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Myelin protein zero mutations were found to produce Charcot-Marie-Tooth disease phenotypes with various degrees of myelin impairment and axonal loss, ranging from the mild 'demyelinating' adult form to severe and early onset forms. Protein zero deficient homozygous mice ( ) show a severe and progressive dysmyelinating neuropathy from birth with compromised myelin compaction, hypomyelination and distal axonal degeneration. A previous study using immunofluorescence showed that motor nerves deficient of myelin protein zero upregulate the Na(V)1.8 voltage gated sodium channel isoform, which is normally present only in restricted populations of sensory axons. The aim of this study was to investigate the function of motor axons in protein zero-deficient mice with particular emphasis on ectopic Na(V)1.8 voltage gated sodium channel. We combined 'threshold tracking' excitability studies with conventional nerve conduction studies, behavioural studies using rotor-rod measurements, and histological measures to assess membrane dysfunction and its progression in protein zero deficient homozygous mutants as compared with age-matched wild-type controls. The involvement of Na(V)1.8 was investigated by pharmacologic block using the subtype-selective Na(V)1.8 blocker A-803467 and chronically in Na(V)1.8 knock-outs. We found that in the context of dysmyelination, abnormal potassium ion currents and membrane depolarization, the ectopic Na(V)1.8 channels further impair the motor axon excitability in protein zero deficient homozygous mutants to an extent that precipitates conduction failure in severely affected axons. Our data suggest that a Na(V)1.8 channelopathy contributed to the poor motor function of protein zero deficient homozygous mutants, and that the conduction failure was associated with partially reversible reduction of the electrically evoked muscle response and of the clinical function as indicated by the partial recovery of function at rotor-rod measurements. As a consequence of these findings of partially reversible dysfunction, we propose that the Na(V)1.8 voltage gated sodium channel should be considered as a novel therapeutic target for Charcot-Marie-Tooth disease. [ABSTRACT FROM AUTHOR]

Objective: In children admitted after an out-of-hospital cardiac arrest (OHCA), this study 1) determines the proportion that undergo physical abuse and toxin exposure evaluation, child protection team (CPT) consultation, and child protective services (CPS) referral, and 2) evaluates the association between demographic, social, clinical characteristics with CPT consultation and CPS referral., Methods: A retrospective chart review was conducted of children <4 years old admitted following an OHCA between November 2012 and February 2023. Associations between demographics, caregiver social risk factors, and clinical characteristics with CPT consultation and CPS referral were examined using logistic regression., Results: Among 157 cases, 70 (45%) had skeletal surveys; 8 (11%) identified an occult fracture. Seventy-five (48%) children had toxicology testing; 16 of the 75 (21%) revealed a toxic ingestion. Sixteen of the 49 (33%) patients receiving ophthalmologic evaluations had significant retinal hemorrhages. Seventy-seven (49%) patients had a CPT consultation, while 74 (47%) were referred to CPS. A history concerning for ingestion perfectly predicted CPT consultation. History of ingestion, injury on exam, positive skeletal survey, and positive toxicology testing perfectly predicted CPS referral. In multivariate analyses, unsafe sleep history (84% versus 41%, P < 0.001) and caregiver social risk factors (82% versus 31%, P < 0.001) were associated with CPT consultation, while caregiver social risk factors (70% versus 34%, P < 0.001) and normal medical work-up (53% versus 38%, P = 0.050) were associated with CPS referral., Conclusions: Following OHCA, a child maltreatment evaluation may be underutilized with medical decision-making around CPT consultation and CPS referral driven by knowledge of caregiver social risk factors., Competing Interests: Declaration of Competing Interest Drs Darwiche, Christian, and Wood’s institution has been paid in cases of child maltreatment for which they have provided expert testimony. Dr Christian has been paid for expert medical-legal work. The other authors report no conflicts of interest., (Copyright © 2025 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

Background: Three sources used for poisoning surveillance-child fatality reviews (CFRs), poison centre (PC) calls and death certificates-employ disparate data methodologies. Our study objectives were to (1) characterise the number of fatalities captured by CFRs and PC data compared with death certificates by age and (2) compare demographic and substance characteristics of fatalities captured by the three sources., Methods: We acquired CFR data from the National Fatality Review-Case Reporting System (NFR-CRS), PC calls from the National Poison Data System (NPDS) and death certificate data from Centers for Disease Control and Prevention's Wide-ranging Online Data for Epidemiologic Research (WONDER) on poisoning fatalities among children 0-17 years old between 2005 and 2020., Results: A total of 6376 poisoning fatalities among children 0-17 years were reported to WONDER, 3460 to NFR-CRS and 1622 to NPDS. Using WONDER as the reference standard, NFR-CRS captured 71.1% of fatalities among infants, and 68.0% among children 1-4 years. NPDS captured 30.9% of fatalities among infants and 59.3% among children 1-4 years. Children≤4 years represented a greater proportion of fatalities in NFR-CRS (25.5%) and NPDS (37.0%) than WONDER (19.9%). NFR-CRS had a slightly higher proportion of fatalities involving Black or African American race (16.8%) compared with WONDER (14.4%). Opioids were the most common fatal substances associated with NFR-CRS and WONDER., Conclusions: Fatality counts, as well as demographic and substance characteristics of those fatalities, differ between poisoning databases used by investigators and health agencies. Reliable death classification can improve data quality. Optimising poisoning fatality capture is critical for informing effective prevention strategies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Our algorithmic understanding of vision has been revolutionized by a reverse engineering paradigm that involves building artificial systems that perform the same tasks as biological systems. Here, we extend this paradigm to social behavior. We embodied artificial neural networks in artificial fish and raised the artificial fish in virtual fish tanks that mimicked the rearing conditions of biological fish. When artificial fish had deep reinforcement learning and curiosity-derived rewards, they spontaneously developed fish-like social behaviors, including collective behavior and social preferences (favoring in-group over out-group members). The artificial fish also developed social behavior in naturalistic ocean worlds, showing that these embodied models generalize to real-world learning contexts. Thus, animal-like social behaviors can develop from generic learning algorithms (reinforcement learning and intrinsic motivation). Our study provides a foundation for reverse-engineering the development of social behavior using image-computable models from artificial intelligence, bridging the divide between high-dimensional sensory inputs and collective action., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

How do newborns learn to see? We propose that visual systems are space-time fitters, meaning visual development can be understood as a blind fitting process (akin to evolution) in which visual systems gradually adapt to the spatiotemporal data distributions in the newborn's environment. To test whether space-time fitting is a viable theory for learning how to see, we performed parallel controlled-rearing experiments on newborn chicks and deep neural networks (DNNs), including CNNs and transformers. First, we raised newborn chicks in impoverished environments containing a single object, then simulated those environments in a video game engine. Second, we recorded first-person images from agents moving through the virtual animal chambers and used those images to train DNNs. Third, we compared the viewpoint-invariant object recognition performance of the chicks and DNNs. When DNNs received the same visual diet (training data) as chicks, the models developed common object recognition skills as chicks. DNNs that used time as a teaching signal-space-time fitters-also showed common patterns of successes and failures across the test viewpoints as chicks. Thus, DNNs can learn object recognition in the same impoverished environments as newborn animals. We argue that space-time fitters can serve as formal scientific models of newborn visual systems, providing image-computable models for studying how newborns learn to see from raw visual experiences., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Pandey et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Childhood behavioral problems are common; despite evidence that parenting interventions improve outcomes, the use of these programs is limited. Virtual delivery may ameliorate attendance barriers, but little is known on the acceptability and feasibility of virtual group parenting interventions. This mixed-methods study explored the feasibility, acceptability, and appropriateness of the virtual delivery of a parenting intervention, Child Adult Relationship Enhancement in Primary Care (PriCARE) among 18 caregivers and 8 facilitators. Subjects completed survey instruments assessing acceptability, appropriateness, feasibility, and telehealth usability and participated in semi-structured interviews exploring these constructs. Directed content analysis of interview transcripts identified themes. Most participants were female with a mean age of 35 years among caregivers and 37 years among facilitators. Slightly less than half of caregivers were Black (44%), with the remaining White. The majority of facilitators were White (88%). Over half (56%) of families received government assistance. Surveys indicated high acceptability, appropriateness, feasibility, and telehealth usability. We identified five overarching themes from qualitative analysis: nuances of feasibility, high acceptability, balancing skills and group dynamics, flexibility within fidelity, and multiple perspectives of disparities. Within these themes, reduced logistical barriers and the normalization of virtual meetings were contrasted with virtual burnout and distractions in the home. The majority of participants expressed that they learned helpful parenting skills, even in the setting of the suboptimal group dynamic of the virtual format. While disparities in technology and support systems were identified, the participation of caregivers who would not have attended in person was highlighted., Competing Interests: Statements and Declarations: This research was partially supported by a National Research Service Award Post-Doctoral Traineeship from the Health Resources and Services Administration sponsored by The Cecil G. Sheps Center for Health Services Research, The University of North Carolina at Chapel Hill, Grant No. 2-T32-HP14001-34-00 (Brittany Raffa). This research is funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (1R01HD103902-01) (Schilling, Wood).

