Sickle cell disease (SCD) is a clinically heterogeneous disease with many acute and chronic complications driven by ongoing vaso-occlusion and hemolysis. It causes a disproportionate burden on Black ...and Hispanic communities. Our objective was to follow the SMDM/ISPOR Task Force recommendations for good practices and create a conceptual model of the progression of SCD under current clinical practice to inform cost-effectiveness analyses (CEA) of promising curative therapies in the pipeline over a lifetime horizon.
We used consultations with experts, providers, and patients to identify acute events and chronic conditions in the conceptual model. We compared our model structure to previous CEA models of interventions for SCD, assessed the prevalence of the identified disease attributes in Medicaid and Medicare claims databases, and identified relevant outcomes following the 2nd Panel in CEA. We determined an appropriate modeling technique and relevant data sources for parameterizing the model.
The conceptual model structure included four dimensions of disease: chronic pain, acute events, chronic conditions, and treatment complications, spanning 26 disease attributes with significant impacts on health-related quality of life and resource. We modeled chronic pain separately to reflect its importance to patients and interaction with all other disease attributes. We identified additional data sources for health state utilities and non-medical costs and benefits of SCD. We will use a microsimulation model with age- and sex-specific transitions between health states predicted by patient demographic characteristics and disease history.
Developing the model structure through an explicit process of model conceptualization can increase the transparency and accuracy of results. We will populate the conceptual model with the data sources described and evaluate the cost-effectiveness of curative therapies.
The basic body plan and major physiological axes have been highly conserved during mammalian evolution, yet only a small fraction of the human genome sequence appears to be subject to evolutionary ...constraint. To quantify cis- versus trans-acting contributions to mammalian regulatory evolution, we performed genomic DNase I footprinting of the mouse genome across 25 cell and tissue types, collectively defining ∼8.6 million transcription factor (TF) occupancy sites at nucleotide resolution. Here we show that mouse TF footprints conjointly encode a regulatory lexicon that is ∼95% similar with that derived from human TF footprints. However, only ∼20% of mouse TF footprints have human orthologues. Despite substantial turnover of the cis-regulatory landscape, nearly half of all pairwise regulatory interactions connecting mouse TF genes have been maintained in orthologous human cell types through evolutionary innovation of TF recognition sequences. Furthermore, the higher-level organization of mouse TF-to-TF connections into cellular network architectures is nearly identical with human. Our results indicate that evolutionary selection on mammalian gene regulation is targeted chiefly at the level of trans-regulatory circuitry, enabling and potentiating cis-regulatory plasticity.
Data derived from instruments on board the Cloud–Aerosol Lidar and Infrared Pathfinder Satellite Observation (CALIPSO) and CloudSat satellites as well as meteorological parameters from reanalysis are ...used to explore situations when moist aerosol layers overlie stratocumulus clouds over the southeast Atlantic during the biomass burning season (June to October). To separate and quantify the impacts of aerosol loading, aerosol type, and humidity on the radiative fluxes (including cloud top cooling), the data are split into different levels of aerosol and moisture loadings. The aerosol classification available from the CALIPSO products is used to compare and contrast situations with pristine air, with smoke, and with other (non-smoke) types of aerosols. A substantial number of cases with non-smoke aerosols above clouds are found to occur under similar meteorological conditions to the smoke cases. In contrast, the meteorology is substantially different for the pristine situations, making a direct comparison with the aerosol cases ambiguous. The moisture content is enhanced within the aerosol layers, but the relative humidity does not always increase monotonously with increasing optical depth. Shortwave (SW) heating rates within the moist aerosol plumes increase with increasing aerosol loading and are higher in the smoke cases compared to the non-smoke cases. However, there is no clear correlation between moisture changes and SW absorption. Cloud top cooling rates do not show a clear correlation with moisture within the overlying aerosol layers due to the strong variability of the cooling rates caused by other meteorological factors (most notably cloud top temperature). No clear influence of aerosol type or loading on cloud top cooling rates is detected. Further, there is no correlation between aerosol loading and the thermodynamic structure of the atmosphere nor the cloud top height.
The effects of different aerosol types on cloud albedo are analysed using the linear relation between total albedo and cloud fraction found on a monthly mean scale in regions of subtropical marine ...stratocumulus clouds and the influence of simulated aerosol variations on this relation. Model experiments from the Coupled Model Intercomparison Project phase 5 (CMIP5) are used to separately study the responses to increases in sulfate, non-sulfate and all anthropogenic aerosols. A cloud brightening on the month-to-month scale due to variability in the background aerosol is found to dominate even in the cases where anthropogenic aerosols are added. The aerosol composition is of importance for this cloud brightening, that is thereby region dependent. There is indication that absorbing aerosols to some extent counteract the cloud brightening but scene darkening with increasing aerosol burden is generally not supported, even in regions where absorbing aerosols dominate. Month-to-month cloud albedo variability also confirms the importance of liquid water content for cloud albedo. Regional, monthly mean cloud albedo is found to increase with the addition of anthropogenic aerosols and more so with sulfate than non-sulfate. Changes in cloud albedo between experiments are related to changes in cloud water content as well as droplet size distribution changes, so that models with large increases in liquid water path and/or cloud droplet number show large cloud albedo increases with increasing aerosol. However, no clear relation between model sensitivities to aerosol variations on the month-to-month scale and changes in cloud albedo due to changed aerosol burden is found.
Abstract
Equilibrium climate sensitivity (ECS) and transient climate response (TCR) are both measures of the sensitivity of the climate system to external forcing, in terms of temperature response to ...CO
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doubling. Here it is shown that, of the two, TCR in current-generation coupled climate models is better correlated with the model projected temperature change from the pre-industrial state, not only on decadal time scales but throughout much of the 21st century. For strong mitigation scenarios the difference persists until the end of the century. Historical forcing on the other hand has a significant degree of predictive power of past temperature evolution in the models, but is not relevant to the magnitude of temperature change in their future projections. Regional analysis shows a superior predictive power of ECS over TCR during the latter half of the 21st century in areas with slow warming, illustrating that although TCR is a better predictor of warming on a global scale, it does not capture delayed regional feedbacks, or pattern effects. The transient warming at CO
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quadrupling (T140) is found to be correlated with global mean temperature anomaly for a longer time than TCR, and it also better describes the pattern of regional temperature anomaly at the end of the century. Over the 20th century, there is a weak correlation between total forcing and ECS, contributing to, but not determining, the model agreement with observed warming. ECS and aerosol forcing in the models are not correlated.
Philosophers argue that many choices in science are influenced by values or have value-implications, ranging from the preference for some research method’s qualities to ethical estimation of the ...consequences of error. Based on the argument that awareness of values in the scientific process is a necessary first step to both avoid bias and attune science best to the needs of society, an analysis of the role of values in the physical climate science production process is provided. Model-based assessment of climate sensitivity is taken as an illustrative example; climate sensitivity is useful here because of its key role in climate science and relevance for policy, by having been the subject of several assessments over the past decades including a recent shift in assessment method, and because it enables insights that apply to numerous other aspects of climate science. It is found that value-judgements are relevant at every step of the model-based assessment process, with a differentiated role of non-epistemic values across the steps, impacting the assessment in various ways. Scrutiny of current philosophical norms for value-management highlights the need for those norms to be re-worked for broader applicability to climate science. Recent development in climate science turning away from direct use of models for climate sensitivity assessment also gives the opportunity to start investigating the role of values in alternative assessment methods, highlighting similarities and differences in terms of the role of values that encourage further study.
A detailed analysis of optical and microphysical properties of aerosol particles during the dry winter monsoon season above the northern Indian Ocean is presented. The Cloud Aerosol Radiative Forcing ...Experiment (CARDEX), conducted from 16 February to 30 March 2012 at the Maldives Climate Observatory on Hanimaadhoo island (MCOH) in the Republic of the Maldives, used autonomous unmanned aerial vehicles (AUAV) to perform vertical in situ measurements of particle number concentration, particle number size distribution as well as particle absorption coefficients. These measurements were used together with surface- based Mini Micro Pulse Lidar (MiniMPL) observations and aerosol in situ and off-line measurements to investigate the vertical distribution of aerosol particles.Air masses were mainly advected over the Indian subcontinent and the Arabian Peninsula. The mean surface aerosol number concentration was 1717 ± 604 cm−3 and the highest values were found in air masses from the Bay of Bengal and Indo-Gangetic Plain (2247 ± 370 cm−3). Investigations of the free tropospheric air showed that elevated aerosol layers with up to 3 times higher aerosol number concentrations than at the surface occurred mainly during periods with air masses originating from the Bay of Bengal and the Indo-Gangetic Plain. This feature is different compared to what was observed during the Indian Ocean Experiment (INDOEX) conducted in winter 1999, where aerosol number concentrations generally decreased with height. In contrast, lower particle absorption at the surface (σabs(520 nm) = 8.5 ± 4.2 Wm−1) was found during CARDEX compared to INDOEX 1999.Layers with source region specific single-scattering albedo (SSA) values were derived by combining vertical in situ particle absorption coefficients and scattering coefficients calculated with Mie theory. These SSA layers were utilized to calculate vertical particle absorption profiles from MiniMPL profiles. SSA surface values for 550 nm for dry conditions were found to be 0.94 ± 0.02 and 0.91 ± 0.02 for air masses from the Arabian Sea (and Middle East countries) and India (and Bay of Bengal), respectively. Lidar-derived particle absorption coefficient profiles showed both a similar magnitude and structure as the in situ profiles measured with the AUAV. However, primarily due to insufficient accuracy in the SSA estimates, the lidar-derived absorption coefficient profiles have large uncertainties and are generally weakly correlated to vertically in situ measured particle absorption coefficients.Furthermore, the mass absorption efficiency (MAE) for the northern Indian Ocean during the dry monsoon season was calculated to determine equivalent black carbon (EBC) concentrations from particle absorption coefficient measurements. A mean MAE of 11.6 and 6.9 m2 g−1 for 520 and 880 nm, respectively, was found, likely representing internally mixed BC containing particles. Lower MAE values for 880 and 520 nm were found for air masses originating from dust regions such as the Arabian Peninsula and western Asia (MAE(880 nm) = 5.6 m2 g−1, MAE(520 nm) = 9.5 m2 g−1) or from closer source regions as southern India (MAE(880 nm) = 4.3 m2 g−1, MAE(520 nm) = 7.3 m2 g−1).
The contribution of changes in cis-regulatory elements or trans-acting factors to interspecies differences in gene expression is not well understood. The mammalian beta-globin loci have served as a ...model for gene regulation during development. Transgenic mice containing the human beta-globin locus, consisting of the linked embryonic (epsilon), fetal (gamma) and adult (beta) genes, have been used as a system to investigate the temporal switch from fetal to adult haemoglobin, as occurs in humans. Here we show that the human gamma-globin (HBG) genes in these mice behave as murine embryonic globin genes, revealing a limitation of the model and demonstrating that critical differences in the trans-acting milieu have arisen during mammalian evolution. We show that the expression of BCL11A, a repressor of human gamma-globin expression identified by genome-wide association studies, differs between mouse and human. Developmental silencing of the mouse embryonic globin and human gamma-globin genes fails to occur in mice in the absence of BCL11A. Thus, BCL11A is a critical mediator of species-divergent globin switching. By comparing the ontogeny of beta-globin gene regulation in mice and humans, we have shown that alterations in the expression of a trans-acting factor constitute a critical driver of gene expression changes during evolution.
We have examined the relationship between nuclear localization and transcriptional activity of the endogenous murine beta-globin locus during erythroid differentiation. Murine fetal liver cells were ...separated into distinct erythroid maturation stages by fluorescence-activated cell sorting, and the nuclear position of the locus was determined at each stage. We find that the beta-globin locus progressively moves away from the nuclear periphery with increasing maturation. Contrary to the prevailing notion that the nuclear periphery is a repressive compartment in mammalian cells, beta(major)-globin expression begins at the nuclear periphery prior to relocalization. However, relocation of the locus to the nuclear interior with maturation is accompanied by an increase in beta(major)-globin transcription. The distribution of nuclear polymerase II (Pol II) foci also changes with erythroid differentiation: Transcription factories decrease in number and contract toward the nuclear interior. Moreover, both efficient relocalization of the beta-globin locus from the periphery and its association with hyperphosphorylated Pol II transcription factories require the locus control region (LCR). These results suggest that the LCR-dependent association of the beta-globin locus with transcriptionally engaged Pol II foci provides the driving force for relocalization of the locus toward the nuclear interior during erythroid maturation.
The hemispheric symmetry of albedo and its contributing factors in satellite observations and global climate models is evaluated. The analysis is performed on the annual mean time scale, on which a ...bimodality in the joint distribution of albedo and cloud fraction is evident, resulting from tropical and subtropical clouds and midlatitude clouds, respectively. Hemispheric albedo symmetry is not found in individual ocean-only latitude bands; comparing the Northern and Southern Hemisphere (NH and SH), regional mean albedo is higher in the NH tropics and lower in the NH subtropics and midlatitudes than in the SH counterparts. This follows the hemispheric asymmetry of cloud fraction. In midlatitudes and tropics the hemispheric asymmetry in cloud albedo also contributes to the asymmetry in total albedo, whereas in the subtropics the cloud albedo is more hemispherically symmetric. According to the observations, cloud contributions to compensation for higher clear-sky albedo in the NH come primarily from cloud albedo in midlatitudes and cloud amount in the subtropics. Current-generation climate models diverge in their representation of these relationships, but common features of the model–data comparison include weaker-than-observed asymmetry in cloud fraction and cloud albedo in the tropics, weaker or reversed cloud fraction asymmetry in the subtropics, and agreement with observed cloud albedo asymmetry in the midlatitudes. Models on average reproduce the NH–SH asymmetry in total albedo over the 60°S–60°N ocean but show higher occurrence of brighter clouds in the SH compared to observations. The albedo bias in both hemispheres is reinforced by overestimated clear-sky albedo in the models.
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