RESUMEN
BACKGROUND: Lymphopenia is defined as a decrease below normal value (often 1.0 x 109 cells/L) of blood circulating lymphocyte count. In the general population, lymphopenia is associated with an increased risk of hospitalisation secondary to infection, independent of traditional clinical risk factors. In hospital, lymphopenia is associated with increased risk of healthcare-associated infection and mortality. By summarising lymphopenia's prevalence and impact on clinical outcomes, we can identify an at-risk population and inform future studies of immune dysfunction following severe illness. METHODS: Peer-reviewed search strategy was performed on three databases. Primary objective was to summarise the pooled prevalence of lymphopenia. Primary outcome was infection including pre-existing lymphopenia as a risk factor for admission with infection and as an in-hospital risk factor for healthcare-associated infection. Secondary outcomes were length of stay and mortality. Mortality data extracted included in-hospital, 28/30-day ('early'), and 90-day/1-year ('late') mortality. Meta-analysis was carried out using random-effects models for each outcome measure. Heterogeneity was assessed using I2 statistic. Joanna Briggs Institute checklist for cohort studies was used to assess risk of bias. The protocol was published on PROSPERO. RESULTS: Fifteen observational studies were included. The pooled prevalence of lymphopenia in all-cause hospitalisations was 38% (CI 0.34-0.42, I2= 97%, p< 0.01). Lymphopenia was not associated with an infection diagnosis at hospital admission and healthcare associated infection (RR 1.03; 95% CI 0.26-3.99, p=0.97, I2 = 55% and RR 1.31; 95% CI 0.78-2.20, p=0.31, I2=97%, respectively), but was associated with septic shock (RR 2.72; 95% CI 1.02-7.21, p=0.04, I2 =98%). Lymphopenia was associated with higher in-hospital mortality and higher 'early' mortality rates (RR 2.44; 95% CI 1.71-3.47, p < 0.00001, I2 = 89% and RR 2.05; 95% CI 1.64-2.56, p < 0.00001, I2 = 29%, respectively). Lymphopenia was associated with higher 'late' mortality (RR 1.59; 1.33-1.90, p < 0.00001, I2 = 0%). CONCLUSIONS: This meta-analysis demonstrates the high prevalence of lymphopenia across all-cause hospitalisations and associated increased risk of septic shock, early and late mortality. Lymphopenia is a readily available marker that may identify immune dysfunctional patients. Greater understanding of immune trajectories following survival may provide insights into longer-term poor clinical outcomes.
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Linfopenia , Choque Séptico , Humanos , Prevalencia , Hospitalización , Evaluación de Resultado en la Atención de Salud , Linfopenia/epidemiología , Linfopenia/etiologíaRESUMEN
Anthropogenic activities are regarded as point sources of pollution entering freshwater bodies worldwide. With over 350,000 chemicals used in manufacturing, wastewater treatment and industrial effluents are comprised of complex mixtures of organic and inorganic pollutants of known and unknown origins. Consequently, their combined toxicity and mode of action are not well understood in aquatic organisms such as Daphnia magna. In this study, effluent samples from wastewater treatment and industrial sectors were used to examine molecular-level perturbations to the polar metabolic profile of D. magna. To determine if the industrial sector and/or the effluent chemistries played a role in the observed biochemical responses, Daphnia were acutely (48 h) exposed to undiluted (100%) and diluted (10, 25, and 50%) effluent samples. Endogenous metabolites were extracted from single daphnids and analyzed using targeted mass spectrometry-based metabolomics. The metabolic profile of Daphnia exposed to effluent samples resulted in significant separation compared to the unexposed controls. Linear regression analysis determined that no single pollutant detected in the effluents was significantly correlated with the responses of metabolites. Significant perturbations were uncovered across many classes of metabolites (amino acids, nucleosides, nucleotides, polyamines, and their derivatives) which serve as intermediates in keystone biochemical processes. The combined metabolic responses are consistent with oxidative stress, disruptions to energy metabolism, and protein dysregulation which were identified through biochemical pathway analysis. These results provide insight into the molecular processes driving stress responses in D. magna. Overall, we determined that the metabolic profile of Daphnia could not be predicted by the chemical composition of environmentally relevant mixtures. The findings of this study demonstrate the advantage of metabolomics in conjunction with chemical analyses to assess the interactions of industrial effluents. This work further demonstrates the ability of environmental metabolomics to characterize molecular-level perturbations in aquatic organisms exposed to complex chemical mixtures directly.
