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1.
BMJ Open Qual ; 9(2)2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32439740

RESUMEN

BACKGROUND: The COVID-19 outbreak has placed the National Health Service under significant strain. Social distancing measures were introduced in the UK in March 2020 and virtual consultations (via telephone or video call) were identified as a potential alternative to face-to-face consultations at this time. LOCAL PROBLEM: The Royal National Orthopaedic Hospital (RNOH) sees on average 11 200 face-to-face consultations a month. On average 7% of these are delivered virtually via telephone. In response to the COVID-19 crisis, the RNOH set a target of reducing face-to-face consultations to 20% of all outpatient attendances. This report outlines a quality improvement initiative to rapidly implement virtual consultations at the RNOH. METHODS: The COVID-19 Action Team, a multidisciplinary group of healthcare professionals, was assembled to support the implementation of virtual clinics. The Institute for Healthcare Improvement approach to quality improvement was followed using the Plan-Do-Study-Act (PDSA) cycle. A process of enablement, process redesign, delivery support and evaluation were carried out, underpinned by Improvement principles. RESULTS: Following the target of 80% virtual consultations being set, 87% of consultations were delivered virtually during the first 6 weeks. Satisfaction scores were high for virtual consultations (90/100 for patients and 78/100 for clinicians); however, outside of the COVID-19 pandemic, video consultations would be preferred less than 50% of the time. Information to support the future redesign of outpatient services was collected. CONCLUSIONS: This report demonstrates that virtual consultations can be rapidly implemented in response to COVID-19 and that they are largely acceptable. Further initiatives are required to support clinically appropriate and acceptable virtual consultations beyond COVID-19. REGISTRATION: This project was submitted to the RNOH's Project Evaluation Panel and was classified as a service evaluation on 12 March 2020 (ref: SE20.09).


Asunto(s)
Infecciones por Coronavirus/epidemiología , Neumonía Viral/epidemiología , Telemedicina/organización & administración , COVID-19 , Hospitales Especializados , Humanos , Ortopedia , Pandemias , Mejoramiento de la Calidad , Medicina Estatal , Reino Unido/epidemiología
2.
Org Lett ; 6(16): 2781-3, 2004 Aug 05.
Artículo en Inglés | MEDLINE | ID: mdl-15281768

RESUMEN

S-Alkyl dithioformates, generated by a cycloreversion process, react as 1,3-dipolarophiles with beta-lactam-based azomethine ylids to provide, after (net) elimination of MeSH, C(2)-unsubstituted penems. The overall cycloreversion/cycloaddition sequence was accelerated by microwave irradiation. [reaction: see text]

3.
Bioorg Med Chem Lett ; 16(18): 4865-71, 2006 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-16839761

RESUMEN

We report here the discovery of a class of MCH R1 ligands based on a biphenyl carboxamide template. A docked-in model is presented indicating key interactions in the putative binding site of the receptor. Parallel high throughput synthetic techniques were utilised to allow rapid exploration of the structure-activity relationship around this template, leading to compound SB-568849 which possessed good receptor affinity and selectivity. This compound proved to be an antagonist with stability in vivo, an acceptable brain-blood ratio and oral bioavailability.


Asunto(s)
Amidas/química , Amidas/farmacología , Compuestos de Bifenilo/síntesis química , Compuestos de Bifenilo/farmacología , Receptores de Somatostatina/antagonistas & inhibidores , Amidas/síntesis química , Amidas/farmacocinética , Animales , Compuestos de Bifenilo/química , Compuestos de Bifenilo/farmacocinética , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Bovinos , Biología Computacional , Humanos , Ligandos , Modelos Moleculares , Estructura Molecular , Receptores de Somatostatina/química , Receptores de Somatostatina/metabolismo , Relación Estructura-Actividad , Azufre/química
4.
Bioorg Med Chem Lett ; 16(18): 4872-8, 2006 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-16839763

RESUMEN

A strategy of systematically targeting more rigid analogues of the known MCH R1 receptor antagonist, SB-568849, serendipitously uncovered a binding mode accessible to N-aryl-phthalimide ligands. Optimisation to improve the stability of this compound class led to the discovery of novel N-aryl-quinazolinones, benzotriazinones and thienopyrimidinones as selective ligands with good affinity for human melanin-concentrating hormone receptor 1.


