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1131.
  • Veteleanu, A., et al. (författare)
  • Alzheimer's disease-associated complement gene variants influence plasma complement protein levels
  • 2023
  • Ingår i: Journal of Neuroinflammation. - 1742-2094. ; 20:1
  • Tidskriftsartikel (refereegranskat)abstract
    • BackgroundAlzheimer's disease (AD) has been associated with immune dysregulation in biomarker and genome-wide association studies (GWAS). GWAS hits include the genes encoding complement regulators clusterin (CLU) and complement receptor 1 (CR1), recognised as key players in AD pathology, and complement proteins have been proposed as biomarkers.Main bodyTo address whether changes in plasma complement protein levels in AD relate to AD-associated complement gene variants we first measured relevant plasma complement proteins (clusterin, C1q, C1s, CR1, factor H) in a large cohort comprising early onset AD (EOAD; n = 912), late onset AD (LOAD; n = 492) and control (n = 504) donors. Clusterin and C1q were significantly increased (p < 0.001) and sCR1 and factor H reduced (p < 0.01) in AD plasma versus controls. ROC analyses were performed to assess utility of the measured complement biomarkers, alone or in combination with amyloid beta, in predicting AD. C1q was the most predictive single complement biomarker (AUC 0.655 LOAD, 0.601 EOAD); combining C1q with other complement or neurodegeneration makers through stepAIC-informed models improved predictive values slightly. Effects of GWS SNPs (rs6656401, rs6691117 in CR1; rs11136000, rs9331888 in CLU; rs3919533 in C1S) on protein concentrations were assessed by comparing protein levels in carriers of the minor vs major allele. To identify new associations between SNPs and changes in plasma protein levels, we performed a GWAS combining genotyping data in the cohort with complement protein levels as endophenotype. SNPs in CR1 (rs6656401), C1S (rs3919533) and CFH (rs6664877) reached significance and influenced plasma levels of the corresponding protein, whereas SNPs in CLU did not influence clusterin levels.ConclusionComplement dysregulation is evident in AD and may contribute to pathology. AD-associated SNPs in CR1, C1S and CFH impact plasma levels of the encoded proteins, suggesting a mechanism for impact on disease risk.
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1132.
  • Zaitlen, Noah, et al. (författare)
  • Informed Conditioning on Clinical Covariates Increases Power in Case-Control Association Studies
  • 2012
  • Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 8:11
  • Tidskriftsartikel (refereegranskat)abstract
    • Genetic case-control association studies often include data on clinical covariates, such as body mass index (BMI), smoking status, or age, that may modify the underlying genetic risk of case or control samples. For example, in type 2 diabetes, odds ratios for established variants estimated from low-BMI cases are larger than those estimated from high-BMI cases. An unanswered question is how to use this information to maximize statistical power in case-control studies that ascertain individuals on the basis of phenotype (case-control ascertainment) or phenotype and clinical covariates (case-controlcovariate ascertainment). While current approaches improve power in studies with random ascertainment, they often lose power under case-control ascertainment and fail to capture available power increases under case-control-covariate ascertainment. We show that an informed conditioning approach, based on the liability threshold model with parameters informed by external epidemiological information, fully accounts for disease prevalence and non-random ascertainment of phenotype as well as covariates and provides a substantial increase in power while maintaining a properly controlled falsepositive rate. Our method outperforms standard case-control association tests with or without covariates, tests of gene x covariate interaction, and previously proposed tests for dealing with covariates in ascertained data, with especially large improvements in the case of case-control-covariate ascertainment. We investigate empirical case-control studies of type 2 diabetes, prostate cancer, lung cancer, breast cancer, rheumatoid arthritis, age-related macular degeneration, and end-stage kidney disease over a total of 89,726 samples. In these datasets, informed conditioning outperforms logistic regression for 115 of the 157 known associated variants investigated (P-value = 1x10(-9)). The improvement varied across diseases with a 16% median increase in chi(2) test statistics and a commensurate increase in power. This suggests that applying our method to existing and future association studies of these diseases may identify novel disease loci.
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1133.
