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Biomedical subjects

P M Farrell

Publications and source records attributed to P M Farrell.

At least 19 recordsLinked to original sources
PubMed2006

Analysis of changes in optical fibers during arc-fusion splicing by use of quantitative phase imaging.

A non-interferometric imaging technique in conjunction with Abel inversion is used to directly and quantitatively examine the changes in optical fibers due to the heating produced during arc-fusion splicing as a function of fusion arc parameters. Phase images in the vicinity of a fusion splice are obtained using Quantitative Phase Microscopy, allowing the refractive-index change to be reconstructed with high spatial resolution. This simple, nondestructive method confirms that, for a fixed arc current, while the fusion time increases, the refractive-index of both fiber cores within the fusion region decreases in magnitude, the core region broadens, and the axial gradient decreases.

Journal Article↗
PubMed2005

Early immune response to the components of the type III system of Pseudomonas aeruginosa in children with cystic fibrosis.

The lungs of patients with cystic fibrosis (CF) are colonized initially by Pseudomonas aeruginosa, which is associated with progressive lung destruction and increased mortality. The pathogenicity of P. aeruginosa is caused by a number of virulence factors, including exotoxin A (ETA) and the type III cytotoxins (ExoS, ExoT, ExoU, and ExoY). P. aeruginosa contacts the plasma membrane to deliver type III cytotoxins through a channel formed by PopB, PopD, and PcrV; ETA enters mammalian cells via receptor-mediated endocytosis. The Wisconsin CF Neonatal Screening Project is a longitudinal investigation to assess the potential benefits and risks of newborn screening for CF; the project was the source of serum samples used in this study. Past studies evaluated the longitudinal appearance of antibodies to ETA and elastase and P. aeruginosa infections in patients with CF. The current study characterized the longitudinal appearance of antibodies to components of the type III system in children with CF. Western blot analyses showed that serum antibodies to PopB, PcrV, and ExoS were common. Longitudinal enzyme-linked immunosorbent assays determined that the first detection of antibodies to pooled ExoS/PopB occurred at a time similar to those of detection of antibodies to a P. aeruginosa cell lysate and the identification of oropharyngeal cultures positive for P. aeruginosa. This indicates that children with CF are colonized early with P. aeruginosa expressing the type III system, implicating it in early pathogenesis, and implies that surveillance of clinical symptoms, oropharyngeal cultures, and seroconversion to type III antigens may facilitate early detection of P. aeruginosa infections.

ADP Ribose Transferases↗
PubMed2001

Acceleration of lung disease in children with cystic fibrosis after Pseudomonas aeruginosa acquisition.

As part of the ongoing Wisconsin Cystic Fibrosis (CF) Neonatal Screening Project, we had the unique opportunity to study the longitudinal relationship between Pseudomonas aeruginosa (Pa) acquisition and infection and developing lung disease in children with CF. The primary objective was to determine whether acquisition of Pa was associated with a measurable change in the progression of lung disease. Two outcome measures were used to study 56 patients who were diagnosed through newborn screening: 1) Wisconsin additive chest radiograph score (WCXR), based on the average of scores from a pulmonologist and a radiologist, and 2) the highest forced expired volume in 1 sec (FEV(1))/forced vital capacity (FVC) ratio. We used two measures of Pa acquisition: 1) time of first positive protocol-determined oropharyngeal (with cough) culture, and 2) the magnitude of antibody titer detected by ELISA assays, using as antigen a crude cell lysate, purified exotoxin A, or an elastase toxoid prepared from three Pa strains. Other predictor variables included age, pancreatic status, height-for age, and weight-for-age-percentiles. The best regression model for predicting changes in the WCXR included time to first positive culture and antibody titer for Pa elastase. Prior to Pa acquisition, WCXR worsened by 0.45 points/year (P > 0.25); after Pa acquisition, the rate of worsening increased significantly (P < 0.001) to 1.40 points/year. Each antibody titer level (log base 2) increased the score by 0.48 points (P < 0.001). The best regression model for predicting change in the FEV(1)/FVC included only time to first positive culture. Prior to Pa acquisition, the FEV(1)/FVC ratio declined by 1.29%/year; after Pa infection, the rate of decrease significantly accelerated to 1.81%/year (P = 0.001). Our data show that Pa acquisition is associated with declining pulmonary status in children with CF, and that this effect is probably gradual rather than precipitous. Because these patients were diagnosed and treated aggressively, our estimates of the effects of Pa acquisition may be conservative. We also conclude that the WCXR appears to be more sensitive than FEV(1)/FVC in detecting early changes in lung disease associated with CF.

Age Distribution↗
PubMed2001

Early diagnosis of cystic fibrosis through neonatal screening prevents severe malnutrition and improves long-term growth. Wisconsin Cystic Fibrosis Neonatal Screening Study Group.

OBJECTIVE: Despite its relative frequency among autosomal recessive diseases and the availability of the sweat test, cystic fibrosis (CF) has been difficult to diagnose in early childhood, and delays can lead to severe malnutrition, lung disease, or even death. The Wisconsin CF Neonatal Screening Project was designed as a randomized clinical trial to assess the benefits and risks of early diagnosis through screening. In addition, the incidence of CF was determined, and the validity of our randomization method assessed by comparing 16 demographic variables. METHODOLOGY: Immunoreactive trypsinogen analysis was applied to dried newborn blood specimens for recognition of CF risk from 1985 to 1991 and was coupled to DNA-based detection of the DeltaF508 mutation from 1991 to 1994. Randomization of 650 341 newborns occurred when their blood specimens reached the Wisconsin screening laboratory. This created 2 groups-an early diagnosis, screened cohort and a standard diagnosis or control group. To avoid selection bias, we devised a unique unblinding method with a surveillance program to completely identify the control subjects. Because sequential analysis of nutritional outcome measures revealed significantly better growth in screened patients during 1996, we accelerated the unblinding and completely identified the control group by April 1998. Having each member of this cohort enrolled and evaluated for at least 1 year and having completed a comprehensive surveillance program, we performed another statistical analysis of anthropometric evaluated indices that includes all CF patients without meconium ileus. RESULTS: The incidence of classical CF, ie, patients diagnosed in this trial with a sweat chloride of 60 mEq/L greater, was 1:4189. By incorporating other CF patients born during the randomization period, including 2 autopsy diagnosed patients and 8 probable patients, we calculate a maximum incidence of 1:3938 (95% confidence interval: 3402-4611). Although there were group differences in the proportion of patients with DeltaF508 genotypes and with pancreatic insufficiency, validity of the randomization plan was demonstrated by analyzing 16 demographic variables and finding no significant difference after adjustment for multiple comparisons. Focusing on patients without meconium ileus, we found a marked difference in the mean +/- standard deviation age of diagnosis for screened patients (13 +/- 37 weeks), compared with the standard diagnosis group (100 +/- 117). Anthropometric indices of nutritional status were significantly higher at diagnosis in the screened group, including length/height, weight, and head circumference. During 13 years of study, despite similar nutritional therapy and the inherently better pancreatic status of the control group, analysis of nutritional outcomes revealed significantly greater growth associated with early diagnosis. Most impressively, the screened group had a much lower proportion of patients with weight and height data below the 10th percentile throughout childhood. CONCLUSIONS: Although the screened group had a higher proportion of patients with pancreatic insufficiency, their growth indices were significantly better than those of the control group during the 13-year follow-up evaluation and, therefore, this randomized clinical trial of early CF diagnosis must be interpreted as unequivocally positive. Our conclusions did not change when the height and weight data before 4 years of age for the controls detected by unblinding were included in the analysis. Also, comparison of growth outcomes after 4 years of age in all subjects showed persistence of the significant differences. Therefore, selection bias has been eliminated as a potential explanation. In addition, the results show that severe malnutrition persists after delayed diagnosis of CF and that catch-up may not be possible. We conclude that early diagnosis of CF through neonatal screening combined with aggressive nutritional therapy can result

Cystic Fibrosis↗
PubMed2001

Genetic counseling and neonatal screening for cystic fibrosis: an assessment of the communication process.

