WITHDRAWN: GLP-1 Has an Anti-Inflammatory Effect on Adipose Tissue Expression of Cytokines, Chemokines, and Receptors in Obese Women.

The above-named article by Manning PJ, Dixit P, Satthenapalli VR, Katare R, and Sutherland WHF (J Clin Endocrinol Metab. [published online ahead of print 21 May 2019]; doi: 10.1210/jc.2018-00197) has been withdrawn by the authors. The authors report, "The reason for this decision is that the statistical methodology we used did not adequately limit the impact of outlier data points on our findings. This was evident after reanalysis of the data using a different method." doi: 10.1210/jc.2019-01393.

Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines: 2016 revision

BACKGROUND: Allergic rhinitis (AR) affects 10% to 40% of the population. It reduces quality of life and school and work performance and is a frequent reason for office visits in general practice. Medical costs are large, but avoidable costs associated with lost work productivity are even larger than those incurred by asthma. New evidence has accumulated since the last revision of the Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines in 2010, prompting its update. OBJECTIVE: We sought to provide a targeted update of the ARIA guidelines. METHODS: The ARIA guideline panel identified new clinical questions and selected questions requiring an update. We performed systematic reviews of health effects and the evidence about patients' values and preferences and resource requirements (up to June 2016). We followed the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) evidence-to-decision frameworks to develop recommendations. RESULTS: The 2016 revision of the ARIA guidelines provides both updated and new recommendations about the pharmacologic treatment of AR. Specifically, it addresses the relative merits of using oral H1-antihistamines, intranasal H1-antihistamines, intranasal corticosteroids, and leukotriene receptor antagonists either alone or in combination. The ARIA guideline panel provides specific recommendations for the choice of treatment and the rationale for the choice and discusses specific considerations that clinicians and patients might want to review to choose the management most appropriate for an individual patient. CONCLUSIONS: Appropriate treatment of AR might improve patients' quality of life and school and work productivity. ARIA recommendations support patients, their caregivers, and health care providers in choosing the optimal treatment.

Three-year experience with access to nationally funded growth hormone (GH) replacement for GH-deficient adults.

OBJECTIVE: Treatment of growth hormone (GH)-deficient adults with GH has been shown to improve a range of metabolic abnormalities and enhance quality of life. However, the results of access to nationally funded treatment have not been reported. DESIGN: Retrospective case series auditing nationally funded treatment of defined GH-deficient adults in New Zealand, with carefully designed entry and exit criteria overseen by a panel of endocrinologists. PATIENTS: Applications for 201 patients were assessed and 191 approved for funded treatment over the initial 3 years since inception. The majority had GH deficiency following treatment of pituitary adenomas or tumours adjacent to the pituitary. RESULTS: After an initial 9-month treatment period using serum IGF-I measurements to adjust GH dosing, all patients reported a significant improvement in quality of life (QoL) score on the QoL-AGHDA(®) instrument (baseline (95%CI) 19 (18-21), 9 months 6 (5-7.5)), and mean serum IGF-I SD scores rose from -3 to zero. Mean waist circumference decreased significantly by 2.8 ± 0.6 cm. The mean maintenance GH dose after 9 months of treatment was 0.39 mg/day. After 3 years, 17% of patients had stopped treatment, and all of the remaining patients maintained the improvements seen at 9 months of treatment. CONCLUSION: Carefully designed access to nationally funded GH replacement in GH-deficient adults was associated with a significant improvement in quality of life over a 3-year period with mean daily GH doses lower than in the majority of previously reported studies.

Leaf metallome preserved over 50 million years.

