Direct medical costs associated with the extrahepatic manifestations of hepatitis C infection in Europe.

Hepatitis C virus (HCV) infection is a systemic disease associated with both hepatic and extrahepatic manifestations. The burden associated with the hepatic manifestation of HCV infection has been well documented in Europe, although that of HCV extrahepatic manifestations remains unknown. In this study, we estimated the annual direct medical costs associated with HCV extrahepatic manifestations in five European countries. A previously validated economic model was used to estimate the annual direct medical cost associated with HCV extrahepatic manifestations. Global excess prevalence of extrahepatic manifestations in HCV patients relative to that in non-HCV patients was obtained from a recent meta-analysis. Per-patient per-year inpatient, outpatient and medication costs to treat each extrahepatic manifestation were from the literature, national databases or expert opinion if unavailable otherwise. All costs were adjusted to 2016 euros (€). The overall direct medical costs associated with HCV extrahepatic manifestations were calculated by multiplying the total per-patient per-year costs of each by the respective excess prevalence rates and then by the size of the HCV-infected population in each country. Treatment impact with direct-acting antivirals (DAAs) was explored using HCV extrahepatic manifestations excess prevalence rates among cured patients compared to untreated HCV patients, as sourced from a meta-analysis. The total annual direct medical cost associated with HCV extrahepatic manifestations was estimated to be 2.17 billion euro (€), with a per-HCV-patient cost ranging from €899 to €1647 annually. DAA treatment was projected to result in cost savings of €316 million per year. We find that the annual economic burden of extrahepatic manifestations is significant and may be partly mitigated by treatment with DAAs.

Shortened therapy of eight weeks with paritaprevir/ritonavir/ombitasvir and dasabuvir is highly effective in people with recent HCV genotype 1 infection.

Paritaprevir/ritonavir/ombitasvir and dasabuvir with or without ribavirin for 12 weeks are approved for treatment of chronic HCV genotype 1 infection. This study assessed the efficacy of shortened duration paritaprevir/ritonavir/ombitasvir and dasabuvir with or without ribavirin for 8 weeks among people with recent HCV infection. In this open-label single-arm trial conducted in Australia, England and New Zealand, adults with recent HCV (duration of infection <12 months) received paritaprevir/ritonavir/ombitasvir and dasabuvir (with weight-based ribavirin for genotypes 1a and 1, no subtype) for 8 weeks. The primary endpoint was sustained virological response at 12 weeks post-treatment (SVR12) in the intention-to-treat (ITT) population. Thirty people (median age 38 years, male 93%) commenced treatment (with ribavirin, 97%), of whom 77% (n = 23) were HIV-positive, 93% (n = 28) had genotype 1a infection and 53% (n = 16) had ever injected drugs. Median maximum ALT in the preceding 12 months was 433 IU/L (IQR 321, 1012). Acute clinical hepatitis with ALT > 10 x ULN was documented in 83% (n = 25); one participant (3%) had jaundice. At baseline, median estimated duration of infection was 30 weeks (range 11, 51), and median HCV RNA was 5.7 log10 IU/mL (range 2.7, 7.3). SVR12 was achieved in 97% (29/30; early discontinuation at week 2, n = 1; per protocol 100%, 29/29). No relapse or reinfection was observed. In conclusion, paritaprevir/ritonavir/ombitasvir and dasabuvir (with ribavirin) for eight weeks were highly effective among HIV-positive and HIV-negative individuals with recent HCV infection. These data support the use of this shortened duration direct-acting antiviral regimen in this population.

Replacing sedentary time with sleep, light, or moderate-to-vigorous physical activity: effects on self-regulation and executive functioning.

Recent attention has highlighted the importance of reducing sedentary time for maintaining health and quality of life. However, it is unclear how changing sedentary behavior may influence executive functions and self-regulatory strategy use, which are vital for the long-term maintenance of a health behavior regimen. The purpose of this cross-sectional study is to examine the estimated self-regulatory and executive functioning effects of substituting 30 min of sedentary behavior with 30 min of light activity, moderate-to-vigorous physical activity (MVPA), or sleep in a sample of older adults. This study reports baseline data collected from low-active healthy older adults (N = 247, mean age 65.4 ± 4.6 years) recruited to participate in a 6 month randomized controlled exercise trial examining the effects of various modes of exercise on brain health and function. Each participant completed assessments of physical activity self-regulatory strategy use (i.e., self-monitoring, goal-setting, social support, reinforcement, time management, and relapse prevention) and executive functioning. Physical activity and sedentary behaviors were measured using accelerometers during waking hours for seven consecutive days at each time point. Isotemporal substitution analyses were conducted to examine the effect on self-regulation and executive functioning should an individual substitute sedentary time with light activity, MVPA, or sleep. The substitution of sedentary time with both sleep and MVPA influenced both self-regulatory strategy use and executive functioning. Sleep was associated with greater self-monitoring (B = .23, p = .02), goal-setting (B = .32, p < .01), and social support (B = .18, p = .01) behaviors. Substitution of sedentary time with MVPA was associated with higher accuracy on 2-item (B = .03, p = .01) and 3-item (B = .02, p = .04) spatial working memory tasks, and with faster reaction times on single (B = -23.12, p = .03) and mixed-repeated task-switching blocks (B = -27.06, p = .04). Substitution of sedentary time with sleep was associated with marginally faster reaction time on mixed-repeated task-switching blocks (B = -12.20, p = .07) and faster reaction time on mixed-switch blocks (B = 17.21, p = .05), as well as reduced global reaction time switch cost (B = -16.86, p = .01). Substitution for light intensity physical activity did not produce significant effects. By replacing sedentary time with sleep and MVPA, individuals may bolster several important domains of self-regulatory behavior and executive functioning. This has important implications for the design of long-lasting health behavior interventions. Trial Registration clinicaltrials.gov identifier NCT00438347.

Underlying sources of cognitive-anatomical variation in multi-modal neuroimaging and cognitive testing.

Healthy adults have robust individual differences in neuroanatomy and cognitive ability not captured by demographics or gross morphology (Luders, Narr, Thompson, & Toga, 2009). We used a hierarchical independent component analysis (hICA) to create novel characterizations of individual differences in our participants (N=190). These components fused data across multiple cognitive tests and neuroanatomical variables. The first level contained four independent, underlying sources of phenotypic variance that predominately modeled broad relationships within types of data (e.g., "white matter," or "subcortical gray matter"), but were not reflective of traditional individual difference measures such as sex, age, or intracranial volume. After accounting for the novel individual difference measures, a second level analysis identified two underlying sources of phenotypic variation. One of these made strong, joint contributions to both the anatomical structures associated with the core fronto-parietal "rich club" network (van den Heuvel & Sporns, 2011), and to cognitive factors. These findings suggest that a hierarchical, data-driven approach is able to identify underlying sources of individual difference that contribute to cognitive-anatomical variation in healthy young adults.

Reduced healthcare utilization following successful hepatitis C virus treatment in HIV-co-infected patients with mild liver disease.

New direct-acting antivirals (DAA) for hepatitis C virus (HCV) infection have achieved high cure rates in many patient groups previously considered difficult-to-treat, including those HIV/HCV co-infected. The high price of these medications is likely to limit access to treatment, at least in the short term. Early treatment priority is likely to be given to those with advanced disease, but a more detailed understanding of the potential benefits in treating those with mild disease is needed. We hypothesized that successful HCV treatment within a co-infected population with mild liver disease would lead to a reduction in the use and costs of healthcare services in the 5 years following treatment completion. We performed a retrospective cohort study of HIV/HCV-co-infected patients without evidence of fibrosis/cirrhosis who received a course of HCV therapy between 2004 and 2013. Detailed analysis of healthcare utilization up to 5 years following treatment for each patient using clinical and electronic records was used to estimate healthcare costs. Sixty-three patients were investigated, of whom 48 of 63 (76.2%) achieved sustained virological response 12 weeks following completion of therapy (SVR12). Individuals achieving SVR12 incurred lower health utilization costs (£5,000 per-patient) compared to (£10 775 per-patient) non-SVR patients in the 5 years after treatment. Healthcare utilization rates and costs in the immediate 5 years following treatment were significantly higher in co-infected patients with mild disease that failed to achieve SVR12. These data suggest additional value to achieving cure beyond the prevention of complications of disease.

