Recent Submissions

  • Multigram scale synthesis of polycyclic lactones and evaluation of antitumor and other biological properties

    Grau, L.; Romero, M.; Privat-Contreras, C.; Presa, Daniela; Viñas, M.; Morral, J.; Pors, Klaus; Rubio-Martinez, J.; Pujol, M.D. (2020-01-01)
    An efficient four-step synthesis of tetracyclic lactones from 1,4-benzodioxine-2-carboxylic acid was developed. Ellipticine derivatives exhibit antitumor activity however only a few derivatives without carbazole subunit have been studied to date. Herein, several tetracyclic lactones were synthesized and biologically evaluated. Several compounds (2a, 3a, 4a and 5a) were found to be inhibitors of the Kras-Wnt pathway. The lactone 2a also exerted a potent inhibition of Tau protein translation and was shown to have capacity for CYP1A1-bioactivation. The results obtained are further evidence of the therapeutic potential of tetracyclic lactones related to ellipticine. Molecular modeling studies showed that compound 2a is inserted between helix α3 and α4 of the KRas protein making interactions with the hydrophobic residues Phe90, Glu91, Ile9364, Hie94, Leu133 and Tyr137and a hydrogen bond with residue Arg97.
  • Loss of CRMP2 O-GlcNAcylation leads to reduced novel object recognition performance in mice

    Muha, V.; Williamson, Ritchie; Hills, R.; McNeilly, A.D.; McWilliams, T.G.; Alonso, J.; Schimpl, M.; Leney, A.C.; Heck, A.J.R.; Sutherland, C.; et al. (2019-11-06)
    O-GlcNAcylation is an abundant post-translational modification in the nervous system, linked to both neurodevelopmental and neurodegenerative disease. However, the mechanistic links between these phenotypes and site-specific O-GlcNAcylation remain largely unexplored. Here, we show that Ser517 O-GlcNAcylation of the microtubule-binding protein Collapsin Response Mediator Protein-2 (CRMP2) increases with age. By generating and characterizing a Crmp2S517A knock-in mouse model, we demonstrate that loss of O-GlcNAcylation leads to a small decrease in body weight and mild memory impairment, suggesting that Ser517 O-GlcNAcylation has a small but detectable impact on mouse physiology and cognitive function.
  • Ancient Mycobacterium leprae genomes from the mediaeval sites of Chichester and Raunds in England

    Kerudin, A.; Müller, R.; Buckberry, Jo; Knüsel, C.J.; Brown, T.A. (2019-12)
    We examined six skeletons from mediaeval contexts from two sites in England for the presence of Mycobacterium leprae DNA, each of the skeletons displaying osteological indicators of leprosy. Polymerase chain reactions directed at the species-specific RLEP multicopy sequence produced positive results with three skeletons, these being among those with the clearest osteological signs of leprosy. Following in-solution hybridization capture, sufficient sequence reads were obtained to cover >70% of the M. leprae genomes from these three skeletons, with a mean read depth of 4–10×. Two skeletons from a mediaeval hospital in Chichester, UK, dating to the 14th–17th centuries AD, contained M. leprae strains of subtype 3I, which has previously been reported in mediaeval England. The third skeleton, from a churchyard cemetery at Raunds Furnells, UK, dating to the 10th to mid-12th centuries AD, carried subtype 3K, which has been recorded at 7th–13th century AD sites in Turkey, Hungary and Denmark, but not previously in Britain. We suggest that travellers to the Holy Land might have been responsible for the transmission of subtype 3K from southeast Europe to Britain.
  • Understanding long-term opioid prescribing for non-cancer pain in primary care: A qualitative study

    McCrorie, C.; Closs, S.J.; House, A.; Petty, Duncan R.; Ziegler, L.; Glidewell, L.; West, R.; Foy, R. (2015-09)
    Background: The place of opioids in the management of chronic, non-cancer pain is limited. Even so their use is escalating, leading to concerns that patients are prescribed strong opioids inappropriately and alternatives to medication are under-used. We aimed to understand the processes which bring about and perpetuate long-term prescribing of opioids for chronic, non-cancer pain. Methods: We held semi-structured interviews with patients and focus groups with general practitioners (GPs). Participants included 23 patients currently prescribed long-term opioids and 15 GPs from Leeds and Bradford, United Kingdom (UK). We used a grounded approach to the analysis of transcripts. Results: Patients are driven by the needs for pain relief, explanation, and improvement or maintenance of quality of life. GPs’ responses are shaped by how UK general practice is organised, available therapeutic choices and their expertise in managing chronic pain, especially when facing diagnostic uncertainty or when their own approach is at odds with the patient’s wishes. Four features of the resulting transaction between patients and doctors influence prescribing: lack of clarity of strategy, including the risk of any plans being subverted by urgent demands; lack of certainty about locus of control in decision-making, especially in relation to prescribing; continuity in the doctor-patient relationship; and mutuality and trust. Conclusions: Problematic prescribing occurs when patients experience repeated consultations that do not meet their needs and GPs feel unable to negotiate alternative approaches to treatment. Therapeutic short-termism is perpetuated by inconsistent clinical encounters and the absence of mutually-agreed formulations of underlying problems and plans of action. Apart from commissioning improved access to appropriate specialist services, general practices should also consider how they manage problematic opioid prescribing and be prepared to set boundaries with patients.
  • Prescribed opioids in primary care: cross-sectional and longitudinal analyses of influence of patient and practice characteristics

    Foy, R.; Leaman, B.; McCrorie, C.; Petty, Duncan R.; House, A.; Bennett, M.; Carder, P.; Faulkner, S.; Glidewell, L.; West, R. (2016-05)
    Objectives: To examine trends in opioid prescribing in primary care, identify patient and general practice characteristics associated with long-term and stronger opioid prescribing, and identify associations with changes in opioid prescribing. Design: Trend, cross-sectional and longitudinal analyses of routinely recorded patient data. Setting: 111 primary care practices in Leeds and Bradford, UK. Participants: We observed 471 828 patient-years in which all patients represented had at least 1 opioid prescription between April 2005 and March 2012. A cross-sectional analysis included 99 847 patients prescribed opioids between April 2011 and March 2012. A longitudinal analysis included 49 065 patient-years between April 2008 and March 2012. We excluded patients with cancer or treated for substance misuse. Main outcome measures: Long-term opioid prescribing (4 or more prescriptions within 12 months), stronger opioid prescribing and stepping up to or down from stronger opioids. Results: Opioid prescribing in the adult population almost doubled for weaker opioids over 2005–2012 and rose over sixfold for stronger opioids. There was marked variation among general practices in the odds of patients stepping up to stronger opioids compared with those not stepping up (range 0.31–3.36), unexplained by practice-level variables. Stepping up to stronger opioids was most strongly associated with being underweight (adjusted OR 3.26, 1.49 to 7.17), increasing polypharmacy (4.15, 3.26 to 5.29 for 10 or more repeat prescriptions), increasing numbers of primary care appointments (3.04, 2.48 to 3.73 for over 12 appointments in the year) and referrals to specialist pain services (5.17, 4.37 to 6.12). Compared with women under 50 years, men under 50 were less likely to step down once prescribed stronger opioids (0.53, 0.37 to 0.75). Conclusions: While clinicians should be alert to patients at risk of escalated opioid prescribing, much prescribing variation may be attributable to clinical behaviour. Effective strategies targeting clinicians and patients are needed to curb rising prescribing, especially of stronger opioids.
  • Application of prescribing recommendations in older people with reduced kidney function: A cross-sectional study in general practice

