Health state utilities associated with attributes of treatments for hepatitis C

BACKGROUND: Cost-utility analyses are frequently conducted to compare treatments for hepatitis C, which are often associated with complex regimens and serious adverse events. Thus, the purpose of this study was to estimate the utility associated with treatment administration and adverse events of hepatitis C treatments. DESIGN: Health states were drafted based on literature review and clinician interviews. General population participants in the UK valued the health states in time trade-off (TTO) interviews with 10- and 1-year time horizons. The 14 health states described hepatitis C with variations in treatment regimen and adverse events. RESULTS: A total of 182 participants completed interviews (50 % female; mean age = 39.3 years). Utilities for health states describing treatment regimens without injections ranged from 0.80 (1 tablet) to 0.79 (7 tablets). Utilities for health states describing oral plus injectable regimens were 0.77 (7 tablets), 0.75 (12 tablets), and 0.71 (18 tablets). Addition of a weekly injection had a disutility of −0.02. A requirement to take medication with fatty food had a disutility of −0.04. Adverse events were associated with substantial disutilities: mild anemia, −0.12; severe anemia, −0.32; flu-like symptoms, −0.21; mild rash, −0.13; severe rash, −0.48; depression, −0.47. One-year TTO scores were similar to these 10-year values. CONCLUSIONS: Adverse events and greater treatment regimen complexity were associated with lower utility scores, suggesting a perceived decrease in quality of life beyond the impact of hepatitis C. The resulting utilities may be used in models estimating and comparing the value of treatments for hepatitis C. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10198-014-0649-6) contains supplementary material, which is available to authorized users

Variability in Working Memory Performance Explained by Epistasis vs Polygenic Scores in the ZNF804A Pathway

Importance: We investigated the variation in neuropsychological function explained by risk alleles at the psychosis susceptibility gene ZNF804A and its interacting partners using single nucleotide polymorphisms (SNPs), polygenic scores, and epistatic analyses. Of particular importance was the relative contribution of the polygenic score vs epistasis in variation explained. Objectives To (1) assess the association between SNPs in ZNF804A and the ZNF804A polygenic score with measures of cognition in cases with psychosis and (2) assess whether epistasis within the ZNF804A pathway could explain additional variation above and beyond that explained by the polygenic score. Design, Setting, and Participants: Patients with psychosis (n = 424) were assessed in areas of cognitive ability impaired in schizophrenia including IQ, memory, attention, and social cognition. We used the Psychiatric GWAS Consortium 1 schizophrenia genome-wide association study to calculate a polygenic score based on identified risk variants within this genetic pathway. Cognitive measures significantly associated with the polygenic score were tested for an epistatic component using a training set (n = 170), which was used to develop linear regression models containing the polygenic score and 2-SNP interactions. The best-fitting models were tested for replication in 2 independent test sets of cases: (1) 170 individuals with schizophrenia or schizoaffective disorder and (2) 84 patients with broad psychosis (including bipolar disorder, major depressive disorder, and other psychosis). Main Outcomes and Measures: Participants completed a neuropsychological assessment battery designed to target the cognitive deficits of schizophrenia including general cognitive function, episodic memory, working memory, attentional control, and social cognition. Results: Higher polygenic scores were associated with poorer performance among patients on IQ, memory, and social cognition, explaining 1% to 3% of variation on these scores (range, P = .01 to .03). Using a narrow psychosis training set and independent test sets of narrow phenotype psychosis (schizophrenia and schizoaffective disorder), broad psychosis, and control participants (n = 89), the addition of 2 interaction terms containing 2 SNPs each increased the R2 for spatial working memory strategy in the independent psychosis test sets from 1.2% using the polygenic score only to 4.8% (P = .11 and .001, respectively) but did not explain additional variation in control participants. Conclusions and Relevance: These data support a role for the ZNF804A pathway in IQ, memory, and social cognition in cases. Furthermore, we showed that epistasis increases the variation explained above the contribution of the polygenic score

Exposure ages from mountain dipsticks in Mac. Robertson Land, East Antarctica, indicate little change in ice-sheet thickness since the Last Glacial Maximum.

