Replacement Doses Research Articles

Optimal thyroid hormone replacement dose in immune checkpoint inhibitor-associated hypothyroidism is distinct from Hashimoto’s thyroiditis

Optimal thyroid hormone replacement dose in immune checkpoint inhibitor-associated hypothyroidism is distinct from Hashimoto’s thyroiditis

The role of lower dose steroid therapy with vitamin D replacement in patients with idiopathic granulomatous mastitis.

Low-dose steroid therapy has been recommended in idiopathic granulomatous mastitis (IGM) in various studies in the literature, but the therapeutic minimum dose has not been determined yet. Furthermore, vitamin D deficiency, the effect of which is accepted in autoimmune diseases, has not been previously examined in IGM. The aim of our study was to evaluate the efficacy of lower dose steroid theraphy with adjustment of vitamin D replacement doses with measuring serum 25-hydroxyvitamin D levels in patients with idiopathic granulomatous mastitis (IGM). Vitamin D levels were evaluated in 30 IGM patients who applied to our clinic between 2017-2019. Vitamin D replacement was performed in patients with serum 25-hydroxyvitamin D level below 30 ng/mL and prednisolone was given to all patients at a dose of 0.05-0.1 mg/kg/ day. Clinical recovery times of the patients were compared with the literature. Vitamin D replacement was given to 22 (73.33%) patients. Recovery time was shorter in patients receiving vitamin D replacement (7.62 ± 2.38; 9.00 ± 3.38; p= 0.680). Average recovery time was 8.00 ± 2.68 weeks. Treatment of IGM can be carried out with lower dose steroid therapy, leading to less complications and lower costs. Measuring serum 25-hydroxyvitamin D level and treating it with the appropriate dose may contribute to the healing process.

Predictors of renal function after adrenalectomy in patients with Cushing or subclinical Cushing syndrome.

The postoperative course of renal function remains unclear in Cushing syndrome. We examined changes in renal function after adrenalectomy in patients with Cushing syndrome and attempted to identify predictors of renal impairment. The study population comprised 76 patients who underwent adrenalectomy for Cushing and subclinical Cushing syndrome between 2001 and 2018. Renal function and other factors were evaluated pre-operation, at 1 postoperative month, and 1 postoperative year. We defined a ≥10% decrease in the estimated glomerular filtration rate at 1 postoperative year as renal impairment, and predictors associated with this reduction were investigated. The relationship between renal function and steroid replacement after surgery was also examined. Mean pre-operative estimated glomerular filtration rate was 82.2 ml/min/1.73 m2 . While mean estimated glomerular filtration rate was significantly lower at 1 postoperative month than the pre-operative value (71.7 ml/min/1.73 m2 [89.1%], p < 0.001), no significant differences were observed between 1 postoperative year and pre-operation (79.5 ml/min/1.73 m2 [97.6%], p = 0.108). Twenty-six patients (34.2%) developed renal impairment. A multivariate analysis identified a low pre-operative adrenocorticotropic hormone level as an independent predictor of renal impairment (odds ratio 6.30, p = 0.031). Among 43 patients with available records of steroid replacement history, 18 (41.9%) developed renal impairment. The ratio of patients with a reduced steroid replacement dose at 1 postoperative month was significantly lower among patients with renal impairment than those without (22.2% vs. 56.0%, p = 0.027). The pre-operative adrenocorticotropic hormone level was a predictor of renal function after adrenalectomy in patients with Cushing or subclinical Cushing syndrome.

Influence of Fineness Levels and Dosages of Light-Burned Dolomite on Portland Cement Performance.

