Evaluation of five multisteroid LC‒MS/MS methods used for routine clinical analysis: comparable performance was obtained for nine analytes.

OBJECTIVES: A mass spectrometry (LC‒MS/MS)-based interlaboratory comparison study was performed for nine steroid analytes with five participating laboratories. The sample set contained 40 pooled samples of human serum generated from preanalyzed leftovers. To obtain a well-balanced distribution across reference intervals of each steroid, the leftovers first underwent a targeted mixing step. METHODS: All participants measured a sample set once using their own multianalyte protocols and calibrators. Four participants used in-house developed measurement platforms, including IVD-CE certified calibrators, which were used by three participants; the 5th lab used the whole LC‒MS kit from an IVD manufacturer. All labs reported results for 17-hydroxyprogesterone, androstenedione, cortisol, and testosterone, and four labs reported results for 11-deoxycortisol, corticosterone, cortisone, dehydroepiandrosterone sulfate (DHEAS), and progesterone. RESULTS: Good or acceptable overall comparability was found in Bland‒Altman and Passing‒Bablok analyses. Mean bias against the overall mean remained less than ±10 % except for DHEAS, androstenedione, and progesterone at one site and for cortisol and corticosterone at two sites (max. -18.9 % for androstenedione). The main analytical problems unraveled by this study included a bias not previously identified in proficiency testing, operator errors, non-supported matrix types and higher inaccuracy and imprecision at lower ends of measuring intervals. CONCLUSIONS: This study shows that intermethod comparison is essential for monitoring the validity of an assay and should serve as an example of how external quality assessment could work in addition to organized proficiency testing schemes.

HYPER: pre-clinical device for spatially-confined magnetic particle hyperthermia.

PURPOSE: Magnetic particle hyperthermia is an approved cancer treatment that harnesses thermal energy generated by magnetic nanoparticles when they are exposed to an alternating magnetic field (AMF). Thermal stress is either directly cytotoxic or increases the susceptibility of cancer cells to standard therapies, such as radiation. As with other thermal therapies, the challenge with nanoparticle hyperthermia is controlling energy delivery. Here, we describe the design and implementation of a prototype pre-clinical device, called HYPER, that achieves spatially confined nanoparticle heating within a user-selected volume and location. DESIGN: Spatial control of nanoparticle heating was achieved by placing an AMF generating coil (340 kHz, 0-15 mT), between two opposing permanent magnets. The relative positions between the magnets determined the magnetic field gradient (0.7 T/m-2.3 T/m), which in turn governed the volume of the field free region (FFR) between them (0.8-35 cm3). Both the gradient value and position of the FFR within the AMF ([-14, 14]x, [-18, 18]y, [-30, 30]z) mm are values selected by the user via the graphical user interface (GUI). The software then controls linear actuators that move the static magnets to adjust the position of the FFR in 3D space based on user input. Within the FFR, the nanoparticles generate hysteresis heating; however, outside the FFR where the static field is non-negligible, the nanoparticles are unable to generate hysteresis loss power. VERIFICATION: We verified the performance of the HYPER to design specifications by independently heating two nanoparticle-rich areas of a phantom placed within the volume occupied by the AMF heating coil.

Treatment of advanced gastroenteropancreatic neuroendocrine neoplasia, are we on the way to personalised medicine?

Gastroenteropancreatic neuroendocrine neoplasia (GEPNEN) comprises clinically as well as prognostically diverse tumour entities often diagnosed at late stage. Current classification provides a uniform terminology and a Ki67-based grading system, thereby facilitating management. Advances in the study of genomic and epigenetic landscapes have amplified knowledge of tumour biology and enhanced identification of prognostic and potentially predictive treatment subgroups. Translation of this genomic and mechanistic biology into advanced GEPNEN management is limited. 'Targeted' treatments such as somatostatin analogues, peptide receptor radiotherapy, tyrosine kinase inhibitors and mammalian target of rapamycin inhibitors are treatment options but predictive tools are lacking. The inability to identify clonal heterogeneity and define critical oncoregulatory pathways prior to therapy, restrict therapeutic efficacy as does the inability to monitor disease status in real time. Chemotherapy in the poor prognosis NEN G3 group, though associated with acceptable response rates, only leads to short-term tumour control and their molecular biology requires delineation to provide new and more specific treatment options.The future requires an exploration of the NEN tumour genome, its microenvironment and an identification of critical oncologic checkpoints for precise drug targeting. In the advance to personalised medical treatment of patients with GEPNEN, clinical trials need to be based on mechanistic and multidimensional characterisation of each tumour in order to identify the therapeutic agent effective for the individual tumour.This review surveys advances in NEN research and delineates the current status of translation with a view to laying the basis for a genome-based personalised medicine management of advanced GEPNEN.

