M.S. - Biomedical Sciences
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Item Anal dysplasia screening and human papillomavirus characterization by Raman-enhanced spectroscopy in individuals infected with human immunodeficiency virus(University of Hawaii at Manoa, 2022) Nagata, Michelle; Lim, Eunjung; Agsalda-Garcia, Melissa; Biomedical SciencesBackground: People living with human immunodeficiency virus (PLHIV) are at increased risk for developing anal cancer and anal dysplasia due to persistent infection by high-risk human papillomavirus (HPV). It is recommended they undergo anal cancer screening with anal cytology and, if abnormal cytology is reported, a more invasive high-resolution anoscopy (HRA) to obtain biopsies for definitive diagnosis. However, HRA and biopsy are invasive, and variable sensitivity and specificity have been reported for both anal cytology and HRA with biopsy. Raman-enhanced spectroscopy (RESpect), a noninvasive laser-based technology that characterizes the chemical and molecular composition of cells and tissues, has demonstrated the potential to improve current standards of anal cancer screening. The feasibility of translating RESpect clinically relies on consistent Raman-based characterization of dysplastic anal tissues and a positive control for squamous epithelial carcinoma. By comparing the spectral profiles of anal tissues biopsied from PLHIV and cervical carcinoma cell lines acquired by RESpect microscope (micro-Raman) and portable RESpect probe instruments, this study evaluates the clinical potential for RESpect probe screening as a real-time, noninvasive supplemental tool in detecting anal dysplasia. Methods: Participants being evaluated for anal cancer screening at the Hawai‘i Center for AIDS clinic were recruited following guidelines approved by the University of Hawai‘i Institutional Review Board. Anal cytology was followed by HRA and biopsy to obtain two tissue samples from the same location: one specimen for RESpect analysis and one specimen for pathology assessment. The tissues for RESpect analysis were cut into two before mounting onto reflective aluminum slides for spectra acquisition by the micro-Raman and RESpect probe instruments. HeLa and SiHa cervical carcinoma cell lines were similarly mounted and analyzed by micro-Raman and RESpect probe. Following baseline correction and smoothing, spectra were averaged to produce a representative spectrum of each cell or tissue specimen and normalized. Averaged spectra representing negative, low-grade squamous intraepithelial lesion (LSIL), and high-grade squamous intraepithelial lesion (HSIL) pathologies were visually inspected to identify significant differences in intensity, as determined by a two-sample t-test. To determine the feasibility of using HeLa and SiHa cell lines as positive controls of HPV-infected squamous epithelial carcinoma, peak differences identified by visual inspection of HeLa and SiHa spectra were compared to the peaks distinguished in anal tissues. Results: Forty-three participants were enrolled to date. Overall agreement between cytology and biopsy results was 71%, with Cohen’s kappa (κ) = 0.484 (95% CI: 0.266–0.741) indicating moderate agreement. Comparison across pathologies (26 negative, 12 LSIL, and 5 HSIL) revealed spectral differences. Based on visual observation, LSIL and HSIL tissues demonstrated averaged spectra closer to each other than to negative tissue. Significant peak differences (p < 0.2) between tissue pathologies were found at three regions in both the micro-Raman and RESpect probe spectra. Between cervical carcinoma cell lines, SiHa cells generally exhibited a higher intensity than HeLa cells, and peak differences were observed at six spectral regions, with a consistent peak difference at 1554 cm–1 corresponding to amide II distinguished in both cells and tissues. Conclusion: Peak differences elucidated from micro-Raman and RESpect probe spectral fingerprints of anal tissues and cervical carcinoma cell lines demonstrate the potential of RESpect to distinguish between pathology grades and support the integration of RESpect technology into the anal cancer screening paradigm. Previous studies have demonstrated similar differences between normal and dysplastic/cancerous cervical tissues at peaks associated with amide as well as similar agreement between cytology and biopsy results. These findings lay the foundation to consider RESpect as a real-time, noninvasive screening tool for further exploration.Item The Impact Of Diet Quality On Microbial Diversity Throughout Pregnancy In An Ethnically Diverse Cohort In Hawai‘i(University of Hawaii at Manoa, 2020) Miller, Corrie; Lee, Men-Jean; Biomedical SciencesAbstractBackground: The gastrointestinal (GIT) microbiome influences metabolism and modulates inflammation during pregnancy, influencing energy regulation, gestational weight gain, and risk of adverse pregnancy outcomes. Manipulating the GIT microbiota has been an area of earnest research interest, with hopes that manipulating an aberrant microbial community may translate to improved pregnancy outcomes. While some dietary patterns have been associated with improved GIT microbial health, few studies have investigated the impact of comprehensive diet quality on this outcome. Our study aimed to associate Diet Quality as defined by the Healthy Eating Index (HEI) with alpha diversity metrics longitudinally across pregnancy in healthy, low risk pregnant women. Methods: Forty-one women were recruited, from the 4 largest ethnic groups in Hawaii. Participants completed Food Frequency Questionnaires (FFQs) during each trimester (12 weeks, 20 weeks and 34-36 weeks), to which HEI Diet Quality Score was assigned. Rectal swabs were collected concomitantly at each time point, from which DNA extraction and 16s rRNA sequencing were performed. Alpha and beta diversity profiles were assigned, and correlated in a linear fashion with HEI Score. Linear regression was also used to account for confounding demographic factors. Results: HEI score did not correlate with any alpha diversity metrics. Those with the highest HEI score had greater amounts of lactobacillaceae (not significant), and several species were associated with higher diet quality. Native Hawaiians had the highest HEI score compared to Filipina participants, and had higher amounts of Acidaminoaceae and lactobacillaceae, respectively. There were no differences observed with microbial diversity among the 4 ethnic groups. All alpha diversity indices decreased from the first to third trimester, as expected from published literature in other cohorts. Conclusion: Alpha diversity decreased throughout pregnancy in this cohort, commensurate with other studies. Hormonal changes of pregnancy had the largest influence in change over time of microbial composition in this cohort, greater than dietary intake, ethnicity, body mass index, or parity.Item Defining role of different virus sensing pathways in modulating ZIKV replication in human Sertoli cells(University of Hawaii at Manoa, 2020) Jiyarom, Boonyanudh; Verma, Saguna; Biomedical SciencesZIKV is shown to establish persistence in the testes; however, the mechanisms remain undefined. We recently demonstrated that ZIKV was able to replicate and persist in human Sertoli cells (SC), an important cell type of seminiferous tubules. In addition, our host transcriptomic data predicted RIG-I and TLR3 as the top virus sensing pathways modulated in SC, however the specific role and efficiency of these pathways in controlling ZIKV is not yet determined. Here, we elucidate the impact of blocking these critical antiviral pathways on ZIKV replication. TLRs and RLRs were inhibited using siRNA or small molecule inhibitors in SC and infected with ZIKV PRVABC59. A549 cells were used as controls in some experiments. Data demonstrated that the independent inhibition of both RIG-I and MDA5, but not TLR3 nor TLR7 signaling increased ZIKV replication. Gene expression of IFNβ showed no change in both siMDA5 and siRIG-I SC, however, there was a reduction in the activation of IRF3 and MXA expression in these PRR deficient SC. Further, we observed that exogenous IFNβ treatment significantly reduced ZIKV titers in SC that was comparable to A549, thus indicating that IFN signaling is active in SC. To delineate the crosstalk of PRRs with other immunosuppressive pathways in the testes, SC were pretreated with TGFβ superfamily members molecules (TGFβ, Activin A, and BMP6) and virus titers measured. We first showed that ZIKV does not induce changes in TGFβ and Activin A mRNA expression. Additionally, there was no change in ZIKV titers in TGFβ and Activin A treated SC. However, ZIKV downregulated BMP6 at later time points of infection and the exogenous BMP6 treatment decreased ZIKV in these cells SC. Interestingly, treatment of BMP6 resulted in an increased in both RIG-I and MDA5 in ZIKV infected SC at 120hpi. Our data suggest that downregulation of BMP6 and downstream signaling by ZIKV at later stages of infection may modulate functioning of antiviral response and facilitate virus persistence. Collectively, these results fill in gaps in our understanding of the antiviral signaling mechanisms underlying ZIKV infection and persistence in human testes.Item Developing a Predictive Model for Measuring Health Literacy in Hawaiʻi’s Adult Populations(University of Hawaii at Manoa, 2017-08) Lubimir, Karen T.; Biomedical SciencesBackground: Adequate health literacy is necessary to effectively participate in one’s own health care, yet many American adults lack the health literacy skills to navigate the US health care system. Lower health literacy has been associated with poorer health status, higher health care utilization, and greater health disparities in studies conducted both nationally and in Hawai’i. Other factors associated with inadequate health literacy include older age, immigrant status, ethnic minority status, poverty and fewer years of education. Successful health interventions aimed at reducing disparities and improving health outcomes should be based on adequately identifying the unique characteristics of the population, including health literacy skills. Direct measurement of health literacy is labor intensive and controversial, hindering its study in population-based research. National health literacy predictive models have been developed to help address this problem. To date, the applicability of national health literacy predictive models in Hawai’i’s ethnically diverse population has not been studied. Objective: To identify demographic variables associated with low health literacy and develop a multivariable predictive model for low health literacy in Hawai’i’s adult population. Methods: We completed a cross-sectional analysis of a representative sample of Hawai’i’s adult population from the annual telephone based Hawai’i Health Survey (HHS) data, years 2008 and 2010. The sample included 11,941 respondents. Descriptive analysis was used to identify individual socio-demographic variables associated with low health literacy. Predictors included age, gender, marital status, educational attainment, race/ethnicity, insurance status, poverty status, rural residence and migration status. We used multivariable logistic regression models, Thesis: Developing a Predictive Model for Measuring Health Literacy in Hawai’i’s Adult Populations Karen T. Lubimir, Candidate for Masters in Clinical Research including sub-group analysis for age over 65 years and migration status, to predict the probability of inadequate health literacy. Results: In the descriptive results, 18% had low health literacy, which was significantly associated with extremes of age (<25 or >84 years old, compared to those ages 25-64 and 64-84 years old ), less than high school education (compared to high school graduates or post high school education), non-white ethnicity, being poor, lack of health insurance, rural residence, and being born outside the U.S. (p<0.01). In the multivariable logistic regression model with the full population, Chinese, Filipinos, Japanese and Pacific Islanders were significantly more likely to have low health literacy compared to whites, even after control for the socio-demographic factors of education, poverty, insurance and rural residence. In the models including migration status, controlling for socio-demographic factors, low health literacy was associated with non-U.S. born, rural residence, lacking health insurance and Hawaiian, Chinese, Filipino, Japanese and “Other” ethnicities (p<0.05). Within the age 65+ year models, only age 85+ years and Pacific Islander ethnicity had increased odds for low health literacy (p<0.05). Across all models, those with less than high school education had twice the odds of having lower health literacy compared to those who completed high school or post-secondary education (p<0.02). Predictive accuracy for all models achieved AUROC between 0.624-0.689. Conclusions: Several of Hawai’i’s Asian American and Pacific Islander ethnic groups have significantly lower health literacy compared to White residents. Based on comparison of Hawai’i and national models’ statistical results, this study found a lack of predictive accuracy for Hawai’i health literacy models, patterned after national models, when applied to Hawai’is’ adult Thesis: Developing a Predictive Model for Measuring Health Literacy in Hawai’i’s Adult Populations Karen T. Lubimir, Candidate for Masters in Clinical Research population. A locally derived multivariable model may lead to better detection of community specific information than using individual predictors of low health literacy, and could supply Hawai’i’s healthcare stakeholders with an additional tool to help focus health interventions.Item Effects of the Accessory Infraorbital Nerve and Foramen on the Morphology of the Infraorbital Nerve and Foramen(University of Hawaii at Manoa, 2016-12) Polo, CarolinaTitle: Effects of the accessory infraorbital nerve on the morphology of the infraorbital nerve and foramen Problem: Anatomical variations of the infraorbital neurovascular bundle are frequently encountered during a host of oral surgical procedures involving the infraorbital region. The accessory infraorbital foramen (AIOF) and its nerve (AION) are variable, but clinical implications are common and include failure of loco-regional anesthesia, risk of neural damage, or hemorrhage following surgical interventions particularly involving the infraorbital nerve (ION) and foramen (IOF). Thus, morphological characterization of the AIOF and AION and relationships to the IOF and ION are essential for optimizing oral surgical procedures. Additionally, predictive features of the AION based on its relationship to ION morphology could facilitate predictive capabilities enabling the surgeon to anticipate its presence and proceed accordingly Purpose: The purpose of this study is to determine whether the presence of an AION affects the size, shape and composition of the infraorbital foramen and nerve. The specific hypothesis tested is that the topography and morphology of the ION and IOF differs between individuals possessing an AION and those lacking this anatomical variant. Data will serve to determine the potential field of innervation of the ION with and without the presence of AION and identify potential morphological correlates between ION and AION features. Procedure: Gross topographic features of IOF (84 hemifaces) were compared between specimens possessing (test) or lacking (control) an AIOF. Nerve fascicle features of ION (60 cadaveric sides) were examined histologically and compared morphometrically between specimen with or without an AION. Results: Occurrence of AIOF was determined as 47.6% of the skulls (20 crania), but only 32.1% of the sides (27 sides). A single AIOF was observed in 24 sides and double AIOF in 3 sides. AIOF occurred bilaterally in seven specimens (16.7%). The majority of AIOF (86.7%) were located superomedial to IOF, but overall a heterogeneous direction of the canal leading to AIOF was noted. A higher frequency of AION was found in left side compared to the right. The number and area of nerve fascicles were determined histologically. The size of the ION without an AION was not significantly different than the ION with AION (1.45x106/1.32x106, p < 0.35). However, the number of ION fascicles was greater in specimens without and AION compared to those with an AION (15.15/12.71, p <0.04) Conclusions: The data indicate that the area of the ION is not affected by an AION, suggesting that the field of innervation of this area will not be modified However the ION appears to divide more proxima in the cases when the AION is present.Item Morphological Study of the Human Hyoid Bone in Cleft Lip and Palate Patients(University of Hawaii at Manoa, 2016-08) Abdelkarim, AhmedQualitative assessment of 3-D reconstructions derived from MRI and CT imaging technologies is critical for the diagnosis and treatment of patients with cleft lip and palate (CLP). However, rapid and reliable quantitative assessment remains elusive. This is particularly true for the analysis of regional deficiencies in morphology of CLP patients. Recent interest has focused on the morphology of the hyoid region of CLP patients since this area is derived from pharyngeal arch 2 and may be indirectly affected by the deficiency in the primary palate derived from pharyngeal arch 1. The objective of this study is to develop and apply novel morphometric methodology to quantitatively assess hyoidal morphology in CLP patients. The hypothesis to be tested is that CLP patients display hyoidal regions that differ quantitatively from patients lacking CLP. Five geometric models with known parameters were designed to simulate size and shape descriptors and used to test the precision and accuracy of ER3D. Cone beam computed tomography (CBCT) images derived from CLP patients as well as patients lacking CLP and these were utilized to generate 3D reconstructions of the hyoidal region in corresponding individuals and compared utilizing affine and non-affine methodologies.. Anatomical landmarks were determined and digitized on the model. Results showed significant accuracy of ER3D morphometric analysis with respect to volumetric and linear measurements and proved the ability of the software to quantitatively record changes in size and shape. For the hyoid models, CLP individuals mostly displayed affine hyoidal changes relative to controls since the defect likely causes size reductions in affected individuals. Non-affine changes were consistent among CLP subjects and were characterized as changes in position with respect to controls rather than shape change. Interestingly, female controls revealed a high degree of diversity compared to both male controls and all CLP groups. These data suggest that the hyoidal region is affected as a result of CLP, but the difference is dominated by size rather than shape change.Item Hospitalization Predicts Functional Decline in Nursing Home Patients(University of Hawaii at Manoa, 2016-05) Takenaka, CodyObjectives: According to CMS data, a higher percentage of nursing home (NH) patients in Hawaii demonstrated functional decline than the national average. We examined the effects of hospitalization on functional and cognitive decline in elderly NH patients. Design: Longitudinal observational study. Setting: A 170-bed hospital-affiliated NH in Honolulu, Hawaii. Participants: All patients admitted to the study NH between January 2003 and December 2006 (n=238) and followed from admission until discharge or death through 6/30/2011, using Minimum Data Set (MDS) assessments, NH and hospital medical records. We excluded patients with total Activities of Daily Living (ADL) dependence or severe cognitive impairment (Cognitive Performance Scale CPS=6) at baseline. Measurements: Our primary outcome was change in function, measured by the MDS-ADL scale (range 1-28, higher=more disability) from admission and quarterly assessments. Our secondary outcome was change in cognition, measured with the MDS-CPS (range 0-6, higher=more cognitive impairment). For all patients, functional and cognitive decline over time was analyzed using multivariable linear regression analyses. Subgroup analysis examined those with at least one hospitalization and MDS data before and after hospitalization for within-person pre/post-hospitalization changes in ADL and CPS scores without covariate adjustment. Results: After exclusions, our analytic sample included 147 patients. Mean age was 82.9 years, 36.1% were male and 91.5% were Asian. Mean baseline ADL score was 18.2 (SD 5.4) and mean baseline CPS score was 2.9 (SD 1.4). Mean follow-up time was 1.5 years (SD 1.2). Linear regression adjusting for Charlson Comorbidity Index showed increased ADL disability (2.9 points, 95%CI(2.13, 3.78), p<0.001) after hospitalization, with slight decreased disability by the 2nd MDS after NH readmission (-2.01, 95%CI(-1.35, -2.67), p<0.001). CPS score worsened by 0.47 (95%CI(0.28, 0.65), p<0.001). On within-person comparisons, ADL disability increased by 4.5 points (95%CI(4.3,5.8), p<0.001) after hospitalization, with slight decreased disability by the 2nd MDS assessment after NH readmission (-1.6, 95%CI(-3.2,-0.1), p=0.04). CPS score worsened by 0.7 points (95%CI(0.4,1.1), p<0.0001). Conclusion: Hospitalization was significantly associated with increased functional decline among elderly NH patients, with slight improvement after readmission to the NH. Treatment of acute illness in the NH should be included as an option during goals of care discussions.Item Association between Oxytocin Use during Dilation and Evacuation and Estimated Blood Loss(University of Hawaii at Manoa, 2015-08) Whitehouse, KatherineObjectives: Many providers use oxytocin during dilation and evacuation (D&E) to prevent or treat hemorrhage. Evidence to support this practice is scarce. We sought to describe the association between oxytocin use, estimated blood loss (EBL), and surgical outcomes during D&E. Study Design: Women undergoing D&E (≥14 weeks) between 2010 and 2014 were included in this retrospective cohort study to assess the association between oxytocin use and EBL. We also determined whether sociodemographic and health-related factors were associated with higher EBL and whether oxytocin use was associated with a lower complication rate. Mean EBL was compared with a t-test. Excessive blood loss, defined as EBL at or above 250 ml, demographics, and complications were compared with a chi-square and Fisher's Exact tests. Logistic regression was performed. Our database, which included 649 women undergoing D&E, had the ability to detect a 7.5% difference in excessive blood loss. Results: Oxytocin was used in 68.3% of the procedures. Asian (p= 0.02) and Native Hawaiian/Pacific Islander (p=0.03) race, abortion indication (p=0.008) and higher gestational age (p<0.001) were associated with osytocin use. Mean EBL [133.1 (sd=133.9) ml versus 105 ml (73.8), p<0.001] and excessive blood loss (11.1% vs. 4.9%, p=0.01) were higher in the oxytocin group. No significant difference in complication rates emerged (4.7% with oxytocin vs. 4.4% without, p=0.579). The adjusted OR for excessive blood loss was 1.61 (95% Cl 0.77, 3.77) when women received oxytocin. Conclusions: Oxytocin use during D&E did not have a significant association with