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| 2. |
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| 3. |
- Beral, V., et al.
(author)
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Ovarian cancer and smoking: individual participant meta-analysis including 28 114 women with ovarian cancer from 51 epidemiological studies
- 2012
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In: The Lancet Oncology. - 1474-5488. ; 13:9, s. 946-956
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Journal article (peer-reviewed)abstract
- Background Smoking has been linked to mucinous ovarian cancer, but its effects on other ovarian cancer subtypes and on overall ovarian cancer risk are unclear, and the findings from most studies with relevant data are unpublished. To assess these associations, we review the published and unpublished evidence. Methods Eligible epidemiological studies were identified by electronic searches, review articles, and discussions with colleagues. Individual participant data for 28 114 women with and 94 942 without ovarian cancer from 51 epidemiological studies were analysed centrally, yielding adjusted relative risks (RRs) of ovarian cancer in smokers compared with never smokers. Findings After exclusion of studies with hospital controls, in which smoking could have affected recruitment, overall ovarian cancer incidence was only slightly increased in current smokers compared with women who had never smoked (RR 1.06, 95% CI 1.01-1.11, p=0.01). Of 17 641 epithelial cancers with specified histology, 2314 (13%) were mucinous, 2360 (13%) endometrioid, 969 (5%) clear-cell, and 9086 (52%) serous. Smoking-related risks varied substantially across these subtypes (p(heterogeneity)<0.0001). For mucinous cancers, incidence was increased in current versus never smokers (1.79, 95% CI 1.60-2.00, p<0.0001), but the increase was mainly in borderline malignant rather than in fully malignant tumours (2.25, 95% CI 1.91-2.65 vs 1.49, 1.28-1.73; p(heterogeneity)=0.01; almost half the mucinous tumours were only borderline malignant). Both endometrioid (0.81, 95% CI 0.72-0.92, p=0.001) and clear-cell ovarian cancer risks (0.80, 95% CI 0.65-0.97, p=0.03) were reduced in current smokers, and there was no significant association for serous ovarian cancers (0.99, 95% CI 0.93-1.06, p=0.8). These associations did not vary significantly by 13 sociodemographic and personal characteristics of women including their body-mass index, parity, and use of alcohol, oral contraceptives, and menopausal hormone therapy. Interpretation The excess of mucinous ovarian cancers in smokers, which is mainly of tumours of borderline malignancy, is roughly counterbalanced by the deficit of endometrioid and clear-cell ovarian cancers. The substantial variation in smoking-related risks by tumour subtype is important for understanding ovarian carcinogenesis.
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| 4. |
- Beral, V., et al.
(author)
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Ovarian Cancer and Body Size : Individual Participant Meta-Analysis Including 25,157 Women with Ovarian Cancer from 47 Epidemiological Studies
- 2012
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In: PLoS Medicine. - : PUBLIC LIBRARY SCIENCE. - 1549-1277 .- 1549-1676. ; 9:4
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Journal article (peer-reviewed)abstract
- Background: Only about half the studies that have collected information on the relevance of women's height and body mass index to their risk of developing ovarian cancer have published their results, and findings are inconsistent. Here, we bring together the worldwide evidence, published and unpublished, and describe these relationships. Methods and Findings: Individual data on 25,157 women with ovarian cancer and 81,311 women without ovarian cancer from 47 epidemiological studies were collected, checked, and analysed centrally. Adjusted relative risks of ovarian cancer were calculated, by height and by body mass index. Ovarian cancer risk increased significantly with height and with body mass index, except in studies using hospital controls. For other study designs, the relative risk of ovarian cancer per 5 cm increase in height was 1.07 (95% confidence interval [CI], 1.05-1.09; p<0.001); this relationship did not vary significantly by women's age, year of birth, education, age at menarche, parity, menopausal status, smoking, alcohol consumption, having had a hysterectomy, having first degree relatives with ovarian or breast cancer, use of oral contraceptives, or use of menopausal hormone therapy. For body mass index, there was significant heterogeneity (p<0.001) in the findings between ever-users and never-users of menopausal hormone therapy, but not by the 11 other factors listed above. The relative risk for ovarian cancer per 5 kg/m(2) increase in body mass index was 1.10 (95% CI, 1.07-1.13; p<0.001) in never-users and 0.95 (95% CI, 0.92-0.99; p = 0.02) in ever-users of hormone therapy. Conclusions: Ovarian cancer is associated with height and, among never-users of hormone therapy, with body mass index. In high-income countries, both height and body mass index have been increasing in birth cohorts now developing the disease. If all other relevant factors had remained constant, then these increases in height and weight would be associated with a 3% increase in ovarian cancer incidence per decade.
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| 6. |
- Bergmann, T K, et al.
(author)
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Impact of CYP2C8*3 on paclitaxel clearance: a population pharmacokinetic and pharmacogenomic study in 93 patients with ovarian cancer
- 2011
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In: PHARMACOGENOMICS JOURNAL. - : Nature Publishing Group. - 1470-269X .- 1473-1150. ; 11:2, s. 113-120
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Journal article (peer-reviewed)abstract
- The primary purpose of this study was to evaluate the effect of CYP2C8*3 and three genetic ABCB1 variants on the elimination of paclitaxel. We studied 93 Caucasian women with ovarian cancer treated with paclitaxel and carboplatin. Using sparse sampling and nonlinear mixed effects modeling, the individual clearance of unbound paclitaxel was estimated from total plasma paclitaxel and Cremophor EL. The geometric mean of clearance was 385 l h(-1) (range 176-726 l h(-1)). Carriers of CYP2C8*3 had 11% lower clearance than non-carriers, P = 0.03. This has not been shown before in similar studies; the explanation is probably the advantage of using both unbound paclitaxel clearance and a population of patients of same gender. No significant association was found for the ABCB1 variants C1236T, G2677T/A and C3435T. Secondarily, other candidate single-nucleotide polymorphisms were explored with possible associations found for CYP2C8*4 (P = 0.04) and ABCC1 g.7356253C andgt; G (P = 0.04).