Pore constrictions in intervessel pit membranes provide a mechanistic explanation for xylem embolism resistance in angiosperms.

Embolism spreading in angiosperm xylem occurs via mesoporous pit membranes between vessels. Here, we investigate how the size of pore constrictions in pit membranes is related to pit membrane thickness and embolism resistance. Pit membranes were modelled as multiple layers to investigate how pit membrane thickness and the number of intervessel pits per vessel determine pore constriction sizes, the probability of encountering large pores, and embolism resistance. These estimations were complemented by measurements of pit membrane thickness, embolism resistance, and number of intervessel pits per vessel in stem xylem (n = 31, 31 and 20 species, respectively). The modelled constriction sizes in pit membranes decreased with increasing membrane thickness, explaining the measured relationship between pit membrane thickness and embolism resistance. The number of pits per vessel affected constriction size and embolism resistance much less than pit membrane thickness. Moreover, a strong relationship between modelled and measured embolism resistance was observed. Pore constrictions provide a mechanistic explanation for why pit membrane thickness determines embolism resistance, which suggests that hydraulic safety can be uncoupled from hydraulic efficiency. Although embolism spreading remains puzzling and encompasses more than pore constriction sizes, angiosperms are unlikely to have leaky pit membranes, which enables tensile transport of water.

Insights to enhance the examination of tool marks in human cartilage.

This work deals with the examination of tool marks in human cartilage. We compared the effectiveness of several cleaning methods on cut marks in porcine cartilage. The method cleaning by multiple casts achieved the significantly highest scores (P = 0.02). Furthermore, we examined the grain-like elevations (dots) located on casts of cut cartilage. The results of this study suggest that the casting material forms these dots when penetrating cartilage cavities, which are areas where the strong collagen fibres leave space for the chondrocytes. We performed fixation experiments to avoid this, without success. In addition, 31 casting materials were compared regarding contrast under light-microscope and 3D tool marks scanner. Under the light-microscope, brown materials achieved significantly higher values than grey (P = 0.02) or black (P = 0.00) whereas under the 3D scanner, black materials reached higher contrast values than grey (P = 0.04) or brown (P = 0.047). To compare the accuracy and reproducibility of 6 test materials for cartilage, we used 10 knives to create cut marks that were subsequently scanned. During the alignment of the individual signals of each mark, the cross-correlation coefficients (Xmax) and lags (LXmax) were calculated. The signals of the marks in agarose were aligned with significantly fewer lags and achieved significantly higher cross-correlation coefficients compared to all tested materials (both P = 0.00). Moreover, we determined the cross-correlation coefficients (XC) for known-matches (KM) per material. Agarose achieved significantly higher values than AccuTrans®, Clear Ballistics™, and gelatine (all P = 0.00). The results of this work provide valuable insights for the forensic investigation of marks in human costal cartilage.

Sharp force trauma with two katana swords: identifying the murder weapon by comparing tool marks on the skull bone.

This paper describes the variety of information that a tool mark analysis on human tissue can provide based on a case of multiple sharp violence. The perpetrator attacked the victim with a sharp-edged weapon against the head, leaving several deep wounds on the back of the skull bone. Three of those marks on the skull bone could be used for a forensic tool mark examination. Silicone casts of the marks were compared by light microscopy with casts of test marks of Japanese katana swords found at the crime scene. One of the swords could be identified as the one responsible for the marks. In addition, the marks and the test marks were scanned in 3D and examined in a visual on-screen comparison confirming the results from the light microscopic examination. Furthermore, a mathematical approach in which the signatures of the marks from the skull bone and the test marks from the sword were compared by cross correlation confirms those findings. In addition, the aforementioned results were used to determine the orientation of the sword in relation to the cranial bone at the time of the respective impact.

Pregnancy outcomes in women receiving growth hormone replacement therapy enrolled in the NordiNet® International Outcome Study (IOS) and the American Norditropin® Studies: Web-Enabled Research (ANSWER) Program.

PURPOSE: Data on the safety of growth hormone (GH) replacement therapy during pregnancy are limited. We report a combined analysis of data from pregnant women treated with GH while enrolled in two non-interventional, multicenter studies: NordiNet® International Outcome Study (IOS) and the American Norditropin® Studies: Web-Enabled Research (ANSWER) Program. METHODS: Pregnancy data were pooled from NordiNet® IOS and the ANSWER Program. Data were collected during routine clinic visits by participating physicians using a web-based system. Patients exposed to GH replacement therapy during pregnancy were included in the analysis. RESULTS: The study population included 40 female patients with typical causes of adult GH deficiency (GHD). Overall, there were 54 pregnancies. Of these, 47 were exposed to GH between conception and delivery. In 48.9% of pregnancies exposed to GH, the dose was > 0.6 mg/day. GH was continued past conception and then stopped during the first, second, and third trimester, in 27.7%, 17.0%, and 2.1% of pregnancies, respectively. In 29.8%, GH was continued throughout pregnancy, with an unchanged dose in most cases. Of the 47 GH-exposed pregnancies, 37 (78.7%) progressed to normal delivery. There were three adverse events reported in two pregnancies. CONCLUSION: These real-world data suggest that there were no new safety signals related to GH exposure in women with GHD during pregnancy. These results are consistent with findings from previous studies reporting data in pregnancies exposed to GH at conception or throughout pregnancy. This observational study in additional pregnancies provides further evidence that GH exposure does not adversely affect pregnancy outcome. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT00960128 (date of registration: August 13, 2009) and NCT01009905 (date of registration: November 5, 2009).

Reactive Exercises with Interactive Objects: Interim Analysis of a Randomized Trial on Task-Driven NMES Grasp Rehabilitation for Subacute and Early Chronic Stroke Patients.

Enriched environments and tools are believed to promote grasp rehabilitation after stroke. We designed S2, an interactive grasp rehabilitation system consisting of smart objects, custom orthoses for selective grasp constraining, and an electrode array system for forearm NMES. Motor improvements and perceived usability of a new enriched upper limb training system for sub-acute stroke patients was assessed in this interim analysis. INCLUSION CRITERIA: sub-acute stroke patients with MMSE>20, ipsilesional MI>80%, and contralesional MI<80%. Effects of 30-min therapy supplements, conventional vs. S2 prototype, are compared through a parallel two-arms dose-matched open-label trial, lasting 27 sessions. Clinical centres: Asklepios Neurologische Klinik Falkenstein, Königstein im Taunus, Germany, and Clinica Villa Beretta, Costa Masnaga, Italy. Assessment scales: ARAT, System Usability, and Technology Acceptance. METHODOLOGY: 26 participants were block randomized, allocated to the study (control N=12, experimental N=14) and underwent the training protocol. Among them, 11 participants with ARAT score at inclusion below 35, n = 6 in the experimental group, and n = 5 in the control group were analysed. RESULTS: participants in the enriched treatment group displayed a larger improvement in the ARAT scale (+14.9 pts, pval=0.0494). Perceived usability differed between clinics. No adverse effect was observed in relation to the treatments. Trial status: closed. CONCLUSIONS: The S2 system, developed according to shared clinical directives, was tested in a clinical proof of concept. Variations of ARAT scores confirm the feasibility of clinical investigation for hand rehabilitation after stroke.

High porosity with tiny pore constrictions and unbending pathways characterize the 3D structure of intervessel pit membranes in angiosperm xylem.

