Design, synthesis and pharmacological evaluation of efficacy selective β2 adrenoceptor agonists

Asthma and chronic obstructive pulmonary disease both involve constriction or obstruction of the airways and are causes of morbidity and mortality worldwide. To treat these conditions, patients are often prescribed β2 adrenoceptor agonists (β2AR). Activation of the β2AR leads to smooth muscle relaxation within the respiratory tract, and therefore increased airflow throughout the lungs. The caveat of current approved drugs, is that due to structural similarities with the β2AR endogenous agonist adrenaline, these compounds can also activate the β1AR. Activation of the β1AR, increases heart rate and force of contraction. This becomes problematic when patients also suffer from heart disease (40% of COPD patients). There is therefore, a requirement for β2AR agonists with efficacy selectivity to the β2AR. This project aims to develop an efficacy selective β2AR agonist by linking a β2AR agonist pharmacophore, to a selective β1AR antagonist pharmacophore, to form a bivalent compound that will exhibit agonism at the β2AR, but antagonism at the β1AR. Analogues of the naturally occurring β2AR agonist, S1319, and the highly selective β1AR antagonist CGP 20712A were synthesised and pharmacologically evaluated (performed by the author and Prof. Jillian Baker). Structure-activity relationship studies were performed in an attempt to identify moieties that were β2AR efficacy selective and β1AR affinity selective. A β2AR agonist group was attached to several β1AR antagonist groups to form a number of bivalent compounds which underwent pharmacological evaluation (performed by Prof Jillian Baker). The results of these studies facilitated the rational design of the efficacy selective β2AR agonist 5.61 which is a partial β2AR agonist– β1AR antagonist

Delivering evidence-based interventions for type 1 diabetes in the virtual world - A review of UK practice during the SARS-CoV-2 pandemic.

Funder: Abbott Diabetes CareFunder: SanofiFunder: Novo NordiskFunder: MedtronicAIMS: This review considers the impact of the SARS-CoV-2 pandemic on access to interventions for those living with type 1 diabetes and discusses the solutions which have been considered and actioned to ensure ongoing access care. METHODS: We performed a focussed review of the published literature, and the guidelines for changes that have been effected during the pandemic. We also drew from expert recommendations and information about local practice changes for areas where formal data have not been published. RESULTS: Evidence based interventions which support the achievement of improved glucose levels and/or reduction in hypoglycaemia include group structured education to support self-management, insulin pump therapy and continuous glucose monitoring. The SARS-CoV-2 pandemic had impacted the ability of diabetes services to deliver these intervention. Multiple adaptations have been put in place - transition to online delivery of education and care, and usage of diabetes technology. CONCLUSIONS: Although various adaptations have been made during the pandemic that have positively influenced uptake of services, there are many areas of delivery that need immediate improvement in the UK. We recommend a proactive approach in recognising the digital divide and inequity in distribution of these changes and we recommend introducing measures to reduce them

Delivering evidence-based interventions for type 1 diabetes in the virtual world - A review of UK practice during the SARS-CoV-2 pandemic.

Funder: Abbott Diabetes CareFunder: SanofiFunder: Novo NordiskFunder: MedtronicAIMS: This review considers the impact of the SARS-CoV-2 pandemic on access to interventions for those living with type 1 diabetes and discusses the solutions which have been considered and actioned to ensure ongoing access care. METHODS: We performed a focussed review of the published literature, and the guidelines for changes that have been effected during the pandemic. We also drew from expert recommendations and information about local practice changes for areas where formal data have not been published. RESULTS: Evidence based interventions which support the achievement of improved glucose levels and/or reduction in hypoglycaemia include group structured education to support self-management, insulin pump therapy and continuous glucose monitoring. The SARS-CoV-2 pandemic had impacted the ability of diabetes services to deliver these intervention. Multiple adaptations have been put in place - transition to online delivery of education and care, and usage of diabetes technology. CONCLUSIONS: Although various adaptations have been made during the pandemic that have positively influenced uptake of services, there are many areas of delivery that need immediate improvement in the UK. We recommend a proactive approach in recognising the digital divide and inequity in distribution of these changes and we recommend introducing measures to reduce them

Nocardia farcinica lung infection in a patient with cystic fibrosis: a case report

<p>Abstract</p> <p>Introduction</p> <p>Respiratory tract infections are the major causes of morbidity and mortality in patients with cystic fibrosis. <it>Nocardia </it>are rarely implicated in these infections and few reports of the involvement of this species are found in the literature.</p> <p>Case presentation</p> <p>We describe a case of lung infection followed by chronic colonization of trimethoprim and sulfamethoxazole resistant <it>Nocardia farcinica </it>in a patient with cystic fibrosis. The chronic colonization of this uncommon bacterium in patients with cystic fibrosis was proved using a newly developed real-time polymerase chain reaction assay, which indicates that this bacterium, despite treatment, is difficult to eradicate.</p> <p>Conclusion</p> <p>Our case report confirms that this organism can be recovered in persons with cystic fibrosis. Its eradication is necessary especially if the patient is to undergo lung transplantation.</p

Addressing men's health policy concerns in Australia: what can be done?

There is a lack of consensus about what men's health constitutes in Australia. The absence of a widely accepted definition has been problematic for establishing state and national men's health policies. I consider that one impediment to the implementation of state and federal men's health policies has been a lack of willingness to approach men's health from a broad public health perspective. In particular, scant attention has been paid to exploring lay perspectives of how men define and understand health, and in turn, how these relate to significant policy problems such as men's health service use. I conclude by suggesting that a focus on men's lay perspectives of their health emerging from the United Kingdom and the Republic of Ireland provides a useful framework to guide men's health policy discussion in Australia

Performance of the CMS Cathode Strip Chambers with Cosmic Rays

The Cathode Strip Chambers (CSCs) constitute the primary muon tracking device in the CMS endcaps. Their performance has been evaluated using data taken during a cosmic ray run in fall 2008. Measured noise levels are low, with the number of noisy channels well below 1%. Coordinate resolution was measured for all types of chambers, and fall in the range 47 microns to 243 microns. The efficiencies for local charged track triggers, for hit and for segments reconstruction were measured, and are above 99%. The timing resolution per layer is approximately 5 ns

Performance and Operation of the CMS Electromagnetic Calorimeter

The operation and general performance of the CMS electromagnetic calorimeter using cosmic-ray muons are described. These muons were recorded after the closure of the CMS detector in late 2008. The calorimeter is made of lead tungstate crystals and the overall status of the 75848 channels corresponding to the barrel and endcap detectors is reported. The stability of crucial operational parameters, such as high voltage, temperature and electronic noise, is summarised and the performance of the light monitoring system is presented

Calibration of the CMS Drift Tube Chambers and Measurement of the Drift Velocity with Cosmic Rays

Peer reviewe

CMS Data Processing Workflows during an Extended Cosmic Ray Run

Peer reviewe

CMS physics technical design report : Addendum on high density QCD with heavy ions

Peer reviewe