How can we optimise inhaled beta2 agonist dose as ‘reliever’ medicine for wheezy pre-school children? Study protocol for a randomised controlled trial

Background: Asthma is a common problem in children and, if inadequately controlled, may seriously diminish their quality of life. Inhaled short-acting beta2 agonists such as salbutamol are usually prescribed as ‘reliever’ medication to help control day-to-day symptoms such as wheeze. As with many medications currently prescribed for younger children (defined as those aged 2 years 6 months to 6 years 11 months), there has been no pre-licensing age-specific pharmacological testing; consequently, the doses currently prescribed (200–1000 μg) may be ineffective or likely to induce unnecessary side effects. We plan to use the interrupter technique to measure airway resistance in this age group, allowing us for the first time to correlate inhaled salbutamol dose with changes in clinical response. We will measure urinary salbutamol levels 30 min after dosing as an estimate of salbutamol doses in the lungs, and also look for genetic polymorphisms linked to poor responses to inhaled salbutamol. Methods: This is a phase IV, randomised, controlled, observer-blinded, single-centre trial with four parallel groups (based on a sparse sampling approach) and a primary endpoint of the immediate bronchodilator response to salbutamol so that we can determine the most appropriate dose for an individual younger child. Simple randomisation will be used with a 1:1:1:1 allocation. Discussion: The proposed research will exploit simple, non-invasive and inexpensive tests that can mostly be performed in an outpatient setting in order to help develop the evidence for the correct dose of salbutamol in younger children with recurrent wheeze who have been prescribed salbutamol by their doctor. Trial registration: EudraCT2014-001978-33, ISRCTN15513131. Registered on 8 April 2015

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways

Monitoring respiration in wheezy preschool children by pulse oximetry plethysmogram analysis

The aim of this study was to investigate whether respiratory information can be derived from pulse oximetry plethysmogram (pleth) recordings in acutely wheezy preschool children. A digital pulse oximeter was connected via 'Bluetooth' to a notebook computer in order to acquire pleth data. Low pass filtering and frequency analysis were used to derive respiratory rate from the pleth trace; the ratio of heart rate to respiratory rate (HR/RR) was also calculated. Recordings were obtained during acute wheezy episodes in 18 children of median age 31 months and follow-up recordings from 16 of the children were obtained when they were wheeze-free. For the acutely wheezy children, frequency analysis of the pleth waveform was within 10 breaths/min of clinical assessment in 25 of 29 recordings in 15 children. For the follow-up measurements, frequency analysis of the pleth waveform showed similarly good agreement in recordings on 15 of the 16 children. Respiratory rate was higher (p < 0.001), and HR/RR ratio was lower (p = 0.03) during acute wheeze than at follow-up. This study suggests that respiratory rate can be derived from pleth traces in wheezy preschool children

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways