Failure of a repeat course of cyclooxygenase inhibitor to close a PDA is a risk factor for developing chronic lung disease in ELBW infants

<p>Abstract</p> <p>Background</p> <p>The optimal treatment regimen or protocol for managing a persistent patent ductus arteriosus (PDA) in extremely low birth weight (ELBW) infants has not been well established. This study was aimed at evaluating the failure rate of a cyclooxygenase (COX) inhibitor (COI) for PDA closure and to determine the incidence of a PDA requiring ligation in ELBW infants. We examined the clinical characteristics and risk factors that may predict the clinical consequences of failure of PDA closure by COI.</p> <p>Methods</p> <p>Medical information on 138 infants with birth weight (BW) < 1000 gm who survived for > 48 hours was retrieved. Clinical characteristics and outcomes of patients whose PDAs closed with COI were compared with those who did not close.</p> <p>Results</p> <p>Of the 138 patients, 112 survived to discharge. Eighty (71.4%) of those who survived received 1-3 courses of COI treatment for a symptomatic PDA. A total of 32 (40%) failed COI treatment and underwent PDA ligation. Multivariable logistic regression analysis suggests that the observed differences in the outcomes in infants with or without symptomatic PDA can be explained by the babies with symptomatic PDA being more immature and sicker. No significant difference was seen in the incidence of chronic lung disease (CLD) in infants whose PDA was treated medically versus those who failed medical treatment and then underwent ligation. However, after adjusting for disease severity and other known risk factors, the odds ratio of developing CLD for surviving babies with a persistent PDA compared to those whose PDA was successfully closed with 1-2 courses of COI is 3.24 (1.07-9.81; p = 0.038).</p> <p>Conclusions</p> <p>When successfully treated, PDA in ELBW infants did not contribute significantly to the adverse outcomes such as CLD, retinopathy of prematurity (ROP) and age at discharge. This suggests that it is beneficial for a hemodynamically significant PDA to be closed. The failure of a repeat course of COI to close a PDA is a major risk factor for developing CLD in ELBW infants.</p

TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum

Ciliary dysfunction leads to a broad range of overlapping phenotypes, termed collectively as ciliopathies. This grouping is underscored by genetic overlap, where causal genes can also contribute modifying alleles to clinically distinct disorders. Here we show that mutations in TTC21B/IFT139, encoding a retrograde intraflagellar transport (IFT) protein, cause both isolated nephronophthisis (NPHP) and syndromic Jeune Asphyxiating Thoracic Dystrophy (JATD). Moreover, although systematic medical resequencing of a large, clinically diverse ciliopathy cohort and matched controls showed a similar frequency of rare changes, in vivo and in vitro evaluations unmasked a significant enrichment of pathogenic alleles in cases, suggesting that TTC21B contributes pathogenic alleles to ∼5% of ciliopathy patients. Our data illustrate how genetic lesions can be both causally associated with diverse ciliopathies, as well as interact in trans with other disease-causing genes, and highlight how saturated resequencing followed by functional analysis of all variants informs the genetic architecture of disorders