• Standards and core components for cardiovascular disease prevention and rehabilitation; BACPR

      Cowie, Aynsley; Buckley, John P.; Doherty, Patrick; Furze, Gill; Hayward, Jo; Jones, Jennifer; Speck, Linda; Dalal, Hayes; Mills, Joseph; University Centre Shrewsbury (BMJ, 30/01/2019)
      In 2017, the British Association for Cardiovascular Prevention and Rehabilitation published its official document detailing standards and core components for cardiovascular prevention and rehabilitation. Building on the success of previous editions of this document (published in 2007 and 2012), the 2017 update aims to further emphasise to commissioners, clinicians, politicians and the public the importance of robust, quality indicators of cardiac rehabilitation (CR) service delivery. Otherwise, its overall aim remains consistent with the previous publications—to provide a precedent on which all effective cardiovascular prevention and rehabilitation programmes are based and a framework for use in assessment of variation in service delivery quality. In this 2017 edition, the previously described seven standards and core components have both been revised to six, with a greater focus on measurable clinical outcomes, audit and certification. The principles within the updated document underpin the six-stage pathway of care for CR, and reflect the extensive evidence base now available within the field. To help improve current services, close collaboration between commissioners and CR providers is advocated, with use of the CR costing tool in financial planning of programmes. The document specifies how quality assurance can be facilitated through local audit, and advocates routine upload of individual-level data to the annual British Heart Foundation National Audit of Cardiac Rehabilitation, and application for national certification ensuring attainment of a minimum quality standard. Although developed for the UK, these standards and core components may be applicable to other countries.
    • Improving the practicality of using non-aversive handling methods to reduce background stress and anxiety in laboratory mice.

      Gouveia, Kelly; Hurst, Jane L; orcid: 0000-0002-3728-9624; email: jane.hurst@liverpool.ac.uk (2019-12-30)
      Handling can stimulate stress and anxiety in laboratory animals that negatively impacts welfare and introduces a confounding factor in many areas of research. Picking up mice by the tail is a major source of handling stress that results in strong aversion to the handler, while mice familiarised with being picked up in a tunnel or cupped on the open hand show low stress and anxiety, and actively seek interaction with their handlers. Here we investigate the duration and frequency of handling required for effective familiarisation with these non-aversive handling methods, and test whether this is sufficient to prevent aversion and anxiety when animals then experience immobilisation and a mild procedure (subcutaneous injection). Very brief handling (2 s) was sufficient to familiarise mice with tunnel handling, even when experienced only during cage cleaning. Brief but more frequent handling was needed for familiarisation with cup handling, while pick up by tail induced strong aversion even when handling was brief and infrequent. Experience of repeated immobilisation and subcutaneous injection did not reverse the positive effects of tunnel handling. Our findings demonstrate that replacing tail with tunnel handling during routine cage cleaning and procedures provides a major refinement with little if any cost for familiarisation.
    • Neferine induces autophagy-dependent cell death in apoptosis-resistant cancers via ryanodine receptor and Ca

      Law, Betty Yuen Kwan; Michelangeli, Francesco; Qu, Yuan Qing; orcid: 0000-0003-3733-3661; Xu, Su-Wei; Han, Yu; Mok, Simon Wing Fai; Dias, Ivo Ricardo De Seabra Rodrigues; Javed, Masood-Ul-Hassan; Chan, Wai-Kit; Xue, Wei-Wei; et al. (2019-12-27)
      Resistance of cancer cells to chemotherapy is a significant clinical concern and mechanisms regulating cell death in cancer therapy, including apoptosis, autophagy or necrosis, have been extensively investigated over the last decade. Accordingly, the identification of medicinal compounds against chemoresistant cancer cells via new mechanism of action is highly desired. Autophagy is important in inducing cell death or survival in cancer therapy. Recently, novel autophagy activators isolated from natural products were shown to induce autophagic cell death in apoptosis-resistant cancer cells in a calcium-dependent manner. Therefore, enhancement of autophagy may serve as additional therapeutic strategy against these resistant cancers. By computational docking analysis, biochemical assays, and advanced live-cell imaging, we identified that neferine, a natural alkaloid from Nelumbo nucifera, induces autophagy by activating the ryanodine receptor and calcium release. With well-known apoptotic agents, such as staurosporine, taxol, doxorubicin, cisplatin and etoposide, utilized as controls, neferine was shown to induce autophagic cell death in a panel of cancer cells, including apoptosis-defective and -resistant cancer cells or isogenic cancer cells, via calcium mobilization through the activation of ryanodine receptor and Ulk-1-PERK and AMPK-mTOR signaling cascades. Taken together, this study provides insights into the cytotoxic mechanism of neferine-induced autophagy through ryanodine receptor activation in resistant cancers.
    • Stent Migration Following Endovascular Sealing of Abdominal Aortic Aneurysms

