Recognising the importance of chronic lung disease: a consensus statement from the Global Alliance for Chronic Diseases (Lung Diseases group).

BACKGROUND: Chronic respiratory diseases are disorders of the airways and other structures of the lung, and include chronic obstructive pulmonary disease (COPD), lung cancer, asthma, bronchiectasis, interstitial lung diseases, occupational lung diseases and pulmonary hypertension. Through this article we take a broad view of chronic lung disease while highlighting (1) the complex interactions of lung diseases with environmental factors (e.g. climate change, smoking and vaping) and multimorbidity and (2) proposed areas to strengthen for better global patient outcomes. CONCLUSION: We suggest new directions for the research agenda in high-priority populations and those experiencing health disparities. We call for lung disease to be made a research priority with greater funding allocation globally.

SISTAQUIT: training health care providers to help pregnant Aboriginal and Torres Strait Islander women quit smoking. A cluster randomised controlled trial.

BACKGROUND: About 44% of Indigenous Australian women smoke during pregnancy, compared with 12% of pregnant non-Indigenous women. Health care providers can assist smoking cessation, but they are not typically trained in culturally appropriate methods. OBJECTIVES: To determine whether a health care worker training intervention increases smoking cessation rates among Indigenous pregnant smokers compared with usual care. METHODS AND ANALYSIS: Supporting Indigenous Smokers to Assist Quitting (SISTAQUIT) study is a multicentre, hybrid type 1, pragmatic, cluster randomised controlled trial that compares the effects of an intervention for improving smoking cessation by pregnant Indigenous women (16 years or older, 32 weeks' gestation or less) with usual care. Twenty-one health services caring for Indigenous people in five Australian jurisdictions were randomised to the intervention (ten sites) or control groups (eleven sites). Health care providers at intervention sites received smoking cessation care training based on the ABCD (ask/assess; brief advice; cessation; discuss psychosocial context) approach to smoking cessation for Indigenous women, an educational resource package, free oral nicotine replacement therapy for participating women, implementation support, and trial implementation training. Health care providers in control group services provided usual care. PRIMARY OUTCOME: abstinence from smoking (self-reported abstinence via survey, validated by carbon monoxide breath testing when possible) four weeks after enrolment in the study. SECONDARY OUTCOMES: health service process evaluations; knowledge, attitudes, and practices of health care providers; and longer term abstinence, perinatal outcomes, and respiratory outcomes for babies (to six months). Ethics approval: The human research ethics committees of the University of Newcastle (H-2015-0438) and the Aboriginal Health and Medical Research Council of NSW (1140/15) provided the primary ethics approval. Dissemination of results: Findings will be disseminated in peer-reviewed publications, at local and overseas conferences, and via public and social media, and to participating health services in art-based formats and reports. Policy briefs will be communicated to relevant government organisations. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry, ACTRN12618000972224 (prospective).

Pregnancy and birth characteristics of Aboriginal twins in two Australian states: a data linkage study.

INTRODUCTION: Perinatal outcomes for singleton pregnancies are poorer, on average, for Aboriginal people than non-Aboriginal people, but little is known about Aboriginal multifetal pregnancies. Yet multifetal pregnancies and births are often more complicated and have poorer outcomes than singleton pregnancies. We describe the pregnancies, births and perinatal outcomes for Aboriginal twins born in Western Australia (WA) and New South Wales (NSW) with comparisons to Aboriginal singletons in both states and to non-Aboriginal births in NSW. MATERIALS AND METHODS: Whole-population birth records and birth and death registrations were linked for all births during 2000-2013 (WA) and 2002-2008 (NSW). Hospital records and the WA Register of Developmental Anomalies - Cerebral Palsy were linked for all WA births and hospital records for a subset of NSW births. Descriptive statistics are reported for maternal and child demographics, maternal health, pregnancy complications, births and perinatal outcomes. RESULTS: Thirty-four thousand one hundred twenty-seven WA Aboriginal, 32,352 NSW Aboriginal and 601,233 NSW non-Aboriginal births were included. Pregnancy complications were more common among mothers of Aboriginal twins than Aboriginal singletons (e.g. 17% of mothers of WA twins had hypertension/pre-eclampsia/eclampsia vs 8% of mothers of singletons) but similar to mothers of NSW non-Aboriginal twins. Most Aboriginal twins were born in a principal referral, women's or large public hospital. The hospitals were often far from the mother's home (e.g. 31% of mothers of WA Aboriginal twins gave birth at hospitals located more than 3 h by road from their home). Outcomes were worse for Aboriginal liveborn twins than Aboriginal singletons and non-Aboriginal twins (e.g. 58% of NSW Aboriginal twins were preterm compared to 9% of Aboriginal singletons and 49% non-Aboriginal twins). CONCLUSIONS: Mothers of Aboriginal twins faced significant challenges during the pregnancy, birth and the postnatal period in hospital and, in addition to accessible specialist medical care, these mothers may need extra practical and psychosocial support throughout their journey.

