Development of resistance to FGFR inhibition in urothelial carcinoma via multiple pathways in vitro.

Alterations of fibroblast growth factor receptors (FGFRs) are common in bladder and other cancers and result in disrupted signalling via several pathways. Therapeutics that target FGFRs have now entered the clinic, but, in common with many cancer therapies, resistance develops in most cases. To model this, we derived resistant sublines of two FGFR-driven bladder cancer cell lines by long-term culture with the FGFR inhibitor PD173074 and explored mechanisms using expression profiling and whole-exome sequencing. We identified several resistance-associated molecular profiles. These included HRAS mutation in one case and reversible mechanisms resembling a drug-tolerant persister phenotype in others. Upregulated IGF1R expression in one resistant derivative was associated with sensitivity to linsitinib and a profile with upregulation of a YAP/TAZ signature to sensitivity to the YAP inhibitor CA3 in another. However, upregulation of other potential therapeutic targets was not indicative of sensitivity. Overall, the heterogeneity in resistance mechanisms and commonality of the persister state present a considerable challenge for personalised therapy. Nevertheless, the reversibility of resistance may indicate a benefit from treatment interruptions or retreatment following disease relapse in some patients. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Substance use, socio-demographic characteristics, and self-rated health of people seeking alcohol and other drug treatment in New South Wales: baseline findings from a cohort study.

OBJECTIVE: To investigate the demographic characteristics, substance use, and self-rated health of people entering treatment in New South Wales public health services for alcohol, amphetamine-type stimulants, cannabis, cocaine, or opioids use, by principal drug of concern. DESIGN: Baseline findings of a cohort study; analysis of data in patient electronic medical records and NSW minimum data set for drug and alcohol treatment services. SETTING, PARTICIPANTS: People completing initial Australian Treatment Outcomes Profile (ATOP) assessments on entry to publicly funded alcohol and other drug treatment services in six NSW local health districts/networks, 1 July 2016 - 30 June 2019. MAIN OUTCOME MEASURES: Socio-demographic characteristics, and substance use and self-rated health (psychological, physical, quality of life) during preceding 28 days, by principal drug of concern. RESULTS: Of 14 087 people included in our analysis, the principal drug of concern was alcohol for 6051 people (43%), opioids for 3158 (22%), amphetamine-type stimulants for 2534 (18%), cannabis for 2098 (15%), and cocaine for 246 (2%). Most people commencing treatment were male (9373, 66.5%), aged 20-39 years (7846, 50.4%), and were born in Australia (10 934, 86.7%). Polysubstance use was frequently reported, particularly by people for whom opioids or amphetamine-type stimulants were the principal drugs of concern. Large proportions used tobacco daily (53-82%, by principal drug of concern group) and reported poor psychological health (47-59%), poor physical health (32-44%), or poor quality of life (43-52%). CONCLUSIONS: The prevalence of social disadvantage and poor health is high among people seeking assistance with alcohol, amphetamine-type stimulants, cannabis, cocaine, or opioids use problems. Given the differences in these characteristics by principal drug of concern, health services should collect comprehensive patient information during assessment to facilitate more holistic, tailored, and person-centred care.

Body image as a predictor of nonsuicidal self-injury in women: A longitudinal study.

OBJECTIVES: To determine whether Body Image Dissatisfaction (BID) predicted NonSuicidal Self-Injury (NSSI) cross-sectionally and longitudinally, independent of comorbidity between NSSI and Disordered Eating (DE). Another aim was to determine whether BID could predict number of NSSI methods present. METHOD: Adult females completed measures of NSSI and DE (n = 283); and a longitudinal sample (n = 106) completed these measures again one year later. RESULTS: BID was a small yet significant predictor of NSSI both cross-sectionally and longitudinally. Poorer BID significantly explained a greater number of NSSI methods cross-sectionally and longitudinally. CONCLUSIONS: BID explains unique variance in NSSI (including increased number of methods), and is not a function of comorbidity with DE. This has the potential to influence theory, as well as inform early intervention initiatives for BID in females. Further research is required to determine other variables implicated in this relationship, as well as whether these findings are applicable to other groups such as adolescents and males.

