Practitioners support and intention to adopt universal access to self-collection in Australia's National Cervical Screening Program.

OBJECTIVE: Primary care practitioners are crucial to engaging people in Australia's national cervical screening program. From July 2022, practitioners have been able to offer all screen-eligible people the choice to collect their own self-collected sample; an option introduced to increase equity. This study explored how practitioners are intending to incorporate universal access to self-collection into their clinical care. METHODS: Semi-structed interviews with 27 general practitioners, nurses, and practice managers from 10 practices in Victoria, Australia conducted between May and August 2022. Interviews were deductively coded, informed by the Consolidated Framework for Implementation Research. The Diffusion of Innovations theory was used to categorise intention to provide self-collection. RESULTS: Participants were supportive of universal access to self-collection, citing benefits for screen-eligible people and that it overcame the limited adaptability of the previous policy. Most participants' practices (n = 7, 70%) had implemented or had plans to offer the option for self-collection to all. Participants deliberating whether to provide universal access to self-collection held concerns about the correct performance of the self-test and the perceived loss of opportunity to perform a pelvic examination. Limited time to change practice-level processes and competing demands within consultations were anticipated as implementation barriers. CONCLUSIONS: The extent to which self-collection can promote equity within the program will be limited without wide-spread adoption by practitioners. Communication and education that addresses concerns of practitioners, along with targeted implementation support, will be critical to ensuring that self-collection can increase participation and Australia's progression towards elimination of cervical cancer.

Associations between pathological features and risk of metachronous colorectal cancer.

Survivors of colorectal cancer (CRC) are at risk of developing another primary colorectal cancer - metachronous CRC. Understanding which pathological features of the first tumour are associated with risk of metachronous CRC might help tailor existing surveillance guidelines. Population-based CRC cases were recruited from the United States, Canada and Australia between 1997 and 2012 and followed prospectively until 2022 by the Colon Cancer Family Registry. Metachronous CRC was defined as a new primary CRC diagnosed at least 1 year after the initial CRC. Those with the genetic cancer predisposition Lynch syndrome or MUTYH mutation carriers were excluded. Cox regression models were fitted to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for the associations. Of 6085 CRC cases, 138 (2.3%) were diagnosed with a metachronous CRC over a median follow-up time of 12 years (incidence: 2.0 per 1000 person-years). CRC cases with a synchronous CRC were 3.4-fold more likely to develop a metachronous CRC (adjusted HR: 3.36, 95% CI: 1.89-5.98) than those without a synchronous tumour. CRC cases with MMR-deficient tumours had a 72% increased risk of metachronous CRC (adjusted HR: 1.72, 95% CI: 1.11-2.64) compared to those with MMR-proficient tumours. Compared to cases who had an adenocarcinoma histologic type, those with an undifferentiated histologic type were 77% less likely to develop a metachronous CRC (adjusted HR: 0.23, 95% CI: 0.06-0.94). Existing surveillance guidelines for CRC survivors could be updated to include increased surveillance for those whose first CRC was diagnosed with a synchronous CRC or was MMR-deficient.

Plasma beta-hydroxy-beta-methylbutyrate availability after enteral administration during critical illness after trauma: An exploratory study.

BACKGROUND: During critical illness skeletal muscle wasting occurs rapidly. Although beta-hydroxy-beta-methylbutyrate (HMB) is a potential treatment to attenuate this process, the plasma appearance and muscle concentration is uncertain. METHODS: This was an exploratory study nested within a blinded, parallel group, randomized clinical trial in which critically ill patients after trauma received enteral HMB (3 g daily) or placebo. Plasma samples were collected at 0, 60, and 180 min after study supplement administration on day 1. Needle biopsies of the vastus lateralis muscle were collected (baseline and day 7 of the HMB treatment intervention period). An external standard curve was used to calculate HMB concentrations in plasma and muscle. RESULTS: Data were available for 16 participants (male n = 12 (75%), median [interquartile range] age 50 [29-58] years) who received placebo and 18 participants (male n = 14 (78%), age 49 [34-55] years) who received HMB. Plasma HMB concentrations were similar at baseline but increased after HMB (T = 60 min: placebo 0.60 [0.44-1.31] µM; intervention 51.65 [22.76-64.72] µM). Paired muscle biopsies were collected from 11 participants (placebo n = 7, HMB n = 4). Muscle HMB concentrations were similar at baseline between groups (2.35 [2.17-2.95]; 2.07 [1.78-2.31] µM). For participants in the intervention group who had the repeat biopsy within 4 h of HMB administration, concentrations were greater (7.2 and 12.3 µM) than those who had the repeat biopsy >4 h after HMB (2.7 and 2.1 µM). CONCLUSION: In this exploratory study, enteral HMB administration increased plasma HMB availability. The small sample size limits interpretation of the muscle HMB findings.

Sex-steroid hormones and risk of postmenopausal estrogen receptor-positive breast cancer: a case-cohort analysis.