Large-scale Synchrotron Rapid Scanning X-ray Fluorescence (SRS-XRF) elemental mapping and X-ray absorption spectroscopy are applied here to fossil leaf material from the 50 Mya Green River Formation (USA) in order to improve our understanding of the chemistry of fossilized plant remains. SRS-XRF of fossilized animals has previously shown that bioaccumulated trace metals and sulfur compounds may be preserved in their original distributions and these elements can also act as biomarkers for specific biosynthetic pathways. Similar spatially resolved chemical data for fossilized plants is sparsely represented in the literature despite the multitude of other chemical studies performed. Here, synchrotron data from multiple specimens consistently show that fossil leaves possess chemical inventories consisting of organometallic and organosulfur compounds that: (1) map discretely within the fossils, (2) resolve fine scale biological structures, and (3) are distinct from embedding sedimentary matrices. Additionally, the chemical distributions in fossil leaves are directly comparable to those of extant leaves. This evidence strongly suggests that a significant fraction of the chemical inventory of the examined fossil leaf material is derived from the living organisms and that original bioaccumulated elements have been preserved in situ for 50 million years. Chemical information of this kind has so far been unknown for fossilized plants and could for the first time allow the metallome of extinct flora to be studied.

Enhancing clinical skill development through an Ambulatory Medicine Teaching Programme: an evaluation study.

BACKGROUND: Teaching of clinical skills traditionally takes place in hospital wards and outpatient settings. However high acuity and short hospital stays means there are fewer suitable inpatients available for teaching; and time pressures limit students' involvement in other settings. The Ambulatory Medicine Programme was established to develop undergraduate medical students' clinical skills by providing increased exposure to patients with a wide range of chronic medical conditions, in a dedicated learning environment. METHOD: A mixed qualitative/quantitative approach was used to evaluate the Programme. This research focuses on staff and student perspectives of teaching and learning in Ambulatory Medicine compared with inpatient and outpatient settings; identifies which teaching methods are considered most effective; and determines the transferability of learning. Patients' perspectives of being involved in student teaching are also reported. RESULTS: Results show that the programme has made a positive impact on students' development of clinical skills, which are transferable to the clinical setting. Patients enjoy being involved and find it personally satisfying. CONCLUSIONS: The Ambulatory Medicine Programme is an effective way of developing medical students' clinical skills by providing focussed teaching with real patients in a dedicated learning environment.

The effect of lipoic acid and vitamin E therapies in individuals with the metabolic syndrome.

The metabolic syndrome is associated with abnormal glucose and lipid metabolism, insulin resistance, increased oxidative stress and pro-inflammatory activity that increase the risk of type 2 diabetes and cardiovascular disease. The aim of this study was to investigate the effect of treatment with the antioxidant α-lipoic acid (ALA) with or without vitamin E supplementation, on markers of insulin resistance and systemic inflammation and plasma nonesterified fatty acid (NEFA) concentrations in individuals with the metabolic syndrome. In a randomized, double-blind, placebo-controlled trial, subjects with the metabolic syndrome received ALA (600 mg/day, n = 34), vitamin E (100 IU/day, n = 36), both ALA and vitamin E (n = 41), or matching placebo (n = 40) for 1 year. Fasting circulating concentrations of glucose and insulin were measure every 3 months and NEFA, markers of inflammation, adiponectin and vitamin E were measured at 6 monthly intervals. Plasma NEFA concentrations decreased [-10 (-18, 0)%] at a marginal level of significance (p = 0.05) in those who received ALA alone compared with placebo and decreased [-8 (-14, -1)% (95% CI)] significantly (P = 0.02) in participants who were randomised to ALA with and without vitamin E compared with those who did not receive ALA. Fasting glucose, insulin, homeostatic model assessment of insulin resistance, adiponectin, and markers of inflammation did not change significantly during the study. These data suggest that prolonged treatment with ALA may modestly reduce plasma NEFA concentrations but does not alter insulin or glucose levels in individuals with the metabolic syndrome.

Minimum convex hull mass estimations of complete mounted skeletons.

Body mass is a critical parameter used to constrain biomechanical and physiological traits of organisms. Volumetric methods are becoming more common as techniques for estimating the body masses of fossil vertebrates. However, they are often accused of excessive subjective input when estimating the thickness of missing soft tissue. Here, we demonstrate an alternative approach where a minimum convex hull is derived mathematically from the point cloud generated by laser-scanning mounted skeletons. This has the advantage of requiring minimal user intervention and is thus more objective and far quicker. We test this method on 14 relatively large-bodied mammalian skeletons and demonstrate that it consistently underestimates body mass by 21 per cent with minimal scatter around the regression line. We therefore suggest that it is a robust method of estimating body mass where a mounted skeletal reconstruction is available and demonstrate its usage to predict the body mass of one of the largest, relatively complete sauropod dinosaurs: Giraffatitan brancai (previously Brachiosaurus) as 23200 kg.

