2017 ACTRI Pilot Project Recipients

Clinical Research | Innovative Technology | Academic-Community | Dissemination and Implementation Research

UC San Diego Altman Clinical and Translational Research Institute (ACTRI) announces the selection of the 2017 Pilot Projects. Fifteen projects were chosen in four categories, including Clinical and Translational Research, Innovative Technology, Academic-Community Partnership, and Dissemination and Implementation. Pilot Project grants are one-year competitive cash awards for researchers to obtain preliminary data. Funding priority is given to junior faculty members. Below are the 2017 projects.

Funding Period is April 1, 2017 through March 31, 2018.


Clinical and Translational Research Pilot Projects

Lori Daniels, MD, MAS Lori Daniels, MD, MAS
UC San Diego Department of Medicine

Title: Kinetics of Cell-Cycle Arrest Biomarkers after Contrast Exposure in Patients at High Risk for Contrast-Induced Nephropathy

Contrast-induced nephropathy (CIN) is defined as an acute worsening of renal function that occurs within a narrow time interval after parenteral administration of iodinated contrast. In patients undergoing percutaneous angiography, the incidence of CIN is between 10-30%. CIN is associated with longer hospital stays and higher risk of cardiovascular events, bleeding, progression to chronic kidney disease, hospital readmissions, and both in-hospital and longer-term mortality.

Presently, no marker can accurately identify CIN patients at an early stage. Although the onset of kidney injury occurs within minutes of contrast exposure, current measures of renal dysfunction such as a rise in serum creatinine (sCr) or the development of oliguria are not seen until 24-48 hours later. Change in sCr level is a validated tool for monitoring change in renal function that has occurred in the recent past, but it is not useful for detecting impending or actively occurring changes. The ability to detect CIN accurately and early could be of great clinical benefit in the diagnosis and management of patients undergoing cardiovascular and other contrast-based procedures.

Recently, two biomarkers of cell-cycle arrest, a manifestation of acute kidney stress and a key mechanism implicated in acute kidney injury (AKI), have been identified. Tissue-inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth-factor binding-protein-7 (IGFBP7) have been validated as early markers of AKI in critically ill patients and in patients undergoing cardiac surgery. Urine [TIMP-2]*[IGFBP7] measured within 12 hours of injury improves prediction of AKI over existing methods. The time-course of [TIMP-2]*[IGFBP7] levels after contrast exposure, and the utility of these markers for evaluating CIN-risk, have not been reported. This project will evaluate the kinetics of [TIMP-2]*[IGFBP7] among high-risk patients undergoing angiography. The ability to translate the early science of cell-cycle arrest markers into clinical practice would have broad implications across a wide variety of scenarios given the ubiquity of contrast use in medicine lately.

This project will involve a multidisciplinary team of cardiologists, nephrologists, radiologists, statisticians, and industry partners.

David Gonzalez, PhDDavid Gonzalez, PhD
UC San Diego Department of Pharmacology

Title: Characterization of the Mitochondria Proteome in Healthy and Diabetic Human Skeletal Muscle

The skeletal muscle (SkM) of type 2 diabetes mellitus (DM2) patients is known to be structurally and metabolically compromised. In DM2 patients, there is a recognized inability of skeletal muscle to properly oxidize glucose and fatty acids and these deficiencies are associated with a loss of mitochondrial density, structure and function, which can foster the development of oxidative stress. In DM2 patients, these metabolic and microstructural changes correlate with reduced exercise capacity and enhanced fatigability. As skeletal muscle is the largest organ per mass, myofiber mitochondrial dysfunction is also believed to importantly contribute to insulin resistance and thus, the severity of DM2. One of the most effective strategies known to mitigate the pathophysiology of DM2 is exercise. However, achieving and/or sustaining this goal may prove to be difficult when diabetic muscle is limited metabolically and bioenergetically. Understanding the mechanistic underpinning of diabetic muscle mitochondrial dysfunction requires an in-depth elucidation of changes in its individual components in particular, of those associated with organelle function. The overall goal of this project is to pursue a rigorous characterization and quantification of the mitochondrial proteome in normal and type 2 diabetic human skeletal muscle using state-of-the-art mass spectrometry technologies. Data to be generated from this study will serve the purpose of establishing a basic and fundamental mitochondrial proteome database of normal and DM2 so as to define the impact that the disease has on the organelle’s structure and/or function. This database will be deposited and thus publically available through UCSD MassIVE and Proteome Xchange. Once such a database is generated, it will be used to compare the impact that specific types of DM2 therapeutic agents or interventions (e.g. metformin or exercise) have on mitochondria structure and/or function and correlate these with changes in the mitochondrial proteome.

