bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lipoprotein Insulin Resistance Score: Validation and Utility in African Ancestry Populations
Authors: Sharma Vandhna Rani , Cravalho Celeste K L , Dawson Joshua , Villalobos-Perez Alfredo , Mabundo Lilian , Matta Samantha , DuBose Christopher , Sumner Anne E , Chung Stephanie Therese 
Published: May 2021

Abstract
Lipoprotein insulin resistance (LPIR) is an emerging biomarker of insulin resistance (IR), and a score of &gt;48 is a strong predictor of incident cardiometabolic disease disease in a predominantly European ancestry population. LPIR is derived from a composite score of nuclear magnetic resonance (NMR) lipoprotein (Lp) parameters: triglyceride-rich (TRLp), low density (LDLp), and high density (HDLp). Yet, there is a paucity of data in African ancestry population, in whom there is low-normal TRLp despite high rates of IR and diabetes. Therefore, we examined Lp profiles and LPIR in a large African ancestry cohort, stratified by sex to determine the relationship of LPIR with established markers of IR. This is a secondary analysis from 2 studies (The Africans in America and Federal Women’s Study) designed to evaluate the genetic, biological and socio-environmental factors of diabetes risk in those of African ancestry. All participants self-identified as healthy and lived in the DC metro area, n= 518: 87.7% African immigrant,12.3% African American; age 39±10 (20-65y); BMI 28.1±4.8 (18.2–45.2 kg/m2); 58% male; 31% with obesity, and 37% with abnormal glucose tolerance; mean±SD (range); median (25th-75th percentile). Fasting measures of IR (LPIR, triglyceride/HDL (TG/HDL) ratio and homeostasis model of insulin resistance (HOMA-IR)) were compared with the whole-body insulin sensitivity index (WBISI) obtained during a multi-sample 75g OGTT, using spearman correlations. Lp particle size and subclass concentrations were measured by the amplitudes of the lipid-methyl group signals (NMR LipoProfile®). Men had lower BMI (27.1±3.9 vs 29.3±5.6 kg/m2), fat mass (23.5±5.5 vs 37.9±6.8 %), insulin resistance (WBISI: 6.2 (3.7–10.1) vs 4.9 (3.2–8.6), HOMA-IR: 1.3 (0.7–2.0) vs 1.6 (0.9–2.4), TG/HDL: 1.4 (1.0–2.2) vs 1.1 (0.8–1.5)), all P&lt;0.001. LDLp (1226 (959–1531) vs 1239 (981–1553) nmol/L) and HDLp (17.6 (16.2–19) vs 17.5 (15.9–19.7) µmol/L) were similar by sex, P&gt;0.6, while small LDLp 734 (523–1039) vs 541 (370–805) nmol/L and TRLp 80.5 (52.2–116.4) vs 53.6 (28.7 -89.3) nmol/L were higher in men. The total mean LPIR score was 28.9±18.7 and was higher in men (34±19 vs. 23±17), P&lt;0.001. LPIR and TG/HDL ratio correlated with WBISI (r≥-0.40) and HOMA-IR (r≥0.40), P&lt;0.001 with no differences by sex. HOMA-IR correlated with WBISI (r=-0.95, P&lt;0.001). Overall, African ancestry individuals had high rates of abnormal glucose tolerance, obesity and LDLp but LPIR was 20 points lower than the established score for predicting cardiometabolic disease. It’s utility for detecting IR was modest but it may be an important adjunct for early cardiometabolic risk stratification in African ancestry populations in whom traditional screening methods have lower sensitivity.