Past changes in East Antarctic Ice Sheet (EAIS) volume are poorly known and difficult to measure, yet are critical for predicting the response of the ice sheet to modern climate change. In particular, it is important to identify the sources of sea-level rise since the Last Glacial Maximum (LGM), and ascertain the present-day stability of the world's largest ice sheet. We present altitudinal transects of Be-10 and Al-26 exposure ages across the Framnes Mountains in Mac. Robertson Land that allow the magnitude and timing of EAIS retreat to be quantified. Our data show that the coastal EAIS thinned by at most 350 m in this region during the past 13 k.y. This reduction in ice-sheet volume occurred over a similar to 5 k.y. period, and the present ice-sheet profile was attained ca. 7 ka, in contrast to the West Antarctic Ice Sheet, which continues to retreat today. Combined with regional offshore and terrestrial geologic evidence, our data suggest that the reduction in EAIS volume since the LGM was smaller than that indicated by contemporary ice-sheet models and added little meltwater to the global oceans. Stability of the ice margin since the middle Holocene provides support for the hypothesis that EAIS volume changes are controlled by growth and decay of Northern Hemisphere ice sheets and associated global sea-level changes. © 2007, Geological Society of Americ

Phase stabilities of MgCO3 and MgCO3 -II studied by Raman spectroscopy, x-ray diffraction, and density functional theory calculations

Carbonates are the major hosts of carbon on Earth's surface and their fate during subduction needs to be known to understand the deep carbon cycle. Magnesite (MgCO$_{3}$) is thought to be an important phase participating in deep Earth processes, but its phase stability is still a matter of debate for the conditions prevalent in the lowest part of the mantle and at the core mantle boundary. Here, we have studied the phase relations and stabilities of MgCO$_{3}$ at these P,T conditions, using Raman spectroscopy at high pressures (∼148GPa) and after heating to high temperatures (∼3600K) in laser-heated diamond anvil cell experiments. The experimental Raman experiments were supplemented by x-ray powder diffraction data, obtained at a pressure of 110 GPa. Density-functional-theory-based model calculations were used to compute Raman spectra for several MgCO$_{3}$ high-pressure polymorphs, thus allowing an unambiguous assignment of Raman modes. By combining the experimental observations with the density-functional-theory results, we constrain the phase stability field of MgCO$_{3}$ with respect to the high-pressure polymorph, MgCO$_{3}$-II. We further confirm that Fe-free MgCO$_{3}$-II is a tetracarbonate with monoclinic symmetry (space group C2/m), which is stable over the entire P,T range of the Earth's lowermost mantle geotherm

Intrinsically Photosensitive Retinal Ganglion Cells

Intrinsically photosensitive retinal ganglion cells (ipRGCs) respond to light in the absence of all rod and cone photoreceptor input. The existence of these ganglion cell photoreceptors, although predicted from observations scattered over many decades, was not established until it was shown that a novel photopigment, melanopsin, was expressed in retinal ganglion cells of rodents and primates. Phototransduction in mammalian ipRGCs more closely resembles that of invertebrate than vertebrate photoreceptors and appears to be mediated by transient receptor potential channels. In the retina, ipRGCs provide excitatory drive to dopaminergic amacrine cells and ipRGCs are coupled to GABAergic amacrine cells via gap junctions. Several subtypes of ipRGC have been identified in rodents based on their morphology, physiology and expression of molecular markers. ipRGCs convey irradiance information centrally via the optic nerve to influence several functions including photoentrainment of the biological clock located in the hypothalamus, the pupillary light reflex, sleep and perhaps some aspects of vision. In addition, ipRGCs may also contribute irradiance signals that interface directly with the autonomic nervous system to regulate rhythmic gene activity in major organs of the body. Here we review the early work that provided the motivation for searching for a new mammalian photoreceptor, the ground-breaking discoveries, current progress that continues to reveal the unusual properties of these neuron photoreceptors, and directions for future investigation

Collection of phloem sap in phytoplasma-infected plants

Phytoplasmas colonize specifically the phloem sieve elements (SEs) of plants and influence effectively the plant physiology. To study and understand the interaction of phytoplasmas and host plants an access to the cellular, microscale volume of SEs is demanded. Different methods are suitable to collect phloem sap of phytoplasma-infected plants. The two most common methods are the EDTA-facilitated exudation and the stylectomy. For the EDTA-facilitated method, the cut end of a leaf is placed into an EDTA solution. The EDTA prevents and avoids the Ca2+ dependent (re-) occlusion of SEs by binding Ca2+ ions and the mass flow of SEs is restarted which results in an outflow of the SE content into the EDTA bathing solution. The advantage is on the one hand a simple application and secondly, feasible for all plant species. The stylectomy method requires piercing-sucking insects like any aphids. During phloem-sap ingestion, the stylet is severed by a microcautery device or a laser from the insect body. Due to the high turgor pressure of the SEs the phloem sap is forced out through the remaining stylet and can be collected with a glass capillary, for example. The stylectomy delivers pure phloem sap, however, the collected volumes are in the range of nano liters and the temporal and staff costs are tremendous. A third method is the spontaneous exudation in phytoplasma-infected apple trees providing only in springtime large volumes of vascular sap after cutting along the bark. For the spontaneous exudation the proportion of phloem sap is unclear. Thus, this third method still needs a closer examination in prospective surveys