bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phase 3 Large International Noninferiority Trial (MPOWERED): Assessing Maintenance of Response to Oral Octreotide Capsules in Comparison to Injectable Somatostatin Receptor Ligands
Authors: Fleseriu Maria , Dreval Alexander V , Pokramovich Yulia , Bondar Irina , Isaeva Elena , Molitch Mark E , Macut Djuro P , Leonova Nina , Raverot Gerald , Grineva Elena , Poteshkin Yury E , Gilgun-Sherki Yossi , Ludlam William H , Patou Gary , Haviv Asi , Gordon Murray B , Biermasz Nienke , Melmed Shlomo K , Strasburger Christian J 
Published: May 2021

Abstract
Background: MPOWERED, a large phase 3 trial, assessed maintenance of response to oral octreotide capsules (OOC; MYCAPSSA®) compared to injectable somatostatin receptor ligands (iSRLs) in patients with acromegaly who responded to OOC and iSRLs (octreotide or lanreotide). OOC were recently approved in the US for patients with acromegaly who responded to and tolerated iSRLs.
Methods: Eligibility criteria included age 18-75 years at screening, acromegaly diagnosis, disease evidence, biochemical control (insulin-like growth factor I [IGF-I] &lt;1.3 × upper limit of normal [ULN] and mean integrated growth hormone [GH] &lt;2.5 ng/mL) at screening, and ≥6 months’ iSRL treatment. Effective OOC dose was determined in a 26-week Run-in phase. Eligible patients (IGF-I &lt;1.3 × ULN and mean integrated GH &lt;2.5 ng/mL, week 24) were randomized to a 36-week controlled treatment phase (RCT), receiving OOC or iSRLs starting at week 26. The primary end point was a noninferiority assessment of proportion of patients biochemically controlled in the RCT (IGF-I &lt;1.3 × ULN using time-weighted average). Other end points included nonresponse imputation of the primary end point, landmark analysis using proportion of responders based on average of last 2 IGF-I values at end of RCT, and change from baseline RCT (week 26) IGF-I and GH levels.
Results: Of 146 enrolled patients, 92 entered the RCT (OOC, n=55; iSRLs, n=37). Both arms were well balanced for age, sex, and acromegaly duration. OOC demonstrated noninferiority to iSRLs in maintaining biochemical response, with 91% (CI, 80%-97%) of OOC and 100% (CI, 91%-100%) of iSRL groups maintaining control during the RCT. Of those responding at end of Run-in, 96% of patients on OOC maintained response during RCT. Using nonresponse imputation, 89% of OOC and 95% of iSRL groups were biochemically controlled in RCT. Landmark analysis of those respnding at end of Run-in showed that 94% of patients in each group maintained response at RCT end. In both groups, IGF-I levels were stable in the RCT, average IGF-I at baseline and RCT end being 0.9 × ULN (OOC) and 0.8 × ULN (iSRL). Mean change in GH from RCT start to RCT end was -0.03 ng/mL (OOC) and +0.29 ng/mL (iSRL). Safety data were mostly similar between groups; the OOC group did not experience injection site reactions.
Conclusion: In this noninferiority trial in patients with acromegaly, OOC demonstrated maintenance of biochemical response compared to iSRLs. Results support the efficacy of OOC as a possible iSRL alternative.
Addition of Cabergoline to Oral Octreotide Capsules May Improve Biochemical Control in Patients With Acromegaly Who Are Inadequately Controlled With Monotherapy
Authors: Fleseriu Maria , Dreval Akexander V , Pokramovich Yulia , Bondar Irina , Isaeva Elena , Molitch Mark E , Macut Djuro P , Leonova Nina , Raverot Gerald , Gilgun-Sherki Yossi , Ludlam William H , Patou Gary , Haviv Asi , Gordon Murray B , Verbovoy Andrey , Dogadin Sergey A , Biermasz Nienke , Strasburger Christian J , Melmed Shlomo 
Published: May 2021

Abstract
Background: Oral octreotide capsules (OOC; MYCAPSSA®) are approved in the US for individuals with acromegaly who responded to and tolerated treatment with injectable somatostatin receptor ligands (iSRLs). Add-on cabergoline therapy has shown effectiveness in patients previously inadequately controlled with iSRLS.1 The phase 3 MPOWERED trial assessed maintenance of response with OOC compared to iSRLs. Patients receiving OOC and ineligible for randomized controlled treatment (RCT) phase were eligible for a sub-study evaluating combination therapy with cabergoline, a dopamine agonist.