Antenatal care for Aboriginal and Torres Strait Islander women.

BACKGROUND: About 6% of Australian births are to an Aboriginal or Torres Strait Islander parent and there is a clear disparity in birth outcomes between Aboriginal and Torres Strait Islander and non-Indigenous Australians. Some issues affecting birth outcomes are similar nationally whilst others will be more particular to certain areas. OBJECTIVE: This paper will highlight important areas that may facilitate improved care for Aboriginal and Torres Strait Islander women. DISCUSSION: A key component of improving pregnancy outcomes is early and ongoing engagement in antenatal care, which is facilitated by the provision of culturally appropriate and evidence based care relevant to the local community. The majority of Aboriginal and Torres Strait Islander peoples live in urban or inner regional areas and receive healthcare through mainstream services and it is important therefore for all practitioners to be aware of how to optimise care to Aboriginal and Torres Strait Islander women.

Chlamydia and gonorrhoea infections and the risk of adverse obstetric outcomes: a retrospective cohort study.

OBJECTIVES: To examine the association between prior chlamydia and gonorrhoea infections and adverse obstetric outcomes. METHODS: Records of women resident in New South Wales, Australia with a singleton first birth during 1999-2008 were linked to chlamydia and gonorrhoea notifications using probabilistic linkage. Obstetric outcomes and potential confounders were ascertained from the birth record. Logistic regression, adjusted for potential confounders was used to estimate the association between a disease notification prior to the birth and adverse birth outcomes: spontaneous preterm birth (SPTB), small for gestational age (SGA) and stillbirth. RESULTS: Among 354 217 women, 1.0% (n=3658) had a prior chlamydia notification; 0.06% (n=196) had a prior gonorrhoea notification. The majority of notifications (>80%) occurred before the estimated conception date. 4.1% of women had a SPTB, 12.1% had a SGA baby and 0.6% of women had a stillbirth. Among women with a prior chlamydia notification, the risk of SPTB and stillbirth was increased, aOR 1.17 (95% CI 1.01 to 1.37) and aOR 1.40 (95% CI 1.00 to 1.96) respectively but there was no association with SGA, aOR 0.99 (95% CI 0.89 to 1.09). For women with gonorrhoea the risks for SPTB, stillbirth and SGA were respectively aOR 2.50 (95%CI 1.39 to 4.50), 2.35 (95% CI 0.58 to 9.56) and 0.98 (95% CI 0.58 to 1.68). Among women with a prior chlamydia diagnosis, the risk of SPTB did not differ between women diagnosed >1 year prior to conception, within the year prior to conception or during the pregnancy, (p=0.9). CONCLUSIONS: Sexually transmissible infections in pregnancy and the preconception period may be important in predicting pregnancy outcomes.

A silent burden-prolapse, incontinence, and infertility in Australian Aboriginal and Torres Strait Islander women: A systematic search and narrative review.

BACKGROUND: Pelvic organ prolapse (POP), urinary incontinence, and infertility are all prevalent conditions associated with considerable reduction in quality of life. As a group, Aboriginal and Torres Strait Islander women may be at higher risk of these conditions, but studies are scarce. OBJECTIVE: To review the literature pertaining to the epidemiology, diagnosis, and management of these conditions in Indigenous Australian women. SEARCH STRATEGY: Medline, Embase, and Scopus were searched for articles published between 1980 and 2021 pertaining to these conditions in Indigenous Australian women. SELECTION CRITERIA: Studies that did not directly address the epidemiology, diagnosis, and management of these conditions were excluded. MAIN RESULTS: It was possible to identify only 11 papers dealing with these conditions in Indigenous Australian women. Only one dealt with POP and was a retrospective audit of a health outreach program in the Northern Territory concluding that there was significant underreporting of the condition. Five papers dealt with urinary incontinence and, again, described significant underreporting and poor referral pathways. Five papers reported small studies about infertility, one reporting poor engagement from clinical directors. CONCLUSION: It was concluded that despite the importance of these conditions, there is almost no body of research and this is an urgent national problem.

Aboriginal and Torres Strait Islander women's health: acting now for a healthy future.

This paper summarises the recent RANZCOG Indigenous Women's Health Meeting with recommendations on how the College and its membership can act now to improve the health of Aboriginal and Torres Strait Islander women and infants.

Synergistic activity of troxacitabine (Troxatyl) and gemcitabine in pancreatic cancer.

BACKGROUND: Gemcitabine, a deoxycytidine nucleoside analog, is the current standard chemotherapy used as first-line treatment for patients with locally advanced or metastatic cancer of the pancreas, and extends life survival by 5.7 months. Advanced pancreatic cancer thus remains a highly unmet medical need and new therapeutic agents are required for this patient population. Troxacitabine (Troxatyl) is the first unnatural L-nucleoside analog to show potent preclinical antitumor activity and is currently under clinical investigation. Troxacitabine was recently evaluated as a first-line therapy in 54 patients with advanced adenocarcinoma of the pancreas and gave comparable overall results to those reported with gemcitabine in recently published randomized trials. METHODS: The human pancreatic adenocarcinoma cell lines, AsPC-1, Capan-2, MIA PaCa-2 and Panc-1, were exposed to troxacitabine or gemcitabine alone or in combination, for 72 h, and the effects on cell growth were determined by electronic particle counting. Synergistic efficacy was determined by the isobologram and combination-index methods of Chou and Talalay. Mechanistic studies addressed incorporation of troxacitabine into DNA and intracellular levels of troxacitabine and gemcitabine metabolites. For in vivo studies, we evaluated the effect of both drugs, alone and in combination, on the growth of established human pancreatic (AsPC-1) tumors implanted subcutaneously in nude mice. Statistical analysis was calculated by a one-way ANOVA with Dunnett as a post-test and the two-tailed unpaired t test using GraphPad prism software. RESULTS: Synergy, evaluated using the CalcuSyn Software, was observed in all four cell-lines at multiple drug concentrations resulting in combination indices under 0.7 at Fa of 0.5 (50% reduction of cell growth). The effects of drug exposures on troxacitabine and gemcitabine nucleotide pools were analyzed, and although gemcitabine reduced phosphorylation of troxacitabine when cells were exposed at equal drug concentrations, there was no effect on phosphorylated pools at drug combinations that were synergistic. The amount of troxacitabine incorporated into DNA was also not affected by the presence of gemcitabine. In vivo testing against a human pancreatic (AsPC-1) xenograft mouse tumor model indicated that both drugs were more than additive at well-tolerated doses and schedule. The biological basis for this synergy is unclear as we did not observe changes in apoptosis, DNA repair, troxacitabine incorporation into DNA or troxacitabine metabolism in the presence of gemcitabine. CONCLUSION: These data, together with phase I clinical data showing tolerability of both agents when combined, suggest combination therapy with troxacitabine and gemcitabine warrants further evaluation in advanced pancreatic cancer patients.

Designing an implementation intervention with the Behaviour Change Wheel for health provider smoking cessation care for Australian Indigenous pregnant women.

BACKGROUND: Indigenous smoking rates are up to 80% among pregnant women: prevalence among pregnant Australian Indigenous women was 45% in 2014, contributing significantly to the health gap for Indigenous Australians. We aimed to develop an implementation intervention to improve smoking cessation care (SCC) for pregnant Indigenous smokers, an outcome to be achieved by training health providers at Aboriginal Medical Services (AMS) in a culturally competent approach, developed collaboratively with AMS. METHOD: The Behaviour Change Wheel (BCW), incorporating the COM-B model (capability, opportunity and motivation for behavioural interventions), provided a framework for the development of the Indigenous Counselling and Nicotine (ICAN) QUIT in Pregnancy implementation intervention at provider and patient levels. We identified evidence-practice gaps through (i) systematic literature reviews, (ii) a national survey of clinicians and (iii) a qualitative study of smoking and quitting with Aboriginal mothers. We followed the three stages recommended in Michie et al.'s "Behaviour Change Wheel" guide. RESULTS: Targets identified for health provider behaviour change included the following: capability (psychological capability, knowledge and skills) by training clinicians in pharmacotherapy to assist women to quit; motivation (optimism) by presenting evidence of effectiveness, and positive testimonials from patients and clinicians; and opportunity (environmental context and resources) by promoting a whole-of-service approach and structuring consultations using a flipchart and prompts. Education and training were selected as the main intervention functions. For health providers, the delivery mode was webinar, to accommodate time and location constraints, bringing the training to the services; for patients, face-to-face consultations were supported by a booklet embedded with videos to improve patients' capability, opportunity and motivation. CONCLUSIONS: The ICAN QUIT in Pregnancy was an intervention to train health providers at Aboriginal Medical Services in how to implement culturally competent evidence-based practice including counselling and nicotine replacement therapy for pregnant patients who smoke. The BCW aided in scientifically and systematically informing this targeted implementation intervention based on the identified gaps in SCC by health providers. Multiple factors impact at systemic, provider, community and individual levels. This process was therefore important for defining the design and intervention components, prior to a conducting a pilot feasibility trial, then leading on to a full clinical trial.

Do Clinicians Ask Pregnant Women about Exposures to Tobacco and Cannabis Smoking, Second-Hand-Smoke and E-Cigarettes? An Australian National Cross-Sectional Survey.

Clinicians often ask pregnant women about tobacco smoking, but their practices of asking about other smoking and nicotine exposures are unknown. This study analysed how often clinicians ask pregnant women about their use of e-cigarettes, cannabis, chewing tobacco, and second-hand smoke (SHS) exposure. Two cross-sectional surveys were undertaken. A random sample of 500 General Practitioner (GP) members were invited from the National Faculty of Aboriginal and Torres Strait Islander Health (NFATSIH) to complete an on-line survey, and 5571 GP and Obstetrician (OBS) members of the Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG) were sent a paper survey by mail. Questions on frequency of asking about the exposures used Likert Scales, later dichotomized to "often-always" and "never-sometimes". Logistic regressions estimated associations between clinician type and asking about cannabis, e-cigarettes, chewing tobacco, and SHS. An adjusted model reduced potential confounders of location, guidelines, gender and population. n = 378 GPs and OBS participated (6.2% response). In total, 13-14% asked "often-always" about e-cigarettes; 58% cannabis; 38% cannabis with tobacco; 27% SHS, and 10% chewing tobacco-compared to 95% of the sample asking about cigarette smoking. After adjustment, the odds of RANZCOG GPs (OR 0.34) and OBS (OR 0.63) asking about cannabis were lower compared to NFATSIH GPs. Clinician type was non-significant for asking about e-cigarettes, chewing tobacco and SHS. Surveyed Australian GPs and obstetricians asked less frequently about e-cigarettes, chewing, SHS exposure, and cannabis, potentially missing important exposures for mother and child.

Chronological narratives from smoking initiation through to pregnancy of Indigenous Australian women: A qualitative study.

OBJECTIVE: One in two Indigenous Australian pregnant women smoke, yet little is known about their trajectory of smoking. This study aimed to explore Aboriginal women's narratives from starting smoking through to pregnancy. METHODS: A female Aboriginal Researcher conducted individual face-to-face interviews with 20 Aboriginal women from New South Wales, Australia. Recruitment, through Aboriginal services and community networks, continued until saturation was reached. Audio-recorded transcripts were independently open coded by two researchers, inductively analysed and reported using a three-dimensional structure of looking backwards, forwards, inwards, outwards and a sense of place, to elucidate the chronology of events, life stages, characters, environments, and turning points of the stories. RESULTS: A chronology emerged from smoking initiation in childhood, coming of age, becoming pregnant, through to attempts at quitting, and relapse post-partum. Several new themes emerged: the role mothers play in women's smoking and quitting; the contribution of nausea to spontaneous quitting; depression as a barrier to quitting; and the hopes of women for their own and their children's future. The epiphany of pregnancy was a key turning point for many - including the interplay of successive pregnancies; and the intensity of expressed regret. CONCLUSIONS: Aboriginal women report multiple influences in the progression of early smoking to pregnancy and beyond. Potential opportunities to intervene include: a) childhood, coming of age, pregnancy, post-natal, in-between births; b) key influencers; c) environments, and d) targeting concurrent substance use. Morning sickness appears to be a natural deterrent to continued smoking. Depression, and its relationship to smoking and quitting in Australian Indigenous pregnant women, requires further research.

Immunohistochemical variation of human equilibrative nucleoside transporter 1 protein in primary breast cancers.

