ACCEL Funding Lifecycle Resources

Adolescent depression is a significant public health concern with approximately 20% of adolescents experiencing at least one major depressive episode in the past year (NIMH, 2023). The effects of adolescent depression can be catastrophic with 10% of high school students attempting suicide annually (CDC, 2023; Verlenden et al., 2024). Depression often begins during adolescence, or earlier, and follows a recurrent course associated with more negative outcomes and impairment along a range of important psychosocial domains that can persist into adulthood (Wilson & Dumornay, 2021). Integrated primary care (IPC) settings provide opportunities to prevent, screen, and treat depressive symptoms. IPC settings have been regarded as the “de facto” mental health system since the 1970s in part due to opportunities to promote service utilization (Hodgkinson et al. 2017), reduce stigma for mental health treatment (Miller-Matero et al., 2019), and reduce the negative impact of social determinants of health (Chakawa et al., 2020). The American Academy of Pediatrics (AAP) recommends that all youth 12 and older be screened for depression annually and those who screen positive or endorse suicidal ideation be referred to psychotherapy and initiate medication treatment (Hua et al., 2024). Preliminary research indicates that pediatric primary care providers (PPCPs) may not consistently adhere to national guidelines surrounding screening and treatment for adolescent depression. PPCPs may also fail to consistently connect adolescents with onsite and community mental health providers and may fail to initiate referrals to crisis services when suicidal ideation is endorsed (Hoffses, 2024). These findings have critical implications for adolescents seeking to connect to mental health services; if PPCPs do not provide information and resources to connect adolescent to mental health treatment, youth may never receive the care they need. The aims of this work are to identify barriers and facilitators reported by PPCPs in connecting adolescents with depressive symptoms to mental health treatment and identify implementation strategies to enhance PPCP uptake and adherence to AAP guidelines on connecting adolescents with a positive depression screen to mental health treatment. These findings are expected to have critical implications for adolescents seeking to connect to mental health treatment and are expected to inform the delivery of mental health services in IPC and reduce rates of depression for at risk adolescents. Results of this study will serve as preliminary data for future grant applications to test identified implementation strategies, with the goal of improving access to mental health services for adolescents.

The reticulospinal tract (RST) is a secondary motor pathway, supporting the corticospinal tract (CST) in tasks such as locomotion, reaching, and grasping. The RST is relevant for motor recovery after CST lesions, such as stroke. There is currently a debate on whether increased RST drive is supportive of motor recovery, or a sign of maladaptive plasticity. A primary reason for the unresolved debate is the lack of methods for measuring function of the reticular formation (RF), a collection of nuclei in the brainstem that originate the RST.

Our group has recently developed StretchfMRI, a non-invasive imaging method that has enabled us to map motor function in the RF in-vivo for the first time. StretchfMRI is enabled by the unique integration of robotics, surface electromyography, and functional magnetic resonance imaging (fMRI). In this project, we aim to study the role of the RST in post-stroke individuals. Our central hypothesis is that the RF is hyper-excitable in post-stroke individuals. To test this hypothesis, we will measure stretch-evoked fMRI signal in the RF during extension perturbations applied to the hemiparetic and non-hemiparetic wrist of 24 post-stroke individuals. We will test whether stretch-evoked fMRI signal is greater for perturbations applied to their hemiparetic arm, compared to the non-hemiparetic arm, and establish the relationship between RF function and post-stroke motor impairment.

The main goal of this project is to understand how different neural pathways contribute to motor control, and whether secondary motor pathways may support post-stroke motor recovery in presence of damage to the corticospinal tract. The knowledge gained will support new interventions that modulate function in specific pathways to enhance motor recovery after stroke.

