Both glucagon-like peptide 1 receptor agonists (GLP-1 RAs) and continuous glucose monitoring (CGM) have been shown to improve glycated hemoglobin A1c (A1c) levels among patients with type 2 diabetes mellitus (T2DM). Recently, a US real-world study found statistically significant improvements in A1c levels among patients using GLP-1 RA and a CGM device, compared with a matched cohort receiving only GLP-1 RA. To assess the cost-effectiveness from a US payer perspective of initiating CGM (FreeStyle Libre Systems) in people living with T2DM using a GLP-1 RA therapy, compared with GLP-1 RA alone. A patient-level microsimulation model was run for 10,000 patients over a lifetime horizon with 3.0% discounting for costs and utilities. Patient characteristics were based on the overall population of the US real-world study and the subgroup of patients not using intensive insulin. The effect of CGM was modeled as a persistent reduction in A1c compared with GLP-1 RA alone (overall = 0.37%; patients not using intensive insulin = 0.34%). Costs ($2,023) and disutilities were applied to diabetes complications and acute diabetic events. Outcomes were assessed as quality-adjusted life years (QALYs). The base-case incremental cost-effectiveness ratio (incremental costs/incremental QALYs) for GLP-1 RA plus CGM vs GLP-1 RA alone was $40,968/QALY in the overall cohort (cost = $484,180 vs $473,938; QALYs = 13.37 vs 13.12). Among patients not using intensive insulin, the incremental cost-effectiveness ratio was $43,095/QALY. Scenario analysis showed that the model results were robust to changing assumptions. Probabilistic sensitivity analysis showed that GLP-1 RA plus CGM had a 64% probability of being cost-effective at a willingness-to-pay threshold of $100,000 per QALY. From a US payer perspective, CGM is cost-effective when added to GLP-1 RA therapies for the treatment of T2DM, including for patients not using intensive insulin.

Measurement of glycated hemoglobin (HbA1c) in human red blood cells plays a critical role in the diagnosis and treatment of diabetes mellitus. However, recent studies have suggested large variation in the relationship between average glucose levels and HbA1c, creating the need to understand glucose variability at the cellular level. Here, we devised a fluorescence-based method to quantitatively observe GLUT1-mediated intracellular glucose analog tracer uptake in individual RBCs utilizing microfluidics and confocal microscopy. For the first time, we demonstrate that intracellular/extracellular tracer percentages can be measured at the single cell level using the fluorescently labeled glucose analog, 2-NBDG. A small donor panel study indicates that the characteristic intracellular 2-NBDG percentages can statistically differ based on race (i.e., Caucasian/Hispanic vs Black). RBC intracellular glucose analog tracer 2-NBDG levels show significant variability both from cell-to-cell and from donor-to-donor. This specific transport mechanism will affect HbA1c formation in erythrocytes. This finding further supports a more personalized, and perhaps improved, diagnostic strategy for diabetes.

Abstract Background The effects of lifestyle on glucose metabolism significantly differ between individuals. Hyperglycemia in type 2 diabetes is driven by tissue-specific insulin resistance and reduced beta-cell capacity, whose relative contribution varies between persons, potentially affecting the impact of lifestyle interventions. We quantified effects of lifestyle on continuously measured glucose (CGM) metrics and evaluated how these differ between type 2 diabetes phenotypes. Methods Forty persons with type 2 diabetes wore a CGM for 11 periods of 4 days, of which 3 control and 4 duplicated intervention periods (2x low carbohydrate diet, 2x Mediterranean diet, 2x walking after each meal and 2x ‘active day’ (hourly 5-minute exercise bouts)). Tissue-specific insulin resistance and beta-cell function were quantified using an OGTT. A linear mixed effects model quantified lifestyle impact on CGM metrics. Results On overage, low carbohydrate diet, walking after meal and active day, but not the Mediterranean diet, resulted in lower mean glucose (7.74, 8.37, 8.40 and 8.70 mmol/L, respectively) as compared to control (8.66 mmol/L) in participants who did not restrict carbohydrate intake at baseline. Notably, the magnitude and direction of effects varied between individuals. For instance, the low carbohydrate diet had more beneficial effects for persons who had liver- or combined insulin resistance with poor beta-cell function than for individuals who only had poor beta-cell function. Conclusions On average, traditional lifestyle interventions improved CGM metrics within 4 days. Importantly, the effects appear to vary depending on the diabetes phenotype, thus pointing to the need for personalized lifestyle treatment. Dutch Trial Register: NL7848.

