Publications by authors named "Sarah Maguire"

52 Publications

Identification of high risk and early stage eating disorders: first validation of a digital screening tool.

J Eat Disord 2021 Sep 6;9(1):109. Epub 2021 Sep 6.

InsideOut Institute for Eating Disorders, Faculty of Medicine and Health, Level 2, The Charles Perkins Centre, D17, The University of Sydney, Johns Hopkins Drive, Camperdown, NSW, 2006, Australia.

Background: Eating disorders are amongst the deadliest of all mental disorders, however detection and early intervention rates remain extremely low. Current standardised screening questionnaires can be arduous or confronting and are ill-validated for online use, despite a universal shift to digital healthcare. The present study describes the development and pilot validation of a novel digital screening tool (the InsideOut Institute-Screener) for high risk and early stage eating disorders to drive early intervention and reduced morbidity.

Methods: We utilised a mixed cross-sectional and repeated measures longitudinal survey research design to assess symptom severity and recognised parameters of statistical validity. Participants were recruited through social media and traditional advertising, and through MTurk. An Eating Disorders Examination Questionnaire (EDE-Q) global score of 2.3 and assessment of eating disorder behaviours was used to determine probable ED. 1346 participants aged 14-74 (mean [SE] age 26.60 [11.14] years; 73.8% female, 22.6% male) completed the survey battery. 19% were randomised to two-week follow-up for reliability analysis.

Results: Strong positive correlations between the IOI-S and both the EDE-Q global (r = .88) and SCOFF (r = .75) total score were found, providing support for the concurrent validity of the scale. Inter-item correlations were moderate to strong (r = .46-.73). Correlations between the IOI-S and two measures of social desirability diverged, providing support for the discriminant validity of the scale. The IOI-S demonstrated high internal consistency (α = .908, ω = .910) and excellent two-week test-retest reliability (.968, 95% CI 0.959-0.975; p ≤ 0.1). The IOI-S accurately distinguished probable eating disorders (sensitivity = 82.8%, specificity = 89.7% [AUC = .944], LR  = 8.04, LR = 0.19) and two stepped levels of risk.

Conclusions And Relevance: The present study provides excellent initial support for the psychometric validity of the InsideOut Institute digital screening tool, which has the potential to streamline early intervention in the hopes of reducing current high morbidity and mortality. Further validation should be undertaken in known clinical populations. Eating disorders are amongst the deadliest of all mental disorders, however detection and early intervention rates remain extremely low. The present study describes the initial psychometric validation of a novel digital screening tool (the InsideOut Institute Screener) for high risk and early stage eating disorders, for self-referral and/or use in primary care. 1346 participants aged 14-74 of all genders completed a survey battery designed to assess common parameters of statistical validity. Strong support was found for the screener's ability to accurately measure eating disorder risk and symptomatology. The screener was highly positively correlated with a well known and extensively validated long form self-report questionnaire for eating disorder symptomatology. This study is a pilot validation and the genesis of a project that aims ultimately to drive early intervention leading to reduced morbidity and mortality rates in this illness group.
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http://dx.doi.org/10.1186/s40337-021-00464-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419810PMC
September 2021

Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element.

Am J Hum Genet 2021 07 18;108(7):1190-1203. Epub 2021 Jun 18.

Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.

A combination of genetic and functional approaches has identified three independent breast cancer risk loci at 2q35. A recent fine-scale mapping analysis to refine these associations resulted in 1 (signal 1), 5 (signal 2), and 42 (signal 3) credible causal variants at these loci. We used publicly available in silico DNase I and ChIP-seq data with in vitro reporter gene and CRISPR assays to annotate signals 2 and 3. We identified putative regulatory elements that enhanced cell-type-specific transcription from the IGFBP5 promoter at both signals (30- to 40-fold increased expression by the putative regulatory element at signal 2, 2- to 3-fold by the putative regulatory element at signal 3). We further identified one of the five credible causal variants at signal 2, a 1.4 kb deletion (esv3594306), as the likely causal variant; the deletion allele of this variant was associated with an average additional increase in IGFBP5 expression of 1.3-fold (MCF-7) and 2.2-fold (T-47D). We propose a model in which the deletion allele of esv3594306 juxtaposes two transcription factor binding regions (annotated by estrogen receptor alpha ChIP-seq peaks) to generate a single extended regulatory element. This regulatory element increases cell-type-specific expression of the tumor suppressor gene IGFBP5 and, thereby, reduces risk of estrogen receptor-positive breast cancer (odds ratio = 0.77, 95% CI 0.74-0.81, p = 3.1 × 10).
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http://dx.doi.org/10.1016/j.ajhg.2021.05.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8322933PMC
July 2021

Olfaction in Anopheles mosquitoes.

Chem Senses 2021 01;46

The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, 855 North Wolfe Street, 434 Rangos Building, Baltimore, 21205 MD, USA.

As vectors of disease, mosquitoes are a global threat to human health. The Anopheles mosquito is the deadliest mosquito species as the insect vector of the malaria-causing parasite, which kills hundreds of thousands every year. These mosquitoes are reliant on their sense of smell (olfaction) to guide most of their behaviors, and a better understanding of Anopheles olfaction identifies opportunities for reducing the spread of malaria. This review takes a detailed look at Anopheles olfaction. We explore a range of topics from chemosensory receptors, olfactory neurons, and sensory appendages to behaviors guided by olfaction (including host-seeking, foraging, oviposition, and mating), to vector management strategies that target mosquito olfaction. We identify many research areas that remain to be addressed.
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http://dx.doi.org/10.1093/chemse/bjab021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256107PMC
January 2021

Prevalence and management of people with eating disorders presenting to primary care: A national study.

Aust N Z J Psychiatry 2021 Mar 15:4867421998752. Epub 2021 Mar 15.

Child Population and Translational Health Research, Children's Hospital at Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, NSW, Australia.

