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It is necessary to analyze the whole-body kinematics (including joint locations and joint angles) to assess risks of fatal and musculoskeletal injuries in occupational tasks. Human pose estimation has gotten more attention in recent years as a method to minimize the errors in determining joint locations. However, the joint angles are not often estimated, nor is the quality of joint angle estimation assessed. In this paper, we presented an end-to-end approach on direct joint angle estimation from multi-view images. Our method leveraged the volumetric pose representation and mapped the rotation representation to a continuous space where each rotation was uniquely represented. We also presented a new kinematic dataset in the domain of residential roofing with a data processing pipeline to generate necessary annotations for the supervised training procedure on direct joint angle estimation. We achieved a mean angle error of $7.19^\circ$ on the new Roofing dataset and $8.41^\circ$ on the Human3.6M dataset, paving the way for employment of on-site kinematic analysis using multi-view images.

The anterior and posterior iliac spine markers frequently used to define the pelvis, are commonly occluded during three-dimensional (3D) motion capture. The occlusion of these markers leads to the use of various tracking marker configurations on the pelvis, which affect kinematic results. The purpose of this investigation was to examine the agreement of CODA pelvis kinematic results when two different tracking marker configurations were used during roofing tasks. 3D motion data were collected on seven male subjects while mimicking two roofing tasks. Hip joint angles (HJAs) were computed using the CODA pelvis with two different tracking marker configurations, the trochanter tracking method (TTM), and virtual pelvis tracking method (VPTM). Agreement between tracking marker configurations was assessed using cross-correlations, bivariate correlations, mean absolute differences (MADs), and Bland–Altman (BA) plots. The correlations displayed no time lag and strong agreement (all [Formula: see text]) between the HJA from the VPTM and TTM, suggesting the timing occurrence of variables are comparable between the two tracking marker configurations. The MAD between the VPTM and TTM displayed magnitude differences, but most of the differences were within a clinically acceptable range. Caution should still be used when comparing kinematic results between various tracking marker configurations, as differences exist.

Musculoskeletal Disorders (MSDs) remain a major concern for workers in the healthcare industry. Healthcare workers are at high risk of work-related MSDs mainly caused by overexertion from manually handling patients. Exoskeletons may be a useful tool to help reduce the risk of MSDs during patient handling. As a review study, we surveyed articles focusing on applying exoskeletons to patient handling tasks specifically. We also reviewed relevant government databases and other studies related to Safe Patient Handling and Mobility (SPHM) programs and exoskeleton applications in general. The exoskeletons specifically designed for patient handling were found to be sparse. To have a better understanding of the needs and challenges of developing and using exoskeletons for reducing risks of work-related MSDs in healthcare workers during patient handling, this critical review (1) provided an overview of the existing issues and projected future burdens related to work-related MSDs during patient handling tasks, (2) recognized current and potential roles and applications of existing exoskeletons, and (3) identified challenges and needs for future exoskeleton products. In conclusion, we do not expect exoskeletons to replace the existing SPHM programs, but rather play a complementary role to these multi-pronged programs. We expect that emerging exoskeleton products can be introduced to uncontrolled or specialized healthcare environments. There are various expectations and requirements for an exoskeleton used in different healthcare settings. Additionally, introducing certain types of exoskeletons for patients to assist them during treatment and rehabilitation may help reduce the MSD risks to the healthcare workers.

Hiking is a common recreational activity that provides numerous health benefits, such as reduced risk of heart disease, reduced blood pressure, and improved cardiorespiratory fitness. The use of specifically designed trekking poles has become popular among participants seeking to alleviate sore knees and increase balance and stability while walking. This review provides an overview of physiologic and biomechanical responses elicited when trekking poles are used during outdoor activities, such as hiking or Nordic walking, and discusses the clinical implications of the use of trekking poles. Google Scholar, PubMed, and ScienceDirect databases, as well as university library catalogues, were searched for literature published between 1980 and 2019. The keywords used to search the literature were hiking poles, trekking poles, and Nordic walking and their combination with physiological responses, ground reaction forces, joint forces, spatiotemporal parameters, kinematics, electromyography, and/or balance. The related topics included the academic disciplines of biomechanics, sports science, and wilderness medicine. Reference lists of located studies were also reviewed for additional sources. During free, unloaded walking, users should compare the cost and benefit of using poles: Trekking poles decrease lower extremity loading and forces but increase cardiovascular demand. When carrying a large external load, trekking poles may offer benefit by decreasing lower extremity muscle activity and increasing balance and stability.

SummaryThe Paleoproterozoic Yerrida, Bryah and Padbury Basins are located on the northern margin of the Archean Yilgarn Craton, and are host to orogenic gold (Peak Hill, Fortnum and Horseshoe), vol...

