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Evidence for the Quercetin Binding Site of Glycogen Phosphorylase as a Target for Liver-Isoform-Selective Inhibitors against Glioblastoma: Investigation of Flavanols Epigallocatechin Gallate and Epigallocatechin
Get PDFGlycogen phosphorylase (GP) is the rate-determining enzyme in glycogenolysis, and its druggability has been extensively studied over the years for the development of therapeutics against type 2 diabetes (T2D) and, more recently, cancer. However, the conservation of binding sites between the liver and muscle isoforms makes the inhibitor selectivity challenging. Using a combination of kinetic, crystallographic, modeling, and cellular studies, we have probed the binding of dietary flavonoids epigallocatechin gallate (EGCG) and epigallocatechin (EGC) to GP isoforms. The structures of rmGPb-EGCG and rmGPb-EGC complexes were determined by X-ray crystallography, showing binding at the quercetin binding site (QBS) in agreement with kinetic studies that revealed both compounds as noncompetitive inhibitors of GP, with EGCG also causing a significant reduction in cell viability and migration of U87-MG glioblastoma cells. Interestingly, EGCG exhibits different binding modes to GP isoforms, revealing QBS as a promising site for GP targeting, offering new opportunities for the design of liver-selective GP inhibitors
Barriers to Effective Cellulitis Management in a Primary Care Setting: An Audit Report
No full textINTRODUCTION AND OBJECTIVES
Cellulitis is a bacterial infection of the skin and underlying tissues,¹ often leading to diagnostic challenges due to its nonspecific presentation. Globally, cellulitis imposes a significant burden on healthcare systems. In the UK, the National Institute for Health and Care Excellence (NICE) NG141 guidelines provide recommendations for managing cellulitis, including proper diagnosis, antimicrobial prescribing, and the provision of safety netting advice.2 These guidelines aim to improve patient outcomes, prevent complications, and address the rising concern of antimicrobial resistance.
This audit was conducted at a general practice (GP) in remote and rural England to assess compliance with the NG141 guidelines in cellulitis management. The primary objectives were to evaluate the accuracy of diagnosing cellulitis, assess the provision of safety netting advice, and determine the appropriateness of antimicrobial prescribing. By auditing these practices, the aim was to identify areas for improvement and ensure that the GP being audited maintains high standards in cellulitis care.
MATERIALS AND METHODS
A retrospective audit was conducted, reviewing the records of 40 patients diagnosed with cellulitis at the GP between 13 December 2022–12 December 2023. Eligible patients were those aged 18 years and over, newly diagnosed with cellulitis during the study period. Exclusions included patients diagnosed in secondary care and those with recurrent cellulitis episodes.
The NICE NG141 guidelines were used to derive three key audit criteria: the exclusion of other causes of skin redness, the provision of safety netting advice, and the prescription of appropriate antimicrobials. Target compliance rates were set at 90% for the first two criteria and 95% for the third. Data were extracted from the Egton Medical Information Systems (EMIS) and analysed using a structured spreadsheet. Each patient’s record was evaluated for adherence to these criteria, and results were compared against the target standards.
RESULTS
The audit revealed varied compliance levels with the NICE NG141 guidelines. For the first criterion, only 45% of patient consultations documented the exclusion of other potential causes of skin redness, falling well below the 90% target. Discussions with clinicians suggested that while differential diagnoses were often considered during consultations, time constraints and inconsistent documentation practices contributed to this low compliance rate.3
For the second criterion, 72% of patients received safety netting advice, which also fell short of the 90% target. The lower rate of safety netting provision was attributed to high clinician workloads and time limitations, which impacted their ability to consistently offer and document this advice during consultations.4
The third criterion, correct antimicrobial prescribing, showed a higher compliance rate of 92%, just below the 95% target. Most patients were prescribed the appropriate antimicrobials according to the NICE guidelines, though a few cases of cellulitis near the eyes and nose involved inappropriate antibiotic selection, highlighting the need for additional training in the management of more complex presentations.
CONCLUSION
This audit identified significant gaps in adherence to the NICE NG141 guidelines at the GP, particularly in documenting the exclusion of differential diagnoses and providing safety netting advice. Whilst antimicrobial prescribing practices were generally strong, the findings highlight the need for further improvement in clinician training and documentation practices.