In cardiovascular therapeutics, procedures such as heart transplants and coronary artery bypass graft are pivotal. However, an acute shortage of organ donors increases waiting times of patients, which is reflected in negative effects on the outcome for the patient. Post-procedural complications such as thrombotic events and atherosclerotic developments may also have grave clinical implications. To address these challenges, tissue engineering is emerging as a solution, using textile technologies to synthesize biomimetic scaffolds resembling natural tissues. This comprehensive analysis explains methodologies including electrospinning, electrostatic flocking, and advanced textile techniques developed from weaving, knitting, and braiding. These techniques are evaluated in the context of fabricating cardiac patches, vascular graft constructs, stent designs, and state-of-the-art wearable sensors. We also closely examine the interaction of distinct process parameters with the biomechanical and morphological attributes of the resultant scaffolds. The research concludes by combining current findings and recommendations for subsequent investigation.

The Bigfoot Unity Diabetes Management System integrates Abbott FreeStyle Libre 2 continuous glucose monitoring (CGM) data into a smart pen cap and mobile app enabling clinician-directed insulin dose recommendations and real-time alerts. The objective was to analyze real world 6-month glycemic control in a prospective study for individuals using the System for multiple daily insulin injections (MDI). We conducted a 6-month analysis from the BURST study (NCT05088265) of individuals with type 1 or type 2 diabetes (T2D). Participants reported baseline demographics, adverse event and other surveys electronically. Either at-home kit or electronic medical record glycated hemoglobin A1c (HbA1c) data were collected. Of 102 participants in the per-protocol cohort, median age was 59 years, 87% had T2D, 42% used CGM previously, 62% were White non-Hispanic and 59% female. Mean HbA1c decreased from 9.1 ± 1.7% at baseline to 8.0 ± 1.2% at 6 months (mean difference -1.1%, 95% confidence interval -1.4 to -0.8, P < 0.001). At 6 months, time in range 70-180 mg/dL, time <70 mg/dL and <54 mg/dL were 56 ± 23%, 1.0 ± 1.4% and 0.04 ± 0.14%, respectively. Six severe hypoglycemia events occurred in 4 participants (none system related) and no diabetic ketoacidosis events occurred in the per-protocol cohort. In this study primarily of older adults with T2D using MDI, durable glycemic improvement occurred using the System at 6 months, with the frequency of hypoglycemia being substantially below established targets of <4% and <1% for time below 70 and 54 mg/dL, respectively.

