Behavioral Milestones Research Articles

Neurodevelopmental timing and socio-cognitive development in a prosocial cooperatively breeding primate (Callithrix jacchus).

Primate brain development is shaped by inputs received during critical periods. These inputs differ between independent and cooperative breeders: In cooperative breeders, infants interact with multiple caregivers. We study how the neurodevelopmental timing of the cooperatively breeding common marmoset maps onto behavioral milestones. To obtain structure-function co-constructions, we combine behavioral, neuroimaging (anatomical and functional), and neural tracing experiments. We find that brain areas critically involved in observing conspecifics interacting (i) develop in clusters, (ii) have prolonged developmental trajectories, (iii) differentiate during the period of negotiations between immatures and multiple caregivers, and (iv) do not share stronger connectivity than with other regions. Overall, developmental timing of social brain areas correlates with social and behavioral milestones in marmosets and, as in humans, extends into adulthood. This rich social input is likely critical for the emergence of their strong socio-cognitive skills. Because humans are cooperative breeders too, these findings have strong implications for the evolution of human social cognition.

Evaluating the Verbal Behavior Milestones Assessment and Placement Program (VB-MAPP) Scores Using Principal Components Analysis.

Introduction TheVerbal Behavior Milestones Assessment and Placement Program (VB-MAPP)is an extensive tool used to assess children with autism and other developmental disabilities who have language delays. Applied behavior analysis (ABA) professionals frequently use the VB-MAPP to create personalized intervention programs catering to each child's needs. The lack of studies examining the VB-MAPPat the pretest, posttest, and differential scores using principal components analysis (PCA) suggests an opportunity to conduct PCAs on these different VB-MAPP scores. In doing so, researchers could better understand the VB-MAPP's dimensionality and factor structure at these levels. This, in turn, could inform the development of more effective assessment strategies and intervention plans for individuals with language and social communication challenges. Materials and methods From January 2018 to July 2021, The Oxford Centerin Brighton and Troy, Michigan, treated autistic children using ABAtherapy. A convenience sample of 13 children was retrospectively analyzed using VB-MAPP, which evaluates various behavioral milestones using a pretest-posttest design. Descriptive data analysis and internal consistency reliability estimates (using Cronbach's alpha) were calculated for pretest, posttest, and difference scores. A Wilcoxen signed-rank test was conducted to determine the statistical significance between thepretest and posttest. Correlation matrices were inspected for relevant relationships between VB-MAPP scales, and a PCAwith orthogonal rotation was alsoperformed on this pretest, posttest, and difference scores. Results The mean age for the children was 4.083 years ± 1.083 years, (95%CI 3.64, 4.36). Around 66.6% of the children had an autism severity level of three, 33.3% had a severity level of two, and none were at level one. Cronbach's alpha for internal consistency reliability of the pretest, posttest, and difference scores, indicating excellent reliability with values of 0.948 for the pretest and 0.937 for theposttest, respectively. The difference scores had a lower but acceptable reliability coefficient of 0.752. PCAon the pretest scores identified three factors that explain85.584% of the total variation, indicating that these components capture most of the data's structure. The posttest PCA also identified three factors, accounting for 84.293% of the variance, suggesting a similar complexity and good model fit as the pretest. PCA revealed four factors explaining 82.317% of the variation for the difference scores. The increase in factors suggests that changes between pretest and posttest scores are complex, likely due to the ABA treatment, and require an additional component to represent the data adequately. There is a good model fit; the underlying structure is more complex than the pretest or posttest alone. Conclusions Robust coefficient alphas combined with the shift to a more detailed factor structure post-ABA treatment highlight ABA therapy's diverse and multi-faceted impact on children. The increase from three to four principal components indicates a richer and more nuanced pattern of improvements across different domains of verbal and social behavior. This detailed factor structure is a testament to the comprehensive and individualized nature of ABA treatment, reflecting the therapy's effectiveness in addressing specific needs and fostering broad developmental gains in children.

Children's syntax is supported by the maturation of BA44 at 4years, but of the posterior STS at 3years of age.