    Wood, S.; Petty, Duncan R.; Glidewell, L.; Raynor, D.K.T. (2018-05)
    Background: Kidney function reduces with age, increasing the risk of harm from increased blood levels of many medicines. Although estimated glomerular filtration rate (eGFR) is reported for prescribing decisions in those aged ≥65 years, creatinine clearance (Cockcroft–Gault) gives a more accurate estimate of kidney function. Aim: To explore the extent of prescribing outside recommendations for people aged ≥65 years with reduced kidney function in primary care and to assess the impact of using eGFR instead of creatinine clearance to calculate kidney function. Design and setting: A cross-sectional survey of anonymised prescribing data in people aged ≥65 years from all 80 general practices (70 900 patients) in a north of England former primary care trust. Method: The prevalence of prescribing outside recommendations was analysed for eight exemplar drugs. Data were collected for age, sex, actual weight, serum creatinine, and eGFR. Kidney function as creatinine clearance (Cockcroft–Gault) was calculated using actual body weight and estimated ideal body weight. Results: Kidney function was too low for recommended prescribing in 4–40% of people aged ≥65 years, and in 24–80% of people aged ≥85 years despite more than 90% of patients having recent recorded kidney function results. Using eGFR overestimated kidney function for 3–28% of those aged ≥65 years, and for 13–58% of those aged ≥85 years. Increased age predicted higher odds of having a kidney function estimate too low for recommended prescribing of the study drugs. Conclusion: Prescribing recommendations when kidney function is reduced are not applied for many people aged ≥65 years in primary care. Using eGFR considerably overestimates kidney function for prescribing and, therefore, creatinine clearance (Cockcroft–Gault) should be assessed when prescribing for these people. Interventions are needed to aid prescribers when kidney function is reduced.
  • To what extent can behaviour change techniques be identified within an adaptable implementation package for primary care? A prospective directed content analysis

    Glidewell, L.; Willis, T.A.; Petty, Duncan R.; Lawton, R.; McEachan, R.R.C.; Ingleson, E.; Heudtlass, P.; Davies, A.; Jamieson, T.; Hunter, C.; et al. (2018-02)
    Background: Interpreting evaluations of complex interventions can be difficult without sufficient description of key intervention content. We aimed to develop an implementation package for primary care which could be delivered using typically available resources and could be adapted to target determinants of behaviour for each of four quality indicators: diabetes control, blood pressure control, anticoagulation for atrial fibrillation and risky prescribing. We describe the development and prospective verification of behaviour change techniques (BCTs) embedded within the adaptable implementation packages. Methods: We used an over-lapping multi-staged process. We identified evidence-based, candidate delivery mechanisms—mainly audit and feedback, educational outreach and computerised prompts and reminders. We drew upon interviews with primary care professionals using the Theoretical Domains Framework to explore likely determinants of adherence to quality indicators. We linked determinants to candidate BCTs. With input from stakeholder panels, we prioritised likely determinants and intervention content prior to piloting the implementation packages. Our content analysis assessed the extent to which embedded BCTs could be identified within the packages and compared them across the delivery mechanisms and four quality indicators. Results: Each implementation package included at least 27 out of 30 potentially applicable BCTs representing 15 of 16 BCT categories. Whilst 23 BCTs were shared across all four implementation packages (e.g. BCTs relating to feedback and comparing behaviour), some BCTs were unique to certain delivery mechanisms (e.g. ‘graded tasks’ and ‘problem solving’ for educational outreach). BCTs addressing the determinants ‘environmental context’ and ‘social and professional roles’ (e.g. ‘restructuring the social and ‘physical environment’ and ‘adding objects to the environment’) were indicator specific. We found it challenging to operationalise BCTs targeting ‘environmental context’, ‘social influences’ and ‘social and professional roles’ within our chosen delivery mechanisms. Conclusion: We have demonstrated a transparent process for selecting, operationalising and verifying the BCT content in implementation packages adapted to target four quality indicators in primary care. There was considerable overlap in BCTs identified across the four indicators suggesting core BCTs can be embedded and verified within delivery mechanisms commonly available to primary care. Whilst feedback reports can include a wide range of BCTs, computerised prompts can deliver BCTs at the time of decision making, and educational outreach can allow for flexibility and individual tailoring in delivery
  • Relative contributions to vergence eye movements of two binocular cues for motion-in-depth

    Giesel, M.; Yakovleva, A.; Bloj, Marina; Wade, A.R.; Norcia, A.M.; Harris, J.M. (Springer Nature Group, 2019-11)
    When we track an object moving in depth, our eyes rotate in opposite directions. This type of “disjunctive” eye movement is called horizontal vergence. The sensory control signals for vergence arise from multiple visual cues, two of which, changing binocular disparity (CD) and inter-ocular velocity differences (IOVD), are specifically binocular. While it is well known that the CD cue triggers horizontal vergence eye movements, the role of the IOVD cue has only recently been explored. To better understand the relative contribution of CD and IOVD cues in driving horizontal vergence, we recorded vergence eye movements from ten observers in response to four types of stimuli that isolated or combined the two cues to motion-in-depth, using stimulus conditions and CD/IOVD stimuli typical of behavioural motion-in-depth experiments. An analysis of the slopes of the vergence traces and the consistency of the directions of vergence and stimulus movements showed that under our conditions IOVD cues provided very little input to vergence mechanisms. The eye movements that did occur coinciding with the presentation of IOVD stimuli were likely not a response to stimulus motion, but a phoria initiated by the absence of a disparity signal.
  • Undertaking sex assessment

    Brickley, M.; Buckberry, Jo (CIFA, 2018)
  • Estimation of juvenile age at death

    Buckberry, Jo; Brickley, M. (CIFA, 2018)
  • Genetic prediction of myopia: prospects and challenges

    Guggenheim, J.A.; Ghorbani Mojarrad, Neema; Williams, C.; Flitcroft, D.I. (2017-09)
    Appeals have been made for eye care professionals to start prescribing anti-myopia therapies as part of their routine management of myopic children. 1–3 These calls are fuelled by two key considerations. Firstly, that interventions to slow myopia progression have shown success in randomized controlled trials (RCTs) 4–7, and secondly, appreciation that the risk of sight-threatening complications rises dose-dependently with the level of myopia. 8,9 Notwithstanding existing gaps in knowledge regarding the efficacy of current treatments (see below), these considerations argue that myopia control interventions should be widely adopted, and that they should be instigated at an early age – especially in children most at risk – in order to reduce the final level of myopia. Therefore in managing a child with myopia, an eye care professional would have to decide not only which therapy to recommend, but at what age to start treatment. In this review we discuss the future role of genetic prediction in helping clinicians treat myopia.
  • A genetic risk score and number of myopic parents independently predict myopia

    Ghorbani Mojarrad, Neema; Williams, C.; Guggenheim, J.A. (2018-09)
    Purpose: To investigate whether a genetic risk score (GRS) improved performance of predicting refractive error compared to knowing a child’s number of myopic parents (NMP) alone. Methods: This was a retrospective analysis of data from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort study. Refractive error was assessed longitudinally between age 7–15 using non-cycloplegic autorefraction. Genetic variants (n=149) associated with refractive error from a Consortium for Refractive Error And Myopia (CREAM) genome-wide association study were used to calculate a GRS for each child. Using refractive error at ages 7 and 15 years as the outcome variable, coefficient of determination (R2) values were calculated via linear regression models for the predictors: NMP, GRS and a combined model. Results: Number of myopic parents was weakly predictive of refractive error in children aged 7 years, R2=3.0% (95% CI 1.8–4.1%,p<0.0001) and aged 15 years, R2=4.8% (3.1–6.5%,p<0.0001). The GRS was also weakly predictive;age 7 years, R2=1.1% (0.4–1.9%,p<0.0001) and 15 years R2=2.6% (1.3–3.9%,p<0.0001). Combining the 2 variables gave larger R2 values at age 7, R2=3.7%(2.5–5.0%,p<0.0001) and 15, R2=7.0% (5.0–9.0%,p<0.0001). The combined model improved performance at both ages (both p<0.0001). Conclusion: A GRS improved the ability to detect children at risk of myopia independently of knowing the NMP. We speculate this may be because NMP captures information concerning environmental risk factors for myopia. Nevertheless, further gains are required to make such predictive tests worthwhile in the clinical environment.
  • Association between polygenic risk score and risk of myopia

    Ghorbani Mojarrad, Neema; Plotnikov, D.; Williams, C.; Guggenheim, J.A. (2019-10)
    Importance: Myopia is a leading cause of untreatable visual impairment and is increasing in prevalence worldwide. Interventions for slowing childhood myopia progression have shown success in randomized clinical trials; hence, there is a need to identify which children would benefit most from treatment intervention. Objectives: To examine whether genetic information alone can identify children at risk of myopia development and whether including a child’s genetic predisposition to educational attainment is associated with improved genetic prediction of the risk of myopia. Design, Setting, and Participants: Meta-analysis of 3 genome-wide association studies (GWAS) including a total of 711 984 individuals. These were a published GWAS for educational attainment and 2 GWAS for refractive error in the UK Biobank, which is a multisite cohort study that recruited participants between January 2006 and October 2010. A polygenic risk score was applied in a population-based validation sample examined between September 1998 and September 2000 (Avon Longitudinal Study of Parents and Children [ALSPAC] mothers). Data analysis was performed from February 2018 to May 2019. Main Outcomes and Measures: The primary outcome was the area under the receiver operating characteristic curve (AUROC) in analyses for predicting myopia, using noncycloplegic autorefraction measurements for myopia severity levels of less than or equal to −0.75 diopter (D) (any), less than or equal to -3.00 D (moderate), or less than or equal to −5.00 D (high). The predictor variable was a polygenic risk score (PRS) derived from genome-wide association study data for refractive error (n = 95 619), age of onset of spectacle wear (n = 287 448), and educational attainment (n = 328 917). Results: A total of 383 067 adults aged 40 to 69 years from the UK Biobank were included in the new GWAS analyses. The PRS was evaluated in 1516 adults aged 24 to 51 years from the ALSPAC mothers cohort. The PRS had an AUROC of 0.67 (95% CI, 0.65-0.70) for myopia, 0.75 (95% CI, 0.70-0.79) for moderate myopia, and 0.73 (95% CI, 0.66-0.80) for high myopia. Inclusion in the PRS of information associated with genetic predisposition to educational attainment marginally improved the AUROC for myopia (AUROC, 0.674 vs 0.668; P = .02), but not those for moderate and high myopia. Individuals with a PRS in the top 10% were at 6.1-fold higher risk (95% CI, 3.4–10.9) of high myopia. Conclusions and Relevance: A personalized medicine approach may be feasible for detecting very young children at risk of myopia. However, accuracy must improve further to merit uptake in clinical practice; currently, cycloplegic autorefraction remains a better indicator of myopia risk (AUROC, 0.87).
  • Interpretation of a probable case of poliomyelitis in the Romano-British social context

    Castells Navarro, Laura; Southwell-Wright, W.; Manchester, Keith; Buckberry, Jo (Archaeological reviews from Cambridge, 2017-07)
    This paper provides the results of re-evaluation of a young adult individual from the Romano-British cemetery of 76 Kingsholm, Gloucester with club foot defomity by (Roberts et al 2004). Our reanalysis revealed an extensive bilateral asymmetry involving the lower and upper limb, spine and cranium and a right scoliosis, indicating more than the lower limb was affected. Consideration of the position and shape of the articulated club foot indicated a positional rather than a developmental condition, probably due to unilateral paralysis. Differential diagnosis considered congenital and acquired neuromuscular conditions; we argue that poliomyelitis is the most likely cause. Poliomyelitis is secondary to the infection with poliovirus that can affect the motor neurons from the spinal cord, causing a flaccid paralysis without sensory affection. Because the virus affects individual nerves, the paralysis is muscle-specific causing muscle imbalances and poor posture which can result in deformities and muscle disuse atrophy. Shortening of the leg is the most characteristic sign, however other typical deformations are in the lower limbs are external rotation of the knee, knee hyperestension, ankle and foot deformities (all observed in K131). The evaluation of K131’s entheses and bone structure suggests that, in life, this individual showed physical deformities consisting of a possibly visible atrophy of the left arm and leg, asymmetric gait, clubfoot and slight scoliosis which would have affected not only his appearance but also his ability to move and perform certain tasks. K131’s burial treatment is entirely normative for the period and the wider cemetery context. This could suggest that despite their impairment, this individual was not necessarily marginalised within their social context. However, historical sources account for extensive marginalisation and cruel treatment of the disabled and deformed in this period. So, whilst K131 was buried in a normative manner, it is difficult to reach definitive conclusions regarding how this individual was treated by their contemporaries.
  • The relationship between Vitamin D deficiency and leprosy in two English medieval populations

    Papadopoulou, S.; Buckberry, Jo (University of Sheffield, 2019)
    In palaeopathology, a well-established approach to malnutrition and ill-health is the study of metabolic conditions. Leprosy is a mycobacterial disease that is manifested on the bones, and is commonly studied in archaeological contexts. Vitamin D is essential for maintaining a normal immune system, and thus a metabolic insufficiency could have a major effect in the resistance of an individual to invading pathogens. It has been indicated by clinical studies that there is an increase in the risk of contracting tuberculosis for individuals with Vitamin D deficiency, and like TB, leprosy is a disease of the poor, and it is more severe in individuals with low resistance to the pathogen. The project investigated the immunological aspect of leprosy by investigating the comorbidity of Vitamin D deficiency and the disease. During the study, the prevalence rates of Vitamin D deficiency (residual rickets and osteomalacia) were compared for adults in two medieval populations: adults with skeletal evidence of lepromatous leprosy from the leprosarium of St James and Mary Magdalene in Chichester (n=62) and adults from the non-leprous population found in Box Lane, Pontefract (n=52), both in England. Macroscopic analysis identified only one probable case of residual rickets and two possible cases of osteomalacia, providing no statistical significance in the relationship between the conditions. The present article focuses on these results, aiming to underline the reasons behind negative results in research, caused either by failed methodology or the insufficient collection of samples.
  • Radiographically recognizable? An investigation into the appearance of osteomalacic pseudofractures

    Jennings, E.; Buckberry, Jo; Brickley, M.B. (2018-12)
    Pseudofractures, lucent bands that occur due to a build-up of osteoid, are a key feature of osteomalacia. In paleopathology, pseudofractures are often marked by small, linear cracks in the cortex of the bone surrounded by irregular, bony spicule formation. Radiography can be used to help diagnose pseudofractures, both clinically and in paleopathology. A detailed understanding of the radiographic appearance of pseudofractures and their development is, therefore, necessary to aid a diagnosis of vitamin D deficiency. The present study examined the clinical literature to determine current ideas on the appearance of pseudofractures with the aim of applying this knowledge to paleopathology. A radiographic study of the characteristics of pseudofractures was performed on five individuals with clear skeletal features of osteomalacia from archaeological sites in Canada and the United Kingdom dating to the medieval period (5th to 15th centuries) and the 18th to 19th century. Results show that the radiographic appearance of pseudofractures could potentially reveal information about the cause of the deficiency and the chronicity of pseudofractures. This type of information has the potential to further our understanding of the lived experiences of archaeological individuals with osteomalacia.
  • 3D printed oral theophylline doses with innovative 'radiator-like' design: Impact of polyethylene oxide (PEO) molecular weight

    Isreb, A.; Baj, K.; Wojsz, M.; Isreb, Mohammad; Peak, M.; Alhnan, M.A. (2019-06-10)
    Despite the abundant use of polyethylene oxides (PEOs) and their integration as an excipient in numerous pharmaceutical products, there have been no previous reports of applying this important thermoplastic polymer species alone to fused deposition modelling (FDM) 3D printing. In this work, we have investigated the manufacture of oral doses via FDM 3D printing by employing PEOs as a backbone polymer in combination with polyethylene glycol (PEG). Blends of PEO (molecular weight 100 K, 200 K, 300 K, 600 K or 900 K) with PEG 6 K (plasticiser) and a model drug (theophylline) were hot-melt extruded. The resultant filaments were used as a feed for FDM 3D printer to fabricate oral dosage forms (ODFs) with innovative designs. ODFs were designed in a radiator-like geometry with connected paralleled plates and inter-plate spacing of either 0.5, 1, 1.5 or 2 mm. X-ray diffraction patterns of the filaments revealed the presence of two distinctive peaks at 2θ = 7° and 12°, which can be correlated to the diffraction pattern of theophylline crystals. Blends of PEO and PEG yielded filaments of variable mechanically resistance (maximum load at break of 357, 608, 649, 882, 781 N for filament produced with PEO 100 K, 200 K, 300 K, 600 K or 900 K, respectively). Filaments of PEO at a molecular weight of 200–600 K were compatible with FDM 3D printing process. Further increase in PEO molecular weight resulted in elevated shear viscosity (>104 Pa.S) at the printing temperature and hindered material flow during FDM 3D printing process. A minimal spacing (1 mm) between parallel plates of the radiator-like design deemed essential to boost drug release from the structure. This is the first report of utilising this widely used biodegradable polymer species (PEOs and PEG) in FDM 3D printing.
  • From ‘fixed dose combinations’ to ‘a dynamic dose combiner’: 3D printed bi-layer antihypertensive tablets

