bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dextroamphetamine Treatment for Children With Hypothalamic Obesity
Authors: van Schaik Jiska , Welling Mila Sofie , De Groot Corjan , Abawi Ozair , Burghard M , Kleinendorst Lotte , van der Voorn Bibian , van Haelst Mieke M , Ophuis S B J Oude , Kamp Gerdien , Rotteveel Joost , van Schouten-Meeteren A Y N , van den Akker Erica L T , van Santen Hanneke Margo 
Published: May 2021

Abstract
Introduction: Hypothalamic obesity (HO) in children can be either genetic or acquired, as a result of a suprasellar tumor or its treatment. HO, resulting from hyperphagia and/or a decreased resting energy expenditure (REE), may have devastating consequences for the child and its family. Currently, no effective drug treatment is yet available for HO. Amphetamines – commonly used in children with attention-deficit/hyperactivity disorder – are known for their stimulant effect on REE and inhibitory effect on appetite. We here present our experiences of dextroamphetamine treatment in children and adolescents with acquired or genetic HO. Methods: A retrospective cohort evaluation was performed of patients (n = 18) treated with dextroamphetamine at 2 endocrine pediatric clinics. Off-label use of dextroamphetamine was initiated in patients with progressive therapy resistant acquired HO (n = 13) and in patients with genetic obesity (n = 5). Initial treatment dosing was once or twice daily 5mg. This dose was weekly increased with 5 mg/day depending on the patient’ wellbeing and the presence of side effects, to a maximum of 0.5 mg/kg/day. Anthropometrics and REE at start and during follow-up, changes in (hyperphagic) behavior, and side effects were assessed.
Results: At start of treatment, mean age was 12.8 years ± 3.4 [range 7.1–17.9] and mean REE was 69.5%± 18.5 (n = 15). At follow-up, mean treatment duration was 18.3 months ± 14.7. Ten out of eighteen children (55.6%) showed clinically relevant weight loss. In 10/13 patients with acquired HO, weight loss was observed (mean ΔBMI SDS -1.09 ± 1.00), in one patient BMI stabilization (ΔBMI SDS +0.03), and in two patients an increase in BMI SDS was seen (mean ΔBMI SDS +0.32 ± 0.05). Of nine children with acquired HO and measurement of REE before and during treatment, a mean REE increase of +15.3% ± 10.5 was observed. In three out of five patients with genetic obesity, initially weight loss was observed resulting in BMI stabilization at end of follow-up due to weight regain (mean ΔBMI SDS -0.08 ± 0.19). In these patients, no difference in REE before and during treatment was observed. In two patients an increase in BMI SDS was seen (mean ΔBMI SDS +0.29 ± 0.25). However, one patient discontinued treatment after one month, due to hypertension. Thirteen out of 18 children (72.2%) reported improvement of either their hyperphagia, energy level, and/or behavior. No serious side effects were reported.
Conclusion: In children and adolescents with acquired HO, treatment with dextroamphetamine may significantly lower BMI, reduce hyperphagia and improve activity level. In genetic HO, these effects were less pronounced. Future studies in a larger cohort and with randomized controlled designs are needed to support these results.
Dehydroepiandrosterone Sulfate, Cortisol and Adrenocorticotropic Hormone Levels in Drug-Naive, First Episode, Male and Female Patients With Psychosis
Authors: Christou Maria , Karampas Andreas , Georgiou Georgios , Plakoutsis Marios , Brikos Spyridon , Petrikis Petros , Tigas Stelios 
Published: May 2021