Dissecting Art: Developing Object-Based Teaching Using Historical Collections.

This book chapter draws on the arts and humanities to discuss how object-based teaching using historical collections can be re-birthed, re-developed, and implemented in higher education settings for the exploration of challenging topics, including medical ethics, within the context of anatomical sciences. Although the authors have focused on the above discipline, the chapter showcases its versatility and adaptability to other areas including vocational degrees such as medicine, dentistry, and nursing. A model lesson plan has been discussed in detail based on 'objects' related to three separate but strongly linked themes: Women as Academics, Women as Artists, and Women as Portrayed as the Subjects of Dissection in Anatomical Art. This is a novel approach that discusses how the combination of existing collections of rare books, rich  in anatomical illustrations, and museum artefacts can be used in a meaningful and structured way to encourage conversations amongst learners while promoting awareness about sensitive topics and increasing confidence in communication. The authors have drawn from personal past experience and the current literature to discuss the above aims and critically explore logistical issues that may be associated with the identification of suitable 'objects'. The authors' ultimate goal is to introduce a concise and easy to adapt 'how to guide' for educationalists who have an interest in the integration of arts and humanities in vocational and science curricula.

Study protocol for a comparative effectiveness trial of two models of perinatal integrated psychosocial assessment: the PIPA project.

BACKGROUND: Studies examining psychosocial and depression assessment programs in maternity settings have not adequately considered the context in which psychosocial assessment occurs or how broader components of integrated care, including clinician decision-making aids, may optimise program delivery and its cost-effectiveness. There is also limited evidence relating to the diagnostic accuracy of symptom-based screening measures used in this context. The Perinatal Integrated Psychosocial Assessment (PIPA) Project was developed to address these knowledge gaps. The primary aims of the PIPA Project are to examine the clinical- and cost-effectiveness of two alternative models of integrated psychosocial care during pregnancy: 'care as usual' (the SAFE START model) and an alternative model (the PIPA model). The acceptability and perceived benefit of each model of care from the perspective of both pregnant women and their healthcare providers will also be assessed. Our secondary aim is to examine the psychometric properties of a number of symptom-based screening tools for depression and anxiety when used in pregnancy. METHODS: This is a comparative-effectiveness study comparing 'care as usual' to an alternative model sequentially over two 12-month periods. Data will be collected from women at Time 1 (initial antenatal psychosocial assessment), Time 2 (2-weeks after Time 1) and from clinicians at Time 3 for each condition. Primary aims will be evaluated using a between-groups design, and the secondary aim using a within group design. DISCUSSION: The PIPA Project will provide evidence relating to the clinical- and cost- effectiveness of psychosocial assessment integrated with electronic clinician decision making prompts, and referral options that are tailored to the woman's psychosocial risk, in the maternity care setting. It will also address research recommendations from the Australian (2011) and NICE (2015) Clinical Practice Guidelines. TRIAL REGISTRATION: ACTRN12617000932369.

Licensed human natural killer cells aid dendritic cell maturation via TNFSF14/LIGHT.

Interactions between natural killer (NK) cells and dendritic cells (DCs) aid DC maturation and promote T-cell responses. Here, we have analyzed the response of human NK cells to tumor cells, and we identify a pathway by which NK-DC interactions occur. Gene expression profiling of tumor-responsive NK cells identified the very rapid induction of TNF superfamily member 14 [TNFSF14; also known as homologous to lymphotoxins, exhibits inducible expression, and competes with HSV glycoprotein D for HVEM, a receptor expressed by T lymphocytes (LIGHT)], a cytokine implicated in the enhancement of antitumor responses. TNFSF14 protein expression was induced by three primary mechanisms of NK cell activation, namely, via the engagement of CD16, by the synergistic activity of multiple target cell-sensing NK-cell activation receptors, and by the cytokines IL-2 and IL-15. For antitumor responses, TNFSF14 was preferentially produced by the licensed NK-cell population, defined by the expression of inhibitory receptors specific for self-MHC class I molecules. In contrast, IL-2 and IL-15 treatment induced TNFSF14 production by both licensed and unlicensed NK cells, reflecting the ability of proinflammatory conditions to override the licensing mechanism. Importantly, both tumor- and cytokine-activated NK cells induced DC maturation in a TNFSF14-dependent manner. The coupling of TNFSF14 production to tumor-sensing NK-cell activation receptors links the tumor immune surveillance function of NK cells to DC maturation and adaptive immunity. Furthermore, regulation by NK cell licensing helps to safeguard against TNFSF14 production in response to healthy tissues.