Within the first years of life, children learn major aspects of their native language. However, the ability to process complex sentence structures, a core faculty in human language called syntax, emerges only slowly. A milestone in syntax acquisition is reached around the age of 4years, when children learn a variety of syntactic concepts. Here, we ask which maturational changes in the child's brain underlie the emergence of syntactically complex sentence processing around this critical age. We relate markers of cortical brain maturation to 3- and 4-year-olds' sentence processing in contrast to other language abilities. Our results show that distinct cortical brain areas support sentence processing in the two age groups. Sentence production abilities at 3years were associated with increased surface area in the most posterior part of the left superior temporal sulcus, whereas 4-year-olds showed an association with cortical thickness in the left posterior part of Broca's area, i.e. BA44. The present findings suggest that sentence processing abilities rely on the maturation of distinct cortical regions in 3- compared to 4-year-olds. The observed shift to more mature regions involved in processing syntactically complex sentences may underlie behavioral milestones in syntax acquisition at around 4years.

The impact of a mobile application on parental attitudes, their knowledge of child development, and sense of parenting self-competence: A pilot study

BackgroundParenting apps have become increasingly used in parents’ everyday life. This growth offers the possibility for simple, low-cost parenting interventions to a wide range of populations. These apps may contribute to a decrease in social inequality as they promote access to information and health. The content provided by these apps varies from prevention messages and parenting tips to more specific parental guidance and activity suggestions. However, few studies have examined their effect on parenting competence and attitudes. The French Gazouyi app aims to promote parenting skills and to provide parents with the means to play in a positive way with their child. ObjectiveThe aim of this study was to examine, over a period of 3 months, the acceptability, the relevance, and the impact of the use of a digital application by parents of young children aged from birth to 2 years of age. The app proposes developmentally appropriate play activities developed by professionals. Materials and methodsIn all, 137 participants were recruited and randomly assigned to an intervention group (n=60) and a control group (n=77). Both groups completed the EPAQ, the QAECEP and the KIDI questionnaires at the beginning of the study (T1) and again three months later (T2). EPAQ is designed to evaluate parental awaremess and attitudes about parenthood and child development. The QAECEP measures the parenting sense of competence. The KIDI assesses practical knowledge of parenting styles, early development processes, and behavioral milestones. The intervention group was asked to perform four activities per week on Gazouyi. The app offers different types of play activities in four aspects of child development: language, motor, sensory and social. ResultsOverall, no significant differences between the two groups were found. Between T1 and T2, both the intervention and the control group had a significant increase in the QAECEP score. At both assessment points, the number of correct responses to the KIDI and the EPAQ score was high in both groups. However, significant links between scores of parenting competence and some sociodemographic factors were observed. Regression analyses showed that, for frequent users, high scores on the EPAQ were positively predicted for at-term delivery and female children. For infrequent users, high scores on the QAECEP were positively predicted for at-term delivery, infants’ growth, and the level of the fathers’ education. Correct answers on the KIDI were positively predicted for low household incomes, female children, at-term delivery, and nursery childcare. ConclusionsAs the first French study to assess the impact of a parenting app and despite its several shortcomings, this study demonstrated that French parents have a strong interest in apps and digital sources of information that may potentially help them in their role as parents. However, further studies should be conducted to improve these apps, to know how parents use them, what effects this type of device can produce, and what improvements could be made.

Effectiveness of Self-Instructional Module on Knowledge Regarding Selected Habit Disorders in Children among Mothers of Preschooler

Background: A child is unique individual. The childhood era is critical for the socialization process, which involves the transmission of attitudes, customs, and behaviour through the influence of family and community. The promotion and maintenance of a child's health is influenced by the family's cultural and religious beliefs, educational level, and lifestyle. Improved child health requires better education, nutrition, family planning, improved health behaviour, and increased use of health services. The form of the caregiver interaction has a significant impact on a child's behavioural development. Parents, especially women, who are emotionally present, sensitive, perceptive, and effective in satisfying their child's needs are more likely to have securely connected children who are more likely to meet crucial behavioral milestones as they grow up.
 Objectives: 
 
 To assess the existing knowledge regarding selected habit disorders in children among mothers of preschooler.
 To assess the effectiveness of self-instructional module on knowledge regarding selected habit disorders in children among mothers of preschooler.
 To determine the posttest knowledge score regarding selected habit disorder in children among mothers of preschooler with demographic variables.
 
