Paediatric reference range for overnight urinary cortisol corrected for creatinine.

OBJECTIVES: Systemic activity of inhaled corticosteroids (ICS) may be assessed via urinary cortisol measurement. Overnight urinary free cortisol corrected for creatinine (OUFCC) has been extensively reported in adult studies. However, a paediatric mass spectrometric (MS) reference range for OUFCC is not established. MS methods for OUFCC avoid cross-reactivity with other steroid hormones and are thus preferable to immunoassays. The aim of the present study was to define an MS OUFCC normative range in children. METHODS: This was a cross-sectional study of healthy pre-pubertal children from 5 to 11 years. Children collected urine from 10 pm or bedtime, whichever was earlier, until 8 am. Urinary free cortisol was measured via a liquid chromatography tandem mass spectrometry (LC-MS/MS) assay (Acquity UPLC with Xevo TQ-S Mass Spectrometer [Waters]) with in-house reagents. Urinary creatinine was measured using a commercial assay (Roche). RESULTS: Complete urine collections were obtained from 72 males and 70 females, mean age (SD) 8.6 (1.9) (range 5.0-11.8) years. The OUFCC 95% prediction interval was 1.7-19.8 nmol/mmol. Geometric mean OUFCC was 5.7; range 1.1-24.8 nmol/mmol. CONCLUSIONS: The obtained normative LC-MS/MS OUFCC reference data facilitate the use of mass spectrometry OUFCC assays in assessment of systemic activity of endogenous and exogenous corticosteroids in children.

Telephone consultation as a substitute for face-to-face consultation during the COVID-19 pandemic.

INTRODUCTION: The health authorities have recommended that face-to-face consultations be substituted by telephone consultations to reduce the risk of virus transmission in out-patient clinics during the coronavirus disease 2019 (COVID-19) pandemic. The aim of the present study was to assess the frequency of such telephone consultations and families' evaluations of them in a paediatric outpatient clinic during the initial weeks of the COVID-19 pandemic lockdown. METHODS: During the period from 16 March to 23 April 2020, telephone consultations substituting face-to-face consultations in children and adolescents from 0 to 19 years of age were prospectively recorded. In subsequent telephone interviews, families were asked about their views on the telephone consultation. RESULTS: During the observation period, the clinic had 499 scheduled face-to-face appointments and 112 (22.4%) substitute telephone consultations. A total of 103 families participated in a telephone interview representing 87 (84.5%) children with atopic diseases and 16 (15.5%) with other conditions. A total of 100 (97.0%) of the families agreed or strongly agreed that they felt good about being offered a substitute telephone consultation; 14 (13.6%) said that a telephone consultation was not the best option, whereas 89 (80.4%) would not have preferred a face-to-face consultation; 98 (95.1%) felt that the telephone consultation was useful to them. CONCLUSIONS: A minority of planned face-to-face consultations was substituted by telephone consultations during the COVID-19 pandemic lockdown. Families were satisfied with substitute telephone consultations. FUNDING: none. TRIAL REGISTRATION: not relevant.

Differential effects of text message reminders on non-attendance and late cancellations in a paediatric outpatient clinic.

INTRODUCTION: SMS text appointment reminders reduce non-attendance rates in outpatient paediatric settings. The potential effect on late cancellation rates, however, has not been assessed. The aim of the present study was to assess if SMS text messaging reminders affect non-attendance and late cancellation rates in a secondary paediatric outpatient centre. METHODS: Non-attendances and late cancellations in children and adolescents aged 0-19 years of age were recorded prospectively during a year before and after the introduction of automatic SMS text messaging reminders. In a telephone interview, the families of late-cancelling patients were asked about the reasons for their cancellation. RESULTS: During the year before the introduction of SMS reminders, the clinic had 4,556 scheduled appointments in 1,466 patients (878 boys (59.9%) and 588 girls (40.1%); the year after the introduction, the clinic had 4,464 scheduled appointments in 1,424 patients (828 boys (58.1%) and 579 girls (41.9%). Before the introduction, 163 (4.3%) non-attendances and 162 (3.5%) late cancellations were recorded; after the introduction, 67 (1.5%) (p < 0.001) non-attendances and 177 (4.0%) (p = 0.28) late cancellations were recorded. During the no-SMS and SMS period, a total of 85 (52.5%) and 115 (65%) (p = 0.26), late cancelling families, respectively, said that that they had forgotten the appointment and could not manage to visit. CONCLUSIONS: SMS text reminders only improved the non-attendance rate; they did not influence the late cancellation rate. Most late cancellations were explained by forgetfulness. FUNDING: none TRIAL REGISTRATION: not relevant.

