric practice guidelines are missing or lack consensus, and it is known that outcomes for affected children can be poor. Ideally, these children should be managed by experienced paediatric airway practitioners working in a team. However, situations can arise where practitioners, unfamiliar and inexperienced with infants, find themselves in charge. So, what happens when such a practitioner encounters this life-or-death scenario and feels ill-equipped to act? The ethical and legal issues surrounding the management of this emergency are clearly defined, but they can be unknown or misunderstood by doctors. Compounding the extreme stress of the scenario is the moral and ethical dilemma of whether to act or not. The following discussion explores these issues and examines the philosophical and psychological perspectives.

The OTX2 Gene Induces Tumor Growth and Triggers Leptomeningeal Metastasis by Regulating the mTORC2 Signaling Pathway in Group 3 Medulloblastomas.

Medulloblastoma (MB) encompasses diverse subgroups, and leptomeningeal disease/metastasis (LMD) plays a substantial role in associated fatalities. Despite extensive exploration of canonical genes in MB, the molecular mechanisms underlying LMD and the involvement of the orthodenticle homeobox 2 (OTX2) gene, a key driver in aggressive MB Group 3, remain insufficiently understood. Recognizing OTX2's pivotal role, we investigated its potential as a catalyst for aggressive cellular behaviors, including migration, invasion, and metastasis. OTX2 overexpression heightened cell growth, motility, and polarization in Group 3 MB cells. Orthotopic implantation of OTX2-overexpressing cells in mice led to reduced median survival, accompanied by the development of spinal cord and brain metastases. Mechanistically, OTX2 acted as a transcriptional activator of the Mechanistic Target of Rapamycin (mTOR) gene's promoter and the mTORC2 signaling pathway, correlating with upregulated downstream genes that orchestrate cell motility and migration. Knockdown of mTOR mRNA mitigated OTX2-mediated enhancements in cell motility and polarization. Analysis of human MB tumor samples (N = 952) revealed a positive correlation between OTX2 and mTOR mRNA expression, emphasizing the clinical significance of OTX2's role in the mTORC2 pathway. Our results reveal that OTX2 governs the mTORC2 signaling pathway, instigating LMD in Group 3 MBs and offering insights into potential therapeutic avenues through mTORC2 inhibition.

Association between maternal closeness with parents and mother-toddler relationship quality.

Objective: Understanding how positive parenting is conveyed across generations informs early childhood policy. Background: The extant literature has focused on how a mother's relationship with her own mother sets the stage for her parenting of her own children, yet less understood is how a mother's relationship with her father supports her responsive parenting and potentially informs her child's attachment security. Method: We analyzed data from 6,400 mothers of singleton infants participating in the Early Childhood Longitudinal Study, Birth Cohort. We examined whether a mother's closeness with her own mother and father (Generation 1) related to her responsiveness and child attachment security (Generation 3) at age 24 months. Results: Most mothers reported being extremely (25.7%) or at least quite close (25.1%) with both their mother and father. How close mothers felt to their own parents was not associated with their observed level of responsiveness to their toddler or their toddler's attachment security, adjusting for sociodemographic covariates. Maternal education was the strongest predictor of responsiveness and attachment security. Conclusion: Maternal education is strongly related to responsiveness, and to a lesser extent, child attachment security, in toddlerhood. Implications: Programs aimed at addressing the challenges of caregiving may overcome the limitations of lower education status.

Glioblastoma Cells Use an Integrin- and CD44-Mediated Motor-Clutch Mode of Migration in Brain Tissue.

Purpose: Glioblastoma (GBM) is an aggressive malignant brain tumor with 2 year survival rates of 6.7% (Stupp et al. in J Clin Oncol Off J Am Soc Clin Oncol 25:4127-4136, 2007; Mohammed et al. in Rep Pract Oncol Radiother 27:1026-1036, 2002). One key characteristic of the disease is the ability of glioblastoma cells to migrate rapidly and spread throughout healthy brain tissue (Lefranc et al. in J Clin Oncol Off J Am Soc Clin Oncol 23:2411-2422, 2005; Hoelzinger et al. in J Natl Cancer Inst 21:1583-1593, 2007). To develop treatments that effectively target cell migration, it is important to understand the fundamental mechanism driving cell migration in brain tissue. Several models of cell migration have been proposed, including the motor-clutch, bleb-based motility, and osmotic engine models. Methods: Here we utilized confocal imaging to measure traction dynamics and migration speeds of glioblastoma cells in mouse organotypic brain slices to identify the mode of cell migration. Results: We found that nearly all cell-vasculature interactions reflected pulling, rather than pushing, on vasculature at the cell leading edge, a finding consistent with a motor-clutch mode of migration, and inconsistent with an osmotic engine model or confined bleb-based migration. Reducing myosin motor activity, a key component in the motor-clutch model, was found to decrease migration speed at high doses for all cell types including U251 and 6 low-passage patient-derived xenograft lines (3 proneural and 3 mesenchymal subtypes). Variable responses were found at low doses, consistent with a motor-clutch mode of migration which predicts a biphasic relationship between migration speed and motor-to-clutch ratio. Targeting of molecular clutches including integrins and CD44 slowed migration of U251 cells. Conclusions: Overall we find that glioblastoma cell migration is most consistent with a motor-clutch mechanism to migrate through brain tissue ex vivo, and that both integrins and CD44, as well as myosin motors, play an important role in constituting the adhesive clutch. Supplementary Information: The online version contains supplementary material available at 10.1007/s12195-024-00799-x.

Supporting victim-survivors during investigations of health practitioner misconduct: early learnings from a trauma-informed service.

OBJECTIVE: In 2021, the Australian Health Practitioner Regulation Agency established a support service to provide additional assistance to victim-survivors involved in complaints related to sexual boundary violations. This study evaluates the first stages of service delivery to understand participants' experiences with the service, gauge the service's reception, and improve support provided in future. DESIGN: Programme data was analysed descriptively to understand uptake and participant engagement since inception. Semistructured interviews with a purposive convenience sample of participants who had recently completed service engagement were conducted over 6 months and analysed using reflexive thematic analysis. Findings were triangulated to judge the effectiveness of the support provided by the service and highlight learning and development opportunities. RESULTS: During the study period, 275 participants were referred to the programme and 175 (64%) of those referred had engaged with the service. At the time of analysis, less than a quarter (21%) had refused support or disengaged following referral. Participants reported appreciation of and satisfaction with the support they received from the service and strongly reiterated the need for support in this context. Flexibility and quality communication as part of the service model was associated with participants feeling supported through three main themes: safety and connection, guidance and process navigation and representation and advocacy. CONCLUSION: Good uptake of the service and positive feedback from participants suggests that the programme has been a valuable and well-received initiative. Exploration of engagement trends as well as a more nuanced analysis of the benefits of support provided would augment these findings.

Exploring the rationale for prescribing ankle-foot orthoses and supramalleolar orthoses in children with cerebral palsy: A narrative synthesis of rationale statements.

BACKGROUND: To help improve outcomes for children with cerebral palsy (CP), ankle-foot orthoses (AFOs) and supramalleolar orthoses (SMOs) are prescribed. However, it is not clear why one intervention is prescribed over the other. OBJECTIVES: To explore the rationale for prescribing AFOs and SMOs in children with CP and its link to the choice of outcome measure used. STUDY DESIGN: Narrative review. METHODS: Six databases were searched (eg, Medline) and data extracted from articles that met the inclusion criteria. Data describing the participant demographics, type of orthosis, and outcome measures used were summarized to provide context for the different rationale for orthotic prescription that were thematically analyzed. DISCUSSION: Forty-seven articles were included. Participants were aged 9 ± 2 years, 59% were male, 79% had diplegia, and 38% were classified as Gross Motor Function Classification System level I. All studies included a rationale for prescribing AFOs that, in most cases, reflected the outcome measures used. These rationale statements were synthesized into 5 specific themes (e.g., reduced energy expenditure and metabolic costs). By comparison, 5 of these studies described the rationale for providing SMOs, and of those that did, most of the rationale statements were nonspecific. CONCLUSIONS: A large and contemporary body of literature describes the rationale for prescribing AFOs for children with CP. There are opportunities for future research that clearly articulates the rationale for prescribing SMOs for children living with CP and to focus the rational for orthotic intervention on the real-world challenges that are most important to children living with CP, such as the ability to participate among peers.