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Aminoácidos , Contaminantes Químicos del Agua , Animales , Aminoácidos/metabolismo , Daphnia , Metabolómica/métodos , Metaboloma , Estrés Oxidativo , Organismos Acuáticos , Contaminantes Químicos del Agua/análisisRESUMEN
RATIONALE: Platelets play an active role in the pathogenesis of acute respiratory distress syndrome (ARDS). Animal and observational studies have shown aspirin's antiplatelet and immunomodulatory effects may be beneficial in ARDS. OBJECTIVE: To test the hypothesis that aspirin reduces inflammation in clinically relevant human models that recapitulate pathophysiological mechanisms implicated in the development of ARDS. METHODS: Healthy volunteers were randomised to receive placebo or aspirin 75â or 1200â mg (1:1:1) for seven days prior to lipopolysaccharide (LPS) inhalation, in a double-blind, placebo-controlled, allocation-concealed study. Bronchoalveolar lavage (BAL) was performed 6â hours after inhaling 50â µg of LPS. The primary outcome measure was BAL IL-8. Secondary outcome measures included markers of alveolar inflammation (BAL neutrophils, cytokines, neutrophil proteases), alveolar epithelial cell injury, systemic inflammation (neutrophils and plasma C-reactive protein (CRP)) and platelet activation (thromboxane B2, TXB2). Human lungs, perfused and ventilated ex vivo (EVLP) were randomised to placebo or 24â mg aspirin and injured with LPS. BAL was carried out 4â hours later. Inflammation was assessed by BAL differential cell counts and histological changes. RESULTS: In the healthy volunteer (n=33) model, data for the aspirin groups were combined. Aspirin did not reduce BAL IL-8. However, aspirin reduced pulmonary neutrophilia and tissue damaging neutrophil proteases (Matrix Metalloproteinase (MMP)-8/-9), reduced BAL concentrations of tumour necrosis factor α and reduced systemic and pulmonary TXB2. There was no difference between high-dose and low-dose aspirin. In the EVLP model, aspirin reduced BAL neutrophilia and alveolar injury as measured by histological damage. CONCLUSIONS: These are the first prospective human data indicating that aspirin inhibits pulmonary neutrophilic inflammation, at both low and high doses. Further clinical studies are indicated to assess the role of aspirin in the prevention and treatment of ARDS. TRIAL REGISTRATION NUMBER: NCT01659307 Results.
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Antiinflamatorios no Esteroideos/uso terapéutico , Aspirina/uso terapéutico , Lipopolisacáridos/administración & dosificación , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Adulto , Biomarcadores/metabolismo , Lavado Broncoalveolar , Proteína C-Reactiva/inmunología , Citocinas/inmunología , Método Doble Ciego , Femenino , Humanos , Inflamación/tratamiento farmacológico , Inhalación , Interleucina-8/inmunología , Masculino , Neutrófilos/inmunología , Estudios Prospectivos , Síndrome de Dificultad Respiratoria/diagnóstico , Síndrome de Dificultad Respiratoria/inmunología , Resultado del Tratamiento , VoluntariosRESUMEN
BACKGROUND: One in three patients hospitalised due to acute exacerbation of COPD (AECOPD) is readmitted within 90â days. No tool has been developed specifically in this population to predict readmission or death. Clinicians are unable to identify patients at particular risk, yet resources to prevent readmission are allocated based on clinical judgement. METHODS: In participating hospitals, consecutive admissions of patients with AECOPD were identified by screening wards and reviewing coding records. A tool to predict 90-day readmission or death without readmission was developed in two hospitals (the derivation cohort) and validated in: (a) the same hospitals at a later timeframe (internal validation cohort) and (b) four further UK hospitals (external validation cohort). Performance was compared with ADO, BODEX, CODEX, DOSE and LACE scores. RESULTS: Of 2417 patients, 936 were readmitted or died within 90â days of discharge. The five independent variables in the final model were: Previous admissions, eMRCD score, Age, Right-sided heart failure and Left-sided heart failure (PEARL). The PEARL score was consistently discriminative and accurate with a c-statistic of 0.73, 0.68 and 0.70 in the derivation, internal validation and external validation cohorts. Higher PEARL scores were associated with a shorter time to readmission. CONCLUSIONS: The PEARL score is a simple tool that can effectively stratify patients' risk of 90-day readmission or death, which could help guide readmission avoidance strategies within the clinical and research setting. It is superior to other scores that have been used in this population. TRIAL REGISTRATION NUMBER: UKCRN ID 14214.
