Recent Submissions

  • BMPRII deficiency impairs apoptosis via the BMPRII-ALK1-BclX-mediated pathway in pulmonary arterial hypertension (PAH)

    Chowdhury, H.M.; Sharmin, N.; Yuzbasioglu Baran, M.; Long, L.; Morrell, N.W.; Trembath, R.C.; Nasim, Md. Talat (2019)
    Pulmonary Arterial Hypertension (PAH) is a devastating cardiovascular disorder characterised by the remodelling of pre-capillary pulmonary arteries. The vascular remodelling observed in PAH patients results from excessive proliferation and apoptosis resistance of pulmonary arterial smooth muscle (PASMCs) and endothelial cells (PAECs). We have previously demonstrated that mutations in the type II receptor for bone morphogenetic protein (BMPRII) underlie the majority of the familial and inherited forms of the disease. We have further demonstrated that BMPRII deficiency promotes excessive proliferation and attenuates apoptosis in PASMCs, but the underlying mechanisms remain unclear. The major objective of this study is to investigate how BMPRII deficiency impairs apoptosis in PAH. Using multidisciplinary approaches, we demonstrate that deficiency in the expression of BMPRII impairs apoptosis by modulating the alternative splicing of the apoptotic regulator, Bcl-x (B-cell lymphoma X) transcripts: a finding observed in circulating leukocytes and lungs of PAH subjects, hypoxia-induced PAH rat lungs as well as in PASMCs and PAECs. BMPRII deficiency elicits cell specific effects: promoting the expression of Bcl-xL transcripts in PASMCs whilst inhibiting it in ECs, thus exerting differential apoptotic effects in these cells. The pro-survival effect of BMPRII receptor is mediated through the activin receptor like kinase 1 (ALK1) but not the ALK3 receptor. Finally, we show that BMPRII interacts with the ALK1 receptor and pathogenic mutations in the BMPR2 gene abolish this interaction. Taken together, dysfunctional BMPRII responsiveness impairs apoptosis via the BMPRII-ALK1-Bcl-xL pathway in PAH. We suggest Bcl-xL as a potential biomarker and druggable target.
  • Uptake of oral anticoagulants for stroke prevention in patients with atrial fibrillation in a single Clinical Commissioning Group in England without restrictions to their use

    Medlinskiene, Kristina; Fay, M.; Petty, Duncan R. (2019)
    Background and Objective In England, the uptake of direct oral anticoagulants (DOACs) for stroke prevention in atrial fbrillation has been slow and varied across diferent Clinical Commissioning Groups (CCGs). This study aimed to profle the prescribing of oral anticoagulants for stroke prevention in patients with atrial fbrillation over 3 years in a CCG without restrictions to DOACs use to understand more about organisational and/or individual barriers to the early uptake of DOACs. Methods Data were collected from nine general practices between 1 April 2012 and 31 March 2015 of patients who were initiated on the oral anticoagulant therapy. Data were analysed descriptively and with independent Student’s t test and Chi square test to explore if there was an association between type of oral anticoagulant initiated and sex, age, type of prescriber and prior aspirin use. Results The early uptake of DOACs signifcantly increased over the study period (p<0.0001; medium size efect φc=0.372). There was no statistically signifcant diference between sex or age and type of oral anticoagulant initiated. Primary-care prescribers were responsible for initiating the majority of oral anticoagulants (71%; N=257) and driving the use of DOACs (72%, N=71). Patients switched from aspirin to an oral anticoagulant were more likely to be initiated on warfarin than a DOAC. Conclusions The early use of DOACs, in a CCG without restrictions to their use, was embraced by primary-care prescribers in this particular CCG.
  • Prophylaxis pharmacotherapy to prevent the onset of post traumatic brain injury depression: a systematic review