Trace metals as biomarkers for eumelanin pigment in the fossil record.

Well-preserved fossils of pivotal early bird and nonavian theropod species have provided unequivocal evidence for feathers and/or downlike integuments. Recent studies have reconstructed color on the basis of melanosome structure; however, the chemistry of these proposed melanosomes has remained unknown. We applied synchrotron x-ray techniques to several fossil and extant organisms, including Confuciusornis sanctus, in order to map and characterize possible chemical residues of melanin pigments. Results show that trace metals, such as copper, are present in fossils as organometallic compounds most likely derived from original eumelanin. The distribution of these compounds provides a long-lived biomarker of melanin presence and density within a range of fossilized organisms. Metal zoning patterns may be preserved long after melanosome structures have been destroyed.

Infrared mapping resolves soft tissue preservation in 50 million year-old reptile skin.

Non-destructive Fourier Transform InfraRed (FTIR) mapping of Eocene aged fossil reptile skin shows that biological control on the distribution of endogenous organic components within fossilized soft tissue can be resolved. Mapped organic functional units within this approximately 50 Myr old specimen from the Green River Formation (USA) include amide and sulphur compounds. These compounds are most probably derived from the original beta keratin present in the skin because fossil leaf- and other non-skin-derived organic matter from the same geological formation do not show intense amide or thiol absorption bands. Maps and spectra from the fossil are directly comparable to extant reptile skin. Furthermore, infrared results are corroborated by several additional quantitative methods including Synchrotron Rapid Scanning X-Ray Fluorescence (SRS-XRF) and Pyrolysis-Gas Chromatography/Mass Spectrometry (Py-GC/MS). All results combine to clearly show that the organic compound inventory of the fossil skin is different from the embedding sedimentary matrix and fossil plant material. A new taphonomic model involving ternary complexation between keratin-derived organic molecules, divalent trace metals and silicate surfaces is presented to explain the survival of the observed compounds. X-ray diffraction shows that suitable minerals for complex formation are present. Previously, this study would only have been possible with major destructive sampling. Non-destructive FTIR imaging methods are thus shown to be a valuable tool for understanding the taphonomy of high-fidelity preservation, and furthermore, may provide insight into the biochemistry of extinct organisms.

The 'Goldilocks' effect: preservation bias in vertebrate track assemblages.

Finite-element analysis was used to investigate the extent of bias in the ichnological fossil record attributable to body mass. Virtual tracks were simulated for four dinosaur taxa of different sizes (Struthiomimus, Tyrannosaurus, Brachiosaurus and Edmontosaurus), in a range of substrate conditions. Outlines of autopodia were generated based upon osteology and published soft-tissue reconstructions. Loads were applied vertically to the feet equivalent to the weight of the animal, and distributed accordingly to fore- and hindlimbs where relevant. Ideal, semi-infinite elastic-plastic substrates displayed a 'Goldilocks' quality where only a narrow range of loads could produce tracks, given that small animals failed to indent the substrate, and larger animals would be unable to traverse the area without becoming mired. If a firm subsurface layer is assumed, a more complete assemblage is possible, though there is a strong bias towards larger, heavier animals. The depths of fossil tracks within an assemblage may indicate thicknesses of mechanically distinct substrate layers at the time of track formation, even when the lithified strata appear compositionally homogeneous. This work increases the effectiveness of using vertebrate tracks as palaeoenvironmental indicators in terms of inferring substrate conditions at the time of track formation. Additionally, simulated undertracks are examined, and it is shown that complex deformation beneath the foot may not be indicative of limb kinematics as has been previously interpreted, but instead ridges and undulations at the base of a track may be a function of sediment displacement vectors and pedal morphology.

Simulating sauropod manus-only trackway formation using finite-element analysis.

The occurrence of sauropod manus-only trackways in the fossil record is poorly understood, limiting their potential for understanding locomotor mechanics and behaviour. To elucidate possible causative mechanisms for these traces, finite-element analyses were conducted to model the indentation of substrate by the feet of Diplodocus and Brachiosaurus. Loading was accomplished by applying mass, centre of mass and foot surface area predictions to a range of substrates to model track formation. Experimental results show that when pressure differs between manus and pes, as determined by the distribution of weight and size of respective autopodia, there is a range of substrate shear strengths for which only the manus (or pes) produce enough pressure to deform the substrate, generating a track. If existing reconstructions of sauropod feet and mass distributions are correct, then different taxa will produce either manus- or pes-only trackways in specific substrates. As a result of this work, it is predicted that the occurrence of manus- or pes-only trackways may show geo-temporal correlation with the occurrence of body fossils of specific taxa.

Archaeopteryx feathers and bone chemistry fully revealed via synchrotron imaging.

Evolution of flight in maniraptoran dinosaurs is marked by the acquisition of distinct avian characters, such as feathers, as seen in Archaeopteryx from the Solnhofen limestone. These rare fossils were pivotal in confirming the dinosauria-avian lineage. One of the key derived avian characters is the possession of feathers, details of which were remarkably preserved in the Lagerstätte environment. These structures were previously simply assumed to be impressions; however, a detailed chemical analysis has, until now, never been completed on any Archaeopteryx specimen. Here we present chemical imaging via synchrotron rapid scanning X-ray fluorescence (SRS-XRF) of the Thermopolis Archaeopteryx, which shows that portions of the feathers are not impressions but are in fact remnant body fossil structures, maintaining elemental compositions that are completely different from the embedding geological matrix. Our results indicate phosphorous and sulfur retention in soft tissue as well as trace metal (Zn and Cu) retention in bone. Other previously unknown chemical details of Archaeopteryx are also revealed in this study including: bone chemistry, taphonomy (fossilization process), and curation artifacts. SRS-XRF represents a major advancement in the study of the life chemistry and fossilization processes of Archaeopteryx and other extinct organisms because it is now practical to image the chemistry of large specimens rapidly at concentration levels of parts per million. This technique has wider application to the archaeological, forensic, and biological sciences, enabling the mapping of "unseen" compounds critical to understanding biological structures, modes of preservation, and environmental context.

Active smoking and second-hand-smoke exposure at home among Irish children, 1995-2007.

OBJECTIVE: This study hypothesised a continual decline in current smoking prevalence over four calendar years (1995, 1998, 2002/03 and 2007) and no significant increase in second-hand-smoke (SHS) exposure levels at home after the workplace smoking ban of March 2004 (2007 versus 2002/03 survey) among Irish school children. METHODS: A modified ISAAC (International Study of Asthma and Allergies in Childhood) protocol was used. Children aged 13-14 years from randomly selected representative post-primary schools were studied: 2670 in 1995, 2273 in 1998, 2892 in 2002-2003, and 2805 in 2007. ISAAC is a cross-sectional self-administered questionnaire survey. Smoking history was self-reported. beta Coefficients (slopes) of smoking rates across the four surveys were computed. Odds ratios for smoking rates were also computed using the baseline year (1995) as the reference period. All analyses were performed using SAS software (v 9.1). RESULTS: There were significant reductions in active smoking rates between 1995 and 2007 (from 19.9% to 10.6%, respectively) resulting in 3.3% survey-to-survey reductions, with a significantly greater survey-to-survey decline among girls compared to boys (3.8% vs 2.7%, respectively). 45% of children were exposed to SHS at home in 2007. There was a statistically non-significant 2% overall decline in SHS exposure levels at home in 2007 relative to 2002/03, which was more pronounced in girls. CONCLUSIONS: The continual reduction in active smoking prevalence in children is welcome. That there was no significant increase in SHS exposure at home after the nationwide workplace smoking ban suggests that the ban did not increase smoking inside homes.

Second-hand smoke exposure in cars and respiratory health effects in children.

We examined potential associations of ever asthma, and symptoms of wheeze (past 12 months), hay fever, eczema and bronchitis (cough with phlegm) among school children exposed to second-hand smoke (SHS) in cars, using a modified Irish International Study of Asthma and Allergies in Childhood (ISAAC) protocol. 2,809 children of 13-14 yrs old and who selected randomly from post-primary schools throughout Ireland completed the 2007 ISAAC self-administered questionnaire. Adjusted OR (adjusted for sex, active smoking status of children interviewed and their SHS exposure at home) were estimated for the associations studied, using multivariable logistic regression techniques. Overall, 14.8% (13.9% in young males, 15.4% in young females) of Irish children aged 13-14 yrs old were exposed to SHS in cars. Although there was a tendency towards increased likelihood of both respiratory and allergic symptoms with SHS exposure in cars, wheeze and hay fever symptoms were significantly higher (adjusted OR 1.35 (95% CI 1.08-1.70) and 1.30 (1.01-1.67), respectively), while bronchitis symptoms and asthma were not significant (1.33 (0.92-1.95) and 1.07 (0.81-1.42), respectively). Approximately one in seven Irish schoolchildren are exposed to SHS in cars and could have adverse respiratory health effects. Further studies are imperative to explore such associations across different population settings.

Effects of gender and age on paediatric headache.

The aim of this study was to evaluate the impact of gender and age on headache characteristics and disability. Headache characteristics were assessed at an initial visit to a paediatric specialty care centre and five follow-up visits. A total number of 4121 patients were evaluated. Fifty-eight per cent of the sample was female. Boys were younger at their first headache and initial visit. They more frequently described headache pain as squeezing and location as top of the head. Girls reported more frequent and longer headaches. Girls more often described headache pain as sharp and location as back of the head. Age accounted for more variance than gender in headache severity, duration, frequency and disability. Gender differences exist in headache characteristics. Age is also an important factor in the variability in characteristics and disability. Longitudinal studies are needed to describe further the natural history of headaches in childhood and compare outcome between genders.

Nitrogen enrichment modifies plant community structure via changes to plant-soil feedback.

We tested the hypothesis that N enrichment modifies plant-soil feedback relationships, resulting in changes to plant community composition. This was done in a two-phase glasshouse experiment. In the first phase, we grew eight annual plant species in monoculture at two levels of N addition. Plants were harvested at senescence and the effect of each species on a range of soil properties was measured. In the second phase, the eight plant species were grown in multi-species mixtures in the eight soils conditioned by the species in the first phase, at both levels of N addition. At senescence, species performance was measured as aboveground biomass. We found that in the first phase, plant species identity strongly influenced several soil properties, including microbial and protist biomass, soil moisture content and the availability of several soil nutrients. Species effects on the soil were mostly independent of N addition and several were strongly correlated with plant biomass. In the second phase, both the performance of individual species and overall community structure were influenced by the interacting effects of the species identity of the previous soil occupant and the rate of N addition. This indicates that N enrichment modified plant-soil feedback. The performance of two species correlated with differences in soil N availability that were generated by the species formerly occupying the soil. However, negative feedback (poorer performance on the soil of conspecifics relative to that of heterospecifics) was only observed for one species. In conclusion, we provide evidence that N enrichment modifies plant-soil feedback relationships and that these modifications may affect plant community composition. Field testing and further investigations into which mechanisms dominate feedback are required before we fully understand how and when feedback processes determine plant community responses to N enrichment.

Ciclesonide versus placebo for chronic asthma in adults and children.

