Outside the Box

Einstein wrote, "you can never solve a problem on the level on which it was created." So we decided to ask diverse groups of randomly selected Arizona citizens to consider health care reform options, rather than continuing to ask health care industry veterans and experts. The ensuing dialogues and their ultimate recommendations are likely to surprise readers as much as they surprised the citizen, civic and business leader participants

Moving Along the Learning Curve: From Values to Public Judgment: Citizen Dialogues on K-12 Education Reform

Based on dialogues with California's public, policy makers, and other stakeholders, assesses the public's priorities for K-12 reform and support for giving districts more authority and resources to meet state standards. Includes implications for leaders

Health Coverage for All Californians: Catching Up With the Public: A Report on Dialogues With the Public and With Business and Civic Leaders

Presents findings on healthcare reforms both employers and the public would support. Assesses the public's support for government-sponsored comprehensive coverage, its concerns about a public health system, and implications for future reform proposals

Voices for Health Care: Public Engagement to Advance Significant Health Care Reform

This document is a progress report from the advocacy group Viewpoint Learning, Inc., on their efforts for health care reform

Voices for Health Care: Public Engagement to Advance Significant Health Care Reform (Progress Report)

Reviews outcomes of discussions with the public and healthcare, political, civic, and business leaders in Kansas, Mississippi, and Ohio and other outreach efforts on healthcare reform choices. Includes a toolkit for conducting community dialogues

Copy Number Variant Analysis and Genome-wide Association Study Identify Loci with Large Effect for Vesicoureteral Reflux

BACKGROUND: Vesicoureteral reflux (VUR) is a common, familial genitourinary disorder, and a major cause of pediatric urinary tract infection (UTI) and kidney failure. The genetic basis of VUR is not well understood. METHODS: A diagnostic analysis sought rare, pathogenic copy number variant (CNV) disorders among 1737 patients with VUR. A GWAS was performed in 1395 patients and 5366 controls, of European ancestry. RESULTS: Altogether, 3% of VUR patients harbored an undiagnosed rare CNV disorder, such as the 1q21.1, 16p11.2, 22q11.21, and triple X syndromes ((OR, 3.12; 95% CI, 2.10 to 4.54; P=6.35×10(−8)) The GWAS identified three study-wide significant and five suggestive loci with large effects (ORs, 1.41–6.9), containing canonical developmental genes expressed in the developing urinary tract (WDPCP, OTX1, BMP5, VANGL1, and WNT5A). In particular, 3.3% of VUR patients were homozygous for an intronic variant in WDPCP (rs13013890; OR, 3.65; 95% CI, 2.39 to 5.56; P=1.86×10(–9)). This locus was associated with multiple genitourinary phenotypes in the UK Biobank and eMERGE studies. Analysis of Wnt5a mutant mice confirmed the role of Wnt5a signaling in bladder and ureteric morphogenesis. CONCLUSIONS: These data demonstrate the genetic heterogeneity of VUR. Altogether, 6% of patients with VUR harbored a rare CNV or a common variant genotype conferring an OR >3. Identification of these genetic risk factors has multiple implications for clinical care and for analysis of outcomes in VUR

The copy number variation landscape of congenital anomalies of the kidney and urinary tract

Congenital anomalies of the kidney and urinary tract (CAKUT) are a major cause of pediatric kidney failure. We performed a genome-wide analysis of copy number variants (CNVs) in 2,824 cases and 21,498 controls. Affected individuals carried a significant burden of rare exonic (that is, affecting coding regions) CNVs and were enriched for known genomic disorders (GD). Kidney anomaly (KA) cases were most enriched for exonic CNVs, encompassing GD-CNVs and novel deletions; obstructive uropathy (OU) had a lower CNV burden and an intermediate prevalence of GD-CNVs; and vesicoureteral reflux (VUR) had the fewest GD-CNVs but was enriched for novel exonic CNVs, particularly duplications. Six loci (1q21, 4p16.1-p16.3, 16p11.2, 16p13.11, 17q12 and 22q11.2) accounted for 65% of patients with GD-CNVs. Deletions at 17q12, 4p16.1-p16.3 and 22q11.2 were specific for KA; the 16p11.2 locus showed extensive pleiotropy. Using a multidisciplinary approach, we identified TBX6 as a driver for the CAKUT subphenotypes in the 16p11.2 microdeletion syndrome