bluuebunny/crossref_metadata_2025_split huggingface dataset:
Results from in vitro and in vivo studies evaluating the bioavailability, effects of food, and administration as crushed tablet suspension on vericiguat pharmacokinetics
Authors: Becker Corina , Boettcher Michael , Muenster Uwe , Loewen Stephanie , Lobmeyer Maximilian , Mueck Wolfgang 
Published: November 2022

Abstract
Objective
This article describes in vitro and in vivo studies that aimed to further characterize the biopharmaceutical properties and pharmacokinetic (PK) profile of vericiguat and to guide dosing recommendations.

Methods
Five open-label, phase I studies characterized the biopharmaceutical aspects of vericiguat, including absolute bioavailability, bioavailabilities of different formulations, dose proportionality, and food effect. Area under the curve (AUC) and maximum plasma concentrations (Cmax), determined by a noncompartmental analysis, were compared by analysis of variance, and a mixed-effects power model was used to assess dose proportionality. The effect of food on the dissolution of vericiguat was evaluated in vitro using media simulating the gastrointestinal tract under fed and fasted conditions. In vitro dissolution of intact vs crushed vericiguat tablet was assessed in quality control medium (HCl at pH 2), acetate buffer at pH 4.5, and phosphate buffer at pH 6.8.

Results
Dissolution of vericiguat increased under fed conditions. In healthy subjects, exposure (AUC and Cmax) increased ~ 40% with food vs fasted state (10 mg intact tablet) confirming a food effect on vericiguat bioavailability. Interindividual variability in exposure decreased ~ 20%, irrespective of meal type. Absolute bioavailability of vericiguat 10 mg (intact tablets, fed) was 93%. Vericiguat 2.5–10 mg demonstrated dose proportionality (intact tablets, fed) in healthy subjects. Dissolution studies showed no differences between the formulations, and this was confirmed with in vivo studies.

Conclusion
Vericiguat tablets should be administered with food and may be crushed for patients who have difficulty swallowing.

Graphical Abstract
Multiple shapes from a single nematic elastomer sheet activated via patterned illumination
Authors: Giudici A. , Clement A. , Duffy D. L. , Shankar M. Ravi , Biggins J. S. 
Published: November 2022

Abstract
Liquid crystal elastomers (LCEs) undergo a large uniaxial contraction upon thermal or optical stimulation. LCE sheets are often fabricated with a spatially patterned direction of contraction, which can sculpt the sheet into a Gauss-curved surface. Here, we instead consider LCE sheets subject to patterned stimulation intensity, leading to a control of contraction strength. We show such patterns may also sculpt a complex surface, but with the advantage that arbitrarily many surfaces may be achieved sequentially in the same sample, thus breaking the link between microstructure and shape. We first consider a monodomain LCE in which some regions are actuated and others are not. We discuss how to join actuated and unactuated regions compatibly, and use this design rule to generate patterns for cones, anti-cones, arrays of cones and a rolling bi-strip. We validate the patterns numerically via elastic shell simulations and demonstrate them experimentally via patterned photo-chemical actuation. Secondly, we consider an LCE disk with an azimuthal director profile actuated by a radially varying stimulus. We show, theoretically and numerically, how to design a stimulation profile to sculpt any surface of revolution. Such re-configurable actuation offers enticing possibilities for haptics, robotics and locomotion.
A road toward zero-spacing photonic waveguides and circuits
Authors: Song Tongtong , Luo Jie , Lai Yun 
Published: November 2022

Abstract
Like their electronic counterparts, photonic integrated circuits face the challenge of further integration and miniaturization. One of the fundamental limitations comes from waveguide spacing, which leads to serious crosstalk between the neighboring waveguides when it is less than half a wavelength. Here we demonstrate a potential approach to remove this limitation and realize zero-spacing photonic waveguides with extreme compactness. This is achieved by designing pure-dielectric photonic crystal waveguides with shifted spatial dispersion and arranging them with normal dielectric waveguides alternately. Amazingly, the coupling and crosstalk between the two types of waveguides are negligible despite the zero spacing between them. Through proper designs, zero-spacing photonic bending waveguides and circuits can also be realized in practice. Such a finding opens a new avenue for ultra-compact photonic waveguides and circuits with 100% space utilization efficiency.
ODP010 Relaxin Receptor RXFP1 Knockout in Adipose Tissue Progenitor Cells Results in Resistance to High Fat Diet-Induced Weigh Gain
Authors: Bennett Robert , Simpson Ronda , Agoulnik Alexander , Hamel Frederick 
Published: November 2022