Pit membranes between xylem vessels play a major role in angiosperm water transport. Yet, their three-dimensional (3D) structure as fibrous porous media remains unknown, largely due to technical challenges and sample preparation artefacts. Here, we applied a modelling approach based on thickness measurements of fresh and fully shrunken pit membranes of seven species. Pore constrictions were also investigated visually by perfusing fresh material with colloidal gold particles of known sizes. Based on a shrinkage model, fresh pit membranes showed tiny pore constrictions of ca. 20 nm, but a very high porosity (i.e. pore volume fraction) of on average 0.81. Perfusion experiments showed similar pore constrictions in fresh samples, well below 50 nm based on transmission electron microscopy. Drying caused a 50% shrinkage of pit membranes, resulting in much smaller pore constrictions. These findings suggest that pit membranes represent a mesoporous medium, with the pore space characterized by multiple constrictions. Constrictions are much smaller than previously assumed, but the pore volume is large and highly interconnected. Pores do not form highly tortuous, bent, or zigzagging pathways. These insights provide a novel view on pit membranes, which is essential to develop a mechanistic, 3D understanding of air-seeding through this porous medium.

Automatic identification of crossovers in cryo-EM images of murine amyloid protein A fibrils with machine learning.

Detecting crossovers in cryo-electron microscopy images of protein fibrils is an important step towards determining the morphological composition of a sample. Currently, the crossover locations are picked by hand, which introduces errors and is a time-consuming procedure. With the rise of deep learning in computer vision tasks, the automation of such problems has become more and more applicable. However, because of insufficient quality of raw data and missing labels, neural networks alone cannot be applied successfully to target the given problem. Thus, we propose an approach combining conventional computer vision techniques and deep learning to automatically detect fibril crossovers in two-dimensional cryo-electron microscopy image data and apply it to murine amyloid protein A fibrils, where we first use direct image processing methods to simplify the image data such that a convolutional neural network can be applied to the remaining segmentation problem. LAY DESCRIPTION: The ability of protein to form fibrillary structures underlies important cellular functions but can also give rise to disease, such as in a group of disorders, termed amyloid diseases. These diseases are characterised by the formation of abnormal protein filaments, so-called amyloid fibrils, that deposit inside the tissue. Many amyloid fibrils are helically twisted, which leads to periodic variations in the apparent width of the fibril, when observing amyloid fibrils using microscopy techniques like cryogenic electron microscopy (cryo-EM). Due to the two-dimensional projection, parts of the fibril orthogonal to the projection plane appear narrower than parts parallel to the plane. The parts of small width are called crossovers. The distance between two adjacent crossovers is an important characteristic for the analysis of amyloid fibrils, because it is informative about the fibril morphology and because it can be determined from raw data by eye. A given protein can typically form different fibril morphologies. The morphology can vary depending on the chemical and physical conditions of fibril formation, but even when fibrils are formed under identical solution conditions, different morphologies may be present in a sample. As the crossovers allow to define fibril morphologies in a heterogeneous sample, detecting crossovers is an important first step in the sample analysis. In the present paper, we introduce a method for the automated detection of fibril crossovers in cryo-EM image data. The data consists of greyscale images, each showing an unknown number of potentially overlapping fibrils. In a first step, techniques from image analysis and pattern detection are employed to detect single fibrils in the raw data. Then, a convolutional neural network is used to find the locations of crossovers on each single fibril. As these predictions may contain errors, further postprocessing steps assess the quality and may slightly alter or reject the predicted crossovers.

Predictors for Pediatric Blunt Cerebrovascular Injury (BCVI): An International Multicenter Analysis.

INTRODUCTION: Practice guidelines for adult BCVI patients have been implemented recently, but data for this devastating injury pattern in children are still limited. An international multicenter analysis was performed to characterize BCVI in the pediatric population. METHODS: The TraumaRegister DGU®, a prospectively maintained database, was analyzed (01/2002-12/2015). Pediatric patients (0-17 years) with major injuries [Injury Severity Score (ISS) ≥ 9 points] were included. BCVI was divided into carotid artery injury and vertebral artery injury (VAI). Data of demographics, injury, imaging, therapy, and outcome characteristics were analyzed with SPSS (Version 25, IBM Inc., Armonk, NY). RESULTS: The study cohort included 8128 pediatric trauma patients. We identified 48 BCVIs in 42 children, resulting in an overall prevalence of 0.5%. Carotid injuries were diagnosed more frequently (n = 30; 0.4%) when compared to VAIs (n = 12; 0.1%). The coincidence of head (p = 0.028), facial (p ≤ 0.001), chest (p ≤ 0.001), and spinal injuries (p ≤ 0.001) was higher in BCVI patients. The risk for thromboembolic complications (8.3% vs. 1%, p = 0.026) and in-hospital mortality (38.1% vs. 7.7%, p ≤ 0.001) was excessive in children with BCVI. We identified various predictors for pediatric BCVI and quantified the cumulative impact of these risk factors. CONCLUSION: BCVI is more uncommon in pediatric than in adult trauma patients. Due to the considerable relevance of this injury for both children and adults, special attention should be paid to this entity and associated complications in the early treatment phase after severe pediatric trauma, especially in high-risk children.

Sequential Treatment Escalation with Dapagliflozin and Saxagliptin Improves Beta Cell Function in Type 2 Diabetic Patients on Previous Metformin Treatment: An Exploratory Mechanistic Study.

We investigated the effect of sequential treatment escalation with dapagliflozin and saxagliptin on beta cell function in patients with T2DM insufficiently controlled on metformin monotherapy during a hyperglycaemic clamp investigation. Twenty-six patients (19 males, age 63.5±7.0 years; duration of diabetes 8.8±4.7 years; HbA1c 63.9±15.8 mmol/mol; mean±SD) were enrolled in the study. During a first treatment period (TP1) all patients received 10 mg dapagliflozin for one month, followed by the addition of 5 mg saxagliptin or placebo for another month (TP2). At baseline and at the end of each treatment period, fasting glucose and insulin levels were analysed, and a hyperglycaemic clamp with the measurement of plasma C-peptide, insulin, proinsulin, and glucagon was performed. Treatment with dapagliflozin reduced fasting glucose levels and insulin resistance (TP1). Within the hyperglycaemic clamp, C-peptide and insulin concentrations increased after the addition of dapagliflozin in TP1 (0.48±0.45 nmol*h/l; 6.24±17.9 mU*h/l) and further improved after the addition of saxagliptin in TP2 (0.38±0.34 nmol*h/l; 6.59±10.15 mU*h/l). Acute insulin response did not change after the addition of dapagliflozin (TP1), but significantly improved after the addition of saxagliptin in TP2 (0.89±0.76 mU*h/l). Both drugs improved the C-peptide/proinsulin ratio. After the addition of saxagliptin, the glucagon/insulin ratio significantly declined (TP2). Treatment escalation with dapagliflozin and saxagliptin exhibit additive effects on beta cell capacity, and improves alpha and beta cell integrity.

Design of the Growth hormone deficiency and Efficacy of Treatment (GET) score and non-interventional proof of concept study.

BACKGROUND: The adverse effects of growth hormone (GH) deficiency (GHD) in adults (AGHD) on metabolism and health-related quality of life (HRQoL) can be improved with GH substitution. This investigation aimed to design a score summarising the features of GHD and evaluate its ability to measure the effect of GH substitution in AGHD. METHODS: The Growth hormone deficiency and Efficacy of Treatment (GET) score (0-100 points) assessed (weighting): HRQoL (40%), disease-related days off work (10%), bone mineral density (20%), waist circumference (10%), low-density lipoprotein cholesterol (10%) and body fat mass (10%). A prospective, non-interventional, multicentre proof-of-concept study investigated whether the score could distinguish between untreated and GH-treated patients with AGHD. A 10-point difference in GET score during a 2-year study period was expected based on pre-existing knowledge of the effect of GH substitution in AGHD. RESULTS: Of 106 patients eligible for analysis, 22 were untreated GHD controls (9 females, mean ± SD age 52 ± 17 years; 13 males, 57 ± 13 years) and 84 were GH-treated (31 females, age 45 ± 13 years, GH dose 0.30 ± 0.16 mg/day; 53 males, age 49 ± 15 years, GH dose 0.25 ± 0.10 mg/day). Follow-up was 706 ± 258 days in females and 653 ± 242 days in males. The GET score differed between the untreated control and treated groups with a least squares mean difference of + 10.01 ± 4.01 (p = 0.0145). CONCLUSIONS: The GET score appeared to be a suitable integrative instrument to summarise the clinical features of GHD and measure the effects of GH substitution in adults. Exercise capacity and muscle strength/body muscle mass could be included in the GET score. TRIAL REGISTRATION: NCT number: NCT00934063 . Date of registration: 02 July 2009.