BACKGROUND Natural killer (NK) cell impairment is a feature of pulmonary arterial hypertension (PAH) and contributes to disease development in mouse models of NK cell deficiency (Ormiston et al, Circulation, 2012; Ratsep et al, AJP Lung, 2018). PAH is also strongly associated with mutations in BMPR2, the gene encoding the type-II bone morphogenetic protein receptor. Genetic and experimental evidence point to a loss of BMPR2 in the pulmonary endothelium as a critical contributor to disease development. However, the impact of endothelial BMPR2 loss on NK cell impairment in PAH remains unknown. METHODS AND RESULTS SiRNA-mediated silencing of BMPR2 in human pulmonary artery endothelial cells (HPAEC) significantly reduced the surface presentation and secretion of the α-type receptor for interleukin-15 (IL-15Rα), a major regulator of NK cell survival, proliferation and activity. Assessment of IL-15Rα transcriptional variants by RNA-Seq and glycosylation by immunoblotting demonstrated that this reduction was not due to changes in receptor transcription or processing. Treatment of HPAECs with the matrix metalloproteinase inhibitor Batimastat also ruled out a role for altered IL-15Rα cleavage with BMPR2 silencing. Instead, confocal microscopy identified impaired trafficking of IL-15Rα through the trans-Golgi-network (TGN) in BMPR2-silenced cells. To evaluate the effects of impaired IL-15 mediated signaling and NK cell loss on PAH development, NK cell-deficient Il15-/- rats and immune-competent Il15+/+ littermates were exposed to either the monocrotaline (MCT) or SUGEN/hypoxia models of experimental pulmonary hypertension. While both male and female Il15-/- rats developed more severe disease than their wildtype counterparts in the SUGEN/Hypoxia model, only male Il15-/- rats demonstrated this enhanced severity in the MCT model, which is the only one of the two models to reproduce the sex-based difference in disease severity that is observed in human PAH patients. Assessment of genes associated with sex hormone signaling and metabolism identified a potential increase in pulmonary Cyp1b1 expression (n=5-7, p=0.08) in male MCT-challenged Il15-/- rats relative to Il15+/+ controls. CONCLUSION We have identified the loss of IL-15 signaling as a novel BMPR2-dependent contributor to NK cell impairment and pulmonary arterial hypertension pathogenesis. Ongoing work includes assessing the contribution of sex hormones to immune-mediated disease processes in PAH.

Socioeconomic and racial (SER) disparities among patients with congenital heart disease (CHD) may limit access to high-quality care. We characterized the national SER landscape and its relationship to early outcomes and identified interactions among determinants mitigating adverse outcome.The Pediatric Health Information System (PHIS) database was queried for patients (age26 years) with CHD between 2016 and 2018. International Classification of Diseases, 10th Revision, codes were mapped to diagnostic categories for complexity adjustment. Correlational and hierarchical regression analyses identified risk factors and characterized interactions.We identified 166,599 unique admissions from 52 hospitals, with 58,395 having interventions. Median age was 0 years (interquartile range [IQR], 4 years). Race/ethnicity was predominantly White (59%), Hispanic (20%), and Black (16%). Median neighborhood household income (NHI) was $41,082 and varied among hospitals. Patient NHI had a parabolic relationship with mortality, with both higher and lower values having increased risk. Black patients had significantly higher death, and this relationship was potentiated by lower NHI and complexity. Hospital length of stay was longer among Black neonates (median, 51 days; IQR, 93 days) compared with neonates of other ethnic groups (median, 32 days; IQR, 71 days; P.0001. Care pathways, including permanent feeding tubes, were also more prevalent among Black neonates (17.8%) compared with White neonates (15%; P = .02).Interactions among SER disparities modify CHD outcomes. Specific hospitals have more SER fragile patients but may have developed care pathways that prolong length of stay to mitigate risk among Black neonates. Adverse outcomes among SER-disadvantaged patients are magnified in complex CHD, suggesting tangible benefits to targeted resource allocation and population health initiatives.

Pediatricians aspire to optimize overall health and development, but there are no comprehensive measures of well-being to guide pediatric primary care redesign. The objective of this article is to describe the Cincinnati Kids Thrive at 5 outcome measure, along with a set of more proximal outcome and process measures, designed to drive system improvement over several years. In this article, we describe a composite measure of “thriving” at age 66 months, using primary care data from the electronic health record. Thriving is defined as immunizations up-to-date, healthy BMI, free of dental pain, normal or corrected vision, normal or corrected hearing, and on track for communication, literacy, and social-emotional milestones. We discuss key considerations and tradeoffs in developing the measure. We then summarize insights from applying this measure to 9544 patients over 3 years. Baseline rates of thriving were 13% when including all patients and 31% when including only patients with complete data available. Interpretation of results was complicated by missing data in 50% of patients and nonindependent success rates among bundle components. There was considerable enthusiasm among other practices and sectors to learn with us and to measure system performance using time-linked trajectories. We learned to present our data in ways that balanced aspirational long-term or multidisciplinary goal-setting with more easily attainable short-term aims. On the basis of our experience with the Thrive at 5 measure, we discuss future directions and place a broader call to action for pediatricians, researchers, policy makers, and communities.

Curcumin is poorly absorbed, which is interest in new preparations. However, little is known about variations in its pharmacokinetics and tissue bioavailability between formulations. In this randomized, crossover study we evaluated the relationship between steady-state plasma and rectal tissue curcuminoid concentrations using standard and phosphatidylcholine curcumin extracts. There was no difference in the geometric mean plasma AUCs when adjusted for the 10-fold difference in curcumin dose between the 2 formulations. Phosphatidylcholine curcumin extract yielded only 20% to 30% plasma demethoxycurcumin and bisdemethoxycurcumin conjugates compared to standard extract, yet yielded 20-fold greater hexahydrocurcumin. When adjusting for curcumin dose, tissue curcumin concentrations were 5-fold greater for the phosphatidylcholine extract. Improvements in curcuminoid absorption due to phosphatidylcholine are not uniform across the curcuminoids. Furthermore, curcuminoid exposures in the intestinal mucosa are most likely due to luminal exposure rather than to plasma disposition. Finally, once-daily dosing is sufficient to maintain detectable curcuminoids at steady state in both plasma and rectal tissues.

The Palaeoproterozoic Yerrida, Bryah and Padbury Group sedimentary rocks are located on the northern margin of the Archaean Yilgarn Craton and are host to epigenetic gold (Peak Hill, Fortnum and Horseshoe), volcanic-hosted massive sulphide (VHMS; Horseshoe Lights, Red Bore and DeGrussa) and epithermal copper deposits (Thaduna). The DeGrussa Cu–Au–Ag VHMS deposit (12.4 Mt @ 4.7% Cu and 1.8 g/t Au) comprises four lenses and is hosted in turbiditic sedimentary rocks and basalts of the DeGrussa host sediments/Karalundi Formation, the lowest mafic volcano-sedimentary unit of the Bryah Group and crosscut by intrusive dolerite of Narracoota Formation age. Immediate wall rocks to the ore lenses are commonly altered to chlorite and talc-carbonate. A number of geochronological techniques were employed to date mineralisation in the DeGrussa deposit. These include rhenium–osmium (Re–Os) of molybdenite, Pb isotopes of galena and pyrite, and U–Pb on zircon. Re–Os geochronology of molybdenite resulted in ages of 2027 ± 7 Ma and 2011 ± 7 Ma and 2013 ± 7 Ma for mineralisation, similar to Pb–Pb model ages for galena of 2060 ± 50 Ma and 2075 ± 50 Ma. U–Pb for magmatic zircons from intrusive dolerite within the mine sequence provided ages of 1991 ± 7 Ma, 1999 ± 7 Ma and 2003 ± 7 Ma with granodiorite rocks providing ages of 2014 ± 7 Ma and 2018 ± 9 Ma. Remobilisation of DeGrussa sulphides occurred at approximately 1980 Ma given Re–Os ages of pyrrhotite (1982 ± 7 Ma and 1984 ± 8 Ma) and Pb–Pb pyrite ages of 1980 ± 30 Ma. Re-examination of the Pb isotopic evolution models for this area and the Capricorn Orogen suggests that the model of Stacey and Kramers (1975) is more appropriate than Cumming and Richards (1975) ; using the former model leads to revised model ages as follows: Horseshoe Lights VHMS 2000 ± 35 Ma; Nathans 1820 ± 30 Ma, Peak Hill (Main pit: 1610 Ma, 1620 Ma, 1705 Ma, and 2070 ± 30 Ma; Fiveways: 1955 Ma; Mt. Pleasant: 1770 Ma), Horseshoe/Cassidy 1940 ± 30 Ma, Mikhaburra 1915 ± 30 Ma, and Labouchere 1800 ± 30 Ma. These new ages coincide with major regional orogenic events – the Glenburgh from 2005 to 1960 Ma, the Capricorn from 1830 to 1780 Ma, the Mangaroon from 1690 to 1620 Ma, and the Edmundian from 920 to 850 Ma. Although orogenic events are compressional, the Yerrida/Bryah Group sedimentary rocks, along with mineralisation at the DeGrussa and Horseshoe Lights deposits, were formed in an extensional basin setting during the Glenburgh Orogeny. These new ages assist in constraining stratigraphic and mineralising events of the Palaeoproterozoic Yerrida, Bryah and Padbury Group with regional orogenic events and may provide guidance for exploration for significant gold and base metal mineralisation, not only in the Bryah, but also throughout the larger Capricorn Orogen.