      Yafawi, Asma; McWilliams, Richard G.; Fisher, Robert K.; England, Andrew; Karouki, Maria; Torella, Francesco (Elsevier, 2019-12-09)
    • Impacts of Reducing UK Beef Consumption Using a Revised Sustainable Diets Framework

      Chalmers, Neil; email: neil.chalmers@abdn.ac.uk; Stetkiewicz, Stacia; email: s.stetkiewicz@lancaster.ac.uk; Sudhakar, Padhmanand; orcid: 0000-0003-1907-4491; email: Padhmanand.Sudhakar@earlham.ac.uk; Osei-Kwasi, Hibbah; orcid: 0000-0001-5084-6213; email: h.oseikwasi@chester.ac.uk; Reynolds, Christian J; orcid: 0000-0002-1073-7394; email: c.reynolds@sheffield.ac.uk (MDPI, 2019-12-02)
      The impact of beef consumption on sustainability is a complex and evolving area, as sustainability covers many areas from human nutrient adequacy to ecosystem stability. Three sustainability assessment frameworks have been created to help policy makers unpack the complexities of sustainable food systems and healthy sustainable dietary change. However, none of these frameworks have yet to be applied to a case study or individual policy issue. This paper uses a hybrid version of the sustainability assessment frameworks to investigate the impact of reducing beef consumption (with a concurrent increase in consumption of plant-based foods, with a focus on legumes) on sustainability at a UK level. The aim of this paper is to understand the applicability of these overarching frameworks at the scale of an individual policy. Such an assessment is important, as this application of previously high-level frameworks to individual policies makes it possible to summarise, at a glance, the various co-benefits and trade-offs associated with a given policy, which may be of particular value in terms of stakeholder decision-making. We find that many of the proposed metrics found within the sustainability assessment frameworks are difficult to implement at an individual issue level; however, overall they show that a reduction in beef consumption and an increase in consumption of general plant-based foods, with a focus around legumes production, would be expected to be strongly beneficial in five of the eight overarching measures which were assessed.
    • Analysis of physical demands during youth soccer match-play: Considerations of sampling method and epoch length

      Doncaster, Greg; Page, Richard; White, Paul; Svenson, Robert; Twist, Craig; Edge HIll University; Stoke City FC; University of Chester (Taylor and Francis, 2019-11-27)
      The purpose of this study was to examine the physical match profiles of professional soccer players using 3 and 5 min fixed and rolling averages as well as fixed 1 min averages, with considerations to training prescription. Twenty-nine, professional U23 soccer outfield players competed across 17 competitive matches during the 2017/18 season, equating to a total of 130 separate physical match profiles. Match activities were recorded using global positioning system (GPS) devices with integrated micro-electrical mechanical systems (MEMS), recording total distance (TD), high-speed running (HSR) and metabolic power (MP). For each individual match profile and variable, 1, 3 and 5 min peak, post-peak, and average values were calculated using fixed-time epochs (FIXED) and rolling averages (ROLL). Linear mixed models were employed to examine the differences in the dependent variables as a function of the method of measurement. Results revealed significantly higher peak values, for relative TD, relative HSR and relative MP when employing the ROLL sampling method, in comparison to the FIXED method, for both 3 min and 5 min epoch lengths. Analysis of epoch length revealed significantly higher peak values, across all positions, for relative TD, relative HSR and MP for 1 min epochs, in comparison to 3 min and 5 min epochs. The data offers a novel insight into the appropriate identification of physical demands during youth soccer match-play. Researchers and practitioners should consider the sampling method and epoch length when assessing the physical demands of competitive match-play, as well as when designing and prescribing sport-specific conditioning drills.
    • A novel method to optimise the utility of underused moulted plumulaceous feather samples for genetic analysis in bird conservation.