OBJECTIVE: To assess the effectiveness of communication between health care providers (physicians, nurses, genetic counselors) in Wisconsin and parents of children identified as heterozygote carriers for cystic fibrosis (CF) in the routine Wisconsin Newborn Screening Program that was implemented using trypsinogen/DNA testing. METHODS: Routine CF neonatal screening, implemented in July 1994, involved a statewide system that recommended but did not mandate follow-up sweat tests at 1 of the Wisconsin's 2 certified CF centers. The Wisconsin Division of Health sent requests to participate to the parents of 483 infants identified as CF carriers between July 1994 and December 1997. Of the 483 parents, 183 agreed to participate and were asked to complete a questionnaire assessing their CF newborn screening experiences and their knowledge of CF genetics and any changes they made in their reproductive behavior as a result of this knowledge. Follow-up telephone interviews by a genetic counselor were attempted within 1 year for those completing the questionnaire. RESULTS: Within 4 months after the mailing, 138 of 183 (75%) parents completed the questionnaire. Subsequently, 123 of the 138 responders (89%) were contacted and interviewed by telephone. We learned that 67.6% of parents recalled receiving genetic counseling, but 32.4% of parents apparently did not participate in a risk communication session. When asked, "Who performed the genetic counseling?" parents indicated that their communication was with physicians in 8% of cases, nurses in 12.4%, and certified genetic counselors in 32.8% of cases; 17.5% of parents did not recall who performed the genetic counseling and 29.2% of parents indicated they did not receive genetic counseling. Based on the 138 responses, it was found that 88.3% of parents understood that their child was a carrier for CF, but 15.4% of parents were unsure whether being a carrier could cause illness. In addition, 12.4% of parents were unsure whether at least 1 of them (parents) was a carrier of the CF gene. Only 57% of parents knew there was a 1 in 4 chance that their child could have a child with CF if he or she reproduced with another carrier of the CF gene. Statistically significant differences were noted when comparing the frequency of correct responses between parents who received genetic counseling and parents who had not. The frequency of accurate responses did not depend on which health care professional provided the genetic counseling. Comparing responses of parents who were seen at a certified CF center with parents seen at other community hospitals and clinics revealed significant differences in the frequency of correct responses, with the former group showing a higher percentage of correct responses. Telephone interviews revealed that 11.4% of parents were unaware that their child was a carrier for CF and that 54.5% wished they had more information made available to them at the time of the initial positive newborn screen result, before the definitive sweat test. Also, 13.8% of parents recommended that community physicians be better informed of the details and implications of positive screening results for CF. CONCLUSION: Genetic counseling is imperative for the success of newborn screening for CF and other congenital diseases. With the completion of the Human Genome Project, more molecular screening for childhood disease is bound to enter the clinical arena. Based on our findings, efforts must be made to ensure that newborn screening programs have the means and the methods to communicate newborn screening results effectively to families. In addition, both the general public and community health providers must be better informed of the implications of all newborn screening results. Additional research is needed to determine whether there are communication styles and approaches that are better suited to counseling parents regarding newborn screening results.

Adult↗
PubMed2001

Assessing the quality of life in children with cystic fibrosis.

Although patients with cystic fibrosis (CF) are experiencing increased longevity, it is unclear that improved quality of life (QoL) accompanies the greater quantity of life. This is especially true of children with CF where the burdens of treatment are substantial. Assessing QoL in such children is difficult, and only one instrument--the Quality of Well-Being (QWB) scale--seems to have been used extensively to assess QoL in children with CF. After thoroughly reviewing the literature, we surveyed the 113 certified CF centers in the United States about QoL assessment. With 84% responding, it was found that only 7 centers are assessing QoL--4 have been using the QWB instrument. Concurrently, we pilot tested the QWB instrument in children being followed longitudinally in the Wisconsin CF Neonatal Screening Project. Our results indicated that QWB scores reflecting QoL decreased as the number of respiratory infections increased, as the number of concurrent medical conditions increased, and as the number of different medications increased. However, we recognized problems with the assessed domains and data interpretation. In fact, the QWB instrument has limited sensitivity and responds more to the extent of physician-determined treatment than to QoL. There is a need for more QoL assessment and better instruments, particularly in young children with CF.

