10 research outputs found

    National Koala Disease Risk Analysis Report Appendices V1.2

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    These appendices comprise the methods and literature reviews that underpin the National Koala Disease Risk Analysis Report (KDRA). That document identifies the knowledge base, information gaps, risk assessments and critical control points for koala disease hazards. The national focus of the KDRA provides a clear, evidence-based assessment of koala disease which will be of value in evaluating disease risk at all regional levels and for koalas in all management situations (captive, rehabilitation and free-ranging). The KDRA is a key guiding document for actions to achieve a vision of ‚Äúsustainable, resilient and healthy populations of koalas, living in positive welfare within healthy ecosystems across their range‚ÄĚ

    National Koala Disease Risk Analysis Report V 1.2

    Get PDF
    The Koala Disease Risk Analysis (KDRA) identifies the knowledge base, information gaps, risk assessments and critical control points for koala disease hazards. The national focus of the KDRA provides a clear, evidence-based assessment of koala disease which will be of value in evaluating disease risk at all regional levels and for koalas in all management situations (captive, rehabilitation and free-ranging). The KDRA is a key guiding document for actions to achieve a vision of “sustainable, resilient and healthy populations of koalas, living in positive welfare within healthy ecosystems across their range

    Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial

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    BACKGROUND: The ESPAC-3 trial showed that adjuvant gemcitabine is the standard of care based on similar survival to and less toxicity than adjuvant 5-fluorouracil/folinic acid in patients with resected pancreatic cancer. Other clinical trials have shown better survival and tumour response with gemcitabine and capecitabine than with gemcitabine alone in advanced or metastatic pancreatic cancer. We aimed to determine the efficacy and safety of gemcitabine and capecitabine compared with gemcitabine monotherapy for resected pancreatic cancer. METHODS: We did a phase 3, two-group, open-label, multicentre, randomised clinical trial at 92 hospitals in England, Scotland, Wales, Germany, France, and Sweden. Eligible patients were aged 18 years or older and had undergone complete macroscopic resection for ductal adenocarcinoma of the pancreas (R0 or R1 resection). We randomly assigned patients (1:1) within 12 weeks of surgery to receive six cycles of either 1000 mg/m(2) gemcitabine alone administered once a week for three of every 4 weeks (one cycle) or with 1660 mg/m(2) oral capecitabine administered for 21 days followed by 7 days' rest (one cycle). Randomisation was based on a minimisation routine, and country was used as a stratification factor. The primary endpoint was overall survival, measured as the time from randomisation until death from any cause, and assessed in the intention-to-treat population. Toxicity was analysed in all patients who received trial treatment. This trial was registered with the EudraCT, number 2007-004299-38, and ISRCTN, number ISRCTN96397434. FINDINGS: Of 732 patients enrolled, 730 were included in the final analysis. Of these, 366 were randomly assigned to receive gemcitabine and 364 to gemcitabine plus capecitabine. The Independent Data and Safety Monitoring Committee requested reporting of the results after there were 458 (95%) of a target of 480 deaths. The median overall survival for patients in the gemcitabine plus capecitabine group was 28·0 months (95% CI 23·5-31·5) compared with 25·5 months (22·7-27·9) in the gemcitabine group (hazard ratio 0·82 [95% CI 0·68-0·98], p=0·032). 608 grade 3-4 adverse events were reported by 226 of 359 patients in the gemcitabine plus capecitabine group compared with 481 grade 3-4 adverse events in 196 of 366 patients in the gemcitabine group. INTERPRETATION: The adjuvant combination of gemcitabine and capecitabine should be the new standard of care following resection for pancreatic ductal adenocarcinoma

    Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

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    Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008‚Äď11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003‚Äď13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0¬∑674), and with age at onset (TRACK-HD, r=0¬∑315; REGISTRY, r=0¬∑234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1¬∑12 √ó 10‚ąí10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2¬∑94 √ó 10‚ąí8 DHFR p=8¬∑37 √ó 10‚ąí7 MTRNR2L2 p=2¬∑15 √ó 10‚ąí9) and to a lesser extent in REGISTRY (MSH3 p=9¬∑36 √ó 10‚ąí4 DHFR p=8¬∑45 √ó 10‚ąí4 MTRNR2L2 p=1¬∑20 √ó 10‚ąí3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1¬∑58 √ó 10‚ąí8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0¬∑4 units per year (95% CI 0¬∑16‚Äď0¬∑66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0¬∑12 units per year (95% CI 0¬∑06‚Äď0¬∑18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

    Schizopsychotic symptom-profiles and biomarkers: Beacons in diagnostic labyrinths

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    Several avenues of investigation through which the \u27labyrinths\u27 of schizopsychotic diagnosis may be examined, are offered by the consideration of the \u27beacons\u27 of symptom-profiles and biomarkers. Neurodevelopmental issues and risk assessment, neurocognitive factors of predictive necessity, supersensitivity in neurotransmitter systems, the implications of prodromal expressions of the disorder, functional dysconnectivity arising from prefrontal to diverse regional patterns and circuits with a neurodevelopmental origin, and heritable gene characteristics are viewed against the backdrop of the schizophrenia spectrum disorders. The associations between adolescent-adult use of cannabis, on the one hand, and, alternatively, the prevalence of chromosomal abnormalities, e.g., GRIK4 and NPAS3, and mental retardation, on the other hand, with the symptom-profiles of schizopsychosis provide further evidence of emerging biomarkers of biological inheritance factors. The involvement of dopamine D1 and D2 receptors, particularly in prefrontal region, with regard to functional integrity of cognitive systems is reviewed. It would appear that considerations of these disorders imply that one essential hub around which much of the neuropathology revolves may be observed in the various expressions of the cognitive and structural insufficiency

    Conditionally and Transiently Disordered Proteins: Awakening Cryptic Disorder To Regulate Protein Function

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    X. Literaturverzeichnis

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    Description and performance of track and primary-vertex reconstruction with the CMS tracker