Suzi Hong, PhDDSuzi Hong, PhD
UC San Diego Department of Psychiatry

Title: Pesticide Exposures and Risks of Adverse Motor and Cognitive System Health Effects Among Latino Residents of Imperial Valley, California

Gradual declines in motor and cognitive functions occur with aging and significantly affect quality of life among the elderly. The extent and time course of these declines vary among individuals, and are affected by multiple factors, including co-morbid health conditions, psychosocial factors, and environmental toxicants. Exposures to some cholinesterase-inhibiting pesticides can induce motor and cognitive dysfunction, which can affect elders and even younger individuals (“accelerated motor and cognitive aging”). Neuro-inflammation is a widely accepted major pathogenesis mechanism for pesticide-induced motor and cognitive system toxicity.

This pilot study will examine the effects of cholinesterase-inhibiting organophosphate and the more recently developed (and presumably less neurotoxic) neonicotinoid insecticides on motor and cognitive functions among residents of a major agricultural community, Imperial Valley, CA, that has a long history of heavy pesticide exposure. Residents routinely experience excessive exposures to pesticides due to agricultural work and living in close proximity to farms. “Premature” motor and cognitive dysfunction, even mild, significantly impairs lifespan quality of life, diminishes productivity, and increases health care costs.

This will be a cross-sectional study of motor and cognitive outcomes among 50 Latinos, aged 45-70, who are long-term (>20 years) residents of Imperial Valley. A comparison population will include 25 Latino residents of El Cajon, CA with similar age and gender distribution, but lesser pesticide exposures. Participants’ residential, occupational, and medical history information will be ascertained from standardized questionnaires. Exposure profiles will be developed by linkage of residential history with publicly available pesticide spray data accumulated since 1974 by the California Pesticide Usage Reporting system. Nurse practitioners will perform clinical assessments based on standardized neurological exams. Inflammatory markers in blood will be assessed using immunoassay to examine degrees of systemic and neuro-inflammation. This combined clinical and biomarker approach can serve as a valuable template for future research on environmental neurotoxicity.

Olivier Harismendy, PhDOlivier Harismendy, PhD
UC San Diego School of Medicine, Biomedical Informatics

 

Title: Sharing Genetic Test Results

An increasing number of patients are undergoing molecular testing as part of their clinical care. These tests include a large number of genes and in a few cases exome-wide or genome-wide information, thus it became important to track and record such data systematically to increase their value for the practice of precision medicine and for patient-centered outcome research. However, the data is currently deposited in a highly heterogeneous format in the Electronic Medical Records (EMR). The results of the tests performed by third-party vendors are generally captured, even as a PDF file upload to the EMR. Consequently, the information is difficult to access and query by clinicians and researchers. Thus, the overall goal of our proposal is to enable the use of EMR for genetic research through the Clinical Data Warehouse (CDW). More specifically, we aim to develop the procedure, including data formatting and SOP, to allow UC San Diego to host mutation-specific information in UC San Diego’s CDW. Ultimately, we will share our procedure with other UC campuses to enable information sharing through a UC-wide clinical data warehouse such as UC Rex in a future study. We will achieve this goal through two specific aims: Aim 1 is to develop the procedure of importing genetic test information into the UC San Diego CDW in a standardized manner. In this process, we will also evaluate the adequacy of existing data standards in representing the genetic information in the CDW. We will use machine-readable test results obtained from Foundation Medicine and Ambry genetics. We will parse and encode the test results following the Fast Healthcare Interoperability Resources (FHIR) specifications for genetic tests before importing them to UC San Diego’s CDW. We will also identify approaches to incorporating data fields not covered by the existing data standards (e.g. structural variants). Aim 2 is to replicate retrospective cancer genetics analysis using CDW. In this aim, we will demonstrate the utility of including the genetic test information in CDW by (1) identifying clinical association in BRCA1/2 carriers, such as the specific difference in diagnostic age, tumor subtype, metastatic potential and chemo-toxicities of BRCA mutation carriers; and (2) determining the impact of Her2 profiling on anti-Her2 therapy. The knowledge to be gained from our pilot project is significant. Aim 1 will contribute significantly to the enrichment of CDW, a critical component of EHR-based research and data sharing to support precision medicine. The tools, data format and computational infrastructure to map genetic test results are currently in development and the completion of Aim 1 will significantly contribute to their improvement and their compatibility with existing systems. In turn, the completion of Aim 2 is essential to putting the results of Aim 1 to the test of real-world use cases. In particular, the completion of Aim 2 may reveal some weaknesses in the mapping of specific clinical data, but will clearly also demonstrate the power of EHR-based genetic research to quickly test hypothesis and generate preliminary data and evidence to support larger research efforts.

