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Background: Prednisolone and prednisone are recommended treatment options for adults with congenital adrenal hyperplasia (CAH); however, there is no randomised comparison of prednis(ol)one with hydrocortisone. Design: Six-month open-label randomised phase 3 study and interim analysis of a single-arm extension study was the design of the study. Methods: The method of the study was hydrocortisone dose equivalent and 09:00-h 17-hydroxyprogesterone (17OHP) from 48 patients taking prednis(ol)one at baseline. Results: At baseline, the median hydrocortisone dose equivalent was 30 mg/day and 17OHP was < 36 nmol/L (3× upper limit of normal) in 56% of patients. Patients were randomised to continue prednis(ol)one or switch to modified-release hydrocortisone capsule (MRHC) at the same hydrocortisone-equivalent dose. At 4 weeks, 94% on MRHC and 71% on prednis(ol)one had 17OHP < 36 nmol/L. At 18 months in the extension study of MRHC, the median MRHC dose was 20 mg/day and 82% had 17OHP < 36 nmol/L. The per cent of patients with 17OHP < 36 nmol/L on a hydrocortisone dose equivalent ≤ 25 mg/day was greater at 18 months in the extension study on MRHC than while on prednis(ol)one at baseline: 57% vs 27%, P = 0.04. In the randomised study, no patients had an adrenal crisis on MRHC and one on prednisolone. In the extension study (221 patient years), there were 12 adrenal crises in 5 patients (5.4/100 patient years). Conclusion: MRHC reduces 17OHP at 09:00 h compared to prednis(ol)one and the dose of MRHC can be down-titrated over time in the majority of patients.

‘What’s in a name? That which we call a rose/By any other name would smell as sweet’ (Juliet, from Romeo and Juliet by William Shakespeare). Shakespeare’s implication is that a name is nothing but a word, and it therefore represents a convention with no intrinsic meaning. While this may be relevant to romantic literature, disease names do have real meanings, and consequences, in medicine. Hence, there must be a very good rationale for changing the name of a disease that has a centuries-old historical context. A working group of representatives from national and international endocrinology, and pediatric endocrine societies now proposes changing the name of ‘diabetes insipidus’ to ‘arginine vasopressin deficiency (AVP-D)’ for central etiologies, and ‘arginine vasopr essin resistance (AVP-R)’ for nephrogenic etiologies. This article provides both the historical context and the rationale for this proposed name change.

Permanent grasslands (PG) feature in the European rural landscape and represent a major agricultural production resource. They support multiple non-provisioning ecosystem services (ES), including climate regulation, flood control, biodiversity, and pollination. PG are at risk of loss or degradation due to agricultural land use and land management changes. The objective of this systematic review is to identify the main economic influences shaping management and maintenance of PG, and the risks and opportunities for delivery of a range of ES. A total of 51 papers were included. Relevant policy interventions and economic drivers are identified in relation to how they shape the management of EU grasslands over time and across farming systems, countries, or biogeographic zones. A high reliance on public payments from the EU Common Agricultural Policy (CAP), with uneven impact on mitigating PG losses and associated ES provisions, was identified, which needs to be considered in relation to ongoing CAP reform. There is a gap in the literature regarding economic tipping points for change. Future research needs to identify and map ES provisions by PG along with trade-offs and synergies, and link this to policy. There are substantive challenges to maintaining Europe’s PG area and management, which must be addressed through EU-wide instruments.

“What's in a name? That which we call a rose / By any other name would smell as sweet” (Juliet, from Romeo and Juliet by William Shakespeare). Shakespeare's implication is that a name is nothing but a word and it therefore represents a convention with no intrinsic meaning. Whilst this may be relevant to romantic literature, disease names do have real meanings, and consequences, in medicine. Hence, there must be a very good rational for changing the name of a disease that has a centuries-old historical context. A working group of representatives from national and international endocrinology and endocrine pediatric societies now proposes changing the name of “diabetes insipidus” to “Arginine Vasopressin Deficiency (AVP-D)” for central etiologies, and “Arginine Vasopressin Resistance (AVP-R)” for nephrogenic etiologies This editorial provides both the historical context and the rational for this proposed name change.

This study used the ECOSSE model (v. 5.0.1) to simulate soil respiration (Rs) fluxes estimated from ecosystem respiration (Reco) for eight European permanent grassland (PG) sites with varying grass species, soils, and management. The main aim was to evaluate the strengths and weaknesses of the model in estimating Rs from grasslands, and to gain a better understanding of the terrestrial carbon cycle and how Rs is affected by natural and anthropogenic drivers. Results revealed that the current version of the ECOSSE model might not be reliable for estimating daily Rs fluxes, particularly in dry sites. The daily estimated and simulated Rs ranged from 0.95 to 3.1 g CO2-C m−2, and from 0.72 to 1.58 g CO2-C m−2, respectively. However, ECOSSE could still be a valuable tool for predicting cumulative Rs from PG. The overall annual relative deviation (RD) value between the cumulative estimated and simulated annual Rs was 11.9%. Additionally, the model demonstrated accurate simulation of Rs in response to grass cutting and slurry application practices. The sensitivity analyses and attribution tests revealed that increased soil organic carbon (SOC), soil pH, temperature, reduced precipitation, and lower water table (WT) depth could lead to increased Rs from soils. The variability of Rs fluxes across sites and years was attributed to climate, weather, soil properties, and management practices. The study suggests the need for additional development and application of the ECOSSE model, specifically in dry and low input sites, to evaluate the impacts of various land management interventions on carbon sequestration and emissions in PG.

Grasslands are at risk of degradation due to unsustainable management practices and climate change. Here, we review the principal soil quality indicators (SQIs) to evaluate the sustainability of different grassland management practices globally. We discuss the importance of SQI assessment and the Soil Quality Minimum Dataset (MDS) specifically in the context of grasslands. We then review two potential solutions, the first of which is adopting grazing management, whereby sustainable grazing management plans (GMPs) offer great potential. The other solution is the development and adoption of novel grassland species, which may improve either drought resistance or infiltration rates, erosion and flooding. Sustainable grassland soil management can promote ecosystem service delivery and improve the resilience of the entire grassland ecosystem to anthropogenic change.

Nitrogen fertilisation is a common form of agricultural intensification, aimed at increasing biomass, which can affect plant species diversity and ecosystem functioning. Using a systematic review and meta-analysis of nitrogen fertilisation studies in European permanent grasslands, we asked: (i) what relationship form exists between nitrogen application rate and change in plant diversity, compared to zero fertilisation controls; and (ii) how grassland, management and study characteristics affect this relationship. Meta-analysis of 34 control-treatment effects from 14 studies conducted across nine European countries revealed a negative linear relationship between nitrogen fertilisation rate and change in plant species richness, equivalent to approximately 1.5 species/m2 lost for every 100 Kg ha−1 yr−1 of nitrogen added. Fertilisation induced reductions in plant species richness were greater when defoliation rates were lower. We found some evidence that grasslands with a higher baseline plant diversity lost more species when fertilised compared to more species poor grasslands, although uncertainty was high. Due to the diverse grassland types included in the analysis, the variability in fertilisation-driven changes in plant diversity was high. We identified several remaining limitations to our understanding, including uncertainty about non-linear effects, which could aid efforts to optimise the trade-off of plant diversity and increasing grassland yields.

