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.

Baroreflex sensitivity after adenotonsillectomy in children with obstructive sleep apnea during wakefulness and sleep.

STUDY OBJECTIVES: Children with obstructive sleep apnea have blunted baroreflex sensitivity and increased blood pressure variability. The aim of the study was to test the hypothesis that treatment of sleep apnea by adenotonsillectomy results in significant improvement of baroreflex sensitivity, lowering of blood pressure and blood pressure variability and increase vagal heart rate modulation. STUDY DESIGN: One hundred ninety-four children aged 9.6 ± 2.3 years were enrolled; 133 had obstructive sleep apnea and 61 were healthy controls. For children with sleep apnea, polysomnography with 3-lead electrocardiography and continuous blood pressure was performed before adenotonsillectomy, then 6 weeks and 6 months postoperatively. Controls underwent the same assessment at study entry and 6 months later. Spontaneous baroreflex sensitivity was measured in the time and frequency domains. Data analyses were performed for available and complete cases. RESULTS: Children with sleep apnea experienced postoperatively an increase in baroreflex sensitivity and decrease in blood pressure variability during wakefulness and sleep. A decrease in blood pressure during sleep and in heart rate during wakefulness was also measured. The improvement in baroreflex sensitivity was predicted by the change in the apnea-hypopnea and arousal indices. A normal pattern of rising baroreflex sensitivity during the night was restored in children with severe apnea after surgery. However, baroreceptor sensitivity did not completely normalize after treatment. CONCLUSION: Treatment of obstructive sleep apnea in children by adenotonsillectomy is associated with gradual improvement in known risk factors for cardiovascular disease. Complete normalization of baroreceptor sensitivity was not achieved 6 months postoperatively.

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 A(1) 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.

Characterizing maternal glycemic control: a more informative approach using semiparametric regression.

OBJECTIVE: To characterize glucose concentrations measured throughout pregnancy in women with type 1 diabetes using semiparametric regression analysis to examine the gestational time-specific association with fetal outcome. METHODS: We conducted a secondary analysis of data from an interdisciplinary program of diabetes in pregnancy of women with type 1 diabetes. Semiparametric regression was used to characterize glucose concentrations measured using reflectance meters throughout pregnancy by examining the time-specific association of maternal glucose with delivery of a large for gestational age (LGA) baby. RESULTS: The optimal model demonstrated that time-specific differences in glycemic profiles of mothers who had LGA versus AGA babies changed at various rates across gestation (p = 0.0007). AGA glucose profiles exceeded LGA profiles in the first trimester and mid pregnancy; conversely LGA glucose profiles exceeded AGA profiles initially during the third trimester. Differences were based on examination of 95% simultaneous confidence bands. CONCLUSIONS: Semiparametric regression techniques enabled synchronous inclusion of all glucose concentrations using multi-step modeling. We identified specific periods of gestation where maternal glucose concentrations differ for the LGA and AGA developing fetus, with greatest distinctions appearing in first and third trimesters. Novel statistical approaches that examine time-specific behavior garner insight into longitudinal assessment of maternal glycemic control.

Relationship of adherence determinants and parental spirituality in cystic fibrosis.

The course of cystic fibrosis (CF) progression in children is affected by parent adherence to treatment plans. The Theory of Reasoned Action (TRA) posits that intentions are the best behavioral predictors and that intentions reasonably follow from beliefs ("determinants"). Determinants are affected by multiple "background factors," including spirituality. This study's purpose was to understand whether two parental adherence determinants (attitude towards treatment and self-efficacy) were associated with spirituality (religious coping and sanctification of the body). We hypothesized that parents' attitudes toward treatment adherence are associated with these spiritual constructs. A convenience sample of parents of children with CF aged 3-12 years (n = 28) participated by completing surveys of adherence and spirituality during a regular outpatient clinic visit. Type and degree of religious coping was examined using principal component analysis. Adherence measures were compared based on religious coping styles and sanctification of the body using unpaired t-tests. Collaborative religious coping was associated with higher self-efficacy for completing airway clearance (M = 1070.8; SD = 35.8; P = 0.012), for completing aerosolized medication administration (M = 1077.1; SD = 37.4; P = 0.018), and for attitude towards treatment utility (M = 38.8; SD = 2.36; P = 0.038). Parents who attributed sacred qualities to their child's body (e.g., "blessed" or "miraculous") had higher mean scores for self-efficacy (airway clearance, M = 1058.6; SD = 37.7; P = 0.023; aerosols M = 1070.8; SD = 41.6; P = 0.020). Parents for whom God was manifested in their child's body (e.g., "My child's body is created in God's image") had higher mean scores for self-efficacy for airway clearance (M = 1056.4; SD = 59.0; P = 0.039), aerosolized medications (M = 1068.8; SD = 42.6; P = 0.033) and treatment utility (M = 38.8; SD = 2.4; P = 0.025). Spiritual constructs show promising significance and are currently undervalued in chronic disease management.

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.

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 (ß -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 (ß 12.3, P = 0.01) and actigraphy (ß 13.6, P = 0.03), and shorter parent-reported sleep duration was associated with higher HDL-cholesterol (ß = -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.

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.

Improving follow-up in hospitalised children.

OBJECTIVE: To improve the clinic follow-up rate of paediatric inpatients in a tertiary care hospital. PATIENTS AND METHODS: Inpatients who received pulmonary consultations from July 2007 to June 2008 at Cincinnati Children's Hospital Medical Center were eligible for this quality-improvement project. Multiple interventions were introduced to improve follow-up in our subspecialty clinic. A χ(2) test for association was used to assess the dependence between the clinic follow-up rate and the type of care coordination intervention. We hypothesised that generalisable care coordination interventions would result in improvements. RESULTS: Two hundred and eleven patients were included. Two interventions were independently associated with improvements in the hospital follow-up rate. When a reminder to follow-up in the pulmonary clinic was inserted into the hospital discharge summary (partial intervention), the clinic follow-up rate improved from 27% to 55%. When the follow-up appointments were made for the families, with the appointments' noted in the discharge summaries, and automated appointment reminder phone calls were provided (full intervention), the follow-up rate improved further from 55% to 80%. The full intervention, when compared with no intervention, improved the clinic follow-up rate from 27% to 80%. CONCLUSION: Establishing clinic appointments for patients and providing appointment reminders increases the hospital follow-up rate for hospitalised children in outpatient clinics.

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.

Wolbachia infection and resource competition effects on immature Aedes albopictus (Diptera: Culicidae).

Wolbachia pipientis Hertig and Wolbach (Rickettsiales: Rickettsiaceae) are intracellular alpha-proteobacteria that occur naturally in Aedes albopictus (Skuse) (Diptera: Culicidae) and numerous other invertebrates. These endosymbionts can invade host populations by manipulating host reproduction. Wolbachia infections have been shown to impart both costs and benefits to hosts in terms of development, survival, and fecundity. Here, we monitor intraspecific competition among independent cohorts of infected or uninfected larvae. Levels of competition are manipulated by varying initial larval densities and food levels. Although larval density is observed to have major impacts on immature survivorship, sex ratio of eclosing adults, and developmental rates, the Wolbachia infection status had minimal impact on male immatures and no effect on immature females under these experimental conditions. Female and male immatures were observed to respond differently to competitive pressure, with the functional relationships of females and males consistent with scramble and contest competition, respectively. The results are discussed in relation to the evolution of naturally occurring Wolbachia infections in Ae. albopictus (i.e., natural population replacement events) and public health strategies that propose the manipulation of Wolbachia infections in Ae. albopictus populations.

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.

Sexual differences in larval molting rates in a protandrous mosquito (Diptera: Culicidae) species, Aedes sierrensis.

Day-old larval Aedes sierrensis collected from six newly flooded treeholes in northern California were reared individually in the laboratory under simulated field conditions to compare larval developmental rates of males and females. Time to adult eclosion ranged from 133 to 219 d for this generally univoltine, winter-developing species. Males experienced significantly shorter first, second, and third larval instars than females. Females spent significantly less time as fourth instars (whose endpoint is determined by photoperiod). Length of pupal stage was equal for males and females. Time to mean adult eclosion differed among treeholes but was not determined by latitudinal position of treehole. Wing lengths were shorter for males than females in this sexually dimorphic species and also differed significantly among treeholes. Wing lengths were significantly correlated with total developmental time, but females spending more time in the fourth instar did not emerge as larger adults. In natural treeholes, resource utilization during rapid development by Ae. sierrensis males may limit the size and number of females produced from the same cohort if resources are limiting.

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.

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 construct's 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.