Asunto(s)
Amidas/farmacología , Compuestos de Bifenilo/farmacología , Receptores de Somatostatina/antagonistas & inhibidores , Amidas/síntesis química , Amidas/química , Anilidas/química , Compuestos de Bifenilo/síntesis química , Compuestos de Bifenilo/química , Humanos , Estructura Molecular , Receptores de Somatostatina/metabolismo , Relación Estructura-Actividad
5.
J Clin Nurs ; 12(3): 422-30, 2003 May.
Artículo en Inglés | MEDLINE | ID: mdl-12709117

RESUMEN

The importance of obtaining the opinions of service users has long been recognized and, traditionally, most contact has focused on measuring their satisfaction with the services they receive. However, there is little evidence that this has had much impact on improving care. The Discovery Interview Process, a technique for listening to patients and carers and using their narratives to improve care, is discussed in this article. This approach has been used in the pilot phases of the UK Coronary Heart Disease Collaborative and Critical Care Collaborative. These narratives develop understanding grounded in experience. Those delivering care can interpret the narratives using their own clinical and professional knowledge and experience to create better or new ways of meeting patients' and carers' needs. Using their own expert knowledge they can identify needs within the narratives, including those that patients and carers did not know they had. The principal techniques for gathering these narratives are outlined, and ways of using such data to inform patient-focused service improvements are discussed. Various locally sensitive methods for presenting the narratives to expert interprofessional teams are also described along with emerging experience of this feedback. We consider the Discovery Interview technique for gathering patient and carer narratives to be a potentially powerful method for informing quality improvements, discovering what really matters to patients and their carers. This pragmatic approach could prove manageable within local quality improvement projects.


Asunto(s)
Entrevistas como Asunto/métodos , Narración , Satisfacción del Paciente , Atención Dirigida al Paciente/organización & administración , Gestión de la Calidad Total/métodos , Inglaterra , Femenino , Humanos , Masculino , Atención Dirigida al Paciente/métodos , Atención Dirigida al Paciente/normas , Cambio Social , Medicina Estatal/organización & administración , Medicina Estatal/normas
6.
J Biol Chem ; 278(23): 20659-66, 2003 Jun 06.
Artículo en Inglés | MEDLINE | ID: mdl-12668674

RESUMEN

d- and l-captopril are competitive inhibitors of metallo-beta-lactamases. For the enzymes from Bacillus cereus (BcII) and Aeromonas hydrophila (CphA), we found that the mononuclear enzymes are the favored targets for inhibition. By combining results from extended x-ray absorption fine structure, perturbed angular correlation of gamma-rays spectroscopy, and a study of metal ion binding, we derived that for Cd(II)1-BcII, the thiolate sulfur of d-captopril binds to the metal ion located at the site defined by three histidine ligand residues. This is also the case for the inhibited Co(II)1 and Co(II)2 enzymes as observed by UV-visible spectroscopy. Although the single metal ion in Cd(II)1-BcII is distributed between both available binding sites in both the uninhibited and the inhibited enzyme, Cd(II)1-CphA shows only one defined ligand geometry with the thiolate sulfur coordinating to the metal ion in the site composed of 1 Cys, 1 His, and 1 Asp. CphA shows a strong preference for d-captopril, which is also reflected in a very rigid structure of the complex as determined by perturbed angular correlation spectroscopy. For BcII and CphA, which are representatives of the metallo-beta-lactamase subclasses B1 and B2, we find two different inhibitor binding modes.


Asunto(s)
Proteínas Bacterianas/química , Proteínas Bacterianas/metabolismo , Cadmio/química , Cobalto/química , beta-Lactamasas/química , beta-Lactamasas/metabolismo , Absorciometría de Fotón , Aeromonas hydrophila , Inhibidores de la Enzima Convertidora de Angiotensina/metabolismo , Sitios de Unión , Captopril/metabolismo , Unión Proteica , Espectrofotometría Ultravioleta
7.
J Biol Chem ; 277(27): 24744-52, 2002 Jul 05.
Artículo en Inglés | MEDLINE | ID: mdl-11940588

RESUMEN

The L1 metallo-beta-lactamase from Stenotrophomonas maltophilia is unique among this class of enzymes because it is tetrameric. Previous work predicted that the two regions of important intersubunit interaction were the residue Met-140 and the N-terminal extensions of each subunit. The N-terminal extension was also implicated in beta-lactam binding. Mutation of methionine 140 to aspartic acid results in a monomeric L1 beta-lactamase with a greatly altered substrate specificity profile. A 20-amino acid N-terminal deletion mutant enzyme (N-Del) could be isolated in a tetrameric form but demonstrated greatly reduced rates of beta-lactam hydrolysis and different substrate profiles compared with that of the parent enzyme. Specific site-directed mutations of individual N terminus residues were made (Y11S, W17S, and a double mutant L5A/L8A). All N-terminal mutant enzymes were tetramers and all showed higher K(m) values for ampicillin and nitrocefin, hydrolyzed ceftazidime poorly, and hydrolyzed imipenem more efficiently than ampicillin in contrast to wild-type L1. Nitrocefin turnover was significantly increased, probably because of an increased rate of breakdown of the intermediate species due to a lack of stabilizing forces. K(m) values for monomeric L1 were greatly increased for all antibiotics tested. A model of a highly mobile N-terminal extension in the monomeric enzyme is proposed to explain these findings. Tetrameric L1 shows negative cooperativity, which is not present in either the monomer or N-terminal deletion enzymes, suggesting that the cooperative effect is mediated via N-terminal intersubunit interactions. These data indicate that while the N terminus of L1 is not essential for beta-lactam hydrolysis, it is clearly important to its activity and substrate specificity.


Asunto(s)
Antibacterianos/farmacocinética , Stenotrophomonas maltophilia/enzimología , beta-Lactamasas/química , beta-Lactamasas/metabolismo , Secuencia de Aminoácidos , Secuencia de Bases , Biotransformación , Cristalografía por Rayos X , Cartilla de ADN , Cinética , Modelos Moleculares , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Estructura Secundaria de Proteína , Subunidades de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Especificidad por Sustrato
8.
Antimicrob Agents Chemother ; 46(6): 1880-6, 2002 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-12019104

RESUMEN

This work describes the discovery and characterization of a novel series of tricyclic natural product-derived metallo-beta-lactamase inhibitors. Natural product screening of the Bacillus cereus II enzyme identified an extract from a strain of Chaetomium funicola with inhibitory activity against metallo-beta-lactamases. SB236050, SB238569, and SB236049 were successfully extracted and purified from this extract. The most active of these compounds was SB238569, which possessed K(i) values of 79, 17, and 3.4 microM for the Bacillus cereus II, Pseudomonas aeruginosa IMP-1, and Bacteroides fragilis CfiA metallo-beta-lactamases, respectively, yet none of the compounds exhibited any inhibitory activity against the Stenotrophomonas maltophilia L-1 metallo-beta-lactamase (50% inhibitory concentration > 1,000 microM). The lack of activity against angiotensin-converting enzyme and serine beta-lactamases demonstrated the selective nature of these compounds. The crystal structure of SB236050 complexed in the active site of CfiA has been obtained to a resolution of 2.5 A. SB236050 exhibits key polar interactions with Lys184, Asn193, and His162 and a stacking interaction with the indole ring of Trp49 in the flap, which is in the closed conformation over the active site groove. SB236050 and SB238569 also demonstrate good antibacterial synergy with meropenem. Eight micrograms of SB236050 per ml gave rise to an eightfold drop in the MIC of meropenem for two clinical isolates of B. fragilis producing CfiA, making these strains sensitive to meropenem (MIC < or = 4 microg/ml). Consequently, this series of metallo-beta-lactamase inhibitors exhibit the most promising antibacterial synergy activity so far observed against organisms producing metallo-beta-lactamases.


Asunto(s)
Chaetomium/química , Inhibidores Enzimáticos/farmacología , Compuestos Heterocíclicos con 3 Anillos/farmacología , Inhibidores de beta-Lactamasas , Bacillus/efectos de los fármacos , Bacillus cereus/efectos de los fármacos , Bacillus cereus/enzimología , Sitios de Unión , Chaetomium/metabolismo , Sinergismo Farmacológico , Fermentación , Cinética , Meropenem , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Tienamicinas/farmacología , beta-Lactamasas/metabolismo
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