Prevalence of mutations in common tumour types in Northern England and comparable utility of national and international Trial Finders.

PURPOSE: Tumour genomic profiling is of increasing importance in early phase trials to match patients to targeted therapeutics. Mutations vary by demographic group; however, regional differences are not characterised. This was investigated by comparing mutation prevalence for common cancers presenting to Newcastle Experimental Cancer Medicine Centre (ECMC) to The Cancer Genome Atlas (TCGA) and utility of trial matching modalities. METHODS: Detailed clinicogenomic data were obtained for patients presenting September 2017-December 2020. Prevalence of mutations in lung, colorectal, breast and prostate cancer was compared to TCGA GDC Data Portal. Experimental Cancer (EC) Trial Finder utility in matching trials was compared to a Molecular Tumour Board (MTB) and commercial sequencing reports. RESULTS: Of 311 patients with advanced cancer, this consisted of lung (n = 131, 42.1%), colorectal (n = 44, 14.1%), breast (n = 36, 11.6%) and prostate (n = 18, 5.6%). More than one mutation was identified in the majority (n = 260, 84%). Significant prevalence differences compared to TCGA were identified, including a high prevalence of EGFR in lung (P = 0.001); RB1 in breast (P = 0.0002); and multiple mutations in prostate cancer. EC Trial Finder demonstrated significantly different utility than sequencing reports in identifying trials (P = 0.007). CONCLUSIONS: Regional differences in mutations may exist with advanced stage accounting for prevalence of specific mutations. A national Trial Finder shows utility in finding targeted trials whilst commercial sequencing reports may over-report 'actionable' mutations. Understanding local prevalence and trial availability could increase enrolment onto matched early phase trials.

A Classic Case of Panton-Valentine Leucocidin MethicillinResistant Staphylococcus Aureus (PVL-MRSA)

Strains of Staphylococcus aureus capable of producing Panton-Valentine leucocidin (PVL-SA) are increasingly implicated in commnity acquired infection. The key principles of preventing and controlling the spread of infection in the community setting centre on early suspicion, rapid diagnosis and appropriate treatment.

Inequity in rehabilitation interventions after hip fracture: a systematic review.

OBJECTIVE: to determine the extent to which equity factors contributed to eligibility criteria of trials of rehabilitation interventions after hip fracture. We define equity factors as those that stratify healthcare opportunities and outcomes. DESIGN: systematic search of MEDLINE, Embase, CINHAL, PEDro, Open Grey, BASE and ClinicalTrials.gov for randomised controlled trials of rehabilitation interventions after hip fracture published between 1 January 2008 and 30 May 2018. Trials not published in English, secondary prevention or new models of service delivery (e.g. orthogeriatric care pathway) were excluded. Duplicate screening for eligibility, risk of bias (Cochrane Risk of Bias Tool) and data extraction (Cochrane's PROGRESS-Plus framework). RESULTS: twenty-three published, eight protocol, four registered ongoing randomised controlled trials (4,449 participants) were identified. A total of 69 equity factors contributed to eligibility criteria of the 35 trials. For more than 50% of trials, potential participants were excluded based on residency in a nursing home, cognitive impairment, mobility/functional impairment, minimum age and/or non-surgical candidacy. Where reported, this equated to the exclusion of 2,383 out of 8,736 (27.3%) potential participants based on equity factors. Residency in a nursing home and cognitive impairment were the main drivers of these exclusions. CONCLUSION: the generalisability of trial results to the underlying population of frail older adults is limited. Yet, this is the evidence base underpinning current service design. Future trials should include participants with cognitive impairment and those admitted from nursing homes. For those excluded, an evidence-informed reasoning for the exclusion should be explicitly stated. PROSPERO: CRD42018085930.

Visualising the past - An evaluation of processes and sequences for fingermark recovery from old documents.