The need for a culturally-tailored gatekeeper training intervention program in preventing suicide among Indigenous peoples: a systematic review.

BACKGROUND: Suicide is a leading cause of death among Indigenous youth worldwide. The aim of this literature review was to determine the cultural appropriateness and identify evidence for the effectiveness of current gatekeeper suicide prevention training programs within the international Indigenous community. METHOD: Using a systematic strategy, relevant databases and targeted resources were searched using the following terms: 'suicide', 'gatekeeper', 'training', 'suicide prevention training', 'suicide intervention training' and 'Indigenous'. Other internationally relevant descriptors for the keyword "Indigenous" (e.g. "Maori", "First Nations", "Native American", "Inuit", "Metis" and "Aboriginal") were also used. RESULTS: Six articles, comprising five studies, met criteria for inclusion; two Australian, two from USA and one Canadian. While pre and post follow up studies reported positive outcomes, this was not confirmed in the single randomised controlled trial identified. However, the randomised controlled trial may have been underpowered and contained participants who were at higher risk of suicide pre-training. CONCLUSION: Uncontrolled evidence suggests that gatekeeper training may be a promising suicide intervention in Indigenous communities but needs to be culturally tailored to the target population. Further RCT evidence is required.

A systematic review: Identifying the prevalence rates of psychiatric disorder in Australia's Indigenous populations.

OBJECTIVE: This review aimed to draw on published literature to identify the prevalence rates of psychiatric disorders in Australia's Indigenous populations, Aboriginal and Torres Strait Islander peoples. METHOD: A systematic review following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) model was conducted using the following electronic databases: PubMed, Scopus, Web of Science, MEDLINE, PsycINFO, PsycARTICLES, and Informit Indigenous and Health Collections. Studies were included for analysis if they were empirical quantitative studies reporting prevalence rates for any psychiatric disorder in Indigenous people. RESULTS: Of the 1584 papers extracted by the search strategy, 17 articles met the eligibility criteria and were reviewed in detail. Methodology, sampling strategy and study design varied greatly across these 17 studies. Prevalence rates varied by disorder and are as follows: major depressive disorder (4.3-51%); mood disorders (7.7-43.1%); post-traumatic stress disorder (14.2-55.2%); anxiety disorders (17.2-58.6%); substance dependence (5.9%-66.2%); alcohol dependence (21.4-55.4%); and psychotic disorders (1.68-25%). While the number of studies on community-based Indigenous populations was limited, available evidence suggested that prevalence rates are higher in prison populations compared with community-based studies. CONCLUSIONS: It was identified that there is limited evidence on the occurrence of psychiatric disorders for Indigenous people in the general community. More research in this area is essential to provide accurate and reliable estimates and to provide a baseline for evaluating the effectiveness of programs aimed at reducing the high mental health burden experienced by Indigenous Australians. Future research needs to ensure that standardised and validated methods are used to accurately estimate the prevalence of psychiatric disorders among Indigenous Australians.

Sociodemographic and Health Factors of the Alcohol Treatment-seeking Population in New South Wales, Australia.