Abstract
Relaxin is a polypeptide hormone that signals through its cognate receptor RXFP1. Previous work demonstrated that global RXFP1-knockout mice developed age-related adipose tissue fibrosis and dysfunction. Our preliminary data suggested that adipose tissue progenitor cells (APC) express RXFP1 in the white adipose tissue in mice. To determine the role of APC in relaxin signaling, we crossed floxed RXFP1 mice (RXFP1-fl/fl) with mice expressing tamoxifen-inducible CRE recombinase under control of the platelet-derived growth factor receptor-β (PDGFRβ) promoter to produce conditional RXFP1 knockout in adipose tissue progenitor cells and fibroblasts (RXFP1-PKO). After tamoxifen treatment, both RXFP1-fl/fl and RXFP1-PKO mice were placed on a high fat diet (58% calories from fat) supplemented with sucrose and fructose in the drinking water, or chow diet for 16 weeks. At the end of the study, body mass composition was measured using an Echo-MRI instrument. Adipose tissue fibrosis was assessed histologically by Sirius red staining. In response to the HFD, the control (fl/fl) mice reached an average weight of 48.3 ± 0.6g, while the RXFP1-PKO mice were resistant to weight gain, reaching only 40.3 ±3g (p&lt;. 05). The body mass composition changed in the RXFP1-fl/fl mice on HFD (34. 0% fat/55.2% lean) compared to chow (14.7% fat/68.9% lean). The RXFP1-PKO mice had a significantly lower gain in fat mass on HFD (29.7% fat/59.1% lean on HFD; 12.6% fat/71. 0% lean on chow) compared to the RXFP-fl/fl mice. Histological analysis of the inguinal white adipose tissue (iWAT) revealed that while RXFP1-fl/fl mice developed adipocyte hypertrophy in response to the HFD, the RXFP1-PKO mice had smaller adipocyte size. This was accompanied by increased pericellular and perivascular fibrosis in the iWAT as determined by Sirius red staining. To determine if differentiation of APC was altered by loss of RXFP1, the stromal-vascular fraction of iWAT was extracted by collagenase treatment, and the APC isolated using antibody-coated magnetic beads (Miltenyi Biotec). The purified cells were cultured to confluence, treated with or without tamoxifen to induce CRE expression, then treated with differentiation cocktail. The APC from the RXFP1-PKO mice had a marked impairment in the ability differentiate to mature adipocytes after treatment with tamoxifen compared to untreated cells. In summary, the loss of RXFP1 in PDGFRβ-expressing cells resulted in resistance to HFD-induced weight and adipose tissue mass gain. This was accompanied by increased fibrosis in the iWAT and decreased adipocyte size. The APC had decreased adipogenic potential after loss of RXFP1. Taken together, the findings support a role for RXFP1 in the differentiation of adipose tissue progenitor cells, and in adipose tissue expansion after exposure to an obesogenic diet.
Presentation: No date and time listed
OR23-4 Intestinal FFA2 and FFA3 Mediate Obesogenic Effects in Mice on a Western Diet
Authors: Gough Sophie , Layden Brian , Nnyamah Chioma , Priyadarshini Medha , Wicksteed Barton , Lednovich Kristen 
Published: November 2022

Abstract
Free fatty acid receptor 2 and free fatty acid receptor 3 (FFA2/3) are two highly similar G protein-coupled receptors belonging to the free fatty acid receptor family. Their ligands are short-chain fatty acids (SCFAs), which are key nutrients that play a diverse role in physiological function, including the regulation of metabolic homeostasis and glycemic control. FFA2/3 are broadly expressed in a multitude of tissues including the intestine, pancreas, adipose and central nervous system, where they contribute to metabolic homeostasis via a summation of tissue-specific effects. Consequently, FFA2/3 have been identified as a potential drug target for metabolic diseases including obesity and type-2 diabetes.
Both FFA2 and FFA3 are highly expressed within the intestinal epithelium – the major site of SCFA generation – and have been identified in hormone-secreting enteroendocrine cells as well as intestinal epithelial cells. However, due conflicting data, the respective roles of FFA2/3 within the intestine and their effects on physiology and metabolism are still largely unclear. Previous in vivo studies involving this receptor have largely relied on global knockout mouse models, making it difficult to isolate their effects in the intestine. To overcome this challenge, we generated a novel intestine-specific knockout mouse model for FFA2 and FFA3 individually, utilizing Cre-mediated recombination under the expression of the villin promoter. Here, we report the first in vivo characterization of FFA2/3 in the intestine and reveal novel insights into receptor function.
Following model validation, we conducted a general metabolic assessment of male Villin-Cre-FFA2 (Vil-FFA2) and Villin-Cre-FFA3 (Vil-FFA3) mice on standard chow and observed no major congenital or time-dependent defects. Because dietary changes are known to alter gut microbial composition, and thereby SCFA production, a pilot study was performed on male Vil-FFA2 and Vil-FFA3 mice and their littermate controls to probe for a phenotype on a high-fat, high-sugar "western diet." Mice were placed on either a low-fat control diet (CD) or western diet (WD) at 10 weeks of age and metabolically profiled for 25 weeks. We found that both Vil-FFA2 and Vil-FFA3 mouse strains were largely protected from diet-induced obesity and had significantly lower fat mass as well as adipose hypertrophy. Additionally, both mouse strains had reduced intestinal inflammation and improved glucose homeostasis. These differences were driven by lower food intake in the Vil-FFA2 strain only. Our findings suggest a novel role of FFA2/3 in mediating the metabolic consequences of a western diet – a state of high inflammation, dysbiosis and metabolic stress. Moreover, these data support an intestine-specific role of FFA2/3 in whole-body metabolic homeostasis and in the development of adiposity and hyperglycemia.
Presentation: Monday, June 13, 2022 12:00 p.m. - 12:15 p.m.
LBODP006 Clinical Usefulness Of The Growth Hormone-releasing Peptide-2 Test For Hypothalamic-pituitary Disorder
Authors: Suzuki Sawako , Ruike Yutarou , Ishiwata Kazuki , Naito Kumiko , Igarashi Katsushi , Ishida Akiko , Fujimoto Masanori , Horiguchi Kentaro , Koide Hisashi , Horiguchi Kentaro , Tatsuno Ichiro , Yokote Koutaro 
Published: November 2022

Abstract

Purpose
Growth hormone deficiency (GHD) develops early in patients with hypothalamic-pituitary disorder and is frequently accompanied by other anterior pituitary hormone deficiencies including secondary adrenal insufficiency (AI). A growth hormone-releasing peptide-2 (GHRP2), which is wildly used for the diagnosis of patients with GHD, has been considered to induce not only growth hormone (GH) release but also ACTH release. However, its clinical usefulness in hypothalamic-pituitary disorder is unclear.

Methods
The GHRP2 test, a cosyntropin stimulation test, corticotropin-releasing hormone (CRH) tests and/or insulin tolerance tests (ITTs) were performed on 36 patients having hypothalamic-pituitary disorder.

Results
Twenty-two (61%) had severe GHD, and 3 (8%) had moderate GHD by GHRP2. There was no difference in baseline ACTH and cortisol between non-GHD, moderate GHD and severe GHD participants. However, a cosyntropin stimulation test and subsequent CRH tests and/or ITTs revealed that 17 (47%) had secondary AI and 16/17 (94%) cases of secondary AI were concomitant with severe GHD. ROC curve analysis demonstrated that the ACTH response in the GHRP2 test was useful for screening pituitary-AI, with a cut-off value of 1.55-fold (83% sensitivity and 88% specificity). Notably, the combination of ACTH response and the peak cortisol level in the GHRP2 test using each cut-off value (1.55-fold and 10 µg/dl, respectively) showed high specificity (100%) with high accuracy (0.94) for diagnosis of pituitary-AI.

