Cluster Analysis of Obesity and Asthma Phenotypes

Asthma is a heterogeneous disease with variability among patients in characteristics such as lung function, symptoms and control, body weight, markers of inflammation, and responsiveness to glucocorticoids (GC). Cluster analysis of well-characterized cohorts can advance understanding of disease subgroups in asthma and point to unsuspected disease mechanisms. We utilized an hypothesis-free cluster analytical approach to define the contribution of obesity and related variables to asthma phenotype.In a cohort of clinical trial participants (n = 250), minimum-variance hierarchical clustering was used to identify clinical and inflammatory biomarkers important in determining disease cluster membership in mild and moderate persistent asthmatics. In a subset of participants, GC sensitivity was assessed via expression of GC receptor alpha (GCRα) and induction of MAP kinase phosphatase-1 (MKP-1) expression by dexamethasone. Four asthma clusters were identified, with body mass index (BMI, kg/m(2)) and severity of asthma symptoms (AEQ score) the most significant determinants of cluster membership (F = 57.1, p<0.0001 and F = 44.8, p<0.0001, respectively). Two clusters were composed of predominantly obese individuals; these two obese asthma clusters differed from one another with regard to age of asthma onset, measures of asthma symptoms (AEQ) and control (ACQ), exhaled nitric oxide concentration (F(E)NO) and airway hyperresponsiveness (methacholine PC(20)) but were similar with regard to measures of lung function (FEV(1) (%) and FEV(1)/FVC), airway eosinophilia, IgE, leptin, adiponectin and C-reactive protein (hsCRP). Members of obese clusters demonstrated evidence of reduced expression of GCRα, a finding which was correlated with a reduced induction of MKP-1 expression by dexamethasoneObesity is an important determinant of asthma phenotype in adults. There is heterogeneity in expression of clinical and inflammatory biomarkers of asthma across obese individuals. Reduced expression of the dominant functional isoform of the GCR may mediate GC insensitivity in obese asthmatics

Cultural measurement on whose terms? Critical friends as an experiment in participant-led evaluation

Critical Friends is an enquiry into the commissioning, planning and delivery of participatory art carried out by the people that such projects claim to empower. Participants become interviewers, researchers and evaluators, acting as ‘productive parasites’ to a process of socially-engaged art. Aims of social cohesion and active citizenship underpinned a series of publicly-funded art commissions in North Greenwich, London (2008-2011). The group of Critical Friends were residents of North Greenwich who came together to investigate what, why and how these socially engaged art projects were happening in their area. Did the projects reflect the ambitious aims to ‘stimulate debate to generate action and change’ and ‘develop connections and relations between people’? Facilitated by myself and Rebecca Maguire over three years, Critical Friends developed their own questions and methods for finding out. While participation and engagement is usually measured for such projects in terms of numbers of people who attend workshops, Critical Friends was a space for enacting a different kind of cultural measurement. The group focused on trying to find out the qualitative experiences of other participants and interrogated the underlying motives, targets and politics behind the commissions. They did this by acting as participant observers in the projects themselves and by interviewing artists, commissioners, board members, their neighbours and friends (http://criticalfriends.sophiehope.org.uk/)

Relationship between river size and nutrient removal

Author Posting. © American Geophysical Union, 2006. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geophysical Research Letters 33 (2006): L06410, doi:10.1029/2006GL025845.We present a conceptual approach for evaluating the biological and hydrological controls of nutrient removal in different sized rivers within an entire river network. We emphasize a per unit area biological parameter, the nutrient uptake velocity (νf), which is mathematically independent of river size in benthic dominated systems. Standardization of biological parameters from previous river network models to νf reveals the nature of river size dependant biological activity in these models. We explore how geomorphic, hydraulic, and biological factors control the distribution of nutrient removal in an idealized river network, finding that larger rivers within a basin potentially exert considerable influence over nutrient exports.This work was funded by NASA-IDS (NNG04GH75G), NSF-LTER OCE-9726921, and NOAA (NA17RJ2612- 344 to Princeton U.)

Economic evaluation of shortened, bedaquiline-containing treatment regimens for rifampicin-resistant tuberculosis (STREAM stage 2): a within-trial analysis of a randomised controlled trial

BACKGROUND: The STREAM stage 2 trial assessed two bedaquiline-containing regimens for rifampicin-resistant tuberculosis: a 9-month all-oral regimen and a 6-month regimen containing an injectable drug for the first 2 months. We did a within-trial economic evaluation of these regimens. METHODS: STREAM stage 2 was an international, phase 3, non-inferiority randomised trial in which participants with rifampicin-resistant tuberculosis were randomly assigned (1:2:2:2) to the 2011 WHO regimen (terminated early), a 9-month injectable-containing regimen (control regimen), a 9-month all-oral regimen with bedaquiline (oral regimen), or a 6-month regimen with bedaquiline and an injectable for the first 2 months (6-month regimen). We prospectively collected direct and indirect costs and health-related quality of life data from trial participants until week 76 of follow-up. Cost-effectiveness of the oral and 6-month regimens versus control was estimated in four countries (oral regimen) and two countries (6-month regimen), using health-related quality of life for cost-utility analysis and trial efficacy for cost-effectiveness analysis. This trial is registered with ISRCTN, ISRCTN18148631. FINDINGS: 300 participants were included in the economic analyses (Ethiopia, 61; India, 142; Moldova, 51; Uganda, 46). In the cost-utility analysis, the oral regimen was not cost-effective in Ethiopia, India, Moldova, and Uganda from either a provider or societal perspective. In Moldova, the oral regimen was dominant from a societal perspective. In the cost-effectiveness analysis, the oral regimen was likely to be cost-effective from a provider perspective at willingness-to-pay thresholds per additional favourable outcome of more than US$4500 in Ethiopia,$1900 in India, $3950 in Moldova, and$7900 in Uganda, and from a societal perspective at thresholds of more than $15 900 in Ethiopia,$3150 in India, and $4350 in Uganda, while in Moldova the oral regimen was dominant. In Ethiopia and India, the 6-month regimen would cost tuberculosis programmes and participants less than the control regimen and was highly likely to be cost-effective in both cost-utility analysis and cost-effectiveness analysis. Reducing the bedaquiline price from$1·81 to $1·00 per tablet made the oral regimen cost-effective in the provider-perspective cost-utility analysis in India and Moldova and dominate over the control regimen in the provider-perspective cost-effectiveness analysis in India. INTERPRETATION: At current costs, the oral bedaquiline-containing regimen for rifampicin-resistant tuberculosis is unlikely to be cost-effective in many low-income and middle-income countries. The 6-month regimen represents a cost-effective alternative if injectable use for 2 months is acceptable. FUNDING: USAID and Janssen Research & Development

Dynamics of N removal over annual time periods in a suburban river network

Author Posting. © American Geophysical Union, 2008. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research 113 (2008): G03038, doi:10.1029/2007JG000660.River systems are dynamic, highly connected water transfer networks that integrate a wide range of physical and biological processes. We used a river network nitrogen (N) removal model with daily temporal resolution to evaluate how elevated N inputs, saturation of the denitrification and total nitrate removal processes, and hydrologic conditions interact to determine the amount, timing and distribution of N removal in the fifth-order river network of a suburban 400 km2 basin. Denitrification parameters were based on results from whole reach 15NO3 tracer additions. The model predicted that between 15 and 33% of dissolved inorganic nitrogen (DIN) inputs were denitrified annually by the river system. Removal approached 100% during low flow periods, even with the relatively low and saturating uptake velocities typical of surface water denitrification. Annual removal percentages were moderate because most N inputs occurred during high flow periods when hydraulic conditions and temperatures are less favorable for removal by channel processes. Nevertheless, the percentage of annual removal occurring during above average flow periods was similar to that during low flow periods. Predicted river network removal proportions are most sensitive to loading rates, spatial heterogeneity of inputs, and the form of the removal process equation during typical base flow conditions. However, comparison with observations indicates that removal by the river network is higher than predicted by the model at moderately high flows, suggesting additional removal processes are important at these times. Further increases in N input to the network will lead to disproportionate increases in N exports due to the limits imposed by process saturation.This work was funded by NSF-DEB- 0614282, NSF-OCE-9726921, NSF-DEB-0111410, and NSF-BCS- 0709685