Abstract Disclosure: M. Lozano: None. A. Pinero-Pilona: None. Background: The reported estimated incidence of pheochromocytoma is approximately 2-8 cases per 1 million people per year. Of those, silent pheochromocytomas will make up about 8%. Thus, biochemically silent and non-secreting pheochromocytomas are a very rare phenomenon. Clinical Case: A 74-year-old Caucasian female with significant past medical history of primary hypothyroidism, hypercholesterolemia, and nasal sinus carcinoma s/p surgery (in remission) presented to the clinic for endocrine evaluation of a right adrenal mass. The patient was asymptomatic and denied headaches, tachycardia, sweating, severe hypertension, diabetes, muscle weakness, easy bruising, or striae. The mass was initially diagnosed as an incidental finding after a contrast CT scan of the abdomen was performed for diverticulitis. The right adrenal enhancing mass was 2.3 x 3.9 x 4.1 cm in diameter. Subsequent MRI abdomen with and without contrast ordered by the referring physician showed that the adrenal mass had grown to 4.9 x 3.8 x 5.4 cm and was hyperenhancing in nature with central T2 hyperintense signal. Notably, multiple “parasitized and arborealized” vessels were detected within the mass. Such findings led us to suspect metastatic versus primary adrenal neoplasm such as cortical carcinoma as a working diagnosis. Other laboratory studies including plasma free metanephrines (&amp;lt;10 pg/mL, normal 0-88 pg/mL), plasma normetanephrines (29.2 pg/mL, normal 0-285.2 pg/mL) and 24-hour urine collections (24 hr urine epinephrine - 3 ug/24 hr [normal 0-20 ug/24 hr]; 24 hr urine norepinephrine - 75 ug/24 hr [normal 0-135 ug/24 hr]; 24 hr urine VMA - 3 mg/24 hr [normal 0-7.5 mg/24 hr]) were negative for pheochromocytoma. As her mass was greater than 4 cm in diameter, surgical referral was then recommended to the patient. Right adrenalectomy was performed. Pathology report was consistent with pheochromocytoma as supported by immunohistochemistry. Ki-67 proliferation index was 0-10% (average 3-4%, rare hotspots 10%). Atrophy and vascular ectasia were present in residual non-neoplastic adrenal cortex and medulla. Histology showed a nested growth pattern, absence of composite tumor elements, absence of necrosis, and no atypical mitoses. The incidence of non-secreting pheochromocytomas has been quoted to be 0.000064% (1). Conclusion: The case illustrates an uncommon presentation of a large, silent pheochromocytoma with negative plasma metanephrines accompanied by negative urine studies, which have a negative predictive value close to 100% in ruling out a pheochromocytoma. Our case emphasizes the importance of considering pheochromocytoma on the differential of adrenal masses with high attenuation or high enhancement even when biochemical studies suggest otherwise. Reference: (1) Radojkovic, D., et al. "CLINICALLY" SILENT GIANT PHEOCHROMOCYTOMA. CASE REPORT." Acta Endocrinologica (1841-0987) 9.1 (2013). Presentation: 6/1/2024

Abstract Disclosure: M. Lozano: None. A. Pinero-Pilona: None. Background: Medullary thyroid cancer (MTC) is a rare neuroendocrine tumor that is derived from calcitonin-producing C-cells that accounts for the smallest portion (&amp;lt;5%) of thyroid cancer. Most of these cases are attributed to mutations in the RET oncogene. Of the remainder, approximately 70% of MTC cases without a RET mutation have been attributed to RAS gene mutations. We report a case of a patient who presented with a thyroid nodule present and stable for years and was found to have MTC with a HRAS mutation. Clinical Case: A 73-year-old Caucasian male with a history of metastatic squamous cell carcinoma (SCC) of the neck, orthostatic hypotension, pacemaker implantation, and coronary artery disease with prior stenting presented to the clinic for evaluation after an abnormal thyroid biopsy. His SCC was diagnosed 16 years ago and was treated with surgery and cetuximab. It was a poorly differentiated squamous cell carcinoma with 2 of 7 lymph nodes positive for malignancy. Fifteen years ago, as part of the evaluation for his SCC, the patient had CAT and PET scans that showed a small nodule with increased uptake in the right lower neck in the thyroid bed (2.7 SUVs) measuring about 1.4 cm in diameter. No further interventions were done back then, and the patient was unaware of the mass until his records were reviewed. The patient was more recently noted to have the incidental thyroid nodule 2 months prior to clinic evaluation after routine carotid ultrasound. The gland was described to be homogeneous; in the mid to inferior portion of the right lobe, there was a 1.2 cm TR5 nodule of which biopsy was recommended. Fine needle aspiration biopsy showed a follicular lesion of unknown significance Bethesda category 3 using AFIRMA GCS RNA molecular analysis. Subsequently, gene sequencing classification was performed and abnormal: results were positive for HRAS mutation. Sonography in the office showed a right-sided, slightly hypoechoic, taller-than-wide vascular nodule with well-preserved borders and intermediate risk of malignancy. No abnormal lymphadenopathy was observed regionally in the central or lateral neck. The patient then underwent total thyroidectomy with modified right level 3 dissection. The right mid-superior nodule was consistent with MTC without tumor necrosis and without lymphatic, perineural, or extrathyroidal extension, but there was angioinvasion of at least 3 vessels. Preoperative calcitonin was elevated at 71 pg/mL and the level was undetectable (&amp;lt;2 pg/mL) 8 weeks post operatively (n&amp;lt;=10 pg/mL). The patient was deemed cured based on these biochemical studies and is recovering uneventfully on supplemental levothyroxine. Conclusion: Given the predominant association of MTC with RET, it is worth noting this case of a sporadic HRAS mutation in a patient with prior SCC. This case illustrates an indolent MTC without aggressive behavior that stayed stable in size and without metastasis for 15 years. Presentation: 6/1/2024