Background: Skeletal surveys (SS) are recommended for the evaluation of suspected physical abuse in children <2 years old. No guidelines exist for SS completion in children between 2 and 5 years old., Objective: To determine rates of SS completion by age and examine variables associated with occult fracture identification in older children., Participants and Setting: Observational cross-sectional multi-center study of 10 US pediatric centers 2/2021-9/2022 including children <6 years old evaluated for physical child abuse., Methods: The principal outcome is occult fracture identified on SS. Non-parametric tests were conducted from comparison between age groups and those with and without occult fractures., Results: The rate of SS completion declined with increasing age from a high of 91 % in infants <6 months old to 7 % in children 5-5.9 years old. The proportion of SS with occult fractures also decreased with age. Of 450 children 2-5 years old with a SS, 20 [4 % (95 % CI: 3-8 %)] had an occult fracture. The rate of occult fractures among children 2-5 years old who were diagnosed with abuse and not admitted to the hospital was 0.3 % (95 % CI 0-0.6 %)]. Over 30 % of children 2-5 years old were diagnosed with child abuse by a child abuse pediatrician without completion of a SS., Conclusion: In children 2-5 years of age being evaluated for physical abuse, use of SS and the rate of occult fractures is low. The number of SS performed in children in this age group could potentially be decreased by up to 60 % by limiting SS to children admitted to the hospital., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: 1) To quantify hospital-level variation in use of neuroimaging to screen for intracranial injury (ICI) among infants without overt signs or symptoms of head trauma undergoing subspecialty evaluations for physical abuse; 2) to assess for disproportionality in neuroimaging based on race and ethnicity and insurance type., Methods: This was a cross-sectional study of infants age <12 months receiving subspecialty child abuse evaluations from February 2021 to December 2022 at 10 sites in CAPNET, a multicenter child abuse research network. Infants were included if they underwent a skeletal survey and lacked overt signs of possible ICI or blunt head injury. Outcome was completion of neuroimaging (computed tomography [CT] or magnetic resonance imaging [MRI]). Multivariable logistic regression was used to assess associations between demographic, clinical, and hospital factors with neuroimaging use., Results: Of 1114 infants, 746 (67%) underwent neuroimaging ranging from 51% to 80% across CAPNET hospitals. In multivariable analysis, young age, presence of rib fracture(s), and site had significant associations with neuroimaging. Insurance type and race and ethnicity did not contribute significantly to the model. After adjustment for case-mix, there was significant variation across hospitals, with neuroimaging use ranging from 51% (95% CI: 43%, 59%) to 79% (95% CI 71%, 88%)., Conclusion: We identified significant variation in neuroimaging use across CAPNET hospitals, highlighting the need for guideline development and care standardization during the care of infants undergoing abuse evaluations., Competing Interests: Declaration of Competing Interest Dr. Berger, Dr. Brink, Dr. Campbell, Dr. Harper, Dr. Henry, Dr. Frasier, Dr. Melville, and Dr. Wood have provided testimony in cases with concern for child physical abuse for which their institutions received payment. Dr. Lindberg and Dr. Frasier have provided paid expert witness testimony in cases with concern for child physical abuse., (Copyright © 2024. Published by Elsevier Inc.)

Genetic deletion and pharmacological inhibition are distinct approaches to unravelling pain mechanisms, identifying targets and developing new analgesics. Both approaches have been applied to the voltage-gated sodium channels Na v 1.7 and Na v 1.8. Genetic deletion of Na v 1.8 in mice leads to a loss of pain and antagonists are effective analgesics. The situation with Nav1.7 is more complex. Complete embryonic loss of Na v 1.7 in humans or in mouse sensory neurons leads to anosmia as well as profound analgesia as a result of diminished neurotransmitter release. This is mediated by enhanced endogenous opioid signaling in humans and mice. In contrast, anosmia is opioid-independent. Sensory neuron excitability and autonomic function appear to be normal. Adult deletion of Na v 1.7 in sensory neurons also leads to analgesia, but through diminished sensory and autonomic neuron excitability. There is no opioid component of analgesia or anosmia as shown by a lack of effect of naloxone. Pharmacological inhibition of Na v 1.7 in mice and humans leads both to analgesia and dramatic side-effects on the autonomic nervous system with no therapeutic window. These data demonstrate that specific Na v 1.7 channel blockers will fail as analgesic drugs. The viability of embryonic null mutants suggests that there are compensatory changes to replace the lost Na v 1.7 channel. Here we show that sensory neuron sodium channels Na v 1.1, Na v 1.2 and β4 subunits detected by Mass Spectrometry are upregulated in Na v 1.7 embryonic null neurons and, together with other proteome changes, potentially compensate for the loss of Na v 1.7. Interestingly, many of the upregulated proteins are known to interact with Nav1.7., Competing Interests: 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 paper., (© 2024 The Author(s).)

Background: Extra-axial cerebrospinal fluid (eaCSF) refers to the CSF in the subarachnoid spaces that surrounds the brain parenchyma. Benign enlargement of the subarachnoid space (BESS), a condition marked by increased eaCSF thickness, has been associated with macrocephaly and may be associated with subdural collections. However, diagnosis of BESS is complicated by the lack of age-specific normative data which hinders rigorous investigation of its clinical associations. Growth charts of eaCSF could shed light on normal CSF dynamics while also providing a normative benchmark to assist the diagnosis of BESS and other associated conditions., Methods: We accessed clinically-acquired T1w MRI scans from 1226 pediatric patients to form a clinical control cohort. Nine scans from subjects with a diagnosis of BESS from a board-certified pediatric neuroradiologist were also reviewed. SynthSeg was used to segment each T1w scan into various tissue types, including eaCSF. Growth charts of eaCSF were modeled using the clinical control cohort. The confirmed BESS cases were then benchmarked against these charts to test the performance of eaCSF growth charts., Results: eaCSF thickness varied nonlinearly with age, steadily decreasing from birth to two years, then trending upwards in early adolescence. Seven of the nine patients with a clinical diagnosis of BESS were above the 97.5 th percentile for their age for at least one eaCSF measure. Centile scores were able to distinguish BESS cases from controls with an area under curve (AUC) greater than 0.95., Discussion: eaCSF thickness evolves in a dynamic pattern throughout childhood and adolescence. Patients with BESS can be differentiated from clinical controls using computational measurements of eaCSF thickness paired with normative modeling. Our findings demonstrate the feasibility of computational extraction of eaCSF with a potential point of clinical relevance, delineation of BESS diagnosis. Enhanced understanding of normative eaCSF is critical in further investigations its clinical associations.

