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Quentin M Anstee,1,2 Kate Hallsworth,1,2 Niall Lynch,3 Adrien Hauvespre,4 Eid Mansour,5 Sam Kozma,5 Juliana Bottomley,6 Gary Milligan,7 James Piercy,8 Victoria Higgins9 1Translational & Clinical Research Institute, Faculty of Medical Sciences, University of Newcastle, Newcastle Upon Tyne, UK; 2Liver Unit, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK; 3Global Value and Access, Gilead Sciences, Hayes, Uxbridge, UK; 4Market Access and Reimbursement, Gilead Sciences, Hayes, Uxbridge, UK; 5Pricing and Market Access (Middle East), Gilead Sciences, Dubai, United Arab Emirates; 6Pricing and Market Access, Gilead Sciences, Hayes, Uxbridge, UK; 7Statistics Department, Adelphi Real World, Bollington, UK; 8Scientific Franchise, Adelphi Real World, Bollington, UK; 9Scientific and NASH Franchise, Adelphi Real World, Bollington, UKCorrespondence: Victoria Higgins, Adelphi Real World, Adelphi Mill, Grimshaw Lane, Bollington, SK10 5JB, UK, Tel +44 1625 577233, Email victoria.higgins@adelphigroup.comObjective: Stratifying disease severity in patients with non-alcoholic steatohepatitis (NASH) is essential for appropriate treatment and long-term management. Liver biopsy is the reference standard for fibrosis severity in NASH, but less invasive methods are used, eg, Fibrosis-4 Index (FIB-4) and vibration-controlled transient elastography (VCTE), for which reference thresholds for no/early fibrosis and advanced fibrosis are available. We compared subjective physician assessment of NASH fibrosis versus reference thresholds to understand classification in a real-world setting.Methods: Data were drawn from Adelphi Real World NASH Disease Specific ProgrammeTM conducted in France, Germany, Italy, Spain and UK in 2018. Physicians (diabetologists, gastroenterologists, hepatologists) completed questionnaires for five consecutive NASH patients presenting for routine care. Physician-stated fibrosis score (PSFS) based on available information was compared with clinically defined reference fibrosis stage (CRFS) determined retrospectively using VCTE and FIB-4 data and eight reference thresholds.Results: One thousand two hundred and eleven patients had VCTE (n = 1115) and/or FIB-4 (n = 524). Depending on thresholds, physicians underestimated severity in 16– 33% (FIB-4) and 27– 50% of patients (VCTE). Using VCTE ≥ 12.2, diabetologists, gastroenterologists and hepatologists underestimated disease severity in 35%, 32%, and 27% of patients, respectively, and overestimated fibrosis in 3%, 4%, and 9%, respectively (p = 0.0083 across specialties). Hepatologists and gastroenterologists had higher liver biopsy rates than diabetologists (52%, 56%, 47%, respectively).Conclusion: PSFS did not consistently align with CRFS in this NASH real-world setting. Underestimation was more common than overestimation, potentially leading to undertreatment of patients with advanced fibrosis. More guidance on interpreting test results when classifying fibrosis is needed, thereby improving management of NASH.Keywords: fibrosis staging, non-alcoholic steatohepatitis, clinically derived reference fibrosis score, physician-stated fibrosis score, real-world evidence

Victoria Higgins, James Piercy, Adam Roughley, Gary Milligan, Andrea Leith, James Siddall, Mike Benford Adelphi Real World, Macclesfield, UK Background: Despite the availability of a variety of treatments, many patients with type 2 diabetes mellitus (T2DM) are not achieving glucose control. We analyzed successive waves of the Adelphi Real World Diabetes Disease Specific Programmes (DSPs) to assess treatment patterns reported by primary care physicians (PCPs) and specialists and the effect of treatment on levels of glucose control.Methods: Data were collected between 2000 and 2015 in the US and EU5 (France, Germany, Italy, Spain, and the UK). Physicians completed patient record forms for the next 10 patients consulting with T2DM. Key aspects captured were change over time in therapy usage, time to insulin introduction, and glycated hemoglobin (HbA1c) levels.Results: Over 12 DSP waves, 3,555 specialists and 5,109 PCPs completed questionnaires for 70,657 patients. Treatment patterns changed considerably over time as new agents were introduced. The number of agents prescribed per patient increased over time, as did HbA1c levels at which physicians stated they would introduce insulin. The greatest improvements in HbA1c levels occurred during 2000–2008, with little improvement since 2008.Conclusion: In this real-world setting, the proportion of patients with T2DM achieving good glucose control has not increased greatly since 2008. A better understanding of how to individualize treatment pathways may be required to improve control in these patients. Keywords: insulinization, real world, type 2 diabetes, treatment trends

