2023

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RAD is an institutional tradition encompassing medicine, public health and basic science. The program provides an opportunity for students, faculty and staff to share their research efforts with the campus community and the public. The program encourages the development of joint research projects and increases the community's awareness of the outstanding quality and range of research conducted at UNT Health Science Center.

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In Silico Analysis to Determine the Association of Specificity Protein (Sp) Transcription Factors, Sp1 and Sp3 and Survivin Expression with the Prognosis of Cancers Affecting Women
(2023) Patel, Pooja; Dutta, Arpam
Background: Breast cancer is the most common invasive cancer in women worldwide. Studies have shown that breast cancer shares risk factors and genetic mutations with ovarian and uterine cancers which are also analyzed to be increasing in incidence. Clinically, diagnosis of concurrent genetically shared cancers like breast, ovarian, and uterine would have an impact on the treatment options and its course. Dysregulation of transcription factors like Specificity protein (Sp) 1 and 3 which remodel chromatin is responsible for many cancers. While the expression of Sp1 is documented to be upregulated in breast and ovarian cancer, and Sp3 only in breast; uterine cancer lacks such evidence. Baculoviral IAP repeat-containing 5 (BIRC5), also known as survivin, is an inhibitor of the apoptotic pathway and is found to be upregulated in breast, ovarian, and uterine cancer. Sp1, Sp3 and survivin are all associated with high expression in numerous cancers and lead to poor prognosis. Objective: The objective of this study is to analyze the expression of Sp1, Sp3 and survivin in breast invasive carcinoma, ovarian serous cystadenocarcinoma, and uterine corpus endometrial carcinoma to evaluate the prognosis (in all patients and by race/ethnicity) of cancer patients using the data deposited in a public database. Methods: Relevant data and Kaplain-Meier curves were obtained from accessing the public database, The Cancer Genome Atlas (TCGA) (a landmark cancer genomics program developed by the National Cancer Institute and the National Human Genome Research Institute). This data was used to screen for the expression status (upregulated or downregulated), significance and relevance to prognosis for all patients and in relation to race/ethnicity for breast invasive carcinoma, ovarian serous cystadenocarcinoma, and uterine corpus endometrial carcinoma. Results: Sp1, Sp3, and survivin expression significantly impacted patient survival in breast invasive carcinoma (n=1211), ovarian serous cystadenocarcinoma (n=302), and uterine corpus endometrial carcinoma (n=581). When looking at Sp1 and combining data for all patients, there was a relevance in prognosis in ovarian serous cystadenocarcinoma (p=0.045). Additionally, there was an association between the marker and poor prognosis for race/ethnicity when looking at breast invasive carcinoma and uterine corpus endometrial carcinoma. Sp3 and survivin presented similarly when looking at combined and racial/ ethnic prognosis. Both Sp3 and survivin indicated a poorer prognosis for overall population survival in uterine corpus endometrial carcinoma (p=0.018 and p=0.015 respectively). They also presented with a worse prognosis when looking at race/ethnicity for all three listed cancers. Conclusion: The findings from this study suggest an association of Sp1, Sp3, and survivin expression in breast invasive carcinoma, ovarian serous cystadenocarcinoma, and uterine corpus endometrial carcinoma and their prognosis. The results also suggest that these markers may contribute to poor prognosis for patients in certain racial/ethnic groups.
A mendelian randomization analysis of obesity on the development of Alzheimer’s disease
(2023) Nolan, Emma; Zhou, Zhengyang
Purpose: To assess the causal associations between obesity and Alzheimer’s disease (AD) using Mendelian randomization analysis based on summary statistics from genome-wide association studies (GWAS). The most recent GWAS as of November 2021 for AD and obesity were used, including newly identified risk single nucleotide polymorphisms (SNPs) that were associated with AD and obesity. Specifically, the AD GWAS identified 42 new risk loci, which have not been utilized in other studies. Thus, this study provides novel evidence for the causal associations of AD and obesity. Methods: Genetic associations for the exposure (i.e., obesity; BMI ≥ 30kg/m2) were evaluated from a GWAS conducted on European individuals over age 18 in the FinnGen project (n = 218,792). Genetic associations for AD were evaluated from the whole exome sequencing data among European individuals aged 37-73 years in the UK Biobank study (n = 111,326 AD cases and 677,633 controls). Based on the above summary statistics, a Two Sample Mendelian randomization (MR) analysis using the Inverse-Variance Weighted (IVW) method was conducted to evaluate the causal association between obesity and AD. Sensitivity analyses including median-based, mode-based, and MR-Egger MR methods were conducted to confirm findings from the main MR analysis. Results: Obesity was found to be associated with a decreased odds in the development of AD (Odds ratio = 0.91, 95% CI = [0.86, 0.95], p = 0.0001) according to the IVW method, suggesting a protective effect of obesity. The results of all sensitivity analyses were consistent with the main findings and determined the absence of horizontal pleiotropy and heterogeneity. Specifically, significant causal relationship between AD and obesity was identified in the IVW method and Weighted Median MR methods. Conclusion: The protective effect of obesity on the development of AD is supported by the MR analysis in this study. Further research should be conducted on the underlying pathological mechanism to inform potential health interventions such as weight modification in mid versus late life.
