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The COVID-19 pandemic raised public awareness about airborne particulate matter (PM) due to the spread of infectious diseases via the respiratory route. The persistence of potentially infectious aerosols in public spaces and the spread of nosocomial infections in medical settings deserve careful investigation; however, a systematic approach characterizing the fate of aerosols in clinical environments has not been reported. This paper presents a methodology for mapping aerosol propagation using a low-cost PM sensor network in ICU and adjacent environments and the subsequent development of the data-driven zonal model. Mimicking aerosol generation by a patient, we generated trace NaCl aerosols and monitored their propagation in the environment. In positive (closed door) and neutral-pressure (open door) ICUs, up to 6% or 19%, respectively, of all PM escaped through the door gaps; however, the outside sensors did not register an aerosol spike in negative-pressure ICUs. The K-means clustering analysis of temporospatial aerosol concentration data suggests that ICU can be represented by three distinct zones: (1) near the aerosol source, (2) room periphery, and (3) outside the room. The data suggests two-phase plume behavior: dispersion of the original aerosol spike throughout the room, followed by an evacuation phase where "well-mixed" aerosol concentration decayed uniformly. Decay rates were calculated for positive, neutral, and negative pressure operations, with negative-pressure rooms clearing out nearly twice as fast. These decay trends closely followed the air exchange rates. This research demonstrates the methodology for aerosol monitoring in medical settings. This study is limited by a relatively small data set and is specific to single-occupancy ICU rooms. Future work needs to evaluate medical settings with high risks of infectious disease transmission.
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COVID-19 , Pandemias , Humanos , Aerosoles y Gotitas Respiratorias , Material Particulado/análisisRESUMEN
The ability to measure and track aerosols in the vicinity of patients with suspected or confirmed COVID-19 is highly desirable. At present, there is no way to measure and track, in real time, the sizes, dispersion and dilution/disappearance of aerosols that are generated by airway manipulations such as mask ventilation; tracheal intubation; bronchoscopy; dental and gastro-intestinal endoscopy procedures; or by vigorous breathing, coughing or exercise. We deployed low-cost photoelectric sensors in five operating theatres between surgical cases. We measured and analysed dilution and exfiltration of aerosols we generated to evaluate air handling and dispersion under real-world conditions. These data were used to develop a model of aerosol persistence. We found significant variation between different operating theatres. Equipment placement near air vents affects air flows, impacting aerosol movement and elimination patterns. Despite these impediments, air exchange in operating theatres is robust and prolonged fallow time before theatre turnover may not be necessary. Significant concentrations of aerosols are not seen in adjoining areas outside of the operating theatre. These models and dispersion rates can predict aerosol persistence in operating theatres and other clinical areas and potentially facilitate quantification of risk, with obvious and far-reaching implications for designing, evaluating and confirming air handling in non-medical environments.
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COVID-19 , Tos , Humanos , Quirófanos , Aerosoles y Gotitas Respiratorias , VentilaciónRESUMEN
BACKGROUND: Little is known about the burden that overweight and obesity impose on Dutch society. The aim of this study is to examine this burden in terms of cost-of-illness and health-related quality of life. METHOD: A bottom-up, prevalence-based burden of disease study from a societal perspective was performed. Cost-of-illness information including healthcare costs, patient and family costs, and other costs was obtained via the Treatment Inventory of Costs in Patients with psychiatric disorders (TiC-P) questionnaire. Health-related quality of life was assessed through the EuroQol (EQ-5D-5L) and the BODY-Q instruments. Non-parametric bootstrapping was applied to test for significant differences in costs. Subgroup analyses were performed on all outcomes. RESULTS: A total of 97 people with overweight and obesity completed the survey. Per respondent, mean healthcare costs were 2907, patient and family costs were 4037, and other costs were 4519, leading to a total societal cost of 11,463 per respondent per year. Total costs were significantly higher for respondents with obesity versus overweight and between low & intermediate versus highly educated respondents. The mean utility score of our population was 0.81. A significantly lower utility score was found for respondents with obesity in comparison with respondents with overweight. BODY-Q results show that respondents with obesity scored a significantly lower Rasch-score than did respondents with overweight in three scales. Respondents with a high education level and having paid work scored significantly higher Rasch-scores in two scales than did those with a low education level and without having paid work. The age group 19-29 have significantly higher Rasch-scores in three scales than respondents in the other two age categories. CONCLUSIONS: Overweight and obesity have a considerable impact on the societal costs and on health-related quality of life. The results show that the impact of overweight and obesity go beyond the healthcare sector, as the other costs have the biggest share of the total costs. Another interesting finding of this study is that obesity leads to significant higher costs and lower health-related quality of life than overweight. These findings draw attention to policy making, as collective prevention and effective treatment are needed to reduce this burden.
