NMR Studies of Nucleic Acids as Drug Targets

Nogalamycin is a member of the anthracycline family of antitumour antibiotics. These are potent cytotoxic agents and are routinely used in cancer chemotherapy. Though nogalamycin is clinically insignificant, it does exhibit three distinct types of non-covalent binding to DNA. Since most other anthracyclines bind to DNA by only one or two of these mechanisms, nogalamycin is an excellent model with which to probe the interaction of this class of anti-tumour agents with DNA. Here, we investigate the binding orientation and stoichiometry of nogalamycin in adjacent TpG(CpA) (and CpG(CpG)) intercalation sites using a combination of NMR techniques and NOE-restrained molecular dynamics simulations. These methods are also employed to investigate the structure of GNA hairpin loops, which are considered to have important biological functions, and assess how their structure and stability are influenced by the introduction of nogalamycin at an adjacent site. The effect of nogalamycin on extrahelical thymine bases incorporated onto either face of the intercalation sites is also investigated in this context. Binding of quadruplex-specific antibodies to telomeric DNA in Stylonychia lemnae macronuclei has recently been detected using immunofluorescence, providing direct evidence for the formation of quadruplex DNA structures in vivo. Guanine-rich quadruplex structures have been extensively studied by NMR and x-ray crystallographic methods. Previous structural studies have failed to unambiguously resolve the conformation preferred by less-stable A-tetrads incorporated into DNA quadruplexes. Additionally, little effort has been made to address the exact number of ions bound to these adenine-containing structures. This forms the basis of our study into quadruplex DNA. Finally, we endeavour to investigate the extent of hydration of both duplex and quadruplex structures using rMD methods, and to comapre hydration patterns in the liquid- and solid-state

NMR Studies of Nucleic Acids as Drug Targets

Nogalamycin is a member of the anthracycline family of antitumour antibiotics. These are potent cytotoxic agents and are routinely used in cancer chemotherapy. Though nogalamycin is clinically insignificant, it does exhibit three distinct types of non-covalent binding to DNA. Since most other anthracyclines bind to DNA by only one or two of these mechanisms, nogalamycin is an excellent model with which to probe the interaction of this class of anti-tumour agents with DNA. Here, we investigate the binding orientation and stoichiometry of nogalamycin in adjacent TpG(CpA) (and CpG(CpG)) intercalation sites using a combination of NMR techniques and NOE-restrained molecular dynamics simulations. These methods are also employed to investigate the structure of GNA hairpin loops, which are considered to have important biological functions, and assess how their structure and stability are influenced by the introduction of nogalamycin at an adjacent site. The effect of nogalamycin on extrahelical thymine bases incorporated onto either face of the intercalation sites is also investigated in this context. Binding of quadruplex-specific antibodies to telomeric DNA in Stylonychia lemnae macronuclei has recently been detected using immunofluorescence, providing direct evidence for the formation of quadruplex DNA structures in vivo. Guanine-rich quadruplex structures have been extensively studied by NMR and x-ray crystallographic methods. Previous structural studies have failed to unambiguously resolve the conformation preferred by less-stable A-tetrads incorporated into DNA quadruplexes. Additionally, little effort has been made to address the exact number of ions bound to these adenine-containing structures. This forms the basis of our study into quadruplex DNA. Finally, we endeavour to investigate the extent of hydration of both duplex and quadruplex structures using rMD methods, and to comapre hydration patterns in the liquid- and solid-state

Measuring moral development in the pharmacy profession from undergraduate to established practitioner: a decadal longitudinal study

© 2023 The Author(s). Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY), https://creativecommons.org/licenses/by/4.0/The aim of this study is to measure and evaluate the moral reasoning of undergraduate pharmacy students as they progress through a British university, and onward through the early years of their professional practice. This study utilizes version 2 of Rest's Defining Issues Test in a longitudinal design, evaluating a single cohort of future pharmacists, which started a 4-year Master of Pharmacy degree program in 2008-09, completed their preregistration training, and progressed through their early careers. The final dataset was collected in 2019. Both descriptive and inferential statistical analysis was subsequently carried out. The cohort experienced significant moral growth during the 4 years of their undergraduate degree, where they were exposed to an ethical education designed to engage students at the "plus one" level of moral reasoning. There is also evidence for work-based augmentation of moral development between graduation from university and qualification as pharmacists. The subjects underwent a marked increase in moral development as they progressed through their undergraduate studies, followed by another sizeable, though not statistically significant developmental progression during the preregistration year. The retrograde step in moral development observed between newly qualified level and established practitioner level requires further investigation: structured interviews with participants, which focus on changes to their experiences in practice and how these affected their moral agency are already underway.Peer reviewe

Disciplinary Action Against UK Health Professionals for Sexual Misconduct: A Matter of Reputational Damage or Public Safety?

© 2021 Federation of State Medical Boards. All Rights Reserved.The regulation of health care professionals in the United Kingdom (UK) falls under the authority of one of nine General Councils, each of which has a statutory duty to ensure the fitness to practice of a subdivision of these professionals. Among the matters that may call fitness to practice into question are deviations from published standards of behavior, which include the maintenance of appropriate sexual boundaries by practitioners. The aim of this article is to examine how the common fitness-to-practice process utilized by General Councils deals with registered health care professionals who have exceeded these boundaries.Deductive thematic analysis was carried out on cases involving academic misconduct among registrants of the General Medical Council, General Dental Council, General Pharmaceutical Council, and Nursing and Midwifery Council, using themes derived from each council’s standards for registrants and guidance for disciplinary panel members.While each of these four cases involved some form of sexually motivated misconduct, the facts in each case were significantly different; however, not only was the outcome the same, but the rationale was similar in each instance. While the protection of the health, safety and well-being of the public may be considered in cases involving sexual misconduct, the need to maintain public and professional confidence in their respective professions is sufficient grounds alone to end the careers of health professionals who engage in sexual misconduct.Peer reviewedFinal Published versio

Fit to practise? Processes for dealing with misconduct among pharmacists in Australia, Canada, the UK and US

© 2018 Elsevier Inc.In many countries with legal systems based on English common law, pharmacy regulators have a responsibility to protect, promote and maintain the health and safety of patients. Where there is a potential risk to patient safety, or where the public's confidence in pharmacy could be adversely affected by the actions of a pharmacist, these regulators have a statutory duty to investigate concerns. The legal provisions underpinning each jurisdiction's disciplinary processes depict distinctive outlooks from the different authorities, as each works towards the same goal. Legal statues, regulations, rules, and guidance affecting the disciplinary process in Great Britain, Australia, New York and New Brunswick were collated, and the processes they describe were attached to a common process flow diagram for step-by-step evaluation of their respective legal provisions. The initial stages of the respective investigation process are broadly similar in all the jurisdictions examined; however, each process has subtle differences that afford some level of advantage or disadvantage over its comparators. Factors including: how matters of discipline are framed; the existence of a separate process for minor and uncontested violations; the ability to effect an interim suspension of a practitioner's license; threshold criteria for escalation of complaints; the membership of disciplinary panels; and the perceived independence of these panels all philosophically affect the public safety remit of each regulator. This work constitutes the first comparison of international regulatory frameworks for the profession of pharmacy. Of the four jurisdictions examined, Great Britain most clearly acts in the interest of the public and the profession – rather than the respondent pharmacist – at every step of its process.Peer reviewe

Dispersing the Mists: An Experimental History of Medicine Study into the Quality of Volatile Inhalations

This document is the Accepted Manuscript version. The final publication is available from Mary Ann Liebert, Inc. Publishers at https://doi.org/10.1089/jamp.2016.1357.Background: Dr. Nelson's Improved Inhaler was first marketed with an advertisement in The Lancet in 1865. Revolutionary at the time for its ease of use and patient-friendliness, the inhaler is still in use for self-treatment by many all over the world. On the occasion of its 150th anniversary, this study reports an experimental historical medicine approach to identify evidence for the quality of vapor inhalers. Methods: Through accessing reviews of the device's use by the contemporary medical establishment, it was established that Dr. Nelson's Inhaler enjoyed a reputation of quality and efficacy among reputable physicians generating empirical evidence of clinical performance. There was a general absence of product performance tests during this period. Therefore, modern inhalation performance testing was applied to test the aerosol delivery performance for Friars' Balsam, and its key chemical constituent, benzoic acid (BA). Results: A respirable dose of 59.9 ± 9.0 μg of BA was aerosolized in a 10 minutes period from a dose of 3.3 mL Friars' Balsam (equivalent to 35.1 ± 0.2 mg of BA) in 375 mL of steaming water using the glass twin stage impinger at a flow rate of 60 L·min−1. The respirable dose from a standardized aqueous BA inhalation formulation increased from 115.9 ± 10.6 to 200.2 ± 19.9 μg by increasing the simulated inhalation period from 5 to 10 minutes. When tested with a simulated inhalation maneuver (500 mL tidal volume, 13 minutes−1 respiration rate, 1:2 inspiratory:expiratory ratio) a respirable dose of 112.8 ± 40.3 μg was produced. Conclusions: This work has highlighted the potential for aerosol drug delivery using steam inhalers that are popular with patients. Physicians should therefore be aware of the potential for lung dosing with irritants when patients self-medicate using the Nelson Inhaler with vaporizing formulations such as Friars' Balsam.Peer reviewedFinal Accepted Versio