Questionnaire about the risk of growth suppression of inhaled corticosteroids.

BACKGROUND: Inhaled corticosteroids are associated with a risk of growth suppression in children. The aim of the present study was to assess what children with asthma, lay people and paediatricians feel about the risk of growth suppression by inhaled corticosteroids. METHODS: A questionnaire was completed by seven populations consisting of 9-19 years old children and adolescents with asthma; 9-19 year olds with another chronic illness; healthy 9-19 year olds; parents to children with chronic conditions; parents to healthy schoolchildren; young adults; and paediatricians. RESULTS: A total of 1216 individuals completed the questionnaire. A total of 867 individuals (74.6%) would not worry about a risk of 1-year growth suppression in the range of 0.5-2 cm (range: 233 (63.3%) in parents to patients in a secondary referral centre to 59 (86.8%) in the group of paediatricians (χ 2 53.3, df 12, p<0.001; γ -223, error 0.042, p<0.001). A total of 745 individuals (64.3%) said that a loss in final height of 0.5-2 cm would not worry them (range: 34 (54.0%) in paediatricians to 119 (76.3%) in parents to healthy children (χ 2 49.5, df 12, p<0.001; γ -0.073, error 0.039, p=0.06). CONCLUSIONS: Most children with asthma, lay people and paediatricians do not worry about the risk of growth suppression of inhaled corticosteroids in the range up to 2 cm. Paediatricians worry less about the risk of 1-year growth suppression but more about final height suppression than children with asthma and other groups of children and adults. Paediatricians need to address the different concerns of some of their patients on this issue.

Molecular Allergy Diagnostics as an Adjunct to Conventional Diagnostics in a Secondary Pediatric Referral Center.

BACKGROUND: Several compositions for determination of specific molecular components in allergens have recently been patented. The role of Molecular Allergy (MA) diagnostics in suspected IgE mediated allergic conditions is currently debated. Guideline reports have concluded that population- based studies involving evaluation of the usefulness of MA diagnostics are needed. OBJECTIVE: To evaluate the usefulness of MA diagnostics in a secondary pediatric referral center. METHODS: A total of 961 children and adolescents aged 0.2-18.8 (mean 7.0) years was included in a prospective observational survey. Inclusion criterion was a suspected diagnosis of an IgE mediated condition based on history and clinical symptoms and signs. If a specific diagnosis could not be reached from conventional investigations suspected peanut allergy, birch pollen allergy and associated crossreactivity, insect allergy and triggering allergens for specific immunotherapy were assessed by MA diagnostics. RESULTS: Based on conventional work-up a diagnostic conclusion was established in 946 patients (98.4%). MA diagnostics were performed in 15 individuals (1.6%), 7 girls and 8 boys aged 3.2 to 17.8 (mean 10.6) years. In 8 cases a specific diagnosis was established based on MA diagnostics; in 7 cases MA diagnostics could not improve diagnosis. MA were most frequently (N = 7 (14%)) used in children with peanut allergy (N = 50). CONCLUSION: Most patients in a secondary pediatric referral center with suspected IgE mediated allergy can be managed by conventional diagnostic methods. MA diagnostics may be useful in small and selected subgroups as in patients with suspected peanut allergy, however, may not be helpful in all cases.

Non-attendance in a secondary paediatric referral centre.

INTRODUCTION: Non-attendance in outpatient clinics may be associated with risks to patients' health, disturb the management of clinics and cause a waste of healthcare resources. The aim of the present study was to measure the non-attendance rate in a secondary paediatric outpatient centre and to assess reasons for non-attendance. METHODS: Non-attendance in children and adolescents aged 0-19 years were recorded prospectively during a year. In a telephone interview, the families of non-attending patients were asked about their reasons for non-attending. RESULTS: The number of scheduled attendances in 1,466 patients was 4,566. A total of 196 non-attendances (4.3%) were recorded in 167 patients (11.4%); 129 were boys (77.2%), 38 girls (22.8%). Patients aged 10-19 years had a higher frequency of non-attendance than patients in the 0-9-year age group (16% (115/715) versus 7% (52/751), respectively, p < 0.001). A total of 110 families (65.9%) stated that the reason for their non-attendance was that they had forgotten the appointment; 19 (11.4%) said that the family had decided not to show up because they had considered that their child had recovered. CONCLUSIONS: The non-attendance rate in the secondary paediatric referral centre studied was low. The majority of non-attendance may be explained by forgetfulness. FUNDING: none. TRIAL REGISTRATION: not relevant.

Prednisolone Effects on Urine Cross-Linked N-Telopeptides of Type I Collagen (Ntx) Diurnal Rhythms in Children.

BACKGROUND: Recently, methods for mimicking endogenous cortisol rhythms hereby potentially reducing the risk of systemic adverse effects of exogenous corticosteroids have been patented. Methods for sensitive detection of adverse effects on bone turnover of various doses, administration routes and regimens of exogenous corticosteroids have been patented. Urine cross-linked Ntelopeptides of Type I collagen (Ntx) have been established as a sensitive bone resorption marker and urine levels of Ntx have been found to exhibit a distinct diurnal rhythm. OBJECTIVE: To assess whether the timing of administration of prednisolone affects the diurnal rhythm of Ntx in urine. METHODS: Four girls and four boys aged 10.6 to 15.8 (mean 13.2) years with normal weight and height and pubertal stages I-IV were studied in an open randomized 2-periods cross-over trial, with a 1-day run in, and two 4-day periods of 5mg prednisolone in the morning and in the evening, respectively, separated by a 3-week washout period. At run in and on the last day of each treatment period, the first sample of urine was collected from 24.00 to 08.00h in the morning of the day of investigation. Thereafter, urine was collected in 4~hour intervals until 24.00 and in another 08.00h interval from 24.00 to 08.00h. RESULTS: Compared to run in and morning prednisolone treatment urine Ntx levels were suppressed from 24.00 to 8.00h during treatment with prednisolone in the evening (P < 0.01 for both comparisons) and no statistically significant circadian rhythm was observed. During morning prednisolone treatment Ntx trough and peak levels occurred from 16.00 to 20.00 and 24.00 to 08.00h, respectively, and the Ntx levels were significantly reduced from 12.00 to 20.00h as compared to run in (P < 0.005) and prednisolone treatment in the evening (P < 0.01). CONCLUSIONS: Depending on the time of administration, prednisolone interferes with diurnal rhythms in urine Ntx.

A Pilot Study of the Normative Range of Overnight Urinary Free Cortisol Corrected for Creatinine in Children.

BACKGROUND: For more than a decade, urinary free cortisol corrected for creatinine (OUFCC) has been used to assess the systemic bioactivity of inhaled corticosteroids in children with asthma. Paediatric normative ranges, however, have not been established. The aim of the present study was to define a preliminary range for OUFCC in Tanner stage 1 children. METHODS: A post hoc analysis was performed of 26 Tanner stage one children (aged 5-11 years) with mild asthma only requiring prn (pro re nata) treatment with short-acting ß2-agonists, who participated in a 3-way cross-over knemometry study. The study comprised a run-in, two washout periods and three treatment periods (2 weeks each). Urine was collected at the end of each period. A normative range was derived using the 95% prediction interval for the geometric mean OUFCC, calculated from run-in and washout periods. RESULTS: Twenty-six children contributed 41 OUFCC values. The geometric mean OUFCC was 9.0 nmol/mmol (95% PI: 3.6, 22.7 nmol/mmol). CONCLUSIONS: The OUFCC preliminary normative range was 3.6 to 22.7 nmol/mmol in Tanner stage one children. A larger study in healthy children is warranted to confirm these findings and to assess potential differences in OUFCC across developmental stages and age groups, and by gender and race. EUDRACT NUMBER: 2013-004719-32, CLINICALTRIALS. GOV IDENTIFIER: NCT02063139.

The timing of administration of exogenous glucocorticoid affects 24hour growth hormone secretion in children.

Exogenous glucocorticoids may suppress linear growth by affecting the diurnal secretory rhythm of GH. OBJECTIVE: To assess whether the timing of exogenous glucocorticoid administration affects GH secretion in children. DESIGN: Four girls and four boys aged 10.6 to 15.8 (mean 13.2) years with normal weight and height and pubertal stages I-IV were studied in an open randomized 2-period cross-over trial, with a 1-day un-in, and two 4-day periods of 5mg prednisolone in the morning or in the evening, respectively, separated by a 3-week washout period. At run-in and on the last day of each treatment period serum was collected every 20min for 24h for assessment of GH. Secondary analyses were serum levels of IGF-I and IGFBP-3 (measured every 8h), and IGFBP-1, insulin, and collagen markers PICP, PINP, ICTP and PIIINP (measured every 2h). RESULTS: Evening prednisolone suppressed 24hour GH secretion (P=0.016), overnight GH secretion (P=0.023) and IGF-I (P=0.024) when compared to morning prednisolone, but not when compared to run-in. Evening prednisolone also increased nocturnal insulin levels as compared to run-in (P=0.010). Irrespective of time of day, prednisolone increased serum collagen markers PICP, PIINP, ICTP and PINP (all P<0.05). CONCLUSIONS: Short-term prednisolone 5mg administered in the morning may alleviate nocturnal GH suppression as compared to evening administration. In analogy, growth rates are less affected by morning as compared to evening administration of exogenous glucocorticoids. In contrast, collagen markers and metabolic indices were not affected by the timing of prednisolone administration.

Short-Term Growth During Treatment with Inhaled Fluticasone Propionate/Formoterol, Fluticasone and Beclomethasone Treatment.

BACKGROUND: Fluticasone propionate/formoterol (FP/FORM) is a pressurized metered-dose inhaler (pMDI; Flutiform®) approved for use in adolescents and adults and under development for pediatric use. OBJECTIVE: To compare short-term growth in asthmatic children treated with FP/FORM, FP pMDI with valved holding chamber, and beclomethasone dipropionate (BDP) in a breath-actuated device. METHODS: Children with persistent asthma (n = 48; 5 to <12 years) participated in an assessor-blinded, randomized, three-way crossover trial with run in, wash out, and active treatment periods, each of 2 weeks duration. Interventions were FP/FORM 100/10 µg b.i.d. with an AeroChamber Plus® Flow-Vu® Spacer, FP pMDI (Flixotide®) 100 µg b.i.d. with a Volumatic® spacer, and extra-fine BDP breath-actuated inhaler (Aerobec®/QVAR® Autohaler®) 100 µg b.i.d. Lower leg growth rate (LLGR) was measured by knemometry. RESULTS: The least square (LS) mean difference in LLGR between FP/FORM and FP (per protocol population) was -0.006 mm/week (95% CI: -0.095 to 0.084; p < 0.001 for noninferiority [noninferiority margin -0.200 mm/week]). Both treatments elicited no change from baseline off-treatment growth rate. The LS mean treatment difference of FP/FORM versus BDP was 0.116 mm/week (95% CI: -0.004 to 0.235; p = 0.057) and of FP versus BDP 0.163 mm/week (95% CI: 0.078-0.249; p < 0.001). Results in the full analysis population were: FP/FORM versus FP -0.012 mm/week (95% CI: -0.080-0.056; p < 0.001); FP/FORM versus BDP 0.143 mm/week (95% CI: 0.064-0.222; p < 0.001); FP versus BDP 0.163 mm/week (95% CI: 0.093-0.233; p < 0.001). CONCLUSIONS: FP/FORM pMDI with AeroChamber and FP pMDI with Volumatic spacer did not affect lower leg growth, measured by knemometry, in asthmatic children. Conversely, extra-fine BDP from a breath-actuated inhaler resulted in short-term growth suppression.