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Sobrepeso , Calidad de Vida , Costo de Enfermedad , Costos de la Atención en Salud , Humanos , Obesidad/epidemiología , Sobrepeso/epidemiología , Encuestas y CuestionariosRESUMEN
In six contiguous estuaries in Southwest Florida (USA) focused management actions over the past several decades have reduced watershed nutrient loads, resulting in an additional 11,672 ha of seagrass meadows between 1999 and 2016, an improvement of 32%. However, in September of 2017, Hurricane Irma made landfall in the state of Florida, affecting the open water and watersheds of each of these six estuaries. In response, seagrass coverage declined by 1203 ha between 2016 and 2018, a system-wide decrease of 3%. The range of decreases associated with Hurricane Irma varied from less than a 1% loss of seagrass coverage in St. Joseph Sound to declines of 7 and 11% in Clearwater Harbor and Lemon Bay, respectively. Areas with the largest losses between 2016 and 2018 were those systems where seagrass coverage had declined in prior years, indicating the effects of Hurricane Irma might have been intensified by prior impacts.
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Tormentas Ciclónicas , Estuarios , Florida , PraderaRESUMEN
BACKGROUND: Guidelines recommend screening of high-risk women using breast magnetic resonance imaging (MRI). Contrast-enhanced mammography (CEM) has matured, providing excellent diagnostic accuracy. To lower total radiation dose, evaluation of single-view (1 V) CEM exams might be considered instead of double-view (2 V) readings as an alternative reading strategy in women who cannot undergo MRI. METHODS: This retrospective non-inferiority feasibility study evaluates whether the use of 1 V results in an acceptable sensitivity for detecting breast cancer (non-inferiority margin, - 10%). CEM images from May 2013 to December 2017 were included. 1 V readings were performed by consensus opinion of three radiologists, followed by 2 V readings being performed after 6 weeks. Cases were considered "malignant" if the final BI-RADS score was ≥ 4, enabling calculation of sensitivity, specificity, and area under the receiver operating characteristic curve (AUC). Histopathological results or follow-up served as a gold standard. RESULTS: A total of 368 cases were evaluated. Mean follow-up for benign or negative cases was 20.9 months. Sensitivity decreased by 9.6% from 92.9 to 83.3% when only 1 V was used for evaluation (p < 0.001). The lower limit of the 90% confidence interval around the difference in sensitivity between 1 V and 2 V readings was - 15% and lies below the predefined non-inferiority margin of - 10%. Hence, non-inferiority of 1 V to 2 V reading cannot be concluded. AUC for 1 V was significantly lower, 0.861 versus 0.899 for 2 V (p = 0.0174). CONCLUSION: Non-inferiority of 1 V evaluations as an alternative reading strategy to standard 2 V evaluations could not be concluded. 1 V evaluations had lower diagnostic performance compared with 2 V evaluations. KEY POINTS: ⢠To lower radiation exposure used in contrast-enhanced mammography, we studied a hypothetical alternative strategy: single-view readings (1 V) versus (standard) double-view readings (2 V). ⢠Based on our predefined margin of - 10%, non-inferiority of 1 V could not be concluded. ⢠1 V evaluation is not recommended as an alternative reading strategy to lower CEM-related radiation exposure.