    Clay, F.; Hicks, A.; Zaman, Hadar; Ponsford, J.; Batty, R.; Perry, L.; Hopwood, M.J. (2019)
    Background: Depression is a common psychiatric problem following traumatic brain injury (TBI) with reported prevalence rates of 30-77% in the first year post-TBI. Given the negative influence of post-TBI depression on cognition, interpersonal, social, physical and occupational functioning; early initiation of pharmacotherapy to prevent post-TBI depression has been considered. This systematic review will synthesize the available evidence from published studies on the effectiveness and harms of pharmacotherapy for the secondary prevention of post-TBI depression. Method: Studies published before November 2017 were reviewed. Six databases were searched, with additional searching of key additional documents. Studies meeting inclusion criteria were evaluated for methodological quality. Results: Six articles addressing five studies met inclusion criteria. Study designs included three randomised controlled trials (RCT), two retrospective cohorts and one case-control. Prophylactic pharmacotherapy included antidepressants, beta-blockers and statins. In one RCT, the number-needed-to-treat with sertraline to prevent one case of depression post-TBI at 24 weeks was 5.9 (95%CI: 3.1-71.1). Prescribing beta-blockers prior to TBI reduced the depression risk regardless of the specific brain trauma. TBI patients with pre-existing hyperlipidemia not treated with statins had an increased depression risk compared to those without hyperlipidemia. Conclusion: Early initiation of sertraline prophylaxis in nondepressed TBI patients shows promise to reduce the odds of post-TBI depression developing. However, in the absence of rigorous study of tolerability, existing data are insufficient to recommend sertraline prophylaxis. Optimal timing and treatment duration with identification of patients most likely to benefit from prophylaxis require further consideration. Dedicated prospective studies assessing the effects of beta-blockers and statins on post-TBI depression are required.
  • Highly-branched poly(N-isopropyl acrylamide) functionalised with pendant Nile red and chain end vancomycin for the detection of Gram-positive bacteria

    Swift, Thomas; Katsikogianni, Maria G.; Hoskins, Richard; Teratarantorn, P.; Douglas, I.; MacNeil, S.; Rimmer, Stephen (2019)
    This study shows how highly branched poly(N-isopropyl acrylamide) (HB-PNIPAM) with a chain pendant solvatochromic dye (Nile red) could provide a fluorescence signal, as end groups bind to bacteria and chain segments become desolvated, indicating the presence of bacteria. Vancomycin was attached to chain ends of HB-PNIPAM or as pendant groups on linear polymers each containing Nile red. Location of the dye was varied between placement in the core of the branched polymer coil or the outer domains. Both calorimetric and fluorescence data showed that branched polymers responded to binding of both the peptide target (D-Ala-D-Aa) and bacteria in a different manner than analogous linear polymers; binding and response was more extensive in the branched variant. The fluorescence data showed that only segments located in the outer domains of branched polymers responded to binding of Gram-positive bacteria with little response when linear analogous polymer or branched polymer with the dye in the inner core was exposed to Staphylococcus aureus.
  • A unifying hypothesis for control of body weight and reproduction in seasonally breeding mammals

    Helfer, Gisela; Barrett, P.; Morgan, P.J. (2019)
    Animals have evolved diverse seasonal variations in physiology and reproduction to accommodate yearly changes in environmental and climatic conditions. These changes in physiology are initiated by changes in photoperiod (daylength) and are mediated through melatonin, which relays photoperiodic information to the pars tuberalis of the pituitary gland. Melatonin drives thyroid‐stimulating hormone transcription and synthesis in the pars tuberalis, which, in turn, regulates thyroid hormone and retinoic acid synthesis in the tanycytes lining the third ventricle of the hypothalamus. Seasonal variation in central thyroid hormone signalling is conserved among photoperiodic animals. Despite this, different species adopt divergent phenotypes to cope with the same seasonal changes. A common response amongst different species is increased hypothalamic cell proliferation/neurogenesis in short photoperiod. That cell proliferation/neurogenesis may be important for seasonal timing is based on (i) the neurogenic potential of tanycytes; (ii) the fact that they are the locus of striking seasonal morphological changes; and (iii) the similarities to mechanisms involved in de novo neurogenesis of energy balance neurones. We propose that a decrease in hypothalamic thyroid hormone and retinoic acid signalling initiates localised neurodegeneration and apoptosis, which leads to a reduction in appetite and body weight. Neurodegeneration induces compensatory cell proliferation from the neurogenic niche in tanycytes and new cells are born under short photoperiod. Because these cells have the potential to differentiate into a number of different neuronal phenotypes, this could provide a mechanistic basis to explain the seasonal regulation of energy balance, as well as reproduction. This cycle can be achieved without changes in thyroid hormone/retinoic acid and explains recent data obtained from seasonal animals held in natural conditions. However, thyroid/retinoic acid signalling is required to synchronise the cycles of apoptosis, proliferation and differentiation. Thus, hypothalamic neurogenesis provides a framework to explain diverse photoperiodic responses.
  • Pharmacist educational interventions for cancer pain management: a systematic review and meta-analysis

    Edwards, Zoe; Ziegler, L.; Craigs, C.; Blenkinsopp, Alison; Bennett, M.I. (2019)
    Educational interventions by pharmacists for patients with cancer pain aim to improve pain management, but little is known about the different components of interventions and their effectiveness. Our aim was to assess the benefit of pharmacist delivered educational interventions for patients with cancer pain. A systematic review and meta‐analysis of experimental trials testing pharmacist delivered educational interventions for cancer pain was carried out to identify the components of interventions and effectiveness at improving pain‐related outcomes for patients with cancer. A literature review was conducted in EMBASE, MEDLINE, CINAHL, PsycINFO, ASSIA, Web of Science and CENTRAL from inception until January 2018 searching for educational interventions involving a pharmacist for patients with cancer pain. Four studies were included involving 944 patients. Meta‐analysis was carried out where possible. Meta‐analysis of three of the four studies found that mean pain intensity in the intervention group was reduced by 0.76 on a 0–10 scale (95% confidence interval), although only two of the studies used validated measures of pain. Improvements in knowledge, side effects and patient satisfaction were seen although with less reliable measures. Pharmacist educational interventions for patients with cancer pain have been found to show promise in reducing pain intensity. Studies were few and of varying quality. Further, good quality studies should be carried out in this area and these should be comprehensively reported. Trials measuring patient self‐efficacy and patient satisfaction are needed before the impact of the pharmacist delivered interventions on these outcomes can be established.
  • A muscle mimetic polyelectrolyte–nanoclay organic–inorganic hybrid hydrogel: its self-healing, shape-memory and actuation properties

    Banerjee, S.L.; Swift, Thomas; Hoskins, Richard; Rimmer, Stephen; Singha, N.K. (2019)
    Here in, we describe a non-covalent (ionic interlocking and hydrogen bonding) strategy of self-healing in a covalently crosslinked organic-inorganic hybrid 15 nanocomposite hydrogel, with special emphasize on it's improved mechanical stability. The hydrogel was prepared via in-situ free radical polymerization of sodium acrylate (SA) and successive crosslinking in the presence of poly(2-(methacryloyloxy)ethyl trimethyl ammonium chloride) (PMTAC) grafted cationically armed starch and organically modified montmorillonite (OMMT). This hydrogel shows stimuli triggered self-healing following damage in both neutral and acidic solutions (pH=7.4 and pH=1.2). This was elucidated by tensile strength and rheological analyses of the hydrogel segments joined at their fractured points. Interestingly this hydrogel can show water based shape memory effects. It was observed that the ultimate tensile strength (UTS) of the self-healed hydrogel at pH = 7.4 was comparable to extensor digitorum longus (EDL) muscle of the New Zealand white rabbit. The as synthesized self-healable hydrogel was found to be non-cytotoxic against NIH 3T3 fibroblast cells.
  • How do we avoid the ‘ever decreasing circles syndrome’ in service improvement?

    Manzoor, A.; Breen, Liz; Marques, Iuri; Edwards, Zoe (2018-09)
  • Description of Potential Energy Surfaces of Molecules using FFLUX Machine Learning Models

    Hughes, Zak E.; Thacker, J.C.R.; Wilson, A.L.; Popelier, P.L.A. (2019)
    A new type of model, FFLUX, to describe the interaction between atoms has been developed as an alternative to traditional force fields. FFLUX models are constructed from applying the kriging machine learning method to the topological energy partitioning method, Interacting Quantum Atoms (IQA). The effect of varying parameters in the construction of the FFLUX models is analyzed, with the most dominant effects found to be the structure of the molecule and the number of conformations used to build the model. Using these models the optimization of a variety of small organic molecules is performed, with sub kJ mol-1 accuracy in the energy of the optimized molecules. The FFLUX models are also evaluated in terms of their performance in describing the potential energy surfaces (PESs) associated with specific degrees of freedoms within molecules. While the accurate description of PESs presents greater challenges than individual minima, FFLUX models are able to achieve errors of <2.5 kJ mol-1 across the full C-C-C-C dihedral PES of n-butane, indicating the future possibilities of the technique.
  • Development and evaluation of nanoemulsion and microsuspension formulations of curcuminoids for lung delivery with a novel approach to understanding the aerosol performance of nanoparticles

    Al Ayoub, Yuosef; Gopalan, Rajendran C.; Najafzadeh, Mojgan; Mohammad, Mohammad A.; Anderson, Diana; Paradkar, Anant R.; Assi, Khaled H. (2019-02-25)
    Extensive research has demonstrated the potential effectiveness of curcumin against various diseases, including asthma and cancers. However, few studies have used liquid-based vehicles in the preparation of curcumin formulations. Therefore, the current study proposed the use of nanoemulsion and microsuspension formulations to prepare nebulised curcuminoid for lung delivery. Furthermore, this work expressed a new approach to understanding the aerosol performance of nanoparticles compared to microsuspension formulations. The genotoxicity of the formulations was also assessed. Curcuminoid nanoemulsion formulations were prepared in three concentrations (100, 250 and 500 µg/ml) using limonene and oleic acid as oil phases, while microsuspension solutions were prepared by suspending curcuminoid particles in isotonic solution (saline solution) of 0.02% Tween 80. The average fine particle fraction (FPF) and mass median aerodynamic diameter (MMAD) of the nebulised microsuspension formulations ranged from 26% and 7.1 µm to 40% and 5.7 µm, for 1000 µg/ml and 100 µg/ml respectively. In a comparison of the low and high drug concentrations of the nebulised nanoemulsion, the average FPF and MMAD of the nebulised nanoemulsion formulations prepared with limonene oil ranged from 50% and 4.6 µm to 45% and 5.6 µm, respectively; whereas the FPF and MMAD of the nebulised nanoemulsion prepared with oleic acid oil ranged from 46% and 4.9 µm to 44% and 5.6 µm, respectively. The aerosol performance of the microsuspension formulations were concentration dependent, while the nanoemulsion formulations did not appear to be dependent on the curcuminoids concentration. The performance and genotoxicity results of the formulations suggest the suitability of these preparations for further inhalation studies in animals.
  • An assessment of supply chain vulnerabilities to dynamic disruptions in the pharmaceutical supply chain

    Yaroson, Emilia V.; Sharief, Karam; Shah, Awn; Breen, Liz (2018-09)
    Objective: The adverse impact of supply chain disruptions on the operational performance of supply chains have been suggested to emanate from its existing vulnerabilities. However, empirical studies regarding this proposition remain limited. This study provides empirical evidence of vulnerabilities in the face of dynamic disruptions in the pharmaceutical supply chain. This is geared at developing resilience strategies capable of curbing these forms of disruptions. Research Approach: In seeking to achieve the objective of this study, the mixed method research design in a longitudinal framework was adopted. It involved a two-step procedure where the study began by conducting semi-structured interviews with the downstream stakeholders of the pharmaceutical supply chain. Here the sampling method adopted was both purposive and snowballing. Data collected from this process was analysed using thematic analysis where key variables were coded for further analysis. Findings from the interviews were employed to construct close ended questionnaires. The questionnaires were administered online, approximately nine months after the first data collection process ended and analysed using various statistical techniques. Findings: The themes that emerged from the first phase of the data generation process were classified into five main pillars which include: supply chain characteristics, regulatory framework (schemas), imbalance of market power, managerial decisions and supply chain structures. These themes were further confirmed by the findings from the survey. The study finds that imbalance of market power generates negative welfare such as time consumption and stress on the downstream stakeholders of the pharmaceutical supply chain. In the same vein, dependence on suppliers and consumers in designing the supply chain exacerbates the impact of a dynamic disruption. The findings from the survey complement these pillars by identifying other vulnerabilities: price manipulation, inadequate policies, inefficient manufacturing processes as well as available training in handling these vulnerabilities. Originality/Value: By providing empirical evidence of the vulnerabilities within the pharmaceutical supply chain in the face of a dynamic disruption, this study extends operations management literature by highlighting vulnerability benchmarks against which resilience strategies can be employed in dynamic disruptive scenarios. The innovative aspect of this research is the ability to identify the vulnerabilities peculiar to the pharmaceutical supply chain which is required in order to successfully develop strategies that are resilient to dynamic disruptions. Research Impact: This study extends existing debates on supply chain vulnerabilities as well as supply chain disruptions. Practical Impact: This study contributes to practical managerial decisions, as the identifications of vulnerabilities to dynamic disruptions will aid pharmaceutical and or operations managers in assessing supplier selection and design.
  • Identifying reverse exchange practices: a comparative study of laundry logistics in public hospitals (Thailand)

    Bandoophanit, T.; Breen, Liz (2018-09-07)
    The effective reverse exchange of healthcare products such as laundry within a hospital environment can support the health system, for achieving the highest goal: ‘to provide regular and timely supply of clean linen to the satisfaction of patients and staff’ (Srikar et al., 2015, p. 593). Previous studies by Bandoophanit et al. (2015, 2017) assert there are constant shortages of linen availability in many Thai public hospitals which can undermine the efficacy of laundry management and quality of medical treatment. This study investigates the practices, culture, and operational performance of three large-sized public hospitals (700-2,000 beds) located in Thailand reflecting on the application of Reverse Exchanges (R/E) theory. This study contributes to the Thai healthcare agenda, a core mission of which is to “Develop the health system with quality, efficiency and equality; with participation of the people, communities and all sectors for good health of all Thai people in order to achieve a good and sustainable society following the King’s Sufficiency Economy philosophy” (Ministry of Public Health, 2018).
  • Identifying green logistics best practices: a case study of Thailand's public hospitals

    Bandoophanit, T.; Breen, Liz; Barber, Kevin D. (2018-09)
    Purpose Previous research (Bandoophanit et al, 2017) has shown that pharmaceuticals are a key input into effective healthcare operations but other equally important inputs are medical supplies, food, utilities, equipment and linen. As stated by the Twelfth National Economic and Social Development Plan (2017-2021) of Thailand, to attempt to deliver national Sustainable Development Goals (SDGs) organisations should preserve resources and minimize waste-generation in all aspects. The principal aim of this research project was to identify green practices and develop a model which supported and promoted healthcare efficiencies. Research Approach This was a mixed methods multi-site study using both qualitative and quantitative data collection and analysis methods. Six public hospitals were selected as case organizations, covering different types/sizes, locations, and environmental performance expertise. The data collection methods included interviews, documentation reviews and in situ observations. Respondents’ selection was purposive and a bespoke form of content analysis was used for the data review before further cross-case analysis, resulting in the identification of best practices using key indicators. Findings and Originality In spite of facing financial crisis, by reviewing key logistical processes and lifecycle, the overuse of healthcare resources and the poor management of waste, were clearly identified within in this study. This had a negative effect on personnel and patient hygiene. The result of identifying effective GL practices were reported as: (i) promoting the usage of multiple-use medical devices that can minimize inputs, waste, and cost, and (ii) producing/selecting organic food materials and fruits and reusing these waste byproducts to create secondary products e.g. fertilizer, biogas and electricity and cleaning/sterilizing liquid. The results also indicated that there was a drive from leaders to introduce green and efficient systems to improve staff personnel awareness and engagement in this area. The output of this study presents a model for GL implementation guidance, grounded in Thailand’s Sufficiency Economy Philosophy (SEP) concept. Research Impacts Currently, healthcare green logistics has received limited attention in developing nations and this study contributes to the reduction of these gaps. The SEP concept promotes sustainable health standards and underpins the focus and the originality/impact of this study. Practical Impacts This study recommends that staff in Thai hospitals focus on effective resource and waste management to contribute to sustainable sufficiency. This allows Thailand to offer an effective healthcare service to its patients. The study presents guidance and support to do this.
  • Emergency Department Pharmacist Practitioners: A new role in the NHS

    Greenwood, D.; Tully, M.P.; Martin, Sandra J.; Steinke, D. (2018-08)
  • Development of an Emergency Department Pharmacist Practitioner service specification

    Greenwood, D.; Steinke, D.; Martin, Sandra J.; Tully, M. (2018-11-02)
  • Can contrast-response functions indicate visual processing levels?