Abstract
Introduction: Impaired response to stress and a pathological activation of the hypothalamic-pituitary-adrenal axis have been implicated in the pathophysiology of schizophrenia. We aimed to measure serum dehydroepiandrosterone sulfate (DHEA-S), cortisol and adrenocorticotropic hormone (ACTH) levels in drug-naïve, first episode patients with psychosis followed-up in a Greek tertiary center. Methods: Data were included from drug-naïve, first episode patients with psychosis and controls matched for age and sex. Serum DHEA-S, cortisol and ACTH levels were recorded. Results are reported as mean (standard deviation, range). Paired t-test or Wilcoxon signed rank test were performed for group comparisons. The level of significance was set at p less than 0.05. Statistical analysis was performed with Stata 15.1. Results: Data were included for 110 subjects (70 men, 40 women); 55 patients and 55 controls. Mean age was 31.3 years (8.7, 18.0-48.0) in patients and 31.4 years (8.9, 17.0-49.0) in controls. Serum DHEA-S was higher in patients [306.5 μg/dl (165.4, 70.0-790.0)] compared to controls [240.1 μg/dl (113.5, 46.0-597.0)] (p=0.011). Serum ACTH was similar between patients and controls [28.5 pg/ml (15.7, 6.2-73.9) versus 26.5 pg/ml (15.3, 7.0-70.5), p=0.636]. Serum cortisol levels and cortisol/DHEA-S ratio were statistically lower in patients [12.6 μg/dl (4.5, 3.5-24.5) and 5.3 (3.6, 1.3-19.5), respectively] compared to controls [15.5 μg/dl (4.9, 4.2-30.1) and 8.0 (4.7, 1.1-25.5), respectively] (p=0.007 and 0.001, respectively). Sub-analysis, revealed that in men, serum DHEA-S was similar between patients and controls [303.7 μg/dl (149.0, 85.0-744.0) versus 275.0 μg/dl (117.4, 89.0-597.0), respectively, p=0.271) whereas in women serum DHEA-S was higher in patients compared to controls [311.4 μg/dl (194.8, 70.0-790.0) versus 179.2 μg/dl (75.9, 46.0-314.0), respectively, p=0.005]. Serum cortisol and ACTH levels were not different in the above subgroups except serum cortisol in men which was lower in patients compared to controls [12.8 μg/dl (4.4, 3.5-21.6) and 15.9 μg/dl (5.4, 4.2-30.1), respectively, p=0.027]. Conclusions: Serum DHEA-S levels were higher in drug-naïve, first episode female patients, with psychosis compared to controls. DHEA-S levels in male patients and controls were similar.
Diagnostic Threshold for Postoperative Secondary Adrenal Insufficiency After Transsphenoidal Resection of Pituitary Adenomas
Authors: German Massiell , Sharma Anu 
Published: May 2021

Abstract
Transsphenoidal surgery (TSS) is the first line treatment for pituitary adenomas. A well-known complication of TSS is secondary adrenal insufficiency with a reported risk of 4-9% after TSS. Currently, glucocorticoid replacement is recommended if postoperative AM cortisol is &lt; 3 ug/dL. Postoperative adrenal insufficiency is ruled out if AM cortisol is &gt; 15 ug/dL. However, further evaluation of the adrenal axis with ACTH stimulation test is recommended for intermediate cortisol levels 3-15 ug/dL. Other studies have proposed postoperative cortisol threshold of &lt; 4-14 ug/dL for glucocorticoid replacement. Retrospective analysis of all patients undergoing TSS at a tertiary center from January 2013 through April 2016 was performed. ACTH producing adenomas (Cushing’s disease) were excluded. Of the 97 patients included, 17.5% (n=17) had secondary adrenal insufficiency requiring glucocorticoid replacement at 1 year post operatively. Mean age at presentation was 56 ± 16 years and 52% were female. Mean adenoma size was 25.3 ± 11.3 mm. Factors associated with adrenal insufficiency at 1 year post operatively were preoperative secondary adrenal insufficiency (AM cortisol 4.5 ± 1.9 vs 11.0 ± 1.0 µg/dL; p = 0.03), and preoperative adenoma contact with optic chiasm (15.7% vs 2.1%; p = 0.01). Day 1-7 postoperative cortisol was lower in the group with adrenal insufficiency at 1 year (5.6 µg/dL (IQR 1.9-11.5) vs 19.8 µg/dL (IQR 12.75-43.2); p=0.02). Age, gender, adenoma size, and cavernous sinus involvement were not associated with adrenal insufficiency at 1 year. A day 1-7 postoperative cortisol concentration of ≥8.0 µg/dL had a sensitivity of 75% and specificity of 92% in predicting adrenal insufficiency at 1 year. In patients with secondary adrenal insufficiency at 1 year (n=17), there was a higher frequency of concomitant loss of other pituitary hormone function at 1 year: secondary hypothyroidism 82% (n=14), secondary hypogonadism 70.6% (n=12) and diabetes insipidus 17.7% (n=3). A lower postoperative cortisol threshold of 8 µg/dL can be adopted for glucocorticoid replacement on discharge after TSS.
Long-Term Corticotroph Function Following Cure of Cushing’s Syndrome
Authors: Schernthaner-Reiter Marie Helene , Wolf Peter , Micko Alexander , Bögl Magda , Beiglböck Ms, Hannes , Scheuba Christian , Riss Philipp , Wolfsberger Stefan , Kautzky-Willer Alexandra , Luger Anton , Vila Greisa 
Published: May 2021