Cancer pain is a growing problem, especially with the substantial increase in cancer survival. Reports indicate that bone metastasis, whose primary symptom is bone pain, occurs in 65-75% of patients with advanced breast or prostate cancer. We optimized a preclinical in vivo model of cancer-induced bone pain (CIBP) involving the injection of Lewis Lung Carcinoma cells into the intramedullary space of the femur of C57BL/6 mice or transgenic mice on a C57BL/6 background. Mice gradually reduce the use of the affected limb, leading to altered weight bearing. Symptoms of secondary cutaneous heat sensitivity also manifest themselves. Following optimization, three potential analgesic treatments were assessed; 1) single ion channel targets (targeting the voltage-gated sodium channels Na V 1.7, Na V 1.8, or acid-sensing ion channels), 2) silencing µ-opioid receptor-expressing neurons by modified botulinum compounds, and 3) targeting two inflammatory mediators simultaneously (nerve growth factor (NGF) and tumor necrosis factor (TNF)). Unlike global Na V 1.8 knockout mice which do not show any reduction in CIBP-related behavior, embryonic conditional Na V 1.7 knockout mice in sensory neurons exhibit a mild reduction in CIBP-linked behavior. Modified botulinum compounds also failed to cause a detectable analgesic effect. In contrast, inhibition of NGF and/or TNF resulted in a significant reduction in CIBP-driven weight-bearing alterations and prevented the development of secondary cutaneous heat hyperalgesia. Our results support the inhibition of these inflammatory mediators, and more strongly their dual inhibition to treat CIBP, given the superiority of combination therapies in extending the time needed to reach limb use score zero in our CIBP model., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: John N Wood reports financial support was provided by Cancer Research UK. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

What are the core learning algorithms in brains? Nativists propose that intelligence emerges from innate domain-specific knowledge systems, whereas empiricists propose that intelligence emerges from domain-general systems that learn domain-specific knowledge from experience. We address this debate by reviewing digital twin studies designed to reverse engineer the learning algorithms in newborn brains. In digital twin studies, newborn animals and artificial agents are raised in the same environments and tested with the same tasks, permitting direct comparison of their learning abilities. Supporting empiricism, digital twin studies show that domain-general algorithms learn animal-like object perception when trained on the first-person visual experiences of newborn animals. Supporting nativism, digital twin studies show that domain-general algorithms produce innate domain-specific knowledge when trained on prenatal experiences (retinal waves). We argue that learning across humans, animals, and machines can be explained by a universal principle, which we call space-time fitting. Space-time fitting explains both empiricist and nativist phenomena, providing a unified framework for understanding the origins of intelligence.

Objective: Because of COVID-19 pandemic social distancing requirements, the in-person Child Adult Relationship Enhancement in Primary Care (PriCARE) positive parenting intervention was adapted for virtual delivery. Objective was to evaluate the efficacy of the virtual PriCARE program to improve parenting capacity, decrease child behavioral problems, and decrease child maltreatment risk., Methods: Caregivers of children 2 to 6 years old recruited from pediatric primary care were randomized to PriCARE (n = 92) or waitlist control (n = 90). Dysfunctional parenting, positive parenting skills, child behaviors, and child maltreatment risk were measured at baseline and 2 to 3 months after intervention using the Parenting Scale (PS), Dyadic Parent-Child Interaction Coding System (DPICS), Eyberg Child Behavior Inventory (ECBI), and Child Abuse Potential Inventory (CAPI). Kruskal-Wallis test compared median change scores from baseline to follow-up by treatment arm., Results: Of 182 enrolled caregivers, 92% (168) were mothers and 67% (122) completed study measures at baseline and follow-up. The median decrease (improvement) in total PS score was greater in the PriCARE group compared with the control group (-0.3 [IQR 0.69] vs -0.1 [IQR 0.56], p = 0.028) as was the median decrease (improvement) in ECBI problem score (-3 [IQR 9] vs -1 [IQR 7], p = 0.045) and ECBI intensity score (-9 [IQR 21] vs 0 [IQR 25], p = 0.006). Improvements in 4 positive parenting skills measured by DPICS were greater in the PriCARE group compared with the control group (all p< 0.003). Median decrease in CAPI abuse score did not differ significantly by study arm ( p = 0.055)., Conclusion: The PriCARE virtual adaptation demonstrated promise in promoting positive parenting and decreasing child behavior problems., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.)

The relationship between transcription and protein expression is complex. We identified polysome-associated RNA transcripts in the somata and central terminals of mouse sensory neurons in control, painful (plus nerve growth factor), and pain-free conditions (Nav1.7-null mice). The majority (98%) of translated transcripts are shared between male and female mice in both the somata and terminals. Some transcripts are highly enriched in the somata or terminals. Changes in the translatome in painful and pain-free conditions include novel and known regulators of pain pathways. Antisense knockdown of selected somatic and terminal polysome-associated transcripts that correlate with pain states diminished pain behavior. Terminal-enriched transcripts included those encoding synaptic proteins (e.g., synaptotagmin), non-coding RNAs, transcription factors (e.g., Znf431), proteins associated with transsynaptic trafficking (HoxC9), GABA-generating enzymes (Gad1 and Gad2), and neuropeptides (Penk). Thus, central terminal translation may well be a significant regulatory locus for peripheral input from sensory neurons., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Abstract: Visceral pain is a leading cause of morbidity in inflammatory bowel disease (IBD), contributing significantly to reduced quality of life. Currently available analgesics often lack efficacy or have intolerable side effects, driving the need for a more complete understanding of the mechanisms causing pain. Whole transcriptome gene expression analysis was performed by bulk RNA sequencing of colonic biopsies from patients with ulcerative colitis (UC) and Crohn's disease (CD) reporting abdominal pain and compared with noninflamed control biopsies. Potential pronociceptive mediators were identified based on gene upregulation in IBD biopsy tissue and cognate receptor expression in murine colonic sensory neurons. Pronociceptive activity of identified mediators was assessed in assays of sensory neuron and colonic afferent activity. RNA sequencing analysis highlighted a 7.6-fold increase in the expression of angiotensinogen transcripts, Agt , which encode the precursor to angiotensin II (Ang II), in samples from UC patients ( P = 3.2 × 10 -8 ). Consistent with the marked expression of the angiotensin AT 1 receptor in colonic sensory neurons, Ang II elicited an increase in intracellular Ca 2+ in capsaicin-sensitive, voltage-gated sodium channel subtype Na V 1.8-positive sensory neurons. Ang II also evoked action potential discharge in high-threshold colonic nociceptors. These effects were inhibited by the AT 1 receptor antagonist valsartan. Findings from our study identify AT 1 receptor-mediated colonic nociceptor activation as a novel pathway of visceral nociception in patients with UC. This work highlights the potential utility of angiotensin receptor blockers, such as valsartan, as treatments for pain in IBD., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