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Neoplasias de la Mama/diagnóstico , Mama/patología , Medios de Contraste/farmacología , Imagen por Resonancia Magnética/métodos , Mamografía/métodos , Anciano , Estudios de Factibilidad , Femenino , Humanos , Persona de Mediana Edad , Curva ROC , Reproducibilidad de los Resultados , Estudios RetrospectivosRESUMEN
In Southwest Florida, a variety of human impacts had caused widespread losses of seagrass coverage from historical conditions. St. Joseph Sound and Clearwater Harbor lost approximately 24 and 51%, respectively, of their seagrass coverage between 1950 and 1999, while Tampa Bay and Sarasota Bay had lost 46% and 15%, respectively, of their seagrass coverage between 1950 and the 1980s. However, over the period of 1999 to 2016, the largest of the six estuaries, Tampa Bay, added 408â¯ha of seagrass per year, while the remaining five estuaries examined in this paper added approximately 269â¯ha per year. In total, seagrass coverage in these six estuaries increased 12,171â¯ha between the 1980s and 2016. Focused resource management plans have held the line on nitrogen loads from non-point sources, allowing seagrass resources to expand in response to reductions in point source loads that have been implemented over the past few decades.
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Monitoreo del Ambiente/métodos , Plantas , Organismos Acuáticos , Conservación de los Recursos Hídricos/métodos , Ecosistema , Estuarios , Florida , Humanos , Nitrógeno , Análisis Espacio-Temporal , Contaminación del AguaRESUMEN
Major mood disorders, which primarily include bipolar disorder and major depressive disorder, are the leading cause of disability worldwide and pose a major challenge in identifying robust risk genes. Here, we present data from independent large-scale clinical data sets (including 29 557 cases and 32 056 controls) revealing brain expressed protocadherin 17 (PCDH17) as a susceptibility gene for major mood disorders. Single-nucleotide polymorphisms (SNPs) spanning the PCDH17 region are significantly associated with major mood disorders; subjects carrying the risk allele showed impaired cognitive abilities, increased vulnerable personality features, decreased amygdala volume and altered amygdala function as compared with non-carriers. The risk allele predicted higher transcriptional levels of PCDH17 mRNA in postmortem brain samples, which is consistent with increased gene expression in patients with bipolar disorder compared with healthy subjects. Further, overexpression of PCDH17 in primary cortical neurons revealed significantly decreased spine density and abnormal dendritic morphology compared with control groups, which again is consistent with the clinical observations of reduced numbers of dendritic spines in the brains of patients with major mood disorders. Given that synaptic spines are dynamic structures which regulate neuronal plasticity and have crucial roles in myriad brain functions, this study reveals a potential underlying biological mechanism of a novel risk gene for major mood disorders involved in synaptic function and related intermediate phenotypes.
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Cadherinas/genética , Trastornos del Humor/genética , Adulto , Amígdala del Cerebelo/fisiopatología , Trastorno Bipolar/genética , Encéfalo/fisiopatología , Cadherinas/metabolismo , Cognición/fisiología , Dendritas , Espinas Dendríticas , Trastorno Depresivo Mayor/genética , Femenino , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Plasticidad Neuronal , Neuronas , Personalidad/genética , Polimorfismo de Nucleótido Simple/genética , Factores de Riesgo , Sinapsis/genética , Sinapsis/metabolismoRESUMEN
Donor alloantigen infusion induces T cell regulation and transplant tolerance in small animals. Here, we study donor splenocyte infusion in a large animal model of pulmonary transplantation. Major histocompatibility complex-mismatched single lung transplantation was performed in 28 minipigs followed by a 28-day course of methylprednisolone and tacrolimus. Some animals received a perioperative donor or third party splenocyte infusion, with or without low-dose irradiation (IRR) before surgery. Graft survival was significantly prolonged in animals receiving both donor splenocytes and IRR compared with controls with either donor splenocytes or IRR only. In animals with donor splenocytes and IRR, increased donor cell chimerism and CD4(+) CD25(high+) T cell frequencies were detected in peripheral blood associated with decreased interferon-γ production of leukocytes. Secondary third-party kidney transplants more than 2 years after pulmonary transplantation were acutely rejected despite maintained tolerance of the lung allografts. As a cellular control, additional animals received third-party splenocytes or donor splenocyte protein extracts. While animals treated with third-party splenocytes showed significant graft survival prolongation, the subcellular antigen infusion showed no such effect. In conclusion, minipigs conditioned with preoperative IRR and donor, or third-party, splenocyte infusions may develop long-term donor-specific pulmonary allograft survival in the presence of high levels of circulating regulatory T cells.