Jane J. Kim, MDJane J. Kim, MD
UC San Diego Department of Pediatrics

 

Title: Linking the Gut Microbiome to Metabolism in Obese Children with Type 1 Diabetes

The global prevalence of Type 1 diabetes (T1D) is increasing dramatically, particularly in children under 5 years old. This rise of T1D follows the same rising trend in childhood obesity. Nearly 40 percent of pediatric T1D patients are overweight or obese. Increased weight may accelerate diabetes onset and put these children at higher risk for cardiovascular disease, the leading cause of early death in T1D. The gut microbiome is the population of microbes within our intestine, containing over 3 million bacterial genes. No studies have examined the gut microbiome in children with both T1D and obesity. Moreover, no studies have measured how body metabolites change in response to these gut bacteria. Here, with a highly collaborative team of investigators with expertise of endocrinology, immunology, microbial biology, and informatics, we propose to employ 16S rRNA sequencing of the stool microbiome and urine metabolite profiling by mass spectrometry in pediatric T1D subjects with increased weight as well as appropriate controls. We hypothesize that individuals with T1DM and increased weight will have a unique metabolome profile and similarly that these same individuals will have a unique gut microbiome pattern. Our specific aims are as follows: 1. To identify distinct gut microbiome profiles in overweight/obese and normal weight children with or without T1D. 2. To identify distinct urine metabolome profiles in overweight/obese and normal weight children with or without T1D. 3. To examine the relationships between these two datasets in order to link how alterations in gut microbiota affect metabolic phenotypes in overweight/obese children with T1D. We will accomplish these aims by collecting stool and urine samples from four groups of children aged 7-17: i) obese/overweight subjects with T1D; ii) normal weight children with T1D; iii) obese/overweight subjects without diabetes; and iv) healthy, age- and gender-matched normal weight controls. These subjects will be recruited from the patient population at Rady Children’s Hospital of San Diego. We will examine how microbial composition and diversity of the gut microbiome changes with T1D and increased weight using 16S rRNA amplicon sequencing, followed by untargeted LC-MS measurement of urine metabolites, and bioinformatics analyses. Integrating the measurement of gut microbial species and urine metabolites will give direct biological insight into the pathways that link obesity and T1D. Our goal is to delineate how obesity accelerates T1D onset and the development of complications leading to early death, leading to novel therapies and improved outcomes for children with T1D.

Daphne (Yvette) LaCoursiere, MDDaphne (Yvette) LaCoursiere, MD
UC San Diego Department of Reproductive Medicine

 

Title: Placental Role in Biopsychosocial Risk for Childhood Obesity and Related Comorbidities (pending UC San Diego IRB approval)

Childhood obesity is a major problem in the U.S. and around the world. There are over 40 million children under age 5 who are overweight or obese. The risk for becoming obese begins before birth. Many factors contribute to this risk. This study will allow us to understand more about how the placenta affects child obesity risk. We expect to find important differences between the placentas of obese and non-obese mothers. The current study will link those differences to children’s weight at 5 years old and other obesity risk factors at age 5. Pregnancy and infancy are vital time points for later maternal and baby health. Findings may help us target those children at highest risk for obesity. We may also be able to identify prenatal markers for intervention, thereby preventing child obesity even before birth. This pilot study will explore how differences in obese and non-obese mothers’ placentas correlate with their child’s weight status and comorbid risk factors. We will study 15 obese and 15 non-obese Hispanic/Latina women and their children using data from medical records, placental biomarkers and direct mother and child assessments. We propose to collect biological and psychosocial data to understand how exposures in the First 1,000 Days relate to child obesity and related comorbidities. Incorporating a life-course approach, we will retrospectively examine maternal pregnancy characteristics, placental histopathology, delivery data, and infant bio-psycho-social characteristics. We will also specifically assess the role of placental epigenetic markers in the path from maternal obesity to child BMI and cardiovascular disease risk. Specifically, we will perform transcriptomic (mRNA and miRNA) and epigenomic (DNA methylation, histone modification) analysis of banked placental samples from enrolled mothers. We will also assess, via questionnaire, the mother’s socioeconomic and psychosocial factors (e.g. education, family characteristics, nutrition history, etc.) and measurement/specimen collection to assess mother and child biological factors (e.g., BMI, physical activity, carbohydrate tolerance, lipid profile, heart rate and blood pressure). Physical activity in the child will be assessed using 7-day accelerometry (child will wear non-intrusive accelerometer on either wrist) to measure activity levels and sedentary time. Our goal will be to examine how these placental, biologic, and psychosocial factors relate to current child weight status at 5 years of age. Findings from this study will support future research powered to detect how obesity-related placental markers may relate to cardiovascular risk in the next generation.