Diagnostics for resource-limited settings in the era of interferon-free HCV therapy.

The field of hepatitis C (HCV) therapy is moving inexorably towards a time when interferon is no longer part of routine HCV treatment. 2015 will see at least two interferon-free directly acting antiviral (DAA) treatments licensed in Europe and the USA. For those parts of the world that can afford it, this will mean the potential for treatment of those who have either failed interferon-based therapy or have been unable to tolerate the side-effects that commonly accompany treatment.

Systematic analysis of funding awarded for viral hepatitis-related research to institutions in the United Kingdom, 1997-2010.

Viral hepatitis is responsible for great health, social and economic burden both globally and in the UK. This study aimed to assess the research funding awarded to UK institutions for viral hepatitis research and the relationship of funded research to clinical and public health burden of viral hepatitis. Databases and websites were systematically searched for information on infectious disease research studies funded for the period 1997-2010. Studies specifically related to viral hepatitis research were identified and categorized in terms of funding by pathogen, disease and by a research and development value chain describing the type of science. The overall data set included 6165 studies (total investment £2.6 billion) of which £76.9 million (3.0%) was directed towards viral hepatitis across 323 studies (5.2%). By pathogen, there were four studies specifically investigating hepatitis A (£3.8 million), 69 studies for hepatitis B (21.4%) with total investment of £14.7 million (19.1%) and 236 (73.1%) hepatitis C studies (£62.7 million, 81.5%). There were 4 studies investigating hepatitis G, and none specifying hepatitis D or E. By associated area, viral hepatitis and therapeutics research received £17.0 million, vaccinology £3.1 million and diagnostics £2.9 million. Preclinical research received £50.3 million (65.4%) across 173 studies, whilst implementation and operational research received £19.4 million (25.3%) across 128 studies. The UK is engaged in much hepatology research, but there are areas where the burden is great and may require greater focus, such as hepatitis E, development of a vaccine for hepatitis C, and further research into hepatitis-associated cancers. Private sector data, and funding information from other countries, would also be useful in priority setting.

Comparison between ozone column depths and methane lifetimes computed by one- and three-dimensional models at different atmospheric O2 levels.

Recently, Cooke et al. (Cooke et al. 2022 R. Soc. Open Sci. 9, 211165. (doi:10.1098/rsos.211165)) used a three-dimensional coupled chemistry-climate model (WACCM6) to calculate ozone column depths at varied atmospheric O2 levels. They argued that previous one-dimensional (1-D) photochemical model studies, e.g. Segura et al. (Segura et al. 2003 Astrobiology 3, 689-708. (doi:10.1089/153110703322736024)), may have overestimated the ozone column depth at low pO2, and hence also overestimated the lifetime of methane. We have compared new simulations from an updated version of the Segura et al. model with those from WACCM6, together with some results from a second three-dimensional model. The discrepancy in ozone column depths is probably due to multiple interacting parameters, including H2O in the upper troposphere, lower boundary conditions, vertical and meridional transport rates, and different chemical mechanisms, especially the treatment of O2 photolysis in the Schumann-Runge (SR) bands (175-205 nm). The discrepancy in tropospheric OH concentrations and methane lifetime between WACCM6 and the 1-D model at low pO2 is reduced when absorption from CO2 and H2O in this wavelength region is included in WACCM6. Including scattering in the SR bands may further reduce this difference. Resolving these issues can be accomplished by developing an accurate parametrization for O2 photolysis in the SR bands and then repeating these calculations in the various models.

Diabetes mellitus is not a predictor of poor TB treatment outcomes.