The paper aims to understand the effect of light-burned dolomite powders (LBD) on ordinary Portland cement (OPC) and evaluate the influence of LBD dosages and fineness levels on the mechanical properties and hydration properties of OPC. The LBD/OPC pastes were prepared by OPC blended with LBD at various replacement dosages and fineness levels. The mechanical properties were studied by flexural and compressive strength tests, while the hydration properties were investigated by X-ray diffraction (XRD), thermogravimetric analysis (TG), differential scanning calorimetry (DSC), and reaction degree of LBD. Experiment results indicated that the flexural and compressive strength of LBD/OPC samples were higher than reference sample at all ages. The fineness levels of LBD was C (C-LBD) with 0.5–1.5 wt% dosages, and the fineness levels of LBD was B (B-LBD) with 1.5–2.5 wt% dosages can significantly improve the strength of cement-based materials. The main mineral components of LBD are MgO and CaCO3, of which MgO could react with water to form Mg(OH)2 quickly, and CaCO3 could hydrate with C3A to from hydrated calcium carboaluminate (C3A·CaCO3·11H2O), which prevents the conversion of AFt to AFm.

Treatment with IgM-enriched intravenous immunoglobulins enhances clearance of stroke-associated bacterial lung infection.

Post-stroke infection is a common complication of stroke that is associated with poor outcome. We previously reported that stroke induces an ablation of multiple sub-populations of B cells and reduces levels of immunoglobulin M (IgM) antibody, which coincides with the development of spontaneous bacterial pneumonia. The loss of IgM after stroke could be an important determinant of infection susceptibility and highlights this pathway as a target for intervention. We treated mice with a replacement dose of IgM-enriched intravenous immunoglobulin (IgM-IVIg) prior to and 24 h after middle cerebral artery occlusion (MCAO) and allowed them to recover for 2- or 5-day post-surgery. Treatment with IgM-IVIg enhanced bacterial clearance from the lung after MCAO and improved lung pathology but did not impact brain infarct volume. IgM-IVIg treatment induced immunomodulatory effects systemically, including rescue of splenic plasma B cell numbers and endogenous mouse IgM and IgA circulating immunoglobulin concentrations that were reduced by MCAO. Treatment attenuated MCAO-induced elevation of selected pro-inflammatory cytokines in the lung. IgM-IVIg treatment did not increase the number of lung mononuclear phagocytes or directly modulate macrophage phagocytic capacity but enhanced phagocytosis of Staphylococcus aureus bioparticles in vitro. Low-dose IgM-IVIg contributes to increased clearance of spontaneous lung bacteria after MCAO likely via increasing availability of antibody in the lung to enhance opsonophagocytic activity. Immunomodulatory effects of IgM-IVIg treatment may also contribute to reduced levels of damage in the lung after MCAO. IgM-IVIg shows promise as an antibacterial and immunomodulatory agent to use in the treatment of post-stroke infection.

Pre-hospital blood products and calcium replacement protocols in UK critical care services: A survey of current practice

IntroductionIn the United Kingdom, prehospital blood products are increasingly carried for the early resuscitation of hypovolaemia in patients who are shocked or in cardiac arrest. There is an association between hypocalcaemia and mortality in trauma patients, but no current national guidelines on the timing or dose of calcium replacement exist. The objective of this study was to establish the availability of prehospital blood products, and the current calcium replacement protocols used by UK prehospital services. MethodsA cross sectional survey of all UK air ambulances and additional prehospital critical care organisations was conducted in April-May 2022 via an on-line questionnaire. The survey asked 11 questions about availability of prehospital blood products, calcium replacement for patients requiring prehospital blood products, and the use of point of care testing. ResultsThere was a 100% response rate with 20/22 UK air ambulances carrying blood products and five additional prehospital services identified. There were 15 different combinations of prehospital blood products. 23/25 services had a standard operating procedure for the replacement of calcium. This was recommended before any blood product administration in 5 services (22%), during or after the 1st unit in 5 services (22%), during or after the 2nd unit in 6 services (26%) and during or after the 4th unit in 7 services (30%). Only six services carried point of care testing and no services routinely used this to measure calcium levels in patients requiring prehospital blood products. ConclusionIn 2022, 91% of UK air ambulances carry prehospital blood products and there is significant variation between services in the combination of blood products provided. There is no consensus on the timing or dose of calcium replacement. Further prospective research should examine the association between traumatic bleeding and ionized calcium levels before and during blood product transfusion in order to produce more robust guidelines for routine calcium replacement.