Knemometry Assessment of Short-term Growth in Children With Asthma Receiving Fluticasone Furoate for 2 Weeks: A Randomized, Placebo-controlled, Crossover Trial.

PURPOSE: A dry powder inhaler formulation of the inhaled corticosteroid fluticasone furoate (FF) is being evaluated for use in children. An important potential risk associated with the use of inhaled corticosteroids in children is growth suppression. Therefore, the aim of this study was to assess the short-term lower leg growth in children with asthma treated for 2 weeks with inhaled FF versus placebo from the ELLIPTA inhaler. METHODS: Prepubertal children with persistent asthma (n = 60; aged 5 to <12 years) were recruited into a randomized, double-blind, placebo-controlled, 2-way crossover, noninferiority study. The study consisted of four 2-week periods: run-in, 2 treatment periods, 1 washout period, and a 1-week follow-up period. Interventions were FF 50 µg and placebo once daily in the evening. Lower leg length was measured by using knemometry. FINDINGS: The randomized ITT population comprised 36 boys and 24 girls with a mean age of 8.7 (standard deviation, 1.5; range, 5-11) years; 58% had a duration of asthma ≥5 years. Fifty-eight subjects completed both treatment periods. The least squares mean growth rate was 0.31 mm/week during treatment with FF and 0.36 mm/week during the placebo period. The difference in adjusted least squares mean growth rates between FF and placebo was -0.052 mm/week with a 95% CI of -0.122 to 0.018. This finding was greater than the prespecified noninferiority margin of -0.20 mm/week. The overall incidence of adverse events was 35% with placebo and 22% with FF. IMPLICATIONS: Inhaled FF 50 µg provided once daily for 2 weeks was noninferior to placebo in terms of effects on short-term lower leg growth in children with asthma. To further quantify the risk of growth suppression in children, intermediate-term growth studies should be conducted. Inhaled FF 50 µg was well tolerated in this study population. ClinicalTrials.gov identifier: NCT02502734.

Pubertal Progression and Reproductive Hormones in Healthy Girls With Transient Thelarche.

Context: Detailed evaluation of pubertal progression in girls from longitudinal studies is sparse, and the phenomenon of transient thelarche (TT), defined as the appearance, regression, and subsequent reappearance of breast buds, in healthy girls remains undescribed. Objective: To describe TT in terms of pubertal progression, growth, genotypes, and reproductive hormones and to apply new puberty nomograms for breast stages, pubic hair, and menarche. Design: A prospective, longitudinal population-based study. Patients or Other Participants: Ninety-eight healthy Danish schoolchildren (Caucasian girls) followed longitudinally as part of the COPENHAGEN Puberty Study were included in the evaluation of TT. A total of 1466 girls from 2 cross-sectional studies were included in the creation of the puberty nomograms. Intervention(s): None. Main Outcome Measure(s): Pubertal progression, specifically thelarche, reproductive hormones, genotype, and growth. Results: Twelve of 98 (12%) girls experienced TT. A larger proportion of girls with TT entered puberty by the pubarche pathway (50%) compared with girls with normal progression (15.4%), P = 0.014. Girls with TT progressed through puberty normally when evaluated using puberty nomograms. Reproductive hormones and growth velocity were lower at the first (transient) thelarche than the second (permanent) thelarche. Conclusion: TT is a frequent phenomenon that appears to be a peripheral occurrence independent of central puberty. It does not appear to affect subsequent pubertal progression as evaluated by our new puberty nomograms.

[The sick songs].

Popular music is ubiquitous, and musicians and songwriters have similar experiences with disease as other people. The aim of this review was to analyze popular songs' content of descriptions of diseases. The most frequently occurring symptom was fever, mostly a metaphor for lovesickness or sexual orgasm. The most frequent and complete descriptions of diseases were in respiratory and psychiatric ailments. In conclusion, popular songs may provide valuable descriptions of symptoms and disease of educational importance to doctors.

Budesonide + formoterol fumarate dihydrate for the treatment of asthma.