Soil condition or quality determines its ability to deliver a range of functions that support ecosystem services, human health and wellbeing. The increasing policy imperative to implement successful soil monitoring programmes has resulted in the demand for reliable soil quality indicators (SQIs) for physical, biological and chemical soil properties. The selection of these indicators needs to ensure that they are sensitive and responsive to pressure and change, e.g. they change across space and time in relation to natural perturbations and land management practices. Using a logical sieve approach based on key policy-related soil functions, this research assessed whether physical soil properties can be used to indicate the quality of British soils in terms of their capacity to deliver ecosystem goods and services. The resultant prioritised list of physical SQIs was tested for robustness, spatial and temporal variability, and expected rate of change using statistical analysis and modelling. Seven SQIs were prioritised: soil packing density, soil water retention characteristics, aggregate stability, rate of soil erosion, depth of soil, soil structure (assessed by visual soil evaluation) and soil sealing. These all have direct relevance to current and likely future soil and environmental policy and are appropriate for implementation in soil monitoring programmes.

The granulation pattern of somatotroph adenomas is well known to be associated with differing clinical and biochemical characteristics, and it has been shown that sparsely granulated tumours respond poorly to commonly used somatostatin receptor ligands (SRLs). We report a challenging case of acromegaly with a sparsely granulated tumour resistant to multiple modalities of treatment, ultimately achieving biochemical control with pasireotide. A 26-year-old lady presented with classical features of acromegaly, which was confirmed by an oral glucose tolerance test. Insulin-like growth factor 1 (IGF1) was 1710 μg/L (103–310 μg/L) and mean growth hormone (GH) was >600 U/L. MRI scan showed a 4 cm pituitary macroadenoma with suprasellar extension and right-sided cavernous sinus invasion. She underwent trans-sphenoidal pituitary surgery. Histology displayed moderate amounts of sparsely granular eosinophilic cytoplasm, staining only for GH. Postoperative investigations showed uncontrolled disease (IGF1:1474 μg/L, mean GH:228 U/L) and residual tumour in the cavernous sinus. She received external beam fractionated radiation. Over the years, she received octreotide LAR (up to 30 mg), lanreotide (up to 120 mg) two weekly, cabergoline, pegvisomant and stereotactic radiosurgery to no avail. Only pegvisomant resulted in an element of disease control; however, this had to be stopped due to abnormal liver function tests. Fifteen years after the diagnosis, she was started on pasireotide 40 mg monthly. Within a month, her IGF1 dropped and has remained within the normal range (103–310 μg/L). Pasireotide has been well tolerated, and there has been significant clinical improvement. Somatostatin receptor subtyping revealed a positivity score of two for both sst5 and sst2a subtypes.

Mutations of the rearranged during transfection (RET) proto-oncogene, located on chromosome 10q11.2, cause multiple endocrine neoplasia type 2A (MEN2A). Patients with mutations at the codon 609 usually exhibit a high penetrance of medullary thyroid cancer (MTC), but a sufficiently low penetrance of phaeochromocytoma that screening for this latter complication has been called to question. Patients with other RET mutations are at higher risk of younger age onset phaeochromocytoma if they also possess other RET polymorphisms (L769L, S836S, G691S and S904S), but there are no similar data for patients with 609 mutations. We investigated the unusual phenotypic presentation in a family with MEN2A due to a C609Y mutation in RET. Sanger sequencing of the entire RET-coding region and exon–intron boundaries was performed. Five family members were C609Y mutation positive: 3/5 initially presented with phaeochromocytoma, but only 1/5 had MTC. The index case aged 73 years had no evidence of MTC, but presented with phaeochromocytoma. Family members also possessed the G691S and S904S RET polymorphisms. We illustrate a high penetrance of phaeochromocytoma and low penetrance of MTC in patients with a RET C609Y mutation and polymorphisms G691S and S904S. These data highlight the need for life-long screening for the complications of MEN2A in these patients and support the role for the screening of RET polymorphisms for the purposes of risk stratification.