Vitamin D supplementation during pregnancy inhibits the activation of fetal membrane NF-κB pathway.

Nuclear Factor-κB (NF-κB) is an important member of the basic cellular inflammatory pathway that regulates inflammation and apoptosis in fetal membranes. Vitamin D (VD) exerts its anti-inflammatory and immunomodulatory effects via the NF-κB pathway. This study was designed to investigate amniotic fluid NF-κB levels in pregnant women undergoing VD replacement therapy. Sixty patients who received antenatal vitamin D supplementation from the 14th week of pregnancy until delivery were included in the study. Participants were selected among those whose serum vitamin D levels were compatible with insufficiency (20-30 ng/mL), according to the Endocrine Society proposal. Participants were divided into three groups with 20 patients in each group and one of the cholecalciferol or placebo treatments was given. Patients in Group 1 were given 500 IU/day of cholecalciferol, while patients in Group 2 were given 1000 IU/day of cholecalciferol. Patients in group 3 were not given cholecalciferol treatment (placebo). Patients in all groups underwent elective cesarean section. Amniotic fluid samples were collected after the fetal membranes were cut and before the fetal parts were manually removed. The amniotic fluid NF-κB level of the control group who did not receive VD replacement was 9.33±2.02 ng/mL. The amniotic fluid NF-κB level of the 500 IU/day VD replacement group was found to be 6.12±1.23 ng/mL. Compared to the control group, NF-κB levels of pregnant women given 500 IU/day VD replacement were significantly lower (9.33±2.02 ng/mL vs. 6.12±1.23 ng/mL, p<0.03). The amniotic fluid NF-κB level of the 1000 IU/day VD replacement group was found to be 3.09±0.44 ng/mL. Compared to the control group, amniotic fluid NF-κB levels of pregnant women given 1000 IU/day VD replacement were significantly lower (9.33±2.02 ng/mL vs. 3.09±0.44 ng/mL, p<0.01). When the VD replacement groups were compared among themselves, the amniotic fluid NF-κB level decreased approximately twice as much in the 1000 IU/day replacement group compared to the 500 IU/day replacement group (3.09±0.44 ng/mL vs. 6.12±1.23 ng/mL, p<0.01). A negative correlation was found between amniotic fluid NF-κB level and VD dose (r=-0.789, p<0.04). The present study showed for the first time that amniotic fluid NF-κB levels decreased in pregnant women who underwent VD replacement dose dependent manner.

Prevalence of Lactose Intolerance in Patients with Hashimoto Thyroiditis and Impact on LT4 Replacement Dose.

Purpose: to determine lactose intolerance (LI) prevalence in women with Hashimoto’s thyroiditis (HT) and assess the impact of LI on LT4 replacement dose. Methods. consecutive patients with HT underwent Lactose Breath Test and clinical/laboratory data collection. Unrelated gastrointestinal disorders were carefully ruled out. Lactose-free diet and shift to lactose-free LT4 were proposed to patients with LI. Results: we enrolled 58 females (age range, 23–72 years) with diagnosis of HT. In total, 15 patients were euthyroid without treatment, and 43 (74%) euthyroid under LT4 (30 of them with a LT4 formulation containing lactose). Gastrointestinal symptoms were present in 84.5% of patients, with a greater prevalence in change in bowel habits in lactose-intolerant patients (p < 0.0001). The cumulative LT4 dose required did not differ in patients with or without LI. No significant difference in both TSH values and LT4 dose were observed in patients shifted to lactose-free LT4 and diet at 3 and 6 months compared to baseline. Conclusion: the prevalence of LI in patients with HT was 58.6%, not different from global prevalence of LI. In the absence of other gastrointestinal disorders, LI seems not to be a major cause of LT4 malabsorption and does not affect the LT4 required dose in HT patients.

