Utilization and safety of proton-pump inhibitors and histamine-2 receptor antagonists in children and adolescents: an observational cohort study

<p><b>Background:</b> Little is known about the use of acid-suppressing treatments and related safety events in children.</p> <p><b>Objective:</b> This study compared patient characteristics and safety outcomes among children prescribed acid-suppressing drugs for the first time.</p> <p><b>Methods:</b> The Health Improvement Network was used to determine the characteristics of children prescribed a proton pump inhibitor (PPI; esomeprazole or another PPI) or a histamine-2 receptor antagonist (H₂RA) by UK primary care physicians between October 2009 and September 2012. Pre-defined safety outcomes were compared among the treatment groups in up to 18 months of follow-up.</p> <p><b>Results:</b> The cohorts comprised 8,172 patients on PPIs (including 24 patients on esomeprazole) and 7,905 on H₂RAs. The baseline characteristics were similar between cohorts, although the children in the PPI cohorts tended to be older. No safety outcomes occurred in the esomeprazole cohort. In the other-PPIs cohort, 92 safety outcomes occurred, most commonly gastroenteritis (<i>n</i> = 36; 39.1%). In the H₂RAs cohort, 193 safety outcomes occurred, most commonly gastroenteritis (<i>n</i> = 62; 32.1%). The incidence of most safety outcomes was higher in the H₂RAs cohort than in the other-PPIs cohort, including failure to thrive (3.11 [95% confidence interval (CI) = 2.25–4.28] vs 0.49 per 1,000 person-years [95% CI = 0.22–1.07]) and gastroenteritis (5.27 [95% CI = 4.11–6.75] vs 3.04 per 1,000 person-years [95% CI = 2.20–4.20]).</p> <p><b>Conclusion:</b> Esomeprazole is rarely prescribed to children when they first require acid-suppressing medication, compared with other PPIs/H₂RAs. Overall, more safety outcomes occurred in the H₂RAs cohort than in the PPI cohorts.</p

Rare and low-frequency coding variants alter human adult heigh

Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways