Sharon L. Ramey - US grants

The structure of the American family has changed significantly -- particularly in terms of size and parental presence. Objective data are needed about actual behavior within the family unit. A conceptual model is proposed to account for the impact of structural variables on the functioning of individual families. General structural variables are hypothesized to exert a more predictable impact on a family when parents' decision making strategies are poor, when positive feelings and commitment within the family are low, and when external social support is minimal. Families (300 black, 300 white/non-Hispanic) will be selected on the basis of number of children (1, 2, and 4 or more) and parental presence (1 vs 2). Family functioning will be assessed via systematic home-based observations, standardized interviews, environmental evaluations, self-ratings, and activity logs. Patterns of social interaction will be coded systematically during 3 4-hr home visits, focusing on amounts and types of interaction among all family members, as well as expression of feelings, household activities, discipline, and teaching. Parents' decision making strategies will be evaluated formally (3 sessions) concerning family decisions related to structure, childcare, discipline, and division of responsibilities. Parents' perceptions of the advantages and disadvantages associated with their own family situation will be measured, as will their current satisfaction and strategies used to solve problems. Child outcomes include school performance, scores on standardized tests, parent ratings of abilities and behavioral characteristics, and observed social and verbal behavior. Variables to be considered in data analysis and interpretation include: age, sex, and spacing of children; stability of family membership; religiosity; and parents' current age, marital history, education, and current work status. The findings are relevant to understanding why some families function well in spite of serious structural obstacles, while others do not. The theoretical model to be tested has significance for developing public policy and family related programs, as well as for increasing scientific knowledge about the impact of environmental variables on children's intellectual and social development.

The proposed research focuses on the social ecology of institutional and community-based residential environments for retarded children and adults. The primary objectives are: (1) to evaluate the effectiveness of alternative treatment strategies to promote positive interaction between retarded individuals and their environments, and (2) to test the validity of a set of hypotheses about how to "match" individuals and environments. Three prospective and observational studies will be conducted on 552 subjects in 69 environments. Study #1 evaluates alternative treatment strategies to improve the quality of institutional life. Study #2 is a pre-post test of subjects placed in specialized community group homes versus institutional controls in small, enriched living units, Study #3 constitutes an experimental test of the practical utility of the principles associated with the proposed model of "person-environment fit". For subjects who are poorly matched to their environments, specific changes -- theoretically designed to encourage positive adaptation -- will be introduced and assessed. The significance of this research relates to its potential for advancing knowledge about what comprises optimal residential environments for retarded individuals.

It has been estimated that 3% of child-bearing women are intellectually limited mothers (ILMs). Literature is emerging from clinicians who deal with the consequences of inadequate childrearing by ILMs. The potential for an adequately nurturing environment supplied by an ILM is ill-defined as is the potential and risk for her child. There needs to be systematic investigation of the incidence and severity of conditions consequent to parenting by ILMs, a risk profile that can estimate the environmental characteristics associated with deleterious child outcomes and identification of characteristics of competent ILMs. The specific aims are to learn: how characteristics of ILMs differ from ,intellectually normal mothers of the same SES, race, age and parity; how children of ILMs differ from the comparison group; which personal-ecological variables contribute the most predictive variance to child competence. Fifty ILMs (IQ 50-75) and 50 low SES mothers (IQ> 85) will be recruited prenatally over a six-month period. All subjects and their children will be monitored for two years to evaluate child outcome (development/ cognitive ability, social competence, nutrition, illness/injury). Potential predictive variables of child outcome were derived from literature and categorized in two clusters: maternal and family ecology. Qualitative, correlation/regression and ANOVA will describe the sample, their characteristic relationships and differences. This information will form a foundation for the development of scientific interventions that could benefit the ILM and her child.

American Indians, comprised of nearly 500 tribes, have been characterized in terms of common values (self-sufficiency, group identity, and strong spirituality) and traditions (traditional healers, practices that promote harmony, and celebrations). Lesser known are the considerable differences across tribal groups, reflecting true cultural differences and the influence of their surrounding communities, economic and educational resources, health care, and other sociopolitical factors. Mental retardation is significantly elevated in American Indians, with school age prevalence estimated to be 11 percent or more. American Indian families have a remarkable heritage of resilience, but there is little information about family supports. This proposal focuses on families affected by mental retardation in 2 distinctive communities: the Sioux Indians on the Pine Ridge Reservation (South Dakota) and the Alabama Indian Affairs Commission, representing 7 tribes, including the recently federally recognized Poarch Band of the Creek Tribe. The proposed study builds upon preliminary research and collaborations with these two Native American organizations. The specific aims are: (1) to document, from an ethnographic perspective, traditional values, beliefs, and cultural responses to mental retardation in 2 diverse American Indian communities; (2) to observe how families use informal and formal support systems, particularly to foster the well-being of their child with mental retardation. Both the societal sustaining system and the nurturing system will be studied in terms of culture- specific and culture-preferred means of maintaining the family's strengths; (3) to gather data about barriers and facilitators related to effective family functioning; (4) to compile family case histories, through collaboration with the families and community leaders, to facilitate future research and improve service delivery and community support for families; and (5) to use the data gathered in Specific Aims 1- 4 to help refine a general eco-cultural conceptual model of family adjustment. This research will be conducted in close collaboration with the Oglala Sioux Tribe and the Alabama Indian Affairs Commission. A multi-method approach will be used, relying on ethnographic and participant observation techniques, valued community informants, semi-structured interviews and family assessment tools (already pilot-tested), and school and clinic records. A series of 5 interrelated studies will include > 200 parents, extended family members, children, teachers, health care workers, neighbors, and community leaders as informants. A population-based sample of 75 Sioux families and 75 Alabama Indian families with children, 5-12 years old, who are mentally retarded, will participate in the longitudinal study of family adaptation. This research will provide the first extensive data base about American Indian families, mental retardation, and the role of culture and community.

This is an application to establish a multidisciplinary Developmental Disabilities Prevention Research Center within a University Affiliated Program (UAP) to investigate critical problems of prevention and amelioration of developmental disabilities with a primary focus on myelin, CNS functional integrity, and critical influences on maturation, health, and human competency (especially the role of nutrition and its interactions with other pre- and postnatal environmental factors). The objectives of the UAB Developmental Disabilities Prevention Research Center are: (1) to conduct research to advance knowledge about the etiology, prevention, and treatment of developmental disabilities; (2) to enhance the research environment by providing high quality core support services; (3) to strengthen programmatic, multidisciplinary inquiry about myelinogenesis, CNS development, and developmental disabilities; (4) to foster new collaborations in promising areas and to recruit new investigators to the field; and (5) to promote timely dissemination of scientific discoveries. Four component research projects are proposed: Project I, Markers of myelinogenesis and nutritional status in high risk newborns and infants; Project II, Effects of material and fetal zinc and folate levels on CNS development; Project III, The role of nitric oxide (NO) in the development of synapses and myelination in the cortex; Project IV: Excitotoxic mechanisms in the developing brain. The proposed core units are: A, Administrative and Communications Core; B, Neurobiology Core; C, Human Subjects and Statistical Analysis Core. In addition, a specialized Myelin Assay Lab (embedded in Project I) will be available for multiple projects. The users of these core units will be the 4 component research projects plus 19 currently funded research projects (6 by NICHD). This proposal builds upon a long history of collaborative inquiry and commitment to developmental disabilities, as well as strong programs of interdisciplinary training and mentoring and a major consortium of programs and centers dedicated to the study of mental retardation and developmental disabilities research -- the Civitan International Research Center. The proposed Center has a unique capacity to conduct urine assays for myelin, unique availability of special proteins to conduct basic developmental neurobiological research related to myelinogenesis, and unique access to large-scale randomized trials of nutrition supplementation in high risk populations.

[unreadable] DESCRIPTION (provided by applicant): This application is to develop a community-linked collaboration in the District of Columbia (DC) to plan a multi-site, multi-level study to investigate disparities in maternal and child health and, ultimately, to improve major outcomes among inner city, high risk African American women and their children. The leading partners are Georgetown University (including a new Center on Health and Education, the Center for the Study of Learning, and the National Center for Education in Maternal and Child Health), MedStar Health (the corporate entity that delivers many babies for high risk, low income African American women), and the D.C. Developing Families Center (a comprehensive, inner city family center that integrates a nurse-midwife model with an Early HeadStart program and case management services). [unreadable] [unreadable] The specific aims in Phase 1 are: (1) to develop a strong community-university collaboration to design and implement clinical research (Phase 2) to reduce health disparities; (2) to conduct exploratory studies to inform decision-making for Phase 2; (3) to provide interdisciplinary research training opportunities for minority scientists and clinicians; (4) to work with NICHD staff and other Phase 1 projects in planning; and (5) to advance the methods and theories related to the key clinical outcomes of fetal loss, low birthweight, prematurity, neonatal and infant mortality, and early childhood morbidity. [unreadable] [unreadable] The Georgetown-DC collaborative team offers expertise in prenatal care, parenting, child neglect and abuse, maternal depression, maternal substance abuse and smoking, early intervention for at-risk children, maternal intellectual disabilities, intergenerational poverty, early childhood care and education, family functioning, welfare reform, health services models for inner city families, maternal infectious diseases, developmental neuroscience, and neuroimaging of young children's brains. Two sample studies are proposed, along with new methodologies, to investigate how the complex interactions among genetic, biological, behavioral, and environmental variables influence key health outcomes. [unreadable] [unreadable]

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DESCRIPTION (provided by applicant): The Community Child Health Network (CCHN) Phase II research proposes to: (1) advance understanding of the combined biomedical, social, behavioral, and environmental influences on the course of prenatal development, pregnancy outcome, and early child development, particularly in physical growth, respiratory function, and language development. CCHN proposes a 5-site, longitudinal study of 2 integrated cohorts: a Birth Cohort Study of 5250 families (1050 per site)) followed by a Subsequent Birth Study (38 percent of mothers expected to have subsequent live birth). These studies focus on the role of stress and allostatic load, as moderated by resilience and supports, on pregnancy outcome, fetal programming, and child development outcomes of prematurity/intrauterine growth restriction, overweight, asthma, and language and cognitive development;and (2) to develop and document active community participation in all phases of the study through the community based participatory research (CBPR) in the community-academic partnerships (CAPs). The findings are intended to advance theory about the etiology and impact of health disparities related to pregnancy and early childhood outcomes, as well as inform the design of future preventive interventions. Innovative features include: 1) focus on the inter- and pre-conception period;2) combining biomedical and psychosocial indicators and outcomes within an integrated conceptual framework;3) multidisciplinary measures of resilience and supports as well as risks;4) including fathers as integral to both pregnancy and child health outcomes;and 5) a participatory research partnership of the community and university at local sites and the national network. The District of Columbia/Georgetown University site brings a multi-partner model to bear to implement the above proposed research. Our site has added two local specific aims: a) to provide support for a citywide consortium of NIH researchers and community partners and b) to help build a citywide network to promote the establishment and sharing of computerized databases related to prenatal care, labor and delivery, interconceptional care, and early childhood health and family social services. The goal of these local aims is to help reduce the well-documented health disparities and to develop, then test promising interventions.

DESCRIPTION (provided by applicant): The District of Columbia has long had unacceptably poor pregnancy outcomes, as indexed very high rates of infant mortality, prematurity, low birth weight, and very low birth weight. Children in the District of Columbia are at elevated risk for respiratory problems (especially asthma), overweight, and developmental delays in language and cognition. For most families, health care and social services for families in the District of Columbia are fragmented, complicated, frequently changing, and not neighborhood-based. A notable exceptional is the Developing Families Center, a multi-service, highly innovative, and responsive form of care for pregnant women, children, and fathers. This application focuses on how to build research capacity and then conduct scientific inquiry about promising service delivery approaches to improve the heath and well-being of inner city, African American, predominately low income families. The specific aims are to: 1) expand and evaluate a community-university research partnership designed to advance knowledge about health of inner city families;2) implement a computerized information system regarding prenatal, birth, post- partum, and pediatric care;social services and supports, and early child development;3)refine, and develop innovative, valid methods to study health disparities;to incorporate local, cultural, and ethnic perspectives;4) conduct a series of descriptive studies on health disparities topics of mutual interest -including Study 1 on neighborhood knowledge and perceptions related to the Developing Families Center, well-being of pregnant women and their families, and experiences with service delivery and Study 2 focused on the inter-pregnancy interval and factors associated with positive health and well-being indicators for mothers, fathers, and young children;5) to disseminate research findings from our partnership and document the use of these findings;and 6) work with other innovative (non-conventional) community-based service providers to create a network for conducting multi-site research trials. Overall, we seek to create a partnership that will promote both receptivity to new knowledge (research findings) and innovation in community service delivery and research on service delivery.

DESCRIPTION (provided by applicant): Unilateral (hemiparetic) cerebral palsy (CP) affects an estimated 229,000 individuals in the U.S., with CP rates increasing in young children. Most traditional forms of therapy have proven ineffective, although they remain in widespread use. Two major research reviews (cf. Huang et al, 2010; Sakzewski et al, 2009) conclude that pediatric constraint-induced movement therapy (CIMT) is one of the most promising new therapies, despite wide variation in and vigorous debate about its key features. Two urgent, unresolved issues concern the effects associated with (a) different dosage levels of pediatric CIMT and (b) different types and duration of constraint. The proposed study is a multi-site, randomized controlled trial (RCT) of 144 children (3 - 6 yrs old) with hemiparetic CP. The multiple baseline 2 X 2 RCT study design will compare the effects of 2 dosage levels (3.0 hrs/day for 21 days versus 1.5 hrs/day for 21 days) under 2 distinct constraint conditions (Full-time cast versus Part-time splint). Children will first be studied in a control condition, receivin their usual therapy over 3 months, and then crossover to be randomly assigned to one of 4 CIMT treatment groups: (1) 3.0 hrs/day dosage, Full-time cast; (2) 3.0 hrs/day, Part-time splint; (3) 1.5 hrs/day, Full-time cast; and (4) 1.5 hrs/day, Part-time splint. For all groups, parents wil receive systematic training to help practice and extend their children's new and improved upper extremity skills. Children will be followed 3 months post-treatment. Children's neuromotor competence will be assessed via a comprehensive battery of standardized and innovative tools, administered 5 times over 8 months by individuals blinded to the subjects' control and treatment conditions. The primary outcome measures are the Assisted Hand Assessment (AHA), the Pediatric Motor Activity Log (PMAL), and the modified QUEST. Independent scoring of videotaped sessions and parent reports will supplement lab assessments, along with data transmitted from accelerometers. Specific Aim 1 focuses on comparing the effects of 2 dosage levels of pediatric CIMT. Specific Aim 2 compares the effects of 2 forms and duration of constraint, selected because of competing hypotheses about their impact on children and cortical re-organization. Specific Aim 3 uses clinical diagnostic and baseline data about subjects' individual differences to explore hypotheses about differential response to CIMT, including their levels of engagement during treatment, the types and magnitude of short- and longer-term changes detected, and whether other changes are documented beyond the realm of neuromotor competence (i.e., spillover effects). The results of this study will advance the development of rigorous, evidence-based standards for the practice of CIMT, with the potential for large-scale implementation to produce major benefits for children with CP.

DESCRIPTION (provided by applicant): Cerebral palsy (CP) is the most common class of childhood neuromotor disabilities, resulting in lifelong impairments in productivity and health as well as high costs. To date, no form of infant therapy has proven efficacious via an adequately powered RCT; further, usual and customary therapies often fail to produce clinically meaningful benefits. This revised application builds on new findings from 2 independent preliminary studies showing benefits for infants who received alternative forms of constraint-induced movement therapy (CIMT). Using a multisite RCT design, 72 infants (6 - 18 mos old) with unilateral or asymmetrical CP will be randomly assigned to receive one of 3 manualized forms of multi-component therapies. Primary outcomes include objective assessments (at baseline then 1 wk, 6 mos, and 12 mos post-therapy) of affected upper extremity (UE) skills in unilateral and bilateral activities, as well as changes in brain lateralization based on a novel fNIRS protocol fo infants. The specific aims are: 1) to compare the effects of 3 promising forms of Infant-CIMT that are identical in dosage (3 hr/day X 21 days) and their key therapy elements (shaping, massed practice, home-based, embedded in play and everyday activities, provided by a trained therapist in partnership with parents) but that differ in their use of constraint - continuous casting, part-time splint, or no constraint; and 2) to assess stress levels and safety related to constraint condition (continuous or part-time) compared to no constraint. Stress will be assessed using multiple salivary cortisol samples from infants and parents, parent self-report, and observations. Safety monitoring will include range of motion, skin integrity, sensory awareness, functional use of the casted arm and hand, as well as changes in laterality scores involving the casted side. Even though prior studies affirm the general safety and acceptability of using constraint with infants, there are strongly competing hypotheses about its potential benefits versus risks. Impact: if one or more of the tested infant therapies produces large magnitude benefits lasting up to 12 mos later, then these findings would have a high impact on future clinical practice. Moreover, highly effective therapy very early in life may lead to much higher levels of independence, learning, social engagement, and quality of life for children with unilateral and asymmetrical CP.

Perinatal arterial stroke (PAS) includes infants with neonatal arterial ischemic stroke and presumed perinatal arterial stroke and has an estimated incidence of 1 in 1150. The majority will develop hemiparesis, often resulting in lifelong and debilitating disability, including lowered cognition and quality of life. There are no evidence-based forms of rehabilitation designated as standard-of-care for these infants. We propose a Phase III trial to address this lack of evidence-based treatments. The I-ACQUIRE Trial is a rigorous, adequately powered, multi-site randomized controlled trial comparing 2 dosages of a pediatric rehabilitation - known as Infant ACQUIRE - to Usual and Customary treatment (U&CT). Prior studies of I- ACQUIRE show high safety, patient acceptability, and evidence of significant and enduring benefits. Briefly, I- ACQUIRE will be used to treat 8 ? 24 mth old infants with PAS in either 3 hrs/day (Moderate Dose) or 6 hrs/day (High Dose), for 5 days/wk for 4 wks. Treatment occurs in a home or natural setting where operant conditioning techniques are applied to achieve goals paced for each infant. I-ACQUIRE includes the core features of pediatric Constraint-Induced Movement Therapy (CIMT). Standardized treatment at all sites is monitored weekly via a Fidelity of CIMT Implementation tool. Clinical Trial Design: 240 infants (N=80/group) will be randomly assigned to: 1) Moderate Dose I-ACQUIRE, 2) High Dose I-ACQUIRE, or 3) U&CT. (N=80). Double-blinded assessments occur at baseline, end of 4 wks of treatment, and 6 mos post-treatment. A Parent Council will be active throughout the trial, supporting NIH's goal of increased stakeholder engagement in clinical trials. The specific aims are: 1) Primary: Determine the efficacy of I-ACQUIRE at 2 dosage levels compared to U&CT to increase upper extremity skills on the hemiparetic side (using a minimal clinically meaningful threshold that is achieved at end of treatment and 6 mos later); 2) Secondary: Determine the efficacy of I- ACQUIRE at 2 dosage levels compared to U&CT to improve use of the hemiparetic upper extremity as an ?assisting hand? in bimanual activities; and 3) Exploratory: Explore the association between I-ACQUIRE treatment at Moderate and/or High Doses and the infant's gross motor development and cognition (i.e., potential cross-domain effects of treatment). The Statistical Analysis Plan controls for multiple comparisons; after testing the major study hypotheses, sensitivity analyses will consider factors that may contribute to variation in treatment outcomes. Public Health Impact: Each year, an estimated 3400+ infants in the U.S. have PAS with high likelihood of lifelong impairment in neuromotor and often cognitive functioning resulting in a high cost burden for families, the healthcare system, and society. If I-ACQUIRE proves efficacious, then the field will have the critically needed Phase III confirmatory evidence and the specific clinical protocol needed to transform rehabilitation and improve clinical outcomes and quality of life for infants with PAS.

Project Summary (Overall) We propose a National Pediatric Rehabilitation Resource Center (PedRehab Ctr) to offer research infrastructure supports to improve investigators' capacity to conduct rigorous clinical trials to test and implement evidence-based interventions in pediatric medical rehabilitation. Our specific aims are: 1) to provide an active and archived program of courses, workshops, webinars, and demonstrations related to the design, conduct, analysis, and reporting of high-quality, high-impact clinical trials - including complex, multicomponent, and multiphase treatments (Didactic Interactions); 2) to support interdisciplinary research collaborations that promote innovation and excellence in conducting multi-site clinical trials (Mentored Collaborative Opportunities); 3) to develop critically needed techniques in measurement and understanding of neurobiological mechanisms and biobehavioral outcomes in pediatric medical rehabilitation (Techniques Development); 4) to fund pilot studies via partnerships with leading national organizations to yield data for informing competitive NIH applications in pediatric medical rehabilitation (Pilot Studies); and 5) to promote PedRehab Ctr expertise by advertising and coordinating with major associations and to prepare a much-needed comprehensive, interdisciplinary reference manual (online and dynamically updated) addressing issues inherent in pediatric medical rehabilitation research (Promoting Center Expertise). Our analysis of critical gaps, obstacles, and opportunities in pediatric rehabilitation research informs the strategies we propose to achieve these aims. The administrative organization and operational plan for PedRehab Ctr will realize efficiencies, leverage resources, and ensure broad outreach through partnerships with leading organizations, research networks, and special interest groups. PedRehab Ctr will convene a National Advisory Group with patient/parent representation to assist in plans for and evaluation of PedRehab Ctr activities. PedRehab Ctr proposes approaches to increase diversity in the pediatric rehabilitation workforce and research. Our PedRehab Ctr core team at Virginia Tech, The Ohio State University, and Nationwide Children's Hospital has deep expertise and unique labs that support developmental science, neuroimaging, pediatric neurology, occupational therapy, physical therapy, medical rehabilitation science, bioengineering, research design and regulations, and Implementation Science. PedRehab Ctr activities will build on our leadership roles in NIH multisite randomized controlled trials (Phase II and III), our Clinical and Translational Science Awards (CTSAs), NIH research networks, NIH training programs in translational biomedical and implementation science, and national organizations. Collectively, PedRehab Ctr has the potential to increase the number of scientifically rigorous, productive, and high-impact clinical trials in pediatric medical rehabilitation. In turn, the expansion and effective implementation of scientific findings from these trials will likely produce widespread and enduring improvements in functional outcomes, health, and productivity of individuals affected by childhood-onset disorders and disabilities.

Project Summary (Administrative Oversight) The PI/Director of the proposed National Pediatric Rehabilitation Resource Center (PedRehab Ctr) will have primary responsibility for the overall administrative oversight with clear distribution of shared administrative and scientific leadership responsibilities among the center's multidisciplinary team of 6 scientists, each of whom serves as Lead for one of the designated core components: Didactic Interactions, Mentored Collaborative Opportunities, Pilot Studies, Techniques Development, and Promoting Center Expertise. All team members are engaged in ongoing clinical trials pediatric rehabilitation research, share a history of productive interdisciplinary collaborations, and assume national leadership roles in organizations and research networks in pediatric medical rehabilitation. The specific aims for Administrative Oversight are: 1) to ensure that PedRehab Ctr core components function well, interact frequently, and strategically utilize their resources to achieve the overall goals for PedRehab Ctr; 2) to engage the PedRehab Ctr team of scientists in a highly efficient, stimulating, and rewarding manner that welcomes their engagement in the administrative aspects of Ped Rehab Ctr; 3) to convene an independent National Advisory Board to assist in reviewing and improving plans and operations, in ways that encourage Board members to join us as colleagues in areas relevant to their research expertise; 4) to achieve consensus about and then establish a continuous information system (open, verifiable, easy to summarize) that can yield useful, timely data about our progress and impact on the targeted research community; and 5) to promote a scientifically vibrant and new P2C in pediatric rehabilitation that will interact with and strengthen the national network of infrastructure support centers sponsored by the Eunice Kennedy Shriver NICHD's National Center for Medical Rehabilitation Research. Our PedRehab Ctr team strongly endorses a model of lateral, shared, and joint decision-making among team members. We seek to minimize administrative burden and avoid duplicative efforts for our team members and support staff as well as for those who use our core's resources. Above all, we seek to leverage the available funds for the PedRehab Ctr to yield maximal benefit for clinical pediatric rehabilitation research.

Project Summary (Center Collaborations with Other Institutions) This proposal to establish a new infrastructure supports center ? the National Pediatric Rehabilitation Resource Center (PedRehab Ctr) - to promote the field of pediatric rehabilitation research is the joint product of a team of six senior rehabilitation scientists who work at Virginia Tech (primary home for the new P2C center), The Ohio State University (OSU), and Nationwide Children's Hospital (NCH). This interdisciplinary team already has been collaborating for many years on multiple NIH Phase II and Phase III clinical rehabilitation trials, as well as a broad array of educational, outreach, and mentoring activities. As such, the team and their institutions have extensive experience in working together to handle the sub-contracts and to monitor the fulfillment of the Scope of Work designated in the sub-contracts and synonymous with the primary funded NIH application. Drs. Jill Heathcock and Amy Darragh are at The Ohio State University (OCU) in Columbus where their research labs and offices are housed. Dr. Heathcock will serve as the Core Lead for Techniques Development. Dr. Darragh will serve as the Core Lead for Pilot Studies. Both will participate in Administrative Oversight on the Steering Committee and will contribute to activities described under Didactic Interactions, Mentored Collaborative Opportunities, and Promoting Center Expertise. Dr. Warren Lo has appointments at OSU and Nationwide Children's Hospital (NCH). The collaborative arrangement will be with NCH, the primary location where Dr. Lo conducts his clinical research activities. Dr. Lo is designated as the Core Lead for Mentored Collaborative Opportunities. He also will participate in Didactic Interactions and Administrative Oversight on the Steering Committee. The complementary and distinctive expertise of this team is described elsewhere in the application under Administrative Oversight (?Roles, Responsibilities, and Qualifications of PedRehab Ctr team?) and in their individual BioSketches. Descriptions about unique research resources provided by OSU and NCH are included in Table 2 of Mentored Collaborative Opportunities and in the Facilities and Other Resources sections of this application.

This Competing Revision application to the parent Stroke Net I-ACQUIRE Phase III Trial (5U01NS106655- 02) proposes a 12-month follow-up assessment for infants and toddlers who received one of two dosages of I- ACQUIRE ? a form of high-intensity pediatric Constraint-Induced Movement Therapy (CIMT). The additional data will provide clinically meaningful and likely novel insights into longer-term outcomes for 160 children (8 - 36 months old when treated) with Perinatal Arterial Ischemic Stroke (PAIS) and hemiparesis. The parent study obtains post-treatment assessments at end-of-treatment and 6 months later. The rationale for this additional assessment is strongly informed by new evidence not available when the I-ACQUIRE Study was launched. The topic of longer-term correlates of treatment outcomes is especially intriguing and clinically impactful because upper extremity skills develop in dramatic ways throughout the early years of life. Accordingly, there may be important functional changes induced by the I-ACQUIRE treatment that are not fully manifest until children are older. Further, a young child's sense of competency may be profoundly changed by the child's progress during the month of intensive I-ACQUIRE treatment; in turn, the child, the family, and treating clinicians may increase their expectations for future achievement and expand the opportunities for the child to participate in a wide array of age-appropriate activities at home and in the community. We propose one new specific aim: To assess whether the end-of-treatment and 6-month post-treatment outcomes (measured in the Phase III I-ACQUIRE Study) for children treated with I-ACQUIRE remain stable, improve, or decline at 12-months follow-up and whether there is a differential pattern observed between the two dosage groups. The 12-month follow-up assessment includes upper extremity movement and functional skills (unilateral and bilateral); cross-domain development in gross motor, language, cognition, and socioemotional development; and children's participation levels in age-typical activities, measured by the inclusion of a new, psychometrically strong standardized tool. The prospective longitudinal dataset generated will afford an unprecedented opportunity to describe developmental trajectories considering children's clinical characteristics, CNS and genetic biomarkers, treatment histories, and environmental opportunities. Public Health Impact: Each year, 3400+ infants in the U.S. have PAIS with high likelihood of lifelong impairment in neuromotor and often cognitive functioning if not treated effectively. If I-ACQUIRE proves efficacious, and particularly if the benefits appear to influence even later developmental patterns, then the field will have the critically needed Phase III confirmatory evidence and the supplemental longer-term follow-up data important to transform rehabilitation and improve clinical outcomes for this vulnerable pediatric population.