 Methodology: A study will be based on Evaluatory research approach with one group pretest and posttest research design. The impact of self instructional module on knowledge regarding selected habit disorders in children among mothers of preschooler will be assessed using non probability convenient sampling technique. selected 60 mothers of preschooler will be assessed knowledge regarding selected habit disorder in children by structured questionnaires and then self instructional module will be given to the selected sample developed by researcher as intervention.
 Expected Results: The aim of this study is to assess the effectiveness of self-instructional module on knowledge regarding selected habit disorders in children among mothers of preschooler. Self instructional module will be useful in improving the respondents' knowledge.

Neonatal Outcomes after Uterus Transplantation: Dallas Uterus Transplant Study.

Limited data are available on the outcome of infants born after uterus transplantation. Our aim was to describe the hospital course and laboratory findings in the first 2 months of life of the 12 infants born in the Dallas UtErus Transplant Study (DUETS). Based on the trial protocol, information about infants was collected in a prospective fashion, including infant demographics, hospital course, and laboratory values. Twelve infants were delivered, all by cesarean section, from 11 mothers who had undergone uterus transplantation (one mother had two pregnancies and delivered two babies). All pregnancies were singleton. The mothers received immunosuppressive therapy, and one had a rejection episode that was detected during pregnancy. The rejection episode resolved after steroid treatment. The infants had a median gestational age of 366/7 weeks (range: 306/7-380/7 weeks) and median birth weight of 2,920 g (range: 1,770-3,470 g). The lowest Apgar's score at 5 minutes was 8. All infants were appropriate size for gestational age. Two infants presented with bandemia but negative blood cultures. At 2 months of age, all infants achieved the developmental and behavioral milestones outlined by the American Academy of Pediatrics. The 12 infants born from mothers with uterus transplants had a neonatal course that reflected the gestational age at delivery. No baby was born with an identified malformation or organ dysfunction. Longer follow-up and a larger number of infants are needed to confirm these observations. · Normal fetal development after uterus transplantation.. · No baby was born with malformations or showed any organ dysfunction.. · At 2 months, all infants achieved appropriate developmental and behavioral milestones..

596: Ethyl pyruvate: A novel approach to protect the fetus against antenatal inflammatory damage

In pregnancies complicated by inflammation, activation of RAGE signaling pathways may be responsible for poor fetal and neonatal outcomes including stillbirth and neonatal brain injury. Ethyl pyruvate (EP) improved survival in murine models of endotoxemia via RAGE inhibition, and was already shown to be safe in humans. We investigated the effect of maternal administration of EP on neonatal growth and neurodevelopmental outcome using a genetically engineered over-expressing RAGETg murine model of in-utero inflammation. Saline or endotoxin (LPS, 5 or 10 μg/dam) were given intra-peritoneal (i.p.) on day 15 (d0=sperm plug), in mice randomly assigned to the following groups: 1) RAGETg and 2) Wild-type (WT) (n=9-30 pups/group) as controls. EP (40 mg/kg) was administered i.p. 2 hours later. Doses were chosen based on prior experiments demonstrating live birth. Pups underwent post-natal daily behavioral testing (i.e. cliff aversion, forelimb grasp, negative geotaxis) from birth to day 14 of life. Using immunohistochemistry (IHC), we assessed cortical neuronal density in animals sacrificed on day 20 of life. 1) In-utero exposure to EP did not increase post-natal mortality rate; 2) Compared to control, weight gain was inhibited in WT receiving LPS5 (p=0.02), which was ameliorated by EP (p=0.0001); 3) WT and RAGETg mice exposed to LPS demonstrated delay in achieving behavioral milestones, an effect reversed by EP (p<0.001, Figure); 4) WT and RAGETg mice showed improved neurobehavioral battery with EP independent of fetal gender; 5) EP protected against LPS-induced cortical neuronal loss (p=0.001) by IHC. We report a novel neuroprotective effect of EP from perinatal inflammatory insult.

