Rhonda VanDyke

Serum Vascular Endothelial Growth Factor-D Prospectively Distinguishes Lymphangioleiomyomatosis From Other Diseases

OBJECTIVES The majority of women with lymphangioleiomyomatosis (LAM) present with cystic lung disease, and most require lung biopsy for definitive diagnosis. The purpose of this study was to determine the prospective diagnostic usefulness of a serologic test for vascular endothelial growth factor-D (VEGF-D), a lymphangiogenic growth factor. METHODS We prospectively measured serum VEGF-D levels by enzyme-linked immunoassay in 48 women presenting with cystic lung disease. Diagnostic test performance was determined from a cohort of 195 women, with tuberous sclerosis complex (TSC), TSC-LAM, sporadic LAM (S-LAM), and other cystic lung diseases in the differential diagnosis, including biopsy-proven or genetically proven pulmonary Langerhans cell histiocytosis, emphysema, Sjögren syndrome, or Birt-Hogg-Dubé syndrome. RESULTS Serum VEGF-D levels were significantly greater in S-LAM (median 1,175 [interquartile range (IQR): 780-2,013] pg/mL; n = 56) than in other cystic lung diseases (median 281 [IQR 203-351] pg/mL; n = 44, P < .001). In the cohort evaluated prospectively, 12 of the 15 individuals ultimately diagnosed with LAM by biopsy had VEGF-D levels of > 800 pg/mL, whereas levels were < 600 pg/mL in all 18 subjects later diagnosed with other causes of cystic lung disease. Receiver operating characteristic curves demonstrated that VEGF-D effectively identified LAM, with an area under the curve of 0.961(95% CI, 0.923-0.992). A VEGF-D level of > 600 pg/mL was highly associated with a diagnosis of LAM (specificity 97.6%, likelihood ratio 35.2) and values > 800 pg/mL were diagnostically specific. Serum VEGF-D levels were significantly elevated in women with TSC-LAM (median 3,465 [IQR 1,970-7,195] pg/mL) compared with women with TSC only (median 370 [IQR 291-520] pg/mL), P < .001). CONCLUSIONS A serum VEGF-D level of > 800 pg/mL in a woman with typical cystic changes on high-resolution CT (HRCT) scan is diagnostically specific for S-LAM and identifies LAM in women with TSC. A negative VEGF-D result does not exclude the diagnosis of LAM. The usefulness of serum VEGF-D testing in men or in women who do not have cystic lung disease on HRCT scan is unknown.

Baroreflex Gain in Children with Obstructive Sleep Apnea

RATIONALE We previously demonstrated that children with obstructive sleep apnea have increased blood pressure associated with changes in left ventricular mass index. Others have shown in adults that blood pressure variability is an important predictor of changes in left ventricular mass. The baroreflex system buffers blood pressure changes by varying heart rate. We have thus hypothesized that (1) baroreflex system gain is increased during sleep, improving blood pressure buffering; (2) children with obstructive sleep apnea lack this baroreflex gain increase; and (3) reduced blood pressure buffering results in exaggerated blood pressure variability that is associated with end-organ damage. OBJECTIVES Compare measures of left ventricular mass index and nighttime baroreflex gain of healthy children to those of children with obstructive sleep apnea. METHODS A total of 169 children (50 control subjects, 63 with mild obstructive sleep apnea, and 56 with severe obstructive sleep apnea) with a mean age of 9.9 years (+/-2.2) underwent echocardiography followed by polysomnography with continuous blood pressure measurement. Baroreflex gain was calculated in time and frequency domains. MEASUREMENTS AND MAIN RESULTS Healthy children demonstrated a nighttime pattern of increasing baroreflex gain. Children with obstructive sleep apnea had decreased nighttime baroreflex gain compared with control subjects. Nighttime blood pressure and blood pressure variability were significantly correlated with left ventricular mass index. CONCLUSIONS Obstructive sleep apnea is associated with a decrease in nighttime baroreflex gain and an increase in blood pressure variability. This increase is correlated with changes in left ventricular mass index.

Does sleep duration predict metabolic risk in obese adolescents attending tertiary services? A cross-sectional study.

STUDY OBJECTIVES To determine, in a clinical sample of obese adolescents, whether shorter sleep duration is associated with metabolic risk and obesity severity. DESIGN Cross-sectional study. SETTING Tertiary care weight-management clinic in Cincinnati, OH, USA. PARTICIPANTS 133 obese adolescents aged 10-16.9 years. INTERVENTIONS N/A. MEASUREMENTS Multifaceted sleep duration data were examined with fasting venipuncture and anthropometric data collected during clinical care. PRIMARY OUTCOME presence of metabolic syndrome. SECONDARY OUTCOMES waist circumference, triglycerides, HDL-cholesterol, blood pressure, glucose, insulin resistance (HOMA-IR), and body mass index (BMI). PREDICTORS Sleep duration by (1) parent-report, (2) self-report, and (3) multi-night actigraphy. ANALYSIS Relationships between sleep duration and each outcome were examined via regression models, adjusted for potential confounders. RESULTS Regardless of how measured, sleep duration showed no strong association with metabolic syndrome (OR 1.1 to 1.5, P = 0.2 to 0.8), BMI (β -0.03 to -0.01, P = 0.2 to 0.8), or most other outcomes. Lower triglycerides were predicted by shorter sleep duration by self-report (β 12.3, P = 0.01) and actigraphy (β 13.6, P = 0.03), and shorter parent-reported sleep duration was associated with higher HDL-cholesterol (β = -2.7, P = 0.002). CONCLUSIONS Contrary to expectations, sleep duration was not associated with metabolic outcomes, and showed limited associations with lipid profiles. Although inadequate sleep may affect other areas of functioning, it appears premature to expect that lengthening sleep will improve BMI or metabolic outcomes in clinical samples of obese adolescents.