Abstract Disclosure: R.A. Mayers: None. A. Szafran-Swietlik: None. RET mutation, observed in multiple endocrine neoplasia type 2 syndromes, is implicated in the development of pheochromocytomas of the kinase signaling cluster. Such tumors have lower metastatic risk and adrenergic production compared to the ones from the other clusters. We present a case of a metastatic, bilateral, small and biochemically active pheochromocytoma .This is the case of a 27-year-old man diagnosed with MEN 2A. He underwent total thyroidectomy due to medullary thyroid carcinoma at 2 years old. He was deemed cured and started on levothyroxine replacement. Since then, his plasma metanephrines by liquid chromatography-mass spectrometry and urine metanephrines done in a yearly basis as screening, were always within range of normality. Over the years, he developed substance abuse disorder with use of Kratom and methamphetamines and was admitted in a rehabilitation center multiple times in the last three years. During this time, the patient was reported to be slightly tachycardiac which was initially attributed to the use of substances. On the last year, an echocardiogram done as evaluation of his tachycardia showed an ejection fraction of 35%. Later, his annual metanephrine levels were markedly elevated (free metanephrine: 137 pg/mL and free normetanephrine : 157 pg/mL, normal ranges reported as less than 57 pg/mL and less than 148 pg/mL respectively). Abdominal tomography showed a right adrenal nodule of 1.2 cm and a left adrenal nodule of 1.6 cm, both with more than 10 Hounsfield Units. A Metaiodobenzylguanidine scan revealed a left adrenal nodule of 1.8 cm with diffuse radiotracer uptake, a right adrenal nodule of 1.2 cm with radiotracer activity and 3 subtle areas of focally increased radiotracer activity in the liver, two in left hepatic lobe and other in posterior right upper lobe. He underwent bilateral adrenalectomy with cortical sparring. Pathology results evidenced a left adrenal with a unifocal mass of 1.8 cm and a right adrenal with a mass of 1.2 cm , both without lymphovascular, capsular, local invasion or necrosis, a mitotic rate of 1-2 without atypical mitosis, not encapsulated with clean margins and positive for synaptophysin , chromogranin and S100 stains. An additional mass of 0.7 cm on the right adrenal gland was described with similar characteristics to the described before except for the involvement of the surgical margins. Currently on the literature there are different opinions regarding screening approach for pheochromocytomas in the presence of RET mutations. There are not strong recommendations regarding the use of imaging as a screening tool in this group of patients. It is important to consider that there are cases, as the one described in this report, that might present metastatic disease even with the presence of small pheochromocytomas that belong to the cluster of kinase signaling. Presentation: 6/3/2024

Abstract Disclosure: M.S. Tkach: None. E. Coughlin: None. A. Pinero-Pilona: None. Fine Needle Aspiration (FNA) is a cornerstone of the diagnosis of thyroid cancer. The Bethesda System for Reporting Thyroid Cytopathology (BS-TCP), developed in 2010, and genomic sequencing classifiers (GSC) now allow clinicians to objectively identify the risk of malignancy of thyroid nodules (“TN”) prior to surgical interventions. For further characterization, the Afirma Xpression Atlas (XA) was created and launched in May 2018, utilizing RNA sequencing to evaluate fusions and variants. As of 2023, the Afirma XA panel includes 905 genomic variants and 235 fusions from 593 genes. Post-validation studies for the Afirma XA have focused on large academic centers, but applicability or extrapolation to smaller endocrinology practices is less clear, potentially due to different patient population and thyroid cancer prevalence. This study was designed to analyze and measure the performance of the Afirma XA in BS-TCP V and VI TN classified as GSC suspicious for malignancy in a small endocrinology practice. We conducted a retrospective cohort analysis comparing all BS-TCP V and VI TN with their respective final surgical pathology results between June 2018 and December 2023. 76 TN meeting the criteria for BS-TCP V or VI classification were identified. We excluded any TN (12 total) for which pathology data was unavailable; reasons ranged from lack of patient follow-up to patient's death with no autopsy available. Forty-seven thyroid TN were therefore included, and the BS-TCP VI category was the predominant cytopathology discovered, representing 78.7% of the TN in this group. Afirma XA was able to identify genomic alterations in 78.7% of all included TN (thus 78.7% is its sensitivity). Sensitivity of XA was found to be 70% in BS-TCP V (n=10) and 81.1% in BS-TCP VI (n=37). 83% of the analyzed TN were from female patients and 17% were from male patients; there was no statistically significant difference between XA frequency in TN from male vs. female patients. 100% of all BS-TCP V and VI TN (n=47) as determined by the cytopathologist were associated with cancer on pathology; thus, the sensitivity of the cytopathology itself is 100%, and positive predictive value of XA in both groups was 100%. Age and nodule size were not significantly associated with XA presence or absence overall. XA was overwhelmingly comprised of BRAF :p:V600E c.1799T&amp;gt;A mutations: 70.2% of of XA findings showed this mutation (50% in V and 75.6% in VI). Our percentage of XA on BS-TCP V and VI nodules reflects similarity to prior large studies in academic centers. Based on this data, we conclude that XA is a valuable tool for high-risk TN classification and treatment guidance; it can both aid in surgical planning and determine options for potential pharmacotherapy. We conclude that in our study, the relation between XA and cytopathology in BS-TCP V and VI nodules correlates well with data from large academic center studies, even in a small private practice. Presentation: 6/3/2024

Abstract Disclosure: R.A. Zielinski: None. M. Khalifa: None. M. Dillon: None. M. Kaur: None. Background: Hyaline trabecular tumor (HTT) is a rare benign follicular thyroid neoplasm characterized by extensive intra-trabecular hyaline stromal material. Resemblances to other follicular neoplasms create difficulty in distinguishing HTT from its more nefarious counterparts such as medullary thyroid cancer (MTC) and papillary thyroid cancer (PTC).Clinical Case:Our patient is a 56-year-old female with Hashimoto’s thyroiditis diagnosed in her twenties who has been on different strengths of levothyroxine based on her fluctuating TSH. A thyroid ultrasound done to evaluate left-sided neck fullness on physical exam showed a solid, hypoechoic 2.3 cm x 1.4 x 0.9 cm left middle thyroid nodule without calcifications (TI-RADS 4) and benign-appearing lymph nodes, the largest of which was 1.5 cm at level 1B. Cytology from a thyroid FNA biopsy was suspicious for PTC, Bethesda category IV. A thyrosure genetic panel was negative for genetic mutations. FNA biopsy of the 1.5 cm lymph node was negative for malignancy. The patient was referred for thyroid lobectomy but instead elected to undergo total thyroidectomy with level VI lymph node dissection. Pathology revealed a 2.2 cm HTT in the left lobe, scattered psammoma bodies in adjacent soft tissue, and a 0.2 cm multifocal papillary microcarcinoma in the right lobe. The microcarcinoma had negative margins, no lymphatic or vascular invasion, and 7/7 benign level VI lymph nodes; staging it as pT1aN0. Immunohistochemistry staining was positive for TTF-1 and thyroglobulin and negative for calcitonin, chromogranin, and synaptophysin. Post-thyroidectomy she was started on Tirosint 175 mcg daily with good response. No I-131 treatment was pursued due to the microcarcinoma being categorized as low risk.Discussion and Conclusion: HTT is a benign neoplasm and management is usually conservative with surgical excision. The diagnosis of HTT by cytology alone is challenging due to the presence of nuclear clearing, grooves and intranuclear pseudo-inclusions that may be mistaken for PTC or MTC. Cell membrane immunoreactivity of MIB1 monoclonal to Ki67 and the molecular identification of the novel PAX8-GLIS1 or PAX8-GLIS3 fusions may aid in making the correct diagnosis.