This study aimed to collect data on the effectiveness of most of the fingermark visualisation reagents currently used on porous surfaces on fingermarks aged for up to 90 years, significantly extending the timescales for which such information exists. A limited subset of the variables associated with processing of old fingermarks was explored, with a focus on the use of 1,8 diazafluoren-9-one (DFO), 1,2-indandione, ninhydrin, and physical developer. These techniques were used in sequence on batches of cheques between 11 and 32 years old, and on documents dating from the 1920s and 1940s. The potential for applying a physical developer enhancement process (blue toning) as the final step in the sequence was also explored. The benefits of using processing sequences on porous items were clearly demonstrated, with all processes in the sequence adding value in terms of additional marks found on the cheques up to 32 years old. In addition, physical developer was found to be capable of developing fingermarks up to 90 years old, whereas the amino acid reagents appear less effective on documents of 70 years and older. An experimental physical developer formulation with reduced environmental impact was found to be as effective as the existing process in these experiments. Blue toning was found to visualise an additional 10-25% of marks, and its wider use after silver-based deposition processes is recommended based on the evidence from this study.

Germline variants in IL4, MGMT and AKT1 are associated with prostate cancer-specific mortality: An analysis of 12,082 prostate cancer cases.

BACKGROUND: Prostate cancer (PCa) is a leading cause of mortality and genetic factors can influence tumour aggressiveness. Several germline variants have been associated with PCa-specific mortality (PCSM), but further replication evidence is needed. METHODS: Twenty-two previously identified PCSM-associated genetic variants were genotyped in seven PCa cohorts (12,082 patients; 1544 PCa deaths). For each cohort, Cox proportional hazards models were used to calculate hazard ratios and 95% confidence intervals for risk of PCSM associated with each variant. Data were then combined using a meta-analysis approach. RESULTS: Fifteen SNPs were associated with PCSM in at least one of the seven cohorts. In the meta-analysis, after adjustment for clinicopathological factors, variants in the MGMT (rs2308327; HR 0.90; p-value = 3.5 × 10-2) and IL4 (rs2070874; HR 1.22; p-value = 1.1 × 10-3) genes were confirmed to be associated with risk of PCSM. In analyses limited to men diagnosed with local or regional stage disease, a variant in AKT1, rs2494750, was also confirmed to be associated with PCSM risk (HR 0.81; p-value = 3.6 × 10-2). CONCLUSIONS: This meta-analysis confirms the association of three genetic variants with risk of PCSM, providing further evidence that genetic background plays a role in PCa-specific survival. While these variants alone are not sufficient as prognostic biomarkers, these results may provide insights into the biological pathways modulating tumour aggressiveness.

Novel associations between blood DNA methylation and body mass index in middle-aged and older adults.

BACKGROUND/OBJECTIVES: There is increasing evidence of a relationship between blood DNA methylation and body mass index (BMI). We aimed to assess associations of BMI with individual methylation measures (CpGs) through a cross-sectional genome-wide DNA methylation association study and a longitudinal analysis of repeated measurements over time. SUBJECTS/METHODS: Using the Illumina Infinium HumanMethylation450 BeadChip, DNA methylation measures were determined in baseline peripheral blood samples from 5361 adults recruited to the Melbourne Collaborative Cohort Study (MCCS) and selected for nested case-control studies, 2586 because they were subsequently diagnosed with cancer (cases) and 2775 as controls. For a subset of 1088 controls, these measures were repeated using blood samples collected at wave 2 follow-up, a median of 11 years later; weight was measured at both time points. Associations between BMI and blood DNA methylation were assessed using linear mixed-effects regression models adjusted for batch effects and potential confounders. These were applied to cases and controls separately, with results combined through fixed-effects meta-analysis. RESULTS: Cross-sectional analysis identified 310 CpGs associated with BMI with P<1.0 × 10-7, 225 of which had not been reported previously. Of these 225 novel associations, 172 were replicated (P<0.05) using the Atherosclerosis Risk in Communities (ARIC) study. We also replicated using MCCS data (P<0.05) 335 of 392 associations previously reported with P<1.0 × 10-7, including 60 that had not been replicated before. Associations between change in BMI and change in methylation were observed for 34 of the 310 strongest signals in our cross-sectional analysis, including 7 that had not been replicated using the ARIC study. CONCLUSIONS: Together, these findings suggest that BMI is associated with blood DNA methylation at a large number of CpGs across the genome, several of which are located in or near genes involved in ATP-binding cassette transportation, tumour necrosis factor signalling, insulin resistance and lipid metabolism.