Pilonidal disease is a painful skin infection that occurs in the crease of the buttocks near the tailbone (gluteal cleft) and affects approximately 1% of the population between the ages of 15-30 years. Medical therapy of pilonidal disease is largely dependent upon continued hair removal, meticulous hygiene to the area, and recurrent courses of antibiotics with intermittent incision and drainage procedures. However, recurrent pilonidal disease after initial incision and drainage can be as high as 40% and wound complications after resection have been reported to be as high as 30%. Recurrence often leads to a substantial burden on patients with dependence on caregivers, long term disability, reduced quality of life, and social withdrawal.

Chronic hair removal to the gluteal cleft is a consistently recommended therapy to prevent pilonidal disease recurrence. Research has demonstrated the efficacy of laser hair depilation of the gluteal cleft to reduce pilonidal disease recurrence compared to standard of care in adult and adolescents. A recent randomized controlled trial (RCT) demonstrated laser hair depilation significantly decreased recurrence rates at 1 year from 33% to 10%. However, in exploratory secondary analyses, there was potential heterogeneity of treatment effect based on self-reported race and ethnicity. Although limited by small numbers of patients in many of the racial and ethnic groups, there was a significant reduction in disease recurrence among Non-Hispanic White patients with laser treatment but no change in recurrence among all other groups. This study will investigate the effects of laser hair depilation on pilonidal disease recurrence among those with darker skin types. We will perform a pilot RCT comparing laser hair depilation and mechanical/chemical depilation to mechanical/chemical depilation alone. The rate of recurrence of pilonidal disease at 1 year will be compared between the two groups. We hypothesize that laser hair depilation will lead to lower rates of disease recurrence at 1 year follow-up compared to standard of care. We will also compare differences in the 1-year morbidity associated with pilonidal disease between the two groups. We hypothesize that laser hair depilation will lead to less morbidity including less disability, higher health related quality of life, higher healthcare satisfaction, and fewer procedures, surgical excisions, and post-operative complications.

The estimate of the efficacy of laser hair removal to decrease pilonidal disease recurrence in darker skin adolescents/young adults from this pilot study is needed to design and perform a critical multi-institutional trial. A focused study of laser hair depilation in patients with darker skin types is essential to promote equitable health care across all patients with pilonidal disease by targeted inclusion of underrepresented populations with darker skin types in a therapeutic trial. Community engagement and partnership with Delaware communities that represent these populations will be critical to engage these underrepresented populations in research and to disseminate and implement research findings into these communities.

Meniscus tears are common and have deleterious impact on both current activities and future onset of knee osteoarthritis. This can be particularly debilitating in the young active population. Therefore, surgical repair of a torn meniscus is regularly performed. While the surgical procedure is well established, unfortunately, there is no consensus on the post-operative rehabilitation protocol. On the one hand, early weight-bearing can facilitate functional recovery. On the other hand, early weight-bearing could compromise the repair’s mechanical integrity. Addressing the unknown effects of post-op rehabilitation is critical. If this question remains unanswered, patients will suffer from unnecessary restriction after surgery, or may compromise the repair and risk re-tear of the meniscus.
Our long-term goal is to provide evidence-based guidelines for post-op rehabilitation protocols following meniscus repair that strikes the optimal balance between functional recovery and healing. Because the main function of the meniscus is to distribute mechanical loads, in order to provide these guidelines, the meniscus and repair site mechanics must be quantified during post-op protocols. Therefore, the objective of this proposal is to investigate in vivo knee biomechanics after meniscus repair: particularly the meniscus and cartilage displacement under conditions that simulate physiological loading in daily activities using a novel MRI-compatible loading device.<br />
We will use one of the most common scenarios for meniscus repair in a young active population: a vertical mattress suture repair for vertical longitudinal tear in the posterior horn. Post-op meniscus healing is usually 6 weeks after repair, and patients start high impact training (e.g. running, jumping…) at 3 months post-op. Therefore, we aim to assess knee mechanics at two time points: early after surgical repair (1 month), and when they are ready for high impact activities (3 months).
We have developed an MRI-compatible knee loading device that can apply physiological joint loading. We have successfully used this device to quantify meniscus and cartilage displacement in the knees of healthy volunteers, by applying compression with the knee in extension and flexion. We will use these innovative methods to pursue the following Aims:
Aim 1: Test the hypothesis that meniscus and cartilage mechanical function under physiological loading conditions is partially restored to intact values at 1-month post-surgery, and fully restored at 3-months under current post-operative rehabilitation protocols.
Aim 1A: Determine the normal variation between right and left knees in healthy controls who are age- and sex- matched to the surgical patients to establish the detectable change for the operative subjects.
Aim 1B: Measure meniscus and cartilage mechanics in surgical patients to determine whether the operative knee has reached functional equivalency comparing to the contralateral non-operative knee, with preserved repair integrity.
This study will establish, for the first time, in vivo quantification of knee biomechanics following loading that simulates physiological loading conditions to the knee joint. The next step in this project will be to expand the rehabilitation protocols being evaluated (either more conservative or aggressive), with the goal of determining a protocol that maximizes early weight-bearing and range of motion while preserving healing of the repaired meniscus.