Methods: Patients who fail to respond to 80 mg/d OOC for ≥2 weeks during the 26-week Run-in phase, or ineligible to enter the RCT on 80 mg/d OOC, due to inadequate biochemical control (insulin-like growth factor I [IGF-I] ≥1.3 × upper limit of normal [ULN] to &lt;2 × ULN or IGF-I &lt;1.3 × ULN and mean integrated growth hormone [GH] ≥2.5 ng/mL) were eligible for sub-study combination OOC 80 mg/d and cabergoline ≤3.5 mg/wk (fixed algorithm) for 36 weeks. End points included categorical changes in IGF-I and mean GH levels at sub-study end and adverse event (AE) incidence and severity. Echocardiogram was performed at sub-study start and every 12 weeks after.
Results: Of 146 patients enrolled in MPOWERED, 14 entered the combination sub-study, 9 having IGF-I ≥1.3 × ULN at sub-study start. Final cabergoline doses were 1 (n=5), 2 (n=3), 3 (n=1), and 3.5 mg (n=5) with 25.4-week (SD, 14.1) mean treatment duration. Week 36 IGF-I improved in most patients (n=12; 85.7%). Of 9 patients with IGF-I ≥1.3 × ULN at sub-study start, 5 (55.6%; 95% CI, 21.2%-86.3%) exhibited IGF-I decreased to predefined responder range (&lt;1.3 × ULN) by week 36. AE incidence and nature with combined treatment were similar to known octreotide safety profile and acromegaly disease burden. There were no serious AEs or AEs leading to discontinuation of either sub-study drug.
Conclusion: We have shown for the first time the benefit of an all-oral combination treatment for acromegaly and avoidance of injection-related burdens. Addition of cabergoline to OOC yielded biochemical control improvement (IGF-I reduction) in patients inadequately controlled with OOC monotherapy. As both combination and OOC monotherapy safety profiles were similar, adjunctive cabergoline may be helpful in patients with acromegaly who do not achieve adequate biochemical control on OOC alone.
1Giustina A, et al. Nat Rev Endocrinol. 2014;10(4):243-248.
Obesity and Covid-19: A Major Mortality Risk in Patients Hospitalized With Covid-19
Authors: Rodriguez Giovanna , Kim Eunice , Cabezas Fausto , Dave Paulomi , Li Jefferson , Kirupakaran Johnathan , Caputo Michael , Idowu Abidemi , Deane Kitson , Tapia Nilson , Korson Michelle , Nunez Dennis , Okaikoi Michael , Rodriguez Paula , Valentine Dhiviyan , Yau Alice , Zheng Beishi , Aye Thida , Jimenez Mabel , Elayaperumal Pramma , Afzal Arslan , Daruwala Orpah Lamuel , Williams Belinda , Karnik Suruchi , Filias Felix , Inoue Taiga , Asif Haris , Singh Gurbaj , Kubbar Alaa , Iwuala Sandra , Zeyneloglu Nejat , Bahtiyar Mert , Bahtiyar Gul 
Published: May 2021

Abstract
The coronavirus disease 2019 COVID-19 pandemic is a major public health crisis. Obesity has emerged as a significant comorbidity for COVID-19 severity. To study the association of both pandemics, we conducted an observational, retrospective cohort study involving 521 patients admitted with Covid-19 to an inner city, community hospital in Brooklyn, NY in the period March 20 to May 2, 2020. Of the cohort, 57.6% was men, mean age was 61.6±17.2 years, and mean BMI was 29.0 ± 8.2 kg /m2. 11% had BMI &gt; 40 kg/m2. 53.9% was Hispanic, 33.3% was African American, 7.1% was White, with a predominance of type 2 diabetes (99%). Diabetes, hypertension, coronary artery disease and chronic kidney disease were found in 45%, 41.5%, 15%, and 20.1% cases, respectively. Mean HbA1c was 5.8%± 1.1 in patients with no history of diabetes, 3% presented with diabetic ketoacidosis, mortality rate was 30.6%. Non-survivors were significantly older (median age 68 vs 56, p &lt; 0.03) and had higher rate of microvascular and macrovascular diseases. In patients with diabetes, mortality rate was 40.1%. HbA1c was similar between survivors and non-survivors. Older age and hyperglycemia on admission were the risk factors for mortality. Only 30% of the cohort had normal weight (BMI&lt;25), 30% was overweight and 40% was obese. In univariate analysis, the characteristics at admission significantly associated with mortality were age, BMI, hyperglycemia, diabetes and DKA in patients with or without diabetes. In age- and sex-adjusted multivariable analysis only BMI 30–39 kg/m2 (OR = 1.63; 95% CI, 1.10, 2.43; p = 0.015), BMI &gt;40 kg/m2 (OR = 2.05; 95% CI, 1.22, 3.44; p = 0.007) and DKA (OR = 1.77; 95% CI, 1.18, 2.64; p = 0.005) remained positively associated with higher mortality. In summary, BMI, and DKA but not diabetes, were positively and independently associated with mortality in patients hospitalized with Covid-19. Reference: (1) Popkin et al., Obesity Reviews 2020 August;21(11):e13128. (2) Cariou et al., Diabetologia 2020 May;63(8): 1500–1515.
Medical Treatment Achieves Similar Quality of Life to Surgically Treated Acromegaly Patients in Remission: The QuaLAT Study
Authors: Arshad Muhammad Fahad , Ogunleye Oluwafunto , Ross Richard John M , Debono Miguel 
Published: May 2021

Abstract
Background: Quality of life (QOL) in acromegaly has been a subject of interest in several published studies; however, there is no consensus on how QOL in patients who require medical treatment after surgery compares with those who achieve remission by surgery only.
Aim: Quality of life after acromegaly treatment (QuaLAT) is a case-control questionnaire-based study with the aim to compare the QOL in those who were treated with surgery only with those who required medical treatment after surgery at a single tertiary centre for acromegaly.
Methods: Patients with acromegaly attending endocrinology clinics were identified via our database. These were matched on the duration of disease into those who underwent surgery and went into disease remission biochemically (Group 1), and those who did not achieve biochemical remission after surgery and therefore required further medical treatment to control the disease (Group 2). Participants were then asked to fill three questionnaires to measure their QOL; Acromegaly Quality of Life Questionnaire (ACROQOL), and two generic questionnaires; 36-Item Short Form Survey (SF36) v2, and Fatigue Severity Scale (FSS).
Results: 20 patients from each group participated in the study. The mean±SD duration of acromegaly (years) was similar in the two groups (9.8±6.9 vs 9.7±6.9 p=0.653). The majority of patients in the medical group were on somatostatin analogues, either alone or in combination (n=14), with four and two patients on cabergoline and pegvisomant alone respectively. There was no difference in QOL scores between groups 1 & 2, as measured by ACROQOL (mean score±SD 54.4±24.8 vs 55.3±26.1 p=0.765), SF36v2 (Physical component score 40.1± 11.1 vs 45.6±12.0 p=0.235; mental component score 41.7±13.0 vs 43.1±16.4 p=0.601), or FSS (mean score±SD 4.4±2.2 vs 4.5±2.0 p=0.985) questionnaires. There was no difference in ages between both groups and there were 75% females in group 1 and 45% in group 2. When compared with healthy controls as reported in the published literature, all three QOL scores were lower in our cohort [1-3].
Conclusions: Medical treatment achieves similar QOL to surgically treated acromegaly patients in remission in the long term. When compared with healthy controls, QOL remains worse in treated acromegaly patients.
References:1. Webb, S.M., et al., Validity and clinical applicability of the acromegaly quality of life questionnaire, AcroQoL: a 6-month prospective study. Eur J Endocrinol, 2006. 155(2): p. 269-77.2. Jenkinson, C., et al., Assessment of the SF-36 version 2 in the United Kingdom. J Epidemiol Community Health, 1999. 53(1): p. 46-50.3. Ongre, S.O., et al., Progression of fatigue in Parkinson’s disease -A nine-year follow-up. Eur J Neurol, 2020.
Outcome of Petrosal Venous Sampling in Consecutive 68 Patients From a Major Neurosurgical Center in the United Kingdom
Authors: Hussein Ziad , Marcus Hani J , Greive Joan , Dorward Neil , Bouloux Pierre M , Baldeweg Stephanie E 
Published: May 2021

Abstract
Background: Cushing’s disease is a challenging endocrine disorder caused by non-physiological cortisol excess from adrenocorticotropic hormone (ACTH) secreting pituitary adenoma. Inferior petrosal venous sampling (IPSS) is considered the gold standard investigation to differentiate Cushing’s disease from ectopic ACTH syndrome. Methods: This retrospective study included all patients who underwent IPSS between January 2011 and October 2020 at The National Hospital for Neurology and Neurosurgery in London. Patients demographics, radiological, surgical, endocrinological and, histological data were retrieved. We assessed the accuracy of IPSS in localizing ACTH secreting pituitary adenoma and its concordance with neuroimaging and surgical findings at the time of tumor resection. Results: In total 68 patients underwent IPSS, 22 males and 46 females. The median age was 42 years. IPSS was performed prior to primary surgery in 61 patients (90%) and before secondary surgery in 4 patients (6%). Three patients (4%) are awaiting surgery at the time of our study. Fifty-two patients (80%) had positive histology of ACTH expressing adenoma. Four patients (8%) had ectopic ACTH syndrome. The sensitivity of IPSS in predicting Cushing’s disease prior to corticotropin-releasing hormone (CRH) stimulation was 91% (95% CI [83% to 97%]) and accuracy of 88% (95% CI [77% to 95%]). The sensitivity of IPSS post CRH administration was 96% (95% CI [87% to 100%]) with accuracy of 86% (95% CI [75% to 93%]). Data on lateralization of pituitary adenoma were available for 63 patients. Prior to CRH stimulation, lateralization was right sided in 35 patients (56%), left sided in 15 (24%), and 13 patients (20%) did not have adequate interpetrosal sinus ACTH ratio. Lateralization post CRH stimulation was right sided in 40 patients (64%), left sided in 20 (32%), and 3 patients (4%) did not achieve adequate ACTH gradient ratio between two sides. Eighteen patients (30%) switched adenoma lateralization between pre and post CRH stimulation. Post CRH IPSS was consistent with neuroradiology in localizing pituitary adenomas in 59% (29 out of 49 patients) and concordant with surgical findings in 41% (25 out of 61 patients). Patients with ectopic ACTH syndrome had negative IPSS at all stages. IPSS procedure failed in 2 patients (3%). No post procedure complications were reported.
Conclusion: IPSS has high sensitivity in diagnosing pituitary driven Cushing’s disease with good safety profile. However, the reliability in lateralizing pituitary adenoma is debated. One third of patients in this cohort switched lateralization before and after CRH administration. Studies on monkeys and rats showed that CRH induces coronary vasodilation and reduction in systemic vascular resistance.
This suggest that CRH might have vasoactive effect on pituitary blood vessels with subsequent influence on IPS:P ACTH gradient ratio between the two sides.
Pituitary Diseases Registry Study in Latvia. Part 1
Authors: Rasa Ingvars , Gurevica Maija 
Published: May 2021

Abstract
Background: Our registry study is designed to create a unified database of pituitary disease patients in Latvia. Methods: We collected 3 yrs data from medical records with pituitary diseases from one clinical university hospital and 4 outpatients clinics. Prospective cohort analysis was performed based on demographic data, MRI, laboratory data, data on medications and regimens used to treat pituitary diseases, information on co-morbidities and concomitant medications used in 355 patients with various pituitary diseases: prolactinomas, clinically nonfunctional adenomas (CNFA), acromegalies, empty sella syndrome, Cushing’s disease (CD), Ratke’s pocket cysts, meningiomas, craniopharyngoma, pituitary aplasia and hypoplasia, TSH-omas, germinoma, glioma, chondrosarcoma, pericytoma. Results: From July 2016 to July 2019, 355 people (71.7% women) with pituitary diseases were registered. The mean age in the cohort was 43.4 yrs (range 18–83 yrs). Prolactinomas were the most common adenomas (40.8%), followed by CNFA (28.5%), acromegaly (16.1%) and empty sella syndrome (5.1%), CD (2.3%), Ratchet pocket cysts (2.3%), meningiomas (1.4%), craniopharyngiomas (1.1%), pituitary aplasia and hypoplasia (0.8%), TSH-omas (0.6%), germinoma (0.3%), glioma (0.3%), chondrosarcoma (0.3%), pericitoma (0.3%). Female dominance was observed in patients with prolactinoma and CNFA, ​​empty sella syndrome, Ratke’s pocket cysts, CD, meningiomas, TSH-omas. Patients in the cohort most often received drug therapy with any type of medication alone (octreotide LAR, lanreotide, bromocriptine, cabergoline, pegvisomant) in 50.5% of cases; various types of combination therapy in 13% of cases. The majority of patients (81.7%) were treated with 1or more medication for co-morbidity. Thyroid disease was slightly more common than cardiovascular disease: 86.1% vs. 81.3%. In 10.1% of the cohort, cancer of various localities was detected. Both types of diabetes or other disorders of carbohydrate metabolism were found in 36.3% of cases. Conclusion: Based on the study of the pituitary disease register in Latvia, a unified database of pituitary disease patients has been created, which allows analyzing the population characteristics of the pituitary diseases, the applied treatment schemes for the treatment of pituitary diseases; types of neurosurgery, medication and radiation therapy. A state register may be set up in the future.