Gemcitabine and capecitabine are nucleoside analogues used in chemotherapy strategies for the treatment of breast cancer. We previously demonstrated that deficiency in hENT1, the most abundant and widely distributed plasma membrane nucleoside transporter in human cells, confers high-level resistance to gemcitabine toxicity in vitro, whereas the relationship between hENT1 activity and capecitabine toxicity is unknown. To determine the relationship between capecitabine cytotoxicity and hENT1 abundance, cultured MDA-MB-435s human mammary carcinoma cells were exposed to graded concentrations of the capecitabine metabolites, 5'-deoxy-5-fluorouridine or 5-fluorouracil, in the presence and absence of nitrobenzylmercaptopurine ribonucleoside (NBMPR), a tight-binding inhibitor of hENT1. The presence of NBMPR reduced the cytotoxic effects of 5'-deoxy-5-fluorouridine, indicating that hENT1 also enabled cellular uptake of this capecitabine metabolite by breast cancer cells. We report here the development of an immunohistochemical method to assess the hENT1 abundance of malignant cells in solid tumors. Frozen sections of 33 primary breast cancers were stained with monoclonal antibodies raised against a synthetic peptide derived from the large intracellular loop of hENT1, and staining intensity was scored on a 0-4+ scale. hENT1 staining intensity varied markedly among breast samples (4 with score 0, 5 with score 1+, 7 with score 2+, 14 with score 3+, 3 with score 4+), suggesting that at least 9 of the tumors were hENT1 deficient. We conclude that because hENT1 deficiency has previously been associated with nucleoside drug resistance, immunohistochemical staining of hENT1 warrants further study as a predictive tool for guiding the appropriate use of gemcitabine and capecitabine in the treatment of breast cancer.

Differential expression of human equilibrative nucleoside transporter 1 (hENT1) protein in the Reed-Sternberg cells of Hodgkin's disease.

Gemcitabine is a cytotoxic nucleoside analog with activity in relapsing/refractory Hodgkin's disease (HD). Because gemcitabine is hydrophilic, it requires plasma membrane nucleoside transporter proteins to access intracellular targets. The most abundant and widely distributed transporter in human cells is human equilibrative nucleoside transporter 1 (hENT1). Because our prior studies showed that a deficiency in hENT1 confers high-level resistance to gemcitabine toxicity in vitro, we developed an immunohistochemical method to assess the hENT1 abundance of cells in tumor tissue. We now report the application of this method for visualizing the hENT1 protein abundance in the plasma membranes of Reed-Sternberg cells in lymph nodes of HD patients. Frozen sections of 30 lymph nodes were stained with monoclonal antibodies (mAb 10D7G2) raised against a synthetic peptide comprised of residues 254-271 from the large intracellular loop of hENT1 and staining intensity was scored on a 0-4 + scale. hENT1-staining intensity varied among HD lymph node samples (score/n; 0/8; 1/10; 2/9; 3/3; 4/0) and suggested that at least 60% of the tumors appeared hENT1 deficient. Because Epstein-Barr virus (EBV) is often associated with HD, staining for Epstein-Barr early RNA was also examined. Although 9/30 patients tested positive for EBV, there was no correlation with hENT1 staining. hENT1-staining intensities were positively correlated with age of the patient but were independent of other clinical, laboratory or pathology features (tumor stage, histologic subtype, presence of B symptoms, staining for CD15 or CD30, serum biochemistry, disease free survival, and overall survival). We conclude that, because hENT1 deficiency has been previously related to nucleoside-drug resistance, immunohistochemical staining for hENT1 warrants evaluation as a predictive tool for guiding the appropriate use of gemcitabine in the treatment of HD.

Resistance to gemcitabine in a human follicular lymphoma cell line is due to partial deletion of the deoxycytidine kinase gene.

BACKGROUND: Gemcitabine is an analogue of deoxycytidine with activity against several solid tumors. In order to elucidate the mechanisms by which tumor cells become resistant to gemcitabine, we developed the resistant subline RL-G from the human follicular lymphoma cell line RL-7 by prolonged exposure of parental cells to increasing concentrations of gemcitabine. RESULTS: In vitro, the IC50 increased from 0.015 microM in parental RL-7 cells to 25 microM in the resistant variant, RL-G. Xenografts of both cell lines developed in nude mice were treated with repeated injections of gemcitabine. Under conditions of gemcitabine treatment which totally inhibited the development of RL-7 tumors, RL-G derived tumors grew similarly to those of untreated animals, demonstrating the in vivo resistance of RL-G cells to gemcitabine. HPLC experiments showed that RL-G cells accumulated and incorporated less gemcitabine metabolites into DNA and RNA than RL-7 cells. Gemcitabine induced an S-phase arrest in RL-7 cells but not in RL-G cells. Exposure to gemcitabine induced a higher degree of apoptosis in RL-7 than in RL-G cells, with poly-(ADP-ribose) polymerase cleavage in RL-7 cells. No modifications of Bcl-2 nor of Bax expression were observed in RL-7 or RL-G cells exposed to gemcitabine. These alterations were associated with the absence of the deoxycytidine kinase mRNA expression observed by quantitative RT-PCR in RL-G cells. PCR amplification of désoxycytidine kinase gene exons showed a partial deletion of the dCK gene in RL-G cells. CONCLUSIONS: These results suggest that partial deletion of the dCK gene observed after selection in the presence of gemcitabine is involved with resistance to this agent both in vitro and in vivo.