Clinical Question Which oral antifungal medication is associated with the highest clinical (ie, normal appearance of the toenail) and mycological (negative culture, microscopy, or both) cure rates vs placebo or other antifungals when used to treat fungal infections? Bottom Line Both terbinafine and azole-based medications were associated with higher clinical and mycological cure rates compared with placebo (high-quality evidence). Azoles were associated with lower cure rates than terbinafine when compared directly.

Nearly 25% of U.S. adults report concurrently taking a prescription medication with a dietary supplement. Some supplements, such as St. John's wort and goldenseal, are known to cause clinically important drug interactions and should be avoided by most patients receiving any pharmacologic therapy. However, many other supplements are predicted to cause interactions based only on in vitro studies that have not been confirmed or have been refuted in human clinical trials. Some supplements may cause interactions with a few medications but are likely to be safe with other medications (e.g., curcumin, echinacea, garlic, Asian ginseng, green tea extract, kava kava). Some supplements have a low likelihood of drug interactions and, with certain caveats, can safely be taken with most medications (e.g., black cohosh, cranberry, ginkgo, milk thistle, American ginseng, saw palmetto, valerian). Clinicians should consult reliable dietary supplement resources, or clinical pharmacists or pharmacologists, to help assess the safety of specific herbal supplement-drug combinations. Because most patients do not disclose supplement use to clinicians, the most important strategy for detecting herb-drug interactions is to develop a trusting relationship that encourages patients to discuss their dietary supplement use.

Silymarin is the most commonly used herbal medicine by patients with chronic liver disease. Silymarin flavonolignans undergo rapid first-pass metabolism primarily by glucuronidation. The aims of this investigation were: (1) to determine the association of UGT1A1*28 polymorphism with the area under the plasma concentration-time curves (AUCs) for silybin A (SA) and silybin B (SB); (2) to evaluate the effect of UGT1A1*28 polymorphism on the profile of flavonolignan glucuronide conjugates found in the plasma; and (3) to investigate the role of UGT1A1 enzyme kinetics on the pharmacokinetics of SA and SB. AUCs and metabolic ratios for thirty-three patients with chronic liver disease administered oral doses of silymarin were compared between different UGT1A1*28 genotypes. The AUCs, metabolic ratios, and the profiles of major SA and SB glucuronides did not differ significantly among the three UGT1A1 genotypes. In contrast, an increase in the proportion of sulfated flavonolignan conjugates in plasma was observed in subjects with UGT1A1*28/*28 genotype compared to subjects carrying wild type alleles. Differences in SA and SB in vitro intrinsic clearance estimates for UGTIA1 correlated inversely with SA and SB exposures observed in vivo indicating a major role for UGT1A1 in silymarin metabolism. In addition, a significant difference in the metabolic ratio observed between patients with NAFLD and HCV suggests that any effect of UGT1A1 polymorphism may be obscured by a greater effect of liver disease on the pharmacokinetics of silymarin. Taken together, these results suggest the presence of the UGT1A1*28 allele does not contribute significantly to a large inter-subject variability in the pharmacokinetics of silybin A and silybin B which may obscure the ability to detect beneficial effects of silymarin in patients with liver disease.

Curcumin is poorly absorbed, which is interest in new preparations. However, little is known about variations in its pharmacokinetics and tissue bioavailability between formulations. In this randomized, crossover study we evaluated the relationship between steady-state plasma and rectal tissue curcuminoid concentrations using standard and phosphatidylcholine curcumin extracts. There was no difference in the geometric mean plasma AUCs when adjusted for the 10-fold difference in curcumin dose between the 2 formulations. Phosphatidylcholine curcumin extract yielded only 20% to 30% plasma demethoxycurcumin and bisdemethoxycurcumin conjugates compared to standard extract, yet yielded 20-fold greater hexahydrocurcumin. When adjusting for curcumin dose, tissue curcumin concentrations were 5-fold greater for the phosphatidylcholine extract. Improvements in curcuminoid absorption due to phosphatidylcholine are not uniform across the curcuminoids. Furthermore, curcuminoid exposures in the intestinal mucosa are most likely due to luminal exposure rather than to plasma disposition. Finally, once-daily dosing is sufficient to maintain detectable curcuminoids at steady state in both plasma and rectal tissues.

The effects of sex, ethnicity, and genetic polymorphism on hepatic CYP2B6 (cytochrome P450 2B6) expression and activity were previously demonstrated in vitro. Race/ethnic differences in CYP2B6 genotype and phenotype were observed only in women. To identify important covariates associated with interindividual variation in CYP2B6 activity in vivo, we evaluated these effects in healthy volunteers using bupropion (Wellbutrin SR GlaxoSmithKline, Research Triangle Park, NC) as a CYP2B6 probe substrate. A fixed 150-mg oral sustained-release dose of bupropion was administered to 100 healthy volunteers comprising four sex/ethnicity cohorts (n = 25 each): Caucasian men and Caucasian, African American, and Hispanic women. Blood samples were obtained at 0 and 6 hours postdose for the measurement of serum bupropion (BU) and hydroxybupropion (HB) concentrations. Whole blood was obtained at baseline for CYP2B6 genotyping. To characterize the relationship between CYP2B6 activity and ethnicity, sex, and genotype when accounting for serum BU concentrations (dose-adjusted log(10)-transformed), analysis of covariance model was fitted in which the dependent variable was CYP2B6 activity represented as the log(10)-transformed, metabolic ratio of HB to BU concentrations. Several CYP2B6 polymorphisms were associated with CYP2B6 activity. Evidence of dependence of CYP2B6 activity on ethnicity or genotype-by-ethnicity interactions was not detected in women. These results suggest that CYP2B6 genotype is the most important patient variable for predicting the level of CYP2B6 activity in women, when measured by the metabolism of bupropion. The bupropion metabolic ratio appears to detect known differences in CYP2B6 activity associated with genetic polymorphism, across different ethnic groups. Prospective studies will be needed to validate the use of bupropion as a probe substrate for clinical use.

The goal of this study was to identify prehospital factors associated with increased likelihood of interfacility transfer of pediatric trauma patients. Such factors might serve as a basis for improvements in future field pediatric trauma triage guidelines.This was a retrospective cohort study of children aged 12 years or younger with blunt, penetrating, or thermal injuries who were transported by ground emergency medical services from the scene to the emergency department of a Level I, II, or III trauma center within the Denver metropolitan area from January 1, 2000, to December 31, 2008. Characteristics predicting subsequent interfacility transfer to a pediatric trauma center (PTC) were assessed.A total of 1673 patients were included in the analysis. Variables hypothesized to be most commonly associated with interfacility transfer were age, sex, mechanism of injury, body region of injury, and Glasgow Coma Scale score. The cohort included 1079 males and 593 females. Logistic regression analysis yielded the following as significant predictors of transfer: younger age (odds ratio [OR], 1.19; 95% confidence interval [CI], 1.15-1.25), lower Glasgow Coma Scale score (OR, 1.08; 95% CI, 1.01-1.16), the presence of burns (OR, 37.52; 95% CI, 7.3-191.7), non-accidental trauma (OR, 6.09; 95% CI, 2.44-15.25), falls (OR, 1.62; 95% CI, 1.06-2.48), other motor vehicle-related incidents (OR, 2.37; 95% CI, 1.08-5.19), abdominal injury (OR, 5.39; 95% CI, 2.31-12.55), head/neck injury (OR, 7.89; 95% CI, 4.21-14.77), limb injury (OR, 5.31; 95% CI, 2.78-10.16), and multiple injuries (OR, 13.01; 95% CI, 5.0-33.8).Factors highly associated with transfer of an injured child from a non-PTC to a PTC included younger age, burns, non-accidental trauma, head/neck injury, and multiple injuries in younger children. Further investigation is warranted to determine whether these factors may have applicability in future improvements in field pediatric trauma patient triage guidelines.

Background Chronic hepatitis C is associated with significant morbidity and mortality as a consequence of progression to cirrhosis, hepatocellular carcinoma, and liver failure. Current treatment for chronic hepatitis C with pegylated interferon (IFN) and ribavirin is associated with suboptimal responses and numerous adverse effects. A number of botanical products have been used to treat hepatic disorders. Silymarin, extracted from the milk thistle plant, Silybum marianum (L) Gaertn. (Asteraceae), has been most widely used for various liver disorders, including chronic hepatitis C, B, and alcoholic liver disease. However, the safety and efficacy of silymarin have not been studied systematically in chronic hepatitis C. Purpose We describe our strategy for a phased approach for studying the impact of silymarin in hepatitis C, in the context of the unique challenges of botanical product clinical trials and the development of specific and curative antiviral therapy. Methods This multicenter, randomized, double-masked, placebo-controlled trial was conducted with four clinical centers and a data-coordinating center in the United States, to assess the impact of silymarin therapy in patients with chronic hepatitis C who failed conventional antiviral therapy. Results Key aspects relevant to performing clinical trials of botanical products include early identification of an appropriate product with standard product chemistry, acquisition of pharmacokinetic and dosing information, selection of the appropriate study group, and choosing rigorous outcome variables. Potential limitations Trial participants were chronic hepatitis C patients who were nonsustained virologic responders to IFN-based therapy; therefore, the findings are not generalizable to all hepatitis C populations. Further, alanine aminotransferase, a biochemical liver test, rather than hepatitis viral RNA or liver histology was the primary end point. Conclusions The challenges identified and addressed during development of this United States multicenter Phase II trial to evaluate silymarin for treatment of patients with chronic hepatitis C infection who had failed to respond successfully to previous IFN-based therapy are common and must be addressed to conduct rigorous trials of botanical products.