VITAL SIGNS AND FIRST OCCURRENCES IN NORMAL AND ABNORMAL NEWBORN ASIAN ELEPHANT ( ELEPHAS MAXIMUS) CALVES.

Sixteen years of medical records documenting 19 births within a herd of Asian elephants ( Elephas maximus) at a private facility in the southeastern United States were reviewed. Of the 19 calves, 11 were normal at birth, requiring no additional veterinary care, and eight were abnormal, requiring veterinary care immediately or within the first week of birth. Descriptive statistics were used to evaluate morphometrics, vital signs, and behavioral milestones in newborn calves both normal and abnormal. Blood work and urinalysis results from all calves were compared to values for adult elephants. Medical management of abnormal calves is described. All calves had faster heart rates and respiratory rates than did adult elephants, but rectal temperatures were the same. Calves were precocious with regard to sitting and standing but could be very slow to nurse. The most-common medical conditions of newborn calves were umbilical abnormalities and problems associated with nursing. Two calves required cardiopulmonary resuscitation after birth but made full recoveries. Some conditions were not apparent at birth but were recognized a few hours or days later. Following veterinary intervention, six of the eight calves made full recoveries, suggesting that early identification and treatment of problems can greatly decrease mortality. This is the first report of multiple veterinary and behavioral parameters in normal and abnormal neonatal Asian elephants from a facility with a calf survival rate above 90%. This information may be helpful to other elephant-holding facilities in providing care to their newborn elephant calves.

Electrocorticography and the early maturation of high-frequency suppression within the default mode network.

OBJECTIVE The acquisition and refinement of cognitive and behavioral skills during development is associated with the maturation of various brain oscillatory activities. Most developmental investigations have identified distinct patterns of low-frequency electrophysiological activity that are characteristic of various behavioral milestones. In this investigation, the authors focused on the cross-sectional developmental properties of high-frequency spectral power from the brain's default mode network (DMN) during goal-directed behavior. METHODS The authors contrasted regionally specific, time-evolving high gamma power (HGP) in the lateral DMN cortex between 3 young children (age range 3-6 years) and 3 adults by use of electrocorticography (ECoG) recordings over the left perisylvian cortex during a picture-naming task. RESULTS Across all participants, a nearly identical and consistent response suppression of HGP, which is a functional signature of the DMN, was observed during task performance recordings acquired from ECoG electrodes placed over the lateral DMN cortex. This finding provides evidence of relatively early maturation of the DMN. Furthermore, only HGP relative to evoked alpha and beta band power showed this level of consistency across all participants. CONCLUSIONS Regionally specific, task-evoked suppression of the high-frequency components of the cortical power spectrum is established early in brain development, and this response may reflect the early maturation of specific cognitive and/or computational mechanisms.

The Perils and Pitfalls of Potty Training.

Although a child may meet the physiologic, developmental, and behavioral milestones required for potty training, the process of potty training remains a formidable task for many parents and toddlers. The primary care physician must be prepared to discuss the signs of readiness as well as the setbacks that may occur in the process of potty training, which include resistance to training, fears of toileting, stool toileting refusal, accidents, and persistent nocturnal enuresis. [Pediatr Ann. 2016;45(6):e199-e201.].

Establishing a Professionalism Score in an Osteopathic Manipulative Medicine Curriculum.

As osteopathic medical education shifts to competency-based learning, course curriculums must adapt to measure behavioral milestones in addition to traditional knowledge and technical skills. Of the core competencies, medical professionalism or lack thereof has been shown to correlate with future state disciplinary board action; therefore, early identification of poor professionalism and intervention is imperative. However, performance indicators, such as humanistic behavior and primacy of patient need, are difficult to measure in most first- and second-year medical school courses. Therefore, A.T. Still University-Kirksville College of Osteopathic Medicine developed a rubric to objectively measure professionalism within the first- and second-year osteopathic manipulative medicine curriculum. The rubric assesses such measures as timeliness and professional appearance. In the present article, the author describes the grading rubric and the methods for implementing a professionalism score within an osteopathic manipulative medicine curriculum.

Orthotopic murine model of a primary malignant bone tumor in the spine: functional, bioluminescence, and histological correlations.

There is currently no reproducible animal model of human primary malignant bone tumors in the spine to permit laboratory investigation of the human disease. Therefore, the authors sought to adapt their previously developed orthotopic model of spinal metastasis to a model for primary malignant bone tumors of the spine. A transperitoneal surgical approach was used to implant osteosarcoma (Krib-1) into the L-3 vertebral body of nude mice via a drill hole. Motor function was evaluated daily using the previously validated qualitative key milestones of tail dragging, dorsal stepping, hindlimb sweeping, and paralysis. A subset of these animals was euthanized upon reaching the various milestones, and the spines were removed, sectioned, and stained. The degree of spinal cord compression was correlated with the occurrence of milestones and assessed by a ratio between the neural elements divided by the area of the spinal canal. Another subset of animals received stably transfected Krib-1 cells with the luciferase gene, and bioluminescence was measured at 10, 20, and 30 days postimplantation. Osteosarcoma xenografts grew in all animals according to a reliable and reproducible time course; the mean time for development of behavioral milestones was noted in relation to the day of implantation (Day 1). Tail dragging (Milestone 1) occurred on Day 19.06 (95% CI 16.11-22.01), dorsal stepping (Milestone 2) occurred on Day 28.78 (95% CI 26.79-30.77), hindlimb sweeping (Milestone 3) occurred on Day 35.61 (95% CI 32.9-38.32), and paralysis of the hindlimb (Milestone 4) occurred on Day 41.78 (95% CI 39.31-44.25). These clinically observed milestones correlated with increasing compression of the spinal cord on histological sections. The authors observed a progressive increase in the local bioluminescence (in photons/cm²/sec) of the implanted level over time with a mean of 2.17 (range 0.0-8.61) at Day 10, mean 4.68 (range 1.17-8.52) at Day 20, and mean 5.54 (range 1.22-9.99) at Day 30. The authors have developed the first orthotopic murine model of a primary malignant bone tumor in the spine, in which neurological decline reproducibly correlates with tumor progression as evidenced by pathological confirmation and noninvasive bioluminescence measurements. Although developed for osteosarcoma, this model can be expanded to study other types of primary malignant bone tumors in the spine. This model will potentially allow animal testing of targeted therapies against specific primary malignant tumor types.

Preparing residents in training to become health-care leaders: a pilot project.

The aim of this study is to describe a successful and exportable training module that addresses Next Accreditation System (NAS) behavioral milestones for leadership competencies. A novel leadership training module, which required the creation of original business plans by teams of residents, was incorporated into a psychiatry PGY-2 training curriculum. In the creation and presentation of their business plans, the residents demonstrated competencies in the NAS functional domains of interpersonal and communication skills, professionalism, practice-based learning and improvement, and systems-based practice. Residents who responded with feedback after completing the course were very positive about their experience. The leadership training module described here allowed residents to acquire and demonstrate many of the competencies specified in leadership-oriented NAS milestones. The module did not require additional funding or a formal rotation or "track," is scalable to accommodate any number of residents and can be modified based on available local teaching resources.

Marking the path forward with milestones.