Edward M Wolin,1 Barbara Jarzab,2 Barbro Eriksson,3 Thomas Walter,4 Christos Toumpanakis,5 Michael A Morse,6 Paola Tomassetti,7 Matthias M Weber,8 David R Fogelman,9 John Ramage,10 Donald Poon,11 Brian Gadbaw,12 Jiang Li,12 Janice L Pasieka,13 Abakar Mahamat,14 Fredrik Swahn,15 John Newell-Price,16 Wasat Mansoor,17 Kjell Öberg3 1Markey Cancer Center, University of Kentucky, Lexington, KY, USA; 2Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland; 3Department of Medical Sciences, Endocrine Oncology Unit, University Hospital, Uppsala, Sweden; 4Department of Medical Oncology, Edouard Herriot Hospital, Lyon, France; 5Gastroenterology and Neuroendocrine Tumours, Royal Free Hospital, London, UK; 6Department of Medical Oncology, Duke University Medical Center, Durham, NC, USA; 7Department of Medical and Surgical Sciences, University Hospital St Orsola, Bologna, Italy; 8Medizinische Klinik und Poliklinik, Johannes Gutenberg-Universität Mainz, Mainz, Germany; 9Department of Gastrointestinal Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA; 10Gastroenterology Unit, North Hampshire Hospital, Basingstoke, UK; 11Department of Medical Oncology, Raffles Hospital and Duke–NUS Graduate Medical School, Singapore; 12Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 13Surgery and Oncology Faculty of Medicine, Foothills Hospital, Calgary, AB, Canada; 14Department of Gastrointestinal Oncology, CHU de Nice Hôpital de l’Archet 1, Nice, France; 15Department of Clinical Science, Intervention and Technology, Karolinska Universitatssjukhuset, Huddinge, Stockholm, Sweden; 16Department of Human Metabolism, School of Medicine and Biomedical Science, The University of Sheffield, and Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK; 17Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK Abstract: In a randomized, double-blind, Phase III study, we compared pasireotide long-acting release (pasireotide LAR) with octreotide long-acting repeatable (octreotide LAR) in managing carcinoid symptoms refractory to first-generation somatostatin analogues. Adults with carcinoid tumors of the digestive tract were randomly assigned (1:1) to receive pasireotide LAR (60 mg) or octreotide LAR (40 mg) every 28 days. Primary outcome was symptom control based on frequency of bowel movements and flushing episodes. Objective tumor response was a secondary outcome. Progression-free survival (PFS) was calculated in a post hoc analysis. Adverse events were recorded. At the time of a planned interim analysis, the data monitoring committee recommended halting the study because of a low predictive probability of showing superiority of pasireotide over octreotide for symptom control (n=43 pasireotide LAR, 20.9%; n=45 octreotide LAR, 26.7%; odds ratio, 0.73; 95% confidence interval [CI], 0.27–1.97; P=0.53). Tumor control rate at month 6 was 62.7% with pasireotide and 46.2% with octreotide (odds ratio, 1.96; 95% CI, 0.89–4.32; P=0.09). Median (95% CI) PFS was 11.8 months (11.0 – not reached) with pasireotide versus 6.8 months (5.6 – not reached) with octreotide (hazard ratio, 0.46; 95% CI, 0.20–0.98; P=0.045). The most frequent drug-related adverse events (pasireotide vs octreotide) included hyperglycemia (28.3% vs 5.3%), fatigue (11.3% vs 3.5%), and nausea (9.4% vs 0%). We conclude that, among patients with carcinoid symptoms refractory to available somatostatin analogues, similar proportions of patients receiving pasireotide LAR or octreotide LAR achieved symptom control at month 6. Pasireotide LAR showed a trend toward higher tumor control rate at month 6, although it was statistically not significant, and was associated with a longer PFS than octreotide LAR. Keywords: neuroendocrine tumors, carcinoid syndrome, somatostatin analogues, pasireotide, symptom control, progression-free survival