Abstract
Introduction: Hyper- and hypofunction of the hypothalamic-pituitary-adrenal (HPA) axis in Cushing’s syndrome (CS) and Addison’s disease (AD) is associated with disturbances of classical feedback mechanisms. Time to recovery of adrenal function after CS remission depends on the etiology of CS and is longest after adrenal CS. To date there are no data on the recovery of corticotroph function following CS remission, and the synacthen test is recommended for testing adrenal function in patients with hypopituitarism. Aim Here we aim to test corticotroph function after long-term cure of Cushing’s syndrome following bilateral adrenalectomy (BADx), compared to patients with primary glucocorticoid deficiency due the presence of 21-hydroxylase antibodies or adrenoleucodystrophy, a pathophysiological model of glucocorticoid and mineralocorticoid deficiency. Methods: We retrospectively evaluated data from patients with CS and AD attending our endocrine department between 2000 and 2020, using the following inclusion criteria: BADx performed for pituitary/ectopic/adrenal or occult CS or primary adrenal insufficiency confirmed either by the presence of 21-hydroxylase antibodies or genetically in adrenoleucodystrophy. Results: Full data were available for 93 patients: 43 patients with BADx due to CS (18 patients with pituitary CS, 14 patients with adrenal CS and 11 patients with ectopic/occult CS, F:M 29:14, mean age at BADx 45.4 years age range 13-74 years) and 50 patients with AD (47 cases with positive 21-hydroxylase antibodies, 3 cases with adrenoleucodystrophy, F:M ratio 27:23, mean age at diagnosis 35 years, age range 6-57 years). The observation period was 537.5 patient-years after BADx (mean 12.5 years, range 1-38 years) and 647 patient-years following AD diagnosis (mean 14.2 years, range 1-46 years). At the last visit, there were no differences between the hormone substitution regimes between the groups. ACTH concentrations during the whole observation period and also at the last visit were lowest in patients with adrenal CS (56.5 pg/ml) when compared to patients with AD (487 pg/ml, p&lt;0.001), or with patients with pituitary CS (377.5 pg/mL, p=0.011). ACTH values in patients with AD in long-term follow-up were significantly higher when compared to all patients with CS (141 pg/mL, p&lt;0.001). Conclusion: These data highlight a long-term defective corticotroph function in patients with CS following BADx. Low ACTH concentrations long term after BADx for adrenal CS corroborate that corticotroph function fails to recover after CS cure. In the light of these findings, the utility of the synacthen test for excluding secondary/tertiary adrenal insufficiency following CS remission is disputable and remains to be evaluated in future studies dedicated to CS cohorts.
The Clinical Significance and Utility of Routine Screening for Macroprolactin in Patients With Hyperprolactinemia
Authors: Zeng Wanling , James King Thomas Frederick , Aw Tar Choon , Shern Lau Michael Chin 
Published: May 2021

Abstract
Background: Macroprolactin is a complex of monomeric prolactin (PRL) molecules with immunoglobulin G (IgG) that can result in the elevation of serum prolactin level. Macroprolactin is biologically less active and failure to screen for macroprolactin may lead to unnecessary investigations and treatments in patients with hyperprolactinaemia. Aim: We sought to evaluate the clinical significance and clinical utility of routine screening of macroprolactin in patients with hyperprolactinemia. Methods: We analysed 141 patients from a retrospective database of patients with elevated serum prolactin in Changi General Hospital from Jan 2017 to Dec 2019 with routine screening of macroprolactin with polyethylene glycol (PEG) precipitation using Abbott Architect Prolactin assay. Clinical, biochemical, radiological data and medication usage were extracted from electronic medical records. Macroprolactinaemia was defined as a PRL recovery of &lt; 60%. Approval was obtained from the local research ethics committee. Results: Thirty-six (26%) patients had macroprolactinaemia with a male predominance (72%). There were no significant differences in the presence of symptoms, the percentages of medication-induced hyperprolactinemia, and magnetic resonance imaging (MRI) pituitary scans done between patients with macroprolactinaemia and those with truly elevated serum prolactin. As such clinical features might not be useful to differentiate patients with macroprolactinaemia. Eight MRI pituitary scans were performed in patients with macroprolactinaemia and pituitary abnormalities were detected in 4 of the patients which are likely non-functioning pituitary lesions. As such, not only were unnecessary scans done but it also led to a cascade of further investigations. Eight patients had simultaneous macroprolactinaemia and elevated bioactive serum prolactin, as such post-PEG prolactin level with corresponding reference ranges rather than the percentage recovery should be use as the threshold for defining macroprolactinaemia to avoid misdiagnosis. Conclusion: Macroprolactinaemia is common and routine screening may avert unnecessary investigations. Post-PEG prolactin level with corresponding reference ranges should be used as diagnostic threshold.
Trauma Symptomatology in Patients Successfully Treated for Pituitary Adenoma
Authors: Kovler Jessica Diller , Prevedello Daniel 
Published: May 2021