To address these gaps, it is recommended that the GP implements regular training sessions to update clinicians on the latest NICE guidelines, with a focus on diagnosis and patient communication. Additionally, introducing standardised documentation templates within the EMIS system could improve the systematic exclusion of differential diagnoses and ensure consistent safety netting advice. A re-audit after 12 months is recommended to evaluate the effectiveness of these interventions and ensure improved compliance. These measures are essential for enhancing the quality of cellulitis care and ensuring continued adherence to national guidelines at the GP
Exploring the current provision of pancreatic transplantations in low- and middle-income countries: Current landscape, challenges, future prospects
Get PDFThis comprehensive review addresses the global health challenge of disparities in pancreas transplant access, particularly in low- and middle-income countries (LMICs) compared to high-income countries. Despite advancements in surgical techniques and immunosuppression for procedures like simultaneous pancreas-kidney, pancreas-after-kidney, and pancreas-transplant alone, LMICs face significant challenges, including limited infrastructure, financial constraints, and a shortage of skilled medical professionals. Donation after brain death remains constrained by sociocultural barriers. Region-specific analyses highlight progress in Latin America, Asia, Russia, and South Africa, showcasing the regional disparities in access and outcomes. Future prospects involve minimally invasive surgeries, telemedicine for enhanced post-operative care, international collaborations with organizations like the European Union of Medical Specialists, and robust funding networks to improve organ availability. In conclusion, the review underscores the importance of multifaceted strategies to address economic, sociocultural, and infrastructural barriers, aiming to improve accessibility, quality, and effectiveness of pancreas transplantation services in LMICs
A Critical Analysis of Learning Development and Knowledge Transfer in Police Training in England and Wales.
Get PDFThis thesis presents a critical analysis of knowledge and skills transfer in police training over an extended period, examining the development and delivery of training, from its conception, through its organisational construction and eventual use within the Police Services of England and Wales. The way in which the police service has addressed some of its training and development needs is an interesting topic area. These developments have on occasions, been innovative and pioneering but frequently unrecognised other than inside the organisation.
The portfolio of projects is linked through taxonomies of adult learning initially devised by Bloom (1956) all of which contain an educational hierarchy.
The research strategy of the thesis is blended or amalgamated use of both inductive and deductive inquiry. The critical analysis, appraising the strengths as well as the limitations, is approached from a reflective standpoint in the first two projects. The critical analysis of the third area is based on the qualitative data gathered from current practitioners.
In examining these issues, the study reflects on the contributions made to learning and development. It examines the way in which these progressive innovations have been processed by the organisations who initiated the work on which they are based.
The rationale supporting this thesis involves the application of the three areas of research presentation; descriptive; critical analysis; comparative, these areas are presented in a complimentary manner.
The thesis argues that the innovations highlighted could have been adopted earlier than they were and that the progress and development available through the use of certain technologies should be capitalised on.
This is allied to the contention that interactive training delivered in a situation that has been ‘contextualised’ for the student, especially in vicarious learning environments, therefore enhances the experience and supports higher achievement in the taxonomies of Bloom (ibid).
Clear conclusions are drawn, and several recommendations made
Victim Safety In The Context Of Abusive Intimate Relationships
Get PDFThis PhD thesis aimed to understand how individuals in abusive relationships increase their sense of safety. It draws on findings from a systematic review of the literature, alongside primary data obtained in three empirical studies. The research underpinning this thesis employed a mixed methods approach, benefitting from both qualitative and quantitative data. A systematic literature review, of 61 papers, was initially conducted. It aimed to examine how victims (of interpersonal violence) have responded when they have been subjected to Intimate Partner Violence (IPV). The Thematic Analysis supported the presence of five overarching themes, that victims of interpersonal violence; 1) seek help after their victimisation, 2) experience barriers to seeking help, 3) employ a range of strategies, 4) cope with victimisation differently and 5) The help-seeking behaviours of victims are contextual. These findings illustrated several things. Firstly, when in abusive relationships, individual behaviour is varied and dynamic. Secondly, how individuals respond to abuse is influenced by a range of environmental, societal, and individual barriers.