INTRODUCTION: One of the most widely used fixed combinations in asthma management is dry powder budesonide+formoterol fumarate dihydrate which is commercially available as Symbicort Turbuhaler(®) (and generic products), Easyhaler Bufomix(®) and DuoRespSpiromax(®) inhaler. The aim of this paper was to review the fixed dry powder combination of inhaled budesonide+formoterol fumarate dihydrate for asthma treatment in adolescents and adults. AREAS COVERED: A literature search using relevant search terms, reference lists for reviews and meta-analyses was performed. EXPERT OPINION: In symptomatic adolescent and adult patients with asthma maintenance and reliever therapy with a single-inhaler fixed combination of dry powder budesonide+formoterol fumarate dihydrate is an evidenced option. The combination treatment is convenient to patients. It reduces the number of exacerbations requiring treatment with oral corticosteroids. In some patients the strategy may also reduce the total intake of inhaled corticosteroids over time. Whether important outcome measures of asthma treatment, such as hospital admission and emergency room visit rates, may be reduced is less well documented since the published studies may have been influenced by publication bias. Non-pharmaceutical company-sponsored research evaluating such measures is needed. There is no evidence for the use of single inhaler fixed combinations of inhaled corticosteroids+long-acting ß(2)-agonists in children (<12 years of age), and budesonide+formoterol fumarate dihydrate should not be prescribed to the age group.

Extra-fine particle inhaled corticosteroids, pharma-cokinetics and systemic activity in children with asthma.

During recent years, extra-fine particle inhaled corticosteroids with a median aerodynamic diameter ≤2 µm have been introduced in the treatment of asthma. The aim of this paper was to review pharmacokinetics and systemic activity of extra-fine particle hydroalkane pressurized metered dose inhaled (pMDI) ciclesonide and beclomethasone dipropionate in children. A literature review was performed. Systemic bioavailability of oral and pulmonary deposition of extra-fine ciclesonide and beclomethasone dipropionate was 52% and 82%, the half-life in serum 3.2 and 1.5 h and first-pass hepatic metabolism >99% and 60%, respectively. Secondary analyses of urine cortisol/creatinine excretion found no effects of ciclesonide pMDI between 40 and 320 µg/day or of beclomethasone dipropionate pMDI between 80 and 400 µg/day. Ciclesonide pMDI 40, 80 and 160 µg/day caused no effects on short-term lower leg growth rate as assessed by knemometry. Ciclesonide 320 µg/day was associated with a numerically short-term growth suppression equivalent to 30% which was similar to 25% and 36% suppression caused by beclomethasone dipropionate HFA and CFC 200 µg/day, respectively. Consistent with the differences in key pharmacokinetic features, beclomethasone dipropionate is associated with a systemic activity detected by knemometry at a lower dose than ciclesonide. Whether that correlates with a clinically important difference remains to be explored. Assessments of systemic activity of beclomethasone dipropionate <200 µg/day and of ciclesonide >180 µg/day as well as head-to-head comparisons are warranted. Preferably, such studies should apply the sensitive method of knemometry.

Pharmacokinetics and Systemic Activity of a New Patent of an Inhaled Corticosteroid/Long-Acting ß2-Agonist Combination for Use in Asthma Therapy: Fluticasone Furoate/Vilanterol Trifenatate.

The present paper reviews pharmacokinetics and systemic activity of a new patent of fluticasone fumarate/vilanterol trifenatate and summarises the efficacy data in children, adolescents and adults with asthma. Bioavailability of oral deposition of fluticasone furoate is approximately 1%, of oral and pulmonary deposition 15%. Fluticasone furoate 400, 600 and 800 µg have been associated with reductions in 24h urine cortisol excretion in adults, whereas several studies on fluticasone furoate/ vilanterol trifenatate 100/25 µg and 200/25 µg once daily found no suppressive effects. Bronchodilation was detected in adults with asthma from 5 minutes after vilanterol trifenatate was inhaled and up to 24 hours after. Five large clinical trials which were sponsored by the manufacturer GlaxoSmithKline provided evidence that dry powder fluticasone furoate/vilanterol trifenatate 100/25 µg and 200/25 µg once daily are efficacious in asthma in patients ≥ 12 years of age. It remains to be proven, however, that once daily dosing may improve asthma control as compared to twice daily dosing. Efficacy and the systemic activity potential for hypothalamic-pituitary-adrenal and growth suppression of fluticasone furoate have not been established in children. The potential for systemic activity of fluticasone furoate in children may be assessed by knemometry.