The Impact of the Social Determinants of Health on a Patient with Renal Cell Cancer: A Case Report
(2023) Luka, Stacy; Hadley, Lesca
Background Renal cancer is the seventh most common cancer and 90% of cases are renal cell carcinoma (RCC). Symptoms of RCC may include hematuria, abdominal/flank pain, or fatigue, but over half of those with RCC are asymptomatic and diagnosed incidentally by an unrelated abdominal imaging study. Renal tumor size provides the greatest insight into a patient’s chance of survival. For every 1 cm increase in tumor size there is a 16% increase in malignant potential and masses greater than 7 cm have only a 7% chance of being benign. RCC has a 40% mortality rate that disproportionately affects those of low socioeconomic status (SES) who often present with larger and more advanced RCC. This correlation with low SES reflects decreased healthcare access and an increased prevalence of poor prognostic factors including obesity, hypertension, and hyperlipidemia. Additionally, patients without health insurance are 5.6% less likely to survive RCC. Case Information A 56-year-old Hispanic male first presented to a community clinic in Fort Worth, Texas in early 2017 for occasional fatigue and right flank pain that began in 2002. In addition to managing his hypertension, diabetes mellitus, and hyperlipidemia, the physician ordered an abdominal and pelvic CT that revealed a 5.4cm cystic and solid-enhancing right renal mass that was highly suspicious for RCC. Further disease progression was suggested with a 2019 ultrasound showing internal blood flow to the solid component of the mass and 2022 laboratory studies that revealed an elevated BUN (21 mg/dL), serum calcium (10.6 mg/dL), and ALT (56U/L). At the end of 2022, the patient brought in his latest CT report that he could not read because it was only provided in English. The CT revealed the 6.4cm x 4.1cm x 3.7cm mass and while medical translators communicated with the patient, differences in language may have impacted his understanding of his condition. For five years imaging and labs were performed repeatedly to monitor the large tumor, but treatment was never initiated because the patient believed he could not afford care without health insurance. The patient was referred to a local charity program for evaluation, but the program had a policy of not providing cancer treatment. The patient was encouraged to seek treatment in the local county health system, but he believed he could not afford treatment there or the expenses to relocate for treatment elsewhere. At this point, no further options exist for the patient. Conclusions Surgery would provide the greatest odds of survival for this patient, and ideally, it would have been performed before the mass reached such a concerning size. However, the patient believed he could not afford care without health coverage. With such a dismal prognosis, one can only speculate how the outcome would have changed if prompt medical care had been accessible to the patient. His financial resources, health coverage, language barrier, documentation status, and lifestyle all contributed to the unfavorable disease progression. This case serves as a single example of how social determinants of health continue to alter patient outcomes.
Increased Fibronectin Serotonylation in Stretched Optic Nerve Head Astrocytes
(2023) Rangan, Rajiv; Clark, Abbot; Tovar-Vidales, Tara
Purpose: Elevated intraocular pressure contributes to glaucomatous optic nerve degeneration by inducing biomechanical stress at the optic nerve head (ONH), especially in the lamina cribrosa (LC). ONH astrocytes (ONHA) in the LC respond to biomechanical signals through extracellular matrix (ECM) remodeling activities, promoting tissue fibrosis and damage to retinal ganglion cell axons. The enzyme transglutaminase 2 (TG2) plays a role in ECM remodeling, in part, due to its ability to post-translationally modify and cross-link ECM proteins. A unique post-translational modification mediated by TG2 is "serotonylation” - the transamidation of the monoamine serotonin (5-hydroxytryptamine, 5HT) to glutamine residues on proteins. It is speculated that serotonylation contributes to fibrotic tissue remodeling, but this process has not been studied in ocular tissues or in primary glial cells. In this study, we examined changes in the serotonylation of fibronectin (FN; a major ECM glycoprotein) by ONHA after exposure to cyclic stretch. Methods: Primary human ONHA strains (n=3) were exposed to 0-12% cyclic stretch for 24h using a FlexCell FX-6000 system. Cell lysates and conditioned medium samples were collected from stretched and control cells. Serotonylation was assessed by probing for serotonin in samples of FN immunoprecipitated out of conditioned media. Protein levels for potential extra- and intra-cellular mediators of serotonylation were examined using western blotting of concentrated conditioned medium samples and cell lysates, respectively. Results: Serotonylated fibronectin was detected in ONHA. Exposure to stretch increased the amount of fibronectin that was serotonylated by 2.49-fold (p=0.0080). After stretching, extracellular FN levels were not changed. Extracellular TG2 levels were increased by 3.76-fold (p=0.0004). In cell lysates, post-stretch levels of both FN and TG2 were decreased by 5.56-fold (p=0.0181) and 2.51-fold (p=0.0441), respectively. Additionally, serotonin 2A and 2C (5HT2A, 5HT2C) receptor levels were unchanged, and serotonin transporter (SERT) levels decreased by 2.94-fold (p=0.0297). Conclusions: Increased FN serotonylation by TG2 is observed in ONHA after exposure to 24h of 0-12% cyclic stretch. Serotonylation may promote increased FN-crosslinking and fibrotic ECM remodeling, an important feature of glaucomatous pathology. The secreted TG2 – which was elevated in response to stretch – is likely to be the primary mediator of this increased serotonylation. The observed decrease in SERT may lead to increased extracellular 5HT levels, which increases the substrate availability for TG2-mediated serotonylation. Though unchanged, activity at the 5HT2A/C G-coupled protein receptors could increase the availability of intracellular calcium required for TG2 activity. Future experiments will be focused on furthering our understanding of how these proteins may interact to promote serotoynlation.
A Rare Case of Synchronous Familial Adenomatous Polyposis and Endometrial Carcinoma
(2023) Nguyen, Khanh; Nguyen, My; Barrera, David
Familial adenomatous polyposis (FAP) is a rare autosomal dominant disease characterized by numerous polyps in the colon. It is caused by a germline mutation of the adenomatous polyposis coli (APC) gene. Patients have a guaranteed risk of having colorectal cancer and can also develop multiple extra-intestinal manifestations, including cutaneous lesions, brain tumors, desmoid tumors, osteomas, and thyroid cancer. Thus, extensive screenings for both colorectal cancer and the manifestations mentioned above are recommended on a frequent basis. Ovarian and endometrial malignancies are not known to be associated with FAP. Here, we present a case of synchronous FAP and endometrial carcinoma. A 51-year-old female with family history of autosomal-dominant-patterned colon cancer, subtotal colectomy at 17 due to multiple polyps, ileostomy with a J-pouch at 35, and recent upper endoscopy suspicious for ampullary adenoma, presented with one-month history of fatigue and night sweats. Review of system was positive for heartburn and easy bruising. The patient did not have formal genetic testing. She has close follow-ups with yearly surveillance upper GI endoscopy (EGD), flexible sigmoidoscopy, and thyroid ultrasound. At 44, she underwent dilation and curettage due to menorrhagia; samples revealed endometrial cancer, which led her to undergo a bilateral salpingo-oophorectomy. Reports of endometrial and ovarian cancers in FAP are rare. In another case, a 57-year-old female with FAP was found to have bilateral ovarian microcystic stromal tumors (MCSTs), papillary thyroid carcinoma, and endometrial carcinoma. Histopathology from the MCSTs and thyroid was positive for beta-catenin, an important marker in FAP. MCST is a rare subtype of ovarian cancer that has been found concurrent with FAP on several occasions. Although our patient did not have genetic testing, the large number of polyps and autosomal dominant pattern of inheritance are consistent with FAP, rather than Lynch or MUTYH-associated polyposis (MAP) syndromes, which could present similarly. It would be important to look at histopathology in our patient to determine whether there is overlapping genetic expression with FAP. Nevertheless, our case represents another rare instance of co-occurrence of endometrial cancer and FAP. More research needs to be done to explore the potential association between endometrial/ovarian malignancies and FAP. Holistic care is an integral part of osteopathic medicine, thus it is important for osteopathic physicians to provide well-rounded care for every patient. This case gives evidence that there might be benefits in future screening of endometrial/ovarian cancer in patients with FAP that could potentially increase life expectancy in these patients.
A Rare Occurrence of Cardiogenic Shock after Cardioversion: A Case Report
(2023) Jain, Kunal; Fajkus, Austin; Takata, Theodore
Background: Atrial fibrillation (AF) is a common cardiac arrhythmia that affects the health and lifespan of people and has been growing in prevalence with the aging population. AF leads to atrial remodeling, which increases the likelihood of developing treatment resistant AF. Risk factors for AF include obstructive sleep apnea, alcohol use, obesity, hypertension, and diabetes. Treatment consists of rhythm control, rate control, and thromboembolism prevention. If a patient fails to convert to sinus rhythm or remains symptomatic despite pharmacological treatment, the next step in management may include Direct Current Cardioversion (DCCV) or catheter ablation. DCCV restores sinus rhythm (SR) by using controlled shocks to the heart and is considered a safe and effective procedure for treating AF. Complications include arrhythmias, skin burns, and cardiac tissue damage. Following the restoration of SR, cardiac output (CO) generally improves. Cardiogenic shock is a rare occurrence after DCCV. This case report details one of these rare occurrences, where a patient with multiple comorbidities developed cardiogenic shock after DCCV for AF. Case Information: A 65-year-old male with a history of heart failure with reduced ejection fraction, AF with prior ablation, atrial flutter, dilated cardiomyopathy, obstructive sleep apnea, chronic kidney disease, and implantable cardioverter defibrillator (ICD), presented to the emergency department (ED) with symptoms of dyspnea and shortness of breath. ECG showed atrial flutter with rapid ventricular response (RVR). Urgent DCCV was performed, restoring SR but precipitating cardiogenic shock, which required intubation and vasopressors. Since stroke volume remains constant in patients with dilated cardiomyopathy, the ICD was reprogrammed to raise the HR. Thereby improving the CO and resolving the cardiogenic shock. The patient remained stable for one month but had recurrent decompensated heart failure. ECG showed AF with RVR with a HR greater than 130 bpm. The patient was cardioverted again to sinus rhythm. However, the patient's condition soon deteriorated, wherein he developed shortness of breath, orthopnea, diaphoresis, and cold extremities. He was intubated due to his respiratory distress and started on milrinone, norepinephrine, furosemide, and an amiodarone drip. He nonetheless converted to AF with RVR, compromising his CO. This was evident clinically by his decrease in urine output, despite furosemide treatment. Urgent AV node ablation with a biventricular ICD upgrade was thus recommended. Postoperatively, as his condition improved, the patient was extubated and switched to oral diuretics. Amiodarone was discontinued, and his heart failure medications were slowly reinstated. Upon discharge, the patient was referred to another facility that specializes in heart failure and transplants. Conclusion: Although DCCV is generally considered a safe and effective procedure, there are still risks associated with it. This case highlights the importance of considering underlying cardiac dysfunction in patients undergoing cardioversion for AF and the need for close monitoring and follow-up in these patients. Since not many cases showcasing these potential complications have been documented, this warrants further research to identify risk factors, complications, and ways to prevent harm to patients who may undergo DCCV.
Addressing Age-Appropriate Cancer Care for Adolescents and Young Adults
(2023) Tran, Kylie; Elledge, Daniel; Hoeft, Alice; Albritton, Karen
Purpose: Adolescents and young adults (AYAs), normally defined as patients between 15 and 39 years of age, are often lost in the healthcare system that concentrates primarily on pediatric and adult cancers1. AYA cancer presentation can differ and treatments are less established compared to pediatric and adult cancers2. Many AYA patients are treated in pediatric facilities, which can lead to age-appropriate needs not being met. The goal of this project is to examine the AYA patient experience and assess if AYAs receive age-appropriate care at Cook Children’s Hospital in Fort Worth, Texas. Methods: Patient reported outcomes surveys were administered to AYA patients diagnosed between 1/1/2016 and 1/1/2020 with at least one of the following cancers: acute lymphoblastic leukemia, acute myeloblastic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, testicular germ cell tumor, ovarian germ cell tumor, or sarcoma. Eighty-five patients were eligible to participate in the study. The survey and chart review included information pertaining to demographics, socioeconomic factors, treatment, and diagnosis-related questions. Results: Seventeen patients have completed the survey. Patients rated age-appropriateness and quality of care on a five-point Likert scale. On average, patients rated the following aspects of their care as highly satisfactory for age-appropriateness: communication with medical staff (M = 4.80, SD = 0.40), staff recognition of life events (M = 4.71, SD = 0.46), provider attitude (M = 4.86, SD = 0.37), and support provided to their families (M = 4.82, SD = 0.40). Although still highly rated, the physical environment (M= 4.38, SD = 0.91) and recreational activities (M= 4.35, SD = 0.87) were reported to be slightly lower than the other categories for age-appropriateness. Conclusions: AYA patients face unique challenges related to their cancer presentation and psychosocial needs. Interactions between patients, their physicians, and their environment all contribute to the patients' treatment experience and providing comprehensive, age-appropriate care is important. Overall, patients reported receiving age-appropriate care at Cook Children’s Hospital but reported slightly less satisfaction with the facilities and age-related activities. Based on these findings, continuing to establish age-appropriate resources and physical spaces for AYA patients can greatly enhance their quality of care and treatment experience. Beginning in 2016, Cook Children’s AYA clinic had already initiated changes to establish more supportive resources for AYAs, including creating and renovating a designated AYA lounge and implementing more programmatic psychosocial care through psychological interventions and AYA-specific support groups. References 1. Alvarez, The Lancet Oncology, 2022 2. Smith, Pediatric Blood & Cancer, 2019
Characterization of Bilingual Mexican Americans among a Community Dwelling Cohort: An HABS-HD Study
(2023) Goehring, Leah; Petersen, Melissa