OBJECTIVES: Although factors associated with alcohol use have been researched at a population level, descriptions of the alcohol and other drug (AOD) treatment-seeking population in New South Wales (NSW), Australia, are limited. This study addresses this gap by analyzing sociodemographic and health characteristics in the NSW AOD treatment-seeking population. METHODS: Self-reported Australian Treatment Outcomes Profile data on substance use, health ratings, and sociodemographic factors were acquired from public AOD services (offering services from counseling to ambulatory/inpatient withdrawal management) in 6 administrative health districts from 2016 to 2019 (n = 14,287). Gaussian and multiple logistic regressions were conducted to examine associations between these factors and alcohol consumption quantity. RESULTS: Data were analyzed for patients seeking treatment for alcohol consumption specifically (n = 5929; median age, 44 years; 65% male). Valid alcohol consumption data were available for 5460 patients, among whom the mean volume of alcohol consumed was 311 standard drinks (3110 grams of ethanol) over the past 28 days and 15 standard drinks (150 grams of ethanol) per occasion. Higher volumes were consumed by males and those with recent experiences of violence and/or injecting drug use. Caring for children younger than 5 years and having above-median health ratings were associated with lower alcohol consumption. CONCLUSIONS: This study contributes to the characterization of the NSW public AOD treatment population and identifies associations between alcohol consumption, sociodemographic factors, and health ratings among people seeking treatment for alcohol consumption. Findings point towards multilevel assessment and comprehensive interventions for people engaging in treatment for alcohol use. Future research should address barriers to treatment.

Predicting impulsive self-injurious behavior in a sample of adult women.

Different types of self-injury have been classified as reflecting impulsive and compulsive characteristics (article by Simeon and Favazza [Self-injurious Behaviors: Assessment and Treatment {pp 1-28}. Washington, DC: American Psychiatric Publishing, Inc, 2001]). The current research used a prospective design to evaluate whether there is a progression between these different types of self-injurious behaviors (SIB) over time. Support was found for a progression from compulsive SIB (including hair pulling, nail-biting, skin picking, scratching, and preventing wounds from healing) to impulsive SIB (including cutting, burning, carving, pin sticking, and punching) in a group of adult women (N = 106). Other factors hypothesized to be linked to this outcome were disordered eating, age, and personality facets of impulsivity (specifically, urgency and lack of perseverance). Of these variables, only urgency positively predicted impulsive SIB at the study's conclusion. These findings are discussed, limitations of the study are noted, and directions for future research are outlined.

Mind Your Heart-II: Protocol for a behavioral randomized controlled trial of mindfulness training to promote self-care in patients with comorbid heart failure and cognitive impairment.

BACKGROUND: Heart failure (HF) self-care is a robust predictor of prognosis in HF patients. Cognitive impairment is a common comorbidity in HF patients and constitutes a major challenge to HF self-care. Mindfulness training (MT) has been shown to improve cognitive function and interoception, two components essential to promoting effective HF self-care. OBJECTIVES: The aims of the Mind Your Heart-II (MYH-II) study are to investigate the effects of MT on HF self-care via changes in cognitive function and interoception in patients with comorbid HF and cognitive impairment, and to study the process by which MT can improve cognitive function via vagal control. We hypothesize that MT will improve cognitive function, interoception, and vagal control, resulting in enhanced HF self-care, compared to control participants. METHODS: MYH-II is a mechanistic parallel phase II behavioral randomized controlled trial. We will enroll 176 English or Spanish-speaking patients with comorbid chronic HF and mild cognitive impairment. Participants will be randomized to either: (1) 8-week phone-delivered MT + Enhanced Usual Care (EUC), or (2) EUC alone. Participants will complete baseline, end-of-treatment (3 months), and follow-up (9 months) assessments. The primary outcome is cognitive function (NIH Toolbox Fluid Cognition Composite Score). Additional key outcomes include: interoception (heartbeat tracking task, Multidimensional Assessment of Interoceptive Awareness), HF self-care (Self-Care of Heart Failure Index v7.2), and vagal control (high-frequency heart rate variability). IMPLICATIONS: If study hypotheses are confirmed, phone-based MT may be a key tool for improving HF self-care, and possibly clinical outcomes, in HF patients with comorbid cognitive impairment.

