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"Garner, Sarah"
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Acne vulgaris
Acne is a chronic inflammatory disease of the pilosebaceous unit resulting from androgen-induced increased sebum production, altered keratinisation, inflammation, and bacterial colonisation of hair follicles on the face, neck, chest, and back by Propionibacterium acnes. Although early colonisation with P acnes and family history might have important roles in the disease, exactly what triggers acne and how treatment affects the course of the disease remain unclear. Other factors such as diet have been implicated, but not proven. Facial scarring due to acne affects up to 20% of teenagers. Acne can persist into adulthood, with detrimental effects on self-esteem. There is no ideal treatment for acne, although a suitable regimen for reducing lesions can be found for most patients. Good quality evidence on comparative effectiveness of common topical and systemic acne therapies is scarce. Topical therapies including benzoyl peroxide, retinoids, and antibiotics when used in combination usually improve control of mild to moderate acne. Treatment with combined oral contraceptives can help women with acne. Patients with more severe inflammatory acne usually need oral antibiotics combined with topical benzoyl peroxide to decrease antibiotic-resistant organisms. Oral isotretinoin is the most effective therapy and is used early in severe disease, although its use is limited by teratogenicity and other side-effects. Availability, adverse effects, and cost, limit the use of photodynamic therapy. New research is needed into the therapeutic comparative effectiveness and safety of the many products available, and to better understand the natural history, subtypes, and triggers of acne.
Journal Article
Biochemical mapping reveals a conserved heme transport mechanism via CcmCD in System I bacterial cytochrome c biogenesis
Heme is a biologically important cofactor for proteins involved with essential cellular functions, such as oxygen transport and energy production. Heme can also be toxic to cells and thus requires tight regulation and specific trafficking pathways. As a result, much effort has been devoted to understanding how this important, yet cytotoxic, molecule is transported. While several heme transporters/importers/exporters have been identified, the biochemical mechanisms of transport are not well understood, representing a major knowledge gap. Here, the bacterial cytochrome c biogenesis pathway, System I (CcmABCDEFGH), is used to elucidate the transmembrane transport of heme via CcmCD. We utilize a cysteine/heme crosslinking approach, which can trap endogenous heme in specific domains, to biochemically map the heme transport channel in CcmCD, demonstrating that CcmCD is a heme transporter. These results suggest a model for heme trafficking by other heme transporters in both prokaryotes and eukaryotes.
Journal Article
Evaluating the corporate social responsibility agenda for high-cost novel therapies: roles for government and civil society
Background
Corporate social responsibility (CSR) activity in the pharmaceutical industry is frequently directed towards improving patient access to medicines amongst low-income populations. This research reports on findings from a mixed literature and key informant study of pharmaceutical sector CSR activity and its applicability in the high-cost novel therapeutics space.
Methods
Academic and grey literature documents were extracted from online databases in a rapid literature review, focusing on four key areas of interest: (i) CSR or benefit company activity, (ii) the pharmaceutical industry, (iii) the development and sale of high-cost novel medicines and (iv) the role of government and civil society in this space. Ten semistructured interviews amongst key informants, including medical activists, pharmaceutical industry representatives, patient advocates, employees at nongovernmental organizations (NGOs), consultants for international organizations and academic researchers were also conducted related to these topics.
Results
We find that CSR strategies vary depending on partner identity and country ability to pay. Differential pricing schemes and flexible patent approaches tend to be pursued unilaterally by companies, whereas companies frequently partner with local private sector, government, nongovernmental organizations and academic actors when implementing patient support programs, medicines donations, medicines delivery programs and rare and neglected disease research and development (R&D) initiatives. Patient support programs are more prevalent in high-income countries with minimal state-subsidized healthcare, whilst differential and tiered pricing strategies are more frequently pursued in lower-income countries.
Conclusions
Pharmaceutical CSR strategies may benefit from greater coordination with government and civil society actors. Opportunities for government and civil society actors to take an active role in better aligning CSR activity with patient needs and universal health coverage include promoting greater adoption of alternative corporate structures and providing active external recognition of successful CSR initiatives through reputational and funding awards.
Journal Article
Pricing and reimbursement mechanisms for advanced therapy medicinal products in 20 countries
Introduction: Advanced Therapy Medicinal Products are a type of therapies that, in some cases, hold great potential for patients without an effective current therapeutic approach but they also present multiple challenges to payers. While there are many theoretical papers on pricing and reimbursement (P&R) options, original empirical research is very scarce. This paper aims to provide a comprehensive international review of regulatory and P&R decisions taken for all ATMPs with centralized European marketing authorization in March 2022. Methods: A survey was distributed in July 2022 to representatives of 46 countries. Results: Responses were received from 20 countries out of 46 (43.5%). 14 countries reimbursed at least one ATMP. Six countries in this survey reimbursed no ATMPs. Conclusion: Access to ATMPs is uneven across the countries included in this study. This arises from regulatory differences, commercial decisions by marketing authorization holders, and the divergent assessment processes and criteria applied by payers. Moving towards greater equality of access will require cooperation between countries and stakeholders, for example, through the WHO Regional Office for Europe’s Access to Novel Medicines Platform.
Journal Article
Managed Entry Agreements for Pharmaceuticals in the Context of Adaptive Pathways in Europe
As per the EMA definition, adaptive pathways is a scientific concept for the development of medicines which seeks to facilitate patient access to promising medicines addressing high unmet need through a prospectively planned approach in a sustainable way. This review reports the findings of activities undertaken by the ADAPT-SMART consortium to identify enablers and explore the suitability of managed entry agreements for adaptive pathways products in Europe. We found that during 2006-2016 outcomes-based managed entry agreements were not commonly used for products with a conditional marketing authorization or authorized under exceptional circumstances. The barriers and enablers to develop workable managed entry agreements models for adaptive pathways products were discussed through interviews and a multi-stakeholder workshop with a number of recommendations made in this paper.