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Quimerismo , Supervivencia de Injerto/inmunología , Isoantígenos/inmunología , Trasplante de Pulmón , Linfocitos T Reguladores/efectos de la radiación , Animales , Femenino , Terapia de Inmunosupresión , Masculino , Modelos Animales , Porcinos , Porcinos Enanos , Linfocitos T Reguladores/inmunología , Donantes de Tejidos , Tolerancia al Trasplante , Trasplante Homólogo , Irradiación Corporal TotalRESUMEN
Ceftolozane is a novel cephalosporin with activity against drug-resistant pathogens, including Pseudomonas aeruginosa and Streptococcus pneumoniae. The in vivo investigation reported here tested the limits of this drug against 20 P. aeruginosa and S. pneumoniae isolates across a wide MIC range and defined resistance mechanisms. The times above the MIC (T>MIC) targets for stasis and 1- and 2-log reductions were 31%, 39%, and 42% for P. aeruginosa and 18%, 24%, and 27% for S. pneumoniae, respectively. The 1-log endpoint was achieved for strains with MICs as high as 16 µg/ml.
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Antibacterianos/farmacología , Cefalosporinas/farmacología , Pseudomonas aeruginosa/efectos de los fármacos , Streptococcus pneumoniae/efectos de los fármacos , Pruebas de Sensibilidad MicrobianaRESUMEN
BACKGROUND: Analyses of the molecular basis underlying allergenicity and allergen cross-reactivity, as well as improvement of allergy diagnostics and therapeutics, are hampered by the lack of human monoclonal IgE antibodies and knowledge about their epitopes. Here, we addressed the consecutive generation and epitope delineation of a human monoclonal IgE against the prototypic allergen Bet v 1. METHODS: Phage-display scFv hybrid libraries of allergic donor-derived VH epsilon and synthetic VL were established from 107 mononuclear cells. An obtained scFv was converted into human immunoglobulin formats including IgE. Using variants of Bet v 1, the epitope of the antibody was mapped and extrapolated to other PR10 proteins. RESULTS: The obtained antibodies exhibited pronounced reactivity with Bet v 1, but were not reactive with the homologous PR10 protein Mal d 1. The epitope as defined by the IgE paratope and a set of chimeric Bet v 1 fusion proteins and fragments could be assigned to a C-terminal helix-structured motif comprised by amino acid residues 132-154, including the critical residue E149. Grafting this motif re-established the reactivity of the per se nonreactive Mal d 1 framework. Cross-reactivities predicted by primary structure analyses of different isoforms and PR10 proteins were verified by allergen chip-based analyses. CONCLUSIONS: The obtained results demonstrate that hybrid IgE repertoires represent a source for human antibodies with genuine paratopes. The IgE-derived information about the IgE epitope nature of Bet v 1 and homologues allows for detailed insights into molecular aspects of allergenicity and cross-reactivity within the PR10 protein family.