Objectives: The aims of this study were to describe chief complaints provided at emergency department triage for young children ultimately given a diagnosed with injuries concerning for physical abuse and compare chief complaints by hospital child protection team assessment (abuse most likely, accident most likely, undetermined) among children younger than 2 years who were the subject of a report to child protective services., Methods: This is a retrospective review of children evaluated by the child protection team at an urban children's hospital over a 5-year period. Children younger than 2 years who were the subject of a report to child protective services for suspected physical abuse were included. Chief complaints noted in emergency department triage notes were categorized as follows: 1, medical sign or symptom; 2, accidental trauma incident; 3, identified injury; 4, concern for abuse; or 5, multiple unrelated complaints. Child protection team assessments were categorized as follows: 1, abuse most likely; 2, accident most likely; or 3, undetermined. We used descriptive statistics and tests of association (χ 2 , Fisher exact, Kruskal-Wallis)., Results: Median age of the 422 children included was 4.9 months. Child protection team assessment was abuse most likely in 44%, accident most likely in 23%, and undetermined in 34%. Chief complaints in the overall sample were 39% medical, 29% trauma incident, 16% injury, 10% abuse concern, and 6% multiple unrelated. When the abuse most likely and accident most likely groups were compared, medical chief complaints were more common in the former (47% vs 19%, P < 0.001), whereas trauma incident chief complaints were more common in the latter (19% vs 64%, P < 0.001). Most common medical complaints in the abuse most likely group were altered mental status, abnormal limb use, swelling, pain, apnea, and vomiting., Conclusion: Many children found to have injuries concerning for abuse (47%) present without mention of trauma, injury, or abuse concern as part of the chief complaint. Our findings suggest important topics to include in training physicians about recognition of abuse., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Mechanically activating (MA) channels transduce numerous physiological functions. Tentonin 3/TMEM150C (TTN3) confers MA currents with slow inactivation kinetics in somato- and barosensory neurons. However, questions were raised about its role as a Piezo1 regulator and its potential as a channel pore. Here, we demonstrate that purified TTN3 proteins incorporated into the lipid bilayer displayed spontaneous and pressure-sensitive channel currents. These MA currents were conserved across vertebrates and differ from Piezo1 in activation threshold and pharmacological response. Deep neural network structure prediction programs coupled with mutagenetic analysis predicted a rectangular-shaped, tetrameric structure with six transmembrane helices and a pore at the inter-subunit center. The putative pore aligned with two helices of each subunit and had constriction sites whose mutations changed the MA currents. These findings suggest that TTN3 is a pore-forming subunit of a distinct slow inactivation MA channel, potentially possessing a tetrameric structure., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Federal legislation mandates healthcare providers to notify child protective service (CPS) agencies and offer a voluntary care plan called a "plan of safe care" (POSC) for all infants born affected by prenatal substance use. While POSCs aim to provide supportive services for families impacted by substance use, little is known about birth parents' perceptions and experiences., Objective: To examine birth parents' perceptions and experiences regarding POSC., Participants and Setting: Parents offered a POSC in Philadelphia in the prior year were included., Methods: This is a qualitative interview study. Participants were recruited from birth hospitals and community-based programs with telephone consent and interview procedures. Transcripts were analyzed using an inductive, grounded theory approach to identify content themes., Results: Twelve birth parents were interviewed (30.7 % of eligible, contacted individuals). Fear of CPS involvement and stigma were common. Some birth parents reported that the increased scrutiny related to POSCs negatively impacted their attitudes toward healthcare providers and medications for opioid use disorder (MOUD). While parents found the consolidated resource information helpful, many did not know how to access services. Finally, parents desired more individualized plans tailored to their unique family needs., Conclusions: Stigma, confusion, and fear of CPS involvement undermine the goal of POSCs to support substance-exposed infants and birth parents. Providers serving this population should be transparent regarding CPS notifications, provide compassionate, non-stigmatizing care, and offer coordination services to support engagement after discharge. Policymakers should consider separating POSCs from CPS to avoid exacerbating fear and mistrust., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier Ltd.)

The last 50 years have witnessed extraordinary developments in understanding mechanisms of carcinogenesis, synthesized as the hallmarks of cancer. Despite this logical framework, our understanding of the molecular basis of systemic manifestations and the underlying causes of cancer-related death remains incomplete. Looking forward, elucidating how tumors interact with distant organs and how multifaceted environmental and physiological parameters impinge on tumors and their hosts will be crucial for advances in preventing and more effectively treating human cancers. In this perspective, we discuss complexities of cancer as a systemic disease, including tumor initiation and promotion, tumor micro- and immune macro-environments, aging, metabolism and obesity, cancer cachexia, circadian rhythms, nervous system interactions, tumor-related thrombosis, and the microbiome. Model systems incorporating human genetic variation will be essential to decipher the mechanistic basis of these phenomena and unravel gene-environment interactions, providing a modern synthesis of molecular oncology that is primed to prevent cancers and improve patient quality of life and cancer outcomes., Competing Interests: Declaration of interests C.A. reports employment at Saga Diagnostics and reports options to own stock in the company. C.A. and C.S. are listed as inventors on a European patent application relating to assay technology to detect tumor recurrence (PCT/GB2017/053289). This patent has been licensed to commercial entities and, under their terms of employment, C.A. and C.S. are due a revenue share of any revenue generated from such license(s). C.A. and C.S. declare a patent application (PCT/US2017/028013) for methods to detect lung cancer. C.A. and C.S. are named inventors on a patent application to determine methods and systems for tumor monitoring (PCT/EP2022/077987). C.A. and C.S. are named inventors on a provisional patent protection related to a ctDNA detection algorithm. J.A.J. has received honoraria for speaking at research symposia organized by Bristol Meyers Squibb and Glenmark Pharmaceuticals and previously served on the SAB of Pionyr Immunotherapeutics. D.H. is a founder and member of the BoD and SAB of Opna Bio, and a member of the SABs of Pfizer, Cellestia Biotech, 4D Molecular Therapeutics, and AtG Therapeutics. F.A. reports travel/accommodation/expenses from AstraZeneca, GlaxoSmithKline, Novartis, Pfizer, and Roche, and his institution has received research funding from AstraZeneca, Daiichi Sankyo, Lilly, Novartis, Pfizer, and Roche. C.M. Consultant/Advisory fees from Amgen, Astellas, AstraZeneca, Bayer, BeiGene, BMS, Celgene, Debiopharm, Genentech, Ipsen, Janssen, Lilly, MedImmune, MSD, Novartis, Pfizer, Roche, Sanofi, Orion. Principal/sub-Investigator of Clinical Trials for AbbVie, Aduro, Agios, Amgen, Argen-x, Astex, AstraZeneca, Aveo pharmaceuticals, Bayer, Beigene, Blueprint, BMS, Boeringer Ingelheim, Celgene, Chugai, Clovis, Daiichi Sankyo, Debiopharm, Eisai, Eos, Exelixis, Forma, Gamamabs, Genentech, Gortec, GSK, H3 biomedecine, Incyte, InnatePharma, Janssen, Kura Oncology, Kyowa, Lilly, Loxo, Lysarc, Lytix Biopharma, Medimmune, Menarini, Merus, MSD, Nanobiotix, Nektar Therapeutics, Novartis, Octimet, Oncoethix, Oncopeptides AB, Orion, Pfizer, Pharmamar, Pierre Fabre, Roche, Sanofi, Servier, Sierra Oncology, Taiho, Takeda, Tesaro, and Xencor. R.B. is founder of Oncosence. M.A.F. is founder and shareholder of Celesta Therapeutics. A.H. is a paid consultant for Calida Therapeutics. M.J.-H. has consulted for, and is a member of, the Achilles Therapeutics Scientific Advisory Board and Steering Committee, has received speaker honoraria from Pfizer, Astex Pharmaceuticals, Oslo Cancer Cluster, Bristol Myers Squibb, and is listed as a co-inventor on a European patent application relating to methods to detect lung cancer PCT/US2017/028013), this patent has been licensed to commercial entities and, under terms of employment, M.J.-H. is due a share of any revenue generated from such license(s). J.W.L. advises Restoration Foodworks, Nanocare Technologies, and Cornerstone Pharmaceuticals. S.L. received research funding to institution from Novartis, Bristol Myers Squibb, MSD, Puma Biotechnology, Eli Lilly, Nektar Therapeutics, AstraZeneca/Daiichi Sankyo, and Seattle Genetics. S.L. has acted as consultant (not compensated) to Seattle Genetics, Novartis, Bristol Myers Squibb, MSD, AstraZeneca/Daiichi Sankyo, Eli Lilly, Pfizer, Gilead Therapeutics, Nektar Therapeutics, PUMA Biotechnologies and Roche-Genentech. S.L. has acted as consultant (paid to institution) to Novartis, GlaxoSmithKline, Roche-Genentech, AstraZeneca/Daiichi Sankyo, Pfizer, Gilead Therapeutics, Seattle Genetics, MSD, Tallac Therapeutics, Eli Lilly, and Bristol Myers Squibb. I.M. is a consultant of LIfT BioSciences. K.M. has received honoraria from LEO Pharma, Pfizer and Bayer PLC. She has received research funding from LEO Pharma and Bayer PLC. S.Q. is a founder, CSO, and holds stock options in Achilles Therapeutics. C.S. acknowledges grants from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Pfizer, Roche-Ventana, Invitae (previously Archer Dx Inc—collaboration in minimal residual disease sequencing technologies), Ono Pharmaceutical, and Personalis. He is Chief Investigator for the AZ MeRmaiD 1 and 2 clinical trials and is the Steering Committee Chair. He is also Co-Chief Investigator of the NHS Galleri trial funded by GRAIL and a paid member of GRAIL’s Scientific Advisory Board. He receives consultant fees from Achilles Therapeutics (also SAB member), Bicycle Therapeutics (also a SAB member), Genentech, Medicxi, China Innovation Centre of Roche (CICoR) formerly Roche Innovation Centre—Shanghai, Metabomed (until July 2022), Relay Therapeutics, and the Sarah Cannon Research Institute. C.S. has received honoraria from Amgen, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Illumina, MSD, Novartis, Pfizer, and Roche-Ventana. C.S. has previously held stock options in Apogen Biotechnologies and GRAIL, and currently has stock options in Epic Bioscience, Bicycle Therapeutics, and has stock options and is co-founder of Achilles Therapeutics. Patents: C.S. declares a patent application (PCT/US2017/028013) for methods to lung cancer); targeting neoantigens (PCT/EP2016/059401); identifying patent response to immune checkpoint blockade (PCT/EP2016/071471), determining HLA LOH (PCT/GB2018/052004); predicting survival rates of patients with cancer (PCT/GB2020/050221); identifying patients who respond to cancer treatment (PCT/GB2018/051912); methods for lung cancer detection (US20190106751A1). C.S. is an inventor on a European patent application (PCT/GB2017/053289) relating to assay technology to detect tumor recurrence. This patent has been licensed to a commercial entity and under their terms of employment C.S. is due a revenue share of any revenue generated from such license(s). K.H.V. is on the board of directors and shareholder of Bristol Myers Squibb and on the science advisory board (with stock options) of PMV Pharma, RAZE Therapeutics, Volastra Pharmaceuticals and Kovina Therapeutics. She is on the SAB of Ludwig Cancer and a co-founder and consultant of Faeth Therapeutics. She has been in receipt of research funding from Astex Pharmaceuticals and AstraZeneca and contributed to CRUK Cancer Research Technology filing of patent application WO/2017/144877. J.W. is an inventor on a US patent application (PCT/US17/53.717) submitted by the University of Texas MD Anderson Cancer Center which covers methods to enhance immune checkpoint blockade responses by modulating the microbiome, reports compensation for speaker’s bureau and honoraria from Imedex, Dava Oncology, Omniprex, Illumina, Gilead, PeerView, Physician Education Resource, MedImmune, Exelixis and Bristol Myers Squibb, and has served as a consultant/advisory board member for Roche/Genentech, Novartis, AstraZeneca, GlaxoSmithKline, Bristol Myers Squibb, Micronoma, OSE therapeutics, Merck, and Everimmune. Dr. Wargo receives stock options from Micronoma and OSE therapeutics. A.W. is on the board of Regain Therapeutics., (Copyright © 2024. Published by Elsevier Inc.)