David Price,1 Mark Small,2 Gary Milligan,2 Victoria Higgins,2 Esther Garcia Gil,3 Jordi Estruch3 1Centre of Academic Primary Care, University of Aberdeen, Aberdeen, UK; 2Adelphi Real World, Adelphi Mill, Bollington, UK; 3Almirall S.A., Barcelona, Spain Background: Sleep quality is often poor in patients with chronic obstructive pulmonary disease (COPD). A cross-sectional European survey investigated the prevalence of night-time symptoms in COPD to evaluate the level of disconnect between physician and patient perceptions of the presence of night-time symptoms, and to compare the characteristics of patients with and without night-time symptoms. Methods: A total of 251 primary care physicians and 251 respiratory specialists completed record forms on 2,807 patients with COPD. The forms captured information on patient demographics, lung function, COPD severity, and symptoms. Patients completed questionnaires on the time of day when their COPD symptoms bothered them, and the impact of COPD on their ability to get up in the morning and on sleep. Data were compared between groups (those with and without night-time symptoms) using t-tests or Wilcoxon signed rank tests. The kappa statistic was used to assess the level of disconnect between physician and patient perceptions of the impact of night-time symptoms. Results: Most patients (78%) reported night-time disturbance. Patients with night-time symptoms experienced more daytime breathlessness (mean modified Medical Research Council dyspnea scale score 2.4 versus 1.1) and exacerbations in the previous 12 months (mean 1.7 versus 0.4), and received more maintenance therapy (mean of 2.8 versus 2.3 products) than those without. Concordance between the frequency of physician-reported (67.9% of patients) and patient-reported (68.5% of patients) night-time symptoms was good. Physicians significantly underestimated the impact of COPD on the patient's ability to get up in the morning and on sleep (fair–moderate agreement). Physician-reported night-time symptoms were present for 41.2% of patients who could be categorized by Global initiative for chronic Obstructive Lung Disease (GOLD) group (n=937), increasing from 20.9% of those in the low-risk group to 77.4% of those in the high-riskgroup. Conclusion: Patients with COPD experience night-time symptoms regardless of GOLD group, that impact on their ability to get up in the morning and on their sleep quality. Keywords: chronic obstructive pulmonary disease, night-time symptoms, sleep quality, burden

Seabird tracking has become an ever more popular tool to aid environmental procedures such as the designation of marine protected areas and environmental impact assessments. However, samples used are usually small and little consideration is given to experimental design and sampling protocol. European shags Phalacrocorax aristotelis were tracked using GPS technology over three breeding seasons and the following foraging trip characteristics: trip duration, trip distance, maximum distance travelled from the colony, size of area used and direction travelled from colony were determined for each foraging trip. The effect of sex, year of study, breeding site, number and age of chicks and the timing of tracking on foraging behaviour were investigated using a general estimation equation model. a range of sampling scenarios reflecting likely field sampling were also tested to compare how foraging behaviour differed depending on composition of the sample of birds tracked. Trip distance, trip duration, maximum distance travelled and size of area used were all significantly affected by the breeding site, and the number of chicks a tracked adult was raising. The effect of sex was also seen when examining trip distance, trip duration and the maximum distance travelled. The direction travelled on a foraging trip was also significantly affected by breeding site. This study highlights the importance of sampling regime and the influence that year, sex, age, number of chicks and breeding site can have on the foraging trip characteristics for this coastal feeding seabird. Given the logistical and financial constraints in tracking large numbers of individuals, this study identifies the need for researchers to consider the composition of their study sample to ensure any identified foraging areas are as representative as possible of the whole colony's foraging area., Introduction In recent years, the number of seabird tracking studies using global positioning system data loggers, satellite transmitters and geolocators has increased substantially due to the availability of cheaper and [...]