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Readmisión del Paciente/tendencias , Enfermedad Pulmonar Obstructiva Crónica/mortalidad , Medición de Riesgo , Enfermedad Aguda , Anciano , Causas de Muerte/tendencias , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Pronóstico , Enfermedad Pulmonar Obstructiva Crónica/terapia , Curva ROC , Factores de Riesgo , Tasa de Supervivencia/tendencias , Reino Unido/epidemiologíaRESUMEN
Planar microcoils with diameter ranging from 20 to 1000 µm I.D. (130-1130 µm O.D.) are evaluated for their applications in NMR spectroscopy. The coils are first overfilled with a standard sucrose solution and compared against each other. Coils with smaller I.D. (≤100 µm) perform extremely well. One hypothesis is that as the coils get smaller the volume occupied by the copper turns increases relative to the open I.D.; as such a large proportion of the sample is brought in close proximity to the coil turns and likely gives rise to strong sample-coil magnetic coupling, which increases the signal. The applications of the planar microcoils are demonstrated on Cypselurus poecilopterus (fish) and Daphnia magna (water flea) eggs. A single D. magna egg on a 50 µm coil yielded at least 3000 times the mass sensitivity (â¼9,000,000 time saving) when compared to a 5 mm probe. This value could be at least 4 times higher if the B1 homogeneity of the coils could be improved. With the current design, 80% of the signal is lost in multiple pulse experiments that rely on phase inversion and signal cancellation between scans. The data were extrapolated to predict that biological samples as small as â¼4 µm may become accessible via planar microcoil designs. To fulfill their potential for in situ metabolic screening, specialized magnetic susceptibility matched sample holders that restrict the sample to the homogeneous B1 field region (i.e. within the 90% RF field) of the coil and advanced experiments that narrow spectral lines, suppress lipids and disperse signals into multiple dimensions will be required.
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Espectroscopía de Resonancia Magnética , Óvulo/efectos de los fármacos , Pruebas de Toxicidad/métodos , Contaminantes Químicos del Agua/análisis , Animales , Beloniformes , Daphnia , Diseño de Equipo , Imagen por Resonancia Magnética , MagnetismoRESUMEN
BACKGROUND: Hospitalisation due to acute exacerbations of COPD (AECOPD) is common, and subsequent mortality high. The DECAF score was derived for accurate prediction of mortality and risk stratification to inform patient care. We aimed to validate the DECAF score, internally and externally, and to compare its performance to other predictive tools. METHODS: The study took place in the two hospitals within the derivation study (internal validation) and in four additional hospitals (external validation) between January 2012 and May 2014. Consecutive admissions were identified by screening admissions and searching coding records. Admission clinical data, including DECAF indices, and mortality were recorded. The prognostic value of DECAF and other scores were assessed by the area under the receiver operator characteristic (AUROC) curve. RESULTS: In the internal and external validation cohorts, 880 and 845 patients were recruited. Mean age was 73.1 (SD 10.3) years, 54.3% were female, and mean (SD) FEV1 45.5 (18.3) per cent predicted. Overall mortality was 7.7%. The DECAF AUROC curve for inhospital mortality was 0.83 (95% CI 0.78 to 0.87) in the internal cohort and 0.82 (95% CI 0.77 to 0.87) in the external cohort, and was superior to other prognostic scores for inhospital or 30-day mortality. CONCLUSIONS: DECAF is a robust predictor of mortality, using indices routinely available on admission. Its generalisability is supported by consistent strong performance; it can identify low-risk patients (DECAF 0-1) potentially suitable for Hospital at Home or early supported discharge services, and high-risk patients (DECAF 3-6) for escalation planning or appropriate early palliation. TRIAL REGISTRATION NUMBER: UKCRN ID 14214.
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Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Medición de Riesgo , Anciano , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Mortalidad Hospitalaria/tendencias , Humanos , Masculino , Valor Predictivo de las Pruebas , Pronóstico , Enfermedad Pulmonar Obstructiva Crónica/mortalidad , Curva ROC , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Factores de Tiempo , Reino Unido/epidemiologíaRESUMEN
BACKGROUND: Ventilator-acquired pneumonia (VAP) remains a significant problem within intensive care units (ICUs). There is a growing recognition of the impact of critical-illness-induced immunoparesis on the pathogenesis of VAP, but the mechanisms remain incompletely understood. We hypothesised that, because of limitations in their routine detection, Mycoplasmataceae are more prevalent among patients with VAP than previously recognised, and that these organisms potentially impair immune cell function. METHODS AND SETTING: 159 patients were recruited from 12 UK ICUs. All patients had suspected VAP and underwent bronchoscopy and bronchoalveolar lavage (BAL). VAP was defined as growth of organisms at >10(4) colony forming units per ml of BAL fluid on conventional culture. Samples were tested for Mycoplasmataceae (Mycoplasma and Ureaplasma spp.) by PCR, and positive samples underwent sequencing for speciation. 36 healthy donors underwent BAL for comparison. Additionally, healthy donor monocytes and macrophages were exposed to Mycoplasma salivarium and their ability to respond to lipopolysaccharide and undertake phagocytosis was assessed. RESULTS: Mycoplasmataceae were found in 49% (95% CI 33% to 65%) of patients with VAP, compared with 14% (95% CI 9% to 25%) of patients without VAP. Patients with sterile BAL fluid had a similar prevalence to healthy donor BAL fluid (10% (95% CI 4% to 20%) vs 8% (95% CI 2% to 22%)). The most common organism identified was M. salivarium. Blood monocytes from healthy volunteers incubated with M. salivarium displayed an impaired TNF-α response to lipopolysaccharide (p=0.0003), as did monocyte-derived macrophages (MDMs) (p=0.024). MDM exposed to M. salivarium demonstrated impaired phagocytosis (p=0.005). DISCUSSION AND CONCLUSIONS: This study demonstrates a high prevalence of Mycoplasmataceae among patients with VAP, with a markedly lower prevalence among patients with suspected VAP in whom subsequent cultures refuted the diagnosis. The most common organism found, M. salivarium, is able to alter the functions of key immune cells. Mycoplasmataceae may contribute to VAP pathogenesis.
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Líquido del Lavado Bronquioalveolar/microbiología , Infección Hospitalaria/microbiología , Macrófagos/microbiología , Monocitos/microbiología , Mycoplasma/patogenicidad , Neumonía Bacteriana/microbiología , Neumonía Asociada al Ventilador/microbiología , Anciano , Broncoscopía , Femenino , Humanos , Unidades de Cuidados Intensivos , Lipopolisacáridos , Masculino , Persona de Mediana Edad , Fagocitosis , Reacción en Cadena de la Polimerasa , Prevalencia , Reino UnidoRESUMEN
BACKGROUND: Very little data exists on the prevalence and impact of sleep-disordered breathing (SDB) in patients with idiopathic pulmonary fibrosis (IPF). The aim of this study was to examine the impact of SDB on newly diagnosed IPF patients and explore associations with lung function parameters. METHODS: From 2005 to 2009, a cohort of 27 newly diagnosed patients with IPF underwent unattended polygraphy. All patients were diagnosed according to ATS 2000 diagnostic criteria and were not on supplemental oxygen or other treatment. Standard statistical analysis was undertaken using SPSS v. 19 (IBM). RESULTS: Of the 27 patients, 19 were men. There was no correlation at baseline of apnoea + hypopnoea per time in bed (AH), oxygen desaturation index, or 4% desaturations with any lung function variables, age, or body mass index. Six patients had significant SDB (AH >20). Two patients were started on CPAP following polygraphy. No variables from the original sleep studies at baseline predicted eventual long-term oxygen therapy (LTOT) use. At 5-year follow-up, 18 of 27 patients had died (67%). Cox regression analysis showed no association of time spent at SpO2 <90% on baseline polygraphy with survival (p = 0.39). There was no association with survival for AH >20 (p = 0.4) or LTOT use (p = 0.19). CONCLUSION: Our results do not support the contention that nocturnal upper airway obstruction in steroid-free patients with IPF is a common problem or correlated with lung function. In this cohort of patients, there was no evidence that significant SDB at baseline was a predictor of survival.
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Fibrosis Pulmonar/diagnóstico , Apnea Obstructiva del Sueño/diagnóstico , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Polisomnografía , Capacidad de Difusión Pulmonar/fisiología , Fibrosis Pulmonar/mortalidad , Fibrosis Pulmonar/fisiopatología , Apnea Obstructiva del Sueño/mortalidad , Apnea Obstructiva del Sueño/fisiopatología , Estadística como Asunto , Tasa de Supervivencia , Capacidad Pulmonar Total/fisiologíaRESUMEN
Current Ebola virus disease (EVD) diagnosis relies on reverse transcription-PCR (RT-PCR) technology, requiring skilled laboratory personnel and technical infrastructure. Lack of laboratory diagnostic capacity has led to diagnostic delays in the current West African EVD outbreak of 2014 and 2015, compromising outbreak control. We evaluated the diagnostic accuracy of the EVD bedside rapid diagnostic antigen test (RDT) developed by the United Kingdom's Defence Science and Technology Laboratory, compared with Ebola virus RT-PCR, in an operational setting for EVD diagnosis of suspected cases admitted to Ebola holding units in the Western Area of Sierra Leone. From 22 January to 16 February 2015, 138 participants were enrolled. EVD prevalence was 11.5%. All EVD cases were identified by a positive RDT with a test line score of 6 or more, giving a sensitivity of 100% (95% confidence interval (CI): 78.2-100). The corresponding specificity was high (96.6%, 95% CI: 91.3-99.1). The positive and negative predictive values for the population prevalence were 79.0% (95% CI: 54.4-93.8) and 100% (95% CI: 96.7-100), respectively. These results, if confirmed in a larger study, suggest that this RDT could be used as a 'rule-out' screening test for EVD to improve rapid case identification and resource allocation.
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Brotes de Enfermedades/prevención & control , Ebolavirus/aislamiento & purificación , Pruebas Hematológicas/métodos , Fiebre Hemorrágica Ebola/diagnóstico , Sistemas de Atención de Punto , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Ebolavirus/genética , Epidemias , Femenino , Fiebre Hemorrágica Ebola/sangre , Fiebre Hemorrágica Ebola/epidemiología , Humanos , Masculino , Valor Predictivo de las Pruebas , Prevalencia , ARN Viral/análisis , Sensibilidad y Especificidad , Sierra Leona/epidemiología , Factores de TiempoRESUMEN
BACKGROUND: Nosocomial infection occurs commonly in intensive care units (ICUs). Although critical illness is associated with immune activation, the prevalence of nosocomial infections suggests concomitant immune suppression. This study examined the temporal occurrence of immune dysfunction across three immune cell types, and their relationship with the development of nosocomial infection. METHODS: A prospective observational cohort study was undertaken in a teaching hospital general ICU. Critically ill patients were recruited and underwent serial examination of immune status, namely percentage regulatory T-cells (Tregs), monocyte deactivation (by expression) and neutrophil dysfunction (by CD88 expression). The occurrence of nosocomial infection was determined using pre-defined, objective criteria. RESULTS: Ninety-six patients were recruited, of whom 95 had data available for analysis. Relative to healthy controls, percentage Tregs were elevated 6-10 days after admission, while monocyte HLA-DR and neutrophil CD88 showed broader depression across time points measured. Thirty-three patients (35%) developed nosocomial infection, and patients developing nosocomial infection showed significantly greater immune dysfunction by the measures used. Tregs and neutrophil dysfunction remained significantly predictive of infection in a Cox hazards model correcting for time effects and clinical confounders {hazard ratio (HR) 2.4 [95% confidence interval (CI) 1.1-5.4] and 6.9 (95% CI 1.6-30), respectively, P=0.001}. Cumulative immune dysfunction resulted in a progressive risk of infection, rising from no cases in patients with no dysfunction to 75% of patients with dysfunction of all three cell types (P=0.0004). CONCLUSIONS: Dysfunctions of T-cells, monocytes, and neutrophils predict acquisition of nosocomial infection, and combine additively to stratify risk of nosocomial infection in the critically ill.