  • Adjuik, Martin A., et al. (författare)
  • The effect of dosing strategies on the therapeutic efficacy of artesunate-amodiaquine for uncomplicated malaria : a meta-analysis of individual patient data
  • 2015
  • Ingår i: BMC Medicine. - : Springer Science and Business Media LLC. - 1741-7015. ; 13
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Artesunate-amodiaquine (AS-AQ) is one of the most widely used artemisinin-based combination therapies (ACTs) to treat uncomplicated Plasmodium falciparum malaria in Africa. We investigated the impact of different dosing strategies on the efficacy of this combination for the treatment of falciparum malaria. Methods: Individual patient data from AS-AQ clinical trials were pooled using the WorldWide Antimalarial Resistance Network (WWARN) standardised methodology. Risk factors for treatment failure were identified using a Cox regression model with shared frailty across study sites. Results: Forty-three studies representing 9,106 treatments from 1999-2012 were included in the analysis; 4,138 (45.4%) treatments were with a fixed dose combination with an AQ target dose of 30 mg/kg (FDC), 1,293 (14.2%) with a non-fixed dose combination with an AQ target dose of 25 mg/kg (loose NFDC-25), 2,418 (26.6%) with a non-fixed dose combination with an AQ target dose of 30 mg/kg (loose NFDC-30), and the remaining 1,257 (13.8%) with a co-blistered non-fixed dose combination with an AQ target dose of 30 mg/kg (co-blistered NFDC). The median dose of AQ administered was 32.1 mg/kg [IQR: 25.9-38.2], the highest dose being administered to patients treated with co-blistered NFDC (median = 35.3 mg/kg [IQR: 30.6-43.7]) and the lowest to those treated with loose NFDC-25 (median = 25.0 mg/kg [IQR: 22.7-25.0]). Patients treated with FDC received a median dose of 32.4 mg/kg [IQR: 27-39.0]. After adjusting for reinfections, the corrected antimalarial efficacy on day 28 after treatment was similar for co-blistered NFDC (97.9% [95% confidence interval (CI): 97.0-98.8%]) and FDC (98.1% [95% CI: 97.6%-98.5%]; P = 0.799), but significantly lower for the loose NFDC-25 (93.4% [95% CI: 91.9%-94.9%]), and loose NFDC-30 (95.0% [95% CI: 94.1%-95.9%]) (P < 0.001 for all comparisons). After controlling for age, AQ dose, baseline parasitemia and region; treatment with loose NFDC-25 was associated with a 3.5-fold greater risk of recrudescence by day 28 (adjusted hazard ratio, AHR = 3.51 [95% CI: 2.02-6.12], P < 0.001) compared to FDC, and treatment with loose NFDC-30 was associated with a higher risk of recrudescence at only three sites. Conclusions: There was substantial variation in the total dose of amodiaquine administered in different AS-AQ combination regimens. Fixed dose AS-AQ combinations ensure optimal dosing and provide higher antimalarial treatment efficacy than the loose individual tablets in all age categories.
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1134.
  • Anguille, Sébastien, et al. (författare)
  • Dendritic cell vaccination as postremission treatment to prevent or delay relapse in acute myeloid leukemia
  • 2017
  • Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 130:15, s. 1713-1721
  • Tidskriftsartikel (refereegranskat)abstract
    • Relapse is a major problem in acute myeloid leukemia (AML) and adversely affects survival. In this phase 2 study, we investigated the effect of vaccination with dendritic cells (DCs) electroporated with Wilms’ tumor 1 (WT1) messenger RNA (mRNA) as postremission treatment in 30 patients with AML at very high risk of relapse. There was a demonstrable antileukemic response in 13 patients. Nine patients achieved molecular remission as demonstrated by normalization of WT1 transcript levels, 5 of which were sustained after a median follow-up of 109.4 months. Disease stabilization was achieved in 4 other patients. Five-year overall survival (OS) was higher in responders than in nonresponders (53.8% vs 25.0%; P 5 .01). In patients receiving DCs in first complete remission (CR1), there was a vaccine-induced relapse reduction rate of 25%, and 5-year relapse-free survival was higher in responders than in nonresponders (50% vs 7.7%; P < .0001). In patients age £65 and >65 years who received DCs in CR1, 5-year OS was 69.2% and 30.8% respectively, as compared with 51.7% and 18% in the Swedish Acute Leukemia Registry. Long-term clinical response was correlated with increased circulating frequencies of polyepitope WT1-specific CD81 T cells. Long-term OS was correlated with interferon-g1 and tumor necrosis factor-a1 WT1-specific responses in delayed-type hypersensitivity-infiltrating CD81 T lymphocytes. In conclusion, vaccination of patients with AML with WT1 mRNA-electroporated DCs can be an effective strategy to prevent or delay relapse after standard chemotherapy, translating into improved OS rates, which are correlated with the induction of WT1-specific CD81 T-cell response. This trial was registered at www.clinicaltrials.gov as #NCT00965224.
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1135.