Importance: Racial bias may affect occult injury testing decisions for children with concern for abuse., Objectives: To determine the association of race on occult injury testing decisions at children's hospitals., Design: In this retrospective study, we measured disparities in: (1) the proportion of visits for which indicated diagnostic imaging studies for child abuse were obtained; (2) the proportion of positive tests., Setting: The Pediatric Health Information System (PHIS) administrative database encompassing 49 tertiary children's hospitals during 2017-2019., Participants: We built three cohorts based on guidelines for diagnostic testing for child abuse: infants with traumatic brain injury (TBI; n = 1952), children <2 years old with extremity fracture (n = 20,842), and children <2 years old who received a skeletal survey (SS; n = 13,081)., Main Outcomes and Measures: For each group we measured: (1) the odds of receiving a specific guideline-recommended diagnostic imaging study; (2) among those with the indicated imaging study, the odds of an abuse-related injury diagnosis. We calculated both unadjusted and adjusted odds ratios (AOR) by race and ethnicity, adjusting for sex, age in months, payor, and hospital., Results: In infants with TBI, the odds of receiving a SS did not differ by racial group. Among those with a SS, the odds of rib fracture were higher for non-Hispanic Black than Hispanic (AOR 2.05 (CI 1.31, 3.2)) and non-Hispanic White (AOR 1.57 (CI 1.11, 2.32)) patients. In children with extremity fractures, the odds of receiving a SS were higher for non-Hispanic Black than Hispanic and non-Hispanic White patients (AOR 1.97 (CI 1.74, 2.23)); (AOR 1.17 (CI 1.05, 1.31)), respectively, and lower for Hispanic than non-Hispanic White patients (AOR 0.59 (CI 0.53, 0.67)). Among those receiving a SS, the rate of rib fractures did not differ by race. In children with skeletal surveys, the odds of receiving neuroimaging did not differ by race. Among those with neuroimaging, the odds of a non-fracture, non-concussion TBI were lower in non-Hispanic Black than Hispanic patients (AOR 0.7 (CI 0.57, 0.86)) and were higher among Hispanic than non-Hispanic White patients (AOR 1.23 (CI 1.02, 1.47))., Conclusions and Relevance: We did not identify a consistent pattern of race-based disparities in occult injury testing when considering the concurrent yield for abuse-related injuries., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Child maltreatment (CM) is a pervasive public health problem and there is a critical need for brief, effective, scalable prevention programs. Because problematic parent-child relationships lie at the core of CM, interventions targeting this relationship hold promise as CM prevention strategies. Evidence-based positive parenting interventions, as discussed here, are manualized behavioral interventions that focus on teaching caregivers positive parenting skills and techniques to improve the effectiveness of their parenting and improve their relationship with their child. In this article, we describe one specific parenting intervention, Child Adult Relationship Enhancement in Primary Care (PriCARE)/Criando Niños con CARIÑO, and review the proposed mechanisms through which PriCARE may contribute to CM prevention. PriCARE is a 6-session group parenting intervention for parents of 2-to-6-year-old children. PriCARE was developed and iteratively adapted with input from racially and ethnically diverse families, including low-income families, and was designed specifically for implementation in primary care with inclusion of strategies to align with usual care workflow to increase uptake and retention. PriCARE has the potential to reduce risk of CM directly through improving parenting behaviors and indirectly through the impact of those changes in parenting behaviors on child behaviors. PriCARE has also been shown to reduce parenting-related stress. Finally, by strengthening and bringing warmth to the parent-child relationship, PriCARE may buffer against the negative health consequences associated with CM and childhood adversity., Competing Interests: Declaration of Competing Interest The authors have no conflicts to disclose., (Copyright © 2023. Published by Elsevier Inc.)

CAPNET is a multicenter child abuse pediatrics research network developed to support research that will make the medical care of potentially abused children more effective, safe, and fair. CAPNET currently collects detailed clinical data from child physical abuse evaluations from 11 leading pediatric centers across the U.S. From its inception, the goal of CAPNET was to support multiple research studies addressing the care of children undergoing evaluations for physical abuse and to create a flexible data collection and quality assurance system to be a resource for the wider community of child maltreatment l researchers. Annually, CAPNET collects rich clinical data on over 4000 children evaluated due to concerns for physical abuse. CAPNET's data are well-suited to studies improving the standardization, equity, and accuracy of evaluations in the medical setting when child physical abuse is suspected. Here we describe CAPNET's development, content, lessons learned, and potential future directions of the network., Competing Interests: Declaration of competing interest Drs. Henry's, Campbell's and Wood's institutions have been paid in cases with concern for child maltreatment for which they have been subpoenaed to provide expert testimony. Dr. Lindberg has provided paid expert witness testimony in cases with concern for child maltreatment., (Copyright © 2024. Published by Elsevier Inc.)

What role does visual experience play in the development of object recognition? Prior controlled-rearing studies suggest that newborn animals require slow and smooth visual experiences to develop object recognition. Here, we examined whether the development of object recognition also requires experience with the surface features of objects. We raised newborn chicks in automated controlled-rearing chambers that contained a single virtual object, then tested their ability to recognize that object from familiar and novel viewpoints. When chicks were reared with an object that had surface features, the chicks developed view-invariant object recognition. In contrast, when chicks were reared with a line drawing of an object, the chicks failed to develop object recognition. The chicks reared with line drawings performed at chance level, despite acquiring over 100 h of visual experience with the object. These results indicate that the development of object recognition requires experience with the surface features of objects.

