Integrating Qualitative Techniques in Model Development: A Case Study Using the Framework Approach

Background Despite their potential, there is limited uptake of formal qualitative methods in model development by modellers and health economists. The aim of this case study was to highlight in a real-world context how a qualitative approach has been applied to gain insight into current practice (delineating existing care pathways) for typhoid fever in Ghana, which can then assist in model structure conceptualisation in a model-based cost-effectiveness analysis. Methods The perspectives of a range of healthcare professionals working in different settings and across different practices in the Eastern region of Ghana were captured with a self-administered survey using open-ended questions and analysed using the framework method. Results A total of 51 completed questionnaires were retrieved representing a 73% response rate. It was found that two main care pathways for typhoid fever exist in Ghana and there was no consensus on how a new test might be applied to the existing pathways. Conclusion The two settings in Ghana have different care pathways and any cost-effectiveness analysis should consider the alternative pathways separately. This study demonstrated that framework analysis is a qualitative methodology that is likely to be accessible and feasible across a wide range of health economic settings

Chemerin Elicits Potent Constrictor Actions via Chemokine-Like Receptor 1 (CMKLR1), not G-Protein-Coupled Receptor 1 (GPR1), in Human and Rat Vasculature

BACKGROUND: Circulating levels of chemerin are significantly higher in hypertensive patients and positively correlate with blood pressure. Chemerin activates chemokine-like receptor 1 (CMKLR1 or ChemR23) and is proposed to activate the "orphan" G-protein-coupled receptor 1 (GPR1), which has been linked with hypertension. Our aim was to localize chemerin, CMKLR1, and GPR1 in the human vasculature and determine whether 1 or both of these receptors mediate vasoconstriction. METHODS AND RESULTS: Using immunohistochemistry and molecular biology in conduit arteries and veins and resistance vessels, we localized chemerin to endothelium, smooth muscle, and adventitia and found that CMKLR1 and GPR1 were widely expressed in smooth muscle. C9 (chemerin149-157) contracted human saphenous vein (pD2=7.30±0.31) and resistance arteries (pD2=7.05±0.54) and increased blood pressure in rats by 9.1±1.0 mm Hg at 200 nmol. Crucially, these in vitro and in vivo vascular actions were blocked by CCX832, which we confirmed to be highly selective for CMKLR1 over GPR1. C9 inhibited cAMP accumulation in human aortic smooth muscle cells and preconstricted rat aorta, consistent with the observed vasoconstrictor action. Downstream signaling was explored further and, compared to chemerin, C9 showed a bias factor=≈5000 for the Gi protein pathway, suggesting that CMKLR1 exhibits biased agonism. CONCLUSIONS: Our data suggest that chemerin acts at CMKLR1, but not GPR1, to increase blood pressure. Chemerin has an established detrimental role in metabolic syndrome, and these direct vascular actions may contribute to hypertension, an additional risk factor for cardiovascular disease. This study provides proof of principle for the therapeutic potential of selective CMKLR1 antagonists.This work was supported by the British Heart Foundation (FS/12/64/30001 [to AJK], FS/14/59/31282 [to CR], and PG/09/050/27734); Wellcome Trust (100780/Z/12/Z [to LY], 101844 [to CWT], 107715/Z/15/Z [to APD and JJM], and 096822/Z/11/Z [to APD and PY]); the Raymond and Beverley Sackler Fellowship (to LY), and the Medical Research Council (MRC MC_PC_14116; to APD) and by the Pulmonary Hypertension Association and the Cambridge Biomedical Research Centre. Biomedical Resources (grant 099156/Z/12/Z)

A Randomised, Placebo-Controlled, Crossover Study Investigating the Optimal Timing of a Caffeine-Containing Supplement for Exercise Performance.

This is the final version. Available from Springer via the DOI in this record.The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.BACKGROUND: Pre-exercise supplements containing low doses of caffeine improve endurance exercise performance, but the most efficacious time for consumption before intense endurance exercise remains unclear, as does the contribution of caffeine metabolism. METHODS: This study assessed the timing of a commercially available supplement containing 200 mg of caffeine, 1600 mg of β-alanine and 1000 mg of quercetin [Beachbody Performance Energize, Beachbody LLC, USA] on exercise performance, perception of effort and plasma caffeine metabolites. Thirteen cyclists (V̇O2max 64.5 ± 1.4 ml kg- 1 min- 1 (± SEM)) completed four experimental visits consisting of 30 min of steady-state exercise on a cycle ergometer at 83 ± 1% V̇O2max followed by a 15-min time trial, with perceived exertion measured regularly. On three of the visits, participants consumed caffeine either 35 min before steady-state exercise (PRE), at the onset of steady-state (ONS) or immediately before the time trial (DUR) phases, with a placebo consumed at the other two time points (i.e. three drinks per visit). The other visit (PLA) consisted of consuming the placebo supplement at all three time points. The placebo was taste-, colour- and calorie-matched. RESULTS: Total work performed during the time trial in PRE was 5% greater than PLA (3.53 ± 0.14 vs. 3.36 ± 0.13 kJ kg- 1 body mass; P = 0.0025), but not ONS (3.44 ± 0.13 kJ kg- 1; P = 0.3619) or DUR (3.39 ± 0.13 kJ kg- 1; P = 0.925), which were similar to PLA. Perceived exertion was lowest during steady-state exercise in the PRE condition (P < 0.05), which coincided with elevated plasma paraxanthine in PRE only (P < 0.05). CONCLUSION: In summary, ingestion of a pre-exercise supplement containing 200 mg caffeine 35 min before exercise appeared optimal for improved performance in a subsequent fatiguing time trial, possibly by reducing the perception of effort. Whether this was due to increased circulating paraxanthine requires further investigation. TRIAL REGISTRATION: ClinicalTrials.Gov, NCT02985606 ; 10/26/2016.Beachbod

A review of assessment methods for river hydromorphology

The work leading to this paper has received funding for the EU’s FP7 under Grant Agreement No. 282656 (REFORM

The Concise Guide to PHARMACOLOGY 2015/16: G protein-coupled receptors

The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.13348/full. G protein-coupled receptors are one of the eight major pharmacological targets into which the Guide is divided, with the others being: ligand-gated ion channels, voltage-gated ion channels, other ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The Concise Guide is published in landscape format in order to facilitate comparison of related targets. It is a condensed version of material contemporary to late 2015, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in the previous Guides to Receptors & Channels and the Concise Guide to PHARMACOLOGY 2013/14. It is produced in conjunction with NC-IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR-DB and GRAC and provides a permanent, citable, point-in-time record that will survive database updates

Hypothyroidism in utero\textit{in utero} stimulates pancreatic beta cell proliferation and hyperinsulinaemia in the ovine fetus during late gestation

Development of pancreatic beta cell mass before birth is essential for normal growth of the fetus and for long-term control of carbohydrate metabolism in postnatal life. Thyroid hormones are also important regulators of fetal growth, and the present study tested the hypotheses that thyroid hormones promote beta cell proliferation in the fetal ovine pancreatic islets, and that growth retardation in hypothyroid fetal sheep is associated with reductions in pancreatic beta cell mass and circulating insulin concentration $\textit{in utero}$. Organ growth and pancreatic islet cell proliferation and mass were examined in sheep fetuses following removal of the thyroid gland in utero. The effects of triiodothyronine (T$_{3}$), insulin and leptin on beta cell proliferation rates were determined in isolated fetal ovine pancreatic islets $\textit{in vitro}$. Hypothyroidism in the sheep fetus resulted in an asymmetric pattern of organ growth, pancreatic beta cell hyperplasia, and elevated plasma insulin and leptin concentrations. In pancreatic islets isolated from intact fetal sheep, beta cell proliferation $\textit{in vitro}$ was reduced by T$_{3}$ in a dose-dependent manner and increased by insulin at high concentrations only. Leptin induced a bimodal response whereby beta cell proliferation was suppressed at the lowest, and increased at the highest, concentrations. Therefore, proliferation of beta cells isolated from the ovine fetal pancreas is sensitive to physiological concentrations of T$_{3}$, insulin and leptin. Alterations in these hormones may be responsible for the increased beta cell proliferation and mass observed in the hypothyroid sheep fetus and may have consequences for pancreatic function in later life.The project was funded in part by the Biotechnology and Biological Sciences Research Council (BB/HO1697X/1). S.E.H. was supported by a Nigel Groome PhD Studentship at Oxford Brookes University. S.E.H. was awarded a practical skills grant from the Society for Endocrinology and a travel grant from the Physiological Society to fund work at the University of Arizona

The UK INFINITY study - early experience and complications of a multicenter series of 504 total ankle arthroplasties.