Health and social characteristics of clients reporting amphetamine type substance use at entry to public alcohol and other drug services in New South Wales, Australia, 2016-2019.

INTRODUCTION: Amphetamine type substances (ATS) are commonly used by Australian alcohol and other drug service entrants. We describe demographic characteristics, patterns of ATS and other substance use, health and social conditions among clients entering New South Wales (NSW) public alcohol and other drug services. METHODS: Retrospective cohort of 13,864 records across six health districts (2016-2019) for clients seeking substance use treatment. These districts service approximately 44% of the NSW population aged 15 years and over. Multivariate analysis was conducted on a subsample for whom full data were available (N = 9981). Data included NSW Minimum Data Set for drug and alcohol treatment services and Australian Treatment Outcomes Profile items. RESULTS: Over the preceding 4 weeks, 77% (n = 10,610) of clients (N = 13,864) reported no recent ATS use, 15% (n = 2109) reported 'low frequency' (1-12 days) and 8% (n = 1145) 'high frequency' (13-28 days) use. ATS use was most common among people attending for ATS or opioids as primary drug of concern. A multinomial regression (N = 9981) identified that clients reporting recent arrest (aOR 1.74, 95% CI 1.36, 2.24), higher cannabis use frequency (aOR 1.01, 95% CI 1.00, 1.02), lower opioid use frequency (aOR 0.98, 95% CI 0.97, 0.99) and poorer quality of life (aOR 0.91, 95% CI 0.86, 0.97) were more likely to report 'high frequency' rather than 'low frequency' ATS use. DISCUSSION AND CONCLUSIONS: People who use ATS experience health and social issues that may require targeted responses. These should be integrated across all services, not only for clients with ATS as principal drug of concern.

Corruption of DNA end-joining in mammalian chromosomes by progerin expression.

Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare genetic condition characterized by features of accelerated aging and a life expectancy of about 14 years. HGPS is commonly caused by a point mutation in the LMNA gene which codes for lamin A, an essential component of the nuclear lamina. The HGPS mutation alters splicing of the LMNA transcript, leading to a truncated, farnesylated form of lamin A termed "progerin." Progerin is also produced in small amounts in healthy individuals by alternative splicing of RNA and has been implicated in normal aging. HGPS is associated with an accumulation of genomic DNA double-strand breaks (DSBs), suggesting alteration of DNA repair. DSB repair normally occurs by either homologous recombination (HR), an accurate, templated form of repair, or by nonhomologous end-joining (NHEJ), a non-templated rejoining of DNA ends that can be error-prone; however a good portion of NHEJ events occurs precisely with no alteration to joined sequences. Previously, we reported that over-expression of progerin correlated with increased NHEJ relative to HR. We now report on progerin's impact on the nature of DNA end-joining. We used a model system involving a DNA end-joining reporter substrate integrated into the genome of cultured thymidine kinase-deficient mouse fibroblasts. Some cells were engineered to express progerin. Two closely spaced DSBs were induced in the integrated substrate through expression of endonuclease I-SceI, and DSB repair events were recovered through selection for thymidine kinase function. DNA sequencing revealed that progerin expression correlated with a significant shift away from precise end-joining between the two I-SceI sites and toward imprecise end-joining. Additional experiments revealed that progerin did not reduce HR fidelity. Our work suggests that progerin suppresses interactions between complementary sequences at DNA termini, thereby shifting DSB repair toward low-fidelity DNA end-joining and perhaps contributing to accelerated and normal aging through compromised genome stability.

The clinical performance and cost-effectiveness of two psychosocial assessment models in maternity care: The Perinatal Integrated Psychosocial Assessment study.