    Sadia, M.; Isreb, Abdullah; Abbadi, I.; Isreb, Mohammad; Aziz, D.; Selo, A.; Timmins, P.; Alhnan, M.A. (2018-10)
    There is an increased evidence for treating hypertension by a combination of two or more drugs. Increasing the number of daily intake of tablets has been reported to negatively affect the compliance of patients. Therefore, numerous fixed dose combinations (FDCs) have been introduced to the market. However, the inherent rigid nature of FDCs does not allow the titration of the dose of each single component for an individual patient's needs. In this work, flexible dose combinations of two anti-hypertensive drugs in a single bilayer tablet with a range of doses were fabricated using dual fused deposition modelling (FDM) 3D printer. Enalapril maleate (EM) and hydrochlorothiazide (HCT) loaded filaments were produced via hot-melt extrusion (HME). Computer software was utilised to design sets of oval bi-layer tablets of individualised doses. Thermal analysis and x-ray diffractometer (XRD) indicated that HCT remained crystalline in the polymeric matrix whilst EM appeared to be in an amorphous form. The interaction between anionic EM and cationic methacrylate polymer may have contributed to a drop in the glass transition temperature (Tg) of the filament and obviated the need for a plasticiser. Across all tablet sets, the methacrylate polymeric matrix provided immediate drug release profiles. This dynamic dosing system maintained the advantages of FDCs while providing a superior flexibility of dosing range, hence offering an optimal clinical solution to hypertension therapy in a patient-centric healthcare service.
  • Improving the quality of insulin prescribing for people with diabetes being discharged from hospital

    Bain, A.; Silcock, Jonathan; Kavanagh, S.; Quinn, Gemma L.; Fonseca, I. (BMJ, 2019-08)
    Medication errors involving insulin in hospital are common, and may be particularly problematic at the point of transfer of care. Our aim was to improve the safety of insulin prescribing on discharge from hospital using a continuous improvement methodology involving cycles of iterative change. A multidisciplinary project team formulated locally tailored insulin discharge prescribing guidance. After baseline data collection, three ‘plan-do-study-act’ cycles were undertaken over a 3-week period (September/ October 2018) to introduce the guidelines and improve the quality of discharge prescriptions from one diabetes ward at the hospital. Discharge prescriptions involving insulin from the ward during Monday to Friday of each week were examined, and their adherence to the guidance measured. After the introduction of the guidelines in the form of a poster, and later a checklist, the adherence to guidelines rose from an average of 50% to 99%. Qualitative data suggested that although it took pharmacists slightly longer to clinically verify discharge prescriptions, the interventions resulted in a clear and helpful reminder to help improve discharge quality for the benefit of patient safety. This project highlights that small iterative changes made by a multidisciplinary project team can result in improvement of insulin discharge prescription quality. The sustainability and scale of the intervention may be improved by its integration into the electronic prescribing system so that all users may access and refer to the guidance when prescribing insulin for patients at the point of discharge.
  • Techniques for identifying the age and sex of children at death

    Buckberry, Jo (2018-05)
    The skeletal remains of infants and children are a poignant reminder of the perilous nature of childhood in the past, yet they offer valuable insight into the life histories of individuals and into the health of populations. Many osteoarchaeological and bioarchaeological analyses are dependent on two vital pieces of information: the age-at-death and sex of the individual(s) under study. This chapter will outline how age-at-death and sex can be estimated from the skeletal remains and dental development of non-adults, and how these are easier or more difficult to determine than for adults, and will discuss the complexities and controversies surrounding different methods.

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