Assessing the ecological impacts of invasive species based on their functional responses and abundances

Invasive species management requires allocation of limited resources towards the proactive mitigation of those species that could elicit the highest ecological impacts. However, we lack predictive capacity with respect to the identities and degree of ecological impacts of invasive species. Here, we combine the relative per capita effects and relative field abundances of invader as compared to native species into a new metric, “Relative Impact Potential” (RIP), and test whether this metric can reliably predict high impact invaders. This metric tests the impact of invaders relative to the baseline impacts of natives on the broader ecological community. We first derived the functional responses (i.e. per capita effects) of two ecologically damaging invasive fish species in Europe, the Ponto-Caspian round goby (Neogobius melanostomus) and Asian topmouth gudgeon (Pseudorasbora parva), and their native trophic analogues, the bullhead (Cottus gobio; also C. bairdi) and bitterling (Rhodeus amarus), towards several prey species. This establishes the existence and relative strengths of the predator-prey relationships. Then, we derived ecologically comparable field abundance estimates of the invader and native fish from surveys and literature. This establishes the multipliers for the above per capita effects. Despite both predators having known severe detrimental field impacts, their functional responses alone were of modest predictive power in this regard; however, incorporation of their abundances relative to natives into the RIP metric gave high predictive power. We present invader/native RIP biplots that provide an intuitive visualisation of comparisons among the invasive and native species, reflecting the known broad ecological impacts of the invaders. Thus, we provide a mechanistic understanding of invasive species impacts and a predictive tool for use by practitioners, for example, in risk assessments

Job titles in health care should be in service of patient safety, not status elevation

© 2024 British Journal of General Practice. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY), https://creativecommons.org/licenses/by/4.0/Peer reviewe

Simplifying the legal management of controlled drugs as medicines in the UK

© The Author(s) 2021. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. This is the accepted manuscript version of an article which has been published in final form at https://doi.org/10.1093/ijpp/riab061Peer reviewe

Impairment and sanction in Medical Practitioners Tribunal Service fitness to practise proceedings

The principal aims of this research were to assess whether, when imposing sanctions, the aggravating and mitigating circumstances considered by the General Medical Council are first considered when determining impairment of fitness to practise and to determine whether the circumstances described by the General Medical Council in their Indicative Sanctions Guidance as warranting erasure from the Medical Register will lead to that outcome. The consideration of specific aggravating circumstances or points of mitigation when determining impairment of fitness to practise was compared to their subsequent consideration by the General Medical Council when deciding on the severity of sanction to be applied. Additionally, the proportion of cases that highlighted aggravating circumstances the General Medical Council deemed sufficiently serious to warrant erasure and the actions taken were monitored. One hundred forty-six cases heard by the General Medical Council between 1 October 2011 and 30 September 2012 met with the inclusion criteria. Fisher’s exact test was used to detect a variation from the expected distribution of data. Three of the four aggravating/mitigating circumstances were more likely to be considered when determining sanction having first been factored into the consideration of impairment. There was a statistically significant correlation between both a risk of harm and dishonesty as aggravating factors and the sanction of erasure from the Medical Register. In general, the General Medical Council consider relevant factors at all stages of their deliberations into practitioner misconduct, as required by the determinations in the cases of Cohen, Zygmunt and Azzam; and subsequently follow the guidance within their Indicative Sanctions Guidance document when determining which sanction to applyPeer reviewe