Long Term Effects of Leptin on Hepatic Fibrosis in Generalized Lipodystrophy
Authors: Lightbourne Marissa , Okawa Marinna , Koh Christopher , Brown Rebecca J 
Published: May 2021

Abstract
Lipodystrophy syndromes are caused by deficiency of adipose tissue leading to severe insulin resistance, hypertriglyceridemia, and non-alcoholic fatty liver disease (NAFLD), which may progress to cirrhosis. Advanced fibrosis/cirrhosis was previously thought to be irreversible; however, eradication of hepatitis C or long-term viral suppression of hepatitis B can reverse cirrhosis. Metreleptin treatment in patients with lipodystrophy improves liver transaminases and NAFLD activity score (NAS) after a mean of 2 years, but the latter improvements were due to lower inflammation and steatosis, with no change in fibrosis. The long-term effects of metreleptin in subjects with advanced fibrosis are unknown. We analyzed 24 subjects with advanced fibrosis (NAS stage 3 or 4) prior to metreleptin. Seven had liver biopsies both before and after ≥ 3 years of metreleptin with mean treatment duration 7.8±2.9 years. Five of six subjects with stage 3 fibrosis at baseline had improved fibrosis scores after metreleptin, and 0 of 1 with stage 4 fibrosis improved. 17 patients (8 with stage 3, 9 stage 4) did not have follow up biopsies after ≥3 years. Of these 17, 4 (all stage 4) died from end stage liver disease, and 1 (stage 3) from other causes. There was no clinical indication for repeat biopsy in 6 patients (2 stage 3, 4 stage 4). 6 were lost to follow up. Of the 24 patients with advanced fibrosis, 13 had congenital generalized lipodystrophy (CGL), 7 had acquired generalized lipodystrophy (AGL), 3 had familial partial lipodystrophy (FPL) and 1 had acquired partial lipodystrophy (APL). Of the 5 subjects with improvement in their fibrosis score, 2 had AGL, 2 had CGL, and one had a novel FPL mutation (1). Of the two patients that did not improve, one had FPL and one had CGL. In conclusion, subjects with stage 3 fibrosis due to lipodystrophy may have regression of fibrosis after long-term metreleptin treatment. This improvement may be secondary to near-elimination of the inciting factors (excess nutrient intake leading to ectopic lipid storage in the liver), analogous to clearance of Hepatitis C infection. However, additional data is needed to determine if metreleptin can reverse fibrosis in subjects with stage 4 fibrosis.
Modulation of Calcium Signaling by Chemogenetic Tools to Elucidate the Pathogenesis of Primary Aldosteronism
Authors: Cosentino Teresa , Fedlaoui Bakhta , Giscos-Douriez Isabelle , Fernandes-Rosa Fabio Luiz , Magnus Christopher , Sternson Scott M , Zennaro Maria-Christina , Boulkroun Sheerazed 
Published: May 2021

Abstract
Primary aldosteronism (PA) is the most frequent form of secondary arterial hypertension. The identification of germline or somatic mutations in different genes coding for ion channels (KCNJ5, CACNA1D, CACNA1H and CLCN2) and ATPases (ATP1A1 and ATP2B3) defines PA as a channelopathy. These mutations promote increased intracellular calcium concentrations and activation of calcium signaling, the main trigger for aldosterone biosynthesis.
The aim of our study was to elucidate the mechanisms underlying the development of PA by modulating calcium signaling using chemogenetic tools.
We have generated two different adrenocortical H295R_S2 cell lines stably expressing different chimeric ion channels generated by fusing the mutated extracellular ligand binding domain of the α7 nicotinic acetylcholine receptor to the ion pore domain of large Cys-loop receptor ion channel family; these receptors constitute PSAM (Pharmacologically Selective Actuator Modules). The mutations introduced in the ligand-binding domain allow to use synthetic ligands, PSEM (Pharmacologically Selective Effector Molecules) to activate the PSAM. We used two different PSAM: the chimeric receptor α7-5HT3 or a mutated acetylcholine receptor nAchR, allowing respectively modulation of sodium or calcium entry into the cells in response to the specific PSEM: Varenicline for α7-5HT3 or Compound 9S for mutated nAChR. The cells lines were characterized in terms of intracellular calcium concentrations, cell proliferation, aldosterone production and steroidogenic gene expression.