      Peters, Catherine; Nelson, Howard, P.; Rusk, Bonnie; Muir, Anna P.; Rusk, Bonnie L.; University of Chester (Springer, 2019-10-24)
      Non-invasive sampling methods are increasingly being used in conservation research as they reduce or eliminate the stress and disturbance resulting from invasive sampling of blood or tissue. Here we present a protocol optimised for obtaining usable genetic material from moulted plumulaceous feather samples. The combination of simple alterations to a ‘user-developed’ method, comprised of increased incubation time and modification of temperature and volume of DNA elution buffer, are outlined to increase DNA yield and significantly increase DNA concentration (W = 81, p <0.01, Cohens’s d= 0.89). We also demonstrate that the use of a primerless Polymerase Chain Reaction (PCR) technique increases DNA quality and amplification success when used prior to PCR reactions targeting avian mitochondrial DNA (mtDNA). A small amplicon strategy proved effective for mtDNA amplification using PCR, targeting three overlapping 314-359bp regions of the cytochrome oxidase I barcoding region which, when combined, aligned with target-species reference sequences. We provide evidence that samples collected non-invasively in the field and kept in non-optimal conditions for DNA extraction can be used effectively to sequence a 650bp region of mtDNA for genetic analysis.
    • Clobazam add-on therapy for drug-resistant epilepsy

      Bresnahan, Rebecca; Williamson, John; Martin-McGill, Kirsty J.; Michael, Benedict D.; Marson, Anthony G. (Wiley, 2019-10-22)
    • Tiagabine add-on therapy for drug-resistant focal epilepsy

      Bresnahan, Rebecca; Martin-McGill, Kirsty J.; Hutton, Jane L.; Marson, Anthony G. (Wiley, 2019-10-14)
    • A UK consensus on optimising CVD secondary prevention care: perspectives from multidisciplinary team members

      The ICON (Integrating Care Opportunities across the NHS) CVD Secondary Prevention Working Group (2019-10-03)
      Although overall cardiovascular (CV) mortality has declined in recent years, patients with clinically manifest cardiovascular disease (CVD) remain at increased risk of recurrent CV events. To minimise the likelihood of future CV events following an acute myocardial infarction (MI), changes in diet and lifestyle, alongside pharmaceutical interventions, such as dual antiplatelet therapy, a β-blocker, an ACE inhibitor, and a statin, are recommended within current clinical guidelines. The use of cardiac rehabilitation (CR) programmes has been shown to be highly effective in reducing mortality and morbidity following MI, and a cost-benefit analysis suggests that increasing the uptake of CR to 65% among eligible patient would result in potential cost savings of over £30 million annually for the NHS. The involvement of a multidisciplinary team (MDT) of healthcare professionals is central to delivering post-MI care, with initial and/or ongoing input from cardiologists, hospital-based specialist pharmacists, specialist nurses, GPs, dietitians, smoking cessation specialists and practice-based and community pharmacists, among others. This consensus statement was developed based on a meeting of HCPs actively involved in delivering CV secondary prevention care at primary and secondary care centres across the UK. Recognising that HCP team configuration and availability of resources/services vary by location, the authors have focused on three common themes which have broad relevance in CVD secondary prevention, specifically: integration of care, medicines optimisation, and encouraging patient activation. Opportunities for MDT members to improve outcomes in post-MI patients are suggested and examples of best practice models which have been implemented successfully are described.
    • Changes in selective biomarkers after transurethral resection of the bladder tumour (TURBT), and their association with Non-muscle invasive bladder cancer (NMIBC) recurrence and progression