PROBLEM: Although perinatal universal depression and psychosocial assessment is recommended in Australia, its clinical performance and cost-effectiveness remain uncertain. AIM: To compare the performance and cost-effectiveness of two models of psychosocial assessment: Usual-Care and Perinatal Integrated Psychosocial Assessment (PIPA). METHODS: Women attending their first antenatal visit were prospectively recruited to this cohort study. Endorsement of significant depressive symptoms or psychosocial risk generated an 'at-risk' flag identifying those needing referral to the Triage Committee. Based on its detailed algorithm, a higher threshold of risk was required to trigger the 'at-risk' flag for PIPA than for Usual-Care. Each model's performance was evaluated using the midwife's agreement with the 'at-risk' flag as the reference standard. Cost-effectiveness was limited to the identification of True Positive and False Positive cases. Staffing costs associated with administering each screening model were quantified using a bottom-up time-in-motion approach. FINDINGS: Both models performed well at identifying 'at-risk' women (sensitivity: Usual-Care 0.82 versus PIPA 0.78). However, the PIPA model was more effective at eliminating False Positives and correctly identifying 'at-risk' women (Positive Predictive Value: PIPA 0.69 versus Usual Care 0.41). PIPA was associated with small incremental savings for both True Positives detected and False Positives averted. DISCUSSION: Overall PIPA performed better than Usual-Care as a psychosocial screening model and was a cost-saving and relatively effective approach for detecting True Positives and averting False Positives. These initial findings warrant evaluation of longer-term costs and outcomes of women identified by the models as 'at-risk' and 'not at-risk' of perinatal psychosocial morbidity.

Disclosure of sensitive material at routine antenatal psychosocial assessment: The role of psychosocial risk and mode of assessment.

PROBLEM: While routine psychosocial assessment is acceptable to most pregnant women, some women will not fully disclose psychosocial concerns to their clinician. AIMS: To assess the impact of psychosocial risk, current symptoms and mode of assessment on women's honesty of disclosure at psychosocial assessment. METHODS: Logistic regression was used to examine associations between disclosure and a range of psychosocial characteristics in women who were 'always honest' and 'not always honest'. Mixed ANOVAs were used to test the influence of mode of assessment and honesty on scores on a repeated measure of psychosocial risk. FINDINGS: 10.8% (N=193 of 1788) of women did not fully disclose at psychosocial assessment. Non-disclosure was associated with a mental health history (aOR=1.78, 95%CI: 1.18-2.67, p<0.01) and lack of social and partner support (aOR=1.74, 95%CI: 1.16-2.62, p<0.05; aOR=2.08, 95%CI: 1.11-3.90, p<0.05, respectively). Those reporting not always being honest at face to face assessment showed a greater increase in psychosocial risk score when the assessment was repeated online via self-report, compared to women who were always honest. DISCUSSION: A history of mental health issues and lack of social and partner support are associated with reduced disclosure at face to face assessment. Online self-report assessment may promote greater disclosure, however this should always be conducted in the context of clinician feedback. CONCLUSION: Greater psychosocial vulnerability is associated with a lower likelihood of full disclosure. Preliminary findings relating to mode of assessment warrant further exploration within a clinical context.

Supporting routine psychosocial assessment in the perinatal period: The concurrent and predictive validity of the Antenatal Risk Questionnaire-Revised.