After a series of meetings between medical personnel and community stakeholders, the Children's Hospital of Philadelphia successfully launched the Adolescent Protection Collaborative in July 2021. This novel clinic created a specialized medical home for sex-trafficked youth. The clinic was staffed by a core team of child abuse pediatrics and adolescent medicine physicians and a social worker who provided coordinated evaluations and same-day services, followed by ongoing long-term care. The Adolescent Protection Collaborative model was built on interdisciplinary collaboration with the goal of consolidating medical services and reducing fragmentation of care. A Community Advisory Committee was formed and aided in linking interested youth with additional services. Healthcare navigation was facilitated through support of a clinic-specific social worker, and transportation barriers were largely eliminated through a grant-funded program. Pilot data from the initial 21 months of clinical operations revealed that 88% of 43 referred patients (ages ranging from 13-22 years with a mean of 16 years) attended a scheduled appointment with 55% returning for follow up. Most patients (68%) identified as Black. All (100%) had past or present involvement with child protective services. Fifty percent of referrals tested positive for a sexually transmitted infection with a total of 33 sexually transmitted infections diagnosed and treated. Patient-desired contraception was facilitated for approximately 67% of referrals. Social care needs, such as referrals for educational support, case management, housing and employment resources, and mental health linkages, were offered alongside standard medical services. The described clinic model demonstrates promise in meeting the unique healthcare needs of sex-trafficked youth., (Copyright © 2024 by the American Academy of Pediatrics.)

Objective: Suspicion for child abuse is influenced by implicit biases. Evaluation by a Child Abuse Pediatrician (CAP) may reduce avoidable child protective services (CPS) referrals. Our objective was to investigate the association of patient demographic, social and clinical characteristics with CPS referral before consultation by a CAP (preconsultation referral)., Methods: Children<5years-old undergoing in-person CAP consultation for suspected physical abuse from February 2021 through April 2022 were identified in CAPNET, a multicenter child abuse research network. Marginal standardization implemented with logistic regression analysis examined hospital-level variation and identified demographic, social, and clinical factors associated with preconsultation referral adjusting for CAP's final assessment of abuse likelihood., Results: Among the 61% (1005/1657) of cases with preconsultation referral, the CAP consultant had low concern for abuse in 38% (384/1005). Preconsultation referrals ranged from 25% to 78% of cases across 10 hospitals (P < .001). In multivariable analyses, preconsultation referral was associated with public insurance, caregiver history of CPS involvement, history of intimate partner violence, higher CAP level of concern for abuse, hospital transfer, and near-fatality (all P < .05). The difference in preconsultation referral prevalence for children with public versus private insurance was significant for children with low CAP concern for abuse (52% vs 38%) but not those with higher concern for abuse (73% vs 73%), (P = .023 for interaction of insurance and abuse likelihood category). There were no differences in preconsultation referral based on race or ethnicity., Conclusions: Biases based on socioeconomic status and social factors may impact decisions to refer to CPS before CAP consultation., Competing Interests: Declaration of Competing Interest Drs Anderst, Lindberg and Letson have provided paid expert witness testimony in cases with concern for child physical abuse. Drs Berger’s, Campbell’s, Harper’s, Henry’s, Melville’s, and Wood’s institutions have been paid in cases with concern for child physical abuse for which they have provided expert testimony. The other authors report no conflicts of interest., (Copyright © 2024 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

Opioids are widely used in the treatment of moderate and severe pain. Nociceptive stimulation has been reported to potentially promote microglial activation and neuroinflammation, which also causes chronic pain sensitization. The aim of this study was to demonstrate whether the novel μ receptor agonist MEL-0614 could inhibit activated microglia directly and the associated signaling pathway. Mice were administered lipopolysaccharide and formalin to induce allodynia. Von Frey test was used to detect the anti-allodynia effect of MEL-0614 before and after LPS and formalin injection. In the spinal cord, the levels of proinflammatory cytokines and microglial activation were determined after MEL-0614 administration. BV2 and primary microglia were cultured to further explore the effect of MEL-0614 on LPS-induced microglial activation and key signaling pathways involved. MEL-0614 partially prevented and reversed allodynia induced by LPS and formalin in vivo, which was not inhibited by the μ receptor antagonist CTAP. Minocycline was effective in reversing the established allodynia. MEL-0614 also downregulated the activation of microglia and related proinflammatory cytokines in the spinal cord. Additionally, in BV2 and primary microglia, MEL-0614 inhibited the LPS-induced upregulation of proinflammatory factors, which was unaffected by CTAP. The NLR family pyrin domain containing 3 (NLRP3) related signaling pathway may be involved in the interaction between MEL-0614 and microglia. The opioid agonist MEL-0614 inhibited the activation of microglia and the subsequent upregulation of proinflammatory factors both in vivo and in vitro. Notably, this effect is partially mediated by the μ receptor., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest in this work., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Congenital insensitivity to pain (CIP) and hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders exclusively or predominantly affecting the sensory and autonomic neurons. Due to the rarity of the diseases and findings based mainly on single case reports or small case series, knowledge about these disorders is limited. Here, we describe the molecular workup of a large international cohort of CIP/HSAN patients including patients from normally under-represented countries. We identify 80 previously unreported pathogenic or likely pathogenic variants in a total of 73 families in the >20 known CIP/HSAN-associated genes. The data expand the spectrum of disease-relevant alterations in CIP/HSAN, including novel variants in previously rarely recognized entities such as ATL3-, FLVCR1- and NGF-associated neuropathies and previously under-recognized mutation types such as larger deletions. In silico predictions, heterologous expression studies, segregation analyses and metabolic tests helped to overcome limitations of current variant classification schemes that often fail to categorize a variant as disease-related or benign. The study sheds light on the genetic causes and disease-relevant changes within individual genes in CIP/HSAN. This is becoming increasingly important with emerging clinical trials investigating subtype or gene-specific treatment strategies., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Melzak and Wall's gate control theory proposed that innocuous input into the dorsal horn of the spinal cord represses pain-inducing nociceptive input. Here we show that input from proprioceptive parvalbumin-expressing sensory neurons tonically represses nociceptor activation within dorsal root ganglia. Deletion of parvalbumin-positive sensory neurons leads to enhanced nociceptor activity measured with GCaMP3, increased input into wide dynamic range neurons of the spinal cord and increased acute and spontaneous pain behaviour, as well as potentiated innocuous sensation. Parvalbumin-positive sensory neurons express the enzymes and transporters necessary to produce vesicular GABA that is known to be released from depolarized somata. These observations support the view that gate control mechanisms occur peripherally within dorsal root ganglia., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Drive from peripheral neurons is essential in almost all pain states, but pharmacological silencing of these neurons to effect analgesia has proved problematic. Reversible gene therapy using long-lived chemogenetic approaches is an appealing option. We used the genetically activated chloride channel PSAM 4 -GlyR to examine pain pathways in mice. Using recombinant AAV9-based delivery to sensory neurons, we found a reversal of acute pain behavior and diminished neuronal activity using in vitro and in vivo GCaMP imaging on activation of PSAM 4 -GlyR with varenicline. A significant reduction in inflammatory heat hyperalgesia and oxaliplatin-induced cold allodynia was also observed. Importantly, there was no impairment of motor coordination, but innocuous von Frey sensation was inhibited. We generated a transgenic mouse that expresses a CAG-driven FLExed PSAM 4 -GlyR downstream of the Rosa26 locus that requires Cre recombinase to enable the expression of PSAM 4 -GlyR and tdTomato. We used Na V 1.8 Cre to examine the role of predominantly nociceptive Na V 1.8+ neurons in cancer-induced bone pain (CIBP) and neuropathic pain caused by chronic constriction injury (CCI). Varenicline activation of PSAM 4 -GlyR in Na V 1.8-positive neurons reversed CCI-driven mechanical, thermal, and cold sensitivity. Additionally, varenicline treatment of mice with CIBP expressing PSAM 4 -GlyR in Na V 1.8+ sensory neurons reversed cancer pain as assessed by weight-bearing. Moreover, when these mice were subjected to acute pain assays, an elevation in withdrawal thresholds to noxious mechanical and thermal stimuli was detected, but innocuous mechanical sensations remained unaffected. These studies confirm the utility of PSAM 4 -GlyR chemogenetic silencing in chronic pain states for mechanistic analysis and potential future therapeutic use., Competing Interests: The authors declare no competing financial interests., (Copyright © 2023 Haroun et al.)