      Ella-Twongiis, Peter (University of ChesterUniversity of Chester, 2019-10-01)
      Introduction Bladder Cancer (BC) is the 10th most common cancer in the UK, with about 10,000 new cases annually. It affects more men than women (ratio 3:1). Major risk factors include tobacco, chemical carcinogens, schistosomiasis infection and age. About 75-85% of BC are non-muscle invasive (NMIBC), which is associated with high recurrence and progression rates (50-60% within 7-10 years). Currently, diagnosis, treatment and management of BC is via clinical procedures such as transurethral resection of the bladder tumour (TURBT) and endoscopy. Concerning laboratory investigations, there are no routine biomarkers currently available for identifying BC patients at increased risk of developing recurrence and progression. By monitoring changes in selective biomarkers post-TURBT, any sustained changes may be a predictor of cancer recurrence or progression. The main-focus of this research study was to evaluate changes in selective novel biomarkers and their association with recurrence and progression in BC. Materials & Methods In this research, 40 patients (n=40) scheduled for TURBT at the Wrexham Maelor Hospital, North Wales were recruited after written informed consent. Ethical approval for the project was granted via IRAS (REC4: 14/WA/0033). Venous blood samples were taken at baseline (pre-operative) and following TURBT surgery at 1, 3 and 6 months post-operatively. Bladder tumour samples were also taken during TURBT according to standard procedure. Selective biomarkers to assess inflammation, angiogenesis and tumour growth, were measured using commercially available ELISA and BioPlex multiplex assay kits. Tissue immunoreactivity of novel biomarkers were also assessed in BC tissues using immunohistochemistry, with clinical outcome measures being recorded for all patients. Results Significant increases in serum Cluster of differentiation 31 (CD31) (p=0.003) and Stem Cell Factor (SCF) (p=0.032) concentration, as well as trends of increasing concentration of serum basic Fibroblast Growth Factor (bFGF) (p=0.14), Vascular Endothelial Growth Factor Receptor-1 and 2 (VEGFR-1) (p=0.15), VEGFR-2 (p=0.15) and Follistatin (p=0.40) were observed in BC patients up to 6 months post-operative. There were also significant decreases in serum Macrophage Inflammatory Protein -2 (MIP-2) (p=0.001), Platelet Derived Growth Factor (PDGF) (p=0.012), Matrix Metalloproteinase-9 (MMP-9) (p=0.002) and Vascular Endothelial Growth Factor C (VEGF-C) (p=0.04) serum concentration. Trends of decreasing concentration in MMP-2 (p=0.79), MMP-3 (p=0.15), interleukin-6 (IL-6) (p=0.26), interleukin-8 (IL-8) (p=0.15) and tumour necrosis factor-α (TNF-α) (p=0.69) were observed in BC patients up to 6 months post-operative. There was significant immunoreactivity of CD31 (p< 0.001), CD34 (p< 0.001), Human epidermal growth factor receptor-2 (HER-2) (p=0.032), S100P (p< 0.001), Cyclooxygenase-2 (COX-2) (p< 0.001), VEGFR-3 (p< 0.001), SOX-2 (p< 0.001) and thrombomodulin (p=0.010) in bladder tumours. Although recurrence was significantly associated with cancer grade, there was no association with antibody immunoreactivity. Conclusion Findings from the present study may indicate an alternative approach in the monitoring and management of patients with BC. It is proposed that by allowing urological surgeons access to laboratory markers such as MIP-2, MMP-9, PDGF, SCF, HER-2, Thrombomodulin and CD31 (biomarker profile), potentially, in the future, these biomarkers may be used in addition to, or in combination with, currently used scoring systems to predict cancer recurrence and progression. However, verification and validation of these biomarkers are needed using larger cohorts.
    • “You Can’t Really Hug a Tiger”: Zookeepers and Their Bonds with Animals

      Birke, Lynda; Hosey, Geoff; Melfi, Vicky (Informa UK Limited, 2019-09-20)
    • Preparation of Primary Rat Hepatocyte Spheroids Utilizing the Liquid-Overlay Technique.

      Kyffin, Jonathan A; Cox, Christopher R; Leedale, Joseph; Colley, Helen E; Murdoch, Craig; Mistry, Pratibha; Webb, Steven D; Sharma, Parveen (2019-09)
      Herein, we describe a protocol for the preparation and analysis of primary isolated rat hepatocytes in a 3D cell culture format described as spheroids. The hepatocyte cells spontaneously self-aggregate into spheroids without the need for synthetic extracellular matrices or hydrogels. Primary rat hepatocytes (PRHs) are a readily available source of primary differentiated liver cells and therefore conserve many of the required liver-specific functional markers, and elicit the natural in vivo phenotype when compared with common hepatic cells lines. We describe the liquid-overlay technique which provides an ultra-low attachment surface on which PRHs can be cultured as spheroids. © 2019 The Authors. Basic Protocol 1: Preparation of agarose-coated plates Basic Protocol 2: Primary rat hepatocyte isolation procedure Basic Protocol 3: Primary rat hepatocyte spheroid culture Basic Protocol 4: Immunofluorescent analysis of PRH spheroids. [Abstract copyright: © 2019 The Authors.]
    • The interaction between the physical and mental loads associated with actual and simulated rugby league performance

      Highton, Jamie; Twist, Craig; Mullen, Thomas (University of Chester, 2019-09)
      The aim of the current thesis was to develop knowledge of the ‘loads’ associated with rugby league match-play, with a particular focus on the effects of altered mental loads before and during exercise indicative of a rugby league match. Chapter 3 examined the test-retest reliability of movement, physiological and perceptual measures during and after a novel rugby match simulation, where movement commands were more random than those typical of match simulations. The most reliable measure of external load during bouts of the simulation was relative distance (typical error [TE] and coefficient of variation [CV%] = 1.5-1.6 m.min-1 and 1.4-1.5%, respectively), with all other movement characteristics possessing a CV% <5%. The most reliable measure of internal load, neuromuscular function and perceptual measures were for %HRmax during bout 1 (TE and CV% = 1.4-1.7% and 1-4-2.1%, respectively), MVC before (TE and CV% = 10.8-14.8 N·m and 3.8-4.6%, respectively), and average RPE (TE and CV% = 0.5-0.8 AU and 3.6-5.5%, respectively). The conclusion of this chapter was that randomisation of the movements during simulated activity to better reflect intermittent team sports has no detrimental effect on its reliability. Studies can therefore confidently examine alterations in several perceptual, neuromuscular, physiological and movement load measures related to rugby activity using stochastic movements. Chapter 4 examined the responses to a simulated rugby league protocol that was designed to include more random commands, and therefore require greater vigilance, than traditional team sport simulation protocols. The randomised simulation (RDM) was matched for the number and types of activity performed every 5.45 min in a control trial (CON), but included no repeated cycles of activity. The RDM trial was more mentally demanding than CON (Effect size (ES) = 0.56; ±0.57). Self-paced mean sprint performance increased in RDM (22.5 ± 1.4 vs. 21.6 ± 1.6 km∙h-1; ES = 0.50; ±0.45), which was accompanied by a higher RPE (14.3 ± 1.0 vs. 13.0 ± 1.4; ES = 0.87; ±0.54) and a greater number of errors in the Stroop Test (10.3 ± 2.5 vs. 9.3 ± 1.4 errors; ES = 0.65; ±0.67). MVC peak torque (CON = -48.4 ± 31.6 N.m, RDM = -39.6 ± 36.6 N.m) and voluntary activation (CON = -8.3 ± 4.8%, RDM = -6.0 ± 4.1%) was similarly reduced in both trials. Providing more random commands, requiring greater vigilance, can therefore alter performance and associated physiological, perceptual and cognitive responses to team sport simulations. Chapter 5 describes the subjective task load of elite rugby league match play using the NASA-TLX and examines their association with several contextual match factors, technical ii performance and external movement demands. Linear mixed modelling revealed that various combinations of contextual factors, technical performance and movement demands were associated with subjective task load (NASA-TLX). Greater number of tackles (η2 = 0.18), errors (η2 = 0.15) decelerations (η2 = 0.12), increased sprint distance (η2 = 0.13), losing matches (η2 = 0.36) and increased perception of effort (η2 = 0.27) lead to most likely – very likely increases in subjective total workload. These data provide a greater understanding of the internal load and their association with several contextual factors, technical performance and external movement demands during rugby league competition. The purpose of the final empirical chapter (Chapter 6) was to describe the effects of mental fatigue on simulated rugby league performance and to determine the effects of caffeine supplementation on simulated rugby league performance in the presence of mental fatigue. Completing a mentally demanding task increases participants’ subjective rating of mental fatigue (pre = 29 ± 25 AU; post = 55 ± 20 AU) immediately before completing a simulation protocol. Impairments in sprint speed (ES = -0.18; ±0.19), sprint to contact speed (ES = -0.20; ±0.27), high-intensity running (ES = -0.30; ±0.24), high metabolic power > 20 W·kg-1 (ES =-0.50; ±0.51) and time to complete a passing accuracy task (ES = 0.54; ±0.63) were observed after mental fatigue. Caffeine supplementation (5 mg.kg-1) attenuated several adverse effects of mental fatigue before exercise replicating the demands of rugby league match play, with increased sprint speed (ES = 0.40; ±0.18), high-intensity running (ES = 0.50; ±0.53), high metabolic power > 20 W·kg-1 (ES = 0.33; ±0.38) and decreased time to complete a passing accuracy test (ES =-0.70; ±0.45). Mental fatigue affected internal loads, external loads and skill performance during simulated rugby league match play that appear to be centrally regulated by a decreased motivation and increased perception of effort. However, a single dose of caffeine taken 60 min before performance can attenuate several of these negative effects. In summary, the current thesis highlights several interactions between the physical and mental loads associated with actual and simulated rugby league performance.
    • Sulthiame add-on therapy for epilepsy