Lithium replacement dose recommendations using Monte Carlo simulations.

Missed medication doses are a common clinical problem, and cause consternation when prescribing lithium because its plasma levels must be kept within a narrow therapeutic window. Therefore, this study set out to determine the potential impact of missed lithium doses on its pharmacokinetics, and to explore the optimal compensatory dosing scheme. This is difficult to determine clinically and in research because of ethical constraints and therefore we modelled the effects using simulations. Monte Carlo simulations were used to simulate lithium concentrations under different missed dose scenarios. For patients with normal renal function, the optimal replacement dosing scheme was selected based on the lowest percentage of deviation from the full adherence scenario. However, for patients with renal impairment the appropriate dosing schedule was selected based on the lowest number of simulated concentrations above the upper range of 1.2mEq/L. The impact of a missed lithium dose depended on its daily dose. The higher the daily dose, the higher the deviation from full adherence. In patients with normal renal function, replacement with a regular dose was most appropriate. But in patients with renal impairment, replacement with a partial dose appeared to be most suitable. This study has enabled insights into the optimal suitable lithium replacement dosing schemes for patients with normal renal function and renal impairment. These proposed schemes can be used cautiously in clinical practice in conjunction with clinician judgment and can also be used as a basis for future clinical research.

PCSK9 and ANGPTL3 levels correlate with hyperlipidemia in HIV-lipoatrophy, are regulated by fasting and are not affected by leptin administered in physiologic or pharmacologic doses

BackgroundMedications leveraging the leptin, PCSK9, ANGPTL3 and FABP4 pathways are being developed for the treatment of insulin resistance and/or lipid disorders. To evaluate whether these pathways are independent from each other, we assessed the levels of PCSK9, ANGPTL3 and FABP4, in normal subjects and subjects exhibiting HIV and highly active antiretroviral therapy (HAART) induced metabolic syndrome with lipoatrophy and hypoleptinemia. Studies were performed at baseline and during food deprivation for three days with either a placebo or leptin administration at physiological replacement doses to correct fasting induced acute hypoleptinemia and in pharmacological doses. MethodsPCSK9, ANGPTL3, FABP4 levels and their correlations to lipoproteins-metabolites were assessed in randomized placebo controlled cross-over studies: a) in 15 normal-weight individuals undergoing three-day admissions in the fed state, in complete fasting with placebo and in complete fasting with leptin treatment in physiologic replacement doses (study 1), b) in 15 individuals day baseline in a fed and three fasting admissions for three days with leptin administered in physiologic, supraphysiologic and pharmacologic doses (study 2), c) in 7 hypoleptinemic men with HIV and HAART-induced lipoatrophy treated with leptin or placebo for two months in the context of a cross over randomized trial (study 3). ResultsCirculating ANGPTL3, PCSK9 and FABP4 were markedly elevated in HIV-lipoatrophy and not affected by leptin treatment. PCSK9 levels correlated with lipids and markers of lipid utilization and lipolysis. ANGPTL3 levels correlated with HDL particles and their lipid composition. FABP4 levels were negatively associated with HDL diameter (HDL-D) and composition. PCSK9 and ANGPTL3 levels decreased during food deprivation by ~65 % and 30 % respectively. Leptin administration at physiologic, supraphysiologic and pharmacologic doses did not affect PCSK9, ANGPTL3 and FABP4 levels. ConclusionsPCSK9, ANGPTL3 and FABP4 levels are associated with markers of lipid metabolism and are higher in HIV-lipoatrophy. PCSK9 and ANGPTL3 but not FABP4 decrease in response to food deprivation. PCSK9 and ANGPTL3 regulation is leptin-independent, suggesting independent pathways for lipid regulation. Thus, combining treatments of leptin with PCSK9 and/or ANGPTL3 inhibitors for metabolic diseases should have additive effects and merit further investigation. Clinical trial informationClinicalTrials.gov no. NCT00140231, NCT00140205, NCT00140244.

Vitamin D Supplementation Improves Follicle Maturation By Regulating Oxidant/Antioxidant Balance in Women With PCOS

Objective: To investigate the effect of vitamin D (VD) supplementation on follicular fluid total oxidant status (TOS) and total antioxidant status (TAS) in women undergoing IVF/ICSI due to PCOS. Materials and Methods: Forty infertile women who were diagnosed with PCOS and decided on IVF/ICSI and whose serum VD levels were lower than 20 ng/mL were included in the study. The VD levels of the patients were determined according to the proposal of Endocrine Society. The patients were divided into two equal groups with 20 patients in each group. While the patients in Group 1 were given 400 IU/day of oral VD3 replacement, the patients in Group 2 were given 600 IU/day of oral VD3. VD treatment was started one month before the controlled ovarian stimulation cycle and continued throughout the following cycle. Fifteen patients with serum VD levels &gt;30 ng/mL were taken as the control group. Oral VD replacement was not given to the patients in the control group. TAS and TOS values were measured in the follicle fluids taken from the patients in the VD replacement group and the patients in the control group on the day of ooist pick-up. Results: When compared with the control group, the follicular fluid TAS levels of both groups with VD replacement were significantly higher, while TOS levels were found to be significantly lower. When 400 IU/day VD replacement and 600 IU/day VD replacement were compared within themselves, follicular fluid TAS and TOS levels were found to be similar. Increasing the VD replacement dose from 400 IU/day to 600 IU/day did not cause a significant change in TAS and TOS values. A positive and significant correlation was found between intrafollicular TAS levels and serum VD, MII oocyte, 2PN zygote and clinical pregnancy rates. A negative correlation was found between intrafollicular TOS levels and serum VD, 2PN zygote and clinical pregnancy rates. Conclusions: VD replacement therapy contributes to follicle maturation by regulating intrafollicular oxidant/ antioxidant balance in PCOS patients.

Daily Glucocorticoid Replacement Dose in Adrenal Insufficiency, a Mini Review.

The Endocrine Society Guidelines and recent reviews of adrenal insufficiency (AI) recommend a daily glucocorticoid replacement dose of 15 to 25 mg with a midpoint of 20 mg of hydrocortisone (HC) (alternatively 3 to 5 mg prednisolone) in divided doses in otherwise healthy individuals with AI. In contrast, a daily glucocorticoid replacement dose of 4.3 to 26 mg/d HC with a midpoint of 15 mg/d is predicted from current measurements of daily cortisol production rates and oral HC bioavailability. The higher HC doses recommended in the current guidelines may result in glucocorticoid overtreatment of some AI patients and associated long-term adverse outcomes. A titration method for determination of the individual patient’s daily glucocorticoid replacement dose and the impact of lower doses are reviewed. Future related research questions are identified.

The effect of nonadherence on phenobarbital concentrations and recommendations on the replacement dose using Monte Carlo simulation.

To determine the impacts of missed phenobarbital (PB) doses on its pharmacokinetics and to investigate the appropriate replacement dosing scheme for various PB missed dose scenarios. Monte Carlo simulations were performed using parameters from the selected population pharmacokinetic study. The impacts of missed PB dose and the proper replacement dosing scheme were assessed based on the percent deviation of simulated concentrations outside the reference range from the full adherence scenario. The impact of missed PB dose on its concentrations depended on the daily dose. The replacement with a respective regular dose and one and a half regular dose was appropriate for the one and two missed doses scenarios for patients receiving PB monotherapy. For patients receiving PB with valproic acid or phenytoin, the same replacement scheme was still appropriate. The results also indicated that weight did not influence the proper replacement dosing scheme. The impacts of missed PB doses on its pharmacokinetics were identified and the proper replacement dosing schemes for different missed dose scenarios were proposed. These schemes should be implemented based on the clinician's justification of the patient's seizure control.