Child↗
PubMed2000

Risk of persistent growth impairment after alternate-day prednisone treatment in children with cystic fibrosis.

BACKGROUND: It is uncertain whether the growth impairment that occurs in children during long-term treatment with glucocorticoids persists after the medication is discontinued and ultimately affects adult height. METHODS: We evaluated growth six to seven years after alternate-day treatment with prednisone had been discontinued in 224 children 6 to 14 years of age with cystic fibrosis who had participated in a multicenter trial of this therapy from 1986 through 1991. Of the children, 151 had been randomly assigned to receive prednisone (either 1 or 2 mg per kilogram of body weight) and 73 to receive placebo. We obtained data on growth up to 1997 from the Cystic Fibrosis Foundation Patient Registry and standardized the data to sex- and age-specific norms from the National Center for Health Statistics. We used z scores to compare growth patterns among treatment groups. RESULTS: In 1997, 68 percent of the patients were 18 years of age or older. The z scores for height declined during prednisone therapy; catch-up growth began two years after treatment with prednisone was discontinued. Among the boys, the z scores for height in those treated with prednisone remained lower than the scores for those who received placebo (P=0.02). The mean heights for boys 18 years of age or older were 4 cm less in the prednisone groups than in the placebo group, an equivalent of 13 percentile points (P=0.03). Among the girls, differences in height between those who were treated with prednisone and those who received placebo were no longer present two to three years after prednisone therapy was discontinued. CONCLUSIONS: Among children with cystic fibrosis who have received alternate-day treatment with prednisone, boys, but not girls, have persistent growth impairment after treatment is discontinued.

Adolescent↗
PubMed2000

The magnitude and challenge of false-positive newborn screening test results.

OBJECTIVES: This study examined for the first time to our knowledge the national data available from newborn screening programs in the United States and determined the salient characteristics of various screening tests for 3 hereditary metabolic disorders and 2 congenital endocrinopathies with emphasis on positive predictive values (PPVs) to delineate the magnitude of false-positive results. METHODS: Reports published by the Council of Regional Networks for Genetic Services for 1990 through 1994 were examined carefully, paying particular attention to phenylketonuria, galactosemia, biotinidase deficiency, congenital hypothyroidism, and congenital adrenal hyperplasia (CAH). Because of recent improvements in data collecting, reporting, and tabulating, we used data from 1993 and 1994 to determine the apparent sensitivity, specificity, relative incidence rates, and PPVs for the 5 disorders. For biotinidase deficiency and CAH, we also calculated relative incidence rates and PPVs for 1991 and 1992. RESULTS: Our analyses revealed the following best estimates for the relative incidence rates of 5 disorders: phenylketonuria, 1:14,000; galactosemia, 1:59,000; biotinidase deficiency, 1:80,000; congenital hypothyroidism, 1:3,300; and CAH, 1:20,000. An apparent sensitivity of 100% has been reported by the various states for most of the disorders, and specificity levels are all above 99%. The PPVs, however, range from 0.5% to 6.0%. Consequently, on average, there are more than 50 false-positive results for every true-positive result identified through newborn screening in the United States. CONCLUSIONS: The magnitude of false-positive results generated in newborn screening programs, particularly for congenital endocrinopathies, presents a great challenge for future improvement of this important public health program. Attention must be given to improved laboratory tests, use of more specific markers, and better risk communication for families of patients with false-positive test results.

Adrenal Hyperplasia, Congenital↗
PubMed2000

Wisconsin cystic fibrosis chest radiograph scoring system: validation and standardization for application to longitudinal studies.