Conclusion
We recommend measuring ACTH as well as GH during the GHRP2 test to avoid overlooking and delays in diagnosis of secondary AI that frequently accompanies GHD.
Presentation: No date and time listed
PSAT031 Dietary Influence (smoothies) on Measurements of Plasma and Urinary Metanephrines in a Patient with Hypertension.
Authors: Nath Priti , Shin Terry , Hoang Thanh , Shakir Mohamed 
Published: November 2022

Abstract

Introduction
Pheochromocytoma can be diagnosed by fractionated plasma and urinary metanephrines. However, these tests have several diagnostic issues. Drugs, such as tricyclic antidepressants, and diets both can affect biochemical testing. We report a patient who was consuming a catecholamine rich diet in the form of smoothies which resulted in falsely elevated metanephrines.

Case history
A 37-year-old female was seen in 2021 for evaluation of secondary hypertension. Patient had a history of intermittent palpitations but denied headaches or excessive sweating. She was taking amlodipine 5mg daily and potassium chloride 20mg daily. Significant past medical history included a partial nephrectomy for renal cell cancer at the age of 35 years. She denies family history of pheochromocytoma or MEN 2. Vital signs showed HR 70/min, BP 138/80 mm Hg. Examination of the heart, lungs and abdomen was normal. Skin exam revealed no bruises or abdominal striae. Labs revealed normal CBC, serum K 3.4, aldosterone 20.1 ng/dL (ref 0.0 - 30.0), renin 1.165 ng/mL/hr (0.167-5.360). Following 1-mg dexamethasone suppression test, serum cortisol was 1.0 mcg/dL. Plasma normetanephrine 113.8 pg/mL (0.0 - 110.1), metanephrine 26.1 pg/mL (0.0 - 88), 24-hour urine metanephrines 465 mg/24hr (74 - 297), normetanephrine 963 mg/24hr (105 - 354). Due to the discordant values between the plasma and urinary metanephrines, a detailed history was taken which revealed that her diets included smoothies, consisting of pineapple juice, bananas, papaya, mango, and sea moss. She drank 15 ounces 3 times per week. Additionally, she was also consuming 1 cup of pistachios and 1 cup of elderberries daily. Patient was counseled to stop drinking the smoothies, and eating pistachios and elderberry. Six weeks later her 24-hour urine metanephrines and normetanephrines returned at 80 mcg/24 hrs and 243 mcg/24 hrs, respectively. Additionally, CT of the adrenal glands confirmed normal adrenal glands.

Conclusion
Previous studies have shown that catecholamines from dietary sources can dramatically affect plasma as well urinary concentrations of the 3-O methylated metabolites of catecholamines. In our patient, consumption of catecholamine rich foods such as bananas, oranges, pineapples, and possibly elderberry may have contributed to the false positive results. Additionally, the discrepancy between the baseline plasma and urine metanephrines, the normal adrenal glands on CT and normalization of the metanephrines after discontinuing the smoothie diets confirmed that the false positive laboratory values indeed resulted from dietary influence. It is recommended that a detailed dietary history be taken prior to ordering laboratory testing for catecholamine-secreting tumors. Possible interfering medications and catecholamine rich foods should be discontinued, if possible, before biochemical testing to avoid false positive results.
Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.
PSAT034 A Case of Adrenal Crisis in Association With a Febrile Response to the bnt162b2 mRNA COVID-19 (Pfizer) Vaccine Heralding a Diagnosis of Primary Adrenal Insufficiency.
Authors: Kamimoto Jorge J , Kharlip Julia , Kobaly Kristen 
Published: November 2022

Abstract

Background
In the face of the COVID-19 pandemic, messenger RNA (mRNA) vaccines were approved for the first time for use in the general population. Vaccination can trigger a febrile flu-like response that is self-limited in healthy individuals. Febrile illness is a classic trigger of acute adrenal insufficiency in patients who are cortisol deficient, but recognizing this clinical scenario is challenging in patients with undiagnosed adrenal insufficiency.