Journal Article
A novel chlorhexidine-hexametaphosphate coating for titanium with antibiofilm efficacy and stem cell cytocompatibility
Dental implants are an increasingly popular way to replace missing teeth. Whilst implant survival rates are high, a small number fail soon after placement, with various factors, including bacterial contamination, capable of disrupting osseointegration. This work describes the development of chlorhexidine-hexametaphosphate coatings for titanium that hydrolyse to release the antiseptic agent chlorhexidine. The aim was to develop a coating for titanium that released sufficient chlorhexidine to prevent biofilm formation, whilst simultaneously maintaining cytocompatibility with cells involved in osseointegration. The coatings were characterised with respect to physical properties, after which antibiofilm efficacy was investigated using a multispecies biofilm model, and cytocompatibility determined using human mesenchymal stem cells. The coatings exhibited similar physicochemical properties to some implant surfaces in clinical use, and significantly reduced formation of multispecies biofilm biomass up to 72 h. One coating had superior cytocompatibility, with mesenchymal stem cells able to perform normal functions and commence osteoblastic differentiation, although at a slower rate than those grown on uncoated titanium. With further refinement, these coatings may have application in the prevention of bacterial contamination of dental implants at the time of surgery. This could aid a reduction in rates of early implant failure.
Journal Article
Cycle Threshold Values as Indication of Increasing SARS-CoV-2 New Variants, England, 2020–2022
Early detection of increased infections or new variants of SARS-CoV-2 is critical for public health response. To determine whether cycle threshold (Ct) data from PCR tests for SARS-CoV-2 could serve as an early indicator of epidemic growth, we analyzed daily mean Ct values in England, UK, by gene target and used iterative sequential regression to detect break points in mean Ct values (and positive test counts). To monitor the epidemic in England, we continued those analyses in real time. During September 2020–January 2022, a total of 7,611,153 positive SARS-CoV-2 PCR test results with Ct data were reported. Spike (S) gene target (S+/S−)–specific mean Ct values decreased 6–29 days before positive test counts increased, and S-gene Ct values provided early indication of increasing new variants (Delta and Omicron). Our approach was beneficial in the context of the first waves of the COVID-19 pandemic and can be used to support future infectious disease monitoring.
Journal Article
Variations in the Consumption of Antimicrobial Medicines in the European Region, 2014–2018: Findings and Implications from ESAC-Net and WHO Europe
Background: Surveillance of antimicrobial consumption (AMC) is important to address inappropriate use. AMC data for countries in the European Union (EU) and European Economic Area (EEA) and Eastern European and Central Asian countries were compared to provide future guidance. Methods: Analyses of 2014–2018 data from 30 EU/EEA countries of the European Surveillance of Antibiotic Consumption network (ESAC-Net) and 15 countries of the WHO Regional Office for Europe (WHO Europe) AMC Network were conducted using the Anatomical Therapeutic Chemical (ATC) classification and Defined Daily Dose (DDD) methodology. Total consumption (DDD per 1000 inhabitants per day) of antibacterials for systemic use (ATC group J01), relative use (percentages), trends over time, alignment with the WHO Access, Watch, Reserve (AWaRe) classification, concordance with the WHO global indicator (60% of total consumption should be Access agents), and composition of the drug utilization 75% (DU75%) were calculated. Findings: In 2018, total consumption of antibacterials for systemic use (ATC J01) ranged from 8.9 to 34.1 DDD per 1000 inhabitants per day (population-weighted mean for ESAC-Net 20.0, WHO Europe AMC Network 19.6, ESAC-Net Study Group, and WHO Europe AMC Network Study Group). ESAC-Net countries consumed more penicillins (J01C; 8.7 versus 6.3 DDD per 1000 inhabitants per day), more tetracyclines (J01A; 2.2 versus 1.2), less cephalosporins (J01D; 2.3 versus 3.8) and less quinolones (J01M; 1.7 versus 3.4) than WHO Europe AMC Network countries. Between 2014 and 2018, there were statistically significant reductions in total consumption in eight ESAC-Net countries. In 2018, the relative population-weighted mean consumption of Access agents was 57.9% for ESAC-Net and 47.4% for the WHO Europe AMC Network. For each year during 2014–2018, 14 ESAC-Net and one WHO Europe AMC Network countries met the WHO global monitoring target of 60% of total consumption being Access agents. DU75% analyses showed differences in the choices of agents in the two networks. Interpretation: Although total consumption of antibacterials for systemic use was similar in the two networks, the composition of agents varied substantially. The greater consumption of Watch group agents in WHO Europe AMC Network countries suggests opportunities for improved prescribing. Significant decreases in consumption in several ESAC-Net countries illustrate the value of sustained actions to address antimicrobial resistance.
Journal Article
Priming analogical reasoning with false memories
Like true memories, false memories are capable of priming answers to insight-based problems. Recent research has attempted to extend this paradigm to more advanced problem-solving tasks, including those involving verbal analogical reasoning. However, these experiments are constrained inasmuch as problem solutions could be generated via spreading activation mechanisms (much like false memories themselves) rather than using complex reasoning processes. In three experiments we examined false memory priming of complex analogical reasoning tasks in the absence of simple semantic associations. In Experiment
1
, we demonstrated the robustness of false memory priming in analogical reasoning when backward associative strength among the problem terms was eliminated. In Experiments
2a
and
2b
, we extended these findings by demonstrating priming on newly created
homonym analogies
that can only be solved by inhibiting semantic associations within the analogy. Overall, the findings of the present experiments provide evidence that the efficacy of false memory priming extends to complex analogical reasoning problems.
Journal Article