Systematic review and meta-analysis of the metabolic effects of modified-release hydrocortisone versus standard glucocorticoid replacement therapy in adults with adrenal insufficiency

Context Published studies exploring the metabolic effects of Modified‐Release Hydrocortisone (MR‐HC) replacement in patients with adrenal insufficiency (AI). Objective To compare metabolic effects of MR‐HC with Standard Glucocorticoid (SG) replacement in adults with AI. Randomised control trials (RCTs) were meta‐analysed; non‐RCT studies described narratively with critical appraisal. Data sources PubMed/Medline, EMBASE, CINAHL and CENTRAL were searched to identify relevant articles, published before Aug 2019. Study selection All study types that reported metabolic profile (including anthropometric, glucose and lipid‐related parameters), on patients switched from SG to MR‐HC replacement. Following independent screening from two reviewers, 390 studies were identified, of which 9 studies were included for review (RCT, n=2; non‐RCT, n=7). Data extraction Two independent reviewers assessed each paper for bias and data extraction. Results Meta‐analysis from RCTs (n=2), 104 patients were switched from SG to MR‐HC replacement. Combining treatment effects, at 3‐months post‐therapy switch there was significant reduction in body weight (‐0.82kg; 95% CI: ‐1.24kg to ‐0.40kg; p<0.001) and HbA1c (‐0.13%; 95% CI: ‐0.214% to ‐0.045%; p=0.003). In the sub‐group with Diabetes Mellitus (DM), reduction in HbA1C was more pronounced (‐0.52%; 95% CI: ‐0.82% to ‐0.23%; p<0.001). Non‐RCT studies showed improved anthropometric measures and glucose metabolism up to 48‐months following switch from SG to MR‐HC replacement. Conclusions In adults with AI, replacement with MR‐HC associates with significant improvements in anthropometric measurements and HbA1c compared with SG replacement, particularly those with DM

Early metabolic benefits of switching hydrocortisone to modified release hydrocortisone in adult adrenal insufficiency

Purpose: To compare metabolic effects of modified release hydrocortisone (MR-HC) with standard hydrocortisone (HC) therapies in adults with Adrenal Insufficiency (AI). Methods: Adult patients (n = 12) with AI, established on HC therapy, were recruited from Endocrinology clinics at University Hospitals Coventry and Warwickshire (UHCW), UK. Baseline (HC) metabolic assessments included fasting serum HbA1C, lipid and thyroid profiles, accurate measures of body composition (BodPod), and 24-h continuous measures of energy expenditure including Sleeping Metabolic Rate (SMR) using indirect calorimetry within the Human Metabolism Research Unit, UHCW. All participants then switched HC to MR-HC with repeat (MR-HC) metabolic assessments at 3 months. Paired-sample t-tests were used for data comparisons between HC and MR-HC assessments: P-value <0.05 was considered significant. Results: Following exclusion of 2 participants, analyses were based on 10 participants. Compared with baseline HC data, following 3 months of MR-HC therapy mean fat mass reduced significantly by −3.2 kg (95% CI: −6.0 to −0.4). Mean (SD) baseline HC fat mass vs repeat MR-HC fat mass: 31.9 kg (15.2) vs 28.7 kg (12.8) respectively, P = 0.03. Mean SMR increased significantly by +77 kcal/24 h (95% CI: 10–146). Mean (SD) baseline HC SMR vs repeat MR-HC SMR: 1,517 kcal/24 h (301) vs 1,594 kcal/24 h (344) respectively, P = 0.03. Mean body fat percentage reduced significantly by −3.4% (95% CI: −6.5 to −0.2). Other measures of body composition, energy expenditure, and biochemical analytes were equivalent between HC and MR-HC assessments. Conclusions: In adults with AI, switching from standard HC to MR-HC associates with early metabolic benefits of reduced fat mass and increased SMR

Comparative analytical performance of multiple plasma Aβ42 and Aβ40 assays and their ability to predict positron emission tomography amyloid positivity

INTRODUCTION: This report details the approach taken to providing a dataset allowing for analyses on the performance of recently developed assays of amyloid beta (Aβ) peptides in plasma and the extent to which they improve the prediction of amyloid positivity. METHODS: Alzheimer's Disease Neuroimaging Initiative plasma samples with corresponding amyloid positron emission tomography (PET) data were run on six plasma Aβ assays. Statistical tests were performed to determine whether the plasma Aβ measures significantly improved the area under the receiver operating characteristic curve for predicting amyloid PET status compared to age and apolipoprotein E (APOE) genotype. RESULTS: The age and APOE genotype model predicted amyloid status with an area under the curve (AUC) of 0.75. Three assays improved AUCs to 0.81, 0.81, and 0.84 (P < .05, uncorrected for multiple comparisons). DISCUSSION: Measurement of Aβ in plasma contributes to addressing the amyloid component of the ATN (amyloid/tau/neurodegeneration) framework and could be a first step before or in place of a PET or cerebrospinal fluid screening study. HIGHLIGHTS: The Foundation of the National Institutes of Health Biomarkers Consortium evaluated six plasma amyloid beta (Aβ) assays using Alzheimer's Disease Neuroimaging Initiative samples. Three assays improved prediction of amyloid status over age and apolipoprotein E (APOE) genotype. Plasma Aβ42/40 predicted amyloid positron emission tomography status better than Aβ42 or Aβ40 alone

Current practice and surgical outcomes of neoadjuvant chemotherapy for early breast cancer : UK NeST study

Funding Information: This work was funded by a grant from the Association of Breast SurgeryPeer reviewedPublisher PD

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Fasting and post prandial pancreatic and enteroendocrine hormone levels in obese and non-obese participants.

Circulating insulin levels are known to be increased in people with higher body mass index (BMI) due to effects of adiposity on insulin resistance, whilst gut hormones have a more complex relationship, with fasting peptideYY (PYY) reported to be inversely related to BMI. This study aimed to further explore fasting and post prandial pancreatic and gut hormone concentrations in plasma samples from obese and non-obese participants. Participants with healthy BMI (n=15), overweight BMI (n=29) and obesity (n=161) had samples taken fasting and 30 min post mixed liquid meal for analysis of glucagon-like peptide-1 (GLP-1), PYY, glucose-dependent insulinotropic polypeptide (GIP), insulin and glucagon. Data visualiation used linear discriminant analysis for dimensionality reduction, to visualise the data and assess scaling of each hormone. Fasting levels of insulin, GIP and PYY were shown to be key classifiers between the 3 groups on ANCOVA analysis, with an observation of increased GIP levels in overweight, but not obese participants. In non-obese subjects, fasting GIP, PYY and insulin correlated with BMI, whereas in subjects with obesity only the pancreatic hormones glucagon and insulin correlated with BMI. Concentrations of total GLP-1 in the fasting state correlated strongly with glucagon levels, highlighting potential assay cross-reactivities. The study, which included a relatively large number of subjects with severe obesity, supported previous evidence of BMI correlating negatively with fasting PYY and positively with fasting insulin. The observation of increased fasting GIP levels in overweight but not obese participants deserves further validation and mechanistic investigation.BBC Novo Nordisk Diabetes U

Motilin fluctuations in healthy volunteers determined by liquid chromatography mass spectrometry.

INTRODUCTION: Motilin is a hormone secreted by specialised enteroendocrine cells in the small intestine, and is known to modulate gastrointestinal motility in humans, regulating the migratory motor complex. It is understudied at least in part due to the lack of commercially available immunoassays. METHOD: A multiplexed liquid chromatography mass spectrometry (LC-MS/MS) method was optimised to measure motilin, insulin, C-peptide, GIP (1-42) and GIP (3-42). Corresponding active ghrelin concentrations were determined by immunoassay. Ten healthy volunteers with no prior history of gastroenterological or endocrine condition attended after overnight fast and had blood samples taken every 15 minutes for 4 hours whilst continuing to fast, and then further sampling for 2 hours following a liquid mixed meal. Hunger scores were taken at each time point using a visual analogue scale. Normal bowel habit was confirmed by 1 week stool diary. RESULTS: Motilin levels fluctuated in the fasting state with an average period between peaks of 109.5 mins (SD:30.0), but with no evidence of a relationship with either ghrelin levels or hunger scores. The mixed meal interrupted cyclical motilin fluctuations, increased concentrations of motilin, insulin, C-peptide, GIP(1-42) and GIP(3-42), and suppressed ghrelin levels. DISCUSSION: This study highlights the utility of LC-MS/MS for parallel measurement of motilin alongside other peptide hormones, and supports previous reports of the cyclical nature of motilin levels in the fasting state and interruption with feeding. This analytical method has utility for further clinical studies into motilin and gut hormone physiology in human volunteers.NIHR, LGC, Mercodi

Motilin fluctuations in healthy volunteers determined by liquid chromatography mass spectrometry