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Enfermedad Crítica/epidemiología , Infección Hospitalaria/epidemiología , Inmunidad Celular/fisiología , Adolescente , Adulto , Anciano , Recuento de Linfocito CD4 , Estudios de Cohortes , Complemento C5a/fisiología , Infección Hospitalaria/microbiología , Femenino , Antígenos HLA-DR/inmunología , Humanos , Masculino , Persona de Mediana Edad , Monocitos/inmunología , Neutrófilos/inmunología , Pronóstico , Estudios Prospectivos , Receptor de Anafilatoxina C5a/biosíntesis , Linfocitos T Reguladores/inmunología , Adulto JovenRESUMEN
BACKGROUND AND OBJECTIVES: There is increasing evidence that monocytes play a key role in the pathogenesis of acute lung inflammation. Mononuclear cell (MNC) leukapheresis can be used to remove large numbers of monocytes from circulating blood; however, the detailed characteristics of monocyte subpopulations removed by MNC leukapheresis, and the biological effects on the lung, remain incompletely defined. MATERIAL AND METHODS: Six healthy male volunteers underwent MNC leukapheresis of four total blood volumes. Blood was collected at 0, 2, 4, 6, 8 and 24 h; bronchoscopy with bronchoalveolar lavage (BAL) was performed at 8-9 h. Multiparameter flow cytometry was used to identify subpopulations of monocytes in blood and monocyte-like cells in BAL fluid. RESULTS: A median of 5·57×10(9) monocytes were retrieved. Blood monocyte counts indicated that the circulating blood monocyte pool was actively replenished during leukapheresis and subsequently contained a greater proportion of classical (CD14(++) CD16(-)) monocytes. A particular subpopulation of monocyte-like cells, reminiscent of classical monocytes, was also prominent in BAL fluid after leukapheresis. CONCLUSION: Mononuclear cell leukapheresis was safe. The greater proportion of classical monocytes present in blood after MNC leukapheresis may be clinically significant. MNC leukapheresis also appears to affect the proportion of monocyte-like cells in the lung; however, we found no evidence that leukapheresis has a clinically important pro-inflammatory effect in the human lung.
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Leucaféresis/métodos , Leucocitos Mononucleares/citología , Pulmón/fisiología , Lavado Broncoalveolar/métodos , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/inmunología , Humanos , Pulmón/citología , Masculino , Adulto JovenRESUMEN
OBJECTIVES: Cutaneous anthrax (CA) is the most common clinical presentation in human anthrax, but the duration of antibiotic therapy in naturally occurring CA is controversial. The aim of this study was to compare the clinical outcomes of patients receiving antibiotic treatment for either 3-5 days (group 1) or 7-10 days (group 2) in uncomplicated CA. METHODS: A total of 66 patients were enrolled; 29 (44%) in group 1 and 37 (56%) in group 2. Infections were classified as mild (n = 22, 33%) or severe (n = 44, 67%) CA. RESULTS: There were no significant differences between the groups in symptom resolution time, fever clearance time, healing of lesions, development and healing of eschars, requirement for surgical intervention or the development of complications. Both edema resolution time and duration of hospital stay were longer in group 2. There were no therapeutic failures, relapses or deaths in either group. Steroid therapy was used in 32% of patients with severe CA, but a beneficial effect on resolution of edema was not demonstrated. CONCLUSIONS: These results suggest that short-course antibiotic therapy is as effective as standard-duration therapy in uncomplicated CA and that steroid therapy may not be effective.
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Carbunco/tratamiento farmacológico , Antibacterianos/uso terapéutico , Adolescente , Adulto , Anciano , Amoxicilina/uso terapéutico , Carbunco/patología , Ciprofloxacina/uso terapéutico , Doxiciclina/uso terapéutico , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Penicilina G Procaína/uso terapéutico , Estudios Prospectivos , Enfermedades Cutáneas Bacterianas , Resultado del Tratamiento , Adulto JovenRESUMEN
Cell surface proteins are excellent targets for diagnostic and therapeutic interventions. By using bioinformatics tools, we generated a catalog of 3,702 transmembrane proteins located at the surface of human cells (human cell surfaceome). We explored the genetic diversity of the human cell surfaceome at different levels, including the distribution of polymorphisms, conservation among eukaryotic species, and patterns of gene expression. By integrating expression information from a variety of sources, we were able to identify surfaceome genes with a restricted expression in normal tissues and/or differential expression in tumors, important characteristics for putative tumor targets. A high-throughput and efficient quantitative real-time PCR approach was used to validate 593 surfaceome genes selected on the basis of their expression pattern in normal and tumor samples. A number of candidates were identified as potential diagnostic and therapeutic targets for colorectal tumors and glioblastoma. Several candidate genes were also identified as coding for cell surface cancer/testis antigens. The human cell surfaceome will serve as a reference for further studies aimed at characterizing tumor targets at the surface of human cells.