Standardized programming to reduce the burden of inappropriate therapies in implantable cardioverter defibrillators - Single centre follow up results.

BACKGROUND: Current algorithms and device morphology templates have been proposed in current Implantable Cardioverter-Defibrillators (ICDs) to minimize inappropriate therapies (ITS), but this has not been completely successful. AIM: Assess the impact of a deliberate strategy of using an atrial lead implant with standardized parameters; based on all current ICD discriminators and technologies, on the burden of ITS. METHOD: A retrospective single-centre analysis of 250 patients with either dual chamber (DR) ICDs or biventricular ICDs (CRTDs) over a (41.9 ± 27.3) month period was performed. The incidence of ITS on all ICD and CRTD patients was chronicled after the implementation of standardized programming. RESULTS: 39 events of anti-tachycardial pacing (ATP) and/or shocks were identified in 20 patients (8% incidence rate among patients). The total number of individual therapies was 120, of which 34% were inappropriate ATP, and 36% were inappropriate shocks. 11 patients of the 250 patients received ITS (4.4%). Of the 20 patients, four had ICDs for primary prevention and 16 for a secondary prevention. All the episodes in the primary indication group were inappropriate, while seven patients (43%) of the secondary indication group experienced inappropriate therapies. CONCLUSIONS: The burden of ITS in the population of patients receiving ICDs was 4.4% in the presence of atrial leads. The proposed rationalized programming criteria seems an effective strategy to minimize the burden of inappropriate therapies and will require further validation.

Transgressive women don't deserve protection: young men's narratives of sexual violence against women in rural Papua New Guinea.

Sexual violence against women and girls is commonplace in Papua New Guinea (PNG). While the experiences of women are rightly given central place in institutional responses to sexual violence, the men who perpetrate violence are often overlooked, an oversight that undermines the effectiveness of prevention efforts. This paper draws on interviews conducted with young men as part of a qualitative longitudinal study of masculinity and male sexuality in a rural highland area of PNG. It explores one aspect of male sexuality: men's narratives of sexual violence. Most striking from the data is that the collective enactment of sexual violence against women and girls is reported as an everyday and accepted practice amongst young men. However, not all women and girls were described as equally at risk, with those who transgress gender roles and roles inscribed and reinforced by patriarchal structures, at greater risk. To address this situation, efforts to reduce sexual violence against women and girls require an increased focus on male-centred intervention to critically engage with the forms of patriarchal authority that give license to sexual violence. Understanding the perceptions and experiences of men as perpetrators of sexual violence is a critical first step in the process of changing normative perceptions of gender, a task crucial to reducing sexual violence in countries such as PNG.

Factors associated with antiretroviral treatment uptake and adherence: a review. Perspectives from Australia, Canada, and the United Kingdom.

International focus on reducing onward HIV transmission emphasizes the need for routine HIV testing and early uptake of antiretroviral treatment (ART). Strategic targets have been set for 2020 to achieve the goal of 90% of people infected with HIV diagnosed, 90% of identified cases on treatment, and 90% of persons on treatment virally suppressed (90-90-90). It is vital to understand the complexity of factors influencing a person's treatment decisions over time and the context which may enable better adherence. In this paper we present findings from the review of published and gray literature (2003-2013) on the documented factors associated with treatment initiation and adherence in the general adult population of Australia, Canada, and the UK. A framework developed by Begley, McLaws, Ross, and Gold [2008. Cognitive and behavioural correlates of non-adherence to HIV anti-retroviral therapy: Theoretical and practical insight for clinical psychology and health psychology. Clinical Psychologist, 12(1), 9-17] in Australia was adapted to summarize the findings. A systematic database search using keywords and a set of inclusion criteria yielded 17 studies (Australia = 6; Canada = 8; UK = 3). In addition 11 reports were included in the review. We found that a person's abilities and motivations (intrapersonal factors, reported in 7 studies) to start and continue ART are influenced by a host of interconnected factors spanning relationship (interpersonal, 3 studies) and broader structural (extrapersonal, 15 studies) factors that are situated within social determinants of health. People therefore evaluate various costs and benefits of starting and staying on treatment, in which biomedical concerns play an important yet often subsidiary role. In this review the economic barriers to care were found to be significant and under-reported, highlighting the persistent health inequities in terms of access to services. Our understanding of the context around people's use of ART remains poor. Qualitative social research within HIV-positive communities is urgently needed to capture people's lived experiences and may address some of this deficit in understanding.