Introduction: Bilingualism has been increasingly studied in the context of neuroprotection particularly as it relates to cognitive decline. Despite higher rates of English/Spanish bilingualism, Mexican Americans also experience a higher risk of cognitive decline related to Alzheimer’s disease (AD) and Alzheimer’s Disease Related Dementias (ADRDs) as compared to Non-Hispanic Whites. Few studies to date have broadly examined the link between bilingualism and specific demographic, cognitive, and biomarkers among this ethnic group.The aim of this study is to examine the relationship between language status (monolingual/bilingual) on select demographic, cognitive, and AD specific blood biomarkers among this racial/ethnic group. Methods: Data were analyzed on n=890 Mexican Americans from the The Health & Aging Brain Study - Health Disparities (HABS-HD) study. Participants completed a clinical interview, which includes a self-report of language status (monolingual/bilingual) as well as various neuropsychological tests and an informant interview in order for clinicians to determine cognitive and functional status. Plasma amyloid (A), tau (T), and neurofilament light chain [NfL](N) blood biomarkers were assayed using the ultra-sensitive Single molecule array (Simoa) technology. Demographic characteristics were generated utilizing independent t-tests or chi square analyses for continuous and/or categorical variables. ANCOVAs were conducted with covariates of age, sex, and education for cognitive test performance and A/T/(N) blood biomarkers split by language status (monolingual, bilingual) as well as by cognitive status (cognitively unimpaired, cognitively impaired). Results: Of the n=890 Mexican Americans, n=393 self reported as monolingual and n=497 as bilingual. Among monolinguals, 70% were diagnosed as cognitively unimpaired, 20% with mild cognitive impairment (MCI), and 10% with Dementia while among bilinguals, 78% received a diagnosis of cognitively unimpaired, 17% with MCI, and 5% with Dementia. Regarding neuropsychological testing, bilingual individuals performed significantly better across measures of global cognition, attention, and processing speed (ps<0.001). While examining blood biased biomarkers, a trending significance of higher total tau was found among bilinguals compared to monolinguals. When separated by cognitive status, total tau was higher among bilingual Mexican Americans who were cognitively unimpaired (p=0.044). Higher Aβeta 40 levels were found to be significantly associated with reduced performance on measures of attention, processing speed, and executive functioning among bilinguals who were cognitively unimpaired (ps<0.001). Among bilinguals with cognitive impairment, higher total tau levels were associated with lower performance on a measure of working memory (p=0.001) and higher NfL levels were associated with lower performance on measures of global cognitive screening measure and working memory (ps=0.001). Discussion: As rates of AD and ADRDs increase in Mexican Americans, their bilingualism may be advantageous in delaying this pathology. Bilingualism is differentially related to cognitive and AD biomarkers. Better understanding the relationship between bilingualism and these markers might be informative regarding potential protective effects for this at risk group.
Demographic Factors Associated with Parents’ Knowledge About Sexually Transmitted Infections
(2023) Johnson, Kaeli; Kinard, Ashlyn; Lemuz, Tiffany; Terrillion, Ryan; Griner, Stacey
Purpose: Gender roles are usually discussed in the context of socialization, however, this can be extended to other facets of behavior, such as compliance with treatment of sexually transmitted infections (STI). Because of this, many times the burden of STI testing and relaying information to partners is left to women. Similarly, within traditional nuclear families, gender roles and norms create expectations for family members, but especially parents. For example, maternal roles often include tending to the children and home, while paternal roles usually include being a provider for the family. Though our current society continues to transform these gendered norms, some of these gender roles still linger. Because of this, it is expected to see these gender norms and roles reflected in knowledge about STIs. Other demographic factors such as race, age, and education level may have an impact on knowledge acquired about STIs. The purpose of this study was to explore the demographic factors, including gender, associated with parental knowledge of STIs. Methods: We recruited parents of children aged 10-17 (n=230) via Centiment, an online survey panel. We assessed STI knowledge using a 27-item validated knowledge scale that included true and false statements. The scale included questions about Chlamydia, Gonorrhea, Herpes Simplex Virus (HSV-2), Human Immunodeficiency Virus (HIV), Human Papillomavirus (HPV), and Hepatitis B. An example of a question included was Genital herpes is caused by the same virus as HIV. Parents indicated their response (true/false/don’t know) and answers were coded (incorrect/correct). Incorrect answers were coded as 0, correct answers were coded as 1, and "don’t know” responses were automatically considered incorrect. There were 27 possible points based on the validated scale. Demographic questions included gender, age, race, parental STI history, and highest level of education. Descriptive statistics, univariate, and bivariate analyses were conducted in SPSS. A p-value of p < .05 was considered statistically significant. Results: The average knowledge score was 12.5 (SD=6.2, range 0-27). Knowledge score was not correlated with parent age (p=.62) or child age (p=.43). There were no significant associations between knowledge and parent gender (p=.06), parent race (p=.70), parent education level (p=.47), child gender (p=.08), or child race (p=.59). However, 28% of parents reported a history of an STI, and knowledge score was significantly different among those with an STI history (14.5) compared to those without (11.6; p=.001). Conclusions: We noted a significant difference in STI knowledge based on STI history. This is expected as those who have had experience with STIs and STI treatment would have increased knowledge about them. However, average knowledge scores were low overall, with no significant differences across several different demographic factors. This emphasizes a need for better sexual education across the life course. This also displays a need for targeted interventions to increase STI awareness and knowledge among parents, in general. Future studies should assess the specific gaps in STI knowledge among older adults and how sexual education information can be disseminated to this age group.