CD11c-expressing microglia are transient, driven by interactions with apoptotic cells.

Microglia, the parenchymal macrophage of the central nervous system serve crucial remodeling functions throughout development. Microglia are transcriptionally heterogenous, suggesting that distinct microglial states confer discrete roles. Currently, little is known about how dynamic these states are, the cues that promote them, or how they impact microglial function. In the developing retina, we previously found a significant proportion of microglia express CD11c (Integrin αX, complement receptor 4, Itgax) which has also been reported in other developmental and disease contexts. Here, we sought to understand the regulation and function of CD11c+ microglia. We found that CD11c+ microglia track with prominent waves of neuronal apoptosis in postnatal retina. Using genetic fate mapping, we provide evidence that microglia transition out of the CD11c state to return to homeostasis. We show that CD11c+ microglia have elevated lysosomal content and contribute to the clearance of apoptotic neurons, and found that acquisition of CD11c expression is, in part, dependent upon the TAM receptor Axl. Using selective ablation, we found CD11c+ microglia are not uniquely critical for phagocytic clearance of apoptotic cells. Together, our data suggest CD11c+ microglia are a transient state induced by developmental apoptosis rather than a specialized subset mediating phagocytic elimination.

Does Transparency of Ankle Implant Costs Influence Surgeon Behavior?

Background: Ankle fractures are a common injury treated by orthopaedic surgeons. Unstable, displaced ankle fractures are often fixed with open reduction internal fixation (ORIF) using different implant constructs at various cost. No study to date has looked at transparency in ankle implant costs to surgeon behavior. Our surgeons self-identified that the biggest barrier for lowering implant cost was the lack of cost transparency. This was a surgeon-led-study to evaluate whether increased transparency in implant costs affected surgeon behavior. Methods: Monthly operative logs from December 2021 to September 2022 were reviewed at our level 1 trauma center for operative fixation of ankle fractures. The cost data of each fixation construct was reported to trauma-trained surgeons at the end of each month from March 2022 to June 2022. Average costs of implants were compared before and after education. A linear mixed model was used to explore what factors were associated with changes in costs. Surgeons also participated in a poststudy survey. Results: The implant costs of 110 ankle fracture fixations were reviewed over the period before education (n = 60), during education (n = 30), and after education (n = 20). The mean implant cost difference for unimalleolar fractures was -$204.80 (P = .68), whereas the mean cost difference for bimalleolar fractures was -$9.82 (P = .98). Trimalleolar fractures had a mean cost difference of +$94.47 (P = .84). Linear mixed model demonstrated fracture pattern as the only factor significantly associated with implant costs (P < .01). Post-education surgeon survey revealed that 6 of 7 surgeons felt that monthly updates affected their implant selection. However, only 2 surgeons demonstrated a change in practice with decreased implant costs during the study. Conclusion: The majority of surgeons self-reported being influenced by the implant cost education, but the detected change in implant cost was only observed in less than one-third of surgeons. Our results suggest implant selection and related costs are not influenced by increased cost transparency education alone. Level of Evidence: Level III, case control study.

Innovative solutions to support individuals with disabilities accessing public transportation: A case study.

Individuals with cognitive disabilities have challenges with personal navigation and wayfinding, especially when traveling on public transportation. The purpose of this case study is to describe the structure and implementation of the Personal Navigation for Individuals with Disabilities (PNID) education and training program, which is based on a socio-technical architecture for individuals with cognitive disabilities within a fixed-route public bus system. A case study methodology was used to describe preliminary findings of the skills, attributes, and experiences of three individuals with cognitive disabilities as it relates to transportation on fixed-route bus systems in a midsized urban setting. The three individuals completed five training activities: safety, public bus, smartphone, WayFinder App, and fixed-route bus system. The case study provided a preliminary mixed-methods overview of training travelers with cognitive disabilities to use the WayFinder system while accessing fixed-route public bus system. The insights and strategies identified through the case study demonstrate the potential opportunities for development, implementation, and sustainability of the PNID program in other midsized urban settings. The PNID program (i.e. AT service delivery process), in combination with the WayFinder system (i.e. assistive technology), has the potential to meet the unique needs of individuals with cognitive disabilities when accessing public transportation.

Pharmacokinetics of Dexamethasone in Children and Adolescents with Obesity.

Dexamethasone is a synthetic glucocorticoid approved for treating disorders of various organ systems in both adult and pediatric populations. Currently, approved pediatric dosing recommendations are weight-based, but it is unknown whether differences in dexamethasone drug disposition and exposure exist for children with obesity. This study aimed to develop a population pharmacokinetic (PopPK) model for dexamethasone with data collected from children with obesity. Dexamethasone was given as either IV or oral/enteral administration, and a salt factor correction was used for dexamethasone sodium phosphate injection. A PopPK analysis using dexamethasone plasma concentration versus time was performed using the software NONMEM. A virtual population of 1000 children with obesity across three age groups was generated for dosing simulations. Data from 59 study participants with 82 PK plasma samples were used in the PopPK analysis. A one-compartment model with first-order absorption and the inclusion of total body weight as a covariate characterized the data. No other covariates were included in the PopPK model. Single and multiple IV dose(s) of 0.5 and 1 mg/kg every 8 h resulted in 68% or more of virtual children with obesity attaining simulated exposures that were within exposure ranges previously reported in adult studies. In conclusion, this was the first study to characterize dexamethasone's PopPK in children with obesity. Simulation results suggest that virtual children with obesity receiving oral doses of 0.5 and 1 mg/kg had generally comparable dexamethasone exposures as adult estimates. Additional studies are needed to characterize the dexamethasone's target exposure in children.

Design and hydrologic performance estimation of highway filter drains using a novel analytical probabilistic model.

Sustainable drainage systems (SuDS) are nature-based methods of managing urban stormwater runoff. Although they are widely used, some SuDS, such as highway filter drains (HFDs), are understudied with respect to sizing and performance. For the first time, we developed an analytical probabilistic model (APM) that can be used to design and estimate the hydrologic performance of HFDs. Unlike the conventionally used design-storm based or continuous simulation approaches, our APM can directly calculate the runoff capture ratios of HFDs using closed-form analytical equations. Validation of the APM presented here shows that it is robust and reliable. The relative differences between the APM-estimated and continuous simulation-determined runoff capture ratios for all the simulated design cases are less than 8.5%.

Wales Infants' and childreN's Genome Service (WINGS): providing rapid genetic diagnoses for unwell children.

INTRODUCTION: This study reviews the first 3 years of delivery of the first National Health Service (NHS)-commissioned trio rapid whole genome sequencing (rWGS) service for acutely unwell infants and children in Wales. METHODS: Demographic and phenotypic data were prospectively collected as patients and their families were enrolled in the Wales Infants' and childreN's Genome Service (WINGS). These data were reviewed alongside trio rWGS results. RESULTS: From April 2020 to March 2023, 82 families underwent WINGS, with a diagnostic yield of 34.1%. The highest diagnostic yields were noted in skeletal dysplasias, neurological or metabolic phenotypes. Mean time to reporting was 9 days. CONCLUSION: This study demonstrates that trio rWGS is having a positive impact on the care of acutely unwell infants and children in an NHS setting. In particular, the study shows that rWGS can be applied in an NHS setting, achieving a diagnostic yield comparable with the previously published diagnostic yields achieved in research settings, while also helping to improve patient care and management.

Comparison of PD-L1 (22C3) Expression in Paired Primary and Metastatic Breast Carcinoma.