Description of Ore Particles from X-Ray Microtomography (XMT) Images, Supported by Scanning Electron Microscope (SEM)-Based Image Analysis.

In this paper, three-dimensional (3D) image data of ore particle systems is investigated. By combining X-ray microtomography with scanning electron microscope (SEM)-based image analysis, additional information about the mineralogical composition from certain planar sections can be gained. For the analysis of tomographic images of particle systems the extraction of single particles is essential. This is performed with a marker-based watershed algorithm and a post-processing step utilizing a neural network to reduce oversegmentation. The results are validated by comparing the 3D particle-wise segmentation empirically with 2D SEM images, which have been obtained with a different imaging process and segmentation algorithm. Finally, a stereological application is shown, in which planar SEM images are embedded into the tomographic 3D image. This allows the estimation of local X-ray attenuation coefficients, which are material-specific quantities, in the entire tomographic image.

The Antiproliferative Role of Lanreotide in Controlling Growth of Neuroendocrine Tumors: A Systematic Review.

BACKGROUND: Neuroendocrine tumors (NETs) are a heterogeneous group of tumors, with >50% of cases involving the gastrointestinal system or pancreas. Somatostatin analogs (SSAs) are used for treating NET-related secretory syndromes and, more recently, for their antiproliferative effects. We conducted a systematic review of published literature on the antiproliferative efficacy and safety of the SSA lanreotide Autogel in the management of NETs to gain a fuller understanding of the evidence and identify future areas of research. METHODS: Searches were conducted in PubMed up to March 16, 2016, and in the proceedings of four congresses from 2013 to 2016. RESULTS: Screening of 1,132 publications identified in the searches found 40 relevant publications, including 27 full-length publications and 13 congress abstracts. Twenty-four of these publications reported antiproliferative efficacy data for lanreotide Autogel. The CLARINET study showed that 120 mg lanreotide Autogel every 4 weeks improves progression-free survival (PFS) in patients with gastroenteropancreatic (GEP)-NETs, with grade 1 or grade 2 (Ki-67 <10%) disease, providing class I evidence of its antiproliferative effects. The CLARINET open-label extension study reported a median PFS of 32.8 months with lanreotide Autogel. Other smaller studies generally support CLARINET. CONCLUSION: Current clinical evidence shows that lanreotide Autogel has good antiproliferative activity with favorable safety and tolerability in patients with GEP-NETs, suggesting it should be considered as an early first-line treatment in this population. Further studies are needed to assess the potential benefits of higher doses and the use of lanreotide Autogel in combination therapy and as maintenance therapy in the absence of disease progression following other therapies. The Oncologist 2017;22:272-285 IMPLICATIONS FOR PRACTICE: This review presents the current clinical evidence for the antiproliferative activity of lanreotide Autogel in patients with midgut or pancreatic neuroendocrine tumors (NETs) and shows its effectiveness, safety, and tolerability in these patient populations. By systematically presenting all the clinical evidence, the review adds to existing publications by discussing results in a broad range of settings. The review also indicates future directions for investigation of the use of lanreotide Autogel in NETs originating in other locations, in combination therapy, or as maintenance therapy in progressive disease.

Is GH dosing optimal in female patients with adult-onset GH deficiency? An analysis from the NordiNet® International Outcome Study.

