Abstract:The effects of a job-training program on both employment and wages are evaluated, using data from a randomized study. Principal stratification is used to address, simultaneously, the complications of noncompliance, wages that are only partially defined because of nonemployment, and unintended missing outcomes. The first two complications are of substantive interest, whereas the third is a nuisance. The objective is to find a parsimonious model that can be used to inform public policy. We conduct a likelihood-based analysis using finite mixture models estimated by the EM algorithm. We maintain an exclusion restriction assumption for the effect of assignment on employment and wages for noncompliers, but not on missingness.We provide estimates under the Missing at Random assumption, and assess the robustness of our results to deviations from it. The plausibility of meaningful restrictions is investigated by means of scaled log-likelihood ratio statistics. Substantive conclusions include the following.For compliers, the effect on employment is negative in the short term; it becomes positive in the long term, but these effects are small at best. For always employed compliers, i.e., compliers who are employed whether trained or not trained, positive effects on wages are found at all time periods. Our analysis reveals that background characteristics of individuals differ markedly across the principal strata. We found evidence that the program should have been better targeted, in the sense of being designed differently for different groups of people, and specific suggestions are offered. Previous analyses of this data set, which did not address all complications in a principled manner, led to less nuanced conclusions about Job Corps.1

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Allosteric inhibition of the hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase enzyme has recently emerged as a viable strategy toward blocking replication of viral RNA in cell-based systems. We report here a novel class of allosteric inhibitor of NS5B that shows potent affinity for the NS5B enzyme and effective inhibition of subgenomic HCV RNA replication in HUH-7 cells. Inhibitors from this class have promising characteristics for further development as anti-HCV agents.

Infections caused by hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. Compounds that block replication of subgenomic HCV RNA in liver cells are of interest because of their demonstrated antiviral effect in the clinic. In followup to our recent report that indole-N-acetamides (e.g., 1) are potent allosteric inhibitors of the HCV NS5B polymerase enzyme, we describe here their optimization as cell-based inhibitors. The crystal structure of 1 bound to NS5B was a guide in the design of a two-dimensional compound array that highlighted that formally zwitterionic inhibitors have strong intracellular potency and that pregnane X receptor (PXR) activation (an undesired off-target activity) is linked to a structural feature of the inhibitor. Optimized analogues devoid of PXR activation (e.g., 55, EC(50) = 127 nM) retain strong cell-based efficacy under high serum conditions and show acceptable pharmacokinetics parameters in rat and dog.

Infections caused by hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The polymerase of HCV is responsible for the replication of viral RNA. We recently disclosed dihydroxypyrimidine carboxylates 2 as novel, reversible inhibitors of the HCV NS5B polymerase. This series was further developed into 5,6-dihydroxy-2-(2-thienyl)pyrimidine-4-carboxylic acids such as 34 (EC50 9.3 microM), which now show activity in the cell-based HCV replication assay. The structure-activity relationship of these inhibitors is discussed in the context of their physicochemical properties and of the polymerase crystal structure. We also report the results of mutagenesis experiments which support the proposed binding model, which involves pyrophosphate-like chelation of the active site Mg ions.