Case Presentation
A 24-year-old male presented to an acute care community hospital with fatigue, fever, and vomiting 12 hours after receiving the second dose of the BNT162b2 mRNA Covid-19 (Pfizer) vaccine. He was 6 feet tall, and his weight was 175 pounds. He had a temperature of 103 F, a blood pressure of 88/42 mmHg, and a heart rate of 100 bmp on admission. Hypotension persisted despite aggressive fluid resuscitation and broad-spectrum antibiotics. CT of the chest and CT angiogram of the abdomen and Pelvis did not identify an etiology for his presentation. Over a period of hours, he became obtunded, disoriented, and required vasopressor support. He received 100 mg of IV hydrocortisone followed by 50 mg every 6 hours for treatment of presumed sepsis and was transferred to an intensive care unit. Within 24 hours of starting glucocorticoid therapy, he was awake and oriented, defervesced, and became normotensive. This rapid improvement led to suspicion of adrenal insufficiency as an underlying diagnosis. Further questioning revealed a 4-month history of recurrent nausea, vomiting, severe fatigue, to the point where he had trouble climbing a flight of stairs, and a 40-pound unintentional weight loss. He visited an emergency department 3 times over this period and had outpatient evaluations by gastroenterology and cardiology without identifying a cause. Inpatient evaluation revealed a morning Cortisol of 1.4 ug/dL (n 4.8-19.5 ug/dL), aldosterone &lt;3 ng/dL (n &lt;16 ng/dL), and ACTH 1071 pg/mL (n 7.2-63.3 pg/mL) leading to the diagnosis of primary adrenal insufficiency. He was started on physiologic doses of adrenal replacement hormones and discharged home in stable condition 4 days after his admission date.

Conclusions
A severe post-vaccination reaction should elicit physicians to look for an alternative diagnosis. Autoimmune adrenalitis is the most common cause of primary adrenal insufficiency and is uniquely associated with a long lag to diagnosis. The diagnosis is often made in the setting of an intervening illness or physiologic stressor when a patient's condition acutely deteriorates. Patients with known adrenal insufficiency should be reminded to address post-vaccination febrile reactions with an increase in glucocorticoid doses.
Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.
PSAT074 Patient-Centered Research in Adrenal Insufficiency for Adults and Children Using a Registry and Longitudinal Cohort
Authors: Regan Elizabeth , Watts Shandi 
Published: November 2022

Abstract

Adrenal insufficiency (AI) leads to loss of critical adrenocortical hormones and untreated can result in death from adrenal crisis. It is the final common manifestation of multiple etiologies including infection, autoimmune disease, trauma, tumor, central nervous system dysfunction and genetic factors. Basal secretion of multiple steroid hormones is reduced or absent and a stress response in cortisol secretion is inadequate or absent. There may be variation in the severity of disease related to etiology and for causes such as autoimmune AI the disease may progress over time. There is limited published data from the US on prevalence, health disparities, outcomes of care and quality of life. A patient registry and longitudinal cohort to study AI in adults was initiated in 2019. This has been expanded to include children with AI. Goals of the Registry are to characterize the natural history of AI, including an at-risk population (family history of AI or active autoimmune disease). Additional goals are to monitor outcomes of care including adrenal crises and provide insight into the impact of AI on children.

Methods
The registry has been reviewed and approved by National Jewish Health and BRANY IRB. Participants provide written informed consent. Contact with the registry is electronic using RedCap for data entry and communication. Information about the registry is disseminated through social media, patient support groups and physician practices with an effort to enroll across a broad geographic and demographic base. Initial enrollment includes characterization of medical history, events, underlying cause of AI, demographics, socioeconomic factors and quality of life inventories (SF-36, AddiQoL and EQ-5D5L). Participants provide copies of medical records and test results to allow classification of AI and these are reviewed and adjudicated. Age-appropriate data collection instruments have been developed using the PROMIS database for children to assess the impact of illness in the domains of anxiety, physical function, fatigue, cognition, and social function. Interval surveys provide longitudinal data.

Results
More than 500 participants have enrolled with completed data entry. More than 150 medical records have been received for adjudication. The majority of participants to date are categorized as primary AI (89%) with 3% CAH and 5% "at-risk".
Sex distribution 82% female and Race, 93% white, 1.5% Black, 4% mixed. Age distribution 18-85 years, mean(SD) = 50(15). Pediatric enrollment to start Feb 2022.

Conclusions
A patient registry for adrenal insufficiency that is accessible electronically is feasible and has the potential to track a geographically diverse population. Initial enrollment has been strong but developing a balanced population that reflects the US will require extensive outreach to institutions and physician practices.
Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.