Many excellent results are obtained in agricultural and forestry research projects, but their practical adoption is often limited. The aim of the European project VALERIE is to increase the transfer and application of innovations produced by research in agriculture and forestry, by facilitating their integration into management practices. The project is still ongoing and the results illustrated in this paper are still temporary and subject to being improved. Here we present the methodology used in VALERIE to extract and summarise knowledge for innovation from research documents with the aim of making it available to final users through ask-Valerie.eu; we also report on current progress. The tasks associated with extracting and summarising knowledge are centred on: i) an ontology; ii) a document base; and iii) a system (ask-Valerie.eu) that allows users to effectively search the document base. An ontology defines a set of concepts and the relations between them. The VALERIE ontology is built by experts in the agricultural and forestry domain and contains 6169 concepts (21st October 2016). The document base is the collection of documents in which the system searches. The VALERIE document base includes scientific and practical documents derived from various sources, written in any of a number of languages. All documents contained in the document base are annotated using the ontology: each term (a word or a short phrase) in the document that matches a concept in the VALERIE-ontology is linked to that concept. Annotation is an automated process that takes place whenever a document is added to the document base. The document base contains 4278 documents (October 2016). Among them, there are 201 minifactsheets written by members of the VALERIE project, each describing an innovation with: a short description of the innovation, a list of correlated projects, and some links to scientific and practical documents. ask-Valerie.eu searches documents and fragments of text from the document base that address the user’s query. ask-Valerie.eu mimics the dialogue between a practitioner and an expert and achieves this functionality by: i) supporting the practitioner in articulating the question (it completes terms that the user starts to type and suggests other possibly relevant terms); ii) expanding the query using synonyms; iii) extracting and ranking text fragments from the documents.

Cushing’s disease is a rare disease with a characteristic phenotype due to significant hypercortisolism driven by over-secretion of adrenocorticotropic hormone and to high morbidity and mortality if untreated. It is caused by a corticotroph adenoma of the pituitary, but the exact mechanisms leading to tumorigenesis are not clear. Recent advances in molecular biology such as the discovery of somatic mutations of the ubiquitin-specific peptidase 8 (USP8) gene allow new insights into the pathogenesis, which could be translated into exciting and much-needed therapeutic applications.

Incidental adrenal masses are commonly detected during imaging for other pathologies. 10% of the elderly population has an 'adrenal incidentaloma', up to 20% of these show low-grade autonomous cortisol secretion and 60% of patients with autonomous cortisol secretion have insulin resistance. Cortisol excess is known to cause insulin resistance, an independent cardiovascular risk marker, however in patients with adrenal incidentalomas it is unknown whether their insulin resistance is secondary to the excess cortisol and therefore potentially reversible. In a proof of concept study we examined the short-term effects of glucocorticoid receptor (GR) antagonism in patients with an adrenal incidentaloma to determine whether their insulin resistance was reversible.In a prospective open-label pilot study, six individuals with adrenal incidentalomas and autonomous cortisol secretion were treated with mifepristone (a GR antagonist) 200 mg twice daily and studied for 4 weeks on a Clinical Research Facility. Insulin resistance at four weeks was assessed by insulin resistance indices, lnHOMA-IR and lnMatsuda, and AUC insulin during a 2-hour glucose tolerance test. Biochemical evidence of GR blockade was shown in all individuals and across the group there was a significant reduction in insulin resistance: lnHOMA-IR (1.0vs0.6; p = 0.03), lnHOMA-%beta (4.8vs4.3; p = 0.03) and lnMatsuda (1.2vs1.6; p = 0.03). Five out of six individuals showed a reduction in insulin AUC >7237 pmol/l.min, and in two patients this showed a clinically significant cardiovascular benefit (as defined by the Helsinki heart study).Short-term GR antagonism is sufficient to reduce insulin resistance in some individuals with adrenal incidentalomas and mild cortisol excess. Further assessment is required to assess if the responses may be used to stratify therapy as adrenal incidentalomas may be a common remediable cause of increased cardiovascular risk.ClinicalTrials.gov NCT00721201.