This study was designed to achieve a final modeling, validation, and standardization plan for the Wisconsin cystic fibrosis (CF) chest radiographic scoring system. Sixty chest radiographs were selected to reflect a range of severity of lung pathology in children with CF. Seven experienced volunteer raters (three radiologists and four pediatric pulmonologists) from five institutions were recruited to evaluate and score the films. Analysis of scores revealed that the subcomponents of the Wisconsin system showed considerable variation from rater to rater, but reliability assessment indicated satisfactory Cronbach's alpha coefficients (0.83-0.90) among the seven raters. It was found that an additive method of total score computation is significantly more reliable (P < 0.05) than either the original multiplicative model or the traditional Brasfield scoring system. Comparison of radiologists and pulmonologists revealed a marked, systematic difference in scoring with the former group being more conservative in interpretation of abnormalities than the pulmonologists, and some of the raters showing very limited sensitivity. Quantitative chest radiology applied to children with cystic fibrosis studied long-term in longitudinal research projects requires the careful use of sensitive scoring methods and careful selection and training of multiple raters. This is particularly important since pulmonologists and radiologists can differ systematically in interpreting/scoring abnormalities.

Child↗
PubMed2000

Collaboration and peer review in medical schools' strategic planning.

The management of medical schools has never been so difficult, but can be facilitated by using a well-developed, broadly accepted strategic plan. While the concept of strategic planning has been reasonably well accepted by both faculty and leaders at most medical schools, using the strategic plan to allocate resources has proved to be a challenge. Achieving "buy-in" by all parties involved can help meet this challenge and can be critical to the success of strategic planning and management. The authors describe the collaborative planning process that the University of Wisconsin Medical School used to develop its 1998-2000 strategic plan. This unique effort culminated in using a peer-review process--similar to that used by the National Institutes of Health (NIH)--and developing criteria to select a limited number of program priorities. This selection occurred after a school-wide process to solicit strategic program proposals had taken place. Over 130 faculty from most departments throughout the school helped develop and revise the strategic plan. There was frequent communication and engagement with faculty at all levels, which was important in gaining the faculty's acceptance and, indeed, endorsement of the process and its outcomes. Because the process was effective in achieving consensus about the school's strategic priorities, it enabled the school to reach a firmer end-point and implementation plan than had been possible with the previous strategic plan. It also identified important weaknesses in some areas of the medical school; the resulting attention to those areas will help strengthen the school. Finally, the process moved much more swiftly than the previous effort. The authors recommend that such an approach be used by other medical schools, and be carried out before a school implements mission-aligned budgeting and management of its fiscal resources.

Curriculum↗
PubMed2000

Nutritional status of patients with cystic fibrosis with meconium ileus: a comparison with patients without meconium ileus and diagnosed early through neonatal screening.

OBJECTIVE: This study was pursued as an extension of a randomized clinical investigation of neonatal screening for cystic fibrosis (CF). The objective was to determine if CF patients with meconium ileus (MI) were more likely to be malnourished compared with those without MI who were diagnosed during early infancy through neonatal screening. METHODOLOGY: Nutritional status was evaluated from early infancy to 13 years of age based on anthropometric, biochemical, and dietary assessments. RESULTS: MI patients (n = 32) were smaller at birth (3117 g compared with 3413 g) and were shorter (22nd percentile compared with 48th percentile) and thinner (24th percentile compared with 49th percentile) compared with non-MI early diagnosed patients (n = 50) up to 13 years of age. Poor growth was particularly evident in 26 MI patients who required surgery for MI (height and weight at the 20th percentile), whereas those treated without surgery (n = 6) showed better height (45th percentile) and weight (37th percentile). Abnormal essential fatty acid profiles were significantly more prevalent in MI compared with non-MI early-diagnosed patients before 3 years of age. Daily intakes of calorie (130% compared with 111% recommended dietary allowances) and protein (339% compared with 279% recommended dietary allowances) were higher but the percentage of fat (37% compared with 38%) and linoleic acid (4.5% compared with 4.7%) in the diet were similar between the two groups. CONCLUSIONS: These results demonstrated a clear association of MI with malnutrition in CF. The observed poor growth among our MI patients was not because of poor dietary intakes, but was related to surgical treatment for MI and poor essential fatty acid status. These findings present new challenges regarding the optimal medical treatment and nutritional intervention for CF patients with MI.

Case-Control Studies↗