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Alérgenos/inmunología , Antígenos de Plantas/inmunología , Epítopos/inmunología , Fagus/inmunología , Inmunoglobulina E/inmunología , Proteínas de Plantas/inmunología , Alérgenos/química , Secuencia de Aminoácidos , Especificidad de Anticuerpos , Antígenos de Plantas/química , Reacciones Cruzadas/inmunología , Epítopos/química , Biblioteca de Genes , Humanos , Inmunoglobulina E/química , Inmunoglobulina E/genética , Cadenas Pesadas de Inmunoglobulina/química , Cadenas Pesadas de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/química , Región Variable de Inmunoglobulina/genética , Modelos Moleculares , Datos de Secuencia Molecular , Biblioteca de Péptidos , Proteínas de Plantas/química , Conformación Proteica , Proteínas Recombinantes/genética , Proteínas Recombinantes/inmunología , Alineación de SecuenciaRESUMEN
The design of appropriate gene delivery systems is essential for the successful application of gene therapy to clinical medicine. Cationic lipid-mediated delivery is a viable alternative to viral vector-mediated gene delivery in applications where transient gene expression is desirable. However, cationic lipid-mediated delivery of DNA to post-mitotic cells such as neurons is often reported to be of low efficiency, due to the presumed inability of the DNA to translocate to the nucleus. Lipid-mediated delivery of RNA is an attractive alternative to non-viral DNA delivery in some clinical applications, because transit across the nuclear membrane is not necessary. Here we report a comparative investigation of cationic lipid-mediated delivery of RNA versus DNA vectors encoding the reporter gene green fluorescent protein (GFP) in Chinese Hamster Ovary (CHO) and NIH3T3 cells following chemical inhibition of proliferation, and in primary mixed neuronal cell cultures. Using optimized formulations and transfection procedures, we assess gene expression by flow cytometry to specifically address some of the advantages and disadvantages of lipid-mediated RNA and DNA gene transfer. Despite inhibition of cell proliferation, over 45% of CHO cells express GFP after lipid-mediated transfection with RNA vectors. Transfection efficiency of DNA encoding GFP in proliferation-inhibited CHO cells was less than 5%. Detectable expression after RNA transfection occurs at least 3h earlier than after DNA transfection, but DNA transfection eventually produces a mean level of per cell GFP expression (as assayed by flow cytometry) that is higher than after RNA transfection. Transfection of proliferation-inhibited NIH3T3 cells and primary mixed neuronal cultures produced similar results, with RNA encoded GFP expression in 2-4 times the number of cells as after DNA encoded GFP expression. These results demonstrate the increased efficiency of RNA transfection relative to DNA transfection in non-dividing cells. We used firefly luciferase encoded by RNA and DNA vectors to investigate the time course of gene expression after delivery of RNA or DNA to primary neuronal cortical cells. Delivery of mRNA resulted in rapid onset (within 1h) of luciferase expression after transfection, a peak in expression 5-7h after transfection, and a return to baseline within 12h after transfection. After DNA delivery significant luciferase activity did not appear until 7h after transfection, but peak luciferase expression was always at least one order of magnitude higher than after RNA delivery. The peak expression after luciferase-expressing DNA delivery occurred 36-48 h after transfection and remained at a significant level for at least one week before dropping to baseline. This observation is consistent with our in vivo delivery results, which are shown as well. RNA delivery may therefore be more suitable for short-term transient gene expression due to rapid onset, shorter duration of expression and greater efficiency, particularly in non-dividing cells. Higher mean levels of expression per cell obtained following DNA delivery and the longer duration of expression confirm a continuing role for DNA gene delivery in clinical applications that require longer term transient gene expression.
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ADN/administración & dosificación , Regulación de la Expresión Génica , Técnicas de Transferencia de Gen , ARN/administración & dosificación , Animales , Células CHO , Cricetinae , Cricetulus , Citometría de Flujo , Terapia Genética/métodos , Vectores Genéticos/química , Proteínas Fluorescentes Verdes/metabolismo , Lípidos/química , Ratones , Células 3T3 NIH , Ratas , Ratas Sprague-Dawley , Factores de Tiempo , TransfecciónRESUMEN
OBJECTIVE: To investigate the costs to society of Alzheimer disease (AD) care in a multinational, randomized, placebo-controlled trial of donepezil in patients with moderate to severe AD. METHODS: A total of 290 patients with AD (screening standardized Mini-Mental State Examination score 5 to 17) were randomized to receive either donepezil (n = 144; 5 mg/day for 28 days, followed by 10 mg/day as per clinician's judgment) or placebo (n = 146) for 24 weeks. The authors collected data on patient and caregiver health resource utilization prospectively using the Canadian Utilization of Services Tracking questionnaire. Costs were calculated for patients and caregivers in each group based on resource utilization multiplied by the unit prices for each resource. A cost (the average Ontario minimum wage for 1998 [Can 6.85 dollars per hour]) was assigned to unpaid time that caregivers spent assisting the patient with activities of daily living (ADL). RESULTS: Patient and caregiver demographics at baseline were similar across the two groups. After adjusting for baseline total cost per patient, the mean total societal cost per patient for the 24-week period was donepezil, Can 9,904 dollars (US 6,686 dollars) and placebo, Can 10,236 dollars (US 6,910 dollars). This net cost saving of Can 332 dollars (US 224 dollars) included the average 24-week cost of donepezil treatment. Most of the cost-saving with donepezil treatment was due to less use of residential care by patients, and caregivers spending less time assisting patients with ADL. CONCLUSION: This cost-consequence analysis reveals economic benefits of treatment of moderate to severe AD with donepezil.