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| 7. |
- Hudson, Thomas J., et al.
(author)
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International network of cancer genome projects
- 2010
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 464:7291, s. 993-998
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Journal article (peer-reviewed)abstract
- The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.
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| 8. |
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| 9. |
- Thompson, Paul M., et al.
(author)
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The ENIGMA Consortium : large-scale collaborative analyses of neuroimaging and genetic data
- 2014
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In: BRAIN IMAGING BEHAV. - : Springer Science and Business Media LLC. - 1931-7557 .- 1931-7565. ; 8:2, s. 153-182
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Journal article (peer-reviewed)abstract
- The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA's first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way.
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| 10. |
- Gore, C., et al.
(author)
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Treatment and secondary prevention effects of the probiotics Lactobacillus paracasei or Bifidobacterium lactis on early infant eczema : randomized controlled trial with follow-up until age 3 years
- 2012
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In: Clinical and Experimental Allergy. - : Wiley. - 0954-7894 .- 1365-2222. ; 42:1, s. 112-122
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Journal article (peer-reviewed)abstract
- Background Allergic disease has been associated with altered intestinal microbiota. Therefore, probiotics have been suggested as a potential treatment for eczema. Objective We investigated whether dietary supplementation of infants with eczema at age 3-6 months with Lactobacillus paracasei CNCM I-2116 or Bifidobacterium lactis CNCM I3446 had a treatment effect or altered allergic disease progression. Methods Primary outcome included eczema severity (SCORing Atopic Dermatitis, SCORAD) 3 months post-randomization. Secondary: SCORAD (other visits); infant dermatitis quality of life (IDQoL); gastrointestinal permeability; urinary eosinophilic protein X; allergen- sensitization; allergic symptoms (age 12, 18, 36 months). A total of 208 infants aged 3-6 months with physician-diagnosed eczema were recruited; 137/208 (SCORAD >= 10, consuming >= 200 mL standard formula/day) were randomized to daily supplements containing L. paracasei or B. lactis or placebo for a 3-month period, while receiving extensively hydrolysed whey-formula (dairy-free diet). There were two open observational groups, one group exclusively breastfed (n = 22) and the other, standard formula-fed (n = 49). Trial number: ISRCTN41490500. Results Eczema severity decreased significantly over time in all groups. No significant difference was observed between randomized groups after 12-week treatment-period (SCORAD-score pre-/post-intervention: B. lactis 25.9 [95% CI: 22.8-29.2] to 12.8 [9.416.6]; L. paracasei 25.4 [22.1-29] to 12.5 [9.2-16.4]; placebo 26.9 [23.4-30.6] to 11.8 [9.6-14.3]; P = 0.7). Results were similar when analysis was controlled for allergen-sensitization, or when only sensitized infants were analysed. No differences were found for secondary outcomes. No difference was observed in SCORAD-score between randomized and observational groups. Conclusion and Clinical Relevance We found no benefit from supplementation with B. lactis or L. paracasei in the treatment of eczema, when given as an adjunct to basic topical treatment, and no effect on the progression of allergic disease from age 1 to 3 years.
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| 11. |
- Green, Richard E., et al.
(author)
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Three crocodilian genomes reveal ancestral patterns of evolution among archosaurs
- 2014
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In: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 346:6215, s. 1335-
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Journal article (peer-reviewed)abstract
- To provide context for the diversification of archosaurs-the group that includes crocodilians, dinosaurs, and birds-we generated draft genomes of three crocodilians: Alligator mississippiensis (the American alligator), Crocodylus porosus (the saltwater crocodile), and Gavialis gangeticus (the Indian gharial). We observed an exceptionally slow rate of genome evolution within crocodilians at all levels, including nucleotide substitutions, indels, transposable element content and movement, gene family evolution, and chromosomal synteny. When placed within the context of related taxa including birds and turtles, this suggests that the common ancestor of all of these taxa also exhibited slow genome evolution and that the comparatively rapid evolution is derived in birds. The data also provided the opportunity to analyze heterozygosity in crocodilians, which indicates a likely reduction in population size for all three taxa through the Pleistocene. Finally, these data combined with newly published bird genomes allowed us to reconstruct the partial genome of the common ancestor of archosaurs, thereby providing a tool to investigate the genetic starting material of crocodilians, birds, and dinosaurs.
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| 12. |
- Hill, M. S., et al.
(author)
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Reconstruction of Family-Level Phylogenetic Relationships within Demospongiae (Porifera) Using Nuclear Encoded Housekeeping Genes
- 2013
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:1, s. e50437-
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Journal article (peer-reviewed)abstract
- Background: Demosponges are challenging for phylogenetic systematics because of their plastic and relatively simple morphologies and many deep divergences between major clades. To improve understanding of the phylogenetic relationships within Demospongiae, we sequenced and analyzed seven nuclear housekeeping genes involved in a variety of cellular functions from a diverse group of sponges. Methodology/Principal Findings: We generated data from each of the four sponge classes (i.e., Calcarea, Demospongiae, Hexactinellida, and Homoscleromorpha), but focused on family-level relationships within demosponges. With data for 21 newly sampled families, our Maximum Likelihood and Bayesian-based approaches recovered previously phylogenetically defined taxa: Keratosap, Myxospongiaep, Spongillidap, Haploscleromorphap (the marine haplosclerids) and Democlaviap. We found conflicting results concerning the relationships of Keratosap and Myxospongiaep to the remaining demosponges, but our results strongly supported a clade of Haploscleromorphap+Spongillidap+Democlaviap. In contrast to hypotheses based on mitochondrial genome and ribosomal data, nuclear housekeeping gene data suggested that freshwater sponges (Spongillidap) are sister to Haploscleromorphap rather than part of Democlaviap. Within Keratosap, we found equivocal results as to the monophyly of Dictyoceratida. Within Myxospongiaep, Chondrosida and Verongida were monophyletic. A well-supported clade within Democlaviap, Tetractinellidap, composed of all sampled members of Astrophorina and Spirophorina (including the only lithistid in our analysis), was consistently revealed as the sister group to all other members of Democlaviap. Within Tetractinellidap, we did not recover monophyletic Astrophorina or Spirophorina. Our results also reaffirmed the monophyly of order Poecilosclerida (excluding Desmacellidae and Raspailiidae), and polyphyly of Hadromerida and Halichondrida. Conclusions/Significance: These results, using an independent nuclear gene set, confirmed many hypotheses based on ribosomal and/or mitochondrial genes, and they also identified clades with low statistical support or clades that conflicted with traditional morphological classification. Our results will serve as a basis for future exploration of these outstanding questions using more taxon- and gene-rich datasets.
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| 13. |
- Lock, Nina, et al.
(author)
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Scrutinizing negative thermal expansion in MOF-5 by scattering techniques and ab initio calculations
- 2013
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In: Dalton Transactions. - : Royal Society of Chemistry (RSC). - 1477-9234. ; 42:6, s. 1996-2007
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Journal article (peer-reviewed)abstract
- Complementary experimental techniques and ab initio calculations were used to determine the origin and nature of negative thermal expansion (NTE) in the archetype metal-organic framework MOF-5 (Zn4O(1,4-benzenedicarboxylate) (3)). The organic linker was probed by inelastic neutron scattering under vacuum and at a gas pressure of 175 bar to distinguish between the pressure and temperature responses of the framework motions, and the local structure of the metal centers was studied by X-ray absorption spectroscopy. Multi-temperature powder-and single-crystal X-ray and neutron diffraction was used to characterize the polymeric nature of the sample and to quantify NTE over the large temperature range 4-400 K. Ab initio calculations complement the experimental data with detailed information on vibrational motions in the framework and their correlations. A uniform and comprehensive picture of NTE in MOF-5 has been drawn, and we provide direct evidence that the main contributor to NTE is translational transverse motion of the aromatic ring, which can be dampened by applying a gas pressure to the sample. The linker motion is highly correlated rather than local in nature. The relative energies of different framework vibrations populated in MOF-5 are suggested by analysis of neutron diffraction data. We note that the lowest-energy motion is a librational motion of the aromatic ring which does not contribute to NTE. The libration is followed by transverse motion of the linker and the carboxylate group. These motions result in unit-cell contraction with increasing temperature.
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| 14. |
- Lopes, Renato D., et al.
(author)
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Highlights from the III International Symposium of Thrombosis and Anticoagulation (ISTA), October 14-16, 2010, Sao Paulo, Brazil
- 2011
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In: Journal of Thrombosis and Thrombolysis. - : Springer Science and Business Media LLC. - 0929-5305 .- 1573-742X. ; 32:2, s. 242-266
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Journal article (peer-reviewed)abstract
- To discuss and share knowledge around advances in the care of patients with thrombotic disorders, the Third International Symposium of Thrombosis and Anticoagulation was held in So Paulo, Brazil, from October 14-16, 2010. This scientific program was developed by clinicians for clinicians, and was promoted by four major clinical research institutes: the Brazilian Clinical Research Institute, the Duke Clinical Research Institute of the Duke University School of Medicine, the Canadian VIGOUR Centre, and the Uppsala Clinical Research Center. Comprising 3 days of academic presentations and open discussion, the symposium had as its primary goal to educate, motivate, and inspire internists, cardiologists, hematologists, and other physicians by convening national and international visionaries, thought-leaders, and dedicated clinician-scientists. This paper summarizes the symposium proceedings.
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| 15. |
- Mukanga, D., et al.
(author)
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Can lay community health workers be trained to use diagnostics to distinguish and treat malaria and pneumonia in children? : Lessons from rural Uganda
- 2011
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In: Tropical medicine & international health. - : Wiley. - 1360-2276 .- 1365-3156. ; 16:10, s. 1234-1242
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Journal article (peer-reviewed)abstract
- OBJECTIVE To determine the competence of community health workers (CHWs) to correctly assess, classify and treat malaria and pneumonia among under-five children after training. METHODS Consultations of 182 under-fives by 14 CHWs in Iganga district, Uganda, were observed using standardised checklists. Each CHW saw 13 febrile children. Two paediatricians observed CHWs' assessment, classification and prescription of treatment, while a laboratory scientist assessed CHW use of malaria rapid diagnostic tests (RDTs). The validity of CHWs' use of RDTs to detect malaria and respiratory timers to diagnose pneumonia was estimated using a laboratory scientist's RDT repeat reading and a paediatrician's repeat count of the respiratory rate, respectively. RESULTS From the 182 consultations, overall CHWs' performance was adequate in taking history (97%), use (following procedures prior to reading result) of timers (96%) and use of RDTs (96%), but inadequate in classification (87%). Breath readings (classified as fast or normal) were 85% in agreement with the paediatrician (kappa = 0.665, P < 0.001). All RDT readings were in agreement with those obtained by the laboratory scientist. Ninety-six per cent (85/89) of children with a positive RDT were prescribed an antimalarial drug, 40% (4/10) with fast breathing (gold standard) were prescribed an antibiotic and 91% (48/53) with both were prescribed both medicines. CONCLUSION Community health workers can be trained to use RDTs and timers to assess and manage malaria and pneumonia in children. We recommend integration of these diagnostics into community case management of fever. CHWs require enhanced practice in counting respiratory rates and simple job aides to enable them make a classification without thinking deeply about several assessment results.
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| 16. |
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| 17. |
- Scaife, A. A., et al.