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Biología Computacional , Proteínas de la Membrana/genética , Antígenos de Superficie/genética , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Neoplasias Colorrectales/genética , Bases de Datos Genéticas , Epigénesis Genética , Variación Genética , Glioblastoma/genética , Humanos , Proteínas de la Membrana/metabolismoRESUMEN
BACKGROUND: Diagnosing ventilator-associated pneumonia (VAP) in an intensive care unit (ICU) is a complex process. Our aim was to collect, evaluate and represent the information relating to current clinical practice for the diagnosis of VAP in UK NHS ICUs, and to explore the potential value and role of a novel diagnostic for VAP, which uses optical molecular alveoscopy to visualise the alveolar space. METHODS: Qualitative study performing semi-structured interviews with clinical experts. Interviews were recorded, transcribed, and thematically analysed. A flow diagram of the VAP patient pathway was elicited and validated with the expert interviewees. Fourteen clinicians were interviewed from a range of UK NHS hospitals: 12 ICU consultants, 1 professor of respiratory medicine and 1 professor of critical care. RESULTS: Five themes were identified, relating to [1] current practice for the diagnosis of VAP, [2] current clinical need in VAP diagnostics, [3] the potential value and role of the technology, [4] the barriers to adoption and [5] the evidence requirements for the technology, to help facilitate a successful adoption. These themes indicated that diagnosis of VAP is extremely difficult, as is the decision to stop antibiotic treatment. The analysis revealed that there is a clinical need for a diagnostic that provides an accurate and timely diagnosis of the causative pathogen, without the long delays associated with return of culture results, and which is not dangerous to the patient. It was determined that the technology would satisfy important aspects of this clinical need for diagnosing VAP (and pneumonia, more generally), but would require further evidence on safety and efficacy in the patient population to facilitate adoption. CONCLUSIONS: Care pathway analysis performed in this study was deemed accurate and representative of current practice for diagnosing VAP in a UK ICU as determined by relevant clinical experts, and explored the value and role of a novel diagnostic, which uses optical technology, and could streamline the diagnostic pathway for VAP and other pneumonias.
RESUMEN
Testing of Cryptococcus neoformans for susceptibility to antifungal drugs by standard microtiter methods has not been shown to correlate with clinical outcomes. This report describes a modified quantitative broth macrodilution susceptibility method showing a correlation with both the patient's quantitative biological response in the cerebrospinal fluid (CSF) and the survival of 85 patients treated with amphotericin B (AMB). The Spearman rank correlation between the quantitative in vitro measure of susceptibility and the quantitative measure of the number of organisms in the patient's CSF was 0.37 (P < 0.01; 95% confidence interval [95% CI], 0.20, 0.60) for the first susceptibility test replicate and 0.46 (P < 0.001; 95% CI, 0.21, 0.62) for the second susceptibility test replicate. The median in vitro estimated response (defined as the fungal burden after AMB treatment) at 1.5 mg/liter AMB for patients alive at day 14 was 5 CFU (95% CI, 3, 8), compared to 57 CFU (95% CI, 4, 832) for those who died before day 14. These exploratory results suggest that patients whose isolates show a quantitative in vitro susceptibility response below 10 CFU/ml were more likely to survive beyond day 14.
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Infecciones Oportunistas Relacionadas con el SIDA/tratamiento farmacológico , Anfotericina B/uso terapéutico , Antifúngicos/uso terapéutico , Cryptococcus neoformans/efectos de los fármacos , Meningitis Criptocócica/tratamiento farmacológico , Infecciones Oportunistas Relacionadas con el SIDA/microbiología , Infecciones Oportunistas Relacionadas con el SIDA/mortalidad , Anfotericina B/farmacología , Antifúngicos/farmacología , Líquido Cefalorraquídeo/microbiología , Recuento de Colonia Microbiana , Cryptococcus neoformans/aislamiento & purificación , Humanos , Meningitis Criptocócica/microbiología , Meningitis Criptocócica/mortalidad , Pruebas de Sensibilidad Microbiana/métodos , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
An unlinked anonymous survey was conducted to measure the prevalence of selected markers for HIV, hepatitis B and C infection in recruits to the UK Armed Forces to inform future screening and hepatitis B vaccination policies. During 2007, nearly 14 000 left-over samples taken from new recruits for blood typing were collected, unlinked from identifiers and anonymously tested for HIV, hepatitis C and current and past cleared hepatitis B infection. Overall, serological evidence of HIV and hepatitis C was found in 0·06% and 0·06% of recruits, respectively. Evidence of past cleared and current hepatitis B infection was found in 3·63% and 0·37% of recruits, respectively. Overall, prevalence rates were broadly consistent with UK population estimates of infection. However, HIV and hepatitis B prevalence was higher in recruits of African origin than in those from the UK (P<0·0001). Screening for these infections is an option that could be considered for those entering Services from high-prevalence countries.
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Infecciones por VIH/epidemiología , Hepatitis B/epidemiología , Hepatitis C/epidemiología , Personal Militar , Femenino , Humanos , Masculino , Estudios Seroepidemiológicos , Reino Unido/epidemiología , Adulto JovenRESUMEN
Undifferentiated febrile illnesses present diagnostic and treatment challenges in the Firm Base, let alone in the deployed austere environment. We report a series of 14 cases from Operation TRENTON in South Sudan in 2017 that coincided with the rainy season, increased insect numbers and a Relief in Place. The majority of patients had headaches, myalgia, arthralgia and back pain, as well as leucopenia and thrombocytopenia. No diagnoses could be made in theatre, despite a sophisticated deployed laboratory being available, and further testing in the UK, including next-generation sequencing, was unable to establish an aetiology. Such illnesses are very likely to present in tropical environments, where increasing numbers of military personnel are being deployed, and clinicians must be aware of the non-specific presentation and treatment, as well as the availability of Military Infection Reachback services to assist in the management of these cases.
Asunto(s)
Fiebre , Personal Militar , Fiebre/diagnóstico , Cefalea/diagnóstico , Humanos , Sudán del Sur/epidemiologíaRESUMEN
Schistosoma mansoni schistosomula recovered from the lungs of mice have previously been shown to express host-derived class I and class II major histocompatibility complex (MHC) antigens. To investigate the tissue origin of parasite-acquired MHC products, lung-stage schistosomula were obtained from a series of parent leads to F1 and F1 leads to parent bone marrow chimeras and the parasites typed by immunofluorescence for the presence of haplotype-specific K region and I region MHC determinants. The results of these experiments indicated that, despite their intravascular residence in the host, schistosomula derive all of their class I antigen from a nonhemapoietic tissue source. In contrast, the class II antigens expressed on the surface of schistosomula were found to originate from bone marrow-derived donor cells. These results support the hypothesis that MHC product acquisition by schistosomes involves selective and specific interactions with host tissue and, in the case of class I antigens, suggest that the endothelium may be a major site of host molecule uptake for the parasite.
Asunto(s)
Antígenos H-2/inmunología , Células Madre Hematopoyéticas/citología , Antígenos de Histocompatibilidad Clase II/inmunología , Esquistosomiasis/inmunología , Animales , Médula Ósea/inmunología , Células de la Médula Ósea , Trasplante de Médula Ósea , Antígenos H-2/genética , Células Madre Hematopoyéticas/inmunología , Antígeno de Histocompatibilidad H-2D , Pulmón/inmunología , Pulmón/parasitología , Masculino , Ratones , Ratones Endogámicos C57BL , Quimera por Radiación , Schistosoma mansoni/crecimiento & desarrollo , Schistosoma mansoni/inmunología , Esquistosomiasis/sangre , Esquistosomiasis/parasitologíaRESUMEN
Recent advances in DNA sequencing technology are providing unprecedented opportunities for comprehensive analysis of cancer genomes, exomes, transcriptomes, as well as epigenomic components. The integration of these data sets with well-annotated phenotypic and clinical data will expedite improved interventions based on the individual genomics of the patient and the specific disease.
Asunto(s)
Estudio de Asociación del Genoma Completo , Neoplasias/genética , Perfilación de la Expresión Génica , HumanosRESUMEN
AIM: To determine whether the survival of patients with suspected acute pulmonary embolism (PE) relates to radiological probability of acute PE assessed using lung scintigraphy scans (LSS). METHODS: Lung scintigraphy scan results from a venous thromboembolism database were categorised as high, indeterminate or low probability using the modified PIOPED criteria and corresponding chest X-rays (CXRs) as normal or abnormal. Mortality data on these cases were obtained from the General Register Office for Scotland, and survival was analysed using the Kaplan-Meier method. RESULTS: Of the 1,818 LSS analysed, 941 (51.8%) were normal, 532 (29.3%) indeterminate and 345 (19.0%) high probability. After an adjustment for age and gender, no significant survival difference was found between patients with normal and high probability LSS (p=0.182). However, patients with indeterminate LSS had significantly lower survival than patients in the other groups. This difference persisted after adjustment for CXR result. CONCLUSIONS: Indeterminate LSS results are associated with a poor prognosis. Careful follow-up of patients with inderminate LSS would appear to be justified.