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Background – The prevalence of hyperthyroidism is very common in the United States (approximately 1.2%) with Graves’ Disease (GD) being the most common non-iatrogenic cause. The limited number of endocrinologists and their concentration in larger cities means that primary care providers (PCPs) must treat a large number of these patients. This paper provides an effective, straightforward protocol for them to do so.Material & Methods – Patients with GD hyperthyroidism were referred to a county endocrinology clinic by PCPs in clinics that cared for medically underserved, mostly minority patients, a challenging population to treat. Hyperthyroidism was diagnosed by elevated free T4 and/or free T4 concentrations, euthyroidism by normal concentrations of both and hypothyroidism by low free T4 or elevated TSH concentrations. Patients were treated with methimazole with initial doses and up-titration based on free T4 and free T3 concentrations and down-titration by free T4 and TSH concentrations.Results – At the initial visit, 155 patients were, and 54 patients were not, respectively, taking an anti-thyroid drug. At the initial visit, patients either remained on methimazole, were started on the drug or were switched to it from propylthiouracil. The 209 patients were followed for up to 18 months. The protocol rapidly reversed the hyperthyroidism in most patients and at the end of the study, 72% were euthyroid, 19% were hyperthyroid and 9% were hypothyroid. Medication non-adherence probably accounted for those who were hyperthyroid at that time.Conclusion – PCPs following this protocol will enable them to effectively treat patients with GD hyperthyroidism.

Nonalcoholic steatohepatitis (NASH) is a more severe form of non-alcoholic liver disease (NAFLD) that is characterized by inflammation and liver damage. Previous studies have identified a strong association between NAFLD and race/ethnicity, but there has been less investigation of a racial disparity specifically in NASH. We tested the association between NASH and race/ethnicity in the adult US population of NHANES 17-18 (n=5492). Hepatic steatosis (HS) was diagnosed by FibroScan® using controlled attenuation parameter (CAP) values (stages): S0 290. Participants with moderate/severe steatosis without the exclusion criteria (elevated transferrin level >50%, chronic hepatitis B, chronic hepatitis C, excessive alcohol use, or prescription medications that might cause HS) were considered to have NAFLD (n=3,292). Subjects with NAFLD and a HAIR score (defined by HOMA-IR, hypertension, and ALT) of ≥ 2 were considered to have NASH, as opposed to simple NAFLD. Data were analyzed using Chi square and multinomial regression adjusting for the other independent variables [demographics: (age, gender, education, poverty), physical activity, smoking, waist-hip ratio, body mass index, triglyceride, cholesterol, glucose, HbA1c, C-reactive protein (hsCRP), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and healthy eating index (HEI)] using SAS (Release V.9.1.3, 2002; SAS) and including sample weights and design. The overall prevalence of NASH was 7.6% and it varied by race/ethnicity. Mexican Americans had the highest prevalence (10.6%), followed by other Hispanics (9.1%); Non-Hispanic Whites had the lowest prevalence (6.8%) (p0.05). We concluded that the prevalence of NASH was highest among Mexican American males relative to the other groups. Targeted interventions for Mexican American males are needed to increase awareness, management and prevention related to NASH. Grants: R01MD012579, R24DA017298, U54MD007598, S21MD000103, UL1TR001881 Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Inhalation of electronic (e)-cigarettes containing nicotine may elevate blood pressure (BP), but the underlying mechanisms are poorly understood. 11β-HSD2 is crucial for BP regulation by inactivating glucocorticoids in the kidney. Little is known about the effect of e-cigarettes on 11β-HSD2 and their contribution to the process of BP elevation. To examine the possible effects of e-cigarette vapor exposures on renal 11β-HSD2 and BP, four groups of mice were exposed to aerosolized PBS, nicotine-free or nicotine-containing e-cigarettes, with concurrent exposure to either saline or the nicotine antagonist hexamethonium (Hex). Mouse renal M1 CCD cells were used to identify the effects of nicotine on 11β-HSD2 and its transcription factor C/EBPβ. Our results showed that mice exposed to e-cigarettes containing nicotine for 4 weeks markedly decreased the expression and activity of renal 11β-HSD2 and elevated the systolic BP in C57BL/6J mice. Reduction of 11β-HSD2 by nicotine inhalation was accompanied by reduction of renal C/EBPβ and responded to elevated plasma nicotine levels. In contrast, these effects were not observed in mice exposed to e-cigarettes vapor without nicotine compared to PBS controls. Treatment with Hex significantly decreased the elevated ratio of urinary corticosterone to 11-DHC along with stimulation of renal C/EBPβ and prevented the raised BP in mice exposed to e-cigarette vapor containing nicotine. Treating CCD M1 cells with vaporized e-cigarettes containing nicotine extract showed comparable effects with those of pure nicotine for suppression of C/EBPβ and 11β-HSD2, and these effects are blocked by Hex, indicating a mechanistic specificity. Our results indicate that the inhalation of nicotine e-cigarette vapors has potential adverse effects on renal health suggesting that disturbance of renal 11β-HSD2 may contribute to e-cigarette nicotine-induced BP elevation. These findings highlight the potential health risk of e-cigarettes. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Monday, June 13, 2022 1:00 p.m. - 1:05 p.m.

Non-alcoholic fatty liver disease (NAFLD) is a serious condition whose prevalence differs by race/ethnicity. Studies have suggested that consumption of high-fructose corn syrup is likely a risk factor for NAFLD. We investigated the associations between fructose consumption and NAFLD, and its distribution by race/ethnicity in the adult US population using NHANES 2017-2018 data (n=3292). NAFLD was diagnosed by FibroScan® using controlled attenuation parameter (CAP) values of =>260 and no exclusion criteria. Fructose consumption was calculated from 24-hour dietary recall data in combination with USDA food nutritional content data files. Fructose consumption was categorized into tertiles (low= 0.95-2.1 g). We analyzed data in SAS 9.4 using Chi squared tests and multinomial logistic regression, adjusting for demographics, behavioral, and laboratory data, and including sample weights and design. Of the 3292 participants, 31.3% were in the middle tertile of the fructose consumption and 35.5% were in the high tertile. There was no significant difference in the prevalence of NAFLD by fructose consumption group [low=44%; middle=48%, and high=51%] (p=0.094). The highest percentage of participants in the high tertile of fructose consumption were in Mexican Americans (48%) and non-Hispanic Blacks (44%), with a much lower percentage of non-Hispanic Whites (33%) (p Presentation: Sunday, June 12, 2022 12:00 p.m. - 12:15 p.m.

Non Alcoholic Fatty Liver Disease (NAFLD) is a public health concern, especially given its increasing prevalence. The spectrum of NAFLD ranges from simple NAFLD to nonalcoholic steatohepatitis (NASH), followed by fibrosis and cirrhosis. There is a known health disparity for NAFLD with Mexican-Americans having a higher prevalence and Blacks having a lower prevalence compared to Non-Hispanic Whites. The objective of this study is to examine the association between race/ethnicity and hepatic fibrosis. Data from the National Health and Nutrition Examination Survey (2017-2018) was used for the analysis. The analytic sample was restricted to participants who were at least 18 years of age (N=5492). Hepatic fibrosis was diagnosed by FibroScan®. Fibrosis stages were F0-F1 (14 kPa). Data were analyzed using Chi square and multinomial regression to determine the association between race/ethnicity and hepatic fibrosis adjusting for the other independent variables [demographics (age, gender, education, poverty), physical activity, smoking, waist-hip ratio, body mass index, triglycerides, cholesterol, glucose, HbA1c, C-reactive protein (hsCRP), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and healthy eating index (HEI)] using SAS (Release V.9.1.3, 2002; SAS) and including sample weights and design. The overall prevalence of hepatic fibrosis was 20.8% (F2=12.7%, F3=4.6%, F4=3.5%). There was no statistically significant difference in hepatic fibrosis prevalence by race/ethnicity (p=0.817). F2 stage was highest among Blacks (14.9%) and other Hispanics (14.8%) and 13.0% in Non-Hispanic Whites. F3 stage was highest among Blacks (5.3%) and Whites (4.9%). F4 was highest among "other Hispanics (4.7%) but none of the differences was statistically significant. In the multinomial adjusted model, race/ethnicity was not associated with having F2 or F3 stages, but it was associated with F4 stage where "other race/ethnic" group were 3 times more likely than Non-Hispanic Whites to have F4 stage (adjusted odds ratio=3.2, 95% confidence interval=1.1-9.4, p=0.03). In the adjusted model, factors associated with high adjusted odds of F4 stage were high waist to hip ratio, low HDL (1 mg/dL, high AST (>40 U/L), HbA1c=>6.5% (diabetes mellitus) (p Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Background Sedentary lifestyles and changes in diet are fueling the worldwide epidemic of obesity and the prevalence of NAFLD and insulin resistance (IR). It has been predicted that NAFLD and its more advanced form, nonalcoholic steatohepatitis (NASH) will be the next epidemic in chronic liver diseases, and NAFLD/NASH will soon replace viral hepatitis as the primary cause of end-stage liver failure and transplantation. NAFLD is a significant risk factor for IR and cardiovascular diseases, and it highlights the importance of finding a way to control the epidemic. CARF is a multifunctional stress-responsive gene and was found to be reduced in response to metabolic stress in the fatty liver of diet-induced obesity mice (DIO). We also showed that CARF expression was down-regulated in palmitate (PA)-treated HepG2 cells. In this study, we aim to understand the consequences of the reduced expression of CARF on the development of NAFLD. Methods We performed RNA seq, RT-PCR and western blotting (WB) to evaluate the effect of CARF knockdown on lipid metabolism in HepG2 cells. Differentially expressed genes were analyzed by gene sort enrichment analysis (GSEA) and Ingenuity Pathway Analysis (IPA) to identify the metabolic pathways affected by CARF depletion. Apoptosis was assessed by TUNEL assay. To induce ER stress, HepG2 cells were treated with thapsigargin and evaluated its effect on CARF. Results By performing Sh-RNA mediated CARF knockdown, RNA-seq analysis, RT-PCR, western blotting (WB), we were able to show that ER-stress and de-novo lipogenesis pathways were significantly affected in HepG2 cells. We showed that GRP78, CHOP, PERK, ERN1a, genes associated with ER-stress were upregulated in CARF-depleted HepG2 cells. Additionally, thapsigargin-induced ER stress was found to reduce the expression of CARF along with the increased expression of ER stress marker genes. We also showed that overexpression of CARF mitigated the thapsigargin-induced ER stress suggesting that CARF protects against ER stress in HepG2 cells. In addition, the genes associated with triglyceride biosynthesis GPAT3, GPAM were significantly upregulated, indicating that lipogenesis was triggered by silencing of CARF in HepG2 cells. BODIPY staining and TG assay confirmed that silencing of CARF enhanced triglyceride biosynthesis in HepG2 cells. Furthermore, we showed that the expression of antioxidant genes GPX2, GPX3, and TXRND3 decreased, resulting in enhanced oxidative stress and higher apoptosis in CARF depleted cells. Conclusion We identified novel roles of CARF regulating cellular ER-Stress, lipid metabolism, and oxidative stress, and its impairment in response to metabolic stress could lead to the development of NAFLD in obese patients with metabolic abnormalities. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Monday, June 13, 2022 12:42 p.m. - 12:47 p.m.