Evolution of Carotid Surgical Practice in the last Decade.

Stroke units provide immediate care and appropriate intervention in the evolving stroke. The aims of this study were to review the practice of carotid endarterectomy (CEA) before and after the establishment of a Stroke Unit in St. James's Hospital. Prior to the introduction of the Stroke Unit, 263 CEA's were performed over a five-year period. 139/263 (53%) of these were for symptomatic disease. 229 were performed in the five years since. 179/229 (78%) of these were for symptomatic disease. The 30-day stroke and death rates were < 2% before the introduction of the Stroke Unit, and have remained unchanged. Since the introduction of the Stroke Unit, there has been a slight decrease in the overall number of CEA's performed with a 25% increase in the proportion of endarterectomies performed for symptomatic disease. Despite the reduction in surgery for asymptomatic disease the overall 30-day stroke and death rate remains excellent at 2/229 (2%).

Sebia Capillarys 2 versus the Helena Biosciences V8 capillary electrophoresis analyser for carbohydrate-deficient transferrin measurement: comparison and analytical evaluation.

This study compares two automated capillary electrophoresis (CE) systems, the Capillarys 2 (Sebia, Surrey, UK) and V8 (Helena Biosciences, Tyne and Wear, UK) for the measurement of carbohydrate-deficient transferrin (CDT). Analytical imprecision was calculated for both platforms using internal quality control material from Sebia and Helena Biosciences, while a patient comparison was performed on 150 patient samples with CDT% levels ranging from 0.3% to 23.7%. Inter- and intra-assay imprecision between the two platforms were comparable. The correlation between platforms using patient samples was r2 = 0.985. However, there was a significant proportional bias at higher CDT concentration ranges, with the Helena system showing negative bias but good correlation over the clinically significant range. Analytical performances from both CE systems have been proven as suitable for routine laboratory use. The V8 CDT results were comparable to the Capillarys 2 in human sera over the clinical range of interest.

Factors impacting HIV testing: a review--perspectives from Australia, Canada, and the UK.

With the current global focus on strengthening HIV prevention through greater testing and treatment uptake, it is increasingly salient to identify and address barriers to testing. A review of the published, peer-reviewed literature and national reports from Australia, Canada, and the UK (2003-2013) on barriers to HIV testing was conducted to provide new information relevant to Australia and to complement earlier reviews from Canada and the UK. A systematic database search using keywords and a set of inclusion criteria yielded 36 studies (Australia = 13; Canada = 6; and the UK = 17). In addition 17 unpublished reports were included in the review. Our study uses a novel, comprehensive framework to describe barriers to HIV testing, and thus contributes to moving beyond the traditional patient-provider-system categorization. Within that framework, barriers are categorized as either intrapersonal (reported in 15 studies), interpersonal (21), or extrapersonal (16) and conceptualized within wider sociocultural and structural contexts. People's abilities and motivations to test (intrapersonal factors) are influenced by a host of interconnected factors spanning relationship (interpersonal) and broader socioeconomic, political and cultural (extrapersonal) factors. We suggest that the relative effects of interventions targeting barriers to HIV testing at the intrapersonal and interpersonal levels are limited by the extent to which the social determinants of health are addressed. The framework may also lend itself to thinking about the enabling factors for HIV testing, and future research may investigate the application of that framework for strategizing the most effective response. Future studies should also capture the lived experiences of barriers to HIV testing experienced by patients, especially in populations which are hard to reach based on social and geographic distance. Context-specific studies to evaluate the feasibility and effectiveness of various interventions proposed in the literature to address barriers to HIV testing are needed.

Multimodality imaging features of hereditary multiple exostoses.

Hereditary multiple exostoses (HME) or diaphyseal aclasis is an inherited disorder characterised by the formation of multiple osteochondromas, which are cartilage-capped osseous outgrowths, and the development of associated osseous deformities. Individuals with HME may be asymptomatic or develop clinical symptoms, which prompt imaging studies. Different modalities ranging from plain radiographs to cross-sectional and nuclear medicine imaging studies can be helpful in the diagnosis and detection of complications in HME, including chondrosarcomatous transformation. We review the role and imaging features of these different modalities in HME.

Biomechanical study of the efficacy of a new design of wrist guard.

BACKGROUND: Upper extremity injuries are frequent in the elderly or those undertaking extreme sporting activities. Commercially available wrist guards reduce the frequency of wrist fractures but are not widely used as they greatly restrict movement. METHODS: A new wrist guard was developed which provided protection to the "impact area" but does not restrict wrist or digital movement. A human hand model and a biomechanical test rig, which allowed the simulation of an adult fall from height, were developed. The ability of the new guard, which was tested with different levels of padding, to reduce peak impact forces and absorb energy on impact was measured and compared to a commercially available wrist guard. FINDINGS: The use of any guard reduced peak impact forces by a minimum of 31.8%. The new guard, despite a substantially reduced impact surface area, demonstrated the same reductions in peak force (48%) and ability to absorb energy on impact as the standard guard when fitted with comparable levels of padding. INTERPRETATION: These results indicate that the new guard, which allows movement of the wrist and digits, demonstrates the same ability to reduce impact forces and absorb energy as a commercially available guard despite its substantially reduced impact area. Such a guard may provide a better compromise between joint flexibility and protection than the status quo.

Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer.

BACKGROUND: Defects in BRCA1, BRCA2, and other members of the homologous recombination pathway have potential therapeutic relevance when used to support agents that introduce or exploit double-stranded DNA breaks. This study examines the association between homologous recombination defects and genomic patterns of loss of heterozygosity (LOH). METHODS: Ovarian tumours from two independent data sets were characterised for defects in BRCA1, BRCA2, and RAD51C, and LOH profiles were generated. Publically available data were downloaded for a third independent data set. The same analyses were performed on 57 cancer cell lines. RESULTS: Loss of heterozygosity regions of intermediate size were observed more frequently in tumours with defective BRCA1 or BRCA2 (P=10(-11)). The homologous recombination deficiency (HRD) score was defined as the number of these regions observed in a tumour sample. The association between HRD score and BRCA deficiency was validated in two independent ovarian cancer data sets (P=10(-5) and 10(-29)), and identified breast and pancreatic cell lines with BRCA defects. CONCLUSION: The HRD score appears capable of detecting homologous recombination defects regardless of aetiology or mechanism. This score could facilitate the use of PARP inhibitors and platinum in breast, ovarian, and other cancers.

Arbuscular mycorrhizal fungi increase organic carbon decomposition under elevated CO2.

The extent to which terrestrial ecosystems can sequester carbon to mitigate climate change is a matter of debate. The stimulation of arbuscular mycorrhizal fungi (AMF) by elevated atmospheric carbon dioxide (CO(2)) has been assumed to be a major mechanism facilitating soil carbon sequestration by increasing carbon inputs to soil and by protecting organic carbon from decomposition via aggregation. We present evidence from four independent microcosm and field experiments demonstrating that CO(2) enhancement of AMF results in considerable soil carbon losses. Our findings challenge the assumption that AMF protect against degradation of organic carbon in soil and raise questions about the current prediction of terrestrial ecosystem carbon balance under future climate-change scenarios.

Dissecting Arabidopsis Gß signal transduction on the protein surface.

The heterotrimeric G-protein complex provides signal amplification and target specificity. The Arabidopsis (Arabidopsis thaliana) Gß-subunit of this complex (AGB1) interacts with and modulates the activity of target cytoplasmic proteins. This specificity resides in the structure of the interface between AGB1 and its targets. Important surface residues of AGB1, which were deduced from a comparative evolutionary approach, were mutated to dissect AGB1-dependent physiological functions. Analysis of the capacity of these mutants to complement well-established phenotypes of Gß-null mutants revealed AGB1 residues critical for specific AGB1-mediated biological processes, including growth architecture, pathogen resistance, stomata-mediated leaf-air gas exchange, and possibly photosynthesis. These findings provide promising new avenues to direct the finely tuned engineering of crop yield and traits.