OBJECTIVE: To evaluate gender differences in GH dosing, IGF-I and cardiovascular risk markers in adults with GH deficiency (GHD). DESIGN: NordiNet® International Outcome Study (NCT00960128), a noninterventional, multicentre study, evaluates the long-term effectiveness and safety of Norditropin® (Novo Nordisk A/S) in the real-life clinical setting. PATIENTS: Nondiabetic patients (n = 252; 41·7% female) with adult-onset GHD (age ≥20 years at GH start), ≥4 years' GH therapy and glycosylated haemoglobin (HbA1c ) data at baseline and 4 years. MEASUREMENTS: Effects of gender (adjusted for baseline age and body mass index [BMI], average GH dose, treatment duration and concomitant medication) on change from baseline to 4 years (∆) in HbA1c , fasting plasma glucose (FPG), IGF-I, lipids and waist circumference were evaluated. RESULTS: GH dose (mean [SE]; mg/day) was similar between females (0·22 [0·02]) and males (0·21 [0·01]) at baseline, but higher in females from year 1 (year 4, females, 0·45 [0·03]; males, 0·32 [0·02]). Mean IGF-I standard deviation score [SDS] was lower in females vs males at each treatment year; more than one-third of females still had an IGF-I SDS below 0 at year 4, compared with only 21·8% of men. An adverse lipid profile at baseline remained poor in more females than males at 4 years. Improvement in total cholesterol was significantly associated with gender (P < 0·0001), improving less in females than in males. CONCLUSIONS: These data highlight that, even after 4 years, GH dose is suboptimal in many female patients, which may impact clinical outcomes; therefore, GH titration for women requires further improvement.

The effect of growth hormone (GH) replacement on blood glucose homeostasis in adult nondiabetic patients with GH deficiency: real-life data from the NordiNet® International Outcome Study.

OBJECTIVE: To assess the effect of 4 years' growth hormone (GH) replacement on glucose homeostasis and evaluate factors affecting glycosylated haemoglobin (HbA1c ) in adults with growth hormone deficiency (GHD). DESIGN: NordiNet® International Outcome Study, a noninterventional study, monitors long-term effectiveness and safety of GH replacement [Norditropin® (somatropin), Novo Nordisk A/S] in real-life clinical practice. PATIENTS: Nondiabetic patients (n = 245) with adult-onset GHD (age ≥20 years at GH start), ≥4 years' GH replacement and HbA1c values at baseline and 4 years were included in the analysis. MEASUREMENTS: Changes from baseline (∆) to 4 years in HbA1c , fasting plasma glucose (FPG), IGF-I, lipids (high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, total cholesterol, triglycerides), waist circumference, glycaemic (HbA1c <5·7%; HbA1c , 5·7-6·5%; HbA1c , ≥6·5%) and metabolic health status were evaluated. Effects of baseline HbA1c , gender, baseline age, average GH dose and baseline body mass index (BMI) on ΔHbA1c were investigated. The models were adjusted for concomitant medication use. RESULTS: Mean (standard deviation) baseline HbA1c was 5·13 (0·65)% and remained at the same level at 4 years. Age at treatment start (P = 0·0094) and BMI (P = 0·0008) had a significant impact on ∆HbA1c . At 4 years, 85% of patients with HbA1c <5·7% (normal levels) at baseline and 55% of patients with HbA1c 5·7-6·5% (impaired glucose tolerance) at baseline remained in the same glycaemic health category. Nineteen patients improved from impaired glucose tolerance to normal HbA1c . Seven patients developed diabetes. CONCLUSIONS: These data demonstrate that 4 years' GH replacement therapy did not adversely affect glucose homeostasis in the majority of adults with GHD.

Hormone secreting gastro-entero-pancreatic neuroendocrine neoplasias (GEP-NEN): When to consider, how to diagnose?