Atauro is a key to understanding the late stage volcanic and subduction history of the Banda Arc to the north of Timor. A volcanic history of bi-modal subaqueous volcanism has been established and new whole rock and trace element geochemical data show two compositional groups, basaltic andesite and dacite–rhyolite. 40Ar/39Ar geochronology of hornblende from rhyo-dacitic lavas confirms that volcanism continued until 3.3 Ma. Following the cessation of volcanism, coral reef marine terraces have been uplifted to elevations of 700 m above sea level. Continuity of the terraces at constant elevations around the island reflects regional-scale uplift most likely linked to sublithospheric processes such as slab detachment. Local scale landscape features of the eastern parts of Atauro are strongly controlled by normal faults. The continuation of arc-related volcanism on Atauro until at least 3.3 Ma suggests that subduction of Australian lithosphere continued until near this time. This data is consistent with findings from the earthquake record where the extent of the Wetar seismic gap to a depth of 350 km suggests slab breakoff, as a result of collision, commenced at ∼4 Ma, leading to subsequent regional uplift recorded in elevated terraces on Atauro and neighbouring islands.

Silymarin, derived from the milk thistle plant Silybum marianum, is widely used for self-treatment of liver diseases, including hepatitis C virus (HCV), and its antiviral activity has been demonstrated in vitro and in HCV patients administered an intravenous formulation of the major silymarin flavonolignans, silybin A and silybin B. The safety and dose-exposure relationships of higher than customary oral doses of silymarin and its acute effects on serum HCV RNA were evaluated in noncirrhotic HCV patients. Four cohorts of 8 patients with well-compensated, chronic noncirrhotic HCV who failed interferon-based therapy were randomized 3:1 to silymarin or placebo. Oral doses of 140, 280, 560, or 700 mg silymarin were administered every 8 hours for 7 days. Steady-state exposures for silybin A and silybin B increased 11-fold and 38-fold, respectively, with a 5-fold increase in dose, suggesting nonlinear pharmacokinetics. No drug-related adverse events were reported, and no clinically meaningful reductions from baseline serum transaminases or HCV RNA titer were observed. Oral doses of silymarin up to 2.1 g per day were safe and well tolerated. The nonlinear pharmacokinetics of silybin A and silybin B suggests low bioavailability associated with customary doses of silymarin may be overcome with doses above 700 mg.

Silymarin, an extract from seeds of Silybum marianum, is used by 8 to 33% of patients to self-treat chronic viral hepatitis C in the United States. Studies in humans and rodents suggest that biliary excretion of glucuronide and sulfate conjugates is the major route for silymarin's elimination. To determine the role of multidrug resistance-associated protein 2 (Mrp2) (Abcc2) in the biliary excretion of silymarin, the hepatobiliary disposition of the six major silymarin flavonolignans was studied using isolated perfused livers (IPRLs) from wild-type (WT) and Mrp2-deficient (TR(-)) Wistar rats. For all the flavonolignans, approximately 96% of the dose was cleared from perfusate within 30 min in both WT and TR(-) livers, and

Silymarin, used by 30 to 40% of liver disease patients, is composed of six major flavonolignans, each of which may contribute to silymarin's hepatoprotective properties. Previous studies have only described the pharmacokinetics for two flavonolignans, silybin A and silybin B, in healthy volunteers. The aim of this study was to determine the pharmacokinetics of the major silymarin flavonolignans in liver disease patients. Healthy volunteers and three patient cohorts were administered a single, 600-mg p.o. dose of milk thistle extract, and 14 blood samples were obtained over 24 h. Silybin A and B accounted for 43% of the exposure to the sum of total silymarin flavonolignans in healthy volunteers and only 31 to 38% in liver disease cohorts as a result of accumulation of silychristin (20-36%). Area under the curve (AUC(0-24h)) for the sum of total silymarin flavonolignans was 2.4-, 3.3-, and 4.7-fold higher for hepatitis C virus (HCV) noncirrhosis, nonalcoholic fatty liver disease (p

The CYP3A5(*)1 allele has been associated with differences in the metabolism of some CYP3A substrates. CYP3A5 polymorphism may also influence susceptibility for certain drug interactions. We have previously noted a correlation between basal CYP3A activity and the inductive effects of dexamethasone using the erythromycin breath test (ERBT). To determine whether CYP3A5 polymorphism influences induction of CYP3A activity, we examined the effect of an antiemetic regimen of dexamethasone, and the prototypical inducer rifampin, on the ERBT in African American volunteers prospectively stratified by CYP3A5(*)1 allele carrier status. Mean basal ERBTs were significantly higher in CYP3A5(*)1 carriers (2.71 +/- 0.53%) versus noncarriers (2.12 +/- 0.37%, P = 0.006). Rifampin increased ERBTs in CYP3A5(*)1 carriers (4.68 versus 2.60%, P = 0.0008) and noncarriers (3.55 versus 2.11%, P = 0.0017), whereas dexamethasone increased ERBTs only in CYP3A5(*)1 noncarriers (3.03 versus 2.14%, P = 0.031). CYP3A5 polymorphism appears to influence susceptibility to induction-type drug interactions for some inducers, and CYP3A5(*)1 noncarriers may be more susceptible to the inductive effects of dexamethasone as a result of lower basal CYP3A activity.

