Adult fracture nonunion risk is related to injury severity and surgical technique, yet nonunion is not fully explained by these risk factors alone; biological risk factors are also important. We test a hypothesis that risk factors associated with pediatric fracture nonunion are similar to adult nonunion risk factors.Inception cohort study in a large payer database of pediatric fracture patients (0–17 years) in the United States in calendar year 2011. Continuous enrollment in the database was required for 12 months, to allow time to capture a nonunion diagnosis. The final database collated demographic descriptors, treatment procedures as per Current Procedural Terminology (CPT) codes, comorbidities as per International Statistical Classification of Diseases and Related Health Problems (ICD-9) codes, and drug prescriptions as per National Drug Code Directory (Red Book) codes. Logistic regression was used to calculate odds ratios (ORs) for variables associated with nonunion.Among 237,033 pediatric fractures in 18 bones, the nonunion rate was 0.85%. Increased nonunion risk was associated with increasing age, male gender, high body-mass index, severe fracture (e.g., open fracture, multiple fractures), and tobacco smoking (all, P < .0001). Nonunion rate varied with fracture location; scaphoid, neck of femur, and tibia/fibula were most likely to go to nonunion. Nonunion ORs were significantly increased for risk factors including; surgical procedure, cardiovascular disease, Vitamin D deficiency, osteoarthritis, osteoporosis, and opioid prescription (all, multivariable P < .001).Nonunion is rare in pediatric patients, but nonunion risk increases with increasing age. We confirm a hypothesis that risk factors for pediatric nonunion are similar to adult nonunion risk factors. Scaphoid fractures in adolescents have nearly the same risk of nonunion as in adults. Opioids should be used cautiously in pediatric patients, as they are associated with a significant and substantial elevation of nonunion risk.Level of Evidence: Prognostic study, Retrospective, Level II.
Biliary atresia (BA) is a multifactorial pathogenic disease with possible genetic components. As a member of membrane skeletal proteins in the liver and bile ducts, a haplotype composed by five single nucleotide polymorphisms (SNPs) on adducin 3 (ADD3) has been identified as associated with BA. However, limited study was designed to further elaborate the mutual relationship amongst those replicated SNPs to disease. We selected three susceptibility SNPs in ADD3 and conducted a replication study using 510 BA cases and 1473 controls to evaluate the individual function of the SNPs and further stratified the potential roles with disease and its subclinical features. Two SNPs in ADD3 were replicated as associated with BA (1.60E-04 ≤ P≤1.70E-04, 1.33 ≤ odds ratio (OR) ≤ 1.58 for rs17095355, 2.10E-04 ≤ P≤5.30E-04, 1.26 ≤ OR ≤ 1.57 for rs2501577). Though we failed to replicate the individual association of rs10509906 to disease, the intragenic epistatic effect between rs10509906 and rs2501577 was suggested as exhibiting susceptibility to BA, further cross-validated by multifactor dimensionality reduction (MDR) (P=0.068, OR = 1.37), which may explain extra hidden heritability of ADD3 to BA. Furthermore, through subclinical stratification, we also observed the association of risk to disease mainly came from the female patients.
Identifying rare genetic variants that drive the onset of disease is challenging, even before considering the additional genetic and environmental influences that likely exist in complex diseases. We recently published a study proposing a rare variant in the NR1H3 gene (p.R415Q, rs61731956) as responsible for the onset of multiple sclerosis (MS) in two multi-incident families (Wang et al., 2016). This publication has generated much discussion, and fortunately the possibility to validate a finding or prove it spurious can occur rapidly in genetic studies. All novel discoveries must be replicated, and best efforts should be made to ensure that these replications use the appropriate samples and approach, and provide the correct interpretation of the results. This Matters Arising Response paper addresses the Minikel and MacArthur (2016) and The International Multiple Sclerosis Genetics Consortium (2016) Matters Arising papers, published concurrently in Neuron.
In view of great difficulties in the pathogenesis analysis of Alzheimer’s disease (AD) presently, profiling the modifiable risk factors is crucial for early detection and intervention of AD. However, the causal associations among them have yet to be identified, and the effective integration and application of these data also remain considerable challenges due to the lack of efficient collection and analysis procedures. To address this issue, we performed comprehensive analyses by two-sample Mendelian randomization (2SMR) and established the AlzRiskMR database (https://github.com/SDBMC/RiskFactors2AD). Four 2SMR analysis methods, including inverse variance weighted (IVW), MR-Egger, weighted median, and weighted mode, were used for the complementary calculation to test the reliability of the results. The database currently comprises 1870 sets of data of Genome-Wide Association Studies (GWAS) from the MR-Base and NHGRI-EBI GWAS Catalog database. AlzRiskMR database not only estimates causal associations between modifiable risk factors and AD but also offers a useful and timely resource for early intervention of AD development incidence.
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