Recombinant canine single chain insulin analogues: Insulin receptor binding capacity and ability to stimulate glucose uptake

Virtually all diabetic dogs require exogenous insulin therapy to control their hyperglycaemia. In the UK, the only licensed insulin product currently available is a purified porcine insulin preparation. Recombinant insulin is somewhat problematic in terms of its manufacture, since the gene product (preproinsulin) undergoes substantial post-translational modification in pancreatic β cells before it becomes biologically active. The aim of the present study was to develop recombinant canine single chain insulin (SCI) analogues that could be produced in a prokaryotic expression system and which would require minimal processing. Three recombinant SCI constructs were developed in a prokaryotic expression vector, by replacing the insulin C-peptide sequence with one encoding a synthetic peptide (GGGPGKR), or with one of two insulin-like growth factor (IGF)-2 C-peptide coding sequences (human: SRVSRRSR; canine: SRVTRRSSR). Recombinant proteins were expressed in the periplasmic fraction of Escherichia coli and assessed for their ability to bind to the insulin and IGF-1 receptors, and to stimulate glucose uptake in 3T3-L1 adipocytes. All three recombinant SCI analogues demonstrated preferential binding to the insulin receptor compared to the IGF-1 receptor, with increased binding compared to recombinant canine proinsulin. The recombinant SCI analogues stimulated glucose uptake in 3T3-L1 adipocytes compared to negligible uptake using recombinant canine proinsulin, with the canine insulin/cIGF-2 chimaeric SCI analogue demonstrating the greatest effect. Thus, biologically-active recombinant canine SCI analogues can be produced relatively easily in bacteria, which could potentially be used for treatment of diabetic dogs

Improving outcomes in adults with epilepsy and intellectual disability (EpAID) using a nurse-led intervention: study protocol for a cluster randomised controlled trial.

BACKGROUND: In adults with intellectual disability (ID) and epilepsy there are suggestions that improvements in management may follow introduction of epilepsy nurse-led care. However, this has not been tested in a definitive clinical trial and results cannot be generalised from general population studies as epilepsy tends to be more severe and to involve additional clinical comorbidities in adults with ID. This trial investigates whether nurses with expertise in epilepsy and ID, working proactively to a clinically defined role, can improve clinical and quality of life outcomes in the management of epilepsy within this population, compared to treatment as usual. The trial also aims to establish whether any perceived benefits represent good value for money. METHODS/DESIGN: The EpAID clinical trial is a two-arm cluster randomised controlled trial of nurse-led epilepsy management versus treatment as usual. This trial aims to obtain follow-up data from 320 participants with ID and drug-resistant epilepsy. Participants are randomly assigned either to a 'treatment as usual' control or a 'defined epilepsy nurse role' active arm, according to the cluster site at which they are treated. The active intervention utilises the recently developed Learning Disability Epilepsy Specialist Nurse Competency Framework for adults with ID. Participants undergo 4 weeks of baseline data collection, followed by a minimum of 20 weeks intervention (novel treatment or treatment as usual), followed by 4 weeks of follow-up data collection. The primary outcome is seizure severity, including associated injuries and the level of distress manifest by the patient in the preceding 4 weeks. Secondary outcomes include cost-utility analysis, carer strain, seizure frequency and side effects. Descriptive measures include demographic and clinical descriptors of participants and clinical services in which they receive their epilepsy management. Qualitative study of clinical interactions and semi-structured interviews with clinicians and participants' carers are also undertaken. DISCUSSION: The EpAID clinical trial is the first cluster randomised controlled trial to test possible benefits of a nurse-led intervention in adults with epilepsy and ID. This research will have important implications for ID and epilepsy services. The challenges of undertaking such a trial in this population, and the approaches to meeting these are discussed. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number: ISRCTN96895428 version 1.1. Registered on 26 March 2013.Cambridgeshire and Peterborough NHS Foundation TrustThis is the final version of the article. It first appeared from BioMed Central via https://doi.org/10.1186/s13063-016-1429-

Training nurses in a competency framework to support adults with epilepsy and intellectual disability: the EpAID cluster RCT.