Polyglandular Autoimmunity: Two Cases of Type 1 diabetes (T1D) accompanied by Addison’s disease (AD)
(2023) Borrego, Natali; Bommakanti, Maalini; Radack, Jill; Hamilton, Luke; Wilson, Don
Background: Type 1 diabetes (T1D), present in ~1:500 children, is often accompanied by other autoimmune conditions, notably chronic lymphocytic thyroiditis. Involvement of other endocrine organs, however, is rare. Autoimmune impairment of more than one endocrine system is referred to as an autoimmune polyglandular syndrome (APS), categorized as type 1 (APS-1) or type 2 (APS-2). In addition to T1D, APS-1 is characterized by 1 or more of the following: candidiasis, hypoparathyroidism, and/or AD; while APS-2 involves AD and/or chronic thyroiditis2. The lifetime risk of developing a 2nd endocrine autoimmune condition in individuals with T1D is ~1:5, and usually occurs during adulthood. While children may be affected, such reports are unusual and generally limited to case studies. APS-2 is rare in childhood, with a prevalence of ~ 1:100,0004. We present two children with APS-2. Case Information: Case 1: A 6-year-old Caucasian male, who was diagnosed with T1D at 3 years-of-age, presented with persistent vomiting which required hospitalization. Although his diabetes was reasonably well controlled prior to his hospitalization, the child was noted to be overly sensitive to insulin during this admission, during which he experienced several episodes of hypoglycemia. Laboratory testing revealed metabolic acidosis, hyponatremia, and hypocortisolemia. Appropriate testing confirmed primary adrenal insufficiency; the latter, along with his T1D, being consistent with APS-2. Case 2: A 15-year-old Caucasian male experienced an unexplained 20 lb. weight loss. After developing fever, routine laboratory tests were reported to be characteristic of diabetic ketoacidosis (DKA) - hyponatremia, metabolic acidosis and hyperglycemia. With treatment, his DKA resolved, and he began conventional insulin therapy. However, follow-up laboratory tests demonstrated persistent hyponatremia. Additional studies confirmed the presence of AD, consistent with APS-2. Conclusion: These previously healthy children developed T1D accompanied by AD, characteristic of APS-2. The presence of both conditions significantly increases the risk of potential life-threatening complications in affected children5. Individuals with both T1D and AD have a 2.5-fold increased risk of adrenal crises, compared to those with isolated AD6. Timely diagnosis of polyglandular autoimmunity is critical to help inform clinical decision-making, and to avoid adverse outcomes. The diagnosis of APS is often hampered by common symptoms such as: fatigue and weakness, unexplained weight loss, increased thirst, frequent urination, irritability, nausea and abdominal pain, and changes in appetite2. Management is complicated by the effects of glucocorticoid levels on insulin sensitivity. For example, these patients have a risk of increased insulin sensitivity and hypoglycemia in the early morning hours prior to the next glucocorticoid dose1. Patient education is key for understanding the interactions between the two conditions as well as the effects of diet, physical activity, and emotional stress2. While the onset of APS is variable, most patients tend to develop autoimmunity sequentially over a period of many years2. APS-2 has been linked primarily to genes coding for major histocompatibility complex, particularly DR3-DQ2 and DR4-DQ8 variants6. Physicians should be vigilant in assessing children with autoimmune-related conditions, such as T1D, and although rare, aware of the potential for additional autoimmune-mediated organ failure in some.
Active suppression of adaptive immunity by Borrelia burgdorferi in the murine host
(2023) Williams, Megan; Zhang, Yan; Kilgore, Rebecca; Allen, Michael
Purpose: Borrelia burgdorferi(Bb), the spirochetal agent of Lyme disease, utilizes a variety of tactics to evade and suppress the host immune response which enable it to persist chronically. These tactics can include complement inhibition, antigenic variation, extracellular matrix degradation, and adaptive immune suppression. Adaptive immune suppression by Bb is still not well understood. Previous studies have shown that lymph node (LN) germinal centers generated in response to Bb collapse one-month post-infection. The resulting humoral immune response is characterized by unusually strong and persistent IgM production and lack of long-lived immunity. Here we aimed to better characterize how Bb manipulates the host humoral immune response, ultimately resulting in failure to clear the infection. Methods: Mice were infected with Bb and concomitantly immunized with recombinant SARS-CoV-2 spike protein to measure the antibody response to the immunization and how it may be dampened by infection with Bb. We also immunized mice at 2-, 4-, and 6-weeks post-infection to test how long this humoral immune suppression lasts. Using RT-qPCR, we also examined changes to gene expression in murine LNs 15 days post-infection to better characterize what may be causing this observed immune dysfunction. Results: Suppression of host antibody production against the rSARS-CoV-2 spike protein peaked at 2 weeks post-infection but continued for all timepoints measured. We also found that live Bb, but not heat-killed (HK) Bb, broadly suppressed many genes related to T cell homing and function. Genes which play a critical role in the establishment and maintenance of T cell zones within the LNs, Ccl19 and Ccr7, were significantly downregulated. This was interesting considering previous studies have provided evidence of disorganization of LN architecture and the disruption of T cell zones beginning around 10 days post-infection. In addition, both Il2 and Il2ra were significantly downregulated, which is typically observed during the resolution of infection and indicates a lack of antigenic restimulation. Conclusion: These data suggest potential T cell disruption by Bb, which may play a role in the failure to mount an appropriate humoral immune response to the infection.
Decrease in Mental Health Among Adolescent Students
(2023) Jones, Courtni; Thompson, Erika
Background: Persistent feelings of sadness or hopelessness has increased among adolescent high school students over time. Lack of physical activity has been identified as a risk factor for persistent feelings of sadness or hopelessness. The purpose of this study was to understand the epidemiology of persistent feelings of sadness or hopelessness and its association with physical activity among adolescents. Methods: Data from the Youth Risk Behavior Survey (YRBS), 2019, consisted of N=13,677. The main variable analyzed was 'felt sad or hopeless’(yes/no)and the association variable was 'were not physically active at least 60 minutes/day on all 7 days of the week’ (yes/no). Demographic variables measured: sex, race/ethnicity, grade, and sexual orientation. Statistical analysis used: logistic regression model, chi-squared test, and t-test using the YRBS data explorer tool. Results: The current (2019) prevalence of feelings of sadness or hopelessness among adolescents is 36.7%, an increase from previous years. Rates for feelings of sadness and hopelessness were highest among these demographic groups: Females (46.6%), Bisexuals (68.2%), 12th Graders (39%), American Indians (45%), Sex with both sexes (74.4%). There was a significant association between feelings of sadness or hopelessness among adolescents and students who were not physically active at least 60 minutes/day on all 7 days of the week, p-value=<0.01. Adolescent students that were not physically active at least 60 minutes per day on all 7 days of the week were more likely to experience feelings of sadness or hopelessness (39.2%), compared to adolescent students who were physically active at least 60 minutes per day on all 7 days of the week (29%). Conclusion: There were differences observed in sex, race/ethnicity, grade-level, and sexual orientation among students that experience feelings of sadness or hopelessness. Lack of physical activity is associated with feelings of sadness or hopelessness. Although the role of lack of physical activity cannot be determined in the causation of poor mental health among adolescent students, future research should focus on examining why there are large differences between different demographics and how to combat that issue to improve mental health. In addition, more research should focus on understanding the role physical activity plays in mental health, and specific solutions for how it can be used as a tool to improve mental health among adolescent students.
Program Director Survey Determining Effects of Single Accreditation and Pass/Fail Licensing Exams on Osteopathic Medical Students Applying for Surgical Residency
(2023) Panchal, Olivia; Pereira, Kenneth; Brennan, Zachary; Taylor, Casey; Paluri, Sarin; Young, Grace; Burns, Bracken; Conrad-Schnetz, Kristen; Gudakunst, Craig
Purpose Prior to the single accreditation system (SAS), some residency programs were accredited by the American Osteopathic Association (AOA), rather than the Accredited Council for Graduate Medical Education (ACGME) and trained osteopathic (DO) graduates only. Recently, United States Medical Licensing Examination (USMLE) Step 1 and Comprehensive Osteopathic Medical Licensing Examination (COMLEX) Level-1 transitioned from numeric scores and pass/fail outcomes to pass/fail only. The purpose of this survey was to examine the effects of these changes on DO students applying for surgical residency. Methods A voluntary, anonymous survey was distributed five times over 9.5 weeks to 1539 surgical program director (PD) emails collected from the Fellowship and Residency Electronic Interactive Database (FREIDA). 302 responses were received (response rate 19.6%) and 244 survey responses were included in statistical analyses. 58 responses were excluded because of incompletion, the respondent was not a PD, or the respondent disqualified DO students from matching. Results For DO applicants, most former-AOA programs recommend Step 1 while most non-AOA programs require it. The majority of both program types require Step 2 CK. When deciding whom to interview, former-AOA programs significantly preferred Level-2 scores and completion of an acting-internship at the program while non-AOA programs significantly preferred the Medical Student Performance Evaluation and clerkship grades/evaluations. Both program types highly valued Step 2 CK scores and letters of recommendation. Conclusion Based on this study, DO applicants should almost certainly take both Step 1 and Step 2 CK (in addition to Level-1 and Level-2) to be considered competitive. Additionally, the results underscore the importance of identifying surgical residency programs as former-AOA or non-AOA– particularly when prioritizing where to complete acting-internships. Despite the SAS, former-AOA and non-AOA surgical residency programs differ in their preferred medical licensure examination and metrics for determining competitiveness. DO students should consider these differences to improve osteopathic surgical match rates.
Relationship of Down Syndrome with Keratoconus and Gonadotropins
(2023) Shrestha, Pawan; Escandon, Paulina; Petersen, Melissa; Hjortdal, Jesper; Ramirez, Lito; Karamichos, Dimitrios
Purpose: Down syndrome (DS), also known as trisomy 21, is a common genetic disorder of chromosomal nondisjunction. DS has been strongly associated with Keratoconus (KC); however, the exact pathobiology remains unexplored. KC is one of the most significant corneal disorders which is characterized by thinning, cone-shaped protrusion, and steepening of the cornea leading to a significant reduction of visual acuity and even blindness. The aim of this study was to investigate the relationship of DS with KC in the context of gonadotrophic hormones. Methods: This study adhered to the declaration of Helsinki. Fifty-eight healthy controls (29 male, 29 female), one hundred and forty-nine KC (112 male, 37 female), and eighty DS (44 male, 36 female) patients were recruited for this study. Plasma samples were collected from all participants. We investigated the expression of Gonadotrophin-releasing hormone (GnRH) and Follicle stimulating hormone (FSH) using enzyme-linked immunosorbent assay (ELISA). Results: Significant downregulation of GnRH expression was observed in KCs when compared with healthy (p = 0.0006) and DSs (p = 0.00249). GnRH was significantly downregulated in KC and DS males, compared to their healthy counterparts, while no significance was observed in females across all diseases. Significant upregulation of FSH levels was observed in DSs compared to both healthy and KCs (p < 0.0001). FSH expression was also significantly elevated in both DS males and females when compared to healthy and KCs. Conclusions: Our results revealed downregulation of GnRH, but upregulation of FSH in DS participants as compared to KCs. These findings provide new insights into the potential association between DS and KC, and substantiate the role of gonadotropins. Further studies are warranted to further understand the underlying mechanisms and potential implications for the treatment and management of these conditions.
Case Study on the Effect of Osteopathic Manipulation on Gallbladder Ejection Fraction
(2023) Lin, Emily; Montalvo, Emily; Adams, Natalie; Garcia Garcia, Diana; Sparks, Clarence
Background: There is minimal research regarding the effects of osteopathic manipulative treatment (OMT) upon biliary emptying. Despite the limited research, OMT has been used to treat gallbladder dysfunctions in clinical practice. Case Information: The purpose of this case study was to examine the effects of OMT on gallbladder ejection fraction (EF) as measured by ultrasound and to determine if there was sufficient evidence of OMT-influenced biliary emptying to base a larger study. OMT was performed by a neuromusculoskeletal medicine board certified osteopathic physician on a medical student, who was acalculous and asymptomatic of any biliary disorder. Interventions included OMT targeting sympathetic and parasympathetic innervation levels, Chapman points, visceral myofascial release, and Sphincter of Oddi release. Results included gallbladder EF as measured by ultrasound. Blinded analysis demonstrated a 8.88% increase in average gallbladder EF following OMT, with a statistically significant difference in mean ejection fraction between OMT (M=46.95, SD=19.83) and no OMT (M=38.07, SD=19.13) conditions (paired t(4)=2.828, p=0.047). Conclusions: A limitation in the design of this study is that the comparison EF was measured 15 days after the OMT intervention. In future studies, we would first measure the EF and then perform OMT and measure the EF at least 4 weeks later. The results of this case study provide an enhanced understanding of OMT’s effect on gallbladder EF. Future studies should apply the biliary OMT protocol to a diverse clinical population with and without functional gallbladder disorder to determine if OMT could be used as an alternative treatment.