  • Borgquist, Signe, et al. (författare)
  • Cholesterol, cholesterol-lowering medication use, and breast cancer outcome in the BIG 1-98 study
  • 2017
  • Ingår i: Journal of Clinical Oncology. - 0732-183X. ; 35:11, s. 1179-1188
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose Cholesterol-lowering medication (CLM) has been reported to have a role in preventing breast cancer recurrence. CLM may attenuate signaling through the estrogen receptor by reducing levels of the estrogenic cholesterol metabolite 27-hydroxycholesterol. The impact of endocrine treatment on cholesterol levels and hypercholesterolemia per se may counteract the intended effect of aromatase inhibitors. Patients and Methods The Breast International Group (BIG) conducted a randomized, phase III, double-blind trial, BIG 1-98, which enrolled 8,010 postmenopausal women with early-stage, hormone receptor-positive invasive breast cancer from 1998 to 2003. Systemic levels of total cholesterol and use of CLM were measured at study entry and every 6 months up to 5.5 years. Cumulative incidence functions were used to describe the initiation of CLM in the presence of competing risks. Marginal structural Cox proportional hazards modeling investigated the relationships between initiation of CLM during endocrine therapy and outcome. Three time-to-event end points were considered: disease-freesurvival, breast cancer-free interval, and distant recurrence-free interval. Results Cholesterol levels were reduced during tamoxifen therapy. Of 789 patients who initiated CLM during endocrine therapy, the majority came from the letrozole monotherapy arm (n = 318), followed by sequential tamoxifen-letrozole (n = 189), letrozole-tamoxifen (n = 176), and tamoxifen monotherapy (n = 106). Initiation of CLM during endocrine therapy was related to improved disease-free-survival (hazard ratio [HR], 0.79; 95% CI, 0.66 to 0.95; P = .01), breast cancer-free interval (HR, 0.76; 95% CI, 0.60 to 0.97; P = .02), and distant recurrence-free interval (HR, 0.74; 95% CI, 0.56 to 0.97; P = .03). Conclusion Cholesterol-lowering medication during adjuvant endocrine therapy may have a role in preventing breast cancer recurrence in hormone receptor-positive early-stage breast cancer. We recommend that these observational results be addressed in prospective randomized trials.
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1136.
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1137.
  • DeMott, Paul J., et al. (författare)
  • The Fifth International Workshop on Ice Nucleation phase 2 (FIN-02) : Laboratory intercomparison of ice nucleation measurements
  • 2018
  • Ingår i: Atmospheric Measurement Techniques. - : Copernicus GmbH. - 1867-1381 .- 1867-8548. ; 11:11, s. 6231-6257
  • Tidskriftsartikel (refereegranskat)abstract
    • The second phase of the Fifth International Ice Nucleation Workshop (FIN-02) involved the gathering of a large number of researchers at the Karlsruhe Institute of Technology's Aerosol Interactions and Dynamics of the Atmosphere (AIDA) facility to promote characterization and understanding of ice nucleation measurements made by a variety of methods used worldwide. Compared to the previous workshop in 2007, participation was doubled, reflecting a vibrant research area. Experimental methods involved sampling of aerosol particles by direct processing ice nucleation measuring systems from the same volume of air in separate experiments using different ice nucleating particle (INP) types, and collections of aerosol particle samples onto filters or into liquid for sharing amongst measurement techniques that post-process these samples. In this manner, any errors introduced by differences in generation methods when samples are shared across laboratories were mitigated. Furthermore, as much as possible, aerosol particle size distribution was controlled so that the size limitations of different methods were minimized. The results presented here use data from the workshop to assess the comparability of immersion freezing measurement methods activating INPs in bulk suspensions, methods that activate INPs in condensation and/or immersion freezing modes as single particles on a substrate, continuous flow diffusion chambers (CFDCs) directly sampling and processing particles well above water saturation to maximize immersion and subsequent freezing of aerosol particles, and expansion cloud chamber simulations in which liquid cloud droplets were first activated on aerosol particles prior to freezing. The AIDA expansion chamber measurements are expected to be the closest representation to INP activation in atmospheric cloud parcels in these comparisons, due to exposing particles freely to adiabatic cooling. The different particle types used as INPs included the minerals illite NX and potassium feldspar (K-feldspar), two natural soil dusts representative of arable sandy loam (Argentina) and highly erodible sandy dryland (Tunisia) soils, respectively, and a bacterial INP (Snomax®). Considered together, the agreement among post-processed immersion freezing measurements of the numbers and fractions of particles active at different temperatures following bulk collection of particles into liquid was excellent, with possible temperature uncertainties inferred to be a key factor in determining INP uncertainties. Collection onto filters for rinsing versus directly into liquid in impingers made little difference. For methods that activated collected single particles on a substrate at a controlled humidity at or above water saturation, agreement with immersion freezing methods was good in most cases, but was biased low in a few others for reasons that have not been resolved, but could relate to water vapor competition effects. Amongst CFDC-style instruments, various factors requiring (variable) higher supersaturations to achieve equivalent immersion freezing activation dominate the uncertainty between these measurements, and for comparison with bulk immersion freezing methods. When operated above water saturation to include assessment of immersion freezing, CFDC measurements often measured at or above the upper bound of immersion freezing device measurements, but often underestimated INP concentration in comparison to an immersion freezing method that first activates all particles into liquid droplets prior to cooling (the PIMCA-PINC device, or Portable Immersion Mode Cooling chAmber-Portable Ice Nucleation Chamber), and typically slightly underestimated INP number concentrations in comparison to cloud parcel expansions in the AIDA chamber; this can be largely mitigated when it is possible to raise the relative humidity to sufficiently high values in the CFDCs, although this is not always possible operationally. Correspondence of measurements of INPs among direct sampling and post-processing systems varied depending on the INP type. Agreement was best for Snomax® particles in the temperature regime colder than -10°C, where their ice nucleation activity is nearly maximized and changes very little with temperature. At temperatures warmer than -10°C, Snomax® INP measurements (all via freezing of suspensions) demonstrated discrepancies consistent with previous reports of the instability of its protein aggregates that appear to make it less suitable as a calibration INP at these temperatures. For Argentinian soil dust particles, there was excellent agreement across all measurement methods; measures ranged within 1 order of magnitude for INP number concentrations, active fractions and calculated active site densities over a 25 to 30°C range and 5 to 8 orders of corresponding magnitude change in number concentrations. This was also the case for all temperatures warmer than -25°C in Tunisian dust experiments. In contrast, discrepancies in measurements of INP concentrations or active site densities that exceeded 2 orders of magnitude across a broad range of temperature measurements found at temperatures warmer than -25°C in a previous study were replicated for illite NX. Discrepancies also exceeded 2 orders of magnitude at temperatures of -20 to -25°C for potassium feldspar (K-feldspar), but these coincided with the range of temperatures at which INP concentrations increase rapidly at approximately an order of magnitude per 2°C cooling for K-feldspar. These few discrepancies did not outweigh the overall positive outcomes of the workshop activity, nor the future utility of this data set or future similar efforts for resolving remaining measurement issues. Measurements of the same materials were repeatable over the time of the workshop and demonstrated strong consistency with prior studies, as reflected by agreement of data broadly with parameterizations of different specific or general (e.g., soil dust) aerosol types. The divergent measurements of the INP activity of illite NX by direct versus post-processing methods were not repeated for other particle types, and the Snomax° data demonstrated that, at least for a biological INP type, there is no expected measurement bias between bulk collection and direct immediately processed freezing methods to as warm as -10°C. Since particle size ranges were limited for this workshop, it can be expected that for atmospheric populations of INPs, measurement discrepancies will appear due to the different capabilities of methods for sampling the full aerosol size distribution, or due to limitations on achieving sufficient water supersaturations to fully capture immersion freezing in direct processing instruments. Overall, this workshop presents an improved picture of present capabilities for measuring INPs than in past workshops, and provides direction toward addressing remaining measurement issues.
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1138.
  • Dougherty, Liam R., et al. (författare)
  • A systematic map of studies testing the relationship between temperature and animal reproduction
  • 2024
  • Ingår i: Ecological Solutions and Evidence. - : John Wiley & Sons. - 2688-8319. ; 5:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Exposure to extreme temperatures can negatively affect animal reproduction, by disrupting the ability of individuals to produce any offspring (fertility), or the number of offspring produced by fertile individuals (fecundity). This has important ecological consequences, because reproduction is the ultimate measure of population fitness: a reduction in reproductive output lowers the population growth rate and increases the extinction risk. Despite this importance, there have been no large-scale summaries of the evidence for effect of temperature on reproduction. We provide a systematic map of studies testing the relationship between temperature and animal reproduction. We systematically searched for published studies that statistically test for a direct link between temperature and animal reproduction, in terms of fertility, fecundity or indirect measures of reproductive potential (gamete and gonad traits). Overall, we collated a large and rich evidence base, with 1654 papers that met our inclusion criteria, encompassing 1191 species. The map revealed several important research gaps. Insects made up almost half of the dataset, but reptiles and amphibians were uncommon, as were non-arthropod invertebrates. Fecundity was the most common reproductive trait examined, and relatively few studies measured fertility. It was uncommon for experimental studies to test exposure of different life stages, exposure to short-term heat or cold shock, exposure to temperature fluctuations, or to independently assess male and female effects. Studies were most often published in journals focusing on entomology and pest control, ecology and evolution, aquaculture and fisheries science, and marine biology. Finally, while individuals were sampled from every continent, there was a strong sampling bias towards mid-latitudes in the Northern Hemisphere, such that the tropics and polar regions are less well sampled. This map reveals a rich literature of studies testing the relationship between temperature and animal reproduction, but also uncovers substantial missing treatment of taxa, traits, and thermal regimes. This database will provide a valuable resource for future quantitative meta-analyses, and direct future studies aiming to fill identified gaps. We summarise 1600+ papers testing the relationship between temperature and animal reproduction, and identify major taxonomic, geographic and methodological research gaps. This database will provide a valuable resource for future analyses, and direct future studies aiming to fill research gaps.image
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1139.