BACKGROUND: Australian clinical practice guidelines support comprehensive psychosocial assessment as a routine component of maternity care. AIM: To examine the concurrent and predictive validity of the Antenatal Risk Questionnaire-Revised (ANRQ-R) when used across the perinatal period. METHODS: Women completed the ANRQ-R and a diagnostic reference standard (SAGE-SR) in the second and third trimesters and at 3-months postpartum. ANRQ-R test performance for cut-off scores at each time-point was assessed using Receiver Operator Characteristic (ROC) analysis. FINDINGS: Overall sample sizes were N=1166 (second trimester), N=957 (third trimester) and N=796 (3-month postpartum). 6.5%, 5.6% and 6.2% of women met SAGE-SR criteria for any depressive or anxiety disorder at these time-points ('cases'), respectively. ROC analysis yielded acceptable areas under the curve (AUC) when the ANRQ-R was used to detect current (AUC=0.789-0.798) or predict future (AUC=0.705-0.789) depression or anxiety. Using an example cut-off score of 18 or more, the ANRQ-R correctly classified 72-76% of concurrent 'cases' and 'non-cases' (sensitivity=0.70-0.74, specificity=0.72-0.76) and correctly predicted 74-78% of postnatal 'cases' and 'non-cases' (sensitivity=0.52-0.72, specificity=0.75-0.79). Completion of the ANRQ-R earlier in pregnancy yielded greater positive likelihood ratios for predicting depression or anxiety at 3-months postpartum (cut-off ≥18: second trimester=3.8; third trimester=2.2). CONCLUSION: The ANRQ-R is a structured psychosocial assessment questionnaire that can be scored to provide an overall measure of psychosocial risk. Cut-off scores need not be uniform across settings. Such decisions should be guided by factors including diagnostic prevalence rates, local needs and resource availability.

Molecular profile of pure squamous cell carcinoma of the bladder identifies major roles for OSMR and YAP signalling.

Pure squamous cell carcinoma (SCC) is the most common pure variant form of bladder cancer, found in 2-5% of cases. It often presents late and is unresponsive to cisplatin-based chemotherapy. The molecular features of these tumours have not been elucidated in detail. We carried out whole-exome sequencing (WES), copy number, and transcriptome analysis of bladder SCC. Muscle-invasive bladder cancer (MIBC) samples with no evidence of squamous differentiation (non-SD) were used for comparison. To assess commonality of features with urothelial carcinoma with SD, we examined data from SD samples in The Cancer Genome Atlas (TCGA) study of MIBC. TP53 was the most commonly mutated gene in SCC (64%) followed by FAT1 (45%). Copy number analysis revealed complex changes in SCC, many differing from those in samples with SD. Gain of 5p and 7p was the most common feature, and focal regions on 5p included OSMR and RICTOR. In addition to 9p deletions, we found some samples with focal gain of 9p24 containing CD274 (PD-L1). Loss of 4q35 containing FAT1 was found in many samples such that all but one sample analysed by WES had FAT1 mutation or deletion. Expression features included upregulation of oncostatin M receptor (OSMR), metalloproteinases, metallothioneins, keratinisation genes, extracellular matrix components, inflammatory response genes, stem cell markers, and immune response modulators. Exploration of differentially expressed transcription factors identified BNC1 and TFAP2A, a gene repressed by PPARG, as the most upregulated factors. Known urothelial differentiation factors were downregulated along with 72 Kruppel-associated (KRAB) domain-containing zinc finger family protein (KZFP) genes. Novel therapies are urgently needed for these tumours. In addition to upregulated expression of EGFR, which has been suggested as a therapeutic target in basal/squamous bladder cancer, we identified expression signatures that indicate upregulated OSMR and YAP/TAZ signalling. Preclinical evaluation of the effects of inhibition of these pathways alone or in combination is merited.

Geographic and maternal characteristics associated with alcohol use in pregnancy.

BACKGROUND: To date, no studies have used population-level data to investigate whether maternal location of residence (metropolitan vs. regional/remote populations) is associated with alcohol use in pregnancy. This information has important implications for appropriate service provision. METHODS: Information on all live births in New South Wales, Australia, was linked to records of alcohol-related admissions for mothers of these births over a 6-year period (2000 to 2006). Cases were women who had at least 1 alcohol-related hospital admission during pregnancy or at birth. Controls were women who had at least 1 live birth over that same time period but no alcohol-related hospital admissions during that time. Admissions were considered to be alcohol-related based on the International Statistical Classification of Diseases and Related Health Problems, 10th Revision, Australian Modification (ICD-10-AM) code. Demographic, obstetric, and neonatal variables were compared. RESULTS: A total of 417,464 singleton birth records were analyzed, 488 of which were coded positive for at least 1 alcohol-related ICD-10-AM diagnosis. Characteristics associated with alcohol-related admissions in pregnancy were residence in a remote/very remote area, being Australian-born, having had a previous pregnancy, smoking in the current pregnancy, and presenting late to antenatal care. Alcohol-exposed pregnancies were associated with a range of poor obstetric and neonatal outcomes, with no geographic differences noted. However, women in regional/remote areas were less likely to attend specialist obstetric hospitals. CONCLUSIONS: This study shows the need for standardized screening programs for alcohol use in pregnancy and where problematic use is detected, for clear clinical guidelines on management and referral.

