RESUMEN
Screening assays using target-based affinity selection coupled with high-sensitivity detection technologies to identify small-molecule hits from chemical libraries can provide a useful discovery approach that complements traditional assay systems. Affinity selection-mass spectrometry (AS-MS) is one such methodology that holds promise for providing selective and sensitive high-throughput screening platforms. Although AS-MS screening platforms have been used to discover small-molecule ligands of proteins from many target families, they have not yet been used routinely to screen integral membrane proteins. The authors present a proof-of-concept study using size exclusion chromatography coupled to AS-MS to perform a primary screen for small-molecule ligands of the purified muscarinic M2 acetylcholine receptor, a G-protein-coupled receptor. AS-MS is used to characterize the binding mechanisms of 2 newly discovered ligands. NGD-3350 is a novel M2-specific orthosteric antagonist of M2 function. NGD-3366 is an allosteric ligand with binding properties similar to the allosteric antagonist W-84, which decreases the dissociation rate of N-methyl-scopolamine from the M2 receptor. Binding properties of the ligands discerned from AS-MS assays agree with those from in vitro biochemical assays. The authors conclude that when used with appropriate small-molecule libraries, AS-MS may provide a useful high-throughput assay system for the discovery and characterization of all classes of integral membrane protein ligands, including allosteric modulators.
Asunto(s)
Espectrometría de Masas/métodos , Antagonistas Muscarínicos/farmacología , Unión Proteica/efectos de los fármacos , Receptor Muscarínico M2/química , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Acetilcolina , Regulación Alostérica , Sitio Alostérico , Animales , Línea Celular , Relación Dosis-Respuesta a Droga , Cobayas , Insectos , Ligandos , Estructura Molecular , Ensayo de Unión Radioligante , Receptor Muscarínico M2/aislamiento & purificaciónRESUMEN
The scope of a healthcare institution's infection prevention and control/healthcare epidemiology program (IPC/HE) should be driven by the size and complexity of the patient population served, that population's risk for healthcare-associated infection (HAI), and local, state, and national regulatory and accreditation requirements. Essential activities of all IPC/HE programs include but are not limited to the following: â Surveillance.â Performance improvement to reduce HAI â Acute event response, including outbreak investigation â Education and training of both healthcare personnel and patients â Reporting of HAI to the Centers for Disease Control and Prevention's National Healthcare Safety Network as well as entities required by law.
Asunto(s)
Infección Hospitalaria/prevención & control , Brotes de Enfermedades/prevención & control , Personal de Salud/educación , Control de Infecciones/normas , Centers for Disease Control and Prevention, U.S. , Humanos , Estados UnidosRESUMEN
The current economic and political environments challenge health care organizations in the United States to provide affordable, accessible, and comprehensive health services. However, changes in reimbursement to health care providers can affect their ability to offer access to cutting-edge services while reducing costs. Consequently, organizations are restructuring, re-engineering, right-sizing, downsizing, and redesigning, all in an effort to save money while also hoping to maintain a reputation for quality and customer service. Dr Vicky Fraser, in her keynote address at the APIC conference in 2000, reminded us that ICHE programs are cost centers rather than revenue generators, and are often targets for budget cuts. Although Haley's Study on the Efficacy of Nosocomial Infection Control (SENIC), published in 1985, was a landmark event demonstrating the importance of our profession's mission, it is becoming dated. Infection control professionals (ICPs) must continue Haley's work, finding innovative ways to market or demonstrate the value of ICHE programs to health care executives. Closing the 1999 APIC conference with a symposium entitled "Breaking Out of the Box," Jackson and Massanari challenged ICPs to educate themselves about the changing health care environment, to be proactive, and constructively help organizations "re-engineer" more efficiently, rather than feel victimized and helplessly await being re-engineered out of existence. The threat of downsizing prompted ICPs at BJC HealthCare to realize that the time had come to change their own culture and attitudes and to focus on the business of infection control. This change required challenging the traditional roles of solo practitioner, data collector, and keeper of infection control data and knowledge. The goals now include leading intervention teams committed to reducing health care-associated infections, partnering rather than accepting sole responsibility for lowering infection rates, and learning to influence without authority. Staying focused on quality and cost-effectiveness and demonstrating improvements in clinical outcomes became a commitment. This article discusses BJC HealthCare's journey through change so that it may provide useful information and tools for ICPs in any setting looking for the necessary change strategies that might keep them in business.
Asunto(s)
Infección Hospitalaria/prevención & control , Atención a la Salud/tendencias , Epidemiología , Profesionales para Control de Infecciones/tendencias , Control de Infecciones/tendencias , Infección Hospitalaria/economía , Recolección de Datos , Humanos , Control de Infecciones/economía , Control de Infecciones/métodos , Profesionales para Control de Infecciones/organización & administraciónRESUMEN
Professional competency has traditionally been divided into 2 essential components: knowledge and skill. More recent definitions have recommended additional components such as communication, values, reasoning, and teamwork. A standard, widely accepted, comprehensive definition remains an elusive goal. For infection preventionists (IPs), the requisite elements of competence are most often embedded in the IP position description, which may or may not reference national standards or guidelines. For this reason, there is widespread variation among these elements and the criteria they include. As the demand for IP expertise continues to rapidly expand, the Association for Professionals in Infection Control and Epidemiology, Inc, made a strategic commitment to develop a conceptual model of IP competency that could be applicable in all practice settings. The model was designed to be used in combination with organizational training and evaluation tools already in place. Ideally, the Association for Professionals in Infection Control and Epidemiology, Inc, model will complement similar competency efforts undertaken in non-US countries and/or international organizations. This conceptual model not only describes successful IP practice as it is today but is also meant to be forward thinking by emphasizing those areas that will be especially critical in the next 3 to 5 years. The paper also references a skill assessment resource developed by Community and Hospital Infection Control Association (CHICA)-Canada and a competency model developed by the Infection Prevention Society (IPS), which offer additional support of infection prevention as a global patient safety mission.
Asunto(s)
Infección Hospitalaria/prevención & control , Control de Infecciones/métodos , Control de Infecciones/normas , Competencia Profesional/normas , HumanosRESUMEN
A novel series of non-ATP-competitive MK2 inhibitors based on a furan-2-carboxyamide scaffold was discovered through high-throughput screening using the affinity selection-mass spectrometry-based Automated Ligand Identification System platform. Medicinal chemistry efforts optimized the initial screening hit to leadlike compounds with significant improvements in biochemical and cellular potencies, while maintaining excellent kinase selectivity and in vitro pharmacokinetic properties. Biophysical and biochemical studies confirmed the unique non-ATP-competitive binding mode of this series and suggested that highly selective inhibitors of MK2 should be feasible by targeting the outside ATP pocket.
RESUMEN
OBJECTIVE: To compare trends in invasive pneumococcal disease (IPD) in non-Indigenous people in north Queensland before and after the introduction of funded pneumococcal vaccines, and to examine the proportion of cases that occurred after vaccine roll-out that could be vaccine-preventable. DESIGN, SETTING AND PARTICIPANTS: In 2005, a 7-valent pneumococcal conjugate vaccine (7vPCV) for non-Indigenous children and a 23-valent pneumococcal polysaccharide vaccine (23vPPV) for non-Indigenous adults aged ≥ 65 years were made freely available. Trends in IPD in the non-Indigenous estimated resident population in north Queensland (about 581 850 in 2006) were compared between the 4 years before (2001-2004) and after (2006-2009) the vaccines were rolled out. MAIN OUTCOME MEASURES: Incidences and serotypes of IPD in non-Indigenous people. RESULTS: After the introduction of the vaccines, there were significant declines for all ages in the average annual incidence of IPD (- 34%; P < 0.05) and 7vPCV serotype IPD (- 77%; P < 0.05). In children aged < 5 years, there was a 91% decline in the incidence of 7vPCV serotype IPD (P < 0.05); in adults aged 15-64 years and ≥ 65 years there were 62% and 77% declines, respectively, in 7vPCV and 23vPPV common-serotype IPD (P < 0.05). There was a 188% increase in 23vPPV-only serotype IPD in adults aged 15-64 years (P < 0.05), whereas there was no significant change in adults aged ≥ 65 years. Serotype 19A was the most frequently identified serotype in 2006-2009, causing 19% of all IPD in those 4 years. CONCLUSIONS: There is circumstantial evidence that 7vPCV has had a powerful indirect effect in preventing IPD in adults in north Queensland; 23vPPV may have had a direct effect in adults aged ≥ 65 years. It is likely that with combined direct and indirect effects, newer conjugate vaccines could prevent more IPD than could be prevented with the two current vaccines.