The effect of nonadherence on phenobarbital concentrations and recommendations on the replacement dose using Monte Carlo simulation.

To determine the impacts of missed phenobarbital (PB) doses on its pharmacokinetics and to investigate the appropriate replacement dosing scheme for various PB missed dose scenarios. Monte Carlo simulations were performed using parameters from the selected population pharmacokinetic study. The impacts of missed PB dose and the proper replacement dosing scheme were assessed based on the percent deviation of simulated concentrations outside the reference range from the full adherence scenario. The impact of missed PB dose on its concentrations depended on the daily dose. The replacement with a respective regular dose and one and a half regular dose was appropriate for the one and two missed doses scenarios for patients receiving PB monotherapy. For patients receiving PB with valproic acid or phenytoin, the same replacement scheme was still appropriate. The results also indicated that weight did not influence the proper replacement dosing scheme. The impacts of missed PB doses on its pharmacokinetics were identified and the proper replacement dosing schemes for different missed dose scenarios were proposed. These schemes should be implemented based on the clinician's justification of the patient's seizure control.

Weight-adjusted dosing of fibrinogen concentrate and cryoprecipitate in the treatment of hypofibrinogenaemic bleeding adult cardiac surgical patients: a post hoc analysis of the Fibrinogen Replenishment in cardiac surgery randomised controlled trial.

Hypofibrinogenaemia is associated with excessive bleeding after cardiac surgery. Our aim was to compare the efficacy and safety of weight-adjusted vs empiric dosing of fibrinogen replacement in cardiac surgery. In the Fibrinogen Replenishment in Cardiac Surgery (FIBRES) RCT, patients (n=735) received fibrinogen concentrate (4 g) or cryoprecipitate (10 units). In this post-hoc analysis, patients were grouped into quartiles based on increasing weight-adjusted dosing. Generalised estimating equations were used to account for hospital site, age, sex, surgical complexity, urgency, and critical preoperative status. The primary outcome was the number of units of red blood cells transfused within 24 h of cardiopulmonary bypass. Secondary outcomes included allogeneic blood components within 24 h, tamponade or major bleeding, and thromboembolic complications, ischaemic complications, or both within 28 days of cardiopulmonary bypass. The median weight-adjusted doses were 52 mg kg-1 of fibrinogen concentrate (inter-quartile range [IQR], 45-61; n=372) and 1.30 units per 10 kg of cryoprecipitate (IQR, 1.11-1.54; n=363). When patients were divided into quartiles of lowest to highest weight-adjusted dosing, no differences were seen in the primary outcome of red blood cell units transfused within 24 h of cardiopulmonary bypass between the lowest and highest quartiles in either the fibrinogen group (adjusted relative risk [RR]=0.90; 95% confidence interval [CI], 0.71-1.13; P=0.36) or the cryoprecipitate group (adjusted RR=1.04; 95% CI, 0.76-1.43; P=0.80). Results were similar for all secondary outcomes. Outcomes for the lowest and highest weight-adjusted doses of fibrinogen replacement were comparable. Weight-adjusted dosing does not appear to offer advantages over empiric dosing in this context. NCT03037424.

The role for long-term use of dehydroepiandrosterone in adrenal insufficiency.