    Breitmeyer, B.G.; Tripathy, Srimant P.; Brown, J.M. (2018-03-01)
    Many visual effects are believed to be processed at several functional and anatomical levels of cortical processing. Determining if and how the levels contribute differentially to these effects is a leading problem in visual perception and visual neuroscience. We review and analyze a combination of extant psychophysical findings in the context of neurophysiological and brain-imaging results. Specifically using findings relating to visual illusions, crowding, and masking as exemplary cases, we develop a theoretical rationale for showing how relative levels of cortical processing contributing to these effects can already be deduced from the psychophysically determined functions relating respectively the illusory, crowding and masking strengths to the contrast of the illusion inducers, of the flankers producing the crowding, and of the mask. The wider implications of this rationale show how it can help to settle or clarify theoretical and interpretive inconsistencies and how it can further psychophysical, brain-recording and brain-imaging research geared to explore the relative functional and cortical levels at which conscious and unconscious processing of visual information occur. Our approach also allows us to make some specific predictions for future studies, whose results will provide empirical tests of its validity.
  • Bottlenecks of motion processing during a visual glance: the leaky flask model

    Ögmen, H.; Ekiz, O.; Huynh, D.; Bedell, H.E.; Tripathy, Srimant P. (2013-12-31)
    Where do the bottlenecks for information and attention lie when our visual system processes incoming stimuli? The human visual system encodes the incoming stimulus and transfers its contents into three major memory systems with increasing time scales, viz., sensory (or iconic) memory, visual short-term memory (VSTM), and long-term memory (LTM). It is commonly believed that the major bottleneck of information processing resides in VSTM. In contrast to this view, we show major bottlenecks for motion processing prior to VSTM. In the first experiment, we examined bottlenecks at the stimulus encoding stage through a partial-report technique by delivering the cue immediately at the end of the stimulus presentation. In the second experiment, we varied the cue delay to investigate sensory memory and VSTM. Performance decayed exponentially as a function of cue delay and we used the time-constant of the exponential-decay to demarcate sensory memory from VSTM. We then decomposed performance in terms of quality and quantity measures to analyze bottlenecks along these dimensions. In terms of the quality of information, two thirds to three quarters of the motion-processing bottleneck occurs in stimulus encoding rather than memory stages. In terms of the quantity of information, the motion-processing bottleneck is distributed, with the stimulus-encoding stage accounting for one third of the bottleneck. The bottleneck for the stimulus-encoding stage is dominated by the selection compared to the filtering function of attention. We also found that the filtering function of attention is operating mainly at the sensory memory stage in a specific manner, i.e., influencing only quantity and sparing quality. These results provide a novel and more complete understanding of information processing and storage bottlenecks for motion processing.
  • β‐Ketoiminato Iridium(III) Organometallic Complexes: Selective Cytotoxicity towards Colorectal Cancer Cells HCT116 p53‐/‐

    Lord, Rianne M.; Zegke, Markus; Henderson, I.R.; Pask, C.M.; Shepherd, H.J.; McGowan, P.C. (2019-01-07)
    This report presents a new library of organometallic iridium(III) compounds of the type [Cp*IrCl(L)] (Cp*=pentamethylcyclopentadienyl and L=a functionalized β‐ketoiminato ligand) showing moderate to high cytotoxicity against a range of cancer cell lines. All compounds show increased activity towards colorectal cancer, with preferential activity observed against the immortalized p53‐null colorectal cell line, HCT116 p53‐/‐, with sensitivity factors (SF) up to 26.7. Additionally, the compounds have excellent selectivity for cancerous cells when tested against normal cell types, with selectivity ratios (SR) up to 35.6, contrary to that of cisplatin, which is neither selective nor specific for cancerous cells (SF=0.43 and SR=0.7–2.3). This work provides a preliminary understanding of the cytotoxicity of iridium compounds in the absence of p53 and has potential applications in treatment of cancers for which the p53 gene is absent or mutant.

View more