Ian M. Paul

Episodic use of an inhaled corticosteroid or leukotriene receptor antagonist in preschool children with moderate-to-severe intermittent wheezing.

BACKGROUND Acute wheezing illnesses in preschoolers require better management strategies to reduce morbidity. OBJECTIVES We sought to examine the effectiveness of episodic use of an inhaled corticosteroid and a leukotriene receptor antagonist in preschoolers with intermittent wheezing. METHODS In a randomized, double-blind, placebo-controlled 12-month trial, 238 children aged 12 to 59 months with moderate-to-severe intermittent wheezing received 7 days of either budesonide inhalation suspension (1 mg twice daily), montelukast (4 mg daily), or placebo in addition to albuterol with each identified respiratory tract illness (RTI). Proportion of episode-free days (EFDs) during the 12-month trial was the primary outcome. RESULTS The 3 treatment groups did not differ in proportions of EFDs, with adjusted mean EFDs of 76% (95% CI, 70% to 81%) for budesonide, 73% (95% CI, 66% to 79%) for montelukast, and 74% (95% CI, 65% to 81%) for conventional therapy (P = .66). The 3 groups did not differ in oral corticosteroid use, health care use, quality of life, or linear growth. However, during RTIs, budesonide and montelukast therapy led to modest reductions in trouble breathing (38% [P = .003] and 37% [P = .003], respectively) and interference with activity scores (32% [P = .01] and 40% [P = .001], respectively) that were most evident in those with positive asthma predictive indices. CONCLUSIONS In preschool children with moderate-to-severe intermittent wheezing, episodic use of either budesonide or montelukast early in RTIs, when added to albuterol, did not increase the proportion of EFDs or decrease oral corticosteroid use over a 12-month period. However, indicators of severity of acute illnesses were reduced, particularly in children with positive asthma predictive indices.

Preventable Newborn Readmissions Since Passage of the Newborns’ and Mothers’ Health Protection Act

BACKGROUND. Congress passed the Newborns’ and Mothers’ Health Protection Act in 1996, reversing the trend of shorter newborn nursery lengths of stay. Hope existed that morbidities would lessen for this vulnerable population, but some reports indicate that the timeliness and quality of postdischarge care may have worsened in recent years. OBJECTIVE. Our goal was to determine risk factors for the potentially preventable readmissions because of jaundice, dehydration, or feeding difficulties in the first 10 days of life in Pennsylvania since passage of the Newborns’ and Mothers’ Health Protection Act. PATIENTS AND METHODS. Birth records from 407826 newborns ≥35 weeks’ gestation from 1998 to 2002 were merged with clinical discharge records. A total of 2540 newborns rehospitalized for jaundice, dehydration, or feeding difficulties in the first 10 days of life were then compared with 5080 control infants. Predictors of readmission were identified by using multiple logistic regression analysis. RESULTS. An unadjusted comparison of baseline characteristics revealed numerous predictors of readmission. Subsequent adjusted analysis revealed that Asian mothers, those 30 years of age or older, nonsmokers, and first-time mothers were more likely to have a readmitted newborn, as were those with diabetes and pregnancy-induced hypertension. For neonates, female gender and delivery via cesarean section were protective for readmission, whereas vacuum-assisted delivery, gestational age <37 weeks, and nursery length of stay <72 hours were predictors of readmission in the first 10 days of life. CONCLUSIONS. Although readmissions for jaundice, dehydration, and feeding difficulties may be less common for some minority groups and Medicaid recipients in the era of the Newborns’ and Mothers’ Health Protection Act compared with nonminorities or privately insured patients, several predictors of newborn readmission have established associations with inexperienced parenting and/or breastfeeding difficulty. This is one indication that this well-intentioned legislation and current practice may not be sufficiently protecting the health of newborns and suggests that additional support for mothers and newborns during the vulnerable postdelivery period may be indicated.