Dehydroepiandrosterone (DHEA) is an androgen produced by the zona reticularis of the adrenal gland. Patients with adrenal insufficiency will have a deficiency of DHEA. Unlike glucocorticoid and mineralocorticoid replacement, DHEA supplementation is not considered essential for life and is therefore not routinely replaced in adrenal failure. DHEA deficiency is associated with morbidity, including adverse impacts on metabolic function, quality of life and sexuality in multiple studies. The role for replacement, however, remains unclear. The benefits of DHEA supplementation have been definitively demonstrated in a number of historical studies of patients with primary and secondary adrenal insufficiency. Beneficial impacts on quality of life, body composition, bone health and metabolic markers have been demonstrated. However, published data are inconsistent; controversies persist around the exact role of DHEA replacement and around which patient cohorts are most likely to benefit. There is also a paucity of recent randomized controlled trials in the medical literature to inform on optimal dose and duration of DHEA replacement in adrenal failure. Here, we review the evidence for DHEA supplementation in patients with adrenal insufficiency. We highlight knowledge gaps in the medical literature and areas that should be prioritized for future research endeavours.

276-OR: Impaired Glucagon-Mediated Suppression of VLDL-TG Secretion in Individuals with MAFLD

Background: Individuals with Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD) have both elevated triglyceride and glucagon levels, although glucagon suppresses the very-low-density lipoprotein-triglyceride (VLDL-TG) secretion in lean individuals. Therefore, we hypothesized that the glucagon-mediated suppression of VLDL-TG secretion is impaired in MAFLD, with greater impairment in individuals with steatohepatitis (MASH) than individuals with simple steatosis (MAFL) . Methods: 28 participants were included in the study (seven overweight control subjects (CON) , patients with MAFL, and with MASH) . We performed a somatostatin-clamp with replacement doses of growth hormone, insulin (0.2 mU/kg/min) and glucagon to suppress endogenous hormone production. Participants were studied during low-dose glucagon infusion (0.65 ng/kg/min, t=0─270 min, LowG) followed by a high-dose glucagon infusion (1.5 ng/kg/min, t=270─450 min, HighG) . We used 14C-labeled VLDL-TG and 3H-labeled glucose tracers to evaluate VLDL-TG secretion and endogenous glucose production (EGP) . Results: HighG suppressed VLDL-TG secretion compared to LowG in all groups, but with a greater reduction in VLDL-TG secretion in CON than in the MAFLD groups (CON 36% (±SD 19%) ; MAFL 10% (±SD 8%) ; MASH 13% (±SD 16%) , p&amp;lt;0.01) . Thus, the suppression was similarly mitigated in both MAFLD groups. This led to insignificant reductions in plasma VLDL-TG, TG and VLDL-TG oxidation rates in the CON group, in contrast to stable or increasing values in the MAFLD groups (CON vs. MAFLD delta-values, p&amp;lt;0.01, p=0.02 and p=0.04) , respectively) . EGP was similar in all groups throughout the LowG period and rose similarly when increasing glucagon infusion rate. Conclusions: Patients with MAFLD, MAFL as well as MASH, have an impaired glucagon-mediated suppression of VLDL-TG secretion which is a probable contributing factor to the dyslipidemia and the increased cardiovascular risk observed in individuals with MAFLD. NCT04042142 Disclosure S.Heebøll: None. J.R.Risikesan: None. H.Gronbaek: Other Relationship; ARLA, Research Support; AbbVie Inc., Intercept Pharmaceuticals, Inc., Speaker's Bureau; AstraZeneca, Novartis AG. E.Søndergaard: None. S.Nielsen: None. Funding Independent Research Fund Denmark (9039-00177B and -00278B) and Aase og Ejnar Danielsens Fond

Fireside Chat on “Optimal Thyroid Hormone Replacement Dose in Immune Checkpoint Inhibitor-Associated Hypothyroidism Is Distinct from Hashimoto's Thyroiditis”

Fireside Chat on “Optimal Thyroid Hormone Replacement Dose in Immune Checkpoint Inhibitor-Associated Hypothyroidism Is Distinct from Hashimoto's Thyroiditis”