Chronic pain affects millions of people worldwide and new treatments are needed urgently. One way to identify novel analgesic strategies is to understand the biological dysfunctions that lead to human inherited pain insensitivity disorders. Here we report how the recently discovered brain and dorsal root ganglia-expressed FAAH-OUT long non-coding RNA (lncRNA) gene, which was found from studying a pain-insensitive patient with reduced anxiety and fast wound healing, regulates the adjacent key endocannabinoid system gene FAAH, which encodes the anandamide-degrading fatty acid amide hydrolase enzyme. We demonstrate that the disruption in FAAH-OUT lncRNA transcription leads to DNMT1-dependent DNA methylation within the FAAH promoter. In addition, FAAH-OUT contains a conserved regulatory element, FAAH-AMP, that acts as an enhancer for FAAH expression. Furthermore, using transcriptomic analyses in patient-derived cells we have uncovered a network of genes that are dysregulated from disruption of the FAAH-FAAH-OUT axis, thus providing a coherent mechanistic basis to understand the human phenotype observed. Given that FAAH is a potential target for the treatment of pain, anxiety, depression and other neurological disorders, this new understanding of the regulatory role of the FAAH-OUT gene provides a platform for the development of future gene and small molecule therapies., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Objectives: Child abuse should be considered in cases of sudden unexpected infant death (SUID). Postmortem skeletal surveys (PM-SS) are recommended to evaluate for abusive fractures in SUID. Little is known about the yield of PM-SS among infants presenting to emergency care with SUID. Our objectives were to (1) describe the presentation and care of infants with SUID at a tertiary children's hospital emergency department and (2) report PM-SS use and findings., Methods: We performed a retrospective study of infants younger than 12 months with SUID presenting to an urban emergency department from 2007 to 2019. We describe their presentation and care, including PM-SS performance and findings, referrals to the medical examiner, and reports to child protective services (CPS). We assessed for associations between race, payer, and presentation with reports to CPS., Results: Of 73 infants with SUID, concern for unsafe sleep was documented in 45 (61.6%) and 71 (97.3%) underwent cardiopulmonary resuscitation by a medical professional. All 73 (100%) underwent PM-SS and were referred to the medical examiner. Twelve definite fractures (11 rib, 1 classic metaphyseal lesion) and 8 possible fractures (7 rib, 1 classic metaphyseal lesion) were identified among 6 (8.2%) infants. Forty-three (58.9%) were reported to CPS. There were no associations between race, payer, age, or history of unsafe sleep and CPS reports., Conclusions: One in 12 cases of SUID had a possible and/or definite fracture identified on plain radiography. Multicenter studies are needed to compare yield across different postmortem imaging modalities and populations., Competing Interests: Disclosure: Children's Hospital of Philadelphia has received payment for expert testimony provided by M.K.H., J.N.W., and P.V.S. after subpoenas to testify in cases of suspected child abuse. The other authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: The US physician workforce is aging, prompting concerns regarding clinical performance of senior physicians. Pediatric emergency medicine (PEM) is a high-acuity, multitasking, diagnostically complex and procedurally demanding specialty. Aging's impact on clinical performance in PEM has not been examined. We aimed to assess PEM physician's' perceptions of peers' clinical performance over career span., Methods: We surveyed 478 PEM physician members of the American Academy of Pediatrics' Section on Emergency Medicine survey study list-serve in 2020. The survey was designed by the investigators with iterative input from colleagues. Respondents rated, using a 5-point Likert scale, the average performance of 4 age categories of PEM physicians in 9 clinical competencies. Additional items included concerns about colleague's performance and preferences for age of physician managing a critically ill child family member., Results: We received 232 surveys with responses to core initial items (adjusted response rate, 49%). Most respondents were 36 to 49 (34.9%) or 50 to 64 (47.0%) years old. Fifty-three percent reported ever having concern about a colleague's performance. For critical care-related competencies, fewer respondents rated the ≥65-year age group as very good or excellent compared with midcareer physicians (36-49 or 50-64 years old). The ratings for difficult communications with families were better for those 65 years or older than those 35 years or younger. Among 129 of 224 respondents (58%) indicating a preferred age category for a colleague managing a critically ill child relative, most (69%) preferred a 36 to 49-year-old colleague., Conclusions: Pediatric emergency medicine physicians' perceptions of peers' clinical performance demonstrated differences by peer age group. Physicians 65 years or older were perceived to perform less well than those 36 to 64 years old in procedural and multitasking skills. However, senior physicians were perceived as performing as well if not better than younger peers in communication skills. Further study of age-related PEM clinical performance with objective measures is warranted., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Voltage-gated sodium (Na V ) channels are critical regulators of neuronal excitability and are targeted by many toxins that directly interact with the pore-forming α subunit, typically via extracellular loops of the voltage-sensing domains, or residues forming part of the pore domain. Excelsatoxin A (ExTxA), a pain-causing knottin peptide from the Australian stinging tree Dendrocnide excelsa, is the first reported plant-derived Na V channel modulating peptide toxin. Here we show that TMEM233, a member of the dispanin family of transmembrane proteins expressed in sensory neurons, is essential for pharmacological activity of ExTxA at Na V channels, and that co-expression of TMEM233 modulates the gating properties of Na V 1.7. These findings identify TMEM233 as a previously unknown Na V 1.7-interacting protein, position TMEM233 and the dispanins as accessory proteins that are indispensable for toxin-mediated effects on Na V channel gating, and provide important insights into the function of Na V channels in sensory neurons., (© 2023. The Author(s).)

Fibromyalgia is a debilitating widespread chronic pain syndrome that occurs in 2 to 4% of the population. The prevailing view that fibromyalgia results from central nervous system dysfunction has recently been challenged with data showing changes in peripheral nervous system activity. Using a mouse model of chronic widespread pain through hyperalgesic priming of muscle, we show that neutrophils invade sensory ganglia and confer mechanical hypersensitivity on recipient mice, while adoptive transfer of immunoglobulin, serum, lymphocytes, or monocytes has no effect on pain behavior. Neutrophil depletion abolishes the establishment of chronic widespread pain in mice. Neutrophils from patients with fibromyalgia also confer pain on mice. A link between neutrophil-derived mediators and peripheral nerve sensitization is already established. Our observations suggest approaches for targeting fibromyalgia pain via mechanisms that cause altered neutrophil activity and interactions with sensory neurons.

Background and Objectives: Fatal poisoning is a preventable cause of death among young children. Understanding factors surrounding these deaths will inform future prevention efforts. Our objective was to describe the characteristics of fatal pediatric poisonings using child death review data., Methods: We acquired data from 40 states participating in the National Fatality Review-Case Reporting System on deaths attributed to poisonings among children aged ≤5 years from 2005 to 2018. We analyzed select demographic, supervisor, death investigation, and substance-related variables using descriptive statistics., Results: During the study period, 731 poisoning-related fatalities were reported by child death reviews to the National Fatality Review-Case Reporting System. Over two-fifths (42.1%, 308 of 731) occurred among infants aged <1 year, and most fatalities (65.1%, 444 of 682) occurred in the child's home. One-sixth of children (97 of 581) had an open child protective services case at time of death. Nearly one-third (32.2%, 203 of 631) of children were supervised by an individual other than the biological parent. Opioids (47.3%, 346 of 731) were the most common substance contributing to death, followed by over-the-counter pain, cold, and allergy medications (14.8%, 108 of 731). Opioids accounted for 24.1% (7 of 29) of the substances contributing to deaths in 2005 compared with 52.2% (24 of 46) in 2018., Conclusions: Opioids were the most common substances contributing to fatal poisonings among young children. Over-the-counter medications continue to account for pediatric fatalities even after regulatory changes. These data highlight the importance of tailored prevention measures to further reduce fatal child poisonings., (Copyright © 2023 by the American Academy of Pediatrics.)