Jair Lage de Siqueira Neto, PhDJair Lage de Siqueira Neto, PhD
UC San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences (pending UC San Diego IRB approval)

 

Title: Zika Virus Drug Discovery

Zika Virus (ZIKV) is a Flavivirus identified in Africa in rhesus monkeys in 1947, causing mild symptoms when affecting humans. An Asia strain of ZIKV caused outbreaks in Micronesia and French Polynesia, and was reported to cause Guillain-Barre syndrome in some cases and affecting the neurodevelopment of fetuses when the mother was infected during pregnancy in some other cases. The Asian strain was introduced in the American continent in 2013 and rapidly spread due to the abundance of the insect vector Aedes aegypti. We recently showed that the circulating Brazilian ZIKV strain (ZIKVBR) is the causative agent responsible for the birth defects epidemic in South America (Cugola et al, Nature 2016). The World Health Organization has declared a Public Health Emergency of International Concern for the rapid spread of ZIKV combined with the serious neurological outcomes and absence of a vaccine or therapy. To address this urgent and unmet medical need, we propose to develop a drug discovery screening assay to identify antiviral chemotherapy candidates.

We will combine the cytopathic effect of the virus with a phenotypic approach to determine and quantify antivirus activity in vitro. Given the clinical relevance of the virus causing neurodevelopment impairment, we will use neural progenitor cells (NPCs) as host cells. We will initially adapt the NPCs to 1536-well microplates and infect with ZIKVBR. Infection outcome readout will be based on host cell viability measured after the addition of resazurin, reduced to fluorescent resofurin by healthy cells. Fluorescence will be detected in Envision (readout 1). We will also perform a phenotypic analysis after DNA staining (Hoechst) to quantify the number of apoptotic cells based on nuclei morphology and intensity using the automated microscope ImageXpress Micro XL (readout 2).

Once the assay conditions are well stablished with Z-factor > 0.5 in both readouts comparing infected and mock (non-infected) controls, we will test a set of compounds. The first set will be composed of ~2,500 FDA approved drugs, including antiviral compounds and selected compounds approved to be used during pregnancy. This initial set aims a drug repurposing strategy in case of identification of a successful antiviral activity. A compound will be considered a hit in a primary screening if it prevents host cell death more than 3 standard deviations from the untreated-controls average from readout 1 or 2 (based on exclusion of inactive compounds). The hits will be then tested in dose-response to determine the potency (IC50). The most potent hits will be re-purchased from a different source for activity confirmation (quality control) and will be later tested against tridimensional culture models, including cerebral corticoid organoids and neurospheres. The efficacy of the compound will be evaluated based on the protection of these structures compared to untreated controls based on size/growth.

Carrie McDonald, PhDHattangadi-GluthCarrie McDonald, PhD
UC San Diego Department of Psychiatry
Jona Hattangadi-Gluth, MD
UC San Diego Department of Radiation Medicine & Applied Sciences

 

Title: Integration of BOLD-FMRI and DTI into Radiation Treatment Planning for Sparing of Eloquent Brain Regions (pending UC San Diego IRB approval)

While radiation therapy (RT) is a mainstay in the treatment of primary and metastatic brain tumors, a majority of patients experience post-RT cognitive decline. RT-induced cognitive impairment can manifest as a range of problems, depending on the location of the tumor and dose delivered to eloquent white matter and cortical structures. Of particular concern is the observation that RT to perisylvian regions (i.e. regions that subserve language and semantic processing) often result in severe deficits in word retrieval, working memory, and other verbally-mediated skills.

Functional MRI (fMRI) and diffusion tensor imaging (DTI) are frequently used to identify eloquent cortex and white-matter pathways, respectively, as critical volumes to avoid during neurosurgery. However, RT planning lags far behind, as these technologies have not been incorporated for sparing eloquent brain from high doses of radiation. This study brings the best of innovative, precision medicine to brain tumor treatment by incorporating information from advanced, multimodal imaging into knowledge-based RT planning. Our specific aims are as follows: to evaluate whether the incorporation of BOLD-fMRI and DTI data into RT planning can be used to spare eloquent brain regions from high doses of radiation in patients undergoing brain RT; and to determine whether sparing eloquent brain regions during RT results in comparable local tumor control and improved language/semantic outcomes (i.e. minimal or no decline from baseline to 3-months post RT) related to a control group for whom fMRI/DTI were not used in RT planning.

This study includes patients with a single primary or metastatic tumor who will be undergoing intracranial RT (fractionated partial brain radiotherapy or stereotactic radiosurgery). They will undergo neuropsychological testing and task-related fMRI/DTI prior to RT. Imaging data will be individually mapped in each patient to identify perisylvian cortex and white matter pathways critical to language, coregistered in 3D space, and imported into RT planning software to be avoided during RT. Patients will then be followed with standard MRI sequences to evaluate for tumor control. At 3 months post-RT, cognitive testing will be repeated. Cognitive outcomes, as well as local tumor control, will be evaluated.

Testing will be conducted to determine whether change in cognitive scores (pre-post RT) differs between patients who received perisylvian sparing versus those whose perisylvian regions were not considered in the RT planning (recruited from a separate on-going study), and whether the proportion of patients who showed a significant decline differs between the two groups.

Shirley M. Tsunoda, PharmDShirley M. Tsunoda, PharmD
UC San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences

 

Title: The Effect of the Microbiome on Drug Metabolizing Enzymes

The gut microbiome is a collection of microorganisms that reside in our intestines. Changes in the microbiome are thought to be important determinants of health and disease. When a drug is taken orally, intestinal and liver enzymes metabolize a portion of the drug affecting its overall bioavailability. The goal of this study is to investigate if changes in the gut microbiome affect how drugs are processed in the body. Organisms in the gut microbiome may interact with gut enzymes responsible for metabolizing drugs. A combination of drugs will be given to phenotype multiple drug metabolizing enzymes simultaneously. We will use a modified validated cocktail (Cooperstown cocktail) of oral drug probes for the following enzymes: caffeine for CYP1A2, N-acetyltransferase 2 (NAT-2), and xanthine oxidase (XO); omeprazole for CYP2C19; dextromethorphan for CYP2D6; and midazolam for CYP3A. The cocktail would be given before and after a 7-day course of cefprozil, a second generation cephalosporin. Blood, urine, skin, and fecal samples will be taken throughout the study. To characterize bacterial strains in fecal matter, 16S rRNA amplicon sequencing method (LEA-Seq) and whole genome sequencing will be employed. 16S rRNA amplicon sequences and 3D mapping of mass spectrometry will be utilized to analyze skin for microbiota composition before, during, and after antibiotic therapy. Targeted MS will be performed on the TSQ operating the instrument in a multiple reaction monitoring (MRM) mode, which increases analytical specificity and increases the sensitivity of analyte detection. The MRM method will be optimized using analytical standards. Untargeted MS will be performed using the Q-Exactive mass spectrometer operated in a data dependent MS/MS mode, which provides high mass resolution MS data as well as MS/MS spectra for the Nth most abundant ions. Blood and urine will be analyzed by liquid chromatography and mass spectrometry as appropriate. Noncompartmental pharmacokinetics will be performed. Statistical analysis will be performed using R. The results of this study may contribute to our understanding of drug variability on therapeutics and toxicity. Understanding the clinical implications of the gut microbiome on drug therapy may form a basis for precision medicine.

Jillian Lee Wiggins, PhDJillian Lee Wiggins, PhD
San Diego State University, Department of Neurosciences

 

Title: Pathways of Risk and Resilience: Neural Predictors of Irritability in At-risk Offspring of Mothers with Depression

Irritability, defined as an abnormally low threshold for anger, is the most common reason parents seek psychiatric care for their children (>40% emergency department cases, >20% psychiatric outpatients). Adolescent irritability is a diagnostic criterion or associated symptom in multiple psychiatric disorders and predicts poorer health and socioeconomic outcomes in adulthood. Maternal depression is one of the best-documented risk factors for irritability: our work shows that 50% of children (ages 3-9) of depressed mothers show severe irritability, 36% of whom fail to remit by pre-adolescence. Yet there is currently no way of identifying, in advance, which at-risk youths will develop irritability problems and require intervention.

To address this, we use an innovative, translational approach that applies neuroimaging tools from basic research to predict future irritability problems in children of depressed mothers. Our preliminary work suggests that irritability may result from two potential pathways: reward processing, whereby children less able to adapt to changing reward conditions may experience more frustration, causing greater irritability; and face emotion recognition, whereby children with impaired ability to recognize face emotions may erroneously perceive hostility and react irritably. However, brain activation patterns that prospectively predict irritability are unknown.

As a step toward life-course research, we propose to acquire fMRI data and assess irritability in offspring of depressed mothers, with a symptom-only follow-up one year later. Our long-term goal is to generate brain information that can be used in interventions to prevent the development of irritability. Our overall objective is to identify brain activation patterns that predict irritability severity in adolescent offspring of mothers with depression. We aim to identify neural predictors of irritability related to reward processing and face emotion recognition, and to characterize the relationship between reward processing and face emotion recognition pathways to irritability. Identifying biomarkers that predict irritability should enable us to deploy preventive interventions to those who need it most and refine interventions based on this pathophysiological information.


Innovative Technology Pilot Projects

Matthew Shtrahman, MD, PhDMatthew Shtrahman, MD, PhD
UC San Diego Department of Neurosciences

Title: Developing Two-Photon Calcium Imaging of Brain Activity for Human Subjects

As highlighted by the NIH Brain Initiative, the field of neuroscience is undergoing a technological revolution with new methods to both manipulate and record neural activity with single-cell resolution. However, rarely have these advances been adapted to the clinic or operating room to facilitate the diagnosis and treatment of human brain disease. Traditionally, electrode-based methods have been the principal technique for monitoring brain activity in both the experimental and clinical settings. However, electrophysiological techniques have clear limits, including tradeoffs between electrode density, tissue invasiveness, and the spatial extent of brain coverage.

More recently, the development of optical approaches for measuring neuronal activity offers many promising features, as light can be delivered and recorded rapidly and non-invasively on temporal and spatial scales that span several orders of magnitude. Specifically, two-photon microscopy takes advantage of pulsed infrared light, which exhibits limited scattering in biological tissue, to record optical signals in thousands of individual cells. In conjunction with fluorophores that report neuronal activity, this approach can track activity in large neuronal networks with single-cell resolution in awake behaving animals, including non-human primates.

There is tremendous potential for two-photon microscopy to impact the diagnosis and treatment of human brain disease. In particular, patients with operable brain disease such as medically refractory epilepsy or intracranial tumors would benefit greatly from techniques offering precise resection of affected tissue. Imaging neuronal network activity with single-cell resolution can reveal both physiological and pathological network dynamics, which should greatly facilitate precise localization and fine discrimination of eloquent cortex and brain areas involved in seizure formation.

Our pilot project aims are to explore the use of two-photon microscopy as a viable clinical tool and to establish the safety of fluorescent indicators of neuronal activity in humans.

Michael Yip, PhDMichael Yip, PhD
UC San Diego Jacobs School of Engineering
Electrical & Computer Engineering

Title: A Robotic, Wristed Cupped Biopsy Forceps for Flexible Endoscopy

The ability to access diseased tissues using minimally invasive tools is critical to preserving the patient’s health and reducing unnecessary trauma. The move from open surgery to laparoscopic surgery has had widespread impact in the past 40 years, and recent techniques to perform endovascular and endoscopic procedures using catheters and endoscopes is an evolution of this principle. Without a doubt, the most non-invasive method for introducing instruments is through a natural orifice. However, few tools offer the small and thin form factor as well as the dexterity required to perform complex interventional tasks required in such tight spaces. Frequently, these tools are long, bulky, and rigid tools that lack a dexterity at the end of the instruments to fully reach all tissues necessary to perform a task in an atraumatic fashion.

The da Vinci Surgical Robot offers a laparoscopic solution to regaining wrist dexterity for laparoscopic surgeries and has revolutionized patient care for surgeries in constrained anatomies such as the prostate or oropharyngeal cavity. However, the da Vinci robot is far too large to operate in the laryngeal, hypopharyngeal, esophageal, or tracheal region and therefore is not an option for these anatomic areas. Practitioners who focus on these areas and other endoluminal regions distal to an orifice such as the lung, stomach, or colon, also have limited options for endoluminal instruments that allow for manipulation of tissue. Current instrumentation does not provide sufficient dexterity and sufficient access to tissues for many procedures, including minimally invasive laryngeal surgery. This can lead to increased trauma from endoscopic treatments, inability to complete procedures endoluminally, and conversion to open surgical procedures, which can be associated with increased morbidity.