      Bresnahan, Rebecca; Milburn-McNulty, Philip; Powell, Graham; Sills, Graeme; Marson, Anthony G.; Martin-McGill, Kirsty J.; University of Chester; University of Liverpool; The Walton Centre NHS Foundation Trust; University of Glasgow; Liverpool Health Partners (Wiley, 2019-08-27)
      Background This is an updated version of the Cochrane Review previously published in the Cochrane Database of Systematic Reviews 2015, Issue 10. Epilepsy is a common neurological condition, characterised by recurrent seizures. Most people respond to conventional antiepileptic drugs, however, around 30% will continue to experience seizures, despite treatment with multiple antiepileptic drugs. Sulthiame, also known as sultiame, is a widely used antiepileptic drug in Europe and Israel. We present a summary of the evidence for the use of sulthiame as add-on therapy in epilepsy. Objectives To assess the efficacy and tolerability of sulthiame as add-on therapy for people with epilepsy of any aetiology compared with placebo or another antiepileptic drug. Search methods For the latest update, we searched the Cochrane Register of Studies (CRS Web), which includes the Cochrane Epilepsy Group’s Specialized Register and CENTRAL (17 January 2019), MEDLINE Ovid (1946 to January 16, 2019), ClinicalTrials.gov and the WHO ICTRP Search Portal (17 January 2019). We imposed no language restrictions. We contacted the manufacturers of sulthiame, and researchers in the field to seek any ongoing or unpublished studies. Selection criteria Randomised controlled trials of add-on sulthiame, with any level of blinding (single, double or unblinded) in people of any age, with epilepsy of any aetiology. Data collection and analysis Two review authors independently selected trials for inclusion, and extracted relevant data. We assessed these outcomes: (1) 50% or greater reduction in seizure frequency between baseline and end of follow-up; (2) complete cessation of seizures during follow-up; (3) mean seizure frequency; (4) time-to-treatment withdrawal; (5) adverse effects; and (6) quality of life. We used intention-to-treat for primary analyses. We presented results as risk ratios (RR) with 95% confidence intervals (CIs). However, due to the paucity of trials, we mainly conducted a narrative analysis. Sulthiame add-on therapy for epilepsy (Review) 1 Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. For Preview Only Main results We included one placebo-controlled trial that recruited 37 infants with newly diagnosed West syndrome. This trial was funded by DESITIN Pharma, Germany. During the study, sulthiame was given as an add-on therapy to pyridoxine. No data were reported for the outcomes: 50% or greater reduction in seizure frequency between baseline and end of follow-up; mean seizure frequency; or quality of life. For complete cessation of seizures during a nine-day follow-up period for add-on sulthiame versus placebo, the RR was 11.14 (95% CI 0.67 to 184.47; very low-certainty evidence), however, this difference was not shown to be statistically significant (P = 0.09). The number of infants experiencing one or more adverse events was not significantly different between the two treatment groups (RR 0.85, 95% CI 0.44 to 1.64; very low-certainty evidence; P = 0.63). Somnolence was more prevalent amongst infants randomised to add-on sulthiame compared to placebo, but again, the difference was not statistically significant (RR 3.40, 95% CI 0.42 to 27.59; very low-certainty evidence; P = 0.25). We were unable to conduct meaningful analysis of time-to-treatment withdrawal and adverse effects due to incomplete data. Authors’ conclusions Sulthiame may lead to a cessation of seizures when used as an add-on therapy to pyridoxine in infants with West syndrome, however, we are very uncertain about the reliability of this finding. The included study was small and had a significant risk of bias, largely due to the lack of details regarding blinding and the incomplete reporting of outcomes. Both issues negatively impacted the certainty of the evidence. No conclusions can be drawn about the occurrence of adverse effects, change in quality of life, or mean reduction in seizure frequency. No evidence exists for the use of sulthiame as an add-on therapy in people with epilepsy outside West syndrome. Large, multi-centre randomised controlled trials are needed to inform clinical practice, if sulthiame is to be used as an add-on therapy for epilepsy
    • Nice to know: impact of NICE guidelines on ketogenic diet services nationwide

      Whiteley, Victoria; Carroll, Jennifer; Taylor, Hannah; Schoeler, Natasha; Martin-McGill, Kirsty J.; Royal Manchester Childrens Hospital; University of Salford; University of Chester; University of Liverpool; University of Plymouth; Sheffield Childrens Hospital; UCL Great Ormond Street Institute of Child Health (Wiley, 2019-08-20)
      Background In 2012, the National Institute for Health and Care Excellence (NICE) Clinical Guidelines for Epilepsies: Diagnosis and Management (CG137) included, for the first time, ketogenic diets (KDs) as a treatment option for drug‐resistant paediatric epilepsy. The recommendation was made to refer children and young people with epilepsy whose seizures have not responded to appropriate anti‐epileptic drugs to a tertiary paediatric epilepsy specialist for consideration of the use of KDs. We aimed to assess the impact of this change in guidance on the numbers of ketogenic centres and patients following KDs for epilepsy in the UK and Ireland. Methods An online survey was circulated to ketogenic dietitians from the UK and Ireland. The results were compared with similar surveys published in 2000 and 2010. Results The number of centres offering KDs for treatment of epilepsy has risen from 22 in 2000, to 28 in 2010, and to 39 in 2017 (77% overall increase). Seven of these centres accept adult referrals, in comparison to only two centres in 2010. Patient numbers have increased from 101 in 2000 to 754 in 2017. In total, 267 patients are waiting to commence KD at 31 centres. Conclusions Over the last 7 years, the number of patients treated with a KD for epilepsy in the UK and Ireland has increased by 647%, with a 77% increase in the number of centres offering KDs. Despite this rapid growth, there is ongoing demand for patients to be considered for dietary therapy, highlighting the need for continued expansion of KD services nationally.
    • Quantifying the impact of tissue metabolism on solute transport in feto-placental microvascular networks