Objective: Evaluate the positive predictive value of International Classification of Disease, 10th Revision, Clinical Modification (ICD-10-CM) codes in identifying young children diagnosed with physical abuse., Methods: We extracted 230 charts of children <24 months of age who had any emergency department, inpatient, or ambulatory care encounters between Oct 1, 2015 and Sept 30, 2020 coded using ICD-10-CM codes suggestive of physical abuse. Electronic health records were reviewed to determine if physical abuse was considered during the medical encounter and assess the level of diagnostic certainty for physical abuse. Positive predictive value of each ICD-10-CM code was assessed., Results: Of 230 charts with ICD-10 codes concerning for physical abuse, 209 (91%) had documentation that a diagnosis of physical abuse was considered during an encounter. The majority of cases, 138 (60%), were rated as definitely or likely abuse, 36 cases (16%) were indeterminate, and 35 (15%) were likely or definitely accidental injury. Other forms of suspected maltreatment were discussed in 16 (7%) charts and 5 (2%) had no documented concerns for child maltreatment. The positive predictive values of the specific ICD-10 codes for encounters rated as definitely or likely abuse varied considerably, ranging from 0.89 (0.80-0.99) for T74.12 "Adult and child abuse, neglect, and other maltreatment, confirmed" to 0.24 (95% CI: 0.06-0.42) for Z04.72 "Encounter for examination and observation following alleged child physical abuse.", Conclusions: ICD-10-CM codes identify young children who experience physical abuse, but certain codes have a higher positive predictive value than others., (Copyright © 2022 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

Objective: Examine the epidemiology of subspecialty physical abuse evaluations within CAPNET, a multicenter child abuse pediatrics research network., Methods: We conducted a cross-sectional study of children <10 years old who underwent an evaluation (in-person or remote) by a child abuse pediatrician (CAP) due to concerns for physical abuse at ten CAPNET hospital systems from February 2021 through December 2021., Results: Among 3667 patients with 3721 encounters, 69.4% were <3 years old; 44.3% <1 year old, 59.1% male; 27.1% Black; 57.8% White, 17.0% Hispanic; and 71.0 % had public insurance. The highest level of care was outpatient/emergency department in 60.7%, inpatient unit in 28.0% and intensive care in 11.4%. CAPs performed 79.1% in-person consultations and 20.9% remote consultations. Overall, the most frequent injuries were bruises (35.2%), fractures (29.0%), and traumatic brain injuries (TBI) (16.2%). Abdominal (1.2%) and spine injuries (1.6%) were uncommon. TBI was diagnosed in 30.6% of infants but only 8.4% of 1-year old children. In 68.2% of cases a report to child protective services (CPS) was made prior to CAP consultation; in 12.4% a report was made after CAP consultation. CAPs reported no concern for abuse in 43.0% of cases and mild/intermediate concern in 22.3%. Only 14.2% were categorized as definite abuse., Conclusion: Most children in CAPNET were <3 years old with bruises, fractures, or intracranial injuries. CPS reports were frequently made prior to CAP consultation. CAPs had a low level of concern for abuse in majority of cases., (Copyright © 2022 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

Background: Child maltreatment (CM) is a pervasive public health problem and there is a critical need for brief, effective, scalable prevention programs. Problematic parent-child relationships lie at the heart of CM. Parents who maltreat their children are more likely to have punitive parenting styles characterized by high rates of negative interaction and ineffective discipline strategies with over-reliance on punishment. Thus, parenting interventions that strengthen parent-child relationships, teach positive discipline techniques, decrease harsh parenting, and decrease child behavioral problems hold promise as CM prevention strategies. Challenges in engaging parents, particularly low-income and minority parents, and a lack of knowledge regarding effective implementation strategies, however, have greatly limited the reach and impact of parenting interventions. Child Adult Relationship Enhancement in Primary Care (PriCARE)/Criando Niños con CARIÑO is a 6-session group parenting intervention that holds promise in addressing these challenges because PriCARE/CARIÑO was (1) developed and iteratively adapted with input from racially and ethnically diverse families, including low-income families and (2) designed specifically for implementation in primary care with inclusion of strategies to align with usual care workflow to increase uptake and retention., Methods: This study is a multicenter randomized controlled trial with two parallel arms. Children, 2-6 years old with Medicaid/CHIP/no insurance, and their English- and Spanish-speaking caregivers recruited from pediatric primary care clinics in Philadelphia and North Carolina will be enrolled. Caregivers assigned to the intervention regimen will attend PriCARE/CARIÑO and receive usual care. Caregivers assigned to the control regimen will receive usual care only. The primary outcome is occurrence of an investigation for CM by child protective services during the 48 months following completion of the intervention. In addition, scores for CM risk, child behavior problems, harsh and neglectful parenting behaviors, caregiver stress, and caregiver-child interactions will be assessed as secondary outcome measures and for investigation of possible mechanisms of intervention-induced change. We will also identify PriCARE/CARIÑO implementation factors that may be barriers and facilitators to intervention referrals, enrollment, and attendance., Discussion: By evaluating proximal outcomes in addition to the distal outcome of CM, this study, the largest CM prevention trial with individual randomization, will help elucidate mechanisms of change and advance the science of CM prevention. This study will also gather critical information on factors influencing successful implementation and how to optimize intervention referrals, enrollment, and attendance to inform future dissemination and practical applications., Trial Registration: This trial was registered on ClinicalTrials.gov (NCT05233150) on February 1, 2022, prior to enrolling subjects., (© 2023. The Author(s).)

Oxaliplatin is a platinum-based chemotherapeutic agent that causes cold and mechanical allodynia in up to 90% of patients. Silent Nav1.8-positive nociceptive cold sensors have been shown to be unmasked by oxaliplatin, and this event has been causally linked to the development of cold allodynia. We examined the effects of pregabalin on oxaliplatin-evoked unmasking of cold sensitive neurons using mice expressing GCaMP-3 in all sensory neurons. Intravenous injection of pregabalin significantly ameliorates cold allodynia, while decreasing the number of cold sensitive neurons by altering their excitability and temperature thresholds. The silenced neurons are predominantly medium/large mechano-cold sensitive neurons, corresponding to the "silent" cold sensors activated during neuropathy. Deletion of α2δ1 subunits abolished the effects of pregabalin on both cold allodynia and the silencing of sensory neurons. Thus, these results define a novel, peripheral inhibitory effect of pregabalin on the excitability of "silent" cold-sensing neurons in a model of oxaliplatin-dependent cold allodynia., Competing Interests: The authors declare no competing financial interests., (Copyright © 2023 Iseppon et al.)

Personalised and targeted interventions have revolutionised cancer treatment and dramatically improved survival rates in recent decades. Nonetheless, effective pain management remains a problem for patients diagnosed with cancer, who continue to suffer from the painful side effects of cancer itself, as well as treatments for the disease. This problem of cancer pain will continue to grow with an ageing population and the rapid advent of more effective therapeutics to treat the disease. Current pain management guidelines from the World Health Organisation are generalised for different pain severities, but fail to address the heterogeneity of mechanisms in patients with varying cancer types, stages of disease and treatment plans. Pain is the most common complaint leading to emergency unit visits by patients with cancer and over one-third of patients that have been diagnosed with cancer will experience under-treated pain. This review summarises preclinical models of cancer pain states, with a particular focus on cancer-induced bone pain and chemotherapy-associated pain. We provide an overview of how preclinical models can recapitulate aspects of pain and sensory dysfunction that is observed in patients with persistent cancer-induced bone pain or neuropathic pain following chemotherapy. Peripheral and central nervous system mechanisms of cancer pain are discussed, along with key cellular and molecular mediators that have been highlighted in animal models of cancer pain. These include interactions between neuronal cells, cancer cells and non-neuronal cells in the tumour microenvironment. Therapeutic targets beyond opioid-based management are reviewed for the treatment of cancer pain., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Haroun, Wood and Sikandar.)