We propose a robot-assisted biopsy forceps for flexible endoscopic procedures. The major innovation is the first wristed instrument that completely reproduces the dexterity of the surgeon’s hand but through the instrument channel of flexible endoscopes. To accommodate the extra wrist degrees-of-freedom, the proposed instrument will be controlled using a small motorized mounting system. With the ability to control the position and orientation of the biopsy forceps, the instrument is teleoperated via a desktop stylus interface, which provides intuitive position/orientation control of the wristed device. With the design of wristed instruments using lightweight motorized mounts in a compact form factor, this instrument requires minimal space and is reasonably lightweight such that it can be used in a doctor’s office for awake procedures or endoscopy suite to allow doctors to provide improved on-site diagnosis and care. The ability to offer significantly improved biopsy and therapy services in a non-hospital setting allows patients to avoid general anesthesia, significant recovery periods, and high hospital costs, and receive more rapid and timely care.


Academic-Community Pilot Projects

Richard Haas, MDGail Reiner, PhDRichard Haas, MD
UC San Diego Department of Neurosciences
Gail Reiner, PhD
Azusa Pacific University San Diego Regional Center

Title: The Impact of Breastfeeding in High-risk Neonates with Hypoxic Ischemic Encephalopathy on Fetal Maternal Bonding and Neurodevelopmental Outcome (pending UC San Diego IRB approval)

The multiple health benefits of breast feeding for both infant and mother are increasingly recognized. There is strong evidence that breastfeeding results in lower risk of hospitalization for respiratory tract infection, otitis media, asthma, atopic dermatitis, gastroenteritis, obesity, leukemia, diabetes and sudden infant death syndrome. Studies also show that breastfeeding improves cognitive ability, including in preterm and very preterm infants, populations that are at high risk of developmental delays. This project will study the impact of breastfeeding in high-risk neonates with hypoxic ischemic encephalopathy on neurodevelopmental outcome and maternal-infant bonding. Study within this group is relevant since these children have a high incidence of developmental sequelae, and optimizing neurodevelopmental outcome is of paramount importance. There are many obstacles to the successful establishment of breastfeeding in this high-risk group. These infants are critically ill and by necessity are physically separated from their mothers in order to undergo 72 hours of hypothermia treatment and to receive the intensive care required. They are kept nil by mouth initially because of a possible compromise of enteral perfusion. When enteral feeds can be safely started, the neurologic injuries these infants have sustained and the sedating medications they often receive commonly cause difficulty with sucking feeds. The psychological stress of having a critically ill infant and the physical impact of a difficult delivery can have an adverse impact on lactation for the mother. All these factors also place maternal-infant bonding at risk. The few studies that examine the impact of neonatal hypoxic ischemic encephalopathy and hypothermia treatment on maternal-infant bonding suggest that there can be a serious impact on parent-infant bonding and that parental feelings of ambivalence or alienation can persist for years. Notwithstanding the obstacles to breastfeeding in this patient group, breastfeeding may have a protective and positive impact on maternal-infant bonding.

A prospective cohort of neonates with neonatal seizures, many of whom have suffered hypoxic ischemic encephalopathy, is under study in the NEOLEV2 trial. The cohort offers an opportunity for a prospective study of breastfeeding in high-risk infants who have suffered hypoxic ischemic encephalopathy. Subjects who received hypothermia treatment for hypoxic ischemic encephalopathy will be identified from the NEOLEV2 database, and outcome data (Bayley III Scores at 24 months and Postpartum Bonding scores) will be compared between the two groups. The Bayley III Neurodevelopmental assessment is a standardized, validated metric of child development with five sub-scores (language, motor, cognitive, social-environmental and adaptive), which yields standardized scaled scores or percentile ranks. The Postpartum Bonding Questionnaire is the best validated tool for the assessment of maternal-infant bonding. This project would provide data and an objective perspective on mother-infant bonding in a high-risk population where barriers to breastfeeding and bonding are significant. It will document whether significant problems with maternal-infant bonding occur in infants with hypoxic ischemic encephalopathy and investigate whether breastfeeding can be protective in this regard.