      Nye, Gareth; Erlich, Alexander; Brownbill, Paul; Chernyavsky, Igor; Jenson, Oliver; University of Manchester (Royal Society, 2019-08-16)
      The primary exchange units in the human placenta are terminal villi, in which fetal capillary networks are surrounded by a thin layer of villous tissue, separating fetal from maternal blood. To understand how the complex spatial structure of villi influences their function, we use an image-based theoretical model to study the effect of tissue metabolism on the transport of solutes from maternal blood into the fetal circulation. For solute that is taken up under first-order kinetics, we show that the transition between flow-limited and diffusion-limited transport depends on two new dimensionless parameters defined in terms of key geometric quantities, with strong solute uptake promoting flow-limited transport conditions. We present a simple algebraic approximation for solute uptake rate as a function of flow conditions, metabolic rate and villous geometry. For oxygen, accounting for nonlinear kinetics using physiological parameter values, our model predicts that villous metabolism does not significantly impact oxygen transfer to fetal blood, although the partitioning of fluxes between the villous tissue and the capillary network depends strongly on the flow regime
    • Cancerous inhibitor of protein phosphatase 2A (CIP2A) modifies energy metabolism via 5′ AMP-activated protein kinase signalling in malignant cells

      Austin, James A.; orcid: 0000-0002-5384-5221; Jenkins, Rosalind E.; Austin, Gemma M.; Glenn, Mark A.; Dunn, Karen; Scott, Laura; Lucas, Claire M.; Clark, Richard E. (Portland Press Ltd., 2019-08-15)
      Abstract Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an adverse biomarker across many malignancies. Using K562 cells engineered to have high or low CIP2A expression, we show that high CIP2A levels significantly bias cellular energy production towards oxidative phosphorylation (OXPHOS) rather than glycolysis. Mass spectrometric analysis of CIP2A interactors and isobaric tagging for relative and absolute protein quantitation (ITRAQ) experiments identified many associated proteins, several of which co-vary with CIP2A level. Many of these CIP2A associating and co-varying proteins are involved in energy metabolism including OXPHOS, or in 5′ AMP-activated protein kinase (AMPK) signalling, and manipulating AMPK activity mimics the effects of low/high CIP2A on OXPHOS. These effects are dependent on the availability of nutrients, driven by metabolic changes caused by CIP2A. CIP2A level did not affect starvation-induced AMPK phosphorylation of Unc-51 autophagy activating kinase 1 (ULK-1) at Ser555, but autophagy activity correlated with an increase in AMPK activity, to suggest that some AMPK processes are uncoupled by CIP2A, likely via its inhibition of protein phosphatase 2A (PP2A). The data demonstrate that AMPK mediates this novel CIP2A effect on energy generation in malignant cells.
    • Lamin A/C dysregulation contributes to cardiac pathology in a mouse model of severe spinal muscular atrophy

      Šoltić, Darija; Shorrock, Hannah K.; Allardyce, Hazel; Wilson, Emma L.; Holt, Ian; Synowsky, Silvia A.; Shirran, Sally L.; Parson, Simon H.; Gillingwater, Thomas H.; Fuller, Heidi R. (Oxford University Press (OUP), 2019-08-09)
      Abstract Cardiac pathology is emerging as a prominent systemic feature of spinal muscular atrophy (SMA), but little is known about the underlying molecular pathways. Using quantitative proteomics analysis, we demonstrate widespread molecular defects in heart tissue from the Taiwanese mouse model of severe SMA. We identify increased levels of lamin A/C as a robust molecular phenotype in the heart of SMA mice, and show that lamin A/C dysregulation is also apparent in SMA patient fibroblast cells and other tissues from SMA mice. Lamin A/C expression was regulated in-vitro by knockdown of the E1 ubiquitination factor UBA1, a key downstream mediator of SMN-dependent disease pathways, converging on β-catenin signalling. Increased levels of lamin A are known to increase the rigidity of nuclei, inevitably disrupting contractile activity in cardiomyocytes. The increased lamin A/C levels in the hearts of SMA mice therefore provide a likely mechanism explaining morphological and functional cardiac defects, leading to blood pooling. Therapeutic strategies directed at lamin A/C may therefore offer a new approach to target cardiac pathology in SMA.