Neuroendocrine neoplasms of the digestive system (GEP-NEN) represent a heterogeneous group of malignancies with various clinical presentation and prognosis. GEP-NENs can potentially affect all organs of the gastrointestinal tract; characteristically they share the biological property to produce and secrete peptides and neuroamines. About 30% of GEP-NENs are hormonally active and can cause specific clinical syndromes. The clinical presentation mainly depends on the primary site of the tumor and its functionality. Because of the wide spectrum of clinical symptoms and their misperceived rarity, diagnosis of GEP-NENs is often delayed for years and tumors are detected first in an advanced stage. Early identification of a specific hormonal syndrome can significantly impact tumor diagnosis and treatment, moreover the preoperative management of NEN hormonal release avoids potential life threatening hormonal crisis. However, GEP-NEN diagnostic work-up is challenging, it requires a multidisciplinary team and needs particular experience; standardized protocols and clinical experience are essential for a proper endocrine diagnostic work-up. In addition to the biochemical diagnostic, further radiologic and endoscopic imaging modalities are required moreover, somatostatin-receptor based functional imaging, using either Octreotide-scintigraphy or novel PET-based techniques with specific isotopes like Ga68-DOTA-octreotate, plays an important role for the detection of the primary tumor as well as for the evaluation of the tumor extent.

Effects on α- and ß-cell function of sequentially adding empagliflozin and linagliptin to therapy in people with type 2 diabetes previously receiving metformin: An exploratory mechanistic study.

AIMS: To investigate the effect of sequential treatment escalation with empagliflozin and linagliptin on laboratory markers of α- and ß-cell function in people with type 2 diabetes mellitus (T2DM) insufficiently controlled on metformin monotherapy. RESEARCH DESIGN AND METHODS: A total of 44 people with T2DM received 25 mg empagliflozin for a duration of 1 month in an open-label fashion (treatment period 1 [TP1]). Thereafter, they were randomized to a double-blind add-on therapy with linagliptin 5 mg or placebo (treatment period 2 [TP2]) for 1 additional month. α- and ß-cell function was assessed using a standardized liquid meal test and an intravenous (i.v.) glucose challenge. Efficacy measures comprised the areas under the curve for glucose, insulin, proinsulin and glucagon after the liquid meal test and the assessment of fast and late-phase insulin release after an i.v. glucose load with a subsequent hyperglycaemic clamp. RESULTS: Empagliflozin reduced fasting and postprandial plasma glucose levels, associated with a significant reduction in postprandial insulin levels and an improvement in the conversion rate of proinsulin (TP1). The addition of linagliptin during TP2 further improved postprandial glucose levels, probably as a result of a marked reduction in postprandial glucagon concentrations (TP2). The insulin response to an i.v. glucose load increased during treatment with empagliflozin (TP1), and further improved after the addition of linagliptin (TP2). CONCLUSION: After metformin failure, sequential treatment escalation with empagliflozin and linagliptin is an attractive treatment option because of the additive effects on postprandial glucose control, probably mediated by complementary effects on α- and ß-cell function.

Gender-, age- and time-dependent dosing of growth hormone in adults - real-world data from a decade of clinical practice in Germany.

We evaluated treatment patterns and gender-dependent dosing of growth hormone (GH) substitution in adults with GH deficiency (AGHD). Data on GH dose were collected (2003-2013) from 509 GH-treated patients (mean age: 48.9 years; 47% female) enroled in the observational German NordiWin study (NCT01543880). The impact of gender, age, treatment duration and calendar year on GH treatment patterns was evaluated by multiple regression analysis. Mean (SD) baseline GH dose (mg/day) was similar between females (0.25 [0.19] and males (0.24 [0.15]), but increased with treatment duration (at year 10, 0.55 [0.48] and 0.31 [0.09] in females and males, respectively), reflecting patient dose titration. GH dose increased more in females than males during treatment; this was statistically significant in years 2-6 (p < 0.05). Over the 10-year study period, a time trend of an overall estimated GH dose increase by 0.06 mg/day (females) and decrease by 0.07 mg/day (males) was shown; this interaction of gender and calendar year was significant (p < 0.0001). In both genders, overall GH dose decreased with increasing age (p < 0.0001). Our study confirms that females and younger patients require higher GH doses compared with males and older patients.