The archetypal foraging behaviour of tropical seabirds is generally accepted to differ from that of their temperate and polar breeding counterparts, with the former exhibiting less predictable foraging behaviour associated with the less predictable prey of the tropical marine environment. Similarly, temperate and polar species have predictable, annual breeding seasons, enabling them to profit during periods of the year when prey availability is highest, while tropical seabird species exhibit considerable variability in their breeding strategies. Until now, the reasons for such variation in breeding strategies between tropical seabirds are yet to be investigated. We hypothesise that while some tropical species breed asynchronously in response to unpredictable fluctuations in prey availability, others adopt a seasonal breeding strategy for the same reasons that temperate and polar species do. Consequently, the predictability of seabird foraging behaviour in the tropics may be related to breeding strategy, with populations that breed seasonally exhibiting more predictable foraging behaviour than those that breed aseasonally. To test these predictions, we used GPS tracking to examine the foraging behaviour of two closely related tropical seabird species that colonise the same island yet exhibit markedly different breeding strategies: the asynchronously breeding brown booby Sula leucogaster and the seasonal breeding masked booby Sula dactylatra. We obtained tracks for 251 birds over five years. We found that brown boobies forage less predictably than masked boobies, indicated by larger core foraging areas, lower levels of foraging area overlap between individuals and exhibit more variability between breeding periods. Our results challenge the view that the foraging behaviour of tropical seabirds is always less predictable than that of seabirds breeding in temperate and polar regions and highlight the considerable variability in the breeding and foraging strategies adopted by tropical seabirds which demand further exploration. [ABSTRACT FROM AUTHOR]

Objective: Diabetes represents a significant challenge for Chinese healthcare providers. Healthcare decisionmaking is generally based on many data sources, including randomised controlled and real-world studies; however, good-quality data from Chinese diabetes patients are scarce. We performed an initial validation to assess the representativeness of one source of real-world data--the Diabetes Adelphi Disease Specific Programme (DSP) in China. Setting: China, UK. Participants: The Chinese DSP included 2060 patients with previously diagnosed type 2 diabetes mellitus (T2DM) sampled by 200 physicians. The reference Chinese population comprised 238 639 patients with previously diagnosed T2DM. The UK DSP contained 1481 patients with T2DM sampled by 125 physicians; the reference UK population comprised 289 patients with diabetes. Primary and secondary outcomes: The primary outcome was comparison of unweighted China DSP and reference data for sex, body mass index (BMI), blood pressure (BP), patients achieving glycosylated haemoglobin (HbA1c)<7%, total cholesterol, coronary heart disease and dyslipidaemia. The secondary outcome was comparison of weighted UK DSP and reference data for BMI, BP, mean HbA1c, total cholesterol, smoking and insulin status. Results: Comparison of unweighted China DSP and reference data revealed statistical equivalence for BMI, systolic BP, proportion of patients achieving HbA1c <7%, total cholesterol, coronary heart disease and dyslipidaemia. Sex, age, diabetes duration, diastolic BP and mean HbA1c level were not equivalent, although differences were generally small. Weighting of data did not substantially affect the results. A similar pattern was observed for UK data. Conclusions: This study provides evidence that the methodology used for the China and UK parts of the Diabetes DSP produces representative samples that are comparable with other independent sources of patient treatment outcomes data, which may ultimately inform public health decision-making. Although this method could be used in other countries, the current validation applies to UK and China. Further research is required for other countries. [ABSTRACT FROM AUTHOR]

There is a need for management strategies to control dominant perennial weeds and restore seminatural communities. We compared the effects of five weed control treatments on dense Pteridium aquilinum relative to an untreated experimental control over an 8-year period with the aim of restoring acid grassland. The weed control treatments tested were as follows: cutting and bruising, both twice and thrice annually, and herbicide treatment (asulam in year 1 followed by annual spot retreatment of all emergent fronds). Pteridium aquilinum performance and plant species composition were monitored. Data were analysed using Bayesian mixed-effect models and multivariate techniques. Cutting twice and thrice yearly and the asulam treatment all reduced frond density to zero; both bruising treatments were ineffective. The plant communities in the cut and asulam-treated plots showed differences from the untreated and bruised plots; the asulam-treated plots contained more ruderal species and the cut plots were more typical of acid grassland. Acid grassland recovery was fastest in the asulam-treated plots, but the cut plots caught up after approximately 5 years. There were two important conclusions. First, an intractable weed like P. aquilinum can be eradicated and a vegetation more suited for grazing can be achieved by the continuous application of some treatments over many years. Here, success was achieved by cutting twice/thrice annually, or by a single asulam application followed by annual spot spraying of all emergent fronds for 8 years. Second, bruising, a treatment favoured by some conservation organisations, did not work and cannot be recommended. The use of long-term, continuously applied treatments might be considered for all perennial weeds with large underground root/rhizome systems. [ABSTRACT FROM AUTHOR]

The free fatty acid receptors ( FFA) 1 (previously designated GPR40) and FFA4 (previously GPR120) are two GPCRs activated by saturated and unsaturated longer-chain free fatty acids. With expression patterns and functions anticipated to directly or indirectly promote insulin secretion, provide homeostatic control of blood glucose and improve tissue insulin sensitivity, both receptors are being studied as potential therapeutic targets for the control of type 2 diabetes. Furthermore, genetic and systems biology studies in both humans and mouse models link FFA4 receptors to diabetes and obesity. Although activated by the same group of free fatty acids, FFA1 and FFA4 receptors are not closely related and, while the basis of recognition of fatty acids by FFA1 receptors is similar to that of the short-chain fatty acid receptors FFA2 and FFA3, the amino acid residues involved in endogenous ligand recognition by FFA4 receptors are more akin to those of the sphingosine 1 phosphate receptor S1 P1. Screening and subsequent medicinal chemistry programmes have developed a number of FFA1 receptor selective agonists that are effective in promoting insulin secretion in a glucose concentration-dependent manner, and in lowering blood glucose levels. However, the recent termination of Phase III clinical trials employing TAK-875/fasiglifam has caused a setback and raises important questions over the exact nature and mechanistic causes of the problems. Progress in the identification and development of highly FFA4 receptor-selective pharmacological tools has been less rapid and several issues remain to be clarified to fully validate this receptor as a therapeutic target. Despite this, the ongoing development of a range of novel ligands offers great opportunities to further unravel the contributions of these receptors. Linked Articles This article is part of a themed section on 5th BPS Focused Meeting on Cell Signalling. To view the other articles in this section visit [ABSTRACT FROM AUTHOR]

Small molecule fluorochromes (synonyms: biosensors, chemosensors, fluorescent probes, vital stains) are widely used to investigate the structure, composition, physicochemical properties and biological functions of living cells, tissues and organisms. Selective entry and accumulation within particular cells and cellular structures are key processes for achieving these diverse objectives. Despite the complexities, probes routinely are applied using standard protocols, often without experimenter awareness of what factors that control accumulation and localization. The mechanisms of many such selective accumulations, however, now are known. Moreover, the influence of physicochemical properties of probes on their uptake and localization often can be defined numerically, hence predicted, using quantitative structure activity relations (QSAR) models with its required numerical structure parameters (or 'descriptors'). The state of the art of this approach is described. Available QSAR models are summarized for uptake into cells and localization in the cytosol, endoplasmic reticulum, generic biomembranes, Golgi apparatus, lipid droplets, lysosomes/endosomes, mitochondria, eukaryotic nuclei (histones and DNA), plasma membrane, and ribosomal RNA (cytoplasmic and nucleolar). Integration of such core models to both aid understanding and troubleshooting of current fluorescent probes and to assist the design of novel probes is outlined and illustrated using case examples. Limitations and generic problems arising with this approach and comments on application of such approaches to xenobiotics other than probes, e.g., drugs and herbicides, together with a brief note about an alternative approach to prediction, are given. [ABSTRACT FROM AUTHOR]