(author)
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Skillful long-range prediction of European and North American winters
- 2014
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In: Geophysical Research Letters. - : American Geophysical Union (AGU). - 0094-8276 .- 1944-8007. ; 41:7, s. 2514-2519
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Journal article (peer-reviewed)abstract
- Until recently, long-range forecast systems showed only modest levels of skill in predicting surface winter climate around the Atlantic Basin and associated fluctuations in the North Atlantic Oscillation at seasonal lead times. Here we use a new forecast system to assess seasonal predictability of winter North Atlantic climate. We demonstrate that key aspects of European and North American winter climate and the surface North Atlantic Oscillation are highly predictable months ahead. We demonstrate high levels of prediction skill in retrospective forecasts of the surface North Atlantic Oscillation, winter storminess, near-surface temperature, and wind speed, all of which have high value for planning and adaptation to extreme winter conditions. Analysis of forecast ensembles suggests that while useful levels of seasonal forecast skill have now been achieved, key sources of predictability are still only partially represented and there is further untapped predictability. The winter NAO can be skilfully predicted months ahead The signal-to-noise ratio of the predictable signal is anomalously low Predictions of the risk of regional winter extremes are possible
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| 18. |
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| 19. |
- Barsheshet, Alon, et al.
(author)
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Mutations in Cytoplasmic Loops of the KCNQ1 Channel and the Risk of Life-Threatening Events Implications for Mutation-Specific Response to beta-Blocker Therapy in Type 1 Long-QT Syndrome
- 2012
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In: Circulation. - 1524-4539. ; 125:16, s. 1988-1988
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Journal article (peer-reviewed)abstract
- Background-beta-Adrenergic stimulation is the main trigger for cardiac events in type 1 long-QT syndrome (LQT1). We evaluated a possible association between ion channel response to beta-adrenergic stimulation and clinical response to beta-blocker therapy according to mutation location. Methods and Results-The study sample comprised 860 patients with genetically confirmed mutations in the KCNQ1 channel. Patients were categorized into carriers of missense mutations located in the cytoplasmic loops (C loops), membrane-spanning domain, C/N terminus, and nonmissense mutations. There were 27 aborted cardiac arrest and 78 sudden cardiac death events from birth through 40 years of age. After multivariable adjustment for clinical factors, the presence of C-loop mutations was associated with the highest risk for aborted cardiac arrest or sudden cardiac death (hazard ratio versus nonmissense mutations = 2.75; 95% confidence interval, 1.29-5.86; P=0.009). beta-Blocker therapy was associated with a significantly greater reduction in the risk of aborted cardiac arrest or sudden cardiac death among patients with C-loop mutations than among all other patients (hazard ratio=0.12; 95% confidence interval, 0.02-0.73; P=0.02; and hazard ratio=0.82; 95% confidence interval, 0.31-2.13; P=0.68, respectively; P for interaction=0.04). Cellular expression studies showed that membrane spanning and C-loop mutations produced a similar decrease in current, but only C-loop mutations showed a pronounced reduction in channel activation in response to beta-adrenergic stimulation. Conclusions-Patients with C-loop missense mutations in the KCNQ1 channel exhibit a high risk for life-threatening events and derive a pronounced benefit from treatment with beta-blockers. Reduced channel activation after sympathetic activation can explain the increased clinical risk and response to therapy in patients with C-loop mutations. (Circulation. 2012; 125: 1988-1996.)
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| 20. |
- Bateman, Eric D., et al.
(author)
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Overall asthma control achieved with budesonide/formoterol maintenance and reliever therapy for patients on different treatment steps
- 2011
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In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 12
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Journal article (peer-reviewed)abstract
- Background: Adjusting medication for uncontrolled asthma involves selecting one of several options from the same or a higher treatment step outlined in asthma guidelines. We examined the relative benefit of introducing budesonide/formoterol (BUD/FORM) maintenance and reliever therapy (Symbicort SMART (R) Turbuhaler (R)) in patients previously prescribed treatments from Global Initiative for Asthma (GINA) Steps 2, 3 or 4. Methods: This is a post hoc analysis of the results of five large clinical trials (> 12000 patients) comparing BUD/FORM maintenance and reliever therapy with other treatments categorised by treatment step at study entry. Both current clinical asthma control during the last week of treatment and exacerbations during the study were examined. Results: At each GINA treatment step, the proportion of patients achieving target levels of current clinical control were similar or higher with BUD/FORM maintenance and reliever therapy compared with the same or a higher fixed maintenance dose of inhaled corticosteroid/long-acting beta(2)-agonist (ICS/LABA) (plus short-acting beta(2)-agonist [SABA] as reliever), and rates of exacerbations were lower at all treatment steps in BUD/FORM maintenance and reliever therapy versus same maintenance dose ICS/LABA (P < 0.01) and at treatment Step 4 versus higher maintenance dose ICS/LABA (P < 0.001). BUD/FORM maintenance and reliever therapy also achieved significantly higher rates of current clinical control and significantly lower exacerbation rates at most treatment steps compared with a higher maintenance dose ICS + SABA (Steps 2-4 for control and Steps 3 and 4 for exacerbations). With all treatments, the proportion of patients achieving current clinical control was lower with increasing treatment steps. Conclusions: BUD/FORM maintenance and reliever therapy may be a preferable option for patients on Steps 2 to 4 of asthma guidelines requiring a more effective treatment and, compared with other fixed dose alternatives, is most effective in the higher treatment steps.
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| 21. |
- Bateman, Eric D., et al.
(author)
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Overall asthma control: The relationship between current control and future risk
- 2010
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In: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 1097-6825 .- 0091-6749. ; 125:3, s. 600-608
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Journal article (peer-reviewed)abstract
- Background: Asthma guidelines emphasize both maintaining current control and reducing future risk, but the relationship between these 2 targets is not well understood. Objective: This retrospective analysis of 5 budesonide/formoterol maintenance and reliever therapy (Symbicort SMART Turbuhaler*) studies assessed the relationship between asthma control questionnaire (ACQ-5) and Global Initiative for Asthma-defined clinical asthma control and future risk of instability and exacerbations. Methods: The percentage of patients with Global Initiative for Asthma defined controlled asthma over time was assessed for budesonide/formoterol maintenance and reliever therapy versus the 3 maintenance therapies; higher dose inhaled corticosteroid (ICS), same dose ICS/long-acting beta(2)-agonist (LABA), and higher dose ICS/LABA plus short-acting beta(2)-agonist. The relationship between baseline ACQ-5 and exacerbations was investigated. A Markov analysis examined the transitional probability of change in control status throughout the studies. Results: The percentage of patients achieving asthma control increased with time, irrespective of treatment; the percentage Controlled/Partly Controlled at study end was at least similar to budesonide/formoterol maintenance and reliever therapy versus the 3 maintenance therapies: higher dose ICS (56% vs 45%), same dose ICS/LABA (56% vs 53%), and higher dose ICS/LABA (54% vs 54%). Baseline ACQ-5 score correlated positively with exacerbation rates. A Controlled or Partly Controlled week predicted at least Partly Controlled asthma the following week (>= 80% probability). The better the control, the lower the risk of an Uncontrolled week. The probability of an exacerbation was related to current state and was lower with budesonide/formoterol maintenance and reliever therapy. Conclusions: Current control predicts future risk of instability and exacerbations. Budesonide/formoterol maintenance and reliever therapy reduces exacerbations versus comparators and achieves at least similar control. (J Allergy Clin Immunol 2010;125:600-8.)
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| 22. |
- Bergmann, Troels K., et al.
(author)
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Impact of ABCB1 Variants on Neutrophil Depression : A Pharmacogenomic Study of Paclitaxel in 92 Women with Ovarian Cancer
- 2012
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In: Basic & Clinical Pharmacology & Toxicology. - : Wiley. - 1742-7835 .- 1742-7843. ; 110:2, s. 199-204
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Journal article (peer-reviewed)abstract
- The standard treatment for ovarian cancer in advanced stages is post-surgery treatment with taxane-platin chemotherapy. Despite an initial high response rate, most patients eventually relapse. The dose-limiting toxicities of paclitaxel are neutropenia and neuropathy, but the inter-individual variability is large. The aim of this prospective study was to investigate the impact of genetic variants in key drug metabolizing/transporter genes on toxicity and compliance. CYP2C8*3 and three ABCB1 polymorphisms were chosen for primary analysis, and a host of other candidate genes was explored in 92 prospectively recruited Scandinavian Caucasian women with primary ovarian cancer who were treated with paclitaxel and carboplatin. A single investigator assessed the clinical toxicity in 97% of the patients. Patients carrying variant alleles of ABCB1 C3435T experienced more pronounced neutrophil decrease (63%, 72% and 80% for 3435CC, CT and TT, respectively; p-value 0.03). A similar association was found for G2677T /A, p-value 0.02. For C1236T, there was a trend with p-value 0.06. No statistically significant correlations were found for paclitaxel compliance and sensory neuropathy in the primary analysis. Variants in the drug transporter ABCB1 gene are possibly associated with the neutrophil suppressing effect of paclitaxel in patients with ovarian cancer. This finding has implications for the understanding of bone marrow suppression and future tailored chemotherapy.
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| 23. |
- Bergmann, Troels K., et al.
(author)
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Retrospective study of the impact of pharmacogenetic variants on paclitaxel toxicity and survival in patients with ovarian cancer
- 2011
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In: European Journal of Clinical Pharmacology. - : Springer Science Business Media. - 0031-6970 .- 1432-1041. ; 67:7, s. 693-700
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Journal article (peer-reviewed)abstract
- Paclitaxel has a broad spectrum of anti-tumor activity and is useful in the treatment of ovarian, breast, and lung cancer. Paclitaxel is metabolized in the liver by CYP2C8 and CYP3A4 and transported by P-glycoprotein. The dose-limiting toxicities are neuropathy and neutropenia, but the interindividual variability in toxicity and also survival is large. The main purpose of this study was to investigate the impact of genetic variants in CYP2C8 and ABCB1 on toxicity and survival. The 182 patients previously treated for ovarian cancer with carboplatin and paclitaxel in either the AGO-OVAR-9 or the NSGO-OC9804 trial in Denmark or Sweden were eligible for this study. Genotyping was carried out on formalin-fixed tissue. The patients toxicity profiles and survival data were derived from retrospective data. CYP2C8*3, ABCB1 C1236T, G2677T/A, and C3435T were chosen a priori for primary analysis; a host of other variants were entered into an exploratory analysis. Clinical data and tissue were available from a total of 119 patients. Twenty-two single nucleotide polymorphisms (SNPs) in 10 genes were determined. Toxicity registration was available from 710 treatment cycles. In the primary analysis, no statistically significant correlation was found between CYP2C8*3, ABCB1 C1236T, G2677T/A, and C3435T and neutropenia, sensoric neuropathy, and overall survival. CYP2C8*3 and the ABCB1 SNPs C1236T, G2677T/A, and C3435T were not statistically significantly correlated to overall survival, sensoric neuropathy, and neutropenia in 119 patients treated for ovarian cancer with paclitaxel/carboplatin.
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| 24. |
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| 25. |
- Geddes, C. C., et al.
(author)
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Optimizing the saccharification of sugar cane bagasse using dilute phosphoric acid followed by fungal cellulases
- 2010
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In: Bioresource Technology. - : Elsevier BV. - 1873-2976 .- 0960-8524. ; 101:6, s. 1851-1857
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Journal article (peer-reviewed)abstract
- A low level of phosphoric acid (1% w/w on dry bagasse basis, 160 degrees C and above, 10 min) was shown to effectively hydrolyze the hemicellulose in sugar cane bagasse into monomers with minimal side reactions and to serve as an effective pre-treatment for the enzymatic hydrolysis of cellulose. Up to 45% of the remaining water-insoluble solids (WIS) was digested to sugar monomers by a low concentration of Biocellulase W (0.5 filter paper unit/g WIS) supplemented with beta-glucosidase, although much higher levels of cellulase (100-fold) were required for complete hydrolysis. After neutralization and nutrient addition, phosphoric acid syrups of hemicellulose sugars were fermented by ethanologenic Escherichia coli LY160 without further purification. Fermentation of these syrups was preceded by a lag that increased with increased pre-treatment temperature. Further improvements in organisms and optimization of steam treatments may allow the co-fermentation of sugars derived from hemicellulose and cellulose, eliminating need for liquid-solid separation, sugar purification, and separate fermentations. (C) 2009 Elsevier Ltd. All rights reserved.
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| 26. |
- Johansson, Daniel, 1975, et al.
(author)
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Multi - model analyses of the economic and energy implications for China and India in a post-Kyoto climate regime
- 2012
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Other publication (other academic/artistic)abstract
- This paper presents a modeling comparison project on how the2°C climate target could affect economic and energy systems development in China and India. The analysis uses a framework that harmonizes baseline developments and soft-links seven national and global models being either economy wide (CGE models) or energy system models. The analysis is based on a global greenhouse gas emission pathway that aims at a radiative forcing of 2.9 W/m2 in 2100 and with a policy regime based on convergence of per capita CO2 emissions with emissions trading. Economic and energy implications for China and India vary across models. Decreased energy intensity is the most important abatement approach in the CGE models, while decreased carbon intensity is most important in the energy system models. Reliance on Coal without Carbon Capture and Storage (CCS) is significantly reduced in most models, while CCS is a central abatement technology in energy system models, as is renewable and nuclear energy. Concerning economic impacts China bears in general a higher cost than India, as China benefits less from emissions trading. Costs are also affected by changes in fossil fuel prices, currency appreciation from capital inflow from carbon trading and timing of emission reductions.
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| 27. |
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| 28. |
- Lalani, Tahaniyat, et al.
(author)
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Analysis of the impact of early surgery on in-hospital mortality of native valve endocarditis: use of propensity score and instrumental variable methods to adjust for treatment-selection bias.
- 2010
-
In: Circulation. - 1524-4539. ; 121:8, s. 1005-13
-
Journal article (peer-reviewed)abstract
- BACKGROUND: The impact of early surgery on mortality in patients with native valve endocarditis (NVE) is unresolved. This study sought to evaluate valve surgery compared with medical therapy for NVE and to identify characteristics of patients who are most likely to benefit from early surgery. METHODS AND RESULTS: Using a prospective, multinational cohort of patients with definite NVE, the effect of early surgery on in-hospital mortality was assessed by propensity-based matching adjustment for survivor bias and by instrumental variable analysis. Patients were stratified by propensity quintile, paravalvular complications, valve perforation, systemic embolization, stroke, Staphylococcus aureus infection, and congestive heart failure. Of the 1552 patients with NVE, 720 (46%) underwent early surgery and 832 (54%) were treated with medical therapy. Compared with medical therapy, early surgery was associated with a significant reduction in mortality in the overall cohort (12.1% [87/720] versus 20.7% [172/832]) and after propensity-based matching and adjustment for survivor bias (absolute risk reduction [ARR] -5.9%, P<0.001). With a combined instrument, the instrumental-variable-adjusted ARR in mortality associated with early surgery was -11.2% (P<0.001). In subgroup analysis, surgery was found to confer a survival benefit compared with medical therapy among patients with a higher propensity for surgery (ARR -10.9% for quintiles 4 and 5, P=0.002) and those with paravalvular complications (ARR -17.3%, P<0.001), systemic embolization (ARR -12.9%, P=0.002), S aureus NVE (ARR -20.1%, P<0.001), and stroke (ARR -13%, P=0.02) but not those with valve perforation or congestive heart failure. CONCLUSIONS: Early surgery for NVE is associated with an in-hospital mortality benefit compared with medical therapy alone.
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| 29. |
- Mackay, John, et al.
(author)
-
Towards decoding the conifer giga-genome
- 2012
-
In: Plant Molecular Biology. - : Springer. - 0167-4412 .- 1573-5028. ; 80:6, s. 555-569
-
Research review (peer-reviewed)abstract
- Several new initiatives have been launched recently to sequence conifer genomes including pines, spruces and Douglas-fir. Owing to the very large genome sizes ranging from 18 to 35 gigabases, sequencing even a single conifer genome had been considered unattainable until the recent throughput increases and cost reductions afforded by next generation sequencers. The purpose of this review is to describe the context for these new initiatives. A knowledge foundation has been acquired in several conifers of commercial and ecological interest through large-scale cDNA analyses, construction of genetic maps and gene mapping studies aiming to link phenotype and genotype. Exploratory sequencing in pines and spruces have pointed out some of the unique properties of these giga-genomes and suggested strategies that may be needed to extract value from their sequencing. The hope is that recent and pending developments in sequencing technology will contribute to rapidly filling the knowledge vacuum surrounding their structure, contents and evolution. Researchers are also making plans to use comparative analyses that will help to turn the data into a valuable resource for enhancing and protecting the world's conifer forests.
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| 30. |
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| 31. |
- McNamara, R. L., et al.
(author)
-
International comparisons of the management of patients with non-ST segment elevation acute myocardial infarction in the United Kingdom, Sweden, and the United States: The MINAP/NICOR, SWEDEHEART/RIKS-HIA, and ACTION Registry-GWTG/NCDR registries
- 2014
-
In: International Journal of Cardiology. - : Elsevier BV. - 0167-5273 .- 1874-1754. ; 175:2, s. 240-247
-
Journal article (peer-reviewed)abstract
- Objectives: To compare management of patients with acute non-ST segment elevation myocardial infarction (NSTEMI) in three developed countries with national ongoing registries. Background: Results from clinical trials suggest significant variation in care across the world. However, international comparisons in "real world" registries are limited. Methods: We compared the use of in-hospital procedures and discharge medications for patients admitted with NSTEMI from 2007 to 2010 using the unselective MINAP/NICOR [England and Wales (UK); n = 137,009], the unselective SWEDEHEART/RIKS-HIA (Sweden; n = 45,069), and the selective ACTION Registry-GWTG/NCDR [United States (US); n = 147,438] clinical registries. Results: Patients enrolled among the three registries were generally similar except those in the US who were younger but had higher rates of smoking, diabetes, hypertension, prior heart failure, and prior MI than in Sweden or in UK. Angiography and percutaneous coronary intervention (PCI) were performed more often in the US (76% and 44%) and Sweden (65% and 42%) relative to the UK (32% and 22%). Discharge betablockers were also prescribed more often in the US (89%) and Sweden (89%) than in the UK (76%). In contrast, discharge statins, angiotensin converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARB), and dual antiplatelet agents (among those not receiving PCI) were higher in the UK (92%, 79%, and 71%) than in the US (85%, 65%, 41%) and Sweden (81%, 69%, and 49%). Conclusions: The care for patients with NSTEMI differed substantially among the three countries. These differences in care among countries provide an opportunity for future comparative effectiveness research as well as identify opportunities for global quality improvement. (C) 2014 The Authors. Published by Elsevier Ireland Ltd.
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| 32. |
- Mukanga, David, et al.
(author)
-
Access, acceptability and utilization of community health workers using diagnostics for case management of fever in Ugandan children : a cross-sectional study
- 2012
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In: Malaria Journal. - : Springer Science and Business Media LLC. - 1475-2875. ; 11, s. 121-
-
Journal article (peer-reviewed)abstract
- Background: Use of diagnostics in integrated community case management (iCCM) of fever is recognized as an important step in improving rational use of drugs and quality of care for febrile under-five children. This study assessed household access, acceptability and utilization of community health workers (CHWs) trained and provided with malaria rapid diagnostic tests (RDTs) and respiratory rate timers (RRTs) to practice iCCM. Methods: A total of 423 households with under-five children were enrolled into the study in Iganga district, Uganda. Households were selected from seven villages in Namungalwe sub-county using probability proportionate to size sampling. A semi-structured questionnaire was administered to caregivers in selected households. Data were entered into Epidata statistical software, and analysed using SPSS Statistics 17.0, and STATA version 10. Results: Most (86%, 365/423) households resided within a kilometre of a CHW's home, compared to 26% (111/423) residing within 1 km of a health facility (p<0.001). The median walking time by caregivers to a CHW was 10 minutes (IQR 5-20). The first option for care for febrile children in the month preceding the survey was CHWs (40%, 242/601), followed by drug shops (33%, 196/601). Fifty-seven percent (243/423) of caregivers took their febrile children to a CHW at least once in the three month period preceding the survey. Households located 1-3 km from a health facility were 72% (AOR 1.72; 95% CI 1.11-2.68) more likely to utilize CHW services compared to households within 1 km of a health facility. Households located 1-3 km from a CHW were 81% (AOR 0.19; 95% CI 0.10-0.36) less likely to utilize CHW services compared to those households residing within 1 km of a CHW. A majority (79%, 336/423) of respondents thought CHWs services were better with RDTs, and 89% (375/423) approved CHWs' continued use of RDTs. Eighty-six percent (209/243) of respondents who visited a CHW thought RRTs were useful. Conclusion: ICCM with diagnostics is acceptable, increases access, and is the first choice for caregivers of febrile children. More than half of caregivers of febrile children utilized CHW services over a three-month period. However, one-third of caregivers used drug shops in spite of the presence of CHWs.
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| 33. |
- O'Byrne, P. M., et al.
(author)
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Measuring asthma control: a comparison of three classification systems
- 2010
-
In: European Respiratory Journal. - : European Respiratory Society (ERS). - 1399-3003 .- 0903-1936. ; 36:2, s. 269-276
-
Journal article (peer-reviewed)abstract
- There are various ways to classify asthma control; however, no classification is universally accepted. This retrospective analysis compared asthma control as assessed by the Asthma Control Questionnaire (5-item version; ACQ-5), Global Initiative for Asthma (GINA) or Gaining Optimal Asthma Control (GOAL) study criteria. Pooled data at the final study week (n=8,188) from three budesonide/formoterol maintenance and reliever therapy studies which measured ACQ-5 were stratified according to GINA or GOAL criteria and ACQ-5 score distribution. The percentages of patients with a controlled/partly controlled week (GINA), totally/well-controlled week (GOAL) and range of ACQ-5 cut-off points were compared. Patients with GINA controlled, partly controlled and uncontrolled asthma had mean ACQ-5 scores of 0.43, 0.75 and 1.62, respectively. Patients with GOAL totally controlled, well-controlled and uncontrolled asthma had ACQ-5 scores of 0.39, 0.78 and 1.63. The kappa measure of agreement was 0.80 for GINA and GOAL criteria, and 0.63 for GINA controlled/partly controlled and ACQ-5 <1.00. ACQ-5 detected clinically important improvements in 49% of patients who, according to GINA criteria, remained uncontrolled at the end of the study. Asthma control measured by GINA or GOAL criteria provides similar results. GINA Controlled/Partly Controlled and GOAL Totally Controlled/Well-Controlled correspond to ACQ-5 <1.00. The ACQ-5 is more responsive to change in a clinical trial setting than a categorical scale.
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| 34. |
- Peterson, EW, et al.
(author)
-
Falls Self-Efficacy Among Adults With Multiple Sclerosis: A Phenomenological Study
- 2010
-
In: OTJR-OCCUPATIONAL THERAPY JOURNAL OF RESEARCH. - : SAGE Publications. - 1539-4492. ; 30:4, s. 148-157
-
Journal article (other academic/artistic)abstract
- This phenomenological study explored and described the lived experience of falls self-efficacy (i.e., perceived self-efficacy in avoiding a fall during basic activities of daily living) among six individuals with multiple sclerosis and its relationship to their overall volition and occupational lives. Participants were interviewed three times over a 3-month period. All interviews were analyzed using the Empirical, Phenomenological, Psychological method. One main theme (managing fall risk as a means of supporting activity) and six subthemes were reflected in participants' lived experiences: (1) understanding personal multiple sclerosis symptoms, abilities, and fall risk; (2) accepting one's changed capacity; (3) focusing on what you can control; (4) ongoing learning by doing; (5) vigilance while doing; and (6) taking personal responsibility to reduce fall risk. The findings show how falls self-efficacy operates as part of a larger volitional process and can be used to inform the development of fall prevention programs for individuals living with multiple sclerosis.
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| 35. |
- Raudsepp-Hearne, Ciara, et al.
(author)
-
Untangling the Environmentalist's Paradox : Why Is Human Well-being Increasing as Ecosystem Services Degrade?
- 2010
-
In: BioScience. - : Oxford University Press (OUP). - 0006-3568 .- 1525-3244. ; 60:8, s. 576-589
-
Journal article (peer-reviewed)abstract
- Environmentalists have argued that ecological degradation will lead to declines in the well-being of people dependent on ecosystem services. The Millennium Ecosystem Assessment paradoxically found that human well-being has increased despite large global declines in most ecosystem services. We assess four explanations of these divergent trends: (1) We have measured well-being incorrectly; (2) well-being is dependent on food services, which are increasing, and not on other services that are declining; (3) technology has decoupled well-being from nature; (4) time lags may lead to future declines in well-being. Our findings discount the first hypothesis, but elements of the remaining three appear plausible. Although ecologists have convincingly documented ecological decline, science does not adequately understand the implications of this decline for human well-being. Untangling how human well-being has increased as ecosystem conditions decline is critical to guiding future management of ecosystem services; we propose four research areas to help achieve this goal.
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| 36. |
- Reddel, H. K., et al.
(author)
-
Effect of different asthma treatments on risk of cold-related exacerbations
- 2011
-
In: European Respiratory Journal. - : European Respiratory Society (ERS). - 1399-3003 .- 0903-1936. ; 38:3, s. 584-593
-
Journal article (peer-reviewed)abstract
- Common colds often trigger asthma exacerbations. The present study compared cold-related severe exacerbations during budesonide/formoterol maintenance and reliever therapy, and different regimens of maintenance inhaled corticosteroids (ICS), with or without long-acting beta(2)-agonists (LABA), and with as-needed short-acting beta(2)-agonists (SABA) or LABA. Reported colds and severe exacerbations (defined by oral corticosteroid use and/or hospitalisation/emergency room visit) were assessed for 12,507 patients during 6-12 months of double-blind treatment. Exacerbations occurring <= 14 days after onset of reported colds were analysed by a Poisson model. The incidence of colds was similar across treatments. Asthma symptoms and reliever use increased during colds. Budesonide/formoterol maintenance and reliever therapy reduced severe cold-related exacerbations by 36% versus pooled comparators plus SABA (rate ratio (RR) 0.64; p=0.002), and for individual treatment comparisons, by 52% versus the same maintenance dose of ICS/LABA (RR 0.48; p < 0.001); there were nonsignificant reductions versus higher maintenance doses of ICS or ICS/LABA (RR 0.83 and 0.72, respectively). As-needed LABA did not reduce cold-related exacerbations versus as-needed SABA (RR 0.96). Severe cold-related exacerbations were reduced by budesonide/formoterol maintenance and reliever therapy compared with ICS with or without LABA and with as-needed SABA. Subanalyses suggested the importance of the ICS component in reducing cold-related exacerbations. Future studies should document the cause of exacerbations, in order to allow identification of different treatment effects.
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| 37. |
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| 38. |
- Ur-Rehman, Tofeeq, et al.
(author)
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Pre-clinical pharmacokinetics and anti-chlamydial activity of salicylidene acylhydrazide inhibitors of bacterial type III secretion
- 2012
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In: The Journal of antibiotics. - : Springer Science and Business Media LLC. - 0021-8820 .- 1881-1469. ; 65, s. 397-404
-
Journal article (peer-reviewed)abstract
- Salicylidene acylhydrazides belong to a class of compounds shown to inhibit bacterial type III secretion (T3S) in pathogenic Gram-negative bacteria. This class of compounds also inhibits growth and replication of Chlamydiae, strict intracellular bacteria that possess a T3S system. In this study a library of 58 salicylidene acylhydrazides was screened to identify inhibitors of Chlamydia growth. Compounds inhibiting growth of both Chlamydia trachomatis and Chlamydophila pneumoniae were tested for cell toxicity and seven compounds were selected for preliminary pharmacokinetic analysis in mice using cassette dosing. Two compounds, ME0177 and ME0192, were further investigated by individual pharmacokinetic analysis. Compound ME0177 had a relatively high peak plasma concentration (C(max)) and area under curve and therefore may be considered for systemic treatment of Chlamydia infections. The other compound, ME0192, had poor pharmacokinetic properties but the highest anti-chlamydial activity in vitro and therefore was tested for topical treatment in a mouse vaginal infection model. ME0192 administered vaginally significantly reduced the infectious burden of C. trachomatis and the number of infected mice.Journal of Antibiotics advance online publication, 6 June 2012; doi:10.1038/ja.2012.43.
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| 40. |
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