Effect of chronic sleep restriction on sleepiness and working memory in adolescents and young adults.

Objectives: To test the feasibility of using a home-based sleep restriction protocol in adolescents and young adults; and to examine the different effects of chronic sleep restriction on a subjective sleepiness scale and working memory task in adolescents and young adults. Method: Twenty adolescents (ages 13–16 years) and 20 young adults (ages 18–20 years) underwent a 2-week home-based sleep manipulation protocol consisting of a week of 5 school days with 8 hr spent in bed per night and another week of 5 school days with 6 hr spent in bed per night. The protocol used a counterbalanced crossover experimental design. Subjective sleepiness was scored by the participant each morning, and working memory tests were administered during the weekend corresponding to each experimental week. Results: Adherence to the prescribed protocol was similar in the two groups, and both groups achieved the desired differences in total sleep duration across the two sleep conditions. Subjective sleepiness scores significantly increased in young adults after sleep restriction, but were not accompanied by significant changes in working memory. However, reaction times during simple verbal and arithmetic working memory tasks increased among adolescents after sleep restriction, without affecting accuracy on task, and without eliciting increases in subjective sleepiness scores. Conclusion: Mild sleep restriction for 5 days impairs reaction times during working memory tasks in adolescents in the absence of increased perception of sleepiness.

Determinants of Regional Cerebral Oxygenation in Children with Sleep-disordered Breathing

RATIONALE An association between neurocognitive deficits and pediatric sleep-disordered breathing has been suggested; however, weak correlations between disease severity and functional outcomes underscore the lack of knowledge regarding factors modulating cognitive morbidity of sleep-disordered breathing. OBJECTIVES To identify the parameters affected by sleep-disordered breathing that modulate cerebral oxygenation, an important determinant of cognition. A further objective was to use these parameters with demographic data to develop a predictive statistical model of pediatric cerebral oxygenation. METHODS Ninety-two children (14 control subjects, 32 with primary snoring, and 46 with obstructive sleep apnea) underwent polysomnography with continuous monitoring of cerebral oxygenation and blood pressure. Analysis of covariance was used to relate the blood pressure, sleep diagnostic parameters, and demographic characteristics to regional cerebral oxygenation. MEASUREMENTS AND MAIN RESULTS To account for anatomic variability, an index of cerebral oxygenation during sleep was derived by referencing the measurement obtained during sleep to that obtained during wakefulness. In a repeated measures model predicting the index of cerebral oxygenation, mean arterial pressure, rapid eye movement (REM) sleep, female sex, age, and oxygen saturation had a positive effect on cerebral oxygenation levels, whereas arousal index and non-REM (NREM) sleep had a negative effect. CONCLUSIONS Increasing mean arterial pressure, age, oxygen saturation, and REM sleep augment cerebral oxygenation, while sleep-disordered breathing, male sex, arousal index, and NREM sleep diminish it. The proposed model may explain the sources of variability in cognitive function of children with sleep-disordered breathing.

Improving Evidence-Based Care in Cystic Fibrosis Through Quality Improvement

OBJECTIVE To increase clinician adherence to prescribing guidelines for pulmonary medications in children with cystic fibrosis (CF). DESIGN Quality improvement project with multiple time series design. SETTING The CF center at a tertiary care pediatric hospital in the United States. PATIENTS Children with CF who were eligible to receive oral azithromycin, nebulized dornase alfa, or inhaled tobramycin sulfate based on prescribing guidelines for CF lung disease. INTERVENTION Evidence-based prescribing guidelines were designed by a local committee to reflect consensus recommendations from the CF Foundation. Clinicians and families were educated about guidelines. Adherence to prescribing guidelines was tracked using a local CF database and record reviews. Weekly meetings were used to highlight adherence failures and promote clinician accountability. MAIN OUTCOME MEASURE The rate of clinician adherence to prescribing guidelines. RESULTS One hundred seventy patients with CF were included. At the start of the project, the rate of clinician adherence to prescribing guidelines was 62%. After 3 months of the project, the rate of clinician adherence to prescribing guidelines was 87% (odds ratio = 4.6; 95% confidence interval, 3.0-7.0). The improvements in adherence to prescribing guidelines were sustained for 21 months of follow-up. CONCLUSIONS Educating clinicians about prescribing guidelines, sharing guidelines with families, and monitoring clinician adherence improve prescribing adherence to evidence-based recommendations.

Inhaled Tobramycin Effectively Reduces FEV1 Decline in Cystic Fibrosis. An Instrumental Variables Analysis

RATIONALE The efficacy of inhaled tobramycin on chronic Pseudomonas aeruginosa infections in patients with cystic fibrosis (CF) has been established in clinical trials. However, little is known about its clinical effectiveness on lung function outside randomized controlled trial settings; conventional analysis of existing registry data has heretofore been confounded by treatment selection bias. OBJECTIVE To determine effectiveness of inhaled tobramycin on FEV1 decline in patients with chronic P. aeruginosa infections using observational data from the Cystic Fibrosis Foundation Patient Registry. METHODS Patient-level tobramycin use was measured at first chronic P. aeruginosa infection (n = 13,686 patients; age, 6-21 yr). Decline in FEV1 2 years after infection was estimated for patients treated with tobramycin and compared with untreated patients. Multiple linear regressions with confounder adjustment and propensity scores were used to estimate mean FEV1 decline for each group. Because care is organized by centers, we used center-specific prescription rates as an instrument to reduce treatment-by-condition bias. MEASUREMENTS AND MAIN RESULTS Using center-level prescribing rates, instrumental variables analysis showed less FEV1 decline for patients who received tobramycin when first eligible compared with those who did not receive tobramycin (difference, 2.55% predicted; 95% confidence interval, 0.16-4.94; P = 0.0366). CONCLUSIONS Inhaled tobramycin is effective in reducing lung function decline among patients 6 to 21 years of age with CF. Because CF care is organized by center, using center-specific prescription rates as an instrumental variable is a feasible approach to using the Cystic Fibrosis Foundation Patient Registry to determine treatment effectiveness. More generally, this approach can correct for treatment-by-condition bias arising from observational studies.

Spirituality's Role in Chronic Disease Self-Management: Sanctification of the Body in Families Dealing With Cystic Fibrosis

Sanctifying the Body (imbuing the body and its care with spiritual significance) is associated with pro-healthy behaviors and may be associated with adherence in families with chronic diseases. Our objective was to determine this constructs relevance to cystic fibrosis (CF) families and test the reliability and validity of a shortened Sanctification measure. The “Sacred Qualities of the Body” and “Manifestation of God in the Body” scales were completed by parents (N = 92) and adolescents with CF (N = 32) in a CF Clinic or by mail. Internal consistency reliability and factor analysis were performed on the parent sample. Parents and adolescents endorsed the construct. Internal consistency and validity was shown for adults and factor analysis showed two factors. Adolescent interest in an electronic spirituality chatroom correlated with increased sanctification. Sanctification is a relevant, measurable construct representing an under-appreciated aspect of the web of values contributing to adherence and health and bears further examination.

Written prayers and religious coping in a paediatric hospital setting

Hospitalised children represent a threatened future to parents. Such stressors call forth peoples coping styles. Some individuals cope religiously or spiritually, and religious coping through prayer may be utilised. A sample of prayers written in a paediatric hospital chapel was coded by styles of religious coping evident within them. Styles associated with coping to gain control of their situation and with coping by seeking comfort from God were present. Seeking to cope for gaining control of a situation was more common than seeking comfort from God during the event. Written prayers did not contain evidence of coping by making meaning. Regression analysis showed that the probability of writing a prayer to gain control decreased over time and a trend towards increasing probability of writing a prayer expressing coping by seeking Gods comfort. Clinical implications are discussed. Future research should include a larger sample and cognitive interviews with prayer writers.

Fetal development in women with diabetes: imprinting for a life-time?

Objective: To test the hypothesis that fetal exposure to a hyperglycemic intrauterine environment in women with type 1 diabetes is associated with asymmetrically distributed excessive fetal growth and imprinting consistent with adverse health issues later in life. Methods: We report findings from a feasibility study on 19 young adults, born to mothers with type 1 diabetes. Long-term follow-up of the offspring in young adulthood included: oral glucose tolerance test, body mass index (BMI), dual X-ray absorptiometry, and blood pressure (BP). We report z-BMI and z-BP to account for varying gender and age. Results: The young adults born to women with diabetes averaged 19.9 years at follow-up; 37% were female, and 21% African American. Maternal glycohemoglobin A1 concentration in the 2nd trimester was 9.2% for offspring born with asymmetric LGA and 7.5% for those born with symmetric LGA or AGA. There was significant correlation between maternal glucose control during pregnancy and fasting glucose, z-BMI and z-systolic BP in the young adults. Conclusion: The hyperglycemic intrauterine environment is associated with short-term morbidity, manifested as asymmetric LGA (the “fat” baby). In addition, increasing level of maternal hyperglycemia during pregnancy is associated with increased adiposity and elevated fasting glucose in the young adult offspring.