Objective: Primary care practitioners are well placed to support diagnosis and appropriate treatment of eating disorders as they are often the first point of contact with the health care system. However, little is known about management of eating disorders in primary care. We aimed to estimate the prevalence of management of eating disorders in primary care and identify how these disorders are managed.

Methods: This study used data from the Bettering the Evaluation of Care of Health programme, which annually surveys 1000 randomly sampled general practitioners in Australia who each record details of 100 successive patient encounters. In total, data were utilised from 1,568,100 primary care encounters between 2000/2001 and 2015/2016.

Results: Eating disorders were managed in less than 1% of primary care encounters between 2000/2001 and 2015/2016. When extrapolated to the Australian population, up to 0.32% of the population were managed in primary care for a primary or probable eating disorder. In the majority of encounters where an eating disorder was managed (58.5%), the encounter was initiated for reasons other than the eating disorder itself. Of a group of patients identified with a clinically significant low body mass index ( = 5917), a small number ( = 118) had either no other diagnosis or a related condition that may be indicative of an eating disorder. In encounters where an eating disorder was managed, referrals to a mental health specialist/service, medical specialist and nutritionist/dietician were provided in 20%, 8% and 6% of encounters, respectively. Mental health treatment plans, which provide subsidised access to mental health services, were ascribed in approximately 7.7% of encounters where an eating disorder was managed.

Conclusion: Primary care provides an opportunity to improve detection and management of eating disorders, particularly when patients present for 'other' issues or with unexplained low body mass index and one or more symptoms related to an eating disorder.
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http://dx.doi.org/10.1177/0004867421998752DOI Listing
March 2021

Modulating the unfolded protein response with ONC201 to impact on radiation response in prostate cancer cells.

Sci Rep 2021 Feb 19;11(1):4252. Epub 2021 Feb 19.

Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, BT9 7AE, UK.

Prostate cancer (PCa) is the most common non-cutaneous cancer in men and a notable cause of cancer mortality when it metastasises. The unfolded protein response (UPR) can be cytoprotective but when acutely activated can lead to cell death. In this study, we sought to enhance the acute activation of the UPR using radiation and ONC201, an UPR activator. Treating PCa cells with ONC201 quickly increased the expression of all the key regulators of the UPR and reduced the oxidative phosphorylation, with cell death occurring 72 h later. We exploited this time lag to sensitize prostate cancer cells to radiation through short-term treatment with ONC201. To understand how priming occurred, we performed RNA-Seq analysis and found that ONC201 suppressed the expression of cell cycle and DNA repair factors. In conclusion, we have shown that ONC201 can prime enhanced radiation response.
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http://dx.doi.org/10.1038/s41598-021-83215-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896060PMC
February 2021

Treatment of compulsive exercise in eating disorders and muscle dysmorphia: protocol for a systematic review.

J Eat Disord 2021 Feb 10;9(1):19. Epub 2021 Feb 10.

InsideOut Institute for Eating Disorders, The Boden Collaboration for Obesity, Nutrition, Exercise and Eating Disorders, The University of Sydney, Sydney, Australia.

Background: Compulsive exercise is a core feature of both eating disorders and muscle dysmorphia. Earlier models of treatment recommended complete abstinence from exercise in eating disorder populations, but recent guidelines advocate for the gradual inclusion of healthier forms of exercise into an overall treatment plan where appropriate. Given the association between problematic exercise behaviour and poorer prognosis, there has been a recent upsurge in the number of treatment interventions for compulsive exercise in eating disorders. However, no systematic review has been published summarising this existing treatment literature. The aim of this review is to determine the efficacy of existing treatments for compulsive exercise in eating disorders and muscle dysmorphia.

Methods: A systematic review will be conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Five electronic databases (PsycInfo, MEDLINE, Embase, Web of Science, and Scopus) will be searched from database inception until November 2020. We will include studies that: (a) sampled adolescents and/or adults with either an eating disorder or muscle dysmorphia; (b) assessed changes in compulsive exercise from pre- to post-intervention; and (c) used a standardised instrument to measure compulsive exercise or related constructs. We will include studies with a comparison group (e.g., randomised controlled trials) and without a comparison group (e.g., pilot studies and case studies) to provide a comprehensive overview of the literature. One reviewer will screen all titles and abstracts against eligibility criteria, with 20% of excluded articles cross-referenced by another reviewer. Full texts will be obtained for articles deemed relevant or where inclusion was uncertain, and will be screened by both reviewers. We will also evaluate the quality of the included studies using a modified Downs and Black (J Epidemiol Community Health 52:377-384, 1998) assessment checklist.

Discussion: Results from this review will help to determine the most efficacious treatment components for compulsive exercise in eating disorders and muscle dysmorphia. We hope that our results will help inform clinical practice guidelines in recommending targeted interventions for the treatment of compulsive exercise.
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http://dx.doi.org/10.1186/s40337-021-00375-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877054PMC
February 2021

3D Functional Genomics Screens Identify CREBBP as a Targetable Driver in Aggressive Triple-Negative Breast Cancer.

Cancer Res 2021 02 28;81(4):847-859. Epub 2021 Jan 28.

Clinical Trials and Statistics Unit, The Institute of Cancer Research, London, England, United Kingdom.

Triple-negative breast cancers (TNBC) are resistant to standard-of-care chemotherapy and lack known targetable driver gene alterations. Identification of novel drivers could aid the discovery of new treatment strategies for this hard-to-treat patient population, yet studies using high-throughput and accurate models to define the functions of driver genes in TNBC to date have been limited. Here, we employed unbiased functional genomics screening of the 200 most frequently mutated genes in breast cancer, using spheroid cultures to model -like conditions, and identified the histone acetyltransferase CREBBP as a novel tumor suppressor in TNBC. CREBBP protein expression in patient tumor samples was absent in 8% of TNBCs and at a high frequency in other tumors, including squamous lung cancer, where CREBBP-inactivating mutations are common. In TNBC, CREBBP alterations were associated with higher genomic heterogeneity and poorer patient survival and resulted in upregulation and dependency on a FOXM1 proliferative program. Targeting FOXM1-driven proliferation indirectly with clinical CDK4/6 inhibitors (CDK4/6i) selectively impaired growth in spheroids, cell line xenografts, and patient-derived models from multiple tumor types with CREBBP mutations or loss of protein expression. In conclusion, we have identified CREBBP as a novel driver in aggressive TNBC and identified an associated genetic vulnerability in tumor cells with alterations in CREBBP and provide a preclinical rationale for assessing CREBBP alterations as a biomarker of CDK4/6i response in a new patient population. SIGNIFICANCE: This study demonstrates that CREBBP genomic alterations drive aggressive TNBC, lung cancer, and lymphomas and may be selectively treated with clinical CDK4/6 inhibitors.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-1822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611219PMC
February 2021

CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers.

Br J Cancer 2021 02 26;124(4):842-854. Epub 2021 Jan 26.

Molecular Epidemiology Group, C080, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Background: Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk.

Methods: We carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry.

Results: For pregnanediol-3-glucuronide, there were no genome-wide significant associations; for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (-49.2%, 95% CI -56.1% to -41.1%, P = 3.1 × 10); in follow-up analyses, rs45446698-C was also associated with lower progesterone (-26.7%, 95% CI -39.4% to -11.6%, P = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82-0.91, P = 6.9 × 10).

Conclusions: The CYP3A7*1C allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women.
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http://dx.doi.org/10.1038/s41416-020-01185-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884683PMC
February 2021

Nurses' Experiences with Implementation of a Postcesarean Birth Opioid-Sparing Protocol.

MCN Am J Matern Child Nurs 2021 Mar-Apr 01;46(2):110-115

Purpose: Opioid-sparing protocols have significantly reduced opioid use postcesarean birth through maximizing nonpharmacologic and nonopioid pain management tools. This study explored nurses' experiences with an opioid-sparing protocol at a single institution, where inpatient opioid prescribing was reduced by over half.

Method: Focus groups were used to identify key facilitators and barriers to implementation of the opioid-sparing protocol. The Consolidated Framework for Implementation Research (CFIR) guided data collection and analysis. Focus groups were recorded, transcribed, thematically coded, and analyzed for barriers and facilitators using predetermined CFIR domains.

Results: Three focus groups of nurses who care for women during postpartum were conducted in March and April 2019. Fourteen nurses participated. They were all women, with an average of 9.3 years (SD = 5.4) of maternity nursing experience. Facilitators of implementation were: 1) high satisfaction with the intervention's efficacy; 2) awareness of opioid harms promoting readiness for opioid-sparing efforts; 3) adequate staffing and the culture of evidence-based practice; and 4) bedside skills in pain management to identify patients' needs. The most significant barrier was a lack of nurse engagement with protocol development and implementation.

Clinical Implications: An increased partnership among the interprofessional team members through all stages of implementation is necessary for the success and sustainability of best patient care practices.
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http://dx.doi.org/10.1097/NMC.0000000000000694DOI Listing
August 2021

Transitioning to digital first line intervention - validation of a brief online screener for early identification of a suspected eating disorder: study protocol.

J Eat Disord 2020 Nov 12;8(1):60. Epub 2020 Nov 12.

InsideOut Institute for Eating Disorders, The Boden Collaboration for Obesity, Nutrition, Exercise and Eating Disorders, The University of Sydney, Sydney, Australia.

Background: Only one in four people with eating disorders seeks treatment, and of those who do seek treatment, 20% go on to experience a chronic course. Early intervention has been associated with better prognosis, with those seeking specialised intervention in the early stages of their illness more than twice as likely to achieve remission. Current screening measures typically require expert administration and are rarely validated across a spectrum of DSM-5 eating disorder presentations or for online use. In light of COVID-19 and increasing reliance on telehealth technologies in the intervention and delivery of mental health services, online assessments suitable for self-referral are likely to be the first step to seeking care. InsideOut Institute has developed a 6-item online screening tool for the purposes of identifying eating disorder risk and symptomatology, aimed specifically at increasing help-seeking behaviour in subsyndromal and early presentations.

Methods: This study investigates the reliability and validity of the InsideOut Institute Screener (IOI-S), using a cross-sectional survey research design. Participants aged 14 and over will complete an extensive baseline survey battery for evaluation. 50% of participants will be randomly selected for one follow-up re-test of the IOI-S only, 2 weeks post initial testing. The IOI-S will be analysed for statistical reliability on two parameters: internal consistency and test re-test reliability, and for statistical validity on four parameters: concurrent validity, sensitivity and specificity, convergent and discriminant validity.

Discussion: The rapid and ongoing shift to digital intervention has highlighted gaps and opportunities in our pathways to care. Adequate screening for eating disorders is a major gap. This study aims to validate an online screening tool for use in telehealth early intervention, designed for users seeking information for a suspected eating disorder. The screener meets those at risk 'where they are' (i.e. online) and may improve timely referrals to relevant services. This is of particular salience as face-to-face healthcare and traditional frontline interventions are disrupted, and we are challenged to re-design our practices to deliver diagnostic and treatment services in highly adaptive digital contexts.
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http://dx.doi.org/10.1186/s40337-020-00339-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657667PMC
November 2020

Factors related to length of stay, referral on discharge and hospital readmission for children and adolescents with anorexia nervosa.

Int J Eat Disord 2021 03 15;54(3):409-421. Epub 2020 Nov 15.

InsideOut Institute of Eating Disorders, Boden Collaboration for Obesity, Nutrition and Eating Disorders, Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia.

Objective: This study examined factors related to hospital length of stay (LOS), reported referral on discharge, and hospital readmission, for children and adolescents (C&A) admitted to public hospitals for anorexia nervosa (AN), in a large health jurisdiction in Australia.

Method: Sociodemographic, illness, treatment, and hospital factors associated with LOS, reported referral to post-hospital treatment, and readmission within 28 days were analyzed for C&A with AN admitted to all New South Wales public hospitals in 2017, using median, multinomial logit and logit models. The sample comprised 289 admissions by 200 C&A aged 9-18 years with a primary or secondary diagnosis of AN.

Results: AN as a primary diagnosis and the presence of some physical and mental co-occurring conditions (e.g., malnutrition and obsessive-compulsive disorders) conferred a longer LOS. The majority of admissions were recorded being referred to primary care physicians (59.86%) and relatively small numbers to outpatient mental health services (5.54%) or outpatient eating disorder services (8.30%), with age, area socioeconomic status, and illness factors related to referral type. Male, low socioeconomic status, the presence of some co-occurring illnesses (e.g., adjustment disorder and viral infection), and rural or remote locations increased the likelihood of readmission.

Discussion: The findings have implications for service design, in particular the pathway to care from hospital into community for AN. Targeted interventions should consider recognizing and treating physical co-occurring illnesses at presentation to the health system, ensuring appropriate referral to community services, and providing services in socioeconomically disadvantaged and rural or remote areas.
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http://dx.doi.org/10.1002/eat.23399DOI Listing
March 2021

Common Susceptibility Loci for Male Breast Cancer.

J Natl Cancer Inst 2021 04;113(4):453-461

Division of Oncology, Department of Clinical Sciences, Lund, Lund University and Skåne University Hospital, Lund, Sweden.

Background: The etiology of male breast cancer (MBC) is poorly understood. In particular, the extent to which the genetic basis of MBC differs from female breast cancer (FBC) is unknown. A previous genome-wide association study of MBC identified 2 predisposition loci for the disease, both of which were also associated with risk of FBC.

Methods: We performed genome-wide single nucleotide polymorphism genotyping of European ancestry MBC case subjects and controls in 3 stages. Associations between directly genotyped and imputed single nucleotide polymorphisms with MBC were assessed using fixed-effects meta-analysis of 1380 cases and 3620 controls. Replication genotyping of 810 cases and 1026 controls was used to validate variants with P values less than 1 × 10-06. Genetic correlation with FBC was evaluated using linkage disequilibrium score regression, by comprehensively examining the associations of published FBC risk loci with risk of MBC and by assessing associations between a FBC polygenic risk score and MBC. All statistical tests were 2-sided.

Results: The genome-wide association study identified 3 novel MBC susceptibility loci that attained genome-wide statistical significance (P < 5 × 10-08). Genetic correlation analysis revealed a strong shared genetic basis with estrogen receptor-positive FBC. Men in the top quintile of genetic risk had a fourfold increased risk of breast cancer relative to those in the bottom quintile (odds ratio = 3.86, 95% confidence interval = 3.07 to 4.87, P = 2.08 × 10-30).

Conclusions: These findings advance our understanding of the genetic basis of MBC, providing support for an overlapping genetic etiology with FBC and identifying a fourfold high-risk group of susceptible men.
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http://dx.doi.org/10.1093/jnci/djaa101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023850PMC
April 2021

Elucidating knowledge and beliefs about obesity and eating disorders among key stakeholders: paving the way for an integrated approach to health promotion.

BMC Public Health 2019 Dec 16;19(1):1681. Epub 2019 Dec 16.

Western Sydney University, Penrith, New South Wales, Australia.

Background: Understanding the knowledge and beliefs of key stakeholders is crucial in developing effective public health interventions. Knowledge and beliefs about obesity and eating disorders (EDs) have rarely been considered, despite increasing awareness of the need for integrated health promotion programs. We investigated key aspects of knowledge and beliefs about obesity and EDs among key stakeholders in Australia.

Methods: Using a semi-structured question guide, eight focus groups and seven individual interviews were conducted with 62 participants including health professionals, personal trainers, teachers and consumer group representatives. An inductive thematic approach was used for data analysis.

Results: The findings suggest that, relative to obesity, EDs are poorly understood among teachers, personal trainers, and certain health professionals. Areas of commonality and distinction between the two conditions were identified. Integrated health promotion efforts that focus on shared risk (e.g., low self-esteem, body dissatisfaction) and protective (e.g., healthy eating, regular exercise) factors were supported. Suggested target groups for such efforts included young children, adolescents and parents.

Conclusions: The findings indicate areas where the EDs and obesity fields have common ground and can work together in developing integrated health promotion programs.
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http://dx.doi.org/10.1186/s12889-019-7971-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6916014PMC
December 2019

Evaluating the role of digital intervention design in treatment outcomes and adherence to eTherapy programs for eating disorders: A systematic review and meta-analysis.

Int J Eat Disord 2019 10 22;52(10):1077-1094. Epub 2019 Jul 22.

School of Psychology, University of Sydney, Sydney, New South Wales, Australia.

Objective: Despite the existence of reviews which document the effectiveness of online therapies, there is little consensus regarding the exact components of online treatment delivery that are most effective in maintaining user engagement and reducing eating disorder (ED) symptomology. The current review and meta-analysis aimed to determine which components of web-based, ED self-help interventions are associated with lower attrition and improved therapeutic outcome.

Method: A systematic search of electronic databases (PsycINFO, Medline, Web of Science, Scopus) was conducted for published studies of web-based interventions for EDs and a meta-analysis of the final included studies was performed. Each intervention was coded across four dimensions, including the multimedia channels employed (e.g., text, audio, videos), degree of user interactivity (e.g., online self-monitoring, skills exercises), level of automated feedback (e.g., reminders, personalized feedback), and technological device through which the program was accessed (e.g., smartphone, computer).