OBJECTIVE: To investigate whether diabetes mellitus (DM) influences TB treatment outcomes.METHODS: This was a retrospective observational cohort study of all notified TB cases from a large London TB centre over a 5-year period. WHO criteria were used to define TB treatment outcomes.RESULTS: The prevalence of DM at TB treatment initiation was 15% (126/838). Most patients (83.3%, 105/126) were on hypoglycaemic treatment and well-controlled (median glycated haemoglobin 53.5 mmol/mol). DM patients were older, more likely to be of Asian ethnicity and had a higher pre-treatment weight. Time from presentation to treatment initiation was longer (median 87.5 vs. 63 days; P < 0.001), while they were significantly more comorbid (median Charlson Comorbidity Index 3 vs. 0; P < 0.001). Overall, favourable treatment outcomes were recorded for 89.5% of patients (87.7% vs. 89.8% for DM and non-DM patients respectively, P = 0.52). In multivariable analysis, DM was not associated with unfavourable TB treatment outcomes (OR 0.49, 95% CI 0.23-1.04, P = 0.06). Independent predictors of unfavourable outcome included age, cavitation, chronic neurological disease and malignant neoplasm.CONCLUSIONS: In a well-resourced setting, with predominantly well-controlled DM patients on treatment, DM was not an independent predictor of unfavourable TB treatment outcomes.

Natural selection in the water: freshwater invasion and adaptation by water colour in the Amazonian pufferfish.

Natural selection and ecological adaptation are ultimately responsible for much of the origin of biodiversity. Yet, the identification of divergent natural selection has been hindered by the spatial complexity of natural systems, the difficulty in identifying genes under selection and their relationship to environment, and the confounding genomic effects of time. Here, we employed genome scans, population genetics and sequence-based phylogeographic methods to identify divergent natural selection on population boundaries in a freshwater invader, the Amazonian pufferfish, Colomesus asellus. We sampled extensively across markedly different hydrochemical settings in the Amazon Basin and use 'water colour' to test for ecological isolation. We distinguish the relative contribution of natural selection across hydrochemical gradients from biogeographic history in the origin and maintenance of population boundaries within a single species and across a complex ecosystem. We show that spatially distinct population structure generated by multiple forces (i.e. water colour and vicariant biogeographic history) can be identified if the confounding effects of genetic drift have not accumulated between selective populations. Our findings have repercussions for studies aimed at identifying engines of biodiversity and assessing their temporal progression in understudied and ecologically complex tropical ecosystems.

HIV testing uptake and acceptability in an inner city polyclinic.

Up to 33% of HIV-infected adults in the UK remain undiagnosed and efforts to increase HIV testing are underway. HIV testing was conducted amongst individuals presenting to a polyclinic at a central London hospital using a point of care test. Demographic and HIV risk data was collected along with a patient feedback questionnaire exploring acceptability of the HIV testing experience. Seventy-one out of 93 (76%) individuals accepted HIV testing. Of those accepting HIV testing, 53/71 (75%) had never previously tested for HIV despite, 45/53 (85%) of these being registered with a GP. Twenty-seven out of 71 (38%) of individuals testing had at least one risk factor associated with HIV acquisition, and of these 17/27 (63%) had never previously tested for HIV infection. There were no new HIV positive diagnoses during the period of testing. Respondents indicated a high level of satisfaction with the service and more than 85% found the service to be helpful, educational and convenient. This small proof of concept pilot showed uptake of HIV testing in this setting to be high and acceptable to patients.

A revised lower estimate of ozone columns during Earth's oxygenated history.

The history of molecular oxygen (O2) in Earth's atmosphere is still debated; however, geological evidence supports at least two major episodes where O2 increased by an order of magnitude or more: the Great Oxidation Event (GOE) and the Neoproterozoic Oxidation Event. O2 concentrations have likely fluctuated (between 10-3 and 1.5 times the present atmospheric level) since the GOE ∼2.4 Gyr ago, resulting in a time-varying ozone (O3) layer. Using a three-dimensional chemistry-climate model, we simulate changes in O3 in Earth's atmosphere since the GOE and consider the implications for surface habitability, and glaciation during the Mesoproterozoic. We find lower O3 columns (reduced by up to 4.68 times for a given O2 level) compared to previous work; hence, higher fluxes of biologically harmful UV radiation would have reached the surface. Reduced O3 leads to enhanced tropospheric production of the hydroxyl radical (OH) which then substantially reduces the lifetime of methane (CH4). We show that a CH4 supported greenhouse effect during the Mesoproterozoic is highly unlikely. The reduced O3 columns we simulate have important implications for astrobiological and terrestrial habitability, demonstrating the relevance of three-dimensional chemistry-climate simulations when assessing paleoclimates and the habitability of faraway worlds.

Intronic polymorphism in CYP3A4 affects hepatic expression and response to statin drugs.

Cytochrome P450 3A4 (CYP3A4) metabolizes ∼50% of all clinically used drugs. Although CYP3A4 expression varies widely between individuals, the contribution of genetic factors remains uncertain. In this study, we measured allelic CYP3A4 heteronuclear RNA (hnRNA) and mRNA expression in 76 human liver samples heterozygous for at least one of eight marker SNPs and found marked allelic expression imbalance (1.6-6.3-fold) in 10/76 liver samples (13%). This was fully accounted for by an intron 6 SNP (rs35599367, C>T), which also affected mRNA expression in cell culture on minigene transfections. CYP3A4 mRNA level and enzyme activity in livers with CC genotype were 1.7- and 2.5-fold, respectively, greater than in CT and TT carriers. In 235 patients taking stable doses of atorvastatin, simvastatin, or lovastatin for lipid control, carriers of the T allele required significantly lower statin doses (0.2-0.6-fold, P=0.019) than non-T carriers for optimal lipid control. These results indicate that intron 6 SNP rs35599367 markedly affects expression of CYP3A4 and could serve as a biomarker for predicting response to CYP3A4-metabolized drugs.

Subchronic oral toxicity study of furan in B6C3F1 Mice.

Furan is a heterocyclic organic compound formed during heat treatment for processing and preservation of various types of food. Rodent studies have previously shown that furan is a hepatocarcinogen. Those studies were conducted over a high dose range, which induced tumors at nearly 100% incidence at all doses. This ninety-day gavage study in mice was conducted to extend the dose to a lower range (0.0, 0.03, 0.12, 0.5, 2.0, and 8.0 mg/kg body weight [bw] per day) to identify a no-observed adverse effect level for hepatotoxicity and to characterize non-neoplastic effects, including those affecting clinical biochemistry, hematology, tissue morphology, and histopathology. The liver was the primary target organ with dose-dependent toxicity. Liver weights were increased at the 8.0 mg/kg bw dose in females only. Levels of the serum enzyme alanine transaminase, representative of liver damage, were increased three-fold at the highest dose. Histological changes in the liver were observed at 2.0 and 8.0 mg/kg bw in both sexes. Although clinical parameters were also altered for the kidney, these differences were not accompanied by histological changes. Based on these clinical biochemical and histological changes, a no-observed adverse effect level of 0.12 mg/kg bw per day of furan in mice is suggested.

Subchronic oral toxicity study of furan in Fischer-344 rats.

Rodent studies have shown that furan is a hepatocarcinogen. Previous studies conducted with high doses showed tumors at nearly 100% incidence at all doses. In this paper, a ninety-day gavage experiment conducted with lower doses (0.0, 0.03, 0.12, 0.5, 2.0, and 8.0 mg/kg bw) to identify a no-observed adverse effect level for hepatotoxicity and to characterize non-neoplastic effects including gross changes and histopathology, clinical biochemistry, hematology, and immunotoxicology is reported. As indicated by changes in serum biomarkers, increased liver weights and gross and histological lesions, the liver is the major target organ affected by furan. There were no changes in body weights, food consumption, or histology in other organs. Some of the serum electrolyte markers, including phosphorus, were altered. There was a significant increase in serum thyroxine and triidothyronine in males. This increase was not accompanied by histological thyroid changes. Immunophenotypic analysis showed that thymic lymphocyte maturation was altered in male rats. Although altered clinical biochemistry and hematological parameters were observed at a dose of > 0.5 mg/kg bw, mild histological lesions in the liver were observed at > 0.12 mg/kg bw. Based on this finding, a furan dose of 0.03 mg/kg bw was proposed as the no-observed adverse effect level for hepatic toxicity.

