Onset of persistent pseudomonas aeruginosa infection in children with cystic fibrosis with interval censored data.

BACKGROUND: Persistent Pseudomonas aeruginosa (PPA) infection promotes lung function deterioration in children with cystic fibrosis (CF). Although early CF diagnosis through newborn screening (NBS) has been shown to provide nutritional/growth benefit, it is unclear whether NBS lowers the risk of PPA infection and how the effect of NBS vary with age. Modeling the onset age of PPA infection is challenging because 1) the onset age of PPA infection is interval censored in patient registry data; and 2) some risk factors such as NBS may have time-varying effects. METHODS: This problem fits into the framework of a recently developed Bayesian dynamic Cox model for interval censored data, where each regression coefficient is allowed to be time-varying to an extent determined by the data. RESULTS: Application of the methodology to data from the CF Foundation Patient Registry revealed interesting findings. Compared with patients with meconium ileus or diagnosed through signs or symptoms, patients diagnosed through NBS had significantly lower risks of acquiring PPA infection between age 1 and 2 years, and the benefit in survival rate was found to last up to age 4 years. Two cohorts of five years apart were compared. Patients born in cohort 2003-2004 had significantly lower risks of the PPA infections at any age up to 4 years than those born in 1998-1999. CONCLUSIONS: The study supports benefits of NBS on PPA infection in early childhood. In addition, our analyses demonstrate that patients in the more recent cohort had significantly lower risks of acquiring PPA infection up to age 4 years, which suggests improved CF treatment and care over time.

Cytosol-localized heat shock factor-binding protein, AtHSBP, functions as a negative regulator of heat shock response by translocation to the nucleus and is required for seed development in Arabidopsis.

Heat shock response (HSR) is a universal mechanism in all organisms. It is under tight regulation by heat shock factors (HSFs) and heat shock proteins (HSPs) after heat shock (HS) to prevent stress damage. On the attenuation of HSR, HSP70 and HSF Binding Protein1 (HSBP1) interact with HSF1 and thus dissociate trimeric HSF1 into an inert monomeric form in humans. However, little is known about the effect of HSBP with thermal stress in plants. This report describes our investigation of the role of AtHSBP in Arabidopsis (Arabidopsis thaliana) by genetic and molecular approaches. AtHSBP was heat inducible and ubiquitously expressed in all tissues; AtHSBP was also crucial for seed development, as demonstrated by AtHSBP-knockout lines showing seed abortion. Thermotolerance results showed that AtHSBP participates in acquired thermotolerance but not basal thermotolerance and is a negative regulator of HSR. Subcellular localization revealed that the cytosol-localized AtHSBP translocated to the nucleus in response to HS. Protoplast two-hybrid assay results confirmed that AtHSBP interacts with itself and with the HSFs, AtHSFA1a, AtHSFA1b, and AtHSFA2. AtHSBP also negatively affected AtHSFA1b DNA-binding capacity in vitro. Quantitative polymerase chain reaction and western-blot analysis demonstrated that altered levels of AtHSBP lead to differential HSP expression, mainly during the recovery from HS. These studies provide a new insight into HSBP in plants and reveal that AtHSBP is a negative regulator of HSR and required for seed development.

Longitudinal evaluation of bronchopulmonary disease in children with cystic fibrosis.

Children with cystic fibrosis (CF) develop bronchopulmonary disease at variable ages. Determining the epidemiology of chronic lung disease and quantifying its severity, however, have been difficult in infants and young children. As part of the Wisconsin CF Neonatal Screening Project, we were presented with an ideal opportunity to assess longitudinally the evolution of symptoms, signs, and quantitative measures of CF respiratory disease. After newborn screening test results led to early recognition, 64 patients diagnosed at a median age of 6.71 weeks were enrolled and studied systematically at a median age of 11.3 years to obtain clinical information, chest radiographs, and pulmonary function tests. Our observations revealed that a frequent cough by history is evident by 10.5 months of age in half the patients. Quantitative chest radiology (CXR scoring) demonstrated that potentially irreversible abnormalities are present in half the children by 2 years. The severity of Wisconsin and Brasfield CXR scores increased in association with respiratory infections. Longitudinal progression of Wisconsin CXR scores was related to age (P < 0.001), pancreatic insufficiency (P = 0.005), and respiratory secretion cultures positive for Staphylococus aureas (P = 0.039). In contrast, serial spirometry showed limited sensitivity, as did lung volume determinations; neither was satisfactory as repeated measures with acceptable quality control until after 7 years of age. Time to event analyses revealed that half the patients had % predicted FEF(25-75) and FEV(1)/FVC values greater than 80% until 10.7 and 9.9 years, respectively. We conclude that of the methods evaluated, quantitative chest radiology is currently the best procedure for frequent assessment of bronchopulmonary disease in CF, and that radiographic progression is evident in approximately 85% of patients by 5 years of age. Our results also suggest that bronchiectasis and other radiographic evidence of chronic infection are apparent prior to airways obstruction in young CF patients.

Delayed diagnosis of US females with cystic fibrosis.

This study was conducted to examine a patient's age and condition at the time of diagnosis as one potential factor contributing to the "gender gap" in cystic fibrosis. The study population consisted of 11,275 US patients diagnosed during 1986-1998 and reported to the Cystic Fibrosis Foundation Registry in the same or the following calendar year. Parallel analyses were performed for Wisconsin patients identified prospectively during 1985-1994 to obtain more detailed information on their condition at diagnosis. Analyses of the registry data showed that females identified because of symptoms other than meconium ileus were diagnosed at significantly older ages (median, 12.7 months) than were males (median, 8.7 months) (p < 0.001). The delay in diagnosis for females was most evident among patients presenting with respiratory symptoms only (median, 40.7 vs. 22.3 months; p < 0.001). Analyses of Wisconsin patients demonstrated no significant gender differences in cough and wheezing experiences or in chest radiographic severity scores between males and females during their first 10 years of life, although a disproportionately high number of males were referred for diagnostic sweat testing. A delay in diagnosis of females with cystic fibrosis was discovered, suggesting either differential recognition of respiratory symptoms or a gender bias.

Bronchopulmonary disease in children with cystic fibrosis after early or delayed diagnosis.

Although early diagnosis of cystic fibrosis (CF) can lead to nutritional benefits, there has been uncertainty about pulmonary outcomes. Using a randomized controlled trial with unique unblinding/surveillance, we evaluated patients with CF who received similar treatment after being assigned to an early diagnosis (screened) group or to a standard diagnosis (control) group. When the youngest patient was 7 years of age, we compared outcomes using pulmonary function data and quantitative chest radiology. In the screened group (56 patients), diagnosis was made at a younger age of 12.4 weeks, compared with the diagnosis in control group (47 control patients) at the age of 95.8 weeks, but included a significantly greater proportion of patients with deltaF508 genotypes and pancreatic insufficiency. The first chest radiograph showed significantly fewer abnormalities in the screened group; but, over time, the two groups converged, and after 10 years of age the screened patients showed worse chest X-ray scores associated with earlier acquisition of Pseudomonas aeruginosa. No differences were detected in any measure of pulmonary dysfunction, which was generally mild in each group. Although CF neonatal screening provides a potential opportunity for better pulmonary outcomes, it appears that respiratory infections and pancreatic status are the dominant factors in pulmonary prognosis.

Cognitive function of children with cystic fibrosis: deleterious effect of early malnutrition.

OBJECTIVE: Patients who have cystic fibrosis (CF) and experience delayed diagnosis by traditional methods have greater nutritional insult compared with peers diagnosed via neonatal screening. The objective of this study was to evaluate cognitive function in children with CF and the influence of both early diagnosis through neonatal screening and the potential effect of early malnutrition. METHODS: Cognitive assessment data were obtained for 89 CF patients (aged 7.3-17 years) during routine clinic visits. Patients had been enrolled in either the screened (N = 42) or traditional diagnosis (control) group (N = 47) of the Wisconsin CF Neonatal Screening Project. The Test of Cognitive Skills, Second Edition was administered to generate the Cognitive Skills Index (CSI) and cognitive factor scores (Verbal, Nonverbal, and Memory). RESULTS: Cognitive scores in the overall study population were similar to normative data (CSI mean [standard deviation]: 102.5 [16.6]; 95% confidence interval: 99.1-105.9). The mean (standard deviation) CSI scores for the screened and control groups were 104.4 (14.4) and 99.8 (18.5), respectively. Significantly lower cognitive scores correlated with indicators of malnutrition and unfavorable family factors such as single parents, lower socioeconomic status, and less parental education. Our analyses revealed lower cognitive scores in patients with low plasma alpha-tocopherol (alpha-T) levels at diagnosis. In addition, patients in the control group who also had vitamin E deficiency at diagnosis (alpha-T < 300 microg/dl) showed significantly lower CSI scores in comparison with alpha-T-sufficient control subjects and both deficient and sufficient alpha-T subsets of screened patients. CONCLUSION: Results suggest that prevention of prolonged malnutrition by early diagnosis and nutritional therapy, particularly minimizing the duration of vitamin E deficiency, is associated with better cognitive functioning in children with CF.