https://ogma.newcastle.edu.au/vital/access/ /manager/Index ${session.getAttribute("locale")} 5 https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:50526 Wed 28 Feb 2024 15:27:25 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:14772 2 diseases) is a product of the design of health care systems which define health care need on the basis of disease status. So does the solution lie in an alternative model of healthcare? Discussion: Strengthening generalist practice has been proposed as part of the solution to tackling multi-morbidity. Generalism is a professional philosophy of practice, deeply known to many practitioners, and described as expertise in whole person medicine. But generalism lacks the evidence base needed by policy makers and planners to support service redesign. The challenge is to fill this practice-research gap in order to critically explore if and when generalist care offers a robust alternative to management of this complex problem. We need practice-based evidence to fill this gap. By recognising generalist practice as a ‘complex intervention’ (intervening in a complex system), we outline an approach to evaluate impact using action-research principles. We highlight the implications for those who both commission and undertake research in order to tackle this problem. Summary: Answers to the complex problem of multi-morbidity won’t come from doing more of the same. We need to change systems of care, and so the systems for generating evidence to support that care. This paper contributes to that work through outlining a process for generating practice-based evidence of generalist solutions to the complex problem of person-centred care for people with multi-morbidity.]]> Wed 11 Apr 2018 13:41:48 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:22707 BRCA₂, has a large number of genetic variants of unknown effect. The variant rs11571833, an A > T transversion in the final exon of the gene that leads to the creation of a stop codon 93 amino acids early (K3326*), is reported as a neutral polymorphism but there is some evidence to suggest an association with an increased risk of breast cancer. We assessed whether this variant was enriched in a cohort of breast cancer cases ascertained through familial cancer clinics compared to population-based non-cancer controls using a targeted sequencing approach. We identified the variant in 66/2634 (2.5%) cases and 33/1996 (1.65%) controls, indicating an enrichment in the breast cancer cases (p = 0.047, OR 1.53, 95% CI 1.00–2.34). This data is consistent with recent iCOGs data suggesting that this variant is not neutral with respect to breast cancer risk. rs11571833 may need to be included in SNP panels for evaluating breast cancer risk.]]> Wed 11 Apr 2018 09:55:17 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:24890 Wed 09 Feb 2022 15:54:09 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:23843 0.999) or in the number of variants predicted to be pathogenic by various in silico tools (Condel, Polyphen2, SIFT, and CADD) in the cases compared to the controls. In addition, there was no difference in the incidence of classic Lynch syndrome cancers in RINT1 rare variant-carrying families compared to RINT1 wild-type families. This study had 90 % power to detect an odds ratio of at least 2.06, and the results do not provide any support for RINT1 being a moderate-penetrance breast cancer susceptibility gene, although larger studies will be required to exclude more modest effects. This study emphasizes the need for caution before designating a cancer predisposition role for any gene based on very rare truncating variants and in silico-predicted missense variants.]]> Wed 02 Mar 2022 14:25:02 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:48284 0.5 (OR 3.95, 95% CI 1.40–12.01, p = 0.006). Sequencing of 21 tumours from 20 heterozygous and 1 homozygous carriers of nine candidate MS variants identified four cases with biallelic inactivation through loss of the wild-type allele, while six lost the variant allele and ten that remained heterozygous. Biallelic loss of the wild-type alleles corresponded strongly with ER- and TN breast tumours, high homologous recombination deficiency scores and mutational signature 3. Using this approach, the p.Gly264Ser variant, which was previously suspected to be pathogenic based on small case–control analyses and loss of activity in in vitro functional assays, was shown to be benign with similar prevalence in cases and controls and seven out of eight tumours showing no biallelic inactivation or characteristic mutational signature. Conversely, evaluation of case–control findings and tumour sequencing data identified p.Ile144Thr, p.Arg212His, p.Gln143Arg and p.Gly114Arg as variants warranting further investigation.]]> Tue 14 Mar 2023 11:29:22 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:45361 BRCA1 and BRCA2, including the identification of new predisposing genes. A total of 11,511 non-BRCA familial BC cases and population-matched cancer-free female controls in the BEACCON study were investigated in two sequencing phases: 1303 candidate genes in up to 3892 cases and controls, followed by validation of 145 shortlisted genes in an additional 7619 subjects. The coding regions and exon–intron boundaries of all candidate genes and 14 previously proposed BC genes were sequenced using custom designed sequencing panels. Pedigree and pathology data were analysed to identify genotype-specific associations. The contribution of ATM, PALB2 and CHEK2 to BC predisposition was confirmed, but not RAD50 and NBN. An overall excess of loss-of-function (LoF) (OR 1.27, p = 9.05 × 10⁻⁹) and missense (OR 1.27, p = 3.96 × 10⁻⁷³) variants was observed in the cases for the 145 candidate genes. Leading candidates harbored LoF variants with observed ORs of 2–4 and individually accounted for no more than 0.79% of the cases. New genes proposed by this study include NTHL1, WRN, PARP2, CTH and CDK9. The new candidate BC predisposition genes identified in BEACCON indicate that much of the remaining genetic causes of high-risk BC families are due to genes in which pathogenic variants are both very rare and convey only low to moderate risk.]]> Thu 27 Oct 2022 15:32:46 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:50311 Mon 17 Jul 2023 15:51:54 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:51355 Fri 01 Sep 2023 13:43:26 AEST ]]>