Hematopoietic cell transplantation (HCT) is commonly used for blood cancer patients to restore the ability to make blood cells after chemotherapy or radiation therapy. Allogeneic HCT (allo-HCT) using hematopoietic stem cells (HSCs) from donors has become increasingly popular in recent years due to improved outcomes. Despite this, relapse rates post-HCT can range from 30-80% depending on various patient- and disease-related factors. Relapse can be treated using an approach called donor lymphocyte infusion (DLI) in which T lymphocytes (T cells) from the HSC donor are collected and infused intravenously. The T cells are alloreactive, especially in cases of human leukocyte antigen (HLA) mismatch, and can attack the patient’s cancer cells. This so-called graft vs leukemia (GvL) effect can be highly efficacious and can cure or prevent relapse in some patients. The alloreactivity of T cells, however, can also target the patient’s healthy cells and tissues and cause graft vs host disease (GvHD), which severely limits the application and potential of DLI, especially for patients whose donors are HLA mismatched. To overcome this hurdle, we propose to selectively turn on T cell alloreactivity in tissues where cancer cells accumulate but not in tissues and organs most at risk of GvHD. Blood cancer cells mostly reside in lymphoid organs including bone marrow, lymph nodes, and spleen. GvHD, however, mainly affects the skin, liver and intestine. We have engineered a completely novel treatment called Lymphoid tissue-Activated Donor T cells (LADTs) that turn on alloreactivity upon sensing the B cells that are numerous in all lymphoid organs or pre-B cells that are only located in the bone marrow. Both B cells and pre-B cells are rare in skin, liver and intestine. After showing that LADTs can function in cell cultures, we are designing animal studies to determine their ability to eliminate cancer cells without causing GvHD. To optimize the design of these in vivo studies, we will determine the values of key experimental parameters such as the degree of HLA mismatch and the number of B cells and pre-B cells in bone marrow by collecting data from relapsed allo-HCT patients previously treated at Nemours and by analyzing their banked bone marrow samples (Aim 1). To test the proof-of-concept of LADT-based DLI in a clinically relevant manner, we will determine the ability of LADTs to kill cancer cells in bone marrow samples of allo-HCT patients collected at the time of relapse (Aim 2). The project, co-led by a physician specialized in HCT and a translational scientist experienced in T cell immunotherapy development, should significantly advance the research of this potentially curative approach to clinical stage.