Study one extended the findings from the systematic review by bringing in the knowledge of professionals that work with victims and survivors of IPV. A survey instrument was developed from the findings of the systematic review, and was completed by 69 professionals who worked with victims of IPV. The survey instrument was designed to explore perceptions of professionals regarding the use of strategies (obtained from the systematic review) by those being harmed by a partner, and their likely effectiveness in increasing these individuals’ sense of safety. The findings indicated that victims may not consistently use strategies that are considered effective in increasing safety. All the strategies were endorsed by the sample. However, no strategy (or strategy type) was perceived to be universally employed by victims, or helpful in increasing victim safety. Extending this, help-seeking strategies that participants considered most likely to be used by victims were also perceived to be effective strategies in increasing safety. However, this was conversely true for coping and safety behaviour strategies. Finally, the strategies that were considered to be most likely to be employed represented those that may be most likely to be within victims’ control, while in abusive relationships.
Building on these findings, study 2 brought in the experiences of survivors who had been in abusive relationships, to gain a more in depth understanding of victim decision-making. Using a qualitative approach, 30 participants (15 survivors and 15 professionals) were interviewed. Separate interview protocols were developed for participants who had been abused and participants who worked with victims of abuse. Interviews were analysed using Thematic Analysis (Braun & Clarke, 2006; 2012) and Grounded Theory (Glaser & Straus, 1967; Strauss & Corbin, 1997). The analysis resulted in 11 themes; 1) Victims are subjected to abuse that has significant long and short term impact, 2) Victims have expectations of what will increase their safety, 3) Safety decisions are influenced by victims’ needs, 4) Decisions to seek help are guided by many influences, 5) Increasing safety can be difficult for victims due to existing barriers, 6) There are emotional influences on victims’ safety behaviour, 7) Not all victims can rely on existing knowledge to inform safety behaviour, 8) Victim decision making is influenced by fear, 9) Victims employ multiple strategies in response to abusive behaviours, 10) Victims amend safety behaviour to manage different abuse contexts, and 11) Victims make appraisals of safety behaviour following their use. The findings provided several insights. Firstly, IPV safety strategy use (and non-use) was influenced by a variety of factors, both internal and external, that can increase or decrease use. Secondly, victim strategy use occurs at various points during an abusive relationship. Strategies to increase safety are not only used at the point of harm being done, but also in preparation for potential harm and after episodes of abuse. This indicates a role of cognition in identifying and planning strategies to increase safety.
Finally, Study 3 extended previous findings by exploring the association between behaviours used to increase safety in abusive relationships, such as coping behaviour and environmental security use, and measures of cognition and emotional reactivity. Study variables were derived from behavioural theory implicating affect and cognition in behavioural motivation (Ajzen, 1985; Liang et al., 2005; Rogers, 1975). Two hundred and eighty victims and survivors of IPV completed a questionnaire battery, including measures to explore their coping and environmental security use. The findings indicated that gender, being female, was associated with differences in cognition and affect. Additionally, participants who reported more (in number) abuse reported lower self-esteem and locus of control, and higher emotional reactivity. Regarding victim behaviour, coping behaviour was predicted by cognition or affect, but environmental security was not. Consequently, this provides further indication that both cognition and affect may play a role in victims’ decision-making, in the context of abusive relationships.
The findings from this thesis support the understanding that individuals in abusive relationships implement a range of strategies to act against abusive partners. The findings describe victim decision making being dynamic, impacted by both external (abuse and environment) and internal (affect and cognition), and that strategies used are developed over time through learning and reappraisals. This work indicates that an inclusive theoretical model, to outline how abuse victims identify and implement safety strategies, is needed. Thus, a victim-informed Integrative Model of Victim Safety Strategies (IMVSS) was developed. It is hoped that this will be used to design future research and to help professionals working with victims and survivors of IPV to recognise the potential influences that can increase or decrease victim safety behaviour
Towards a Better Transition to University: A Student-Centric Welcome Day for the New Undergraduate Students in a Mathematics Department
Get PDFThis case study delves into a Welcome Day event organised by the Department of Mathematical Sciences at a UK university for the incoming first year students in the department. This report reflects some of the practicalities and the evaluation of the event. The event, primarily focused on student engagement activities along with reduced amount of traditional presentations, was aimed at facilitating peer networking and smoothing the transition from school to university, hence nurturing a sense of belonging within the student community. The structure of the event was crafted to align with the department's unique ethos, with an emphasis on activities that resonate with the field of mathematics. Evaluation of the event is done based on the responses from the students during the event via an online questionnaire. The event not only demonstrated high levels of student satisfaction but also served as a good example of department-specific orientation programs. These localized events can complement university-wide initiatives, offering a more tailored setting for new students to acclimate to their specific academic environment. This paper has the prospect to guide others and to reinforce the notion of seeking to tailor welcome days to match the needs of new cohorts
Community Resilience to Socio-Environmental Disasters in Itajaí Valley, Brazil
No full textThe Itajaí Valley (Brazil) is historically hit by disasters characterized by landslides and floods. Despite some level of preparedness, the changing rainfall regimes which became less predictable and more severe, is exacerbated by uncertainties of climate change challenging the state of resilience in the area. Community perception in disaster risk areas is one of the key components for identifying the state of resilience to disasters. Hence, to better understand the nature of changing resilience, this research aims to identify and compare the state of resilience of communities (SC) in the Itajaí Valley by analyzing risk perception of local communities. A descriptive-evaluative methodology is used through a quantitative survey approach in the at-risk areas in two distinct phases. Data collection in the first phase took place between March and July 2023, a period temporally distant from the last major disaster, which occurred in 2008. The second phase of data collection took place between the floods of October and November 2023. The results of the research indicate that exposure to the October 2023 floods had a substantial impact on the population's perception of risk, in which changes were observed in all the aspects of community resilience analyzed. In this sense, there was a significant increase in resilience during the reorganization phase, strengthening the consensus with studies related to adaptive cycles. The results enable a more precise understanding of vulnerable areas, allowing decision-makers to pinpoint where resources and efforts should be directed with greater accuracy
Binding Studies Between Dinotefuran and Bovine Serum Albumin Using Multiple Analytical Approaches
No full textThe present study examines the interaction between bovine serum albumin (BSA) and dinotefuran utilizing spectroscopic, electrochemical, and computational approaches. The examination of fluorescence spectroscopy demonstrates the formation of a stable complex (protein-ligand) between dinotefuran and BSA, with a binding coefficient of 3.8 × 108 M−1 and a stoichiometry of 2:1 (dinotefuran to BSA). The presence of static quenching phenomena indicates the creation of a non-covalent compound. UV spectroscopy and circular dichroism spectroscopy confirm the development of the dinotefuran-BSA complex. Molecular docking simulations reveal the interaction between dinotefuran and specific amino acid residues of BSA with a binding energy (B.E.) of −5.4 kcal mol−1. The stability of the dinotefuran-BSA complex is confirmed using molecular dynamics simulations, as evidenced by extracted trajectories. Electrochemical investigations reveal a slow and continuous interaction between dinotefuran and BSA, as indicated by the steady reduction in the intensity of the dinotefuran peak over time. This thorough examination offers unique insights into the molecular interactions between dinotefuran and BSA, providing new perspectives on their binding mechanisms and implications in biological systems
Skin Cancer Surgery in the Community: Alleviating the Burden on Secondary Care
Get PDFSkin cancer is one of the most common types of cancer worldwide, with its prevalence steadily increasing due to factors such as ageing populations, UV exposure, and lifestyle choices. The majority of skin cancers are non-melanoma types, including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), which account for around 95% of all cases [1].The further five percent are made up of other skin cancers such as melanoma which is considered more serious due to its potential for metastasis. In the UK, majority of non-melanoma skin cancers are identified in primary care but are commonly managed in secondary care. However, shifting the management of these cancers to primary and community-based settings has a significant potential to reduce the burden on secondary care and in turn free up resources for more complex cases. This shift could lead to improved efficiency, reduced waiting times, lower healthcare costs and ultimately greater patient satisfaction