A Comparison of Short-Term Growth During Treatment with Two Dry Powder Combinations of Inhaled Corticosteroids and Long-Acting ß2-Agonists.

BACKGROUND: A combination of the inhaled corticosteroid budesonide and the long-acting ß2-agonist formoterol has been formulated in a novel dry powder inhaler, Spiromax(®). The objective was to compare lower leg growth in children with asthma treated with inhaled budesonide+formoterol (BF) delivered from the Spiromax inhaler with BF from the Symbicort Turbohaler(®). METHODS: Prepubescent children with persistent asthma (n=75, aged 6-11 years) were included in a randomized, double-blind, double-dummy, placebo-controlled, three-way crossover study with active treatment and placebo periods of 2 weeks duration. Lower leg length was measured every second week. As a secondary outcome parameter, 24-hr urine was collected for assessment of free cortisol. Interventions were dry powder BF 160+9 µg twice daily (b.i.d.; delivered dose) from the Spiromax inhaler and dry powder BF 200+12 µg b.i.d. (metered dose) from the Symbicort Turbohaler. RESULTS: The least squares mean difference in lower leg growth rates (LLGR) between BF Spiromax and Symbicort Turbohaler was -0.086 mm/week [95% confidence interval (CI) -0.203, 0.032]. The pre-specified non-inferiority margin was -0.200 mm/week, so the lower limit of the 95% CI was just outside this margin. The difference between BF Spiromax and placebo was -0.20 mm/week (95% CI: -0.322, 0.086); p<0.001), between Symbicort Turbohaler and placebo -0.118 mm/week (95% CI: -0.236, -0.001; p=0.048). No statistically significant differences were seen in urine free cortisol assessments. CONCLUSIONS: As the lower limit of the CI of LLGR was marginally outside of the pre-specified non-inferiority margin between BF Spiromax 160+9 µg b.i.d. and Symbicort Turbohaler 200+12 µg b.i.d., non-inferiority could not be demonstrated. Further studies may be needed for comparison of systemic activity of BF Spiromax and Symbicort Turbohaler in children before firm conclusions about their comparability may be drawn.

Reference intervals for insulin-like growth factor-1 (igf-i) from birth to senescence: results from a multicenter study using a new automated chemiluminescence IGF-I immunoassay conforming to recent international recommendations.

CONTEXT: Measurement of IGF-I is a cornerstone in diagnosis and monitoring of GH-related diseases, but considerable discrepancies exist between analytical methods. A recent consensus conference defined criteria for validation of IGF-I assays and for establishment of normative data. OBJECTIVES: Our objectives were development and validation of a novel automated IGF-I immunoassay (iSYS; Immunodiagnostic Systems) according to international guidelines and establishment of method-specific age- and sex-adjusted reference intervals and analysis of their robustness. SETTING AND PARTICIPANTS: We conducted a multicenter study with samples from 12 cohorts from the United States, Canada, and Europe including 15 014 subjects (6697 males and 8317 females, 0-94 years of age). MAIN OUTCOME MEASURES: We measured concentrations of IGF-I as determined by the IDS iSYS IGF-I assay. RESULTS: A new IGF-I assay calibrated against the recommended standard (02/254) and insensitive to the 6 high-affinity IGF binding proteins was developed and rigorously validated. Age- and sex-adjusted reference intervals derived from a uniquely large cohort reflect the age-related pattern of IGF-I secretion: a decline immediately after birth followed by an increase until a pubertal peak (at 15 years of age). Later in life, values decrease continuously. The impact of gender is small, although across the lifespan, women have lower mean IGF-I concentrations. Geographical region, sampling setting (community or hospital based), and rigor of exclusion criteria in our large cohort did not affect the reference intervals. CONCLUSIONS: Using large cohorts of well-characterized subjects from different centers allowed construction of robust reference ranges for a new automated IGF-I assay. The strict adherence to recent consensus criteria for IGF-I assays might facilitate clinical application of the results.