BACKGROUND: Inhaled corticosteroids are an integral part of asthma management, and act as an anti-inflammatory agent in the airways of the lung. These agents confer significant benefit in terms of symptom management and improvement in lung function, but may also cause harm in terms of local and systemic side-effects. Ciclesonide is a novel steroid that has efficient distribution and release properties that mean it can be taken once daily, making it potentially useful in ongoing asthma management. OBJECTIVES: To assess the efficacy of inhaled ciclesonide in adults and children with chronic asthma. SEARCH STRATEGY: We searched the Cochrane Airways Group register of trials with pre-defined terms. Additional searches of CENTRAL and PubMed were undertaken. The literature searches for this review are current up to June 2007. SELECTION CRITERIA: Randomised parallel or crossover studies were eligible for the review. We included studies comparing ciclesonide with placebo, and we also included studies comparing ciclesonide at different doses. DATA COLLECTION AND ANALYSIS: Two authors assessed studies for inclusion in the review, extracted data independently and checked each others' work. We contacted study investigators in order to obtain additional data. Extracted data were entered into RevMan 4.2 and analysed as fixed effect mean differences for continuous data, and fixed effect risk ratios for dichotomous data. MAIN RESULTS: Eighteen trials (reporting 20 study comparisons) met the review entry criteria. We report findings from 18 group comparisons where data were available (6343 participants, of whom 1692 were children). Ciclesonide versus placebo: The short duration of the included studies means that there is a lack of data with respect to the impact of ciclesonide on asthma exacerbations. At doses of 100 mcg/d or less up to 400 mcg/d in mild to moderate asthma, ciclesonide improved lung function, asthma symptoms and rescue inhaler use, compared with placebo.Dose response outcomes: Comparisons of 100 versus 200 mcg/d, 100 versus 400 mcg/d and 400 versus 800 mcg/d did not yield significant differences in lung function outcomes. Adverse event data were not available in sufficient detail to permit assessment of the safety profile of this drug. AUTHORS' CONCLUSIONS: Ciclesonide was more effective than placebo, in the short term, in improving lung function in patients with mild to moderate asthma previously treated with inhaled corticosteroids. There remain questions as to dose response, and the lack of data on the longer term impact on exacerbations and safety profile should be addressed in future studies.

Ciclesonide versus other inhaled steroids for chronic asthma in children and adults.

BACKGROUND: Inhaled corticosteroids (ICS) are an integral part of asthma management, and act as an anti-inflammatory agent in the airways of the lung. These agents confer both significant benefit in terms of symptom management and improvement in lung function, but may also cause harm in terms of local and systemic side-effects. Ciclesonide is a novel steroid that is metabolised to its active component in the lung, making it a potentially useful for reducing local side effects. OBJECTIVES: To assess the efficacy and adverse effects of ciclesonide relative to those of other inhaled corticosteroids in the management of chronic asthma. SEARCH STRATEGY: We searched the Cochrane Airways Group register of trials with pre-defined terms. Additional searches of PubMed and Clinicalstudyresults.org were undertaken. The literature searches for this review are current up to June 2007. SELECTION CRITERIA: Randomised parallel or crossover studies were eligible for the review. We included studies comparing ciclesonide with other steroids both at nominally equivalent dose or lower doses of ciclesonide. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. Study authors were contacted for additional information. Adverse effects information was collected from the trials. MAIN RESULTS: Twenty one trials involving 7243 participants were included. Equal daily doses of ciclesonide and beclomethasone (BDP) or budesonide (BUD) gave similar results for peak expiratory flow rates (PEF), although forced vital capacity (FVC) was higher with ciclesonide. Data on forced expired volume in one second (FEV1) were inconsistent. Withdrawal data and symptoms were similar between treatments. Compared with the same dose of fluticasone (FP), data on lung function parameters (FEV1, FVC and PEF) did not differ significantly. Paediatric quality of life score favoured ciclesonide. Candidiasis was less frequent with ciclesonide, although other side-effect outcomes did not give significant differences in favour of either treatment. When lower doses of ciclesonide were compared to BDP or BUD, the difference in FEV1 did not reach significance but we cannot exclude a significant effect in favour of BDP/BUD. Other lung function outcomes did not give significant differences between treatments. Paediatric quality of life scores did not differ between treatments. Adverse events occurred with similar frequency between ciclesonide and BDP/BUD. Comparison with FP at half the nominal dose was undertaken in three studies, which indicated that FEV1 was not significantly different, but was not equivalent between the treatments (per protocol: -0.05 L 95% confidence intervals -0.11 to 0.01). AUTHORS' CONCLUSIONS: The results of this review give some support to ciclesonide as an equivalent therapy to other ICS at similar nominal doses. The studies assessed low doses of steroids, in patients whose asthma required treatment with low doses of steroids. At half the dose of FP and BDP/BUD, the effects of ciclesonide were more inconsistent The effect on candidiasis may be of importance to people who find this to be problematic. The role of ciclesonide in the management of asthma requires further study, especially in paediatric patients. Further assessment against FP at a dose ratio of 1:2 is a priority.