Recognizing the Central Nervous System as a Site of Pediatric Sarcoma Relapse: A 3-Patient Series
(2023) Smith, Danielle; Hamby, Tyler; Heym, Kenneth; Mohamed, Ashraf; Vallance, Kelly; Ray, Anish
Background: Sarcomas are diverse malignancies derived from primitive mesenchymal cells that are difficult to diagnose and treat. Advances in local control techniques, chemotherapy regimens, and imaging modalities have led to improvements in both morbidity and mortality in pediatric patients. However, one-third of patients develop disease relapse. Previously, intracranial metastasis was thought to be rare. The incidence of sarcoma brain metastasis is thought to have increased and is associated with grim outcomes. Case Information: Case 1 – A male Asian infant was born with a mass involving lower left extremity requiring through the knee amputation shortly after birth. Pathology confirmed infantile fibrosarcoma (IF). He was started an IF-based regimen after pulmonary biopsy confirmed metastatic disease. Two months after chemotherapy completion, 5.6 x 7.2 x 6.3 cm intracranial tumor was found with pathology confirming metastatic IF. Despite salvage chemotherapy and entrectinib, he continued to have increased neurological symptoms and died. Case 2 - Ten-year-old Caucasian female presented with 8-month history of progressively enlarging right foot mass measuring 6.2 x 4.5 x 4.2 cm, consistent with Ewing Sarcoma upon biopsy. PET scan showed bilateral pulmonary metastatic disease with lymph node involvement. Chemotherapy and radiation therapy (XRT) were started. After completion of cycle 6, she had increased neurological symptoms and imaging showed 5 x 6 cm temporal mass with hemorrhage. Brain XRT, palliative chemotherapy, and Ruxolitnib were started; however, the patient subsequently died. Case 3 – Six-year-old Hispanic female with large mass arising from right proximal humeral metaphysis with evidence of bilateral pulmonary metastasis. Biopsy confirmed metastatic osteosarcoma and chemotherapy was started. Although the patient was treated further with methotrexate, salvage chemotherapy, palliative XRT, and Pazopanib, she began to develop neurological symptoms over several weeks before passing. Conclusions: We note this is the only report of IF brain metastasis, a rare report of sarcoma lymph node metastasis, and each patient was treated with an immunotherapy agent. Caregivers in cases 2 and 3 reported new-onset neurological manifestations prior to identification of new brain metastasis, indicating a lag in detection of new intracranial relapse in asymptomatic sarcoma patients. We suggest implementing a brief review of systems screening tool focused on concerning neurological manifestations to screen for brain metastasis.
Implementation of changing clinical practices: Prenatal syphilis screening in Texas
(2023) Terrillion, Ryan; Lemuz, Tiffany; Kinard, Ashlyn; Johnson, Kaeli; Griner, Stacey
Purpose: Congenital syphilis can cause negative health outcomes including stillbirths, miscarriages, birth defects, and infant death. From 2016-2020, national congenital syphilis rates have increased from 16.2 to 57.3 cases per 100,000 live births. Texas congenital syphilis rates are significantly higher than the national rates and have increased 835% from 2016-2020. Prenatal syphilis screening by providers can avert maternal and neonatal mortality and morbidity, although there are conflicts between national professional organization’s recommended guidelines and individual state screening mandates. State dissemination and clinical integration of updated screening mandates are imperative to reduce the rates of congenital syphilis in Texas. The purpose of this study is to understand the factors influencing implementation of prenatal syphilis screening guidelines into clinical practice. Methods: Prenatal providers including physicians (MD/DO) and mid-level providers (CNM/NP/PA) in Texas were recruited to participate in an in-depth interview. Recruitment strategies included social media advertising, newsletters of professional organizations, and direct email recruitment. The interview guide was based on constructs from the Consolidated Framework for Implementation Research, an implementation science theory focused on identifying determinants, or factors, that influence translation into practice. Interviews were approximately 45 minutes in length, were conducted via Zoom or phone, were audio recorded and then transcribed by a professional. Data were thematically analyzed with emergent and theory-based codes. Results: Respondents were certified nurse midwives and physicians (n=9) who discussed implementation of changing clinical practices in the context of the Texas Department of State Health Services (TDSHS) updated mandate for prenatal syphilis screening at delivery in 2019. Participants expressed difficulty with having clear communication and resources from TDSHS about changes, reliance on email updates from professional organizations for new screening recommendations, and both formal and informal colleague dialogues as sources of policy updates. Specific difficulties expressed were the confusing TDSHS website interface, ineffective email communications that are not practice-specific, and lack of data to understand the need for a change in practice for their populations. The interviewees discussed how population and professional ethics affect prenatal screening practices and the ease of changing orders once new policy changes were agreed upon by management stakeholders. Conclusion: Varied responses from participants regarding the source of TDSHS updated mandates for prenatal syphilis screening indicate that there are no universally effective methods of communication between TDSHS and clinicians to understand, be notified of, and/or implement new mandates in a timely and uniform manner. The clinicians also noted deference to national professional organizations as institutions that they could rely on for clear communication about policy recommendations that highlighted their practice needs while considering TDSHS communications as required for practice rather than a source of clinically relevant state and community health data. Understanding of how clinician perceptions of prenatal syphilis risk for their patient populations would change with relevant local statistics within TDSHS communications would further elucidate roadblocks to integration of state mandates into clinical practice. The development of context specific implementation strategies for providers in Texas can improve prenatal syphilis screening and ultimately reduce the adverse neonatal outcomes.
Title: Understanding Type II Diabetes Insulin Management During The COVID-19 Pandemic: Findings from a Hospital and a Clinic
(2023) Opara, Chinemerem; White, Annesha; Xiao, Yan; Jodray, Megan; Fulda, Kimberly
Purpose: COVID-19 disrupted the care of people with diabetes. It is not clear how the disrupted care impacted medication safety and diabetic control outcomes. During the pandemic, questions emerged regarding whether patients experienced changes in care that led to higher glucose levels, inappropriate medication changes and poorer health outcomes. The role of strategies to control glucose, such as the use of antidiabetic drugs has been established. We examined safety issues related to the association between insulin use and diabetic control among diabetic patients during COVID-19. Results: After examining 42 patient cases, it is noted that most (55%) patients had controlled A1C (pre-Covid vs Covid-era). (55%) of patients whose A1C was < 8% (pre-Covid vs Covid era) were prescribed insulin compared to (45%) of patients who had an A1C >8% (pre-Covid vs Covid era). The cease in insulin prescribing (pre-Covid vs Covid era) increased the A1C levels for uncontrollable patients. Conclusion: During the COVID pandemic, gaps in insulin prescriptions were associated with occurrences of diabetic control status changing to uncontrolled status, indicating patient safety issues. Monitoring insulin prescribing among diabetic patients during the pandemic may identify care gaps and help to improve patient care outcomes.
A Case Report of Multiple Myeloma in a Middle-Aged Male Patient
(2023) Frangenberg, Alexander; Warner, Amanda; Lafonte-Nunez, Eric; Desai, Shivani
Background Multiple Myeloma is a neoplastic plasma cell disorder that results in proliferation, and thus overactivity, of plasma cells to produce immunoglobulin light chains, causing end-organ damage due to proteinemia. Clinical symptoms commonly manifest as renal insufficiency, with hypercalcemia and high blood creatinine, bone marrow dysfunction, such as anemia and osteolytic bone lesions or severe osteopenia, and infection due to suppression of humoral and cell-mediated immunity. While a majority of patients affected are older than 60, younger patients can also be affected; however, clinical factors such as reversibility of renal function, response to chemotherapy, molecular markers, and the need for hemodialysis show greater clinical correlation to differences in outcomes. Case Information This patient is a 42 y.o. male with no past medical history who presented to the ED after his PCP informed him that he had "abnormal labs.” Patient reported back and chest pain for 3 months, which he attributed to a motor vehicle accident, as well as increased fatigue and weight loss ~25 lbs in past 2.5 months. Labs were remarkable for anemia, of Cr 26 (previous baseline of 0.7 1 year ago), BUN 136, Ca 17.8, and K 6.7. CT CAP revealed multiple lytic lesions throughout and was admitted to ICU for continuous renal replacement therapy (CRRT) and evaluation of acute kidney failure in the setting of lytic bone lesions. At this time, nephrology, hematology/oncology and palliative services were consulted for management of patients’ renal function, concerning lab findings with lytic lesions, and pain, respectively. Serum protein electrophoresis (SPEP) was ordered and indicated a kappa light chain myeloma, later confirmed by bone biopsy. He completed 5 days of plasmapheresis and was started on chemotherapy treatment for multiple myeloma, consisting of the CyBorD therapy regimen (cyclophosphamide, bortezomib, dexamethasone). Patient was transferred out of the ICU and began conventional hemodialysis (HD). At time of discharge, patient would follow with Oncology and undergo HD on an outpatient basis. Patient was also treated with Denosumab given his hypercalcemia with plan to continue as outpatient after dental clearance as well as EPO in the outpatient setting given his anemia. Conclusions Multiple Myeloma is a disease primarily affecting older patients, with rates peaking in the seventh decade, and as is common with multiple types of cancer, was commonly thought to have been more severe when presenting in younger patients, as a higher proportion may have cytogenetic abnormalities and physical manifestations of disease on imaging. There does not seem to be any defining presenting clinical features that may differentiate between younger and older patients presenting with signs of Myeloma. Regardless of age, certain presenting clinical factors have been associated with poor outcomes, some of the main ones being creatinine on presentation, platelet count, and serum albumin. In regards to the patient mentioned in this case, creatinine on presentation and maintenance of renal function on hemodialysis are risk factors relating to his disease prognosis, although individual patient factors and treatment options should not be overlooked.
Effect of Monocarboxylate Transporter 2 Loss on Retinal Ganglion Cell Survival and Function
(2023) Murinda, Kudakwashe; Morgan, Autumn; Inman, Denise; Kiehlbauch, Charles
Purpose: There is currently no cure for the vision loss in glaucoma that is characterized by retinal ganglion cell (RGC) loss and irreversible optic neuropathy. Monocarboxylate transporter 2 (MCT2s) that transport pyruvate, lactate, and ketone bodies, are exclusively found in neurons such as the RGCs. We have previously shown that MCT2 is lost during glaucoma, in advance of RGC loss, and MCT2 overexpression protects RGC number and function. This study was undertaken to test whether MCT2s are necessary for RGC survival and function. Methods: To test this hypothesis, we used tamoxifen injection into Thy1-ERT2-cre: MCT2fl/fl mice to conditionally knock out MCT2 from Thy1-positive RGCs. Control mice carried the MCT2 flox’d allele but were Thy1-ERT2-cre-negative. Control and experimental mice were subjected to ocular hypertension using the magnetic microbead model; separate naïve controls from each genotype were also evaluated. Intraocular pressure (IOP) was measured using the TonoLab rebound tonometer. Pattern electroretinogram (PERG) was used to analyze RGC function. We used unbiased stereology (Stereo Investigator, Micro Brightfield) to count the number of retinal ganglion cells in wholemount retina, and ATP levels in retina were also measured. Results: IOP was higher in the ocular hypertension (OHT) groups. MCT2 knockout alone did not impact IOP, nor did it alter baseline PERG amplitude or latency. After OHT, PERG amplitude was significantly lower in the MCT2-knockout mice (p=0.0013). MCT2 knockout alone did not change RGC density. After OHT, RGC density decreased, though in this preliminary analysis, RGC density among the groups was not significantly different. ATP production in the OHT+ Tamoxifen group was significantly higher (1.81 +/- 0.89 ug/ul) than in the naïve control group (0.68 +/- 0.42 ug/ul). Conclusions: MCT2 knockout from RGCs did not change IOP or PERG, suggesting that MCT2 is not necessary for RGC survival. Ocular hypertension decreased PERG amplitude and RGC density, though the magnitude of the decrease may not have been increased by MCT2 knockout. These preliminary data suggest that RGCs are capable of meeting their immediate metabolic needs through means beyond MCT2.

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