Bronchopulmonary dysplasia (BPD) is the most common chronic respiratory disease in infants and has life-long morbidity risks for disorders such as chronic obstructive pulmonary disease (COPD). Standard-of-care treatment approaches are non-specific and non-localized, and accordingly, they fail to prevent morbidity risks and have adverse effects on neurodevelopment and immunity. Development of both more precise immunotherapies and more effective local treatment methods for affected infants would offer critically needed strategies to improve patient therapeutic outcomes while reducing side effects. Extracellular vesicles (EVs) are an emerging class of drug delivery vehicles with unique capacity for local cargo transport between cells, including efficient loading and transfer of nucleic acids. We recently discovered a new, nanoparticle (NP)-driven strategy to amplify and tune EV production in bone marrow macrophages (BMMs), with exciting potential as a localized treatment approach to generate and distribute therapeutically-relevant EVs in BPD lung in situ. Intriguingly, alveolar macrophage-derived EVs are known to provide signals to pulmonary epithelial cells that modulate inflammatory responses, with high untapped therapeutic potential in BPD given the vital role of macrophage-derived EVs (Mac-EVs) in immunoregulation and tissue repair. In this proposal we aim to 1. Understand the therapeutic benefits, localization behavior, and retention kinetics of Mac-EVs after lung delivery in murine models of BPD and 2. Develop NP-driven approaches to amplify Mac-EV production and maximize mRNA loading in Mac-EVs using BMMs and alveolar macrophages (MH-S) as versatile Mac-EV generation models. Our team of experts represents an innovative new collaborative group with an ideal fusion of engineering expertise in pulmonary drug delivery and nucleic acid delivery (Fromen and Sullivan teams, University of Delaware) with clinical and biomedical expertise in BPD treatment, pathogenesis, and preclinical model development (Alapati team, Nemours Hospital). Our proposal will establish both new fundamental understanding of the role of EVs in modulating BPD pathogenesis, as well as new enabling principles for the generation of translationally-relevant Mac-EV therapies, spanning the basic science to preclinical phases of the translational spectrum. These approaches will position our team for future advancement of a variety of advanced Mac-EV treatments for BPD, including future strategies aimed at harnessing NPs as a versatile tool relevant to both ex vivo and in situ / in vivo generation of therapeutically beneficial Mac-EVs in BPD and other lung diseases.

More children are being diagnosed with autism than ever before. When parents of autistic children try to learn about this complex condition, they are met with several barriers. First, online informational content is readily accessible, but parents are likely to encounter autism information that is either inaccurate or that depicts autism in an overly negative light. Further, the autism information provided through widely accessible resources (e.g., via online sources) does not reflect the diverse social circumstances of families at Nemours, where over half of families have low access to socioeconomic resources. Overall, families of autistic children want autism educational resources that are 1) accurate and holistic in their portrayals of autism and 2) applicable to families from diverse social circumstances.

This community-based, mixed methods project has three aims. The first aim is to characterize, through qualitative interviews, the informational needs of autistic children’s families at Nemours. The second aim uses mixed methods to identify neurodiversity-affirming and socially contextualized methods to maximize families’ use and access to autism educational materials. Qualitative interviews will query families on strategies that optimize the usability and accessibility of autism educational materials. Quantitative questionnaires will ask families to rate existing autism educational materials. The third aim is to adapt, refine, and develop digital educational resources on autism that healthcare professionals can provide to families after their child is diagnosed with autism.

Purposive sampling will be used to ensure the recruitment and enrollment of families across the socioeconomic/socioecological spectrum. For Aims 1 and 2, we hypothesize data gathered may differ as a function of family socioeconomic/socioecological resources. Interview data will be analyzed using content and applied thematic analyses. Questionnaire data will be analyzed using descriptive statistics (means, SDs). We will engage with our community advisory board and healthcare stakeholders to consider the findings of Aims 1 and 2 and iteratively develop prototype educational materials designed to fill identified informational gaps (Aim 3).

The direct outcomes of this project will position me to subsequently examine families’ satisfaction and the efficacy of developed materials to increase families’ autism knowledge and empowerment. Further, this project has the potential to positively impact service delivery by developing an innovative solution that service providers can feasibly implement within an overburdened service system to meet families’ autism service needs.

Balance is needed to maintain posture and prevent falls in everyday life. The medial (MG) and lateral (LG) gastrocnemius and soleus (SOL) muscles produce torque at the ankle for postural realignment. Having reduced plantar flexor strength is also linked with poorer balance, which may also lead to falls. Evidence also suggests that during quiet stance, both heads of the gastrocnemius and soleus have different activation rates in young adults and may play a more significant role in balance compared with overall strength. Considering this, it is important to gain a better understanding of the relationship between individual calf muscle activation, strength and balance in older adults so interventions may be implemented if deficits arise due to aging or neurological conditions. As such, it is the purpose of this study to investigate the relationship between calf muscle function and postural sway in older adults. It is hypothesized that muscle activation will have a stronger positive relationship with postural sway performance compared with peak plantar flexor strength.

Those with mild cognitive impairment and Alzheimer’s disease have a reduced capacity to rapidly decide and move, which has been linked to fatal outcomes including broken hips from falling and car accidents. Mild cognitive impairment leads not only to impaired decision-making, but also movement deficits that predict the development of Alzheimer’s disease. Recent behavioral work has suggested a common mechanism that throttles the speed of both decisions and reaching movements, which is supported by converging neural evidence that finds an interaction between decision-making and movement (motor) circuits. Yet it remains unknown how the interplay between decision-making and motor neural circuits becomes impaired and impedes rapid responses for those with mild cognitive impairment. Here we test the central hypothesis that there is an impaired interaction between decision-making and motor neural circuits with mild cognitive impairment. To test this idea, we have developed a novel reaching paradigm that provides a real time readout of the evolving deliberation—prior to a final decision—via hand movement. Magnetic resonance elastography (MRE), a state-of-the-art imaging technique, will be used to quantify viscoelastic (stiffness and damping) properties in brain areas linked to decision making and motor control. Further, we will combine computational models of decision-making and motor control to capture human movement behavior with or without mild cognitive impairment in a theory driven manner. In Aim 1 we will use human reaching experiments to establish that mild cognitive impairment disrupts the interplay of decision making and motor control. We expect those with mild cognitive impairment will display less hand movement relative to neurotypical age matched controls. In Aim 2 we will use MRE to elucidate whether brain stiffness in decision-making and motor brain regions are related to altered movement behavior. Compared to neurotypical age matched controls, we expect that those with mild cognitive impairment will have lower brain stiffness in decision making and motor areas. Further, we expect lower brain stiffness will be related to decreased hand movement. The expected outcome is a mechanistic understanding of how impaired decision making and motor neural circuits impact movement for those with mild cognitive impairment. Our work will have a positive impact by providing sensitive biomarkers for early detection of Alzheimer’s disease and paving the way for informed and effective neurorehabilitation.

Preventive interventions that support the mental health of early childhood educators using known levers for change such as stress reduction, positive collegial relationships, and effective collaboration are needed. This project focuses on the development and refinement of one such intervention called the RELATE intervention. The objective of this project is to (a) refine and expand, alongside early educators, the RELATE intervention aimed at reducing depression symptomology for this population and (b) determine the feasibility of this intervention in the early childhood settings. This first aim is to refine and expand the RELATE intervention for early childhood teacher by using feedback from researchers and teachers, assistant teachers, administrators, and early childhood coaches from partner sites. The second aim is to determine potential supports and barriers to implementing the RELATE intervention in early childhood settings. Using the race-conscious adaptation of the Consolidated Framework for Implementation Research, ten classroom teams will participate in the RELATE intervention training and provide monthly written feedback as they implement the RELATE strategies and receive coaching. Additionally, two observations of the use of training strategies in the classrooms along with notes on barriers and supports will be conducted. Interviews will be conducted with classroom team members at the conclusion of the intervention to gain final insights into implementation supports and barriers. This project’s contribution is expected to be significant because early childhood educators report higher levels of depression than average workers and are disproportionately women of color who face additional stressors that may threaten their mental health. Moreover, the proposed research is innovative because it challenges the status quo of individual-focused mental health interventions by addressing workplace mental health supports through skills training and ongoing coaching.