IntroductionMotilin is a hormone secreted by specialised enteroendocrine cells in the small intestine, and is known to modulate gastrointestinal motility in humans, regulating the migratory motor complex. It is understudied at least in part due to the lack of commercially available immunoassays.MethodA multiplexed liquid chromatography mass spectrometry (LC-MS/MS) method was optimised to measure motilin, insulin, C-peptide, GIP (1–42) and GIP (3–42). Corresponding active ghrelin concentrations were determined by immunoassay. Ten healthy volunteers with no prior history of gastroenterological or endocrine condition attended after overnight fast and had blood samples taken every 15 minutes for 4 hours whilst continuing to fast, and then further sampling for 2 hours following a liquid mixed meal. Hunger scores were taken at each time point using a visual analogue scale. Normal bowel habit was confirmed by 1 week stool diary.ResultsMotilin levels fluctuated in the fasting state with an average period between peaks of 109.5 mins (SD:30.0), but with no evidence of a relationship with either ghrelin levels or hunger scores. The mixed meal interrupted cyclical motilin fluctuations, increased concentrations of motilin, insulin, C-peptide, GIP(1-42) and GIP(3-42), and suppressed ghrelin levels.DiscussionThis study highlights the utility of LC-MS/MS for parallel measurement of motilin alongside other peptide hormones, and supports previous reports of the cyclical nature of motilin levels in the fasting state and interruption with feeding. This analytical method has utility for further clinical studies into motilin and gut hormone physiology in human volunteers

Early and Late Outcomes Following Valve Sparing Aortic Root Reconstruction: The ANZSCTS Database

Background: Valve sparing aortic root reconstruction (VSARR) has become an alternative to traditional aortic root replacement with a valved conduit. There have been various modifications but the two broad types are aortic root reimplantation and the aortic root remodelling procedure. We present the early and late outcomes following valve sparing aortic root reconstruction surgery in Australia. Methods: We reviewed the ANZSCTS database for patients undergoing these procedures. Preoperative, intraoperative and postoperative variables were analysed. Multivariable regression was performed to determine independent predictors of 30-day mortality. We also obtained five- and 10-year survival estimates by cross-linking the ANZSCTS database with the Australian Institute of Health and Welfare's National Death Index. Results: Between January 2001 and January 2012, 169 consecutive patients underwent VSARR procedures. The mean age of the study population was 54.4 years with 31.4% being females. Overall, nine patients (5.9%) died within 30 days post procedure and five patients (3%) had permanent strokes. However, out of 132 elective cases, only five patients died (3.8%). Independent predictors of 30-day mortality were female gender [OR 5.65(1.24-25.80), p=0.025], preoperative atrial arrhythmia [OR 6.07(1.14-32.35), p=0.035] and acute type A aortic dissection [OR 7.71(1.63-36.54), p=0.01]. Long-term survival was estimated as 85.3% and 72.7% at five- and 10-years, respectively. Conclusions: Along with an acceptable rate of early mortality and stroke, VSARR procedures provide good long-term survival according to the ANZSCTS database. As promising procedure for pathologies that impair the aortic root integrity, they can be adopted more widely, especially in Australian and New Zealand centres with experienced aortic units.Future studies are planned to assess freedom from valve deterioration and repeat surgery

The Aortic Root Replacement Procedure: 12-year Experience From the Australian and New Zealand Society of Cardiac and Thoracic Surgeons Database

Background: The aortic root replacement procedure (ARR), is often considered the gold standard in the management of aortic root and ascending aorta aneurysms. Our aim was to review the Australian experience with this procedure to ascertain early and late outcomes of mortality and morbidity. Methods: We reviewed the Australian and New Zealand Society of Cardiac and Thoracic Surgeons' (ANZSCTS) database for patients undergoing ARR. Preoperative, intraoperative and postoperative variables were analysed. Multiple regression was performed to determine independent predictors of 30-day mortality and permanent stroke, and predictors of late death. Survival estimates were obtained by cross-linking the ANZSCTS database with the Australian Institute of Health and Welfare's National Death Index database. Results: Between January 2001 and December 2011, 954 patients underwent ARR with a mean age of 56. ±. 15.2 years. The overall 30-day mortality was 5.9% (n = 56) with a permanent stroke rate of 2.3% (n = 21). The elective surgery mortality was 3.6%. Long-term survival was estimated as 84.4% and 68.7% at 5 and 10 years, respectively. Conclusions: Aortic root replacement surgery reveals acceptable early mortality, low postoperative stroke rates, and acceptable long-term survival