Background Prostate cancer (PCa) is a leading cause of cancer-associated death among men worldwide. Although localized prostate cancer can be cured by surgery and radiation therapy, metastatic PCa remains a challenge. Androgen therapy (ADT) and androgen signaling inhibitors are the first line of therapy against PCa. However, resistance against these treatments develops, leading to the emergence of castration resistance prostate cancer (CRPC). Studies are required to identify the pathways that contribute to the emergence of CRPC and identify pharmaceutical targets. CARF is a putative transcription regulator reported to play a pivotal role in different cancers, including breast cancer and hepatocarcinoma. We observed that CARF is highly expressed in prostate tumors, but the biological function of CARF in PCa is unknown yet. Methods We performed RNA seq, RT-PCR, and western blot (WB) analyses to show how knockdown of CARF affects the global gene expression in PC3 cells. Gene sort enrichment analysis (GSEA) and Ingenuity Pathway Analysis (IPA) of differentially expressed genes were done to identify the cellular pathways affected upon silencing of CARF. Scratch assay and trans-well migration assay were conducted to show how CARF overexpression influences the motility of the cells. The effect of CARF on PC3 cells growth and proliferation was evaluated by colony-forming and MTT assays. In addition, we analyzed patient datasets to show the relevance of CARF expression, androgen signaling, and epithelial-mesenchymal transformation (EMT) pathways in PCa. Results The silencing of CARF inhibited the growth and proliferation of PC3 cells, suggesting the necessity of CARF for PC3 growth and survival. In agreement, overexpression of CARF enhanced the PC3 cells proliferation. We found that silencing of CARF reduced PC3 cells motility in trans-well assay. Mechanistically, RNA seq analysis after CARF knockdown uncovered that gene of AR signaling and EMT pathways were significantly altered in PC3 cells. RT-PCR and WB data confirmed that silencing of CARF enhanced E-cadherin expression and reduced the expression of N-cadherin in PC3 cells, suggesting that CARF regulates EMT in PCa. Silencing of CARF altered the AR-regulated metastatic genes expression in PC3 cells. Our data revealed that the expression of PMEPA1, a negative regulator of metastasis, was increased, but the expression of SGK1, an inducer of EMT, was decreased in CARF cells. Furthermore, CARF could regulate the prostaglandins metabolism by suppressing the expression of HGPD1 and triggering inflammation and angiogenesis in prostate cancer. Conclusion We conclude that by controlling the AR and EMT signaling pathways, CARF may play a crucial role in the development of metastatic CRPC. Future studies by integrating the RNA seq and Chip-Seq will uncover how CARF regulates the AR and EMT signaling pathways contributing to the development and progression of CRPC and paving a way to find a target for intervention. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Sunday, June 12, 2022 1:18 p.m. - 1:23 p.m.