Abstract
The emotional symptomatology accompanying pituitary adenomas has long been recognized, though research has been scant, varied, and more focused on studies related to quality of life. The present study sought to better codify the psychological presentation of pituitary adenoma patients through the lens of trauma and PTSD symptomatology. 128 patients who were successfully treated for pituitary adenoma were recruited from the Wexner School of Medicine at Ohio State University. Ranging in age from 23 to 74, the participants’ mental health functioning was assessed by the Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5), the Brief Symptom Inventory (BSI), and the Dissociative Experiences Scale (DES). The findings of this pilot study showed that the rate of traumatization (PTSD) for pituitary adenoma patients was significantly higher than that of the general population. With regard to comorbid trauma-related mental health impairment, our results demonstrated that when moderated by sex, pituitary adenoma patients had significantly higher psychopathology than the non-clinical population. Replicating the existing research, there was a significant positive correlation between trauma symptoms and trauma-related psychopathology in patients successfully treated for pituitary adenoma. Overall, the results of this study demonstrate the traumatic nature of this disease and the need for applied clinical intervention. Further research is needed to replicate these findings, in light of potential selection bias and sample size.
Validity of Different Copeptin Assays in the Differential Diagnosis of the Polyuria-Polydipsia Syndrome
Authors: Sailer Clara Odilia , Refardt Julie , Blum Claudine Angela , Schnyder Ingeborg , Molina-Tijeras Jose Alberto , Fenske Wiebke Kristin , Christ-Crain Mirjam 
Published: May 2021

Abstract
Background: Copeptin is used in the differential diagnosis of diabetes insipidus. Different copeptin immunoassays exist but inter-assay comparability is unclear. The aim of this study was to correlate three commercially available copeptin assays and their diagnostic accuracy in the differential diagnosis of the polyuria-polydipsia-syndrome.
Methods: Analyzed data include three different studies: repeated copeptin measures of 8 healthy volunteers undergoing osmotic stimulation; copeptin measures of 40 patients hospitalized with pneumonia; osmotically stimulated copeptin measures of 40 patients with polyuria-polydipsia-syndrome. Copeptin was measured using the automated B.R.A.H.M.S. KRYPTOR, the manual B.R.A.H.M.S. LIA and the manual Cloud Clone ELISA assay. Primary outcome was the diagnostic accuracy in the polyuria-polydipsia-syndrome.
Results: In total, 150 copeptin measurements were analyzed. In healthy volunteers, there was a moderate correlation for the KRYPTOR and LIA (interrater correlation coefficient (ICC) 0.74; 95%-CI 0.07-0.91), and a poor correlation for the KRYPTOR and ELISA (ICC 0.07; 95%-CI -0.06-0.29), as for the LIA and ELISA (ICC 0.04; 95%-CI -0.04-0.17). The KRYPTOR had the highest diagnostic accuracy (98% (95%-CI: 83-100)), comparable to the LIA (88% (95%-CI: 74-100)), while the ELISA had a poor diagnostic accuracy (55% (95%-CI: 34-68)) in the differential diagnosis of the polyuria-polydipsia-syndrome.
Conclusion: The KRYPTOR and LIA yield comparable copeptin levels and a high diagnostic accuracy, while the ELISA correlates poorly with the other two assays and shows a poor diagnostic accuracy between polyuria-polydipsia patients. Redefining cut-off levels for copeptin assays other than KRYPTOR and LIA must take place before their use in the differential diagnosis of diabetes insipidus.
Dose Escalating and Bioavailability Phase 1 Studies Assessing Safety and Tolerability and Pharmacokinetics of Tildacerfont, a Small-Molecule CRF1 Receptor Antagonist
Authors: Barnes Chris , Offman Elliot , Darago Nora , Moriarty David 
Published: May 2021

Abstract
Background: Tildacerfont (SPR001; LY2371712), a second generation, potent, selective, nonsteroidal, oral small-molecule antagonist of corticotropin-releasing factor type-1 (CRF1) receptors in the pituitary gland, is in late stage development as a potential treatment for adults with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD). We report the results of 3 randomized Phase 1 studies of safety, tolerability, and pharmacokinetics (PK) of tildacerfont in healthy adults and compare the relative bioavailability of 2 tildacerfont formulations. Methods: Two Phase 1 studies were double-blind, placebo-controlled and evaluated escalating doses (2–800 mg QD) as single doses (SAD; n=18) and 50-200mg as multiple doses (MAD; n=47). The studies also included pilot food effect and drug-drug interaction sub studies, respectively. A randomized, balanced, open-label, crossover study (n=42) examined the relative bioavailability (BA) of single oral doses of 2 tildacerfont formulations, 200 mg powder-in-capsule (PIC) compared to 200 mg low-drug load tablet. Results: In the SAD and MAD studies, the most common, non-procedural adverse events were headache and cough. In the BA study, the most common, non-procedural adverse events were constipation and headache. There were no study drug-related serious adverse events (SAEs) in any study. In the SAD and MAD (PIC formulation), tildacerfont concentrations declined in a multi-exponential manner with Cmax occurring moderately late, ~5 hours post dose, and a high degree of variability was observed in AUC and Cmax (CV range: 54–122%). A food effect was observed in the SAD. Fourteen days of dosing achieved near steady state exposure with an AUC accumulation ratio of 2.51 to 3.65 in the MAD study. Midazolam, a sensitive probe substrate for CYP3A4 exhibited ~2-fold increase in AUC and a 1.8 increase in Cmax when co-administered with tildacerfont suggesting moderate CYP3A4 inhibition. The tablet formulation reduced the variability (AUC and Cmax CV range: 69–72%) compared to the PIC formulation resulting in a more predictable pharmacokinetic profile. The half-life of the tablet was ~60 hrs. Bioequivalence in AUC was established with the tablet and PIC formulations (fed state) with Cmax ~20% higher for tablet than PIC due to a reduction in and more consistent Tmax, median [range], from 6 [4.5, 24] hours to 3 [2, 6] hours.
Conclusions: These results suggest that tildacerfont is safe and generally well-tolerated in healthy adults and suitable for further study in patients with CAH. The tablet formulation provided a more consistent pharmacokinetic profile with reduced variability in all parameters and is being evaluated in late stage studies of tildacerfont in adult CAH.
The Effect of Cardiorespiratory Fitness and Insulin Resistance on Bone Health in Hispanic Children
Authors: Shawar Reem S , Puyau Maurice , Shypailo Roman , Musaad Salma , Bacha Fida F 
Published: May 2021

Abstract
Obesity appears to have a negative impact on pediatric bone health, and insulin resistance may mediate this relationship. It is unclear if cardiorespiratory fitness (CRF) has a protective effect on bone in obese children. We tested the hypothesis that CRF attenuates the negative effect of obesity and insulin resistance on skeletal health in a large cohort of Hispanic youth.
We studied 413 (193 males and 220 females) children and adolescents from the Viva la Familia Study. They were all pubertal; mean age (SD) 13.4 ± 2.3 years; 27% were normal weight (NW), 19% overweight (OW) and 54% obese (OB). They underwent measurement of body composition, total body bone mineral content (BMC) and density (BMD) by DXA scan; VO2peak using the ramp protocol on a treadmill for CRF; fasting glucose and insulin. The homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. BMC increased from NW to OW to OB (mean 1.35 ± 0.4, 1.41 ± 0.4, and 1.49 ± 0.4 kg, respectively, p=.005). Peak VO2 decreased from NW to OW to OB (41.3 ± 9.7, 35.5 ± 7.7, 28.9. ± 5.5 mL/kg per min, respectively, p &lt;.001). After adjusting for sex, age and lean body mass, BMC was inversely related to fat mass (r = -0.34, p &lt;.001) and HOMA-IR (r = -0.29, p &lt;.001). Similar relationships were found for BMD. In a regression model with BMC as the dependent variable, lean body mass (standardized coefficient (β)=0.95, p &lt;.001) was positively and fat mass (β=-0.18, p &lt;0.001) negatively associated with BMC (model R2=0.88, p&lt;.001). HOMA-IR (β=-0.07, p =0.001) and VO2peak (β=0.09, p =0.003) had significant and opposite associations with BMC (model p&lt;.001) but fat mass was no longer a significant contributor. With BMD as the dependent variable, lean body mass (β=0.82, p &lt;.001), HOMA-IR (β=-0.06, p =0.04) and peak VO2 (β=0.17, p &lt;.001), but not fat mass, contributed to the variance in BMD (R2=0.79, p&lt;.001).
In conclusion, lean body mass is the major determinant of BMC and BMD in Hispanic youth. Adiposity associated insulin resistance has a negative effect on BMC and BMD. CRF contributes positively to the variance in BMC and BMD. This suggests that CRF and higher lean mass attenuate the adverse effects of insulin resistance on bone health in children.