Toxicokinetics of p-tert-octylphenol in male and female Sprague-Dawley rats after intravenous, oral, or subcutaneous exposures.

This study was undertaken to characterize the toxicokinetics of p-tert-octylphenol (OP), a weak estrogenic compound, in male and female rats. Male and female Sprague-Dawley rats were given a single dose of OP either by oral gavage (50, 125 or 250 mg/kg), by intravenous (iv) injection (2, 4, or 8 mg/kg), or by subcutaneous (sc) injection (125 mg/kg). In a repeated dosing experiment, rats were given OP (oral) daily (25, 50, or 125 mg/kg) for 35 d (female) or 60 d (male). Blood and tissue samples were collected and analyzed for OP content using gas chromatography with detection by mass spectrometry. Blood OP concentrations were generally higher in female than male rats following a single oral or sc administration but were similar following a single iv injection. Tissue OP concentrations were also higher in female than male rats following oral exposure, consistent with the faster metabolism of OP observed in male rat liver microsomes. After subchronic administration, blood OP concentrations were higher at the end of exposure for female (33 d) (2.26-fold, not significant) and male (57 d) (3.47-fold) rats than single dosing but there was no change in the tissue OP concentrations. Gender differences in tissue OP concentrations may contribute, in part, to gender differences in the toxicity of OP in rats. The fact that OP was found in all reproductive tissues confirms its potential for direct endocrine-like effects.

Determination of p-tert-octylphenol in blood and tissues by gas chromatography coupled with mass spectrometry.

A sensitive and reproducible procedure using gas chromatography coupled with mass spectrometry is described for the determination of p-tert-octylphenol (OP), a persistent degradation product of alkylphenol ethoxylates that binds to the estrogen receptor in blood and tissues. The first step involved the extraction of blood (200 microL) or tissue homogenate (400 microL) with methyl tert-butyl ether, including p-tert-butylphenol (BP) as internal standard. After extraction, the sample was evaporated to dryness with a gentle stream of nitrogen at 45 degrees C, and OP and BP were derivatized with an acetylation reaction involving acetic anhydride and catalyzed by pyridine. Samples were then analyzed by a gas chromatograph equipped with a mass spectrometer (single ion monitoring) with a Varian VF-5ms capillary column. The limit of detection and the limit of quantification of the method in blood were 4.6 and 15.5 ng/mL, respectively. The linearity and reproducibility of the method were acceptable, with coefficients of variation of approximately 10% for blood and ranging between 9% and 27% for tissues. This method was applied to the determination of unchanged OP in blood and tissues obtained from Sprague-Dawley rats after oral and IV OP administration.

An investigation of the role acceptor side chains play in the processibility and efficiency of organic solar cells fabricated from small molecular donors featuring 3,4-ethylenedioxythiophene cores.

Organic photovoltaic devices fabricated from small molecular donors continue to receive significant interest due to their desirable properties such as convenient synthesis, purification and batch-to-batch reproducibility. In this study, we have synthesized two small molecules based on an alternating A-D-A structure, utilizing a central EDOT donor moiety and either 2-ethylhexyl cyanoacetate (SAM-72) or N-(2-ethylhexyl)cyanoacetamide (SAM-80) units as acceptor termini. The small molecules were incorporated into bulk heterojunction solar cells with PC71BM. Our investigations have shown that the side chains utilized for SAM-80 only allow for solution processing using volatile solvents, such as chloroform, which limits the reproducibility of device fabrication. However, SAM-72 displays better solubility and devices fabricated using a SAM-72:PC71BM active layer reached average power conversion efficiencies of 1.9%, with fill factors reaching 60%. Post-processing methods such as thermal and solvent vapor annealing were found to significantly increase the stability of devices, but were not able to improve overall device performance.