Results: A final 23 papers were included. The results of meta-regressions indicated that higher scores on the multimedia subscale were associated with greater ED symptom improvement in treatment groups. Conversely, a higher degree of feedback in the treatment group was associated with a group difference in ED psychopathology favoring the control group. Other intervention components were not associated with treatment outcome or dropout.

Discussion: The results are discussed in relation to limitations of the scale used to quantify digital intervention features, as well as the limited diversity and technological sophistication of available ED digital interventions. Such findings indicate the importance of understanding the digital components, which differentiate online therapeutic programs.
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http://dx.doi.org/10.1002/eat.23131DOI Listing
October 2019

Intolerance of uncertainty and eating disorder behaviour: Piloting a consumption task in a non-clinical sample.

J Behav Ther Exp Psychiatry 2019 12 31;65:101492. Epub 2019 May 31.

School of Psychology, UNSW Sydney, Sydney, NSW, Australia.

Background And Objectives: Intolerance of uncertainty (IU) is a transdiagnostic process contributing to the maintenance of anxiety disorders, and is a potential target for treatment. Recent literature has investigated IU as a cognitive process underpinning pathological fear and anxiety in Anorexia Nervosa (AN). The current study was designed to examine trait and state IU, and their relationship to restrictive eating disorder symptoms, anxiety, worry, cognitive rigidity and eating behaviour.

Methods: A sample of undergraduate women (N = 85) completed measures of eating disorder symptoms, IU, cognitive rigidity and worry. Participants were randomised to complete an eating task under one of two conditions: the "certain" condition received a high-calorie meal and nutritional information, while the "uncertain" condition received the meal alone. During the meal, state IU and state anxiety were examined at three time-points (baseline, pre-eating, post-eating).

Results: Trait IU was correlated with cognitive rigidity, worry, global eating disorder symptoms, and, in particular, dietary restraint. No differences emerged between conditions with respect to eating-related anxiety, or amount of food eaten. Controlling for condition and eating disorder symptoms, state IU predicted pre-eating anxiety. Beyond the contribution of condition, BMI and eating disorder symptoms, state IU predicted consumption, specifically greater dietary restriction.

Limitations: The study employed a non-clinical sample.

Conclusions: IU may be implicated in a rigid cognitive style, the anxiety response to energy-dense food, and restrictive eating behaviour. Should these findings be replicated in a clinical sample, then IU might emerge as an adjunctive treatment target for AN.
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http://dx.doi.org/10.1016/j.jbtep.2019.101492DOI Listing
December 2019

Diet Drugs Trick Mosquitoes into Feeling Full.

Trends Pharmacol Sci 2019 07 20;40(7):449-451. Epub 2019 May 20.

The Johns Hopkins University School of Medicine, Solomon H. Snyder Department of Neuroscience, Baltimore, MD 21205, USA. Electronic address:

After a bloodmeal, Aedesaegypti mosquitoes lose interest in bloodfeeding. Duvall et al. (Cell 2019;176:687-701) determined that the neuropeptide Y (NPY)-like receptor 7 (NPYLR7) controls mosquito satiety and also identified six NPYLR7 drug targets that suppress biting. This work highlights an innovative approach in vector control linking insect behavior to drug discovery.
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http://dx.doi.org/10.1016/j.tips.2019.04.016DOI Listing
July 2019

Evaluating the effectiveness of an evidence-based online training program for health professionals in eating disorders.

J Eat Disord 2019 13;7:14. Epub 2019 May 13.

1InsideOut Institute, Charles Perkins Centre, The University of Sydney, Camperdown, Sydney, 2006 NSW Australia.

Background: Early detection and treatment are essential to ensuring the best possible health outcomes for people with eating disorders (EDs). However, low diagnostic accuracy and a lack of specific ED training are common workforce challenges in Australia and internationally. Online learning provides a potential solution in facilitating the access to evidence-based training programs. The InsideOut Institute has developed the first online clinical training program in EDs to assist with educating health professionals in the identification, assessment, and management of EDs. The aim of the study is to evaluate the effectiveness of the online training program, , in mitigating barriers to health professionals treating patients with EDs.

Methods: Pre and post training questionnaires assessed participants' attitudes, knowledge, and skills in relation to treating people with EDs. Demographic and work-related information (gender, discipline, work setting, practice length and remoteness) and participants' ratings of the online learning experience and satisfaction on completion were collected. The Wilcoxon signed rank test was applied to test for changes in learning outcomes before and after completion of the program. A multivariate linear regression model was estimated for each of the learning outcomes with personal and work-related characteristics as covariates.

Results: Among 1813 health professionals who registered for program between 1 October 2013 and 31 July 2018, 1160 completed at least 80% of the five learning modules. There were significant improvements in confidence, knowledge, skills to treat EDs and a reduction in stigmatised beliefs among the 480 participants who completed both pre and post assessments. Results from the regression models suggest that psychologists, dieticians, and those working in rural areas were more willing to treat EDs after completing the program. Additionally, those working in hospitals and regional or rural areas experienced the largest improvement in confidence for treating patients with EDs.

Conclusions: program represents a new and effective way of meeting the educational needs of partaking health professionals working with ED patients. Greater investment in the development and testing of evidence-based online training programs for EDs may help to address some of the considerable workforce development challenges in EDs.
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http://dx.doi.org/10.1186/s40337-019-0243-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6513519PMC
May 2019

Involuntary Treatment and Quality of Life.

Psychiatr Clin North Am 2019 06;42(2):299-307

School of Psychology and Inside Out Institute, University of Sydney, Brain Mind Centre, Room 321, 94 Mallett Street, Camperdown, New South Wales 2050, Australia.

The issues centering on the involuntary treatment of severe and enduring anorexia nervosa are daunting. There is a general consensus that people with this illness are likely to have high levels of disability, be underemployed/unemployed, and receive welfare. Anorexia nervosa shows a similar degree of impairment to those with depression or schizophrenia on quality-of-life measures. It is possible to mount a cogent argument as to why a rehabilitation model of care needs to be considered for those with persistent eating disorders. In such cases, harm minimization and improved quality of life should be prioritized and involuntary treatment used judiciously.
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http://dx.doi.org/10.1016/j.psc.2019.01.011DOI Listing
June 2019

Olfactory Neurons and Brain Centers Directing Oviposition Decisions in Drosophila.

Cell Rep 2018 08;24(6):1667-1678

Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, 855 N. Wolfe Street, Baltimore, MD 21205, USA. Electronic address:

The sense of smell influences many behaviors, yet how odors are represented in the brain remains unclear. A major challenge to studying olfaction is the lack of methods allowing activation of specific types of olfactory neurons in an ethologically relevant setting. To address this, we developed a genetic method in Drosophila called olfactogenetics in which a narrowly tuned odorant receptor, Or56a, is ectopically expressed in different olfactory neuron types. Stimulation with geosmin (the only known Or56a ligand) in an Or56a mutant background leads to specific activation of only target olfactory neuron types. We used this approach to identify olfactory sensory neurons (OSNs) that directly guide oviposition decisions. We identify 5 OSN-types (Or71a, Or47b, Or49a, Or67b, and Or7a) that, when activated alone, suppress oviposition. Projection neurons partnering with these OSNs share a region of innervation in the lateral horn, suggesting that oviposition site selection might be encoded in this brain region.
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http://dx.doi.org/10.1016/j.celrep.2018.07.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6290906PMC
August 2018

Capture Hi-C identifies putative target genes at 33 breast cancer risk loci.

Nat Commun 2018 03 12;9(1):1028. Epub 2018 Mar 12.

Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, SW3 6JB, UK.

Genome-wide association studies (GWAS) have identified approximately 100 breast cancer risk loci. Translating these findings into a greater understanding of the mechanisms that influence disease risk requires identification of the genes or non-coding RNAs that mediate these associations. Here, we use Capture Hi-C (CHi-C) to annotate 63 loci; we identify 110 putative target genes at 33 loci. To assess the support for these target genes in other data sources we test for associations between levels of expression and SNP genotype (eQTLs), disease-specific survival (DSS), and compare them with somatically mutated cancer genes. 22 putative target genes are eQTLs, 32 are associated with DSS and 14 are somatically mutated in breast, or other, cancers. Identifying the target genes at GWAS risk loci will lead to a greater understanding of the mechanisms that influence breast cancer risk and prognosis.
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http://dx.doi.org/10.1038/s41467-018-03411-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5847529PMC
March 2018

Examining a staging model for anorexia nervosa: empirical exploration of a four stage model of severity.

J Eat Disord 2017 27;5:41. Epub 2017 Nov 27.

School of Psychology, University of Sydney, Sydney, Australia.

Background: An illness staging model for anorexia nervosa (AN) has received increasing attention, but assessing the merits of this concept is dependent on empirically examining a model in clinical samples. Building on preliminary findings regarding the reliability and validity of the Clinician Administered Staging Instrument for Anorexia Nervosa (CASIAN), the current study explores operationalising CASIAN severity scores into stages and assesses their relationship with other clinical features.

Method: In women with DSM-IV-R AN and sub-threshold AN (all met AN criteria using DSM 5), receiver operating curve (ROC) analysis ( = 67) assessed the relationship between the sensitivity and specificity of each stage of the CASIAN. Thereafter chi-square and post-hoc adjusted residual analysis provided a preliminary assessment of the validity of the stages comparing the relationship between stage and treatment intensity and AN sub-types, and explored movement between stages after six months (Time 3) in a larger cohort ( = 171).

Results: The CASIAN significantly distinguished between milder stages of illness (Stage 1 and 2) versus more severe stages of illness (Stages 3 and 4), and approached statistical significance in distinguishing each of the four stages from one other. CASIAN Stages were significantly associated with treatment modality and primary diagnosis, and CASIAN Stage at Time 1 was significantly associated with Stage at 6 month follow-up.

Conclusions: Provisional support is provided for a staging model in AN. Larger studies with longer follow-up of cases are now needed to replicate and extend these findings and evaluate the overall utility of staging as well as optimal staging models.
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http://dx.doi.org/10.1186/s40337-017-0155-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5702958PMC
November 2017

Evaluation of CDK12 Protein Expression as a Potential Novel Biomarker for DNA Damage Response-Targeted Therapies in Breast Cancer.

Mol Cancer Ther 2018 01 13;17(1):306-315. Epub 2017 Nov 13.

The Breast Cancer Now Research Centre, The Institute of Cancer Research, London, United Kingdom.

Disruption of Cyclin-Dependent Kinase 12 () is known to lead to defects in DNA repair and sensitivity to platinum salts and PARP1/2 inhibitors. However, has also been proposed as an oncogene in breast cancer. We therefore aimed to assess the frequency and distribution of CDK12 protein expression by IHC in independent cohorts of breast cancer and correlate this with outcome and genomic status. We found that 21% of primary unselected breast cancers were CDK12 high, and 10.5% were absent, by IHC. CDK12 positivity correlated with HER2 positivity but was not an independent predictor of breast cancer-specific survival taking HER2 status into account; however, absent CDK12 protein expression significantly correlated with a triple-negative phenotype. Interestingly, CDK12 protein absence was associated with reduced expression of a number of DDR proteins including ATR, Ku70/Ku80, PARP1, DNA-PK, and γH2AX, suggesting a novel mechanism of CDK12-associated DDR dysregulation in breast cancer. Our data suggest that diagnostic IHC quantification of CDK12 in breast cancer is feasible, with CDK12 absence possibly signifying defective DDR function. This may have important therapeutic implications, particularly for triple-negative breast cancers. .
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http://dx.doi.org/10.1158/1535-7163.MCT-17-0760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6284786PMC
January 2018

Intranasal oxytocin in the treatment of anorexia nervosa: Randomized controlled trial during re-feeding.

Psychoneuroendocrinology 2018 Jan 14;87:83-92. Epub 2017 Oct 14.

School of Psychology, University of Sydney, Sydney, NSW, Australia. Electronic address:

Background: Nutritional rehabilitation in anorexia nervosa (AN) is impeded by fear of food, eating and change leading to treatment resistance. Oxytocin (OT) exerts prosocial effects and modulates trust, fear, anxiety and neuroplasticity. The current placebo-controlled RCT examined the effects of intranasal oxytocin (IN-OT) in AN. The aim was to ascertain whether repeated doses of IN-OT enhance treatment outcomes in AN.

Methods: AN patients self-administered 36 IU IN-OT or placebo daily for 4-6 weeks during hospital treatment. The outcome measures were change in the Eating Disorders Examination (EDE) scale, weight gain, cognitive rigidity, social anxiety, obsessive and autistic symptoms. The effects of the first and last doses of IN-OT were assessed relative to placebo before and after a high-energy afternoon snack, to determine potential dampening of cortisol and anxiety levels by OT.

Results: Weight gain was similar in both groups. The EDE eating concern subscale score was significantly lower after IN-OT treatment as was cognitive rigidity. There were no significant differences in social anxiety or any of the other outcomes at follow-up. After four weeks IN-OT, salivary cortisol levels were significantly lowered in anticipation of an afternoon snack compared to placebo. Morning plasma OT levels did not change after chronic IN-OT or with weight restoration.

Conclusion: IN-OT might enhance nutritional rehabilitation in AN by reducing eating concern and cognitive rigidity. Lower salivary cortisol levels in response to IN-OT suggest diminished neuroendocrine stress responsiveness to food and eating. Such effects require replication with inclusion of more sensitive subjective measures.
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http://dx.doi.org/10.1016/j.psyneuen.2017.10.014DOI Listing
January 2018

Intolerance of Uncertainty in eating disorders: An update on the field.

Clin Psychol Rev 2017 Aug 5;56:94-105. Epub 2017 Jul 5.

School of Psychology, UNSW Australia, Sydney, NSW, Australia.

Pathological fear and anxiety regarding food, eating, weight and body shape are at the core of eating disorder (ED) psychopathology. To manage anxiety, patients develop complicated repertoires of ritualistic and repetitive behaviours, which can lead to total functional impairment. Yet the cognitive processes underlying anxiety, fear, and anxiety-driven behaviours in EDs remain poorly understood. Intolerance of Uncertainty (IU) is defined as a tendency to react negatively on an emotional, cognitive, and behavioural level to uncertain situations and events. There is substantial evidence that IU is a transdiagnostic process that contributes to the maintenance of anxiety disorders; however, IU may also be relevant to the understanding and treatment of EDs. The current review summarises the growing literature examining IU in relation to ED symptoms, including restriction, bingeing, purging, ritualised behaviours, reassurance-seeking and body checking. Extending from the obsessive-compulsive disorder (OCD) and anxiety disorder literature, we propose that IU provides a novel theoretical and clinical framework from which to understand the anxiety, fixation with rules and rituals, and the cognitively rigid profile that is characteristic of ED presentations. We conclude with suggestions for future research, and discuss IU as a potential treatment target for core features of EDs and comorbid symptoms.
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http://dx.doi.org/10.1016/j.cpr.2017.07.002DOI Listing
August 2017

The Role of Regular Eating and Self-Monitoring in the Treatment of Bulimia Nervosa: A Pilot Study of an Online Guided Self-Help CBT Program.

Behav Sci (Basel) 2017 Jun 26;7(3). Epub 2017 Jun 26.

School of Psychology, University of Sydney, Sydney, NSW 2006, Australia.

: Despite cognitive behavioural therapy (CBT) being regarded as the first-line treatment option for bulimia nervosa (BN), barriers such as its time-consuming and expensive nature limit patient access. In order to broaden treatment availability and affordability, the efficacy and convenience of CBT could be improved through the use of online treatments and selective emphasis on its most 'potent' components of which behavioural techniques form the focus. Twenty-six individuals with BN were enrolled in an online CBT-based self-help programme and 17 completed four weeks of regular eating and food-monitoring using the online Food Diary tool. Participants were contacted for a weekly check-in phone call and had their bulimic symptom severity assessed at five time points (baseline and weeks 1-4). : There was a significant decrease in the frequency of self-reported objective binge episodes, associated loss of control and objective binge days reported between pre- and post-treatment measures. Significant improvements were also observed in most subscales of the Eating Disorder Examination-Questionnaire. : This study provides encouraging preliminary evidence of the potential of behavioural techniques of online CBT in the treatment of BN. Online therapy with this focus is potentially a viable and practical form of treatment delivery in this illness group. These preliminary findings support the need for larger studies using control groups.
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http://dx.doi.org/10.3390/bs7030039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5618047PMC
June 2017

Are the Gut Bacteria Telling Us to Eat or Not to Eat? Reviewing the Role of Gut Microbiota in the Etiology, Disease Progression and Treatment of Eating Disorders.

Nutrients 2017 Jun 14;9(6). Epub 2017 Jun 14.

Boden Institute of Obesity, Nutrition, Exercise & Eating Disorders, Charles Perkins Centre, University of Sydney, Sydney, NSW 2006, Australia.

Traditionally recognized as mental illnesses, eating disorders are increasingly appreciated to be biologically-driven. There is a growing body of literature that implicates a role of the gut microbiota in the etiology and progression of these conditions. Gut bacteria may act on the gut-brain axis to alter appetite control and brain function as part of the genesis of eating disorders. As the illnesses progress, extreme feeding patterns and psychological stress potentially feed back to the gut ecosystem that can further compromise physiological, cognitive, and social functioning. Given the established causality between dysbiosis and metabolic diseases, an altered gut microbial profile is likely to play a role in the co-morbidities of eating disorders with altered immune function, short-chain fatty acid production, and the gut barrier being the key mechanistic links. Understanding the role of the gut ecosystem in the pathophysiology of eating disorders will provide critical insights into improving current treatments and developing novel microbiome-based interventions that will benefit patients with eating disorders.
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http://dx.doi.org/10.3390/nu9060602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5490581PMC
June 2017

The Anorexia Nervosa Genetics Initiative: Study description and sample characteristics of the Australian and New Zealand arm.

Aust N Z J Psychiatry 2017 Jun 5;51(6):583-594. Epub 2017 Apr 5.

1 Genetic Epidemiology Laboratory, QIMR Berghofer Institute of Medical Research, Brisbane, QLD, Australia.

Objectives: Anorexia nervosa is a severe psychiatric disorder with high mortality rates. While its aetiology is poorly understood, there is evidence of a significant genetic component. The Anorexia Nervosa Genetics Initiative is an international collaboration which aims to understand the genetic basis of the disorder. This paper describes the recruitment and characteristics of the Australasian Anorexia Nervosa Genetics Initiative sample, the largest sample of individuals with anorexia nervosa ever assembled across Australia and New Zealand.

Methods: Participants completed an online questionnaire based on the Structured Clinical Interview Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV) eating disorders section. Participants who met specified case criteria for lifetime anorexia nervosa were requested to provide a DNA sample for genetic analysis.

Results: Overall, the study recruited 3414 Australians and 543 New Zealanders meeting the lifetime anorexia nervosa case criteria by using a variety of conventional and social media recruitment methods. At the time of questionnaire completion, 28% had a body mass index ⩽ 18.5 kg/m. Fasting and exercise were the most commonly employed methods of weight control, and were associated with the youngest reported ages of onset. At the time of the study, 32% of participants meeting lifetime anorexia nervosa case criteria were under the care of a medical practitioner; those with current body mass index < 18.5 kg/m were more likely to be currently receiving medical care (56%) than those with current body mass index ⩾ 18.5 kg/m (23%). Professional treatment for eating disorders was most likely to have been received from general practitioners (45% of study participants), dietitians (42%) and outpatient programmes (42%).

Conclusions: This study was effective in assembling the largest community sample of people with lifetime anorexia nervosa in Australia and New Zealand to date. The proportion of people with anorexia nervosa currently receiving medical care, and the most common sources of treatment accessed, indicates the importance of training for general practitioners and dietitians in treating anorexia nervosa.
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http://dx.doi.org/10.1177/0004867417700731DOI Listing
June 2017

Three-dimensional modelling identifies novel genetic dependencies associated with breast cancer progression in the isogenic MCF10 model.

J Pathol 2016 11;240(3):315-328

The Breast Cancer Now Toby Robins Research Centre, Division of Breast Cancer, The Institute of Cancer Research, London, UK.

The initiation and progression of breast cancer from the transformation of the normal epithelium to ductal carcinoma in situ (DCIS) and invasive disease is a complex process involving the acquisition of genetic alterations and changes in gene expression, alongside microenvironmental and recognized histological alterations. Here, we sought to comprehensively characterise the genomic and transcriptomic features of the MCF10 isogenic model of breast cancer progression, and to functionally validate potential driver alterations in three-dimensional (3D) spheroids that may provide insights into breast cancer progression, and identify targetable alterations in conditions more similar to those encountered in vivo. We performed whole genome, exome and RNA sequencing of the MCF10 progression series to catalogue the copy number and mutational and transcriptomic landscapes associated with progression. We identified a number of predicted driver mutations (including PIK3CA and TP53) that were acquired during transformation of non-malignant MCF10A cells to their malignant counterparts that are also present in analysed primary breast cancers from The Cancer Genome Atlas (TCGA). Acquisition of genomic alterations identified MYC amplification and previously undescribed RAB3GAP1-HRAS and UBA2-PDCD2L expressed in-frame fusion genes in malignant cells. Comparison of pathway aberrations associated with progression showed that, when cells are grown as 3D spheroids, they show perturbations of cancer-relevant pathways. Functional interrogation of the dependency on predicted driver events identified alterations in HRAS, PIK3CA and TP53 that selectively decreased cell growth and were associated with progression from preinvasive to invasive disease only when cells were grown as spheroids. Our results have identified changes in the genomic repertoire in cell lines representative of the stages of breast cancer progression, and demonstrate that genetic dependencies can be uncovered when cells are grown in conditions more like those in vivo. The MCF10 progression series therefore represents a good model with which to dissect potential biomarkers and to evaluate therapeutic targets involved in the progression of breast cancer. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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http://dx.doi.org/10.1002/path.4778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5082563PMC
November 2016

Teaching multimorbidity management to GP trainees: a pilot workshop.

Educ Prim Care 2015 Nov;26(6):410-5

a Donegal Specialist Training Scheme in General Practice, Education Centre , St. Conal's Hospital , Letterkenny , Ireland.

Multimorbidity, the presence of more than one chronic condition simultaneously, has a significant impact on people who experience it and on the healthcare system. General Practitioners (GPs) are ideally situated to provide the complex care required for someone whose health needs to cross the boundaries of individual specialties. It has been suggested that medical and postgraduate general practice education needs to adapt to address the new challenges of multimorbidity. We present an educational approach to the teaching of multimorbidity management in a postgraduate general practice training setting. We demonstrate that a workshop using simulated multimorbidity cases and facilitated by experienced GPs improves knowledge of and confidence in managing multimorbidity in primary care.
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http://dx.doi.org/10.1080/14739879.2015.1101848DOI Listing
November 2015
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