BACKGROUND: People with an intellectual (learning) disability (ID) and epilepsy have an increased seizure frequency, higher frequencies of multiple antiepileptic drug (AED) use and side effects, higher treatment costs, higher mortality rates and more behavioural problems than the rest of the population with epilepsy. The introduction of nurse-led care may lead to improvements in outcome for those with an ID and epilepsy; however, this has not been tested in a definitive clinical trial. OBJECTIVE: To determine whether or not ID nurses, using a competency framework developed to optimise nurse management of epilepsy in people with an ID, can cost-effectively improve clinical and quality-of-life outcomes in the management of epilepsy compared with treatment as usual. DESIGN: Cluster-randomised two-arm trial. SETTING: Community-based secondary care delivered by members of community ID teams. PARTICIPANTS: Participants were adults aged 18-65 years with an ID and epilepsy under the care of a community ID team and had had at least one seizure in the 6 months before the trial. INTERVENTIONS: The experimental intervention was the Learning Disability Epilepsy Specialist Nurse Competency Framework. This provides guidelines describing a structure and goals to support the delivery of epilepsy care and management by ID-trained nurses. MAIN OUTCOME MEASURES: The primary outcome was the seizure severity scale from the Epilepsy and Learning Disabilities Quality of Life questionnaire. Measures of mood, behaviour, AED side effects and carer strain were also collected. A cost-utility analysis was undertaken along with a qualitative examination of carers' views of participants' epilepsy management. RESULTS: In total, 312 individuals were recruited into the study from 17 research clusters. Using an intention-to-treat analysis controlling for baseline individual-level and cluster-level variables there was no significant difference in seizure severity score between the two arms. Altogether, 238 complete cases were included in the non-imputed primary analysis. Analyses of the secondary outcomes revealed no significant differences between arms. A planned subgroup analysis identified a significant interaction between treatment arm and level of ID. There was a suggestion in those with mild to moderate ID that the competency framework may be associated with a small reduction in concerns over seizure severity (standard error 2.005, 95% confidence interval -0.554 to 7.307;p = 0.092). However, neither subgroup showed a significant intervention effect individually. Family members' perceptions of nurses' management depended on the professional status of the nurses, regardless of trial arm. Economic analysis suggested that the competency framework intervention was likely to be cost-effective, primarily because of a reduction in the costs of supporting participants compared with treatment as usual. LIMITATIONS: The intervention could not be delivered blinded. Treatment as usual varied widely between the research sites. CONCLUSIONS: Overall, for adults with an ID and epilepsy, the framework conferred no clinical benefit compared with usual treatment. The economic analysis suggested that there may be a role for the framework in enhancing the cost-effectiveness of support for people with epilepsy and an ID. Future research could explore the specific value of the competency framework for those with a mild to moderate ID and the potential for greater long-term benefits arising from the continuing professional development element of the framework. TRIAL REGISTRATION: Current Controlled Trials ISRCTN96895428. FUNDING: This trial was funded by the NIHR Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 22, No. 10. See the NIHR Journals Library website for further project information.This trial was funded by the NIHR Health Technology Assessment programm

Chronic Activation of γ2 AMPK Induces Obesity and Reduces β Cell Function.

Despite significant advances in our understanding of the biology determining systemic energy homeostasis, the treatment of obesity remains a medical challenge. Activation of AMP-activated protein kinase (AMPK) has been proposed as an attractive strategy for the treatment of obesity and its complications. AMPK is a conserved, ubiquitously expressed, heterotrimeric serine/threonine kinase whose short-term activation has multiple beneficial metabolic effects. Whether these translate into long-term benefits for obesity and its complications is unknown. Here, we observe that mice with chronic AMPK activation, resulting from mutation of the AMPK γ2 subunit, exhibit ghrelin signaling-dependent hyperphagia, obesity, and impaired pancreatic islet insulin secretion. Humans bearing the homologous mutation manifest a congruent phenotype. Our studies highlight that long-term AMPK activation throughout all tissues can have adverse metabolic consequences, with implications for pharmacological strategies seeking to chronically activate AMPK systemically to treat metabolic disease

Physics case for an LHCb Upgrade II - Opportunities in flavour physics, and beyond, in the HL-LHC era

The LHCb Upgrade II will fully exploit the flavour-physics opportunities of the HL-LHC, and study additional physics topics that take advantage of the forward acceptance of the LHCb spectrometer. The LHCb Upgrade I will begin operation in 2020. Consolidation will occur, and modest enhancements of the Upgrade I detector will be installed, in Long Shutdown 3 of the LHC (2025) and these are discussed here. The main Upgrade II detector will be installed in long shutdown 4 of the LHC (2030) and will build on the strengths of the current LHCb experiment and the Upgrade I. It will operate at a luminosity up to 2×1034 cm−2s−1, ten times that of the Upgrade I detector. New detector components will improve the intrinsic performance of the experiment in certain key areas. An Expression Of Interest proposing Upgrade II was submitted in February 2017. The physics case for the Upgrade II is presented here in more depth. CP-violating phases will be measured with precisions unattainable at any other envisaged facility. The experiment will probe b → sl+l−and b → dl+l− transitions in both muon and electron decays in modes not accessible at Upgrade I. Minimal flavour violation will be tested with a precision measurement of the ratio of B(B0 → μ+μ−)/B(Bs → μ+μ−). Probing charm CP violation at the 10−5 level may result in its long sought discovery. Major advances in hadron spectroscopy will be possible, which will be powerful probes of low energy QCD. Upgrade II potentially will have the highest sensitivity of all the LHC experiments on the Higgs to charm-quark couplings. Generically, the new physics mass scale probed, for fixed couplings, will almost double compared with the pre-HL-LHC era; this extended reach for flavour physics is similar to that which would be achieved by the HE-LHC proposal for the energy frontier

LHCb upgrade software and computing : technical design report

This document reports the Research and Development activities that are carried out in the software and computing domains in view of the upgrade of the LHCb experiment. The implementation of a full software trigger implies major changes in the core software framework, in the event data model, and in the reconstruction algorithms. The increase of the data volumes for both real and simulated datasets requires a corresponding scaling of the distributed computing infrastructure. An implementation plan in both domains is presented, together with a risk assessment analysis

Increasing frailty is associated with higher prevalence and reduced recognition of delirium in older hospitalised inpatients: results of a multi-centre study

Purpose: Delirium is a neuropsychiatric disorder delineated by an acute change in cognition, attention, and consciousness. It is common, particularly in older adults, but poorly recognised. Frailty is the accumulation of deficits conferring an increased risk of adverse outcomes. We set out to determine how severity of frailty, as measured using the CFS, affected delirium rates, and recognition in hospitalised older people in the United Kingdom. Methods: Adults over 65 years were included in an observational multi-centre audit across UK hospitals, two prospective rounds, and one retrospective note review. Clinical Frailty Scale (CFS), delirium status, and 30-day outcomes were recorded. Results: The overall prevalence of delirium was 16.3% (483). Patients with delirium were more frail than patients without delirium (median CFS 6 vs 4). The risk of delirium was greater with increasing frailty [OR 2.9 (1.8–4.6) in CFS 4 vs 1–3; OR 12.4 (6.2–24.5) in CFS 8 vs 1–3]. Higher CFS was associated with reduced recognition of delirium (OR of 0.7 (0.3–1.9) in CFS 4 compared to 0.2 (0.1–0.7) in CFS 8). These risks were both independent of age and dementia. Conclusion: We have demonstrated an incremental increase in risk of delirium with increasing frailty. This has important clinical implications, suggesting that frailty may provide a more nuanced measure of vulnerability to delirium and poor outcomes. However, the most frail patients are least likely to have their delirium diagnosed and there is a significant lack of research into the underlying pathophysiology of both of these common geriatric syndromes

Abstracts from the 8th International Conference on cGMP Generators, Effectors and Therapeutic Implications

This work was supported by a restricted research grant of Bayer AG

The impact of an epilepsy nurse competency framework on the costs of supporting adults with epilepsy and intellectual disability. Findings from the EpAID study.

Background: The development of a nurse-led approach to managing epilepsy in adults with an intellectual disability offers the potential of improved outcomes and lower costs of care. We undertook a cluster randomised trial to assess the impact on costs and outcomes of the provision of intellectual disability nurses working to a designated epilepsy nurse competency framework. Here, we report the impact of the intervention on costs. Method: Across the UK, 8 sites randomly allocated to the intervention recruited 184 participants, 9 sites allocated to treatment as usual recruited 128 participants. Cost and outcome data were collected mainly by telephone interview at baseline and after six months. Total costs at six months were compared from the perspective of health & social services, and society, with adjustments for pre-specified participant and cluster characteristics at baseline including costs. Missing data was imputed using Multiple Imputation. Uncertainty was quantified by bootstrapping. Results: The intervention was associated with lower per participant costs from a health & social services perspective of -£357 (2014/15 GBP) (95% CI -£986, £294) and from a societal perspective of -£631 (95% CI -£1,473, £181). Results were not sensitive to the exclusion of accommodation costs. Conclusions: Our findings suggest that the competency framework is unlikely to increase the cost of caring for people with epilepsy and intellectual disability and may reduce costs.This paper presents independent research commissioned by the National Institute for Health Research (NIHR) under its Health Technology Assessment Programme (Grant 10/104/16 PI Dr H Ring). During the time that this research was carried out, H Ring also received support from the NIHR Collaboration for Leadership in Applied Health Research and Care (CLAHRC) East of England at Cambridgeshire and Peterborough NHS Foundation Trust