INTRODUCTION: PD-L1 immunohistochemistry (IHC) is being used as a predictive marker of the benefit derived from immunotherapy in several cancer types, including breast cancer. However, the insight gleaned of the prognostic and predictive value of PD-L1 status and its correlation with molecular characteristics during breast cancer progression remains limited. METHODS: We performed an PD-L1 (22C3) assay in pre-treatment primary and metastatic tumor sections from 33 patients with breast carcinoma, matched for post neoadjuvant chemotherapy (p-NACT). PD-L1 expression was evaluated using 3 scoring methods: immune cell (IC) and tumor cell (TC) with a 1% as the cutoff value, and combined positive scores (CPS) with a 1 as the cutoff value. Twenty-two samples from 11 patients had successful fluorescence in situ hybridization (FISH)-based molecular data available for analysis. RESULTS: In the 33 pre-treatment primary tumors, PD-L1 IC, TC, and CPS showed positive correlation with stromal tumor infiltrate lymphocytes (sTIL), histological grade 3, and triple negative breast carcinoma (TNBC). In the matched metastatic tumors, only PD-L1 IC showed a positive correlation with sTIL. The primary tumors showed a higher PD-L1 expression than the matched metastatic tumors by IC and CPS. Negative to positive conversion by CPS was identified in the metastatic tumors from lung, pleura and liver. p-NACT tumors also showed a trend of lower PD-L1 expression compared to the pre-treatment tumors. Six patients had matched samples for molecular and PD-L1 comparison, and none of them showed consistent gene alterations or PD-L1 expression among the primary, p-NACT and metastatic tumors. CONCLUSION: Our study showed a decrease in PD-L1 expression and disconnected molecular features during breast cancer progression. Repeating PD-L1 IHC testing could be considered in some specific metastatic sites if primary tumors were negative. Further studies are needed to identify other predictive factors for immune checkpoint inhibitor (ICI) therapy in patients with breast carcinoma.

Using Real-World Data to Externally Evaluate Population Pharmacokinetic Models of Dexmedetomidine in Children and Infants.

Dexmedetomidine is a sedative used in both adults and off-label in children with considerable reported pharmacokinetic (PK) interindividual variability affecting drug exposure across populations. Several published models describe the population PKs of dexmedetomidine in neonates, infants, children, and adolescents, though very few have been externally evaluated. A prospective PK dataset of dexmedetomidine plasma concentrations in children and young adults aged 0.01-19.9 years was collected as part of a multicenter opportunistic PK study. A PubMed search of studies reporting dexmedetomidine PK identified five population PK models developed with data from demographically similar children that were selected for external validation. A total of 168 plasma concentrations from 102 children were compared with both population (PRED) and individualized (IPRED) predicted values from each of the five published models by quantitative and visual analyses using NONMEM (v7.3) and R (v4.1.3). Mean percent prediction errors from observed values ranged from -1% to 120% for PRED, and -24% to 60% for IPRED. The model by James et al, which was developed using similar "real-world" data, nearly met the generalizability criteria from IPRED predictions. Other models developed using clinical trial data may have been limited by inclusion/exclusion criteria and a less racially diverse population than this study's opportunistic dataset. The James model may represent a useful, but limited tool for model-informed dosing of hospitalized children.

Closing the Information Gap: Making COVID-19 Information Accessible for People with Disabilities.

It is essential that people with disabilities have equitable access to COVID-19 communication resources to protect themselves, their families, and their communities. The Accessible Materials and Culturally Relevant Messages for Individuals with Disabilities project aimed to deliver essential COVID-19 information in braille, American Sign Language (ASL), simplified text, and other alternative formats, along with providing additional tools and trainings that people with disabilities and organizations that serve them can use to apply the COVID-19 guidance. Lessons learned from this project can be implemented in future public health emergencies as well as in general public health messaging for people with disabilities. This project, led by Georgia Tech's Center for Inclusive Design and Innovation (CIDI) and with technical assistance from the Centers for Disease Control and Prevention (CDC), was supported by the CDC Foundation, using funds from the CDC Foundation's COVID-19 Emergency Response Fund.