Ph.D. - Biomedical Sciences
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Item Evaluation of Sepsis-Related Cytokines on Endothelial Cell Permeability(University of Hawaii at Manoa, 2022) Campbell, Carmen Elaine; Rodriguez, Beatriz; Boisvert, William; Biomedical SciencesSepsis elicits a complex immune response in which endothelial cell function is affected by various critical inflammatory mediators and coagulation factors. The endothelial cell lining plays a central role in the pathogenesis of sepsis leading to Severe Inflammatory Response Syndrome (SIRS) and Multiple Organ Failure Syndrome (MOFS). Although diagnostic methods to assess endothelial cell function would be valuable for evaluating the effectiveness of therapeutic interventions designed to repair damaged endothelium in septic patients, no such tools exist at this time. Thus, the overall goal of this research was to characterize vascular endothelial cell monolayer integrity and barrier function changes that may be induced by inflammatory cytokines in vitro. To meet this objective, we recorded dynamic responses of endothelial cell monolayers treated with a selection of sepsis-related cytokines including TNF-, IL-1, IL-6, IL- 8, IL-10, IL-12, IFN-, and TGF- in-vitro using a novel method known as Electric Cell-substrate Impedance Sensing (ECIS). Our results demonstrate that Human Aortic Endothelial Cell (HAoEC) monolayer permeability is significantly increased when treated with TNF-α, IL-1β, IL-6, IL-10, or IFN-γ compared to untreated controls reflected by impedance changes of cell-covered electrodes. The data revealed a significant decrease in normalized impedance (ohm@16kHz) changes at early time-points (<2 hrs.) between untreated control cells compared to: IL1- (p<0.001), IL-6 (p=0.0019), IL-10 (p<0.0001), TNF- (p<0.001), or IFN- (p=0.0288) treatment groups. On the other hand, the response of cells treated with IL-8 (p<0.0001) resulted in a significant increase in the normalized impedance change compared to untreated controls. No significant difference in the normalized impedance at early time-points was observed for the TGF- or IL-12 treated cells. Using the ECIS modeling parameters, significant differences in permeability of cell monolayers treated with sepsis-related cytokines were revealed. A significant reduction in Rb resulting in increased permeability was observed for TNF- (p=0.0112), IL1- (p=0.0196), and IL-10 (p=0.0010) treatment groups. Conversely, the Rb values were significantly increased in the case of IL-6 (p=0.0007), IL-8 (p=0.0016), and TGF- (p<0.0001). No significant difference in Rb was observed for cells treated with IL-12. Significant reductions in Rb values were observed in monolayers treated with cytokines combined. IL-1β combined with TNF-α at ratios of 1:1, 5:1, and 10:1 resulted in significant reduction in Rb compared to mock-treated controls. In the case of IL-12 and IFN- combined, Rb is significantly increased when treated with IL-12:IFN- (10:1) and IL-12:IFN- (5:1) ratios but is significantly decreased when treated with IL-12:IFN- (1:1). Interestingly, Rb of HAoECs is significantly increased when treated with TGF-:TNF- (1:1) (p<0.0001), IL-10:TNF- (1:1) (p<0.0001), IL-10:TNF- (10:1) (p<0.0001), or IL-12:TNF- (5:1) (p<0.0001) compared to TNF- alone. Likewise, preincubation of the anti-TNF-α monoclonal antibody with TNF-α led to loss of cytokine effect and no significant reduction in barrier resistance (Rb) was observed compared to mock treated controls. Results from these in vitro studies provide further evidence to support the translation of new technological approaches from bench-top research tools to clinical applications. More research using the ECIS technology in a clinical setting, using plasma from patients with sepsis, would be of great value to extend these findings and identify early evidence of damage of the endothelial cell integrity of the vasculature and its barrier function. This could potentially lead to more timely treatments and improvement of outcomes in people with sepsis.Item Health Care Needs Of Homeless Women With Children Living In Honolulu(University of Hawaii at Manoa, 2021) Kissinger, Deborah; Rodriguez, Beatriz; Biomedical SciencesHomeless individuals often experience significant physical, psychological, and social health problems associated with experiencing high level of social determinants of health deficits. This particularly vulnerable population requires specialized health care tailored to their needs. This study aimed to address a gap in the literature regarding self-reported health care needs and barriers to care experienced by homeless women with children. A mixed study using individual open-format and closed-format interview questions was conducted involving homeless women (n = 20) with children living in Honolulu, Hawaii. Qualitative data analysis revealed five main themes related to health care: 1) self-remedy; 2) personal criteria for pivoting to professional health care; 3) connection; 4) barriers to care; and surviving conditions of homelessness. Findings emphasize the gap between perceived and evaluated health care needs of homeless women with children and the strategies these women use to manage the disparity. This study provides a sketch of how the practice of these strategies may bridge the gap experienced by homeless individuals between self-perceived illness symptoms and illness symptoms evaluated and treated by a care provider. This mixed methods study addressed a gap in the literature and allowed a better understanding of the health, health care needs, barriers to health care, and health services use patterns of sheltered homeless women with children living in the City and County of Honolulu (Honolulu), on the Island of Oahʻu, Hawaiʻi. Therefore, it encourages health care providers to be more aware and inclusive of self-remedies in treatment plans as well as to regularly solicit information about patient’s self-remedy practices, to ensure safety. The findings are expected to be beneficial in efforts to improve tailoring health care approaches to the needs and health outcomes of homeless women with children.Item Divergent Microbial Profiles in Tumor and Adjacent Normal Tissue across Cancer Types(University of Hawaii at Manoa, 2019) Rodriguez, Rebecca Maria; Hernandez, Brenda Y.; Deng, Youping; Biomedical SciencesBackground: There is growing evidence that microbial variation can influence cancer development, progression, response to therapy, and outcomes. We wanted to examine the microbial composition of paired tumor and adjacent normal tissue across various cancer types in order to provide an improved understanding of microbial diversity and abundance patterns of the tumor microenvironment and their influence on clinical presentation and survival. Methods: Using raw whole exome sequencing data from 22 cancer types from the The Cancer Genome Atlas (TCGA) network, we examined differential relative abundance and diversity data in primary tumor and adjacent solid tissue normal (adjacent normal), nine of which are presented in this work. Data were processed through a bioinformatics pipeline designed to extract microbial profiles from human sequencing data based on PathoScope 2.0. Differential abundance and diversity metrics were calculated using R-package tools to compare primary tumor and adjacent normal within cancer types and across cancer cohorts correlating to clinical features including histologic and pathologic features and survival data. Analyses were controlled for demographic, exposures and batch effects. Findings were then validated by qPCR for selected cancer types with tissue from the Hawaii Tumor Registry RTR. Results: As part of a pilot project we have created microbial composition and diversity profiles for a subset of solid tumors within TCGA cancers building a platform for ongoing and future studies. We screened over 10,000 files encompassing a total of 1,838 paired cases from which 813 are discussed here. From those, 767 tumors and 753 adjacent normal samples had positive microbial (viral and bacterial) sequence reads detection. Microbial composition and diversity (richness, within sample alpha diversity, evenness and beta diversity) varied across cohorts with similar patterns at the phylum level in compositional structures. Bacterial shifts were evident in tumor compared to adjacent normal. Proteobacteria phyla was observed to be increased in tumors of all cohorts except for STAD, where Proteobacteria species were reduced and Firmicutes levels increased. Differences between patient samples were evident at the higher taxonomic levels. Differential abundance analyses revealed significant differences in stomach adenocarcinoma (STAD) and colon adenocarcinoma (COAD). Compared to adjacent normal, tumor samples were found to have lower number of species present overall and lower diversity indices. We found significant association between microbial relative abundance and diversity to clinicopathological presentation and survival dependent on race in some cancers, particularly those of infectious origin like STAD and LIHC. Conclusion. This project demonstrates the feasibility of the utilization of exome sequencing data to derive complex microbial data with easy to interpret results. This project facilitates the understanding of the role of bacteria play in cancer pathogenesis across different race groups as demonstrated in LIHC and STAD cancer cohorts. In these cancers, relative abundance was associated with tumor stage and overall survival days and within sample diversity was associated with race in fully adjusted models.Item Assessment of Non-Pharmacologic Patient-Centered Pain Control Adjuncts on Pain Scores during First Trimester Abortion.(University of Hawaii at Manoa, 2017-05) Tschann, Mary S.; Biomedical SciencesObjectives: The objective of this study is to review the literature regarding non-pharmacologic pain management techniques during first trimester abortion and to determine if a patient-centered approach to non-pharmacologic pain management is associated with lower pain scores during a first-trimester surgical abortion. Study Design: Chapter one contains an integrative review of the literature regarding predictors of pain during first trimester abortion and of the efficacy of non-pharmacologic pain management techniques. Chapter two presents a randomized controlled trial of a patient-centered non-pharmacologic pain management approach during first trimester surgical abortion. Results: The integrative review found that pre-procedure anxiety and depression are associated with increased pain during first-trimester surgical abortion. The trials of non-pharmacologic pain management techniques found that none of the interventions had a significant impact on pain scores during the procedure. The randomized controlled trial presented in Chapter Two found no difference between the intervention (patient-centered non-pharmacologic pain management) and control (standard care) groups. Conclusions: Anxiety, depression and isolation have consistently been shown to be a good predictor of patient pain levels during first-trimester surgical abortion. The studies in the integrative review and the randomized controlled trial attempted to mitigate these impacts through non-pharmacologic pain management techniques. While none of the trials demonstrated an association between these techniques and reduced pain scores, patients were consistently positive about the use of these techniques. Adding these interventions to clinical practice could be a low-cost, low-risk quality improvement measure.Item Evaluation of Tumor Localization in Respiration Motion-Corrected Stereotactic Body Radiotherapy Patients Treated with TomoTherapy.(University of Hawaii at Manoa, 2017-05) Hirata, Emily Y.; Biomedical SciencesLung cancer is the second most common cancer in both men and women, estimated to account for 158,080 deaths in 2016 according to the American Cancer Society(1). Approximately 85% of all lung cancers are non-small cell lung cancer (NSCLC). While surgical resection remains the standard therapy for operable stage I lung cancer patients(2), stereotactic body radiation therapy (SBRT) is a noninvasive alternative for the inoperable population(2–4). SBRT is a technique that delivers high doses of radiation to tumors, generally in one to five treatments which are known as “fractions”. Since SBRT demands a high degree of confidence in tumor definition and localization, it requires the assessment and management of tumor motion (i.e. the respiratory excursion of the tumor)(3–7). Respiratory motion is of particular concern for TomoTherapy (Accuray, Inc, Sunnyvale, CA), which utilizes a continuously rotating gantry (maximum speed of 12 seconds per rotation) synchronized with a linearly moving couch to irradiate a target volume in a helical manner(8,9). The interplay between the motion of the radiation and the motion of the tumor can cause a discrepancy between the desired dose and the dose actually delivered. This is commonly referred to as the “interplay effect.” The goal of this work was to investigate the interplay effect using a cohort of patient respiratory waveforms and a motion phantom. Respiratory waveforms were characterized using principal component analysis of tumor displacement sampled via four-dimensional computed tomography (4DCT). These waveforms, programmed into the motion phantom were used to evaluate both the imaging and treatment accuracy of TomoTherapy. Ion chamber and film measurements were collected for the static condition, motion at the native breath frequency of the patient, and a modified motion averaging 5 breaths per minute (bpm). TomoTherapy megavoltage CT (MVCT) scans did not show marked interplay effect. Scanning in fine mode resulted in smaller positional errors, though larger imaging artifacts were visible. Lower breath frequencies were significantly associated with larger variance in dose, and larger amplitude of tumor displacement correlated with larger penumbral blurring. Banding of hot and cold were observed on film for several cases, although ion chamber measurements were mostly within the recommended 2% criteria. Strategies for minimizing the interplay effect involve maintaining an elevated breath frequency, improving regularity of the respiratory waveform, and avoiding the use of TomoTherapy plans with a fast gantry period of 12 seconds per rotation. The results of this dissertation provide a clinically based evaluation of the interplay effect on TomoTherapy for SBRT treatments.Item Prophylactic Pregabalin to Decrease Pain during Medical Abortion: A Randomized Controlled Trial(University of Hawaii at Manoa, 2017-05) Friedlander, EmmaKate B.; Biomedical SciencesOBJECTIVE: To evaluate whether prophylactic pregabalin reduces the level of maximum pain experienced with mifepristone-misoprostol medical abortion. METHODS: We conducted a