Effect of Dextromethorphan, Diphenhydramine, and Placebo on Nocturnal Cough and Sleep Quality for Coughing Children and Their Parents

OBJECTIVES To determine whether the commonly used over-the-counter medications dextromethorphan and diphenhydramine are superior to placebo for the treatment of nocturnal cough and sleep difficulty associated with upper respiratory infections and to determine whether parents have improved sleep quality when their children receive the medications when compared with placebo. METHODS Parents of 100 children with upper respiratory infections were questioned to assess the frequency, severity, and bothersome nature of the nocturnal cough. Their answers were recorded on 2 consecutive days, initially on the day of presentation, when no medication had been given the previous evening, and then again on the subsequent day, when either medication or placebo was given before bedtime. Sleep quality for both the child and the parent were also assessed for both nights. RESULTS For the entire cohort, all outcomes were significantly improved on the second night of the study when either medication or placebo was given. However, neither diphenhydramine nor dextromethorphan produced a superior benefit when compared with placebo for any of the outcomes studied. Insomnia was reported more frequently in those who were given dextromethorphan, and drowsiness was reported more commonly in those who were given diphenhydramine. CONCLUSIONS Diphenhydramine and dextromethorphan are not superior to placebo in providing nocturnal symptom relief for children with cough and sleep difficulty as a result of an upper respiratory infection. Furthermore, the medications given to children do not result in improved quality of sleep for their parents when compared with placebo. Each clinician should consider these findings, the potential for adverse effects, and the individual and cumulative costs of the drugs before recommending them to families.

Azithromycin or montelukast as inhaled corticosteroid–sparing agents in moderate-to-severe childhood asthma study

BACKGROUND Clinical trials in children with moderate-to-severe persistent asthma are limited. OBJECTIVE We sought to determine whether azithromycin or montelukast are inhaled corticosteroid sparing. METHODS The budesonide dose (with salmeterol [50 microg] twice daily) necessary to achieve control was determined in children 6 to 17 years of age with moderate-to-severe persistent asthma. After a budesonide-stable period of 6 weeks, children were randomized in a double-masked, parallel, multicenter study to receive once-nightly azithromycin, montelukast, or matching placebos plus the established controlling dose of budesonide (minimum, 400 microg twice daily) and salmeterol twice daily. Primary outcome was time from randomization to inadequate asthma control after sequential budesonide dose reduction. RESULTS Of 292 children screened, only 55 were randomized. Inadequate adherence to study medication (n = 80) and improved asthma control under close medical supervision (n = 49) were the major reasons for randomization failure. A futility analysis was requested by the Data Safety Monitoring Board. In data available for analyses, no differences were noted for either treatment compared with placebo in time to inadequate control status (median: azithromycin, 8.4 weeks [95% confidence limit, 4.3-17.3]; montelukast, 13.9 weeks [95% confidence limit, 4.7-20.6]; placebo, 19.1 weeks [95% confidence limit, 11.7-infinity]), with no difference between the groups (log-rank test, P = .49). The futility analysis indicated that even if the planned sample size was reached, the results of this negative study were unlikely to be different, and the trial was prematurely terminated. CONCLUSION Based on these results, neither azithromycin nor montelukast is likely to be an effective inhaled corticosteroid-sparing alternative in children with moderate-to-severe persistent asthma.

Postpartum Anxiety and Maternal-Infant Health Outcomes

OBJECTIVE: Postpartum anxiety screening does not typically occur, despite changes in life roles and responsibility after childbirth. We sought to determine the prevalence of postpartum anxiety during the maternity hospitalization and its associations with maternal and child outcomes. We further aimed to compare correlates of anxiety with correlates of depression. METHODS: For a randomized controlled trial of mothers with “well” newborns ≥34 weeks’ gestation comparing 2 post–hospital discharge care models, mothers completed baseline in-person interviews during the postpartum stay and telephone surveys at 2 weeks, 2 months, and 6 months to assess health care use, breastfeeding duration, anxiety, and depression. All participants intended to breastfeed. State anxiety scores ≥40 on the State Trait Anxiety Inventory (STAI) and depression scores ≥12 on the Edinburgh Postnatal Depression Survey (EPDS) were considered positive. RESULTS: A total of 192 (17%) of 1123 participating mothers had a positive baseline STAI; 62 (6%) had a positive EPDS. Primiparity was associated with a positive STAI (20% vs 15%, P = .02), but not a positive EPDS (4% vs 7%, P = .05). Positive STAI scores were associated with cesarean delivery (22% vs 15%, P = .001), reduced duration of breastfeeding (P = .003), and increased maternal, but not infant total unplanned health care utilization within 2 weeks of delivery (P = .001). Positive STAI scores occurred more frequently than positive EPDS scores at each assessment through 6 months postpartum. CONCLUSIONS: Postpartum state anxiety is a common, acute phenomenon during the maternity hospitalization that is associated with increased maternal health care utilization after discharge and reduced breastfeeding duration. State anxiety screening during the postpartum stay could improve these outcomes.

Harnessing cloud computing with Galaxy Cloud

As next-generation sequencing becomes an indispensible tool for biomedical research, it is crucial to provide analysis solutions that are usable and cost effective for biomedical researchers. Galaxy Cloud addresses this by combining the accessible Galaxy interface with automated management of cloud computing resources. Unlike purpose-built solutions, Galaxy allows users either to use existing tested best practices in the form of workflows or to construct their own analyses for novel tasks. Galaxy Cloud instances are owned and controlled entirely by the user who created them and can be used effectively in secure private clouds. Thus, Galaxy Cloud provides a solution that retains user control and privacy, makes complex analysis accessible and enables the use of practically limitless on-demand computing resources.Continuing evolution of DNA sequencing has transformed modern biology. Reduced sequencing costs coupled with novel sequencing based assays has led to rapid adoption of next generation sequencing (NGS) across diverse areas of life science research1-4. Sequencing has moved out of the genome centers into core facilities and individual labs where any investigator can access them for modest and progressively declining cost. While easy to generate in tremendous quantities, sequence data is still difficult to manage and analyze. Sophisticated informatics techniques and supporting infrastructure are needed to make sense of even conceptually simple sequencing experiments — let alone the more complex analysis techniques being developed. The most pressing challenge facing the sequencing community today is providing the informatics infrastructure and accessible analysis methods needed to make it possible for all investigators to realize the power of high-throughput sequencing to advance their research.

Dynamics of mitochondrial heteroplasmy in three families investigated via a repeatable re-sequencing study

BackgroundOriginally believed to be a rare phenomenon, heteroplasmy - the presence of more than one mitochondrial DNA (mtDNA) variant within a cell, tissue, or individual - is emerging as an important component of eukaryotic genetic diversity. Heteroplasmies can be used as genetic markers in applications ranging from forensics to cancer diagnostics. Yet the frequency of heteroplasmic alleles may vary from generation to generation due to the bottleneck occurring during oogenesis. Therefore, to understand the alterations in allele frequencies at heteroplasmic sites, it is of critical importance to investigate the dynamics of maternal mtDNA transmission.ResultsHere we sequenced, at high coverage, mtDNA from blood and buccal tissues of nine individuals from three families with a total of six maternal transmission events. Using simulations and re-sequencing of clonal DNA, we devised a set of criteria for detecting polymorphic sites in heterogeneous genetic samples that is resistant to the noise originating from massively parallel sequencing technologies. Application of these criteria to nine human mtDNA samples revealed four heteroplasmic sites.ConclusionsOur results suggest that the incidence of heteroplasmy may be lower than estimated in some other recent re-sequencing studies, and that mtDNA allelic frequencies differ significantly both between tissues of the same individual and between a mother and her offspring. We designed our study in such a way that the complete analysis described here can be repeated by anyone either at our site or directly on the Amazon Cloud. Our computational pipeline can be easily modified to accommodate other applications, such as viral re-sequencing.

Pediatric Fatalities Associated With Over the Counter (Nonprescription) Cough and Cold Medications

STUDY OBJECTIVE The use of nonprescription cough and cold medicines is widespread, but their use has been sporadically associated with severe toxicity and death. We evaluate the role of these medications in pediatric fatalities and identified factors that contributed to the death. METHODS Fatalities that involved a child younger than 12 years and mentioned a cough and cold ingredient were obtained from 5 sources. An independent panel of 8 experts (pediatrics, pediatric critical care, pediatric toxicology, clinical toxicology, forensic toxicology, forensic pathology) used explicit definitions to assess the causal relationship between medication ingestion and death. Contributing factors were identified. RESULTS Of 189 cases included, 118 were judged possibly, likely, or definitely related to a cough and cold ingredient. Of these 118 cases, 103 involved a nonprescription drug, whereas 15 cases involved a prescription medication alone. Of 103 cases associated with nonprescription drugs, the evidence indicated that 88 involved an overdosage. A dosage could not be assessed in the remaining 15 cases. Several contributing factors were identified: age younger than 2 years, use of the medication for sedation, use in a daycare setting, use of 2 medicines with the same ingredient, failure to use a measuring device, product misidentification, and use of a nonprescription product intended for adult use. All cases that occurred in a daycare setting involved a child younger than 2 years. CONCLUSION In our sample, pediatric fatalities caused by nonprescription cough and cold medications were uncommon, involved overdose, and primarily affected children younger than 2 years. The intent of caregivers appears to be therapeutic to relieve symptoms in some cases and nontherapeutic to induce sedation or to facilitate child maltreatment in other cases.

Do human milk concentrations of persistent organic chemicals really decline during lactation? Chemical concentrations during lactation and milk/serum partitioning.

Background Conventional wisdom regarding exposures to persistent organic chemicals via breast-feeding assumes that concentrations decline over the course of lactation and that the mother’s body burden reflects her cumulative lifetime exposure. Two important implications stemming from these lines of thought are, first, that assessments of early childhood exposures should incorporate decreasing breast milk concentrations over lactation; and, second, that there is little a breast-feeding mother can do to reduce her infant’s exposures via breast-feeding because of the cumulative nature of these chemicals. Objectives We examined rates of elimination and milk/serum partition coefficients for several groups of persistent organic chemicals. Methods We collected simultaneous milk and blood samples of 10 women at two times postpartum and additional milk samples without matching blood samples. Results Contrary to earlier research, we found that lipid-adjusted concentrations of polybrominated diphenyl ethers, polychlorinated biphenyls, polychlorinated dibenzo-p-dioxins and furans, and organochlorine pesticides in serum and milk do not consistently decrease during lactation and can increase for some women. Published research has also suggested an approximate 1:1 milk/serum relationship (lipid adjusted) on a population basis for 2,3,7,8-tetrachlorodibenzo-p-dioxin; however, our results suggest a more complex relationship for persistent, lipophilic chemicals with the milk/serum relationship dependent on chemical class. Conclusions Decreases in concentration of lipophilic chemicals on a lipid-adjusted basis during lactation should no longer be assumed. Thus, the concept of pumping and discarding early milk as means of reducing infant exposure is not supported. The hypothesis that persistent lipophilic chemicals, on a lipid-adjusted basis, have consistent concentrations across matrices is likely too simplistic.

Opportunities for the Primary Prevention of Obesity during Infancy

Many parents, grandparents, and clinicians have associated a baby’s ability to eat and gain weight as a sign of good health, and clinicians typically only call significant attention to infant growth if a baby is failing to thrive or showing severe excesses in growth. Recent evidence, however, has suggested that pediatric healthcare providers should pay closer attention to growth patterns during infancy. Both higher weight and upward crossing of major percentile lines on the weight-for-age growth chart during infancy have long term health consequences, and are associated with overweight and obesity later in life. Clinicians should utilize the numerous available opportunities to discuss healthy growth and growth charts during health maintenance visits in the first two years after birth. Further, providers should instruct parents on strategies to promote healthy behaviors that can have long lasting obesity preventive effects.