surgical outcomes including EBL and complications in our population. Implications: Routine use of interventions for bleeding, such as intravenous oxytocin, should be based on scientific evidence or not performed. Findings from our study provide information on how oxytocin use is associated with blood loss during D&E.Item Polymorphisms in Kynurenine Pathway Genes and Psychological Distress in HIV Patients(University of Hawaii at Manoa, 2015-08) Tanizaki, NaomiBackground: HIV infection, neuroinflammation and psychopathology are each associated with imbalances in the kynurenic pathway (KP), which includes kynurenine-3-monooxygenase (KMO) and kynurenine aminotransferase II (KATII). Both KMO and KATII enzymes mediate levels of kynurenic acid (KYNA), which increases with HIV infection, and may decrease with psychopathological symptoms such as depression. Since people with HIV are more vulnerable to neuroinflammation and comorbid depression, variations in the genes of these enzymes may influence psychopathological symptoms in HIV. Methods: 72 HIV seronegative (SN) and 72 HIV positive participants were evaluated using the Center for Epidemiologic Studies Depression and Symptom Checklist-90-Revised scales, and were genotyped at KATII rs1480544 at KMO rs1053230. Cerebrospinal fluid kynurenic acid concentration [KYNA] was measured in 51 SN and 49 HIV participants. T-test, and one-way and two-way AN(C)OVA were used to compare effects of genetic variation and HIV status on psychological symptoms or KYNA levels. Pearson or Spearman analyses was used to find correlation between psychopathological symptom scores and KYNA levels. Results: For psychopathological symptoms, overall, HIV participants had higher scores than SN, and SN KATII C-carriers tended to have lower scores than SN TT homozygotes. Older age correlated with higher CSF [KYNA] in KATII C-carriers and KMO CC-homozygotes independently of serostatus. HIV participant psychopathological scores did not differ between KMO genotypes. Conclusions: KATII genotypes and HIV serostatus were associated with psychopathological symptoms. Furthermore, CSF [KYNA] varies with age depending on both KMO and KATII genotypes. Together, this supports a functional role of these variations in the dysregulation of the KP that may moderate psychopathological symptoms in HIV and SN individuals. Understanding the KP mechanisms in HIV may lead to novel treatments for psychopathological symptoms.Item Family History of Substance Use Problems on Cortical Morphometry in Healthy Children(University of Hawaii at Manoa, 2015-08) Lee, KristinBackground Common structural brain abnormalities reported in substance use related (SUD) related regions were found in children with family history (FH) of SUD. However, the effect of FH-degree of SUD is not well examined. Therefore, the influence of degree of FH of substance use problems (SUP) on cortical morphometry was investigated. Methods 921 typically developing children (ages 3-20 years old; 470 boys/451 girls) had structural MRI and executive functions measures. The influence of first and/or second-degree FH (Any-FH) and the separate effects of first-degree (First-FH) and second-degree FH of SUP (Second-FH) on cortical structures were investigated using FreeSurfer. The relationships between FH related cortical alterations and executive functioning were examined. Sex interactions with FH-degree on cortical morphometry were also investigated. Results Any-FH children had volume alterations mediated by changes in surface areas. FH children have larger left prefrontal and right superior areas and volumes when compared to No-FH children. First-FH and Second-FH show a variable effect on cortical volumes particularly for regions in the posterior frontal and anterior parietal regions as well as the right fusiform gyrus. Sex differences for cortical morphometry between First-FH and Second-FH children were widespread, but strongest in the left frontal regions. The left supramarginal and right fusiform gyri, regions specifically reduced for First-FH children, were also related to differential executive functioning and this same association was found in First-FH girls. Importantly, the majority of results remained even when controlling for confounders such as ADHD. Conclusion The children with FH of SUP have overall differences in prefrontal regions. First-FH and Second-FH children showed different morphometric alterations in parietal and temporal regions, which may contribute to deficits in executive function. Further studies are need to explore the sex-specific influences in cortical morphometry of children with FH of SUP, and the possible consequences on cognition.