Assessing fitness to drive is part of the role of general practitioners. Cognitive impairment may affect an individual's ability to drive safely. The aims of our study were to question GPs about their experience of assessing patients with cognitive impairment for driving fitness and to explore their attitudes to this role. We carried out a quantitative cross-sectional anonymous postal survey of 200 GPs in counties Galway, Mayo and Roscommon. Ethical approval was obtained from the Irish College of General Practitioners. Data was analysed using Epi Info. The response rate was 62.5% (n=125). 86 (68.8%) GPs used guidelines when assessing fitness to drive in cognitive impairment. 83 (66.4%) respondents formally assess cognitive function. 52 (41.6%) GPs would certify someone as fit to drive with verbal restrictions. 102 (81.6%) respondents feel confident in assessing fitness to drive. 98 (78.4%) GPs have referred patients for further assessment.

To test the hypothesis that the etiology of reading difficulties may differ for males and females in more severely impaired samples, reading performance data from monozygotic (MZ), same-sex dizygotic (DZss), and opposite-sex dizygotic (DZos) twin pairs were analyzed using a model-fitting implementation of the DeFries-Fulker (DF) model (Purcell & Sham, 2003, Behavior genetics, 33, 271–278). Five non-independent samples were selected using cut-offs of −1 (N = 737 pairs), −1.5 (N = 654), −2 (N = 468), −2.5 (N = 335), and −3 (N = 198) standard deviations (s) below the mean composite reading score of control twins. Male/female gender ratios for children with reading difficulties were significantly higher than 1.0 for all five samples and increased as a function of severity (viz., 1.15, 1.17, 1.40, 1.61, and 1.88, respectively). When the DF model was fit to the data, estimates of heritability (h g 2 ) and shared environmental influences (c g 2 ) were not significantly different for males and females in any of the groups. Consequently, the most parsimonious model that provided a good fit to the data at all five levels of severity equated the heritabilities and shared environmental influences for males and females, and fixed the DZos coefficient of genetic relatedness at 0.5. Thus, these results provide no evidence for a differential etiology of reading difficulties as a function of gender in more severely impaired samples, and suggest that the same genetic and environmental influences contribute to reading difficulties in males and females, irrespective of severity.

– Minnow trapping was used to determine the distribution and abundance of two small, benthic species of fish, common bullies (Gobiomorphus cotidianus) and koaro (Galaxias brevipinnis), in five oligotrophic lakes varying in both turbidity and the extent of water-level variation. Koaro were 5–20 times more abundant in the large turbid lakes than in the clear ones, indicating that turbidity may reduce the extent of salmonid predation on koaro. However, the scarcity of koaro in the clear lakes was related mainly to the prevalence of brown trout (Salmo trutta) compared with rainbow trout (Oncorhynchus mykiss) as the former were more piscivorous and had a stronger inverse relationship with koaro. Common bullies were more abundant at sites 20 m or more away from the shoreline, and at depths of 9–12 m irrespective of season, year and turbidity level. However, the overall abundance of bullies was reduced by 70–90% in the turbid lakes. As bullies are relatively insensitive to the direct effects of increased turbidity, indirect effects such as reductions in macrophytes from reduced water clarity or smothering of benthic habitats by settled solids are thought to influence their abundance in the lakes affected by glacial turbidity. There was no relationship between the extent of water-level fluctuation and the abundance of koaro or common bullies in the lakes, but the depth distribution of bullies was shallowest in the lake with the least water-level fluctuation and was deepest in the lake with the greatest water-level fluctuation.