Derivation of thyroid progenitors from human induced pluripotent stem cells

Abstract Objective Despite the availability of synthetic thyroid hormone for therapeutic use, a significant number of patients with hypothyroidism do not feel well on replacement doses of thyroid hormones suggesting that better-individualized therapy is needed. For this reason, hypothyroidism resulting from congenital lack of functional thyrocytes, surgical tissue removal, or gland ablation, represents a particularly attractive endocrine disease target that may be conceivably cured by transplantation of long-lived functional thyroid progenitors or mature follicular epithelial cells. Methods To generate thyroid follicular progenitors from human induced pluripotent stem cells (hiPSCs), we sought to develop a directed differentiation approach by activating or inhibiting endogenous developmental signaling pathways previously identified in the mouse. To facilitate tracking and purification of candidate human thyroid progenitors, we engineered a hiPSC-line carrying a tdTomato reporter targeted to the PAX8 locus and a GFP reporter targeted to the NKX2-1 locus. Results We adapted our published in vitro differentiation protocol previously used to differentiate mouse PSCs into thyroid progenitors and observed tdTomato/GFP co-expressing cells first emerging from our hiPSC line by day 12 of culture and persisting for at least 2 months of further culture in thyroid maturation media, supplemented with TSH. Thus, we profiled all cells deriving from hiPSCs by single-cell RNA sequencing &amp;gt;6,000 cells captured on days 12 and 29 of in vitro differentiation. At day 12, tdTomato/GFP co-expression was observed in 12% of all cells and these cells appeared to be early thyroid follicular progenitors as they uniquely co-expressed the tetrad of thyroid lineage selective transcription factors, NKX2-1, PAX8, FOXE1, and HHEX. By day 29 tdTomato+/GFP+ cells represented 69% of all cells and had upregulated TG, TSHR, NIS and TPO expression in addition to the previously described four thyroid lineage markers, suggesting time-dependent differentiation and maturation of thyroid follicular epithelial cells. Conclusion Thus, we have employed a novel hiPSC line to optimize a protocol able to generate human thyroid progenitors and mature follicular epithelial cells, representing a purifiable source of human thyroid lineage cells whose functional and thyroid reconstituting potential can be tested in vivo in animal models of hypothyroidism.

An altered state of consciousness while using anticoagulants and the incidental discovery of a pituitary lesion: considering pituitary apoplexy.

SummaryPituitary apoplexy (PA) is a medical emergency with complex diagnosis and management. In this study, we describe a case of PA in a 63-year-old male treated with oral anticoagulant therapy for atrial fibrillation. In the patient, PA manifested itself with asthenia and severe headache not responsive to common analgesics. Despite the finding of a pituitary mass through CT, and in anticipation of the endocrinological evaluation and pituitary MRI, the patient’s clinical condition worsened with an escalation of headache and asthenia associated with deterioration of the visual field and impairment of consciousness level. The emergency assessments revealed an adrenal failure, whereas MRI showed a haemorrhagic pituitary macroadenoma with compression of the optic chiasm. Intravenous fluids repletion and high-dose hydrocortisone were started with a rapid improvement of the patient’s health and visual field abnormalities. Hydrocortisone was gradually reduced to a replacement dose. During the follow-up, panhypopituitarism was documented, and replacement therapies with l-thyroxine and testosterone were introduced. Three months later, a pituitary MRI showed a 50% reduction in the pituitary adenoma volume.Learning pointsPituitary apoplexy (PA) is a medical emergency that can result in haemodynamic instability and abnormalities in the level of consciousness.The management of PA requires a multidisciplinary team that includes endocrinologists, ophthalmologists, neuro-radiologists, and neuro-surgeons.Pituitary MRI with gadolinium is the diagnostic gold standard for PA.PA therapy aims to improve general conditions and treat compression symptoms, especially visual field abnormalities.Adrenocorticotrophic hormone deficiency is a common and severe complication of PA. Thus, all patients with PA must be promptly treated with injective synthetic glucocorticoids (e.g. hydrocortisone 100 mg) and i.v. saline.PA must be taken into consideration in case of sudden headache in patients with a pituitary macroadenoma, especially if other risk factors are recognized.