• To Infinity and Beyond: The Use of GPS Devices within the Football Codes

      Malone, James; Barrett, Stephen; Barnes, Chris; Twist, Craig; Drust, Barry; Liverpool Hope University; Hull City FC; CB Sports Performance; University of Chester; Liverpool John Moores University (Taylor and Francis, 2019-10-17)
      The quantification of external load through global positioning systems (GPS) is now commonplace across the different football codes. Despite this acceptance amongst sports science practitioners, confusion still remains around which are the most appropriate metrics to use when monitoring their athletes. In addition, the translation of the message between the data gathered and the athletes and coaches can often be lost. The aim of this commentary is to provide discussion and recommendations when using GPS for athlete monitoring.
    • 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)
    • Physiological responses during performance of the 15-metre Multistage Shuttle Run Test (15mMSFT), with reference to the Police Fitness Standards

      Manser, Andrew (University of ChesterUniversity of Chester, 2019-09-13)
      The objective of this review is to provide a broad outline of the research surrounding the validity and reliability of the 15-metre multi-stage fitness test (MSFT) for measuring the aerobic fitness of police officers. Maintenance of optimal cardiorespiratory fitness (CRF) in the emergency services is vital for health maintenance, injury prevention, and physical preparation for on-duty tasks. Police officers in England and Wales are required to attend annual fitness testing with minimal standards in place for entry into police safety training (PST). The current minimal standard is level 5:4, an estimated V̇O2max of 35ml·kg-1 ·min-1 , with the requirements increasing for specialist roles. This is assessed using the 15-metre MSFT previously developed and validated against laboratory obtained measures. Previous validation studies have compared the physiological responses between the 15-metre MSFT and training protocols for varying police roles. For example, Brewer, Buckle & Castle (2013) validated the level 5:4 standard by assessing the heart rate responses between the PST and level 5:4 of the 15-metre MSFT. Despite greater peak heart rate responses reported in the 15-metre MSFT (Peak heart rate: 175±13 b·min-1 vs. 152±12 b·min-1 ), the standard was maintained with concerns the aerobic fitness of police officers would be suboptimal for the role and below that of the general population. Using a similar methodology, the minimal entry requirements for 13 additional roles were developed and validated. However to date, the validity and reliability of the 15-metre MSFT has not been assessed using direct measures of gas analysis, previously relying on indirect measures to assess demands.
    • 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.
    • Individual, social, and environmental factors affecting salivary and fecal cortisol levels in captive pied tamarins (Saguinus bicolor)

      Wormell, Dominic; Smith, Tessa E.; Price, Eluned E.; Ahsmann, J.; Glendewar, G.; Hunt, J.; Coleman, Robert, C.; University of Chester (Wiley, 2019-08-01)
      Pied tamarins (Saguinus bicolor) are endangered New World primates, and in captivity appear to be very susceptible to stress. We measured cortisol in 214 saliva samples from 36 tamarins and in 227 fecal samples from 27 tamarins, and investigated the effects of age, sex, pregnancy, rearing history, social status, weight, group composition, and enclosure type using generalized linear mixed models. There was no effect of age on either fecal or salivary cortisol levels. Female pied tamarins in late pregnancy had higher fecal cortisol levels than those in early pregnancy, or nonpregnant females, but there was no effect of pregnancy on salivary cortisol. Females had higher salivary cortisol levels than males, but there was no effect of rearing history. However, for fecal cortisol, there was an interaction between sex and rearing history. Hand‐reared tamarins overall had higher fecal cortisol levels, but while male parent‐reared tamarins had higher levels than females who were parent‐ reared, the reverse was true for hand‐reared individuals. There was a trend towards lower fecal cortisol levels in subordinate individuals, but no effect of status on salivary cortisol. Fecal but not salivary cortisol levels declined with increasing weight. We found little effect of group composition on cortisol levels in either saliva or feces, suggesting that as long as tamarins are housed socially, the nature of the group is of less importance. However, animals in off‐show enclosures had higher salivary and fecal cortisol levels than individuals housed on‐show. We suggest that large on‐show enclosures with permanent access to off‐exhibit areas may compensate for the effects of visitor disturbance, and a larger number of tamarins of the same species housed close together may explain the higher cortisol levels found in tamarins living in off‐show accommodation, but further research is needed.
    • Felbamate add‐on therapy for drug‐resistant focal epilepsy

