Applying Generalisability Theory to examine the distinction between state and trait in the State and Trait Anxiety Inventory (STAI)

Accurate distinction between state and trait anxiety is necessary for monitoring of individual anxiety levels over time and developing effective interventions to reduce anxiety, which is especially important in the current COVID-19 pandemic situation increasing anxiety of the world population. The widely used State and Trait Anxiety Inventory (STAI) with 78,600 Google scholar citations to date, was specifically designed to measure both state and trait anxiety. However, ability of the STAI to accurately distinguish between the two and the overall reliability and generalisability of its assessment scores were not rigorously investigated using appropriate methodology. Generalisability theory (G-theory) is increasingly used as the most robust method to distinguish between state and trait and establish the overall reliability while accounting for specific error sources in the assessment of psychological conditions. G-theory was applied to the 40-item STAI completed by 139 participants on three occasions separated by two-week intervals. Both subscales of the STAI demonstrated excellent reliability in measuring trait anxiety with high generalizability of scores across occasions (G=0.84-0.92) but fail to distinguish state from trait. This means that the state subscale of the STAI is not suitable to detect changes over time and reliably measure state anxiety. A minor amount of error variance identified in the STAI subscales were mainly attributed to interaction between person and occasion, which reflected state anxiety, and interaction between person, item and occasion. Dynamic aspects of anxiety were identified in both subscales including feelings of satisfaction, nervousness, feeling pleasant, restlessness, perceived failure, lack of calmness, feeling insecure, feeling inadequate and sensitivity to disappointments. This study derived a sensitive state anxiety scale using G-theory that includes items the most sensitive to state changes. State anxiety can be measured with higher accuracy by using the proposed short state scale without modifications of the original STAI format. Dynamic aspects of anxiety identified using G-theory, are more amendable, and proposed as the primary target of interventions aiming at effectively reducing anxiety. Further enhancement of state anxiety measurement informed by G- theory is warranted. Overall, this study contributed to enhanced assessment of state and trait anxiety and informs psychological interventions aiming at more effective reduction of anxiety

Learning together for and with the Martuwarra Fitzroy River

Co-production across scientific and Indigenous knowledge systems has become a cornerstone of research to enhance knowledge, practice, ethics, and foster sustainability transformations. However, the profound differences in world views and the complex and contested histories of nation-state colonisation on Indigenous territories, highlight both opportunities and risks for Indigenous people when engaging with knowledge co-production. This paper investigates the conditions under which knowledge co-production can lead to improved Indigenous adaptive environmental planning and management among remote land-attached Indigenous peoples through a case study with ten Traditional Owner groups in the Martuwarra (Fitzroy River) Catchment in Western Australia’s Kimberley region. The research team built a 3D map of the river and used it, together with an interactive table-top projector, to bring together both scientific and Indigenous spatial knowledge. Participatory influence mapping, aligned with Traditional Owner priorities to achieve cultural governance and management planning goals set out in the Fitzroy River Declaration, investigated power relations. An analytical framework, examining underlying mechanisms of social learning, knowledge promotion and enhancing influence, based on different theories of change, was applied to unpack the immediate outcomes from these activities. The analysis identified that knowledge co-production activities improved the accessibility of the knowledge, the experiences of the knowledge users, strengthened collective identity and partnerships, and strengthened Indigenous-led institutions. The focus on cultural governance and management planning goals in the Fitzroy River Declaration enabled the activities to directly affect key drivers of Indigenous adaptive environmental planning and management—the Indigenous-led institutions. The nation-state arrangements also gave some support to local learning and decision-making through a key Indigenous institution, Martuwarra Fitzroy River Council. Knowledge co-production with remote land-attached Indigenous peoples can improve adaptive environmental planning and management where it fosters learning together, is grounded in the Indigenous-led institutions and addresses their priorities