Evaluation of ORCHIDEE-MICT-simulated soil moisture over China and impacts of different atmospheric forcing data

Soil moisture is a key variable of land surface hydrology, and its correct representation in land surface models is crucial for local to global climate predictions. The errors may come from the model itself (structure and parameterization) but also from the meteorological forcing used. In order to separate the two source of errors, four atmospheric forcing datasets, GSWP3 (Global Soil Wetness Project Phase 3), PGF (Princeton Global meteorological Forcing), CRU-NCEP (Climatic Research Unit-National Center for Environmental Prediction), and WFDEI (WATCH Forcing Data methodology applied to ERA-Interim reanalysis data), were used to drive simulations in China by the land surface model ORCHIDEE-MICT(ORganizing Carbon and Hydrology in Dynamic EcosystEms: aMeliorated Interactions between Carbon and Temperature). Simulated soil moisture was compared with in situ and satellite datasets at different spatial and temporal scales in order to (1) estimate the ability of ORCHIDEE-MICT to represent soil moisture dynamics in China; (2) demonstrate the most suitable forcing dataset for further hydrological studies in Yangtze and Yellow River basins; and (3) understand the discrepancies of simulated soil moisture among simulations. Results showed that ORCHIDEE-MICT can simulate reasonable soil moisture dynamics in China, but the quality varies with forcing data. Simulated soil moisture driven by GSWP3 and WFDEI shows the best performance according to the root mean square error (RMSE) and correlation coefficient, respectively, suggesting that both GSWP3 and WFDEI are good choices for further hydrological studies in the two catchments. The mismatch between simulated and observed soil moisture is mainly explained by the bias of magnitude, suggesting that the parameterization in ORCHIDEE-MICT should be revised for further simulations in China. Underestimated soil moisture in the North China Plain demonstrates possible significant impacts of human activities like irrigation on soil moisture variation, which was not considered in our simulations. Finally, the discrepancies of meteorological variables and simulated soil moisture among the four simulations are analyzed. The result shows that the discrepancy of soil moisture is mainly explained by differences in precipitation frequency and air humidity rather than differences in precipitation amount.</p

Climate-Induced Changes in Spring Snowmelt Impact Ecosystem Metabolism and Carbon Fluxes in an Alpine Stream Network

Although stream ecosystems are recognized as an important component of the global carbon cycle, the impacts of climate-induced hydrological extremes on carbon fluxes in stream networks remain unclear. Using continuous measurements of ecosystem metabolism, we report on the effects of changes in snowmelt hydrology during the anomalously warm winter 2013/2014 on gross primary production (GPP), ecosystem respiration (ER), and net ecosystem production (NEP) in an Alpine stream network. We estimated ecosystem metabolism across 12 study reaches of the 254 km2 subalpine Ybbs River Network (YRN), Austria, for 18 months. During spring snowmelt, GPP peaked in 10 of our 12 study reaches, which appeared to be driven by PAR and catchment area. In contrast, the winter precipitation shift from snow to rain following the low-snow winter in 2013/2014 increased spring ER in upper elevation catchments, causing spring NEP to shift from autotrophy to heterotrophy. Our findings suggest that the YRN transitioned from a transient sink to a source of carbon dioxide (CO2) in spring as snowmelt hydrology differed following the high-snow versus low-snow winter. This shift toward increased heterotrophy during spring snowmelt following a warm winter has potential consequences for annual ecosystem metabolism, as spring GPP contributed on average 33% to annual GPP fluxes compared to spring ER, which averaged 21% of annual ER fluxes. We propose that Alpine headwaters will emit more within-stream respiratory CO2 to the atmosphere while providing less autochthonous organic energy to downstream ecosystems as the climate gets warmer