Gemcitabine administered at a fixed dose rate of 10 mg/m(2) per min has been reported to achieve plasma steady-state concentrations ranging from 10 to 20 microM in patients with acute leukemia. These concentrations have been shown to saturate the intracellular accumulation of the active triphosphate metabolite. We designed this pharmacokinetic study to assess the ability of a fixed dose rate of gemcitabine to achieve the desired steady-state concentration in the absence and presence of paclitaxel in patients with solid tumors.A group of 14 patients with advanced non-small-cell lung cancer received paclitaxel 110 mg/m(2) over 3 h on days 1 and 8 and gemcitabine 800 mg/m(2) over 80 min on days 1 and 8 every 21 days. Patients received gemcitabine alone on cycle (C) 1, day (D) 1. Pharmacokinetic samples were collected at 0, 15, 30, 45, 60 and 80 min during infusion and 0.25, 0.5, 1, 2, 4, 6, and 8 h after infusion on C1D1, C1D8, C2D1, C4D1 and C6D1.Of 13 patients included in the pharmacokinetic analysis, 61% achieved the desired steady-state concentration (C(ss)) with gemcitabine alone (C1D1), whereas only 0 to 45% of patients achieved the desired C(ss) with paclitaxel and gemcitabine, depending on the treatment cycle. Paclitaxel significantly decreased systemic clearance (Cl(T); P=0.012) and volume of distribution (V(d); P=0.050) and significantly increased C(ss) ( P=0.009). Gemcitabine plasma pharmacokinetic parameters demonstrated great interpatient variability in the absence of paclitaxel (C(ss) 30%, Cl(T) 30%, V(d) 55%). Interpatient and intrapatient variability in gemcitabine pharmacokinetics were not observed when gemcitabine was administered in combination with paclitaxel (P0.05).Gemcitabine plasma pharmacokinetic parameters are significantly altered in the presence of paclitaxel.

This study examined the effects of 2 manipulations--a brief, regular period of human contact and diet--on the behavior of dogs confined in a public animal shelter. A behavioral battery designed to assess reactions to novel situations, and a test of responsiveness to an unfamiliar human were administered both prior to (pretest) and immediately following (posttest) the 8-week intervention period. Overall, the regular periods of increased human contact together with a diet that contained augmented levels of digestible protein, fat, calories, and animal-derived ingredients reduced signs of behavioral reactivity from pretest to posttest. In some cases, the comparison diet appeared more effective, but only for dogs receiving minimal human interaction. The results indicate that a combination of human interaction and high quality diet may positively affect the behavior of dogs in animal shelters.

Objective—To determine whether a program of human interaction or alterations in diet composition would alter activity of the hypothalamic-pituitaryadrenal (HPA) axis in dogs housed in an animal shelter. Design—Prospective study. Animals—40 dogs. Procedure—Dogs were (n = 20) or were not (20) enrolled in a program of regular supplemental human interaction (20 min/d, 5 d/wk, for 8 weeks) involving stroking, massaging, and behavioral training. In addition, half the dogs in each group were fed a typical maintenance-type diet, and the other half were fed a premium diet. Plasma cortisol and ACTH concentrations were measured during weeks 0, 2, 4, and 8 and before and after exposure to a battery of novel situations during weeks 0 and 8. Results—Plasma cortisol concentration was significantly decreased by week 2, but plasma ACTH concentration was not significantly decreased until week 8 and then only in dogs fed the premium diet. Following exposure to novel situations, plasma cortisol and ACTH concentrations were significantly increased. However, during week 8, dogs enrolled in the program of human interaction had significantly lower increases in cortisol concentration than did dogs not enrolled in the program. Conclusions and Clinical Relevance—Results suggest that both a program of human interaction and alterations in diet composition have moderating effects on activity of the HPA axis in dogs housed in an animal shelter and that activity of the HPA axis may be increased for a longer period during shelter housing than measurement of plasma cortisol concentration alone would suggest. (J Am Vet Med Assoc 2002;221:65–71)

With the advent of the direct-acting antiviral agents, significant drug-drug interaction (DDI) potential now exists for patients treated for chronic hepatitis C virus (HCV) infection. However, little is known about how often patients with HCV infection use medications that may interact with newer HCV treatments, especially those with cytochrome P450 3A (CYP3A) DDI potential.Using a large US commercial insurance database, medication use and comorbidity burden were examined among adult patients with a chronic HCV diagnosis from 2006 to 2010. Medications were examined in terms of total number of prescription claims, proportion of patients exposed, and DDI potential with the prototypical CYP3A direct-acting antiviral agents boceprevir and telaprevir, for which data were available.Patient comorbidity burden was high and increased over the study period. Medication use was investigated in 53 461 patients with chronic HCV. Twenty-one (53%) of the top 40 most utilized medications were classified as having interaction potential, with 62% of patients receiving at least one of the top 22 interacting medications by exposure. Of these, 59 and 41% were listed in a common DDI resource but not in medication-prescribing information, 77 and 77% had not been investigated in DDI studies, 41 and 36% did not have clear recommendations for DDI management, and only 14 and 23% carried a recommendation to avoid coadministration for boceprevir and telaprevir, respectively.Practitioners may expect a medication with CYP3A DDI potential in two-thirds of patients with HCV and may expect almost one-half of the most frequently used medications to have CYP3A DDI potential. However, DDI potential may not be reflected in prescribing information.