randomized, double-blind, placebo-controlled clinical trial of women initiating a medical abortion up to 70 days of gestation. After taking mifepristone, participants were randomized to a capsule of pregabalin 300 mg or a matched placebo to be taken at the time of buccal misoprostol. All participants were dispensed ibuprofen and oxycodone with acetaminophen as additional analgesia to be taken as needed. Electronic surveys were sent via text message link at six time points over 72 hours to assess the primary outcome of maximum pain, as well as secondary outcomes such as analgesic use and adverse effects. RESULTS: From June 2015 to October 2016, 110 women were randomized to receive 300 mg of pregabalin or a matched placebo. Demographic characteristics were similar between groups. The primary outcome of maximum pain score in the pregabalin group was 5.0 versus 5.5 in the placebo group (standard deviations 2.6 and 2.2, respectively; p=0.32). More participants in the pregabalin group did not need additional analgesia. No ibuprofen was taken by 27% of the pregabalin group versus 12% placebo (p=0.04). No oxycodone with acetaminophen was taken by 69% of the pregabalin group versus 50% placebo (p=0.04). Satisfaction scores for the abortion process were highest in the pregabalin group (very satisfied: 41% versus 22%; p=0.03), as were satisfaction scores for the analgesic regimen (very satisfied: 47% versus 22%; p=0.006). CONCLUSION: Maximum pain scores were not significantly different between the pregabalin and placebo groups, though women who received pregabalin were less likely to require any ibuprofen or oxycodone with acetaminophen, and were more likely to report higher satisfaction scores.Item Kūkulu Ola Hou. Rebuilding Native Hawaiian Health by Reconnecting Ancestral Practices of Traditional Medicine: An Inventory of Researched Customs, Rituals, and Practices Relating to Hawaiian Mai.(University of Hawaii at Manoa, 2017-05) Fox, Leanne K.; Biomedical SciencesThis qualitative health study examined customs, rituals, and practices relating to Hawaiian maʻi, —kānaka ʻōiwi perceptions of imbalance, illness, sickness and disease—and produced a comprehensive inventory of findings. Maʻi shape biomedical classification of illness by Native Hawaiians from their Ka „Oihana Mauli Ola; recounted here from the nosology within their traditional Hawaiian health structure. A Hawaiian medical epistemological framework was developed to conduct this mixed method study across eight arms before interpreting both ancient and contemporary knowledge and beliefs. Primary data collection consisted of key informant interviews (N=25) and one focus group (N=25) sampling from experts and learners of traditional Hawaiian medicine. Secondary data collection, synthesis and analyses were conducted in English and ʻōlelo Hawaiʻi utilizing over 100,000 records in multiple archives (N=11). Study significance indicates the first comprehensive medical inventory documenting knowledge of Hawaiian maʻi across time periods and traditional practices, systematically referencing more than 7,000 Hawaiian maʻi terms and dozens of unique disease classes and categories. Findings suggest this integrative medical inventory and taxonomy can inform the diagnostic process and improve diagnosis procedures for health care and prevention. Further, it can create new quality standards for culturally and linguistically appropriate services for Native Hawaiian health.Item Dietetics Practice and Culturally Safe Care in the Diverse Pacific Region(University of Hawaii at Manoa, 2017-05) Endrizal, Cynthia L.; Biomedical Sciencesntroduction. The prevalence of non-communicable disease (NCD) rates in the diverse Pacific region is deeply concerning. The impact of these diseases and associated complications is overwhelming to families and communities and are a common point of discussion in medical, political and social domains. While much research has been dedicated to the prevention and treatment of NCDs, less research is focused on interactions between health care practitioners and their patients with NCDs. With the Pacific region representing a very diverse community of Indigenous peoples, migrated groups and new-comers; this creates a consequential mix in cultural worldviews and values. Health care providers are challenged with recognizing and understanding these cultural values. Registered Dietitian Nutritionists (RDNs) are particularly challenged as their scope of practice includes having knowledge and expertise in the dietary and lifestyle values of the populations they serve. Cultural safety, a theory of practice in regions with similar demographics as the Pacific, will be used to guide and inform this research. Objectives. To examine the practice of dietetics in the Pacific region to understand specific needs and unique practices relevant to the culturally diverse populations served. To identify dimensions of dietetics practice that describe culturally safe care. Methods. Descriptive analysis will be conducted using data from a dietetics practitioner survey. Interpretative Phenomenological Analysis will be used to identity RDN experiences that reveal culturally safe care in the Pacific from key informant interviews. Findings. Survey results describe the practice of dietetics in the Pacific region (n=106), by demographics of RDNs and populations served, and RDN identified needs for culturally relevant and disease-specific nutrition resources, particularly resources for Pacific Islander and Asian populations and NCDs. Key informant interviews (n=18) of practicing dietitians in the Pacific reveal dimensions of cultural safety in the following themes: (i) self-awareness and self-reflection to one’s own historical and social culture and location; (ii) relationship building and creating an environment of respect, caring, trust, empathy, and acceptance between client/patient and RDN; (iii) working through a social justice lens, recognition of power imbalance or struggles, and potential for repressed cultural identities as described through their practice experiences. Conclusion. Understanding dietetics practice in the Pacific as unique with needs specific to the region is important to inform the identification and development of the necessary nutrition resources to enhance dietetics practice and patient care experiences. Identifying and describing practice experiences of culturally safe care could inform new practice guidelines in the dietetics profession. This has promising implications for improving health care services in the Pacific region, and to places where Pacific groups have migrated in other parts of the world.Item The Association between Occupational Exposure to Pesticides and Cardiovascular Disease Incidence: The Kuakini Honolulu Heart Program(University of Hawaii at Manoa, 2017-05) Berg, Zara K.; Biomedical SciencesPreviously, Kuakini Honolulu Heart Program researchers reported that occupational exposure to pesticides is significantly associated with total mortality. Objective: The current study examines occupational exposure to pesticides on the job in relation to incident cardiovascular diseases (CVD), that is, coronary heart disease (CHD) incidence and cerebrovascular accident (CVA) incidence, combined. Methods: Using the OSHA exposure scale as an estimate of exposure, statistical analyses were performed using a cohort of 7,557 Japanese-American men from The Kuakini Honolulu Heart Program. Results: In the first 10 years of follow-up of the cohort, a positive correlation was observed between age-adjusted CVD incidence and pesticide exposure with a p-value of 0.021. This relationship remained significant after adjustment for other CVD risk factors. No significant association for coronary heart disease or stroke incidence and pesticide exposure was observed when examined separately, possibly due to a smaller number of events. The biochemical mechanisms leading to CVD and associated risk factors will be discussed. Conclusion: These results are novel, as the association between occupational exposure to pesticides and cardiovascular disease incidence has not been examined previously in this cohort. These findings may contribute to our understanding of the role of occupational exposure to pesticides plays in the development of cardiovascular diseases.Item The Ebola Virus and West Africa: Medical and Sociocultural Aspects(University of Hawaii at Manoa, 2015-12) Ikuomola, FelixProblem: Little attention has been given to the undeniable impact of the socio-cultural factors on communicable disease, especially Ebola. We have failed at managing Ebola outbreaks in Africa. Most of the preparatory and intensive training of health personnel attending to the needs of those societies where culture is at the center of life have given only lip service to the importance of integrating this culture into the medical training curriculum and practice. Purpose: To itemize and emphasize the role of sociocultural factors in Ebola virus disease acquisition, transmission, containment, prevention, surveillance, screening, and control. To propose cultural modification of the aspects of the West African cultural practices that enhanced the Ebola virus disease spread through constructive community engagement. To recommend integration, collaboration, and cooperation between traditional medicinal practitioners and medical practitioners. Procedure: Gathered data on Ebola virus disease and West Africa and sociocultural factors through Pubmed, government websites, organizations, media, and personal stories. The data were synthesized into comparative, descriptive, and exploratory analyses. Conclusion: This cognitive and literature review paper will generate data to support the impact of cultural practices on Ebola spread and containment. Recommendations from this paper will not only contribute greatly to preventing any further Ebola spread but also be useful in surveillance, screening, patient tracing, and disease control.