This paper examines the processes involved in the establishment of a minimum occupational fitness standard, with particular reference to the interplay that inevitably occurs between objective measurements and subjective decisions. The areas considered include: the determination of the critical task on which to base a standard; establishing minimum acceptable performance and methods of best practice for the execution of these tasks; determining the physical demands of a task and a reasonable relative workload; producing the final standard. Finally, the impact of the subjective component of the development of an occupational fitness standard on its defensibility is discussed. It is concluded that all standards involve some subjective aspects; the extent of these could be reduced by further research. In the meantime, it would be prudent for those developing standards to detail the rationale, methods and evidence by which subjective decisions were reached, to provide an audit trail for subsequent investigation. [ABSTRACT FROM AUTHOR]

The counter-regulatory axis of the renin-angiotensin system (RAS) is a novel therapeutic target in cardiovascular disease. Pathophysiological effects mediated via angiotensin II (Ang II) are well established in regulation of blood pressure, cardiac and vascular remodeling, and renal sodium handling, which lead to disorders such as hypertension and associated end-organ damage, atherosclerosis and heart failure. The counter-regulatory axis of the RAS is centered on the angiotensin-converting enzyme 2/angiotensin-1-7 (Ang-[1-7])/Mas receptor axis and has been shown to inhibit many detrimental phenotypes in cardiovascular disease. More recently, an alternative peptide, angiotensin-(1-9) (Ang-[1-9]), has been reported as a potential new member of this axis. This review will discuss the cardiovascular regulatory roles of Ang-(1-7) and Ang-(1-9) in the counter-regulatory axis of the RAS, and the potential for new therapeutic approaches in cardiovascular disease. [ABSTRACT FROM AUTHOR]

Activation of the small GTPase RhoA following angiotensin II stimulation is known to result in actin reorganization and stress fiber formation. Full activation of RhoA, by angiotensin II, depends on the scaffolding protein β-arrestin 1, although the mechanism behind its involvement remains elusive. Here we uncover a novel partner and function for β-arrestin 1, namely, in binding to ARHGAP21 (also known as ARHGAP10), a known effector of RhoA activity, whose GTPase-activating protein (GAP) function it inhibits. Using yeast two-hybrid screening, a peptide array, in vitro binding studies, truncation analyses, and coimmunoprecipitation techniques, we show that β-arrestin 1 binds directly to ARHGAP21 in a region that transects the RhoA effector GAP domain. Moreover, we show that the level of a complex containing β-arrestin 1 and ARHGAP21 is dynamically increased following angiotensin stimulation and that the kinetics of this interaction modulates the temporal activation of RhoA. Using information gleaned from a peptide array, we developed a cell-permeant peptide that serves to inhibit the interaction of these proteins. Using this peptide, we demonstrate that disruption of the β-arrestin 1/ARHGAP21 complex results in a more active ARHGAP21, leading to less-efficient signaling via the angiotensin II type 1A receptor and, thereby, attenuation of stimulated stress fiber formation [ABSTRACT FROM AUTHOR]

Retaining structures and earth support systems form an important part of geotechnical engineering. In the first 60 years of Géotechnique, some 110 publications have appeared that related to such structures. These are discussed in this review under five headings: case histories and full-scale observations; ground movements associated with retaining structures; numerical analyses; compaction stresses acting on structures; and Symposia in Print. Individual comments are made on approximately half of the papers published, highlighting key contributions to the advancement of the understanding of retaining structures. Many of the papers have provided important information subsequently incorporated into standard reference documents for geotechnical engineers, notably three reports published by the Construction Industry Research and Information Association (CIRIA): Temporary propping of deep excavations: Guidance on design; The observational method in ground engineering: Principles and applications; and Embedded retaining walls: Guidance for economic design. In this way, and through the contributions of individual papers to other aspects of performance, Géotechnique has made a valuable contribution to the improved analysis, engineering design, construction and monitoring of retaining structures. [ABSTRACT FROM AUTHOR]