      Shi, Li LI; Bresnahan, Rebecca; Martin-McGill, Kirsty J.; Dong, JianCheng; Ni, HengJian; Geng, JinSong; Medical School of Nantong University, China; University of Liverpool; University of Chester (John Wiley & Sons, Ltd, 2019-08-01)
      Background This is an updated version of the Cochrane Review previously published in 2017. Epilepsy is a chronic and disabling neurological disorder, affecting approximately 1% of the population. Up to 30% of people with epilepsy have seizures that are resistant to currently available antiepileptic drugs and require treatment with multiple antiepileptic drugs in combination. Felbamate is a second-generation antiepileptic drug that can be used as add-on therapy to standard antiepileptic drugs. Objectives To evaluate the efficacy and tolerability of felbamate versus placebo when used as an add-on treatment for people with drug-resistant focal-onset epilepsy. Search methods For the latest update we searched the Cochrane Register of Studies (CRS Web), MEDLINE, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP), on 18 December 2018. There were no language or time restrictions. We reviewed the reference lists of retrieved studies to search for additional reports of relevant studies. We also contacted the manufacturers of felbamate and experts in the field for information about any unpublished or ongoing studies. Selection criteria We searched for randomised placebo-controlled add-on studies of people of any age with drug-resistant focal seizures. The studies could be double-blind, single-blind or unblinded and could be of parallel-group or crossover design. Data collection and analysis Two review authors independently selected studies for inclusion and extracted information. In the case of disagreements, the third review author arbitrated. Review authors assessed the following outcomes: 50% or greater reduction in seizure frequency; absolute or percentage reduction in seizure frequency; treatment withdrawal; adverse effects; quality of life. Main results We included four randomised controlled trials, representing a total of 236 participants, in the review. Two trials had parallel-group design, the third had a two-period cross-over design, and the fourth had a three-period cross-over design. We judged all four studies to be at an unclear risk of bias overall. Bias arose from the incomplete reporting of methodological details, the incomplete and selective reporting of outcome data, and from participants having unstable drug regimens during experimental treatment in one trial. Due to significant methodological heterogeneity, clinical heterogeneity and differences in outcome measures, it was not possible to perform a meta-analysis of the extracted data. Only one study reported the outcome, 50% or greater reduction in seizure frequency, whilst three studies reported percentage reduction in seizure frequency compared to placebo. One study claimed an average seizure reduction of 35.8% with add-on felbamate while another study claimed a more modest reduction of 4.2%. Both studies reported that seizure frequency increased with add-on placebo and that there was a significant difference in seizure reduction between felbamate and placebo (P = 0.0005 and P = 0.018, respectively). The third study reported a 14% reduction in seizure frequency with add-on felbamate but stated that the difference between treatments was not significant. There were conflicting results regarding treatment withdrawal. One study reported a higher treatment withdrawal for placebo-randomised participants, whereas the other three studies reported higher treatment withdrawal rates for felbamate-randomised participants. Notably, the treatment withdrawal rates for felbamate treatment groups across all four studies remained reasonably low (less than 10%), suggesting that felbamate may be well tolerated. Felbamate-randomised participants most commonly withdrew from treatment due to adverse effects. The adverse effects consistently reported by all four studies were: headache, dizziness and nausea. All three adverse effects were reported by 23% to 40% of felbamate-treated participants versus 3% to 15% of placebo-treated participants. We assessed the evidence for all outcomes using GRADE and found it as being very-low certainty, meaning that we have little confidence in the findings reported. We mainly downgraded evidence for imprecision due to the narrative synthesis conducted and the low number of events. We stress that the true effect of felbamate could likely be significantly different from that reported in this current review update. Authors' conclusions In view of the methodological deficiencies, the limited number of included studies and the differences in outcome measures, we have found no reliable evidence to support the use of felbamate as an add-on therapy in people with drug-resistant focal-onset epilepsy. A large-scale, randomised controlled trial conducted over a longer period of time is required to inform clinical practice.
    • Stochastic ordering of simulated rugby match activity produces reliable movements and associated measures of subjective task load, cognitive and neuromuscular function

      Mullen, Thomas; Twist, Craig; Highton, Jamie; University of Chester (Taylor and Francis, 2019-07-31)
      The study assesses the test–retest reliability of movement and physiological measures during a simulated rugby match that employed activities performed in a stochastic order. Twenty male rugby players (21.4 ± 2.1 y) completed two trials of a 2 × 23 min rugby movement simulation protocol during which the order of events was performed in a stochastic order, with 7–10 days between trials. Movement characteristics, heart rate (HR), RPE, maximum voluntary contraction (MVC), voluntary activation (VA%) of the quadriceps, Stroop test and subjective task load rating (NASA-TLX) were measured. The most reliable measures of external load was relative distance (typical error [TE] and 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 (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 Stroop test, NASA-TLX and blood lactate produced the least reliable measures (CV% >5%). Future studies can confidently examine changes in several perceptual, neuromuscular, physiological and movement measures related to rugby activity using stochastic movements.
    • Comment on "PP2A inhibition sensitizes cancer stem cells to ABL tyrosine kinase inhibitors in BCR-ABL human leukemia".

      Perrotti, Danilo; Agarwal, Anupriya; Lucas, Claire; Narla, Goutham; Neviani, Paolo; Odero, Maria D.; Ruvolo, Peter P.; Verrills, Nicole M. (American Association for the Advancement of Science, 2019-07-17)
      LB100 does not sensitize CML stem cells to tyrosine kinase inhibitor–induced apoptosis.
    • A preliminary cohort study assessing routine blood analyte levels and neurological outcome following spinal cord injury.