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Enfermedad de Alzheimer/economía , Inhibidores de la Colinesterasa/economía , Costo de Enfermedad , Recursos en Salud/economía , Indanos/economía , Nootrópicos/economía , Piperidinas/economía , Actividades Cotidianas , Anciano , Enfermedad de Alzheimer/tratamiento farmacológico , Atención Ambulatoria/economía , Australia , Canadá , Cuidadores/economía , Inhibidores de la Colinesterasa/uso terapéutico , Análisis Costo-Beneficio , Consejo/economía , Donepezilo , Costos de los Medicamentos , Femenino , Francia , Recursos en Salud/estadística & datos numéricos , Servicios de Atención de Salud a Domicilio/economía , Atención Domiciliaria de Salud/economía , Hospitalización/economía , Humanos , Indanos/uso terapéutico , Institucionalización/economía , Masculino , Persona de Mediana Edad , Nootrópicos/uso terapéutico , Casas de Salud/economía , Piperidinas/uso terapéutico , Estudios Prospectivos , Encuestas y CuestionariosRESUMEN
OBJECTIVE: To investigate the efficacy and safety of donepezil in a subgroup of patients with Alzheimer's disease (AD) of moderate severity from a previous trial. METHODS: Two hundred and seven patients with moderate AD (standardized Mini-Mental State Examination [sMMSE] score 10-17) were randomized to treatment in this 24-week, double-blind, placebo-controlled trial. Patents received either donepezil, 5 mg/day for the first 28 days and 10 mg/day thereafter according to the clinician's judgement (n = 102), or placebo (n = 105). The primary outcome measure was the Clinician's Interview-Based Impression of Change with caregiver input (CIBIC-plus) at week 24 using a last observation carried forward (LOCF) analysis. RESULTS: Baseline patient demographics were similar between treatment groups. Mean age was 74.3 years (range 48-92). Least-squares (LS) mean sMMSE scores at baseline were 13.6 +/- 0.3 for the donepezil group and 13.9 +/- 0.3 for the placebo group. LS mean CIBIC-plus scores for donepezil-treated patients were improved from, or close to, baseline severity at all visits, and were significantly different from placebo at weeks 8, 12, 18, and 24 (week 24 LOCF mean difference = 0.53, p = 0.0003). LS mean change from baseline scores on the sMMSE and Severe Impairment Battery (SIB) for the donepezil group improved throughout the study, and were significantly different from placebo at each visit for the sMMSE (week 24 LOCF mean difference = 2.06, p = 0.0002) and from week 8 for the SIB (week 24 LOCF mean difference = -4.44, p = 0.0026). LS mean change scores on the Disability Assessment for Dementia remained at or above baseline levels throughout the study for the donepezil group, while the placebo group showed a steady decline; treatment differences were significant at each visit (week 24 LOCF mean difference = -9.25, p < 0.0001). LS mean change scores on the Neuropsychiatric Inventory 12-item total improved throughout the study for the donepezil group and were significantly different from placebo at weeks 4 and 24 (week 24 LOCF mean difference = 5.92, p = 0.0022). Eighty-one per cent of donepezil-treated and 89% of placebo-treated patients completed the trial, with 9% and 5%, respectively, discontinuing due to adverse events (AEs). Eighty-two per cent of donepezil-treated and 80% of placebo-treated patients experienced AEs, the majority of which were rated mild in severity and, in general, were similar between treatment groups. CONCLUSION: The significant treatment responses observed with donepezil in these patients reinforce the findings from earlier studies that show donepezil to have important benefits, compared wih placebo, across functional, cognitive, and behavioral symptoms, with good tolerability, in patients with AD of moderate severity.
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Enfermedad de Alzheimer/tratamiento farmacológico , Conducta/efectos de los fármacos , Cognición/efectos de los fármacos , Indanos/uso terapéutico , Nootrópicos/uso terapéutico , Piperidinas/uso terapéutico , Actividades Cotidianas , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/fisiopatología , Donepezilo , Método Doble Ciego , Femenino , Humanos , Indanos/efectos adversos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Piperidinas/efectos adversos , Índice de Severidad de la EnfermedadAsunto(s)
Antígenos CD55/genética , Proteínas Inactivadoras del Complemento 1/uso terapéutico , Rechazo de Injerto/prevención & control , Trasplante de Riñón/inmunología , Trasplante Heterólogo/inmunología , Enfermedad Aguda , Animales , Animales Modificados Genéticamente , Antígenos CD/genética , Proteína Inhibidora del Complemento C1 , Inhibidores de Cisteína Proteinasa/uso terapéutico , Quimioterapia Combinada , Rechazo de Injerto/inmunología , Terapia de Inmunosupresión/métodos , Trasplante de Riñón/patología , Macaca fascicularis , Porcinos , Trasplante Heterólogo/patologíaRESUMEN
OBJECTIVE: To describe the process of training for measuring nuchal translucency at five clinical centers in North America and to evaluate methods of quality assurance and feedback. DESIGN: Throughout a period of 18 months, the performance of sonographers in measuring fetal nuchal translucency was monitored using qualitative and quantitative methods of review. After 12 months, different approaches (written and personal feedback) were used to inform sonographers of technical aspects that needed to or could be improved. RESULTS: On initial qualitative review, discrepancies in judgment from different reviewers coincided with suboptimal magnification, failure to visualize the amniotic membrane and/or use of cross-shaped calipers. At subsequent global review, 13 (29%) images of nuchal translucency measurements were considered unacceptable. Quantitative assessment revealed that, during the first part of the study, the means from four sonographers were significantly smaller and the mean from the fifth sonographer was significantly larger than expected on the basis of findings from The Fetal Medicine Foundation (P < 0.0001). Following feedback, sonographers who underestimated nuchal translucency and who received a written report only did not change measurements overall (P = 0.9759). In contrast, those who received additional intervention showed a marked difference (P < 0.0001). CONCLUSIONS: Global qualitative review of images from one sonographer may be preferable to assessment of individual aspects of images. Results from global qualitative review correspond well with findings from quantitative analysis, indicating that the latter can be applied for ongoing audit. Observation of divergent results should prompt extensive personal feedback, rather than a written report, to prevent sonographers from settling in their own, inappropriate technique.
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Técnicos Medios en Salud/educación , Cuello/diagnóstico por imagen , Garantía de la Calidad de Atención de Salud/métodos , Trisomía/diagnóstico , Ultrasonografía Prenatal/normas , Análisis de Varianza , Retroalimentación , Femenino , Humanos , Cuello/embriología , Embarazo , Primer Trimestre del Embarazo/fisiologíaRESUMEN
At present, the major barrier to successful discordant xenotransplantation of unmodified or complement regulator transgenic porcine xenografts is acute vascular xenograft rejection (AVR). AVR is associated with the intragraft deposition of induced recipient xenoreactive antibodies and subsequent complement activation. In a life-supporting pig to primate kidney xenotransplantation setting using h-DAF transgenic donor organs and postoperative immunosuppression, episodes of AVR were either treated with boluses of cyclophosphamide and steroids or with the same regimen supplemented by a three-day course of C1-Inhibitor, a multifunctional complement regulator. In 8 out of 10 animals stable initial graft function was achieved; in all animals one or more episodes of AVR were observed. When, in 4 animals, C1-Inhibitor was added to the standard anti-rejection treatment regimen, AVR was successfully reversed in 6 out of 7 episodes, while in another group of 4 animals receiving the standard anti-rejection treatment 0 out of 4 episodes of AVR responded to treatment. Response to anti-rejection treatment was associated with a significant increase in recipient survival time. We conclude that AVR of h-DAF transgenic porcine kidneys can be successfully treated by additional short-term fluid phase complement inhibition.
