Next-generation sequencing provides the opportunity to practice predictive medicine based on identified variants. Putative loss-offunction (pLOF) variants are common in genomes and understanding their contribution to disease is critical for predictive medicine. To this end, we characterized the consequences of pLOF variants in an exome cohort by iterative phenotyping. Exome data were generated on 951 participants from the ClinSeq cohort and filtered for pLOF variants in genes likely to cause a phenotype in heterozygotes. 103 of 951 exomes had such a pLOF variant and 79 participants were evaluated. Of those 79, 34 had findings or family histories that could be attributed to the variant (28 variants in 18 genes), 2 had indeterminate findings (2 variants in 2 genes), and 43 had no findings or a negative family history for the trait (34 variants in 28 genes). The presence of a phenotype was correlated with two mutation attributes: prior report of pathogenicity for the variant (p ¼ 0.0001) and prior report of other mutations in the same exon (p ¼ 0.0001). We conclude that 1/30 unselected individuals harbor a pLOF mutation associated with a phenotype either in themselves or their family. This is more common than has been assumed and has implications for the setting of prior probabilities of affection status for predictive medicine.

Introduction Hepatitis C virus (HCV) is the major cause of liver disease in hemophilia. Few data exist on the proportion with liver fibrosis in this group after long-term HCV and HIV co-infection. Aim We conducted a cross-sectional multi-center study to determine impact of HIV on the prevalence and risk factors for fibrosis in hemophilic men with chronic hepatitis C. Methods Biopsies were independently scored by Ishak, Metavir, and Knodell systems. Variables were tested for associations with fibrosis by logistic regression and receiver operating curves (ROC). Results Of 220 biopsied HCV(+) men, 23.6% had Metavir ≥F3 fibrosis, with higher mean Metavir fibrosis scores among HIV/HCV co-infected than HCV mono-infected, 1.6 vs. 1.3 (p=0.044). Variables significantly associated with fibrosis included AST, ALT, APRI score (AST/ULN×100/platelet ×109/L), alpha-fetoprotein (all p<0.0001), platelets (p=0.0003), and ferritin (p=0.0008). In multiple logistic regression of serum markers, alpha-fetoprotein, APRI, and ALT were significantly associated with ≥ F3 fibrosis, AUROC=0.77 (95%CI 0.69, 0.86). Alpha-fetoprotein, APRI, and ferritin were significant in HIV(−), (AUROC 0.82 (95%CI 0.72, 0.92), and alpha-fetoprotein and platelets in HIV(+) (AUROC=0.77 (95%CI 0.65, 0.88). In a multivariable model of demographic and clinical variables, transformed (natural logarithm) of alpha-fetoprotein (p=0.0003), age (p=0.006), and HCV treatment (p=0.027) were significantly associated with fibrosis. Conclusion Nearly one-fourth of hemophilic men have Metavir ≥ 3 fibrosis. The odds for developing fibrosis are increased in those with elevated alpha-fetoprotein, increasing age, and past HCV treatment.

No abstract

Kallikrein-4 is known to be highly expressed during the maturation stage of enamel formation and is thought to be critical for the final phase of crystallite growth. The purpose of this study was to evaluate the enamel phenotype in humans with a known KLK-4 mutation (g.2142G>A). Primary teeth from two individuals with a known KLK-4 mutation were evaluated using amino acid analysis and light and electron microscopy. Light microscopy showed the enamel was of normal thickness but opaque throughout its width compared with normal enamel. Electron microscopy showed enamel affected by the KLK-4 mutation had a normal prismatic structure and generally had a well-organized and discernable crystallite composition. In some areas, globular structures were present where crystallites were not discernable or appeared to have an altered morphology. The KLK-4 mutant enamel had an increased protein content compared with normal enamel. Human enamel formed with a lack of functioning KLK-4 proteinase is altered primarily in the completeness of crystallite growth, while enamel thickness and prism structure remains essentially normal. Collectively, these studies suggest that the KLK-4 proteinase is essential for the final crystallite growth of enamel but is not critical for crystallite orientation, prism formation or enamel thickness.

Maine's Growth Management law provides an opportunity to examine public attitudes about state-mandated local comprehensive planning. A survey revealed an overall favorable public reaction, but important differences appeared among some subgroups. It was apparent that some socioeconomic characteristics offered the best predictors of support for local comprehensive planning, although the literature is not consistent on this issue. Attitudes on related issues such as environmental spending and highway development were only weakly linked to those on comprehensive planning. The results suggest directions for public policy development in states considering passage of growth management laws.