Among Latinx older adults, our current understanding of barriers to eye exam often fails to consider the impact of patient and provider burnout which can decrease treatment adherence and recommendation receptivity in this group. The purpose of this study was to examine correlates of eye exam frequency among Latinx older adults in South Los Angeles and explore associations reflecting patient and/or provider burnout. Data analysis was informed by the Secret Self-Management Loop and the Burnout Dyad conceptual models. This secondary analysis used data collected from a convenience sample of non-institutionalized Latinx adults 55+ in South LA (n=165) and used multinomial regression analysis. Outcome variable is recency of eye exam, independent variables are self-reported health, including diabetes mellitus diagnosis, and either patient or provider burnout (that are functions of grouped demographic or quality of care variables). Variables associated with Provider Burnout, appear to represent a larger influence on eye examination frequency then variables associated with Patient Burnout, with the most influential factor being provider recommendation. A surprising finding was the number of participants who had never received this recommendation from a provider (21%). One-third (32%) of participants with diabetes mellitus had not had an eye examination within 12 months and almost one-fifth (13%) of participants with diabetes who had received this recommendation had not received the exam. Further exploration is needed to support a better understanding of how both patient and provider burnout impacts adherence to eye examination and other preventive care recommendations for diabetes mellitus among Latinx older adults.

Cushing’s syndrome is a rare disorder that can severely affect the patient. It is the result of prolonged exposure to high levels of exogenous or endogenous glucocorticoids. Symptoms of patients with Cushing’s syndrome include weight gain, easy bruising, menstrual irregularities, increased appetite, trouble sleeping, depression or mood swings, anxiety, fatigue and altered mentation (trouble concentrating or decreased memory) (1–3). Physical abnormalities include new onset obesity (primarily in the abdominal and buttock regions), buffalo hump, filling in of the regions above the collarbone, thinning of the extremities, rounding and reddening of the face, thin skin, decreased muscle strength, high blood pressure, stretch marks, and excess hair growth in women. Although some patients may have most or all of these signs and symptoms so that the diagnosis of Cushing’s syndrome may be easy to make, other patients may have mild Cushing’s syndrome and go to their health care providers at an early stage of the disease. This is especially true as Cushing’s syndrome has been publicized in the lay literature, (4) and with the proliferation of Internet-related information sites and Cushing’s support groups, more patients are aware that Cushing’s syndrome may explain their medical problems. Thus, patients are seeking medical attention earlier. However, other medical conditions may also result in some of the signs, symptoms, and laboratory abnormalities seen in patients with Cushing’s syndrome, without the patient actually having Cushing’s syndrome. These conditions are called pseudo-Cushing’s states and include conditions such as severe stresses (illness or emotional stress), alcoholism or alcohol withdrawal, and psychiatric conditions such as depression, panic disorders, and psychotic conditions. The pathophysiology leading to increased cortisol production in alcoholism and depression is discussed later. Pseudo-Cushing’s states are classically defined as those conditions associated with increased cortisol production [usually measured by urinary-free cortisol (UFC) measurements], but with less clinical signs and symptoms than true Cushing’s syndrome. Resolution of the underlying primary condition leads to disappearance of the signs and symptoms of Cushing’s syndrome. In this chapter, we will also discuss conditions that mimic the clinical stigmata of Cushing’s syndrome, but lack elevated cortisol production.

Yeast mutants lacking activity of the enzyme hypoxanthine: guanine phosphoribosyltransferase (H:GPRT) have been isolated by selecting for resistance to 8-azaguanine in a strain carrying the wild type allele, ade4+ of the gene coding for amidophosphoribosyltransferase (PRPPAT), the first enzyme of de novo purine synthesis. The mutants excrete purines and are cross-resistant to 8-azaadenine. They are recessive and represent a single complementation group, designated hpt1. Ade4-su, a prototrophic allele of ade4 with reduced activity of PRPPAT, is epistatic to hpt1, suppressing purine excretion and resistance to azaadenine but not resistance to azaguanine. The genotype ade2 hpt1 does not respond to hypoxanthine. Hpt1 complements and is not closely linked to the purine excreting mutants pur1 to pur5. Hpt1 and pur6, a regulatory mutant of PRPPAT, are also unlinked but do not complement, suggesting a protein-protein interaction between H:G-PRT and PRPPAT. Mycophenolic acid (MPA), an inhibitor of de novo guanine nucleotide synthesis, inhibits the growth of hpt1 and hpt1+. Xanthine allows both genotypes to grow in the presence of MPA whereas guanine only allows growth of hpt1+. Activity of A-PRT, X-PRT and H:G-PRT is present in hpt+. Hpt1 lacks activity of H:G-PRT but has normal A-PRT and X-PRT.