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PURPOSE: Cystic fibrosis (CF), caused by pathogenic variants in the CF transmembrane conductance regulator (CFTR), affects multiple organs including the exocrine pancreas, which is a causal contributor to cystic fibrosis-related diabetes (CFRD). Untreated CFRD causes increased CF-related mortality whereas early detection can improve outcomes. METHODS: Using genetic and easily accessible clinical measures available at birth, we constructed a CFRD prediction model using the Canadian CF Gene Modifier Study (CGS; n = 1,958) and validated it in the French CF Gene Modifier Study (FGMS; n = 1,003). We investigated genetic variants shown to associate with CF disease severity across multiple organs in genome-wide association studies. RESULTS: The strongest predictors included sex, CFTR severity score, and several genetic variants including one annotated to PRSS1, which encodes cationic trypsinogen. The final model defined in the CGS shows excellent agreement when validated on the FGMS, and the risk classifier shows slightly better performance at predicting CFRD risk later in life in both studies. CONCLUSION: We demonstrated clinical utility by comparing CFRD prevalence rates between the top 10% of individuals with the highest risk and the bottom 10% with the lowest risk. A web-based application was developed to provide practitioners with patient-specific CFRD risk to guide CFRD monitoring and treatment.
Asunto(s)
Fibrosis Quística , Diabetes Mellitus , Biomarcadores , Canadá , Fibrosis Quística/complicaciones , Fibrosis Quística/diagnóstico , Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Diabetes Mellitus/epidemiología , Diabetes Mellitus/genética , Estudio de Asociación del Genoma Completo , Humanos , Recién NacidoRESUMEN
With increasing life expectancy and the need for lung transplantation in the cystic fibrosis (CF) population, there are increasing reports of chronic kidney disease (CKD). However, values for baseline or longitudinal glomerular filtration rate (GFR) as measured by exogenous clearance markers are lacking in this population. Retrospective cross-sectional study in 2 to 18-year-olds cared for at a single CF center who had a GFR measured by plasma disappearance of Technetium-99 m diethylenetriaminepentaacetic acid (mGFR). The primary outcome was evidence of renal dysfunction as defined by CKD stage II or below (mGFR <90 ml/min/1.73 m(2), persistent abnormalities in urinary sediment, abnormal renal imaging). Of 63 patients evaluated, four had apparent renal dysfunction, one demonstrated decreased mGFR, and three others had persistent microscopic hematuria. The mean mGFR was substantially higher (140 ± 24 ml/min/1.73 m(2)) than expected or previously reported for healthy children. We did not demonstrate the presence of significant renal impairment after limited aminoglycoside exposure in the first decade following diagnosis with CF. However, we did document the presence of glomerular hyperfiltration in a significant proportion of our CF patients.
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Fibrosis Quística/complicaciones , Tasa de Filtración Glomerular , Enfermedades Renales/epidemiología , Adolescente , Niño , Preescolar , Estudios Transversales , Fibrosis Quística/fisiopatología , Femenino , Humanos , Enfermedades Renales/etiología , Enfermedades Renales/fisiopatología , Pruebas de Función Renal , Masculino , Prevalencia , Estudios RetrospectivosRESUMEN
Newborn screening for Cystic Fibrosis has been implemented in most programs worldwide, but the approach used varies, including combinations of immunoreactive trypsinogen (IRT) and CFTR mutation analysis on one or more specimens. The British Columbia (BC) newborn screening program tests ~45,000 infants per year in BC and the Yukon Territory, covering almost 1.5 million km2 in western Canada. CF screening was initiated using an IRT-DNA-IRT approach with a second bloodspot card at 21 days of age for all CFTR mutation heterozygotes and any non-carriers in the top 0.1% for IRT. This second IRT was implemented to avoid sweat testing of infants without persistent hypertrypsinemia, reducing the burden of travel for families. Over nine years (2010-2018), 401,977 infants were screened and CF was confirmed in 76, and a further 28 were deemed CF screen positive inconclusive diagnosis (CFSPID). Day 21 IRT was normal in 880 CFTR mutation carriers who were quoted a very low CF risk and offered optional sweat testing. Only 13% of families opted for sweat testing and a total of 1036 sweat tests were avoided. There were six false negative CF cases (and three CFSPID) due to a low initial IRT or no CFTR mutations. Although one CFSPID case had a normal repeat IRT result, the addition of the day 21 IRT did not contribute to any CF false negatives.
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Understanding patient decision making with respect to clinical trial participation has the potential to improve both the efficiency of recruitment for clinical trials and their management. In this mini-review we consider 3 key factors influencing clinical trial recruitment outcomes that include; 1) patient personal characteristics, 2) enabling factors that involve patient centered attitudes or circumstances, and 3) aversion. These factors are explored across both Australian rural and urban settings and contrasted to reported outcomes from research across other countries. Australia has the lowest number of publications on rural clinical trial participation when compared to rural research in America and Canada. Across Australian urban areas where all 3 factors have been studied, trends are similar to those reported in other developed countries. In conclusion we suggest that trial participation could be improved if participants are better informed about a trial as this is a valuable factor to enable recruitment.
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Ensayos Clínicos como Asunto/métodos , Toma de Decisiones , Participación del Paciente/psicología , Australia , Canadá , Conocimientos, Actitudes y Práctica en Salud , HumanosRESUMEN
This article is concerned with forensic medical evidence and the several forms in which it was supplied to courts in early modern England. A specific trial is described and interpreted in detail, with particular attention being given to the kinds of information derived from the decomposed body of a young Quaker woman, believed either to have drowned or been murdered. The role of medical and lay evidence is evaluated and attention directed towards the ways in which the proceedings were recounted and recycled in post-trial publications. Major themes include popular attitudes towards dissection, the roles of lay and professional witnesses and the role of women as traditional sources of knowledge about the body.