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Anticuerpos Heterófilos/inmunología , Antígenos CD55/fisiología , Rechazo de Injerto/prevención & control , Inmunosupresores/uso terapéutico , Trasplante de Riñón/inmunología , Riñón/irrigación sanguínea , Inhibidores de Serina Proteinasa/farmacología , Trasplante Heterólogo/inmunología , Animales , Animales Modificados Genéticamente , Antígenos CD55/genética , Activación de Complemento/efectos de los fármacos , Ciclofosfamida/uso terapéutico , Ciclosporina/uso terapéutico , Quimioterapia Combinada , Humanos , Inmunosupresores/administración & dosificación , Pruebas de Función Renal , Macaca fascicularis , Metilprednisolona/uso terapéutico , Prednisolona/uso terapéutico , Proteínas Recombinantes de Fusión/fisiología , Porcinos , Factores de TiempoRESUMEN
Clinical trials and independent reviews support the use of cholinesterase inhibitors for treating the symptoms of patients with mild to moderate Alzheimer's disease (AD). Before initiating cholinesterase inhibitor therapy, patients should be thoroughly assessed, and the diagnosis confirmed, preferably by a specialist. Compliance with cholinesterase inhibitor therapy should be monitored and the response (in global, cognitive, functional and behavioural domains) reassessed after 2-3 months of treatment. Vitamin E may be protective against AD, and therapy with 1000 IU twice daily may be considered. There is insufficient evidence to support the use of other antioxidant agents, anti-inflammatory agents, monoamine oxidase B inhibitors, folate/homocysteine or antihypertensive drugs in patients with AD, or hormone replacement therapy in affected women.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de la Colinesterasa/uso terapéutico , Humanos , Guías de Práctica Clínica como Asunto , Estados Unidos , United States Food and Drug AdministrationRESUMEN
OBJECTIVE: To investigate the efficacy and safety of donepezil in patients with moderate to severe AD (standardized Mini-Mental State Examination [sMMSE] scores of 5 to 17; Functional Assessment Staging score < or =6 at baseline). METHODS: Two-hundred ninety patients were randomized to treatment in this 24-week, double-blind, placebo-controlled trial. Patients received either donepezil 5 mg/day for the first 28 days and 10 mg/day thereafter as per the clinician's judgment (n = 144) or placebo (n = 146). The primary outcome measure was the Clinician's Interview-Based Impression of Change with caregiver input (CIBIC+). RESULTS: Patients' mean age was 73.6 years (range 48 to 92 years). Baseline demographics were similar between the treatment groups. Least squares (LS) mean +/- SE sMMSE scores at baseline were 11.7 +/- 0.35 for the donepezil group and 12.0 +/- 0.34 for the placebo group. Patients receiving donepezil showed benefits on the CIBIC+, compared with placebo, at all visits up to week 24 (p < 0.001) and at week 24 last observation carried forward (LOCF) (p < 0.0001). All other secondary measures (including sMMSE, Severe Impairment Battery, Disability Assessment for Dementia, Functional Rating Scale, and Neuropsychiatric Inventory) showed significant differences between the groups in favor of donepezil at week 24 LOCF. Eighty-four percent of donepezil- and 86% of placebo-treated patients completed the trial. Adverse events (AE) were experienced by 83% of donepezil- and 80% of placebo-treated patients, the majority of which were rated mild in severity; 8% of donepezil- and 6% of placebo-treated patients discontinued because of AE. Laboratory and vital sign abnormalities were similar between the treatment groups. CONCLUSION: These data suggest that donepezil's benefits extend into more advanced stages of AD than those previously investigated, with very good tolerability.