Asunto(s)
Infecciones Neumocócicas/epidemiología , Vacunas Neumococicas/inmunología , Adolescente , Adulto , Anciano , Preescolar , Humanos , Persona de Mediana Edad , Infecciones Neumocócicas/inmunología , Infecciones Neumocócicas/prevención & control , Queensland/epidemiología , Serotipificación , Vacunación , Vacunas Conjugadas/inmunologíaRESUMEN
OBJECTIVE: To examine trends in invasive pneumococcal disease (IPD) in Indigenous people in north Queensland following the introduction of the 7-valent pneumococcal conjugate vaccine (7vPCV). DESIGN: Trends in IPD were compared over three 3-year periods: before the introduction of 7vPCV for Indigenous children (1999-2001), and two consecutive periods after its introduction (2002-2004 and 2005-2007). MAIN OUTCOME MEASURES: Incidences of IPD in Indigenous children and adults in 1999-2001 and 2005-2007; trends in IPD caused by 7vPCV and non-7vPCV serotypes; and trends in indirect protective effects and emergence of non-7vPCV serotype IPD. RESULTS: From 1999-2001 to 2005-2007, there was a 60% decline in IPD, with the virtual elimination of 7vPCV serotype IPD in young (< 5 years) Indigenous children. There is no evidence yet of an increase in non-7vPCV serotype IPD in these children. Although the annual incidence of IPD in Indigenous adults remained virtually unchanged, there was a 75% decline in 7vPCV serotype IPD in these adults (chi2(trend) = 11.65, P < 0.001). However, the incidence of IPD caused by non-7vPCV serotypes more than tripled in adults (chi2(trend) = 7.58, P = 0.006). Serotype 1 IPD has been prominent over the 9 years, but there is no evidence of a recent increase in serotype 19A IPD. CONCLUSIONS: Vaccinating Indigenous children with 7vPCV has protected Indigenous adults in north Queensland through an indirect "herd immunity" effect. However, this benefit has been offset by a recent increase in non-7vPCV IPD in Indigenous adults. Newer pneumococcal conjugate vaccines could prevent, both directly and indirectly, a considerable amount of the persisting IPD in Indigenous people in the region.
Asunto(s)
Vacunación Masiva , Nativos de Hawái y Otras Islas del Pacífico , Infecciones Neumocócicas/epidemiología , Infecciones Neumocócicas/prevención & control , Adolescente , Adulto , Niño , Preescolar , Vacuna Neumocócica Conjugada Heptavalente , Humanos , Inmunidad Colectiva , Incidencia , Lactante , Vacunas Meningococicas/uso terapéutico , Vacunas Neumococicas/uso terapéutico , Queensland/epidemiología , Serotipificación , Streptococcus pneumoniae/clasificaciónRESUMEN
OBJECTIVE: To describe the epidemiology of invasive pneumococcal disease (IPD), and the impact of pneumococcal vaccines on IPD, in Indigenous people in north Queensland. SETTING: North Queensland, 1999-2004; there are about 53 750 Indigenous people in the region, including nearly 6900 children < 5 years and nearly 5650 adults > or = 50 years. MAIN OUTCOME MEASURES: Incidences of IPD in Indigenous children and in Indigenous adults compared between the 3 years before and after the introduction of a 7-valent pneumococcal conjugate vaccine (7vPCV) (1999-2001 versus 2002-2004). RESULTS: Estimated annual incidence of IPD in Indigenous children < 5 years of age declined from 170 to 78 cases per 100 000 in the 3 years following the introduction of 7vPCV in 2001. The annual incidence of vaccine-preventable IPD in Indigenous adults had declined by 86% since a 23-valent pneumococcal polysaccharide vaccine (23vPPV) was introduced to the region in 1996, to 15 cases per 100 000 (95% CI, 8-25) in 2002-2004. CONCLUSION: Although there was a rapid decline in IPD in young Indigenous children, it is unlikely that the incidence will fall much further with the current 7-valent vaccine. There was a suggestion that vaccinating Indigenous children indirectly protected those aged 5-14 years and Indigenous adults > or =15 years of age. Incidence of IPD in Indigenous adults in 2002-2004 was the lowest on record in the region.