Sarah Rieth, PhDSarah Rieth, PhD
San Diego State University Department of Child and Family Development

Title: Building Capacity for Evidence-Based Early Intervention in Imperial County: A Community Collaborative Approach

Access to evidence-based approaches to diagnosing and treating young children with autism spectrum disorders (ASD) in community services is limited, particularly for ethnic and language minority groups. Disparities in timely identification of ASD and subsequent delays in treatment entry are common, with minority children often not identified until after age eight. For those individuals who do access care, research suggests that ethnic minority families are less likely to receive high-quality, evidence-based care. There are national policy directives to develop and test strategies to reduce these disparities for ASD (Interagency Autism Coordinating Committee Strategic Plan for Autism Research) and more broadly (NIMH Strategic Plan). Locally, there is a critical need to reduce disparities to evidence-based intervention for children at risk for ASD in Imperial County. This has been identified as a high-priority goal by the primary funder of early intervention services in Imperial County (San Diego Regional Center), community provider organizations, and families. The population of this rural County is nearly 90% Hispanic, and 20% of that population is estimated to live below the poverty line (U.S. Census, 2015). In a 2012-2013 survey, there was one mental-health provider for every 17,514 County residents. Leaders have identified the need for an educated workforce as the single most important issue for county development (Imperial County Comprehensive Economic Development Strategy Committee, 2016). SDRC aims to improve access to early intervention services for Imperial County families, including decreasing disparities for Spanish-speaking families. Approaches to reducing disparities include conducting community-partnered research and identifying workforce development strategies. In San Diego County, the BRIDGE Collaborative was formed to select and adapt an evidence-based intervention model for delivery in early intervention services. Since its formation in 2007, BRIDGE has formed a sustained partnership infrastructure and is testing the impact of in-person provider training on child outcomes. The goal of the proposed project is to apply the BRIDGE model of partnership development to form a new academic-community collaborative to reduce disparities in access to evidence-based early intervention for children identified at risk for ASD in Imperial County. Partnership development and research will be conducted in partnership with San Diego Regional Center, the primary funder of early intervention services in Imperial County. Our project aims are as follows: Apply the BRIDGE Collaborative approach to form a new academic-community collaborative in Imperial County, aimed to reduce disparities in access to evidence-based early interventions for young children with-risk for ASD and their families; Conduct a community needs assessment to inform adaptations to a parent mediated naturalistic developmental behavioral intervention for toddlers at-risk for ASD; Pilot test a distance training model of the intervention with early intervention providers working in Imperial County and the families they serve.

Initial project activities will focus on identifying members and establishing collaborative infrastructure (communication methods, decision-making processes) to form a group of community service providers, funding agency representative, parents of children with ASD, and researchers.

Co-PIs on the project are Terri Cook-Clark, San Diego Regional Center, and Lauren Brookman-Frazee, PhD, associate professor of psychiatry, UC San Diego.


Dissemination and Implementation Research Pilot Project

Elizabeth Twamley, PhDElizabeth Twamley, PhD
UC San Diego Department of Psychiatry

Title: Working to Improve Supported Employment Fidelity (WISE Fidelity)

Employment is an important part of recovery for people with severe mental illness and is essential to recovery-oriented psychosocial treatment. Supported employment (SE) is the evidence-based practice to assist people with severe mental illness (SMI) in getting and keeping competitive work. Key principles of SE include rapid job searching, a focus on competitive work and client preferences, and job development with community employers. Various initiatives are underway to increase the availability of SE both within San Diego County and throughout the U.S., but there is no standard implementation approach to support high fidelity, sustained utilization, and there are no implementation studies to inform implementation efforts. The County of San Diego Behavioral Health Services seeks to make SE available to persons with SMI and has awarded contracts to community organizations to provide SE services in 13 different programs throughout San Diego County. SE fidelity reviews based on the current supported employment fidelity scale (SEFS) are time-consuming and expensive. The current SEFS is a 25-item tool that includes fidelity indicators across three core dimensions (staffing, organization, and service provision). Each item assesses the extent to which specific components of SE are delivered, based on a behaviorally-anchored 5-point scale. As part of a new program of research focused on developing tools and processes that will facilitate the broader implementation and sustainment of high fidelity SE, in this study we seek to do the following: conduct SE fidelity reviews in “real world” settings to develop estimates of the benefits and burdens associated with assessing each of the 25 existing fidelity items; and conduct secondary data analyses on a set of previously collected SE fidelity reviews to identify which individual items are most strongly and uniquely associated with total fidelity scores and desired outcomes like competitive employment rates. This information will help inform the development of a substantially shorter version of the SEFS that will be easier and cheaper to administer.