  • Green, Jonathan M. H., et al. (författare)
  • Research priorities for managing the impacts and dependencies of business upon food, energy, water and the environment
  • 2017
  • Ingår i: Sustainability Science. - : Springer Science and Business Media LLC. - 1862-4065 .- 1862-4057. ; 12:2, s. 319-331
  • Tidskriftsartikel (refereegranskat)abstract
    • Delivering access to sufficient food, energy and water resources to ensure human wellbeing is a major concern for governments worldwide. However, it is crucial to account for the 'nexus' of interactions between these natural resources and the consequent implications for human wellbeing. The private sector has a critical role in driving positive change towards more sustainable nexus management and could reap considerable benefits from collaboration with researchers to devise solutions to some of the foremost sustainability challenges of today. Yet opportunities are missed because the private sector is rarely involved in the formulation of deliverable research priorities. We convened senior research scientists and influential business leaders to collaboratively identify the top forty questions that, if answered, would best help companies understand and manage their food-energy-water-environment nexus dependencies and impacts. Codification of the top order nexus themes highlighted research priorities around development of pragmatic yet credible tools that allow businesses to incorporate nexus interactions into their decision-making; demonstration of the business case for more sustainable nexus management; identification of the most effective levers for behaviour change; and understanding incentives or circumstances that allow individuals and businesses to take a leadership stance. Greater investment in the complex but productive relations between the private sector and research community will create deeper and more meaningful collaboration and cooperation.
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1140.
  • Gruber, Günther, et al. (författare)
  • Prognostic value of extracapsular tumor spread for locoregional control in premenopausal patients with node-positive breast cancer treated with classical cyclophosphamide, methotrexate, and fluorouracil: long-term observations from International Breast Cancer Study Group Trial VI.
  • 2005
  • Ingår i: Journal of clinical oncology : official journal of the American Society of Clinical Oncology. - 0732-183X. ; 23:28, s. 7089-97
  • Tidskriftsartikel (refereegranskat)abstract
    • PURPOSE: We sought to determine retrospectively whether extracapsular spread (ECS) might identify a subgroup that could benefit from radiotherapy after mastectomy, especially patients with 1 to 3 positive lymph nodes (LN1-3+). PATIENTS AND METHODS: We randomized 1,475 premenopausal women with node-positive breast cancer to three, six, or nine courses of "classical" CMF (cyclophosphamide, methotrexate, and fluorouracil). After a review of all pathology forms, 933 patients (63%) had information on the presence or absence of ECS. ECS was present in 49.5%. The median follow-up was 10 years. RESULTS: In univariate analyses, ECS was associated with worse disease-free survival (DFS) and overall survival (OS). In multivariate analyses adjusting for tumor size, vessel invasion, surgery type, and age group, ECS remained significant (DFS: hazard ratio, 1.61; 95% CI, 1.34 to 1.93; P < .0001; OS: 1.67; 95% CI, 1.34 to 2.08; P < .0001). However, ECS was not significant when the number of positive nodes was added. The locoregional failure rate +/- distant failure (LRF +/- distant failure) within 10 years was estimated at 19% (+/- 2%) without ECS, versus 27% (+/- 2%) with ECS. The difference was statistically significant in univariate analyses, but not after adjusting for the number of positive nodes. No independent effect of ECS on DFS, OS, or LRF could be confirmed within the subgroup of 382 patients with LN1-3+ treated with mastectomy without radiotherapy. CONCLUSION: Our results do not support an independent prognostic value of ECS, nor its use as an indication for irradiation in premenopausal patients with LN1-3+ treated with classical CMF. However, we could not examine whether extensive ECS is of prognostic importance.
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