In this issue of Pediatrics Schumacher et al1 provide an analysis of the resource domains needed to implement the Pediatrics Milestones into residency training. While noting the promise of Pediatrics Milestones “for developing a valid . . . way to track residents’ development and provide a roadmap for their learning,” the authors question the ability of training programs to marshal necessary resources. Faculty raise similar concerns with variants of the following questions: Why change (from the current training and assessment system)? What is the evidence (that milestone assessment works)? and What can be done to increase efficiencies and limit unnecessary costs?Even if there were no regulatory mandate for milestones from the Accreditation Council for Graduate Medical Education, adhering to the old apprentice training and assessment model has been superseded by a host of external forces including societal insistence on patient safety and improved health outcomes.2 A learner-centered approach to training and assessment (competency-based medical education [CBME]), predicated on the needs of the populations served, has been the response to these forces. This approach allows faculty and residents to jointly assess the resident’s progress toward specific behavioral milestones on the road toward mastery.3,4Milestone implementation will require incremental resources, but the current system also has costs, albeit less visible ones borne by trainees who receive inaccurate feedback5 and patients who experience substandard care associated with deficits in residency training.6 The ultimate perspective on costs is a societal one, where the current investment in medical education of a mere 0.3% of total health expenditures may be insufficient to produce desired outcomes.7“Where is the evidence that CBME produces better doctors?” There are 2 major barriers to answering this question: a limited number of assessment tools with the validity evidence to make accurate judgments about trainee performance and learner outcomes and an inability to link educational outcomes to patient care outcomes. But research in this area is already underway. A small pediatrics pilot study has demonstrated the feasibility and utility of strategies and tools to assess milestones.8,9 Larger-scale studies of competencies and milestones are in the planning phase and will begin from a position of equipoise and a commitment to methodological rigor to develop tools with the validity evidence to determine whether milestones improve educational outcomes for learners. Data Commons (http://mydatacommons.org/), a consortium of some major medical education and certifying organizations, is creating an information technology hub that could link deidentified educational and patient care outcome data.Designing assessment tools and strategies across the educational continuum allows for efficiencies of scale. Medical school faculty can focus on the same core competencies for students and residents by using assessment tools that are generalizable to both. Similarly, trainees who have been exposed to real-time competency assessments in medical school should adapt readily to CBME in residency.Faculty development can be targeted to the needs of the faculty. Although all teaching faculty need basic direct observation skills, a small cadre will need the expertise to lead others in assessment. The latter group needs financial support and academic recognition independent of the Milestone Project. Medical education has become a subspecialty that requires a body of knowledge and skill beyond the generalist. Acknowledgment of this expertise is overdue.The data management systems and assessment tools, particularly those providing information needed for high-stakes decisions, should be developed as part of a collaborative effort, thus sparing each individual program from having to repeat what others have done. The American Board of Pediatrics will work with others to advance that objective. We support the other proposed solutions,1 namely handheld devices at the point of care, relational database support of a residency management system that synthesizes information from an array of tools, and the ability of this system to generate formative reports for learners as well as evidence of learner and program progress for institutions and regulatory bodies.We also agree with Schumacher et al1 that all regulatory bodies involved in resident education should collaborate to help programs avoid duplication of effort, make data submission easier, and satisfy multiple regulatory requirements with the single submission of 1 data set. Isolated discussions have begun between regulatory bodies, but it is time for a full-scale summit to target a systematic approach toward reduction of administrative burdens for residency training programs.Schumacher et al1 have advanced resident education by articulating the extensive resources necessary to fully implement the Pediatrics Milestones. The old assessment system is inadequate. The new one is untested. But, as in the past, a concerted effort by all invested in training future physicians can overcome the challenges for the benefit of trainees and their future patients.10

Experimental Modelling of the Consequences of Brief Late Gestation Asphyxia on Newborn Lamb Behaviour and Brain Structure

Brief but severe asphyxia in late gestation or at the time of birth may lead to neonatal hypoxic ischemic encephalopathy and is associated with long-term neurodevelopmental impairment. We undertook this study to examine the consequences of transient in utero asphyxia in late gestation fetal sheep, on the newborn lamb after birth. Surgery was undertaken at 125 days gestation for implantation of fetal catheters and placement of a silastic cuff around the umbilical cord. At 132 days gestation (0.89 term), the cuff was inflated to induce umbilical cord occlusion (UCO), or sham (control). Fetal arterial blood samples were collected for assessment of fetal wellbeing and the pregnancy continued until birth. At birth, behavioral milestones for newborn lambs were recorded over 24 h, after which the lambs were euthanased for brain collection and histopathology assessments. After birth, UCO lambs displayed significant latencies to (i) use all four legs, (ii) attain a standing position, (iii) find the udder, and (iv) successfully suckle - compared to control lambs. Brains of UCO lambs showed widespread pathologies including cell death, white matter disruption, intra-parenchymal hemorrhage and inflammation, which were not observed in full term control brains. UCO resulted in some preterm births, but comparison with age-matched preterm non-UCO control lambs showed that prematurity per se was not responsible for the behavioral delays and brain structural abnormalities resulting from the in utero asphyxia. These results demonstrate that a single, brief fetal asphyxic episode in late gestation results in significant grey and white matter disruption in the developing brain, and causes significant behavioral delay in newborn lambs. These data are consistent with clinical observations that antenatal asphyxia is causal in the development of neonatal encephalopathy and provide an experimental model to advance our understanding of neuroprotective therapies.

Modeling Transformations of Neurodevelopmental Sequences across Mammalian Species

A general model of neural development is derived to fit 18 mammalian species, including humans, macaques, several rodent species, and six metatherian (marsupial) mammals. The goal of this work is to describe heterochronic changes in brain evolution within its basic developmental allometry, and provide an empirical basis to recognize equivalent maturational states across animals. The empirical data generating the model comprises 271 developmental events, including measures of initial neurogenesis, axon extension, establishment, and refinement of connectivity, as well as later events such as myelin formation, growth of brain volume, and early behavioral milestones, to the third year of human postnatal life. The progress of neural events across species is sufficiently predictable that a single model can be used to predict the timing of all events in all species, with a correlation of modeled values to empirical data of 0.9929. Each species' rate of progress through the event scale, described by a regression equation predicting duration of development in days, is highly correlated with adult brain size. Neural heterochrony can be seen in selective delay of retinogenesis in the cat, associated with greater numbers of rods in its retina, and delay of corticogenesis in all species but rodents and the rabbit, associated with relatively larger cortices in species with delay. Unexpectedly, precocial mammals (those unusually mature at birth) delay the onset of first neurogenesis but then progress rapidly through remaining developmental events.

Matched Exome Sequencing in Mothers and Infants with MLL-Negative Acute Leukemia

Abstract 536 Introduction:Infant leukemia (IL) is an extremely rare, sporadic, but often fatal, form of cancer that is defined as leukemia occurring within the first year of life. Unlike leukemia in older children where survival rates for acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) are approximately 70% and 85%, respectively, infants have a survival rate of ∼50%. Unfortunately, despite years of research and clinical trials, overall survival for IL hasn’t improved substantially since the advent of hematopoietic stem cell transplantation, and those infants that survive are often left with lifelong deficits in cognition, development, end organ function, behavioral milestones and/or other complications due to the intensity of treatment (Pui, NEJM 2003; Chow, J Pediatr 2007). The incidence rate of IL is increasing (Linabery, Cancer 2008) in the US, but cannot be attributed to chromosomal anomalies (Uckun, Blood 1998), environmental exposures (Ross, Epidemiol Rev 1994), or highly penetrant genetic polymorphisms alone. Clearly, a critical component of IL pathophysiology remains undiscovered. Rare variation has been implicated in a host of complex phenotypes and diseases, but the impact of rare germline variants on the etiology and outcome of IL has not been fully explored. The Rare Variant Hypothesis predicts that a population of affected individuals would harbor a diverse collection of functionally significant variants in genes involved in etiologically relevant pathways. Given this model, we hypothesize that the onset of IL requires heritable deleterious germline variants, which act alone or in combination with somatic mutations to induce leukemic transformation. Methods:To explore this possibility, we completed a pilot exome sequencing project on 25 pairs of germline DNA from mothers and their infants with MLL-negative IL collected from the Children’s Oncology Group (COG) AE24 “Epidemiology of Infant Leukemia” study. Twelve infants had ALL, 13 had AML and none of the mothers had cancer. We asked if a) infants harbored rare or novel deleterious germline variants in known leukemia genes, b) these variants were inherited from mothers and c) the genes affected by these germline variants fell in common pathways or share common regulatory mechanisms. Results:We found an average of 16,056 variants per exome with an average of 3,082 (19.2%) being novel. Comparing these results to the COSMIC database (http://www.sanger.ac.uk/genetics/CGP/cosmic/), infants with AML had novel, non-synonymous, deleterious germline variants in 82 genes associated with hematologic malignancies, infants with ALL had similar variants in 64 genes, and 42 additional genes (40%) overlapped between ALL or AML. For infants with ALL, 45% of these variants were inherited from healthy mothers compared to only 23% in AML infants. Presumably, the remaining variants were inherited from fathers, but without paternal DNA, we cannot exclude de novo germline mutation, although such mutations are exceedingly rare and would only account for a few non-maternal variants. We used the g:Profiler (http://biit.cs.ut.ee/gprofiler/) algorithm to determine if any of these genes acted in common leukemia-related pathways or shared regulatory mechanisms. We found that many candidate genes were regulated by microRNAs (MIR) previously implicated in cancer, including MIR10a, MIR29c, MIR291b-3p, MIR369-5p, MIR469, MIR519a, MIR721. Five MIRs have been associated with leukemia, four with acute leukemia. Two MIRs, 291b-3p and 721, are also associated with embryonic stem cell cycle regulation and apoptosis, respectively. Ongoing work is focusing on additional exome sequencing, epidemiologic analysis and in vitro functional studies. Conclusion:It is clear that the incidence, clinical behavior and outcomes of IL cannot be explained fully through either environmental exposures or somatic mutations alone. We are leveraging the largest epidemiologic study of IL to date to explore the intersection of functional congenital genetic variation, clinical outcomes and maternal prenatal/pregnancy exposures to augment our understanding of IL. A better understanding of the natural history of IL will aid in future recommendations for pre- and post-natal genetic diagnostics, risk stratification of affected infants and ultimately therapeutic decisions. Disclosures:No relevant conflicts of interest to declare.

How Do I Code for Black Fingernail Polish? Finding the Missing Adolescent in Managed Mental Health Care

AbstractIn this article, I examine clinical dilemmas in treating adolescents with eating disorders under theU.S. managed healthcare system. Managed care is built on a rational choice model of human behavior with little room for considering developmental processes. In this model, adolescents figure as little more than failed adults. This poses significant problems: if treatment providers prioritize developmental issues over quantifiable behavioral milestones, they risk jeopardizing continued coverage for their clients. If they prioritize quantifiable behavioral change without attending to underlying developmental concerns, they risk not affecting lasting change. Through a case study of a client in treatment for an eating disorder, I illustrate how this dilemma frames everyday encounters and negatively impacts client care, while at the same time missing developmentally meaningful opportunities for healing. An outline for a proposed applied psychiatric anthropology is presented, together with specific recommendations for adolescent mental health policy, research, and practice.

Brief Report: Childhood Disintegrative Disorder: A Brief Examination of Eight Case Studies

Childhood disintegrative disorder (CDD) is a rare condition characterized by distinct regression of developmental and behavioral functioning following a period of apparently normal development for at least 2 years. The purpose of this article is to present the developmental, behavioral, psychosocial, and medical histories of eight children who have been diagnosed with CDD in an attempt to advance the understanding of this rare disorder. Results indicate the average age of onset was 3.21 years. Three cases reported an insidious onset while two cases exhibited acute onset. Developmental and behavioral milestones were met at age appropriate times in each case and significant deterioration of formerly acquired skills and abnormalities in functioning were clinically present in all eight cases.

Neurodevelopmental support and early intervention in NICU

Methods of routine care delivery affect outcomes for infants exposed to the lifesaving rigors of newborn intensive care. The vulnerable immature or sick infant responds to environmental and caretaking stressors with deleterious physiologic and behavioral effects which compromise physiologic stability and the attainment of target neuromotor, behavioral, and growth milestones. When care is structured to support the individual infant's physiologic stability and neurobehavioral organization, stress is reduced for that infant. Routines of intensive care should be altered and adapted based on specific observations of each infant's response to care giving and environmental stimuli. This article will briefly review the four major categories of interventions that nurses can incorporate into their daily care for the infant to help improve outcomes for the premature infant.