Notch signalling stabilises boundary formation at the midbrain-hindbrain organiser.

The midbrain-hindbrain interface gives rise to a boundary of particular importance in CNS development as it forms a local signalling centre, the proper functioning of which is essential for the formation of tectum and cerebellum. Positioning of the mid-hindbrain boundary (MHB) within the neuroepithelium is dependent on the interface of Otx2 and Gbx2 expression domains, yet in the absence of either or both of these genes, organiser genes are still expressed, suggesting that other, as yet unknown mechanisms are also involved in MHB establishment. Here, we present evidence for a role for Notch signalling in stabilising cell lineage restriction and regulating organiser gene expression at the MHB. Experimental interference with Notch signalling in the chick embryo disrupts MHB formation, including downregulation of the organiser signal Fgf8. Ectopic activation of Notch signalling in cells of the anterior hindbrain results in an exclusion of those cells from rhombomeres 1 and 2, and in a simultaneous clustering along the anterior and posterior boundaries of this area, suggesting that Notch signalling influences cell sorting. These cells ectopically express the boundary marker Fgf3. In agreement with a role for Notch signalling in cell sorting, anterior hindbrain cells with activated Notch signalling segregate from normal cells in an aggregation assay. Finally, misexpression of the Notch modulator Lfng or the Notch ligand Ser1 across the MHB leads to a shift in boundary position and loss of restriction of Fgf8 to the MHB. We propose that differential Notch signalling stabilises the MHB through regulating cell sorting and specifying boundary cell fate.

Epidemiology of Platelet Transfusions in Hospitalized Children: A Pediatric Hospital Information System Database Study.

OBJECTIVES: To describe the epidemiology and complications of platelet transfusions among hospitalized pediatric patients during 2010 to 2019. METHODS: We performed a retrospective cohort study of hospitalized children within the Pediatric Health Information System database. Pediatric encounters receiving at least one platelet transfusion during hospitalization from 2010 to 2019 were identified. Data regarding demographics, diagnoses, procedures required during hospitalization, complications, and outcomes were extracted for eligible encounters. RESULTS: Within the Pediatric Health Information System database, 6 284 264 hospitalizations occurred from 2010 to 2019. A total of 244 464 hospitalizations required at least one platelet transfusion, yielding a prevalence of 3.89% (95% confidence interval [CI], 3.87%-3.91%). Transfusion prevalence did not change significantly across the decade (P value = .152). Two-thirds of children receiving platelet transfusions were in their first 6 years of life, and the majority identified as male (55%). Recipients most commonly had diseases of the circulatory system (21%, 52 008 of 244 979), perinatal disorders (16%, 38 054 of 244 979), or diseases of the hematologic/immune systems (15%, 37 466 of 244 979). When adjusted for age, support by extracorporeal membrane oxygenation, mechanical ventilation, surgical intervention, and diagnostic category, the odds of thrombosis, infection, and mortality increased by 2% (odds ratio [OR], 1.02; 95% CI, 1.016-1.020), 3% (OR, 1.03; 95% CI, 1.028-1.033), and 7% (OR, 1.07; 95% CI, 1.067-1.071), respectively, with each additional transfusion. CONCLUSIONS: The prevalence of platelet transfusions among pediatric inpatients remained consistent across the decade. Our finding that increasing numbers of transfusions may be associated with elevated morbidity and mortality is consistent with other observation and experimental studies, highlighting the need to be thoughtful in weighing risks and benefits when prescribing repeated platelet transfusions to hospitalized children.

Lrrn1 is required for formation of the midbrain-hindbrain boundary and organiser through regulation of affinity differences between midbrain and hindbrain cells in chick.

The midbrain-hindbrain boundary (MHB) acts as an organiser/signalling centre to pattern tectal and cerebellar compartments. Cells in adjacent compartments must be distinct from each other for boundary formation to occur at the interface. Here we have identified the leucine-rich repeat (LRR) neuronal 1 (Lrrn1) protein as a key regulator of this process in chick. The Lrrn family is orthologous to the Drosophila tartan/capricious (trn/caps) family. Differential expression of trn/caps promotes an affinity difference and boundary formation between adjacent compartments in a number of contexts; for example, in the wing, leg and eye imaginal discs. Here we show that Lrrn1 is expressed in midbrain cells but not in anterior hindbrain cells. Lrrn1 is down-regulated in the anterior hindbrain by the organiser signalling molecule FGF8, thereby creating a differential affinity between these two compartments. Lrrn1 is required for the formation of MHB--loss of function leads to a loss of the morphological constriction and loss of Fgf8. Cells overexpressing Lrrn1 violate the boundary and result in a loss of cell restriction between midbrain and hindbrain compartments. Lrrn1 also regulates the glycosyltransferase Lunatic Fringe, a modulator of Notch signalling, maintaining its expression in midbrain cells which is instrumental in MHB boundary formation. Thus, Lrrn1 provides a link between cell affinity/compartment segregation, and cell signalling to specify boundary cell fate.

Learned temporal statistics guide information seeking and shape memory.

Curiosity drives information seeking and promotes learning. Prior work has focused on how curiosity is elicited by intrinsic qualities of information, leaving open questions about how curiosity, exploration, and learning are shaped by the environment. Here we examine how temporal dynamics of the learning environment shape curiosity and learning. Participants (n = 71) foraged for the answer to trivia questions in two conditions that differed only in their temporal statistics. In one condition, the timing of information delivery followed a uniform distribution, while in another it followed a heavy-tailed distribution. We found that the two conditions elicited distinct responses in both behavior and pupil dilation: participants were more likely to wait for information and to later remember it in the uniform distribution. By contrast, participants showed greater surprise, evidenced in a spike in pupil dilation, when presented with the answers in the heavy-tailed distribution. Furthermore, pupil dilation was inversely related to curiosity and memory, suggesting that temporal uncertainty may interfere with the positive effects of curiosity on learning. Our findings demonstrate that the predicted timing of information delivery influences information seeking, memory, and physiological arousal, suggesting that information is best learned when it is both intrinsically interesting and presented within a temporally predictable environment. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

A Conceptual Model of Biopsychosocial Mechanisms of Transition from Acute to Chronic Postsurgical Pain in Children and Adolescents.

Acute and chronic pain are highly prevalent and impactful consequences of surgery across the lifespan, yet a comprehensive conceptual model encompassing biopsychosocial factors underlying acute to chronic pain transition is lacking, particularly in youth. Building on prior chronic postsurgical pain models, we propose a new conceptual model of biopsychosocial mechanisms of transition from acute to chronic postsurgical pain. This review aims to summarize existing research examining key factors underlying acute to chronic postsurgical pain transition in order to guide prevention and intervention efforts aimed at addressing this health issue in children. As pain transitions from acute nociceptive pain to chronic pain, changes in the peripheral and central nervous system contribute to the chronification of pain after surgery. These changes include alterations in sensory pain processing and psychosocial processes (psychological, behavioral, and social components), which promote the development of chronic pain. Patient-related premorbid factors (eg, demographic factors, genetic profile, and medical factors such as premorbid pain) may further modulate these changes. Factors related to acute injury and recovery (eg, surgical and treatment factors), as well as biological response to surgery (eg, epigenetic, inflammatory, and endocrine factors), may also influence this process. Overall, longitudinal studies examining temporal pathways of biopsychosocial processes including both risk and resiliency factors will be essential to identify the mechanisms involved in the transition from acute to chronic pain. Research is also needed to unravel connections between the acute pain experience, opioid exposure, and sensory pain processing during acute to chronic pain transition. Furthermore, future studies should include larger and more diverse samples to more fully explore risk factors in a broader range of pediatric surgeries. The use of conceptual models to guide intervention approaches targeting mechanisms of transition from acute to chronic pain will significantly advance this field and improve outcomes for children and adolescents undergoing surgery.

Components of Effective Cognitive-Behavioral Therapy for Pediatric Headache: A Mixed Methods Approach.

Internet-delivered treatment has the potential to expand access to evidence-based cognitive-behavioral therapy (CBT) for pediatric headache, and has demonstrated efficacy in small trials for some youth with headache. We used a mixed methods approach to identify effective components of CBT for this population. In Study 1, component profile analysis identified common interventions delivered in published RCTs of effective CBT protocols for pediatric headache delivered face-to-face or via the Internet. We identified a core set of three treatment components that were common across face-to-face and Internet protocols: 1) headache education, 2) relaxation training, and 3) cognitive interventions. Biofeedback was identified as an additional core treatment component delivered in face-to-face protocols only. In Study 2, we conducted qualitative interviews to describe the perspectives of youth with headache and their parents on successful components of an Internet CBT intervention. Eleven themes emerged from the qualitative data analysis, which broadly focused on patient experiences using the treatment components and suggestions for new treatment components. In the Discussion, these mixed methods findings are integrated to inform the adaptation of an Internet CBT protocol for youth with headache.

Long-Term Pain and Recovery After Major Pediatric Surgery: A Qualitative Study With Teens, Parents, and Perioperative Care Providers.

Research developing targeted treatment focused on coping with children's long-term pain after surgery is needed because of the high prevalence of chronic pain after surgery. This qualitative study aimed to: 1) understand the child's and family's experiences of pain over the course of their surgical experience, and 2) gather stakeholder input regarding potential barriers and facilitators of perioperative intervention delivery. Fifteen children ages 10 to 18 years who underwent recent major surgery, their primary caregivers, and 17 perioperative health care providers were interviewed. Interviews were coded using semantic thematic analysis. The perioperative period presented emotional challenges for families. Families felt unprepared for surgery and pain. Recovery and regaining physical functioning at home was challenging. Families struggled to return to valued activities. Families reported interest in a perioperative psychosocial intervention. Providers endorsed that families would benefit from enhanced coping skills. They emphasized that families would benefit from more detailed preparatory information. Providers suggested that flexible intervention delivery at home would be ideal. Research developing interventions addressing pain and anxiety in children undergoing major surgery is critically needed. The findings of the present study can inform intervention development with the aim of improving short- as well as long-term recovery in children undergoing major surgery. PERSPECTIVE: This qualitative study examined children and their parents' experience of long-term pain and recovery after major surgery, identifying barriers and facilitators of perioperative intervention delivery. Families experienced surgery as stressful, and felt underprepared for pain and recovery. Families and health care providers expressed interest in a preoperative intervention teaching coping skills.

Follistatin regulates bone morphogenetic protein-7 (BMP-7) activity to stimulate embryonic muscle growth.

Bone morphogenetic proteins (BMPs) can either promote growth of embryonic muscle by expanding the Pax-3-expressing muscle precursor population or restrict its development by inducing apoptosis. Follistatin, a proposed BMP antagonist, is expressed in embryonic muscle. Deficiency in Follistatin results in muscle defects and postnatal asphyxia. Here, we report that during chick limb development Follistatin enhances BMP-7 action to induce muscle growth but prevents the ability of BMP-7 to induce apoptosis and muscle loss. Follistatin, unlike another BMP-binding protein, Noggin, promotes Pax-3 expression and transiently delays muscle differentiation and thus exerts proliferative signalling during muscle development. We provide data which show that Follistatin binds BMP-7 and BMP-2 at low affinities and that the binding is reversible. These data suggest that Follistatin acts to present BMPs to myogenic cells at a concentration that permits stimulation of embryonic muscle growth.