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Background: No pharmacologic therapy has conclusively proved to be effective for the treatment of nonalcoholic steatohepatitis, which is characterized by insulin resistance, steatosis, and necroinflammation with or without centrilobular fibrosis. Pioglitazone is a thiazolidinedione that ameliorates insulin resistance and improves glucose and lipid metabolism in type 2 diabetes mellitus.Methods: We randomly assigned 55 patients with impaired glucose tolerance or type 2 diabetes and liver biopsy-confirmed nonalcoholic steatohepatitis to 6 months of treatment with a hypocaloric diet (a reduction of 500 kcal per day in relation to the calculated daily intake required to maintain body weight) plus pioglitazone (45 mg daily) or a hypocaloric diet plus placebo. Before and after treatment, we assessed hepatic histologic features, hepatic fat content by means of magnetic resonance spectroscopy, and glucose turnover during an oral glucose tolerance test ([14C]glucose given with the oral glucose load and [3H]glucose given by intravenous infusion).Results: Diet plus pioglitazone, as compared with diet plus placebo, improved glycemic control and glucose tolerance (P<0.001), normalized liver aminotransferase levels as it decreased plasma aspartate aminotransferase levels (by 40% vs. 21%, P=0.04), decreased alanine aminotransferase levels (by 58% vs. 34%, P<0.001), decreased hepatic fat content (by 54% vs. 0%, P<0.001), and increased hepatic insulin sensitivity (by 48% vs. 14%, P=0.008). Administration of pioglitazone, as compared with placebo, was associated with improvement in histologic findings with regard to steatosis (P=0.003), ballooning necrosis (P=0.02), and inflammation (P=0.008). Subjects in the pioglitazone group had a greater reduction in necroinflammation (85% vs. 38%, P=0.001), but the reduction in fibrosis did not differ significantly from that in the placebo group (P=0.08). Fatigue and mild lower-extremity edema developed in one subject who received pioglitazone; no other adverse events were observed.Conclusions: In this proof-of-concept study, the administration of pioglitazone led to metabolic and histologic improvement in subjects with nonalcoholic steatohepatitis. Larger controlled trials of longer duration are warranted to assess the long-term clinical benefit of pioglitazone. (ClinicalTrials.gov number, NCT00227110 [ClinicalTrials.gov] .). [ABSTRACT FROM AUTHOR]

The Great Unconformity marks a major gap in the continental geological record, separating Precambrian basement from Phanerozoic sedimentary rocks. However, the timing, magnitude, spatial heterogeneity, and causes of the erosional event(s) and/or depositional hiatus that lead to its development are unknown. We present field relationships from the 1.07-Ga Pikes Peak batholith in Colorado that constrain the position of Cryogenian and Cambrian paleosurfaces below the Great Unconformity. Tavakaiv sandstone injectites with an age of ≥676 ± 26 Ma cut Pikes Peak granite. Injection of quartzose sediment in bulbous bodies indicates near-surface conditions during emplacement. Fractured, weathered wall rock around Tavakaiv bodies and intensely altered basement fragments within unweathered injectites imply still earlier regolith development. These observations provide evidence that the granite was exhumed and resided at the surface prior to sand injection, likely before the 717-Ma Sturtian glaciation for the climate appropriate for regolith formation over an extensive region of the paleolandscape. The 510-Ma Sawatch sandstone directly overlies Tavakaiv-injected Pikes granite and drapes over core stones in Pikes regolith, consistent with limited erosion between 717 and 510 Ma. Zircon (U-Th)/He dates for basement below the Great Unconformity are 975 to 46 Ma and are consistent with exhumation by 717 Ma. Our results provide evidence that most erosion below the Great Unconformity in Colorado occurred before the first Neoproterozoic Snowball Earth and therefore cannot be a product of glacial erosion. We propose that multiple Great Unconformities developed diachronously and represent regional tectonic features rather than a synchronous global phenomenon., Competing Interests: Competing interest statement: P.F.H. and F.A.M. are coauthors on three papers, most recently in 2017.

Background: Despite years of intervention, few studies describe the extent to which recommended tobacco use prevention and cessation activities occur in community-based family practices. This study was designed to discover current practice patterns in these areas and to describe physician outcome and efficacy expectations., Methods: An exploratory comparative case study of 11 family practices used direct observation of practices and clinical encounters, chart reviews, and in-depth interviews. Qualitative and quantitative information was gathered on (1) intensity of tobacco use prevention and cessation; (2) physicians' attitudes and beliefs regarding outcome expectations; and (3) physicians' perceptions of their ability to counsel. Qualitative content analysis and descriptive statistics were used to construct case studies for comparisons., Results: Themes common to most practices included the "provision of little prevention" and "a lack of perceived need to address smokeless tobacco." Responsibility for tobacco activities fell almost solely to physicians. Although physicians felt confident in their counseling skills, the skills they identified were fairly basic. Most physicians were pessimistic about the positive effects of these activities. None of the practices was using any specifically developed "package," and pharmaceutical companies provided almost all patient education material. There was considerable variation in intensity of activities because of differences in attitudes, expectation, and background., Conclusions: To increase tobacco control activities, practice systems need to be individually evaluated to identify what is needed, how it will fit within the practice culture, and how it can best be implemented in this specific practice. One-size-fits-all interventions probably will not be widely implemented.