Cells expressing α7-5HT3 treated for 24h with increasing concentrations of Varenicline (10–9 to 10-5M) showed increased intracellular calcium concentrations and an increase in expression of steroidogenic genes such as StAR CYP17A1, CYP21A2 and CYP11B2. Cell proliferation was not affected. Calcium entry into cells expressing the mutated nAChR receptor treated for 24h with increasing concentrations of Compound 9S (10–9 to 10-5M) induced an increase in expression of steroidogenic genes such as StAR, CYP21A2 and HSD3B2, but not CYP11B2. Similarly to the results obtained in cells expressing α7-5HT3, cell proliferation was unaffected in response to Compound 9S.
These cell lines, in which we can modulate the intracellular calcium concentration « on demand », are a useful tool for a better understanding of the alterations of intracellular ion balance and calcium signaling in the pathophysiology of PA.
The Effect of Temperature on the Stability of PCSK-9 Monoclonal Antibody: An Experimental Study
Authors: Kongmalai Tanawan , Chuanchaiyakul Nalinee , Tansit Tunsuda , Sripatumtong Chattip , Srinoulprasert Yuttana , Klinsukon Nareerak , Thongtang Nuntakorn 
Published: May 2021

Abstract
Background: PCSK9 monoclonal antibody lowers plasma PCSK9 and LDL-cholesterol levels. The manufacturers recommend drug storage at 2–8°C, and not above 25°C. This study aimed to investigate drug stability at various temperatures that this drug could be exposed to during medication handling and transportation in tropical countries. Methods: Alirocumab and evolocumab were tested in 3 study conditions: room temperature (RT), cooler device with cold pack, and freeze-thaw for 9 and 18 hours. Heated drugs were used as negative control. Free plasma PCSK9 levels from 9 hyperlipidemia subjects were measured with ELISA. Results: Average subject age was 49.2±18.4 years. Percent PCSK9 inhibition significantly declined in heated drugs compared to baseline. Average RT during the study period was 30.4°C. Change in percent PCSK9 inhibition of PCSK9 mAb at RT from baseline was -5.8±4.4 (p=0.005) and -11.0±8.9% (p=0.006) for alirocumab at 9 hours and 18 hours, and -9.7±11.8% (p=0.04) and -15.1±14.3% (p=0.01) for evolocumab at 9 and 18 hours, respectively. In contrast, there were no significant changes in percent PCSK9 inhibition from baseline when PCSK9 mAb was stored in a cooler. In freeze-thaw condition, changes in percent PCSK9 inhibition from baseline to 9 and 18 hours were -5.2±2.9% (p=0.001) and -2.6±4.9% (p=0.16) for alirocumab, and -1.8±4.2% (p=0.24) and 0.4±6.1% (p=0.83) for evolocumab. Conclusion: Proper drug storage according to manufacturer’s recommendation is essential. Drug storage at RT in tropical climate for longer than 9 hours significantly decreased drug efficacy; however, storage in a cooler device with cold pack for up to 18 hours is safe.
Pregnancy in Familial Chylomicronemia Syndrome: Plasmapheresis as Therapeutic Approach
Authors: Leskovar Dunja , Šabić Marina , Perica Dražen , Šućur Nediljko , Hauptman Ana Godan , Merćep Iveta , Borovečki Fran , Jelaković Bojan , Reiner Željko , Pećin Ivan 
Published: May 2021

Abstract
Introduction: Familial Chylomicronemia Syndrome (FCS) is a rare autosomal recessive disease where functional loss of lipoprotein lipase results in severe hypertriglyceridemia. Patients often experience recurrent acute pancreatitis, a life-threatening disease. Serum triglycerides (TGs) are physiologically elevated several folds during pregnancy, which especially endanger patients with FCS to develop hypertriglyceridemic pancreatitis (HP) and complications like miscarriage. Despite the development of new drugs for FCS, their safety in pregnancy has not yet been confirmed and their treatment represents a big challenge.
Clinical Case: A 30-year women was hospitalized for planned reevaluation while 22 weeks pregnant. She was diagnosed with FCS at the age of one month with failure to thrive, jaundice and lipemic blood serum (homozygous for the LPL gene variation C.1019-2A&gt;T). During childhood she was treated with low-fat diet with average TG levels 10–15 mmol/l (n&lt;1,7 mmol/l). In the past five years, she was hospitalized for HP five times due to loss of compliance to diet (serum TGs &gt; 30 mmol/l). The last episode of HP was provoked by pregnancy and resulted in miscarriage. At the admission, the patient was asymptomatic, with BMI:18,5 kg/m2, TGs: 32,2 mmol/l (n&lt;1,7 nmol/l), lipase: 21 U/L (n&lt;60 U/L). Gynecology status and child growth parameters were normal. Due to inability to achieve lower TG levels plasmapheresis was started two times per week. The overall mean of pre plasmapheresis values of TGs were 21,68 nmol/l (ranging from 15,9 to 26,3 nmol/l) and post plasmapheresis were 7,15 mmol/L (ranging from 4,9 to 9,9 mmol/l). Due to the frequent need for plasmapheresis and high risk pregnancy, the patient was transferred to the Gynecology department. The patient had no adverse reactions and fetal monitoring was performed before, during and after procedure with no abnormalities registered. Plasmapheresis was performed using Spectra OPTIA via peripheral veins with 5% albumin replacement, proceeded by 250-500ml of 0.9% saline infusion. At 40th gestational week Cesarean section was performed and a healthy baby boy (weight: 3540 g, lenght: 49 cm) was born with Apgar score 10/10. We followed baby boy the first five years of the childhood. So far the patient has not experienced HP and the baby boy has normal levels of TGs.
Conclusion: Our case showed a succesfull pregnancy outcome in female patient with FCS achieved by multidisciplinary approach including plasmapheresis. For the first time therapeutic plasmaferesis was used in order to prevent pancreatitis and potential complications for both mother and child.
Scientific and Regulatory Considerations for the Approval of the First Generic Glucagon
Authors: Pang Eric , Chong William , Luke Markham C 
Published: May 2021

Abstract
Glucagon for Injection (NDA 020928) is a polypeptide hormone identical to human glucagon approved 20 years ago for severe hypoglycemia in patients with diabetes mellitus. On Dec 28, 2020, the U.S. FDA approved the first generic version of glucagon for injection USP, 1 mg/vial packaged in an emergency kit. The generic and the reference listed drug (RLD) version, i.e., the innovator version, of glucagon were each produced through different manufacturing processes. The RLD version of glucagon is produced via recombinant DNA in yeast while the generic version of glucagon is produced by peptide synthesis. The FDA published its current thinking on how to ensure sameness between the generic and innovator peptide products prepared with different manufacturing processes in a Draft Guidance for Industry: Submission of Abbreviated New Drug Applications for Certain Highly Purified Synthetic Peptide Drug Products, which applies to five peptide drug products, including glucagon. In this presentation, we aim to provide an overview of the regulatory recommendations for submitting generic glucagon drug products for approval, as outlined in the aforementioned draft guidance. Although glucagon may be produced using different manufacturing processes, the sameness in glucagon can be adequately demonstrated using analytical methods, which involve demonstrating physicochemical properties, as well as primary and secondary structures, oligomers and aggregation states. Biological assays may also be used as part of the demonstration of active pharmaceutical ingredient sameness. Synthetic glucagon may have different impurity profiles when compared to the RLD recombinant product. As part of the ANDA review, impurities in the synthetic drugs are analyzed and controlled, in addition, the potential immunogenicity of new impurities, which are not in the RLD products, are assessed and compared using non-clinical assays. In this work, we will discuss non-clinical assays for assessing the immunogenicity risk of these impurities, for both adaptive and innate immune responses. In conclusion, the sameness of an approved generic synthetic glucagon to an RLD can be adequately established through various analytical methods and biological assays.
Sex Disparities in Thermoregulatory and Metabolic Responses to Mild Cold Exposure Largely Explained by Differences in Body Mass and Body Surface Area
Authors: Ivanova Yoanna M , Swibas Tracy , Haman François , Hildreth Kerry L , Miao Yubin , Kohrt Wendy M , Carpentier Andre , Melanson Edward L , Blondin Denis P 
Published: May 2021

Abstract
Sex-related differences in thermoregulatory responses to cold exposure, such as differences in metabolic heat production and fuel selection, are often attributed to differences in morphology and body composition. Whether these differences persist in response to cold when comparing lean, healthy men and women with equivalent total body mass (BM, heat producing capacity) and body surface areas (BSA, heat loss capacity) remains unknown. In this study, we aimed to compare thermoregulatory and metabolic responses to cold exposure in both men and women, before and after matching for BM (± 0.6 kg) and BSA (± 0.01 m2). Data included in this study were derived from four previously published studies and an additional 13 men and 23 women who recently completed an identical 3h mild cold exposure protocol. Included in the analyses were 45 healthy men and 23 healthy women [27 years (95% CI: 25 to 28) in men vs. 34 years (95% CI: 30 to 38) in women, P = 0.0003], including 7 men and women of the same age [28 years (95% CI: 22 to 34) vs. 29 years (95% CI: 22 to 37), P = 0.78] matched for BM and BSA. Using a combination of indirect calorimetry, electromyography and positron emission tomography with 11C-acetate and 18F-fluorodeoxyglucose, we quantified mean skin temperature, whole-body energy expenditure (EE), shivering intensity, brown adipose tissue (BAT) oxidative metabolism and glucose uptake. The cold-induced decrease in mean skin temperature was greater in women than men [-6.4°C (95% CI: -6.7 to -6.0) vs. -5.4°C (95% CI: -5.8 to -5.1), P = 0.0004], whereas EE was higher in men compared to women both during room temperature and cold exposure, with the cold-induced increase in EE being slightly greater in men than women [3.8 kJ·min-1 (95% CI: 3.2 to 4.5) vs. 2.8 kJ·min-1 (95% CI: 2.0 to 3.7), P = 0.07]. In contrast, shivering intensity (%MVC) was higher in women compared to men [3.0 %MVC (95% CI: 2.1 to 3.8) vs.1.8 %MVC (95% CI: 1.5 to 2.2), P = 0.0069]. Cold exposure also increased BAT oxidative index to a similar magnitude in men and women, increasing ~4-fold in men and ~3-fold in women (effect of sex, P = 0.2067). Both fractional glucose uptake [0.022 min-1 (95%CI: 0.017 to 0.027) in men and 0.021 min-1 (95%CI: 0.013 to 0.030) in women, P = 0.02] and net glucose uptake in BAT [92 nmol.g-1.min-1 (95%CI: 69 to 115) in men and 91 nmol.g-1.min-1 (95%CI: 53 to 129) in women] were not different between the sexes without or with matching for BM and BSA. The sex differences in mean skin temperature, energy expenditure and shivering intensity were all lost once participants were matched for BM and BSA. The present results suggest that much of the sexual dimorphism in thermoregulatory and metabolic responses to mild cold exposure can be explained by differences in BM and BSA.
The SSBP3 Co-Regulator Is a Novel Driver of Islet Cell Structure and Function
Authors: Toren Eliana , Liu Yanping , Hunter Chad 
Published: May 2021

Abstract
The activities of transcriptional complexes drive the proper development and function of insulin producing beta-cells, ultimately required for the regulation of glucose homeostasis. Our prior work helped to establish that the LIM-homeodomain transcription factor (TF), Islet-1 (Isl1), directly interacts with the Ldb1 co-regulator in developing and adult beta-cells. We further found that a member of the Single Stranded DNA-Binding Protein (SSBP) co-regulator family, SSBP3, interacts with the Isl1:Ldb1 complex in beta-cells and primary islets to impact critical target genes MafA and Glp1R. Members of the SSBP family of co-regulators stabilize TF complexes in various tissues, ranging from brain to skin, by binding directly to Ldb1 and protecting the factors from ubiquitin-mediated turnover. Because of this, we hypothesized that SSBP3 would have similarly critical roles as Isl1 and Ldb1 for beta-cell development and function in vivo. To assess this, we first developed a novel SSBP3 floxed mouse line, where Cre-mediated recombination is predicted to impart loss of the Ldb1-interacting domain, plus an early termination. We bred this mouse into a Pax6-Cre transgenic line to recombine SSBP3 in the developing pancreatic islet, a model termed SSBP3islet. We found that SSBP3islet neonates become progressively hyperglycemic and both male and female mice are glucose intolerant as early as postnatal day (P) 21. These results are similar to previous Ldb1 and Isl1 knockouts in the embryonic islet, both of which were hyperglycemic by P10. We observed a reduction of the beta-cell maturity marker, MafA, and disruptions in islet cell architecture with an apparent increase in both glucagon+ alpha-cells and ghrelin+epsilon-cells at P10 and P28. In ongoing studies we are generating embryonic day (E)18.5 embryos to determine islet development defects and will conduct chromatin immunoprecipitation (ChIP) experiments to determine the beta-cell and islet genes directly bound by SSBP3 in vivo. These experiments will further elucidate the regulation of islet function by LIM complexes, knowledge that is central not only for our understanding of glucose homeostasis but for the development of novel diabetes therapeutics.
Evaluating the Use of Telemedicine in Endocrinology Clinic
Authors: Nemati Maryam , Reddy Archana , Jung Syung , Nguyen Jessica 
Published: May 2021

Abstract
The COVID-19 pandemic changed patient-physician interaction. As the need to reduce COVID-19 transmission, many clinic providers have converted their in-person visits to video or phone visits. Our endocrinology clinic initiated tele visits early on when the pandemic had just started. Telemedicine may help with patient’s compliance by decreasing various burdens. Some studies show that patients and providers hope telemedicine will continue after the crisis. In this study we evaluated benefits and challenges of telemedicine in our endocrinology clinic. Patients who had a telemedicine endocrinology visit after informed consent were surveyed on 10 questions regarding benefits and limitations of the tele visits compared to the clinic visit. Patient also responded if they want to continue with telehealth after COVID-19 pandemic. Providers also were surveyed about the benefits and limitations of telemedicine and responded if they want to continue with telemedicine after pandemic. We also analyzed no-show rate from January 2020 through May 2020 for 6 weeks before and after the implementation of telemedicine. Among 109 patients who were interviewed 65% declared that they would like to continue with telemedicine after pandemic. Total of 42% of patients prefer video visit and 37% prefer phone calls. Among Interviewers 45% report benefit of spending less time, however 54% stat the time of meeting, itself was about the same. 54% believe they spent less money with telemedicine. 37% of interviewers report no limitation for telehealth while 25% report connection difficulty. 63% of patients state they do not have any difficulty traveling to the hospital. 90% of the patients declare all their question and concerns were responded and 77% stated the quality of care with telemedicine is almost the same via clinic visit. Among providers 75% want to continue telehealth after COVID-19 pandemic. 50% of providers mention patient satisfaction and 25% notice time saving as benefits. 46% of the providers mention lack of physical exam and 40% mention technology connection as the limitation for video visit. 60% of providers believe lack of exam is the limitation of phone visit. 87% of the providers believe the quality of care via phone is not like in clinic visit while 75% of the providers believe the quality of care is similar in video visit compare to in clinic visits. No show rate decreased from 30% to 27% after the implementation of telemedicine in 6 weeks prior and after pandemic. Endocrinology clinic has significant number of patients who need long term close follow up for medication adjustments, symptom checks and counseling. Given patients and providers satisfaction rate, telemedicine can be incorporated as part of regular clinic visits after the Covid crisis ends. Telehealth can be more efficient for both patients and providers but there are challenges which needs to be addressed.