Introduction/Purpose: This is the first report from the UK INFINITY study. This is a multicentre, non-inventor, prospective observational study of 504 INFINITY fixed bearing total ankle arthroplasties. We report our early experience, complications, radiographic and functional outcomes of this prosthesis. Methods: Patients were recruited from 11 specialist centres between June 2016 and November 2019. Demographic, radiographic, and functional outcome data (Ankle Osteoarthritis Scale, Manchester Oxford Questionnaire and Euroquol 5D-5L) were collected preoperatively, at 6 months (454 patients), 1 year (328 patients) and 2 years (104 patients). The average age was 67.8 (range 23.9 to 88.5) and average BMI 29.9 (18.9 to 48.0). The COFAS grading system was used to stratify deformity. There were 259 (51.4%) COFAS Type 1, 122 (24.2%) COFAS Type 2, 32 (6.3%) COFAS 3 and 87 (17.3%) COFAS type 4. 38 patients (7.54%) presented with inflammatory arthritis. 101 (20.0%) of implantations utilised patient specific instrumentation (Prophecy). 169 (33.5%) of patients underwent an additional procedure at the time of surgery. Early and late complications and reoperations were recorded as adverse events. Radiographs were assessed for lucencies, cysts and/or subsidence. Results: There was a significant (p<0.01) improvement across all functional outcome scores at 6 months, which was sustained at one and two years. There was no significant difference with the use of patient specific instrumentation. 167 (33.1%) underwent additional procedures at index surgery. At the latest follow up 3 implants (0.6%) have been revised. One patient at 6 weeks for deep infection, one patient at 6 months for subsidence and one patient at 18 months for loosening. There were an additional 13 reoperations (2.6%) at the latest follow up. Conclusion: The UK INFINITY study is the largest reported multicentre study of a Total Ankle Arthroplasty to date. This study has shown a low early revision rate and high functional outcomes of the INFINITY prosthesis

Declining Orangutan Encounter Rates from Wallace to the Present Suggest the Species Was Once More Abundant

BACKGROUND: Bornean orangutans (Pongo pygmaeus) currently occur at low densities and seeing a wild one is a rare event. Compared to present low encounter rates of orangutans, it is striking how many orangutan each day historic collectors like Alfred Russel Wallace were able to shoot continuously over weeks or even months. Does that indicate that some 150 years ago encounter rates with orangutans, or their densities, were higher than now? METHODOLOGY/PRINCIPAL FINDINGS: We test this hypothesis by quantifying encounter rates obtained from hunting accounts, museum collections, and recent field studies, and analysing whether there is a declining trend over time. Logistic regression analyses of our data support such a decline on Borneo between the mid-19th century and the present. Even when controlled for variation in the size of survey and hunting teams and the durations of expeditions, mean daily encounter rates appear to have declined about 6-fold in areas with little or no forest disturbance. CONCLUSIONS/SIGNIFICANCE: This finding has potential consequences for our understanding of orangutans, because it suggests that Bornean orangutans once occurred at higher densities. We explore potential explanations-habitat loss and degradation, hunting, and disease-and conclude that hunting fits the observed patterns best. This suggests that hunting has been underestimated as a key causal factor of orangutan density and distribution, and that species population declines have been more severe than previously estimated based on habitat loss only. Our findings may require us to rethink the biology of orangutans, with much of our ecological understanding possibly being based on field studies of animals living at lower densities than they did historically. Our approach of quantifying species encounter rates from historic data demonstrates that this method can yield valuable information about the ecology and population density of species in the past, providing new insight into species' conservation needs

Timing of immune escape linked to success or failure of vaccination

Successful vaccination against HIV should limit viral replication sufficiently to prevent the emergence of viral immune escape mutations. Broadly directed immunity is likely to be required to limit opportunities for immune escape variants to flourish. We studied the emergence of an SIV Gag cytotoxic T cell immune escape variant in pigtail macaques expressing the Mane-A*10 MHC I allele using a quantitative RT-PCR to measure viral loads of escape and wild type variants. Animals receiving whole Gag expressing vaccines completely controlled an SIVmac251 challenge, had broader CTL responses and exhibited minimal CTL escape. In contrast, animals vaccinated with only a single CTL epitope and challenged with the same SIVmac251 stock had high levels of viral replication and rapid CTL escape. Unvaccinated na&iuml;ve animals exhibited a slower emergence of immune escape variants. Thus narrowly directed vaccination against a single epitope resulted in rapid immune escape and viral levels equivalent to that of na&iuml;ve unvaccinated animals. These results emphasize the importance of inducing broadly directed HIV-specific immunity that effectively quashes early viral replication and limits the generation of immune escape variants. This has important implications for the selection of HIV vaccines for expanded human trials.<br /