Homologous recombination DNA repair defects in PALB2- associated breast cancers

Abstract: Mono-allelic germline pathogenic variants in the Partner And Localizer of BRCA2 (PALB2) gene predispose to a high-risk of breast cancer development, consistent with the role of PALB2 in homologous recombination (HR) DNA repair. Here, we sought to define the repertoire of somatic genetic alterations in PALB2-associated breast cancers (BCs), and whether PALB2-associated BCs display bi-allelic inactivation of PALB2 and/or genomic features of HR-deficiency (HRD). Twenty-four breast cancer patients with pathogenic PALB2 germline mutations were analyzed by whole-exome sequencing (WES, n = 16) or targeted capture massively parallel sequencing (410 cancer genes, n = 8). Somatic genetic alterations, loss of heterozygosity (LOH) of the PALB2 wild-type allele, large-scale state transitions (LSTs) and mutational signatures were defined. PALB2-associated BCs were found to be heterogeneous at the genetic level, with PIK3CA (29%), PALB2 (21%), TP53 (21%), and NOTCH3 (17%) being the genes most frequently affected by somatic mutations. Bi-allelic PALB2 inactivation was found in 16 of the 24 cases (67%), either through LOH (n = 11) or second somatic mutations (n = 5) of the wild-type allele. High LST scores were found in all 12 PALB2-associated BCs with bi-allelic PALB2 inactivation sequenced by WES, of which eight displayed the HRD-related mutational signature 3. In addition, bi-allelic inactivation of PALB2 was significantly associated with high LST scores. Our findings suggest that the identification of bi-allelic PALB2 inactivation in PALB2-associated BCs is required for the personalization of HR-directed therapies, such as platinum salts and/or PARP inhibitors, as the vast majority of PALB2-associated BCs without PALB2 bi-allelic inactivation lack genomic features of HRD

Development and validation of a targeted gene sequencing panel for application to disparate cancers

Next generation sequencing has revolutionised genomic studies of cancer, having facilitated the development of precision oncology treatments based on a tumour’s molecular profile. We aimed to develop a targeted gene sequencing panel for application to disparate cancer types with particular focus on tumours of the head and neck, plus test for utility in liquid biopsy. The final panel designed through Roche/Nimblegen combined 451 cancer-associated genes (2.01 Mb target region). 136 patient DNA samples were collected for performance and application testing. Panel sensitivity and precision were measured using well-characterised DNA controls (n = 47), and specificity by Sanger sequencing of the Aryl Hydrocarbon Receptor Interacting Protein (AIP) gene in 89 patients. Assessment of liquid biopsy application employed a pool of synthetic circulating tumour DNA (ctDNA). Library preparation and sequencing were conducted on Illumina-based platforms prior to analysis with our accredited (ISO15189) bioinformatics pipeline. We achieved a mean coverage of 395x, with sensitivity and specificity of >99% and precision of >97%. Liquid biopsy revealed detection to 1.25% variant allele frequency. Application to head and neck tumours/cancers resulted in detection of mutations aligned to published databases. In conclusion, we have developed an analytically-validated panel for application to cancers of disparate types with utility in liquid biopsy

HER2-enriched subtype and novel molecular subgroups drive aromatase inhibitor resistance and an increased risk of relapse in early ER+/HER2+ breast cancer

BACKGROUND: Oestrogen receptor positive/ human epidermal growth factor receptor positive (ER+/HER2+) breast cancers (BCs) are less responsive to endocrine therapy than ER+/HER2- tumours. Mechanisms underpinning the differential behaviour of ER+HER2+ tumours are poorly characterised. Our aim was to identify biomarkers of response to 2 weeks’ presurgical AI treatment in ER+/HER2+ BCs. METHODS: All available ER+/HER2+ BC baseline tumours (n=342) in the POETIC trial were gene expression profiled using BC360™ (NanoString) covering intrinsic subtypes and 46 key biological signatures. Early response to AI was assessed by changes in Ki67 expression and residual Ki67 at 2 weeks (Ki672wk). Time-To-Recurrence (TTR) was estimated using Kaplan-Meier methods and Cox models adjusted for standard clinicopathological variables. New molecular subgroups (MS) were identified using consensus clustering. FINDINGS: HER2-enriched (HER2-E) subtype BCs (44.7% of the total) showed poorer Ki67 response and higher Ki672wk (p<0.0001) than non-HER2-E BCs. High expression of ERBB2 expression, homologous recombination deficiency (HRD) and TP53 mutational score were associated with poor response and immune-related signatures with High Ki672wk. Five new MS that were associated with differential response to AI were identified. HER2-E had significantly poorer TTR compared to Luminal BCs (HR 2.55, 95% CI 1.14–5.69; p=0.0222). The new MS were independent predictors of TTR, adding significant value beyond intrinsic subtypes. INTERPRETATION: Our results show HER2-E as a standardised biomarker associated with poor response to AI and worse outcome in ER+/HER2+. HRD, TP53 mutational score and immune-tumour tolerance are predictive biomarkers for poor response to AI. Lastly, novel MS identify additional non-HER2-E tumours not responding to AI with an increased risk of relapse

Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity.

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant