Initial development and pilot testing of observer-reported outcomes (ObsROs) for children with cystic fibrosis ages 0-11years.

PURPOSE: Patient-reported outcomes are important clinical trial endpoints. Young children may not be able to reliably report on how they feel or function, so observer-reported outcomes (ObsROs) may be more appropriate for them. The purpose of this study was to develop and pilot field test electronic parent-reported observational instruments for children with cystic fibrosis (CF) 0-6 and 7-11years of age. METHODS: We performed concept elicitation interviews with parents of children with CF ≤11years of age to elicit the respiratory signs they could observe at baseline and during an acute respiratory illness. The resulting instruments were refined based on interviews with parents and clinicians. We conducted a pilot field test to evaluate test-retest reliability and the ability of items to distinguish well and sick periods. RESULTS: The instruments consist of 17 items assessing respiratory signs and observable CF-related impacts. Test-retest reliability was acceptable for both age groups but discrimination was low for ages 7-11, likely reflecting less direct observation of older children by their parents. CONCLUSIONS: An ObsRO for children with CF ages 0-6 appears promising, while self-report may be more appropriate for children >6years of age. Next steps for the 0-6year old instrument will be utilizing it as an exploratory endpoint in clinical trials to enable item reduction, scale development, and further reliability and validity testing. Ultimately, this ObsRO could be a promising endpoint for early intervention trials in young children with CF.

Failure of Syndrome-Based Diarrhea Management Guidelines to Detect Shigella Infections in Kenyan Children.

BACKGROUND: Shigella is a leading cause of childhood diarrhea mortality in sub-Saharan Africa. Current World Health Organization guidelines recommend antibiotics for children in non cholera-endemic areas only in the presence of dysentery, a proxy for suspected Shigella infection. METHODS: To assess the sensitivity and specificity of the syndromic diagnosis of Shigella-associated diarrhea, we enrolled children aged 6 months to 5 years presenting to 1 of 3 Western Kenya hospitals between November 2011 and July 2014 with acute diarrhea. Stool samples were tested using standard methods for bacterial culture and multiplex polymerase chain reaction for pathogenic Escherichia coli. Stepwise multivariable logit models identified factors to increase the sensitivity of syndromic diagnosis. RESULTS: Among 1360 enrolled children, median age was 21 months (interquartile range, 11-37), 3.4% were infected with human immunodeficiency virus, and 16.5% were stunted (height-for-age z-score less than -2). Shigella was identified in 63 children (4.6%), with the most common species being Shigella sonnei (53.8%) and Shigella flexneri (40.4%). Dysentery correctly classified 7 of 63 Shigella cases (sensitivity, 11.1%). Seventy-eight of 1297 children without Shigella had dysentery (specificity, 94.0%). The combination of fecal mucous, age over 23 months, and absence of excessive vomiting identified more children with Shigella-infection (sensitivity, 39.7%) but also indicated antibiotics in more children without microbiologically confirmed Shigella (specificity, 82.7%). CONCLUSIONS: Reliance on dysentery as a proxy for Shigella results in the majority of Shigella-infected children not being identified for antibiotics. Field-ready rapid diagnostics or updated evidence-based algorithms are urgently needed to identify children with diarrhea most likely to benefit from antibiotic therapy.

Chest Radiographs for Pediatric TB Diagnosis: Interrater Agreement and Utility.

The chest radiograph (CXR) is considered a key diagnostic tool for pediatric tuberculosis (TB) in clinical management and endpoint determination in TB vaccine trials. We set out to compare interrater agreement for TB diagnosis in western Kenya. A pediatric pulmonologist and radiologist (experts), a medical officer (M.O), and four clinical officers (C.Os) with basic training in pediatric CXR reading blindly assessed CXRs of infants who were TB suspects in a cohort study. C.Os had access to clinical findings for patient management. Weighted kappa scores summarized interrater agreement on lymphadenopathy and abnormalities consistent with TB. Sensitivity and specificity of raters were determined using microbiologically confirmed TB as the gold standard (n = 8). A total of 691 radiographs were reviewed. Agreement on abnormalities consistent with TB was poor; k = 0.14 (95% CI: 0.10-0.18) and on lymphadenopathy moderate k = 0.26 (95% CI: 0.18-0.36). M.O [75% (95% CI: 34.9%-96.8%)] and C.Os [63% (95% CI: 24.5%-91.5%)] had high sensitivity for culture confirmed TB. TB vaccine trials utilizing expert agreement on CXR as a nonmicrobiologically confirmed endpoint will have reduced specificity and will underestimate vaccine efficacy. C.Os detected many of the bacteriologically confirmed cases; however, this must be interpreted cautiously as they were unblinded to clinical features.

Studies with choriocarcinoma and normal pregnancy serum chorionic gonadotrophin.

Serum obtained from either normally pregnant women or those with choriocarcinoma was pooled and purified by ammonium acetate/alcohol extraction followed by ionic exchange and gel filtration chromatography. The CG activity was monitored using a double antibody radioimmunoassay utilizing anti hCG both as the labelled ligand and standard. Biological activity was measured by the rat luteal cell radioreceptor assay. Both purified preparations exhibited heterogeneity in terms of the behaviour during ionic exchange chromatography and isoelectric focussing. The Stokes radii were 33A and 33.3A for normal pregnancy and choriocarcinoma hCG respectively. Material from both sources focussed between pH 4.5 and 5.5. Relative to the second international hCG standard the immunological activity of normal pregnancy hCG was 9,100 iu/mg and that of choriocarcinoma CG was 10,970 iu/mg. The corresponding biological potencies were 8,190 iu/mg and 7,569 iu/mg respectively. There was a significant difference between the biological to immunological activity of choriocarcinoma hCG (0.69) when compared with that of normal pregnancy CG (0.90). This was confirmed with a subsequent follow up study when individual serum samples from normal pregnancy were compared with those from choriocarcinoma patients (p = 0.01). It was concluded that in a third world situation this significant difference in the ratio of biological to immunological activity may be a useful method for evaluating treatment of choriocarcinoma patients.