Prevalence and predictors of alcohol use in pregnancy and breastfeeding among Australian women.

BACKGROUND: Previous research suggests that alcohol use during pregnancy and breastfeeding has a negative impact on birth and neonatal outcomes. No threshold for this effect has been determined. The aim of this study is to determine the prevalence and correlates of alcohol use in pregnancy and lactation in a large representative sample of Australian women. METHOD: Data were used from a large representative sample of Australian women drawn from the 2007 National Drug Strategy Household Survey. A complex sampling framework was used to elicit prevalence estimates for alcohol use during pregnancy and lactation. A logistic regression analysis was used to determine the psychosocial characteristics associated with alcohol use during the perinatal period. RESULTS: Alcohol use was reported by 29 percent of women who were pregnant in the past 12 months. In addition, 43 percent of women who were breastfeeding in the past 12 months reported alcohol use, whereas 36 percent of women who were both pregnant and breastfeeding in the past 12 months reported alcohol use. Most women (95%) reported a reduction in the quantity of their alcohol use while pregnant or breastfeeding. Older age was significantly associated with alcohol use in pregnancy, and also with alcohol use while breastfeeding (after controlling for other psychosocial characteristics). Higher educational attainment, and breastfeeding for more weeks in the past 12 months were significantly associated with alcohol use while breastfeeding, after controlling for confounding psychosocial factors. CONCLUSIONS: More research is needed to ease uncertainty about "safe" levels of alcohol use during pregnancy and while breastfeeding. A high proportion of the sample reported alcohol use during pregnancy or lactation, despite uniform international government guidelines recommending that no alcohol should be consumed during the prenatal and postnatal periods. These results indicate that public health education campaigns about the risks of alcohol during these periods are needed.

The antenatal risk questionnaire-revised: Development, use and test-retest reliability in a community sample of pregnant women in Australia.

BACKGROUND: Routine psychosocial assessment during pregnancy and the first postnatal year is a public health strategy that prioritises early identification of known risk factors for poor perinatal mental health. We aimed to report on the development and use of the Antenatal Risk Questionnaire-Revised (ANRQ-R), contribute normative data for a community sample of pregnant women and examine its test-retest reliability. METHODS: The ANRQ-R was developed in consultation with an expert advisory group. Women completed the ANRQ-R with their midwife at their first antenatal appointment. Test-retest analysis was restricted to women who consented to follow-up and completed a repeat ANRQ-R within four weeks. RESULTS: 7183 women completed the ANRQ-R (total score M = 12.05, Mdn=10; range =5-49). There were some statistically significant differences in total score across maternal age group (χ2=69.75, p<.001), country of birth (χ2=144.01, p<.001) and socioeconomic quintiles (χ2=20.13, p<.001), however the effect sizes of all differences were either small or not clinically significant. Test-retest reliability for the ANRQ-R total score was good (N = 1670; ICC=0.77). Item-level test-retest reliabilities were moderate to good (ICC range=0.65-0.80; kappa coefficient range=0.31-0.74). LIMITATIONS: The study was conducted at a single site. Although there was significant diversity in terms of maternal age and country of birth, the majority of participants were partnered and resided in socio-economically advantaged areas, limiting the generalisability of results. CONCLUSIONS: This study contributes significant normative data for the ANRQ-R and offers valuable insights for clinicians and researchers working with particular sub-groups of the perinatal population. Additional psychometric examination of the ANRQ-R, including its concurrent and predictive validity, is required.