Treatment of Postsurgical Clinically Nonfunctioning Pituitary Adenomas Remnants With Cabergoline
Authors: Vieira Marina C M , Lima José V , Scalco Renata C , Scalissi Nilza M , Bueno Cristina B F 
Published: May 2021

Abstract
Background: The standard first-line therapy for clinically nonfunctioning adenomas (NFPA) is transsphenoidal surgery, however there is no consensus of the optimal postsurgical treatment for residual adenoma. Medical therapy, such as cabergoline (CAB), may be an alternative for preventing growth of postoperative pituitary tumor remnants. The moment of introduction dopamine agonist (DA) is still uncertain. Objective: To assess tumor behavior in patients who used CAB in the postoperative period. Design and methods: A retrospective cross-sectional study was performed with twenty one patients with NFPA treated surgically. All patients stayed with residual tumor and were divided in two groups: patients who received CAB early in postoperative period (Group A, n=6) and when tumor growth were detected during follow-up (Group B, n=15). CAB dosage was 1.5mg or 3.5mg per week. A change in tumor size was considered significant and recorded as such if a difference of at least 5 mm in major diameter was observed. MRI was performed four months after surgery and yearly thereafter in all patients. Subjects in treatment groups also underwent MRI 6 months following medical therapy. No patients were treated by irradiation before or during the follow-up. Statistical analysis was performed using the Fisher’s exact test. Results: From 21 patients, 11 were men and 10 women with similar mean age in two groups (p=0.651). MRI in group A showed stabilization of residual tumor in 50% (3/6) and tumor reduction in 50% (3/6) in group A. In group B, tumor shrinkage was observed in 47% (7/15), stabilization in 27% (4/15) and enlarged in 27% (4/15). No statistical difference between groups was obtained regarding tumor shrinkage and stabilization with the treatment (Group A n=6 versus Group B n=11, p=0.281). In contraste Batista et al., 2016, have already shown that CAB was effective alternative in residual tumor reduction in a study with 74 patients. Conclusion: A multicenter study is necessary to define the role of CAB in the treatment of residual tumor in postsurgical patients with NFPA.
In Silico Perspectives on Gonadotropin Crosstalk
Authors: Atre Ishwar , Hausken Krist , Levavi-Sivan Berta 
Published: May 2021

Abstract
The pivotal role of the gonadotropins (GtHs) luteinizing hormone (LH) and follicle stimulating hormone (FSH) in vertebrate reproduction is well documented. LH and FSH bind to the leucine-rich repeats of the extracellular domains of their cognate receptors (R) in the gonads to actuate steroidogenesis and gametogenesis. Though these GtHs specifically bind only to their cognate receptors in mammals, this interaction becomes inconsistent in the case of fish. Whilst in some fish species the gonadotropins show receptor specificity much like their mammalian homologs, FSH and LH have demonstrated mutual and/or singular cross-activation of the FSH and/or LH receptors in several fish species. These complications regarding receptor specificity are further magnified by cross activation by orthologous GtHs from different species. So far no consistent pattern has been established to chart or predict this cross-talk in specific species or higher taxonomic orders. In the current study, we strived to understand the promiscuous nature of FSH and LH through in silico perspectives. While our studies in Russian sturgeon (Acipenser gueldenstaedtii) have shown FSH and LH to exhibit mutual promiscuity but of varying magnitude, in common carp (Cyprinus carpio) only LH showed singular cross-activation of FSHR. In Nile tilapia (Oreochromis niloticus) these gonadotropins exhibited strict specificity towards their cognate receptors similar to humans. Taking these species as representatives of varying degrees of cognate binding shown by the gonadotropins, we have generated docked models of these hormones and the extracellular domain of these receptors using in silico tools. We have further tried to compare these models, their docked poses, and key residues involved in the binding of these hormone-receptor complexes. We have further tried to compare parameters such as phosphorylation sites, N-linked glycosylation motifs, surface charge, etc. of these models to better understand the docking of these complexes. Our results suggest that in cases of cross activation by FSH and/or LH within or across the species, though binding sites are present at the leucine rich repeats on concaved face of the receptor extracellular domain, the docked position and residues involved in binding may vary significantly. Furthermore, though the seatbelt loop and GTHβ loop-2 (gonadotropin hormone subunit- beta) of the gonadotropin hormones act as the key players in binding, the docking of the hormone may vary in conformation. Due the large size and flexibility of these hormones and the receptor binding interface, it seems apparent that there are multiple binding sites that activate the resulting signaling pathway. Our study aspires to provide better insights towards the promiscuous nature of these hormones and attempt to overcome the handicap of lack of individual physical models using in silico tools.