      Brown, Sharon J.; Bernardo Harrington,; Hulme, Charlotte; Morris, Rachel; Bennett, Anna; Tsang, Wai-Hung; Osman, Aheed; Chowdhury, Joy; Kumar, Naveen; Wright, Karina T. (2019-07-16)
      There is increasing interest in the identification of biomarkers that could predict neurological outcome following a spinal cord injury (SCI). Although initial American Spinal Injury Association (ASIA) Impairment Scale (AIS) grade is a good indicator of neurological outcome, for the patient and clinicians, an element of uncertainty remains. This preliminary study aimed to assess the additive potential of routine blood analytes following Principal Component Analysis (PCA) to develop prognostic models for neurological outcome following spinal cord injury. Routine blood and clinical data were collected from SCI patients (n=82) and PCA used to reduce the number of blood analytes into related factors. Outcome neurology was obtained from AIS scores at 3- and 12-months post-injury, with Motor (AIS and Total including all myotomes) and Sensory (AIS, Touch and Pain) being assessed individually. Multiple regression models were created for all outcome measures. Blood analytes relating to 'liver function' and 'acute inflammation and liver function' factors were found to significantly increase prediction of neurological outcome at both 3 months (Touch, Pain and AIS Sensory) and at 1 year (Pain, R2 increased by 0.025 and Total Motor, R2 increased by 0.016). For some models 'liver function' and 'acute inflammation and liver function' factors were both significantly predictive with the greatest combined R2 improvement of 0.043 occurring for 3m Pain prediction. These preliminary findings support ongoing research into the use of routine blood analytes in the prediction of neurological outcome in SCI patients.
    • A pilot randomised controlled trial of a programme of psychosocial interventions (Resettle) for high risk personality disordered offenders

      Nathan, Rajan; Centifanti, Luna; Baker, Vikki; Hill, Jonathan (Elsevier, 2019-07-08)
      Abstract Background Offenders with personality disorder experience significant co-morbid mental health problems and present with an increased risk of offending. The evidence for the effectiveness of interventions for personality disordered offenders in the community is limited. This study was a pilot study to determine the feasibility of a randomised controlled trial (RCT) of an intervention known as Resettle for personality disordered offenders and to explore the possible effects of this intervention. Methods Potential participants were recruited from referrals of male prisoners to Resettle. Those consenting underwent baseline assessments before being randomised to Resettle or treatment as usual. Officially recorded and self-report offending was assessed over two years following release from custody. Of the 110 eligible participants, 72 (65%) participated in the study of whom 38 were randomised to Resettle and 34 to treatment as usual. The two groups had a similar psychiatric and offending profile. Results Analysis of officially recorded offences at two years found mixed results, but whether adopting an intent-to-treat approach or including only those who received the intervention there was no clear evidence of an effect of the intervention. A comparison of self-report offending found no effect of Resettle in an intent-to-treat analysis, but there was an effect when the analysis involved only those participating in the intervention. Conclusions This study demonstrated that with some adjustments it was possible to carry out an RCT of a complex intervention for personality disordered offenders in a criminal justice setting. Some, but not conclusive, evidence was found in favour of the intervention.
    • Promoting patient utilization of outpatient cardiac rehabilitation: A joint International Council and Canadian Association of Cardiovascular Prevention and Rehabilitation position statement

      Santiago de Araújo Pio, Carolina; Varnfield, Marlien; Sarrafzadegan, Nizal; Beckie, Theresa M.; Babu, Abraham S.; Baidya, Sumana; Buckley, John P.; Chen, Ssu-Yuan; Gagliardi, Anna; Heine, Martin; et al. (Elsevier, 2019-07-04)
      Background: Cardiac Rehabilitation (CR) is a recommendation in international clinical practice guidelines given its’ benefits, however use is suboptimal. The purpose of this position statement was to translate evidence on interventions that increase CR enrolment and adherence into implementable recommendations. Methods: The writing panel was constituted by representatives of societies internationally concerned with preventive cardiology, and included disciplines that would be implementing the recommendations. Patient partners served, as well as policy-makers. The statement was developed in accordance with AGREE II, among other guideline checklists. Recommendations were based on our update of the Cochrane review on interventions to promote patient utilization of CR. These were circulated to panel members, who were asked to rate each on a 7-point Likert scale in terms of scientific acceptability, actionability, and feasibility of assessment. A web call was convened to achieve consensus and confirm strength of the recommendations (based on GRADE). The draft underwent external review and public comment. Results: The 3 drafted recommendations were that to increase enrolment, healthcare providers, particularly nurses (strong), should promote CR to patients face-to-face (strong), and that to increase adherence part of CR could be delivered remotely (weak). Ratings for the 3 recommendations were 5.95±0.69 (mean ± standard deviation), 5.33±1.12 and 5.64±1.08, respectively. Conclusions: Interventions can significantly increase utilization of CR, and hence should be widely applied. We call upon cardiac care institutions to implement these strategies to augment CR utilization, and to ensure CR programs are adequately resourced to serve enrolling patients and support them to complete programs.