1 Fusion proteins were constructed between the human 5-HT(1A) receptor and pertussis toxin-resistant forms of both G(i1)alpha and G(o1)alpha mutated at residue(351) from cysteine to either glycine or isoleucine. Each of these was expressed stably in HEK293 cells. 2 Increasing concentrations of GDP inhibited binding of the agonist [(3)H]-8-OH-DPAT but not the antagonist [(3)H]-MPPF to each construct. 3 The IC(50) for GDP was greater for constructs containing isoleucine at residue(351) of the G proteins compared to those with glycine at this position. 4 The G protein antagonist suramin had similar effects to GDP on the binding of [(3)H]-8-OH-DPAT. 5 The proportion of 5-HT(1A) receptor binding sites detected by [(3)H]-MPPF that displayed high affinity for 8-OH-DPAT was significantly greater when the interacting G protein contained isoleucine rather than glycine at residue(351). 6 The 5-HT(1A) receptor displayed similar avidity of interaction with G(i1)alpha and G(o1)alpha. 7 These results indicate that a higher avidity ternary complex is formed between 8-OH-DPAT, the 5-HT(1A) receptor and G proteins when isoleucine rather than glycine is located at residue(351) of the interacting G protein. [ABSTRACT FROM AUTHOR]

Recombinant RGS1, RGS16 and RGS–GAIP, but not RGS2, were able to substantially further stimulate the maximal GTPase activity of G[sub o1]α promoted by agonists at the α[sub 2A]-adrenoreceptor in a concentration-dependent manner. Kinetic analysis of the regulation of an α[sub 2A]-adrenoreceptor–G[sub o1]α fusion protein by all three RGS proteins revealed that they had similar affinities for the receptor–G protein fusion. However, their maximal effects on GTP hydrolysis varied over threefold with RGS16 > RGS1 > RGS–GAIP. Both RGS1 and RGS16 reduced the potency of the α[sub 2A]-adrenoreceptor agonist adrenaline by some 10-fold. A lower potency shift was observed for the partial agonist UK14304 and the effect was absent for the weak partial agonist oxymetazoline. Each of these RGS proteins altered the intrinsic activity of both UK14304 and oxymetazoline relative to adrenaline. Such results require the RGS interaction with G[sub o1]α to alter the conformation of the α[sub 2A]-adrenoreceptor and are thus consistent with models invoking direct interactions between RGS proteins and receptors. These studies demonstrate that RGS1, RGS16 and RGS–GAIP show a high degree of selectivity to regulate α[sub 2A]-adrenoreceptor-activated G[sub o1]α rather than G[sub i1]α, G[sub i2]α or G[sub i3]α and different capacities to inactivate this G protein. [ABSTRACT FROM AUTHOR]

To assess the relative capacity of the human δ opioid receptor to activate closely related G proteins, fusion proteins were constructed in which the α-subunits of either G[sub i1] or G[sub o1], containing point mutations to render them insensitive to the actions of pertussis toxin, were linked in-frame with the C-terminus of the receptor. Following transient and stable expression in HEK 293 cells, both constructs bound the antagonist [[sup 3]H]naltrindole with high affinity. d-ala[sup 2],d-leu[sup 5] Enkephalin effectively inhibited forskolin-stimulated adenylyl cyclase activity in intact cells in a concentration-dependent, but pertussis toxin-insensitive, manner. The high-affinity GTPase activity of both constructs was also stimulated by d-ala[sup 2],d-leu[sup 5] enkephalin with similar potency. However, enzyme kinetic analysis of agonist stimulation of GTPase activity demonstrated that the GTP turnover number produced in response to d-ala[sup 2],d-leu[sup 5] enkephalin was more than three times greater for G[sub i1]α than for G[sub o1]α. As the effect of agonist in both cases was to increase V[sub max] without increasing the observed K[sub m] for GTP, this is consistent with receptor promoting greater guanine nucleotide exchange, and thus activation, of G[sub i1]α compared with G[sub o1]α. An equivalent fusion protein between the human µ opioid receptor-1 and G[sub i1]α produced a similar d-ala[sup 2],d-leu[sup 5] enkephalin-induced GTP turnover number as the δ opioid receptor-G[sub i1]α fusion construct, consistent with agonist occupation of these two opioid receptor subtypes being equally efficiently coupled to activation of G[sub i1]α. [ABSTRACT FROM AUTHOR]