PURPOSE: Sex-steroid hormones are associated with postmenopausal breast cancer but potential confounding from other biological pathways is rarely considered. We estimated risk ratios for sex-steroid hormone biomarkers in relation to postmenopausal estrogen receptor (ER)-positive breast cancer, while accounting for biomarkers from insulin/insulin-like growth factor-signaling and inflammatory pathways. METHODS: This analysis included 1208 women from a case-cohort study of postmenopausal breast cancer within the Melbourne Collaborative Cohort Study. Weighted Poisson regression with a robust variance estimator was used to estimate risk ratios (RRs) and 95% confidence intervals (CIs) of postmenopausal ER-positive breast cancer, per doubling plasma concentration of progesterone, estrogens, androgens, and sex-hormone binding globulin (SHBG). Analyses included sociodemographic and lifestyle confounders, and other biomarkers identified as potential confounders. RESULTS: Increased risks of postmenopausal ER-positive breast cancer were observed per doubling plasma concentration of progesterone (RR: 1.22, 95% CI 1.03 to 1.44), androstenedione (RR 1.20, 95% CI 0.99 to 1.45), dehydroepiandrosterone (RR: 1.15, 95% CI 1.00 to 1.34), total testosterone (RR: 1.11, 95% CI 0.96 to 1.29), free testosterone (RR: 1.12, 95% CI 0.98 to 1.28), estrone (RR 1.21, 95% CI 0.99 to 1.48), total estradiol (RR 1.19, 95% CI 1.02 to 1.39) and free estradiol (RR 1.22, 95% CI 1.05 to 1.41). A possible decreased risk was observed for SHBG (RR 0.83, 95% CI 0.66 to 1.05). CONCLUSION: Progesterone, estrogens and androgens likely increase postmenopausal ER-positive breast cancer risk, whereas SHBG may decrease risk. These findings strengthen the causal evidence surrounding the sex-hormone-driven nature of postmenopausal breast cancer.

Risk factors for metachronous colorectal cancer and advanced neoplasia following primary colorectal cancer: a systematic review and meta-analysis.

BACKGROUND: Identifying risk factors for metachronous colorectal cancer (CRC) and metachronous advanced neoplasia could be useful for guiding surveillance. We conducted a systematic review and meta-analysis to investigate risk factors for metachronous CRC and advanced neoplasia. METHODS: Searches were conducted in MEDLINE, Embase, Web of Science and Cochrane Central Registry of Controlled Trials for articles (searching period: 1945 to Feburary, 2021) that reported the results of an association between any factor and metachronous advanced neoplasia or metachronous CRC. There were no restrictions on the publication date or language. Random effects models were fitted to estimate the combined association between the risk factors and metachronous CRC or advanced neoplasia. The Risk of Bias In Non-Randomised Studies of Interventions tool (ROBINS-I) was used to assess the risk of bias of included studies. RESULTS: In total, 22 observational studies with 625,208 participants were included in the systematic review and meta-analysis. Of these, 13 studies investigated risk factors for metachronous CRC and 9 for advanced neoplasia. The risks of metachronous CRC or advanced neoplasia were higher if the first CRC was diagnosed in the presence of a synchronous advanced lesion (pooled risk ratio (RR) from 3 studies: 3.61, 95% confidence interval (CI): 1.44-9.05; and pooled RR from 8 studies: 2.77, 95% CI: 2.23-3.43, respectively). The risk of metachronous CRC was lower, but the risk of metachronous advanced neoplasia was higher if the first CRC was distal (compared with proximal) (pooled RR from 3 studies: 0.48, 95% CI: 0.23-0.98; and pooled RR from 2 studies: 2.99, 95% CI: 1.60-5.58 respectively). The risk of metachronous advanced neoplasia increased with age (pooled RR from 3 studies: 1.07 per year of age, 95% CI: 1.03-1.11). There was no evidence that any lifestyle risk factors studied were associated with the risk of metachronous CRC or advanced neoplasia. CONCLUSIONS: The identified risk factors for metachronous CRC and advanced neoplasia might be useful to tailor the existing surveillance guidelines after the first CRC. There were potential limitations due to possible misclassification of the outcome, confounding and risk of bias, and the findings cannot be generalised to high-risk genetic syndrome cases.

Sex-steroid hormones and risk of postmenopausal estrogen receptor-positive breast cancer: a case-cohort analysis.

Purpose: Sex-steroid hormones are associated with postmenopausal breast cancer but potential confounding from other biological pathways is rarely considered. We estimated risk ratios for sex-steroid hormone biomarkers in relation to postmenopausal estrogen receptor (ER)-positive breast cancer, while accounting for biomarkers from insulin/insulin-like growth factor-signaling and inflammatory pathways. Methods: This analysis included 1,208 women from a case-cohort study of postmenopausal breast cancer within the Melbourne Collaborative Cohort Study. Weighted Poisson regression with a robust variance estimator was used to estimate risk ratios (RRs) and 95% confidence intervals (CIs) of postmenopausal ER-positive breast cancer, per doubling plasma concentration of progesterone, estrogens, androgens, and sex hormone binding globulin (SHBG). Analyses included sociodemographic and lifestyle confounders, and other biomarkers identified as potential confounders. Results: Increased risks of postmenopausal ER-positive breast cancer were observed per doubling plasma concentration of progesterone (RR: 1.22, 95% CI: 1.03 to 1.44), androstenedione (RR: 1.20, 95% CI: 0.99 to 1.45), dehydroepiandrosterone (RR: 1.15, 95% CI: 1.00 to 1.34), total testosterone (RR: 1.11, 95% CI: 0.96 to 1.29), free testosterone (RR: 1.12, 95% CI: 0.98 to 1.28), estrone (RR: 1.21, 95% CI: 0.99 to 1.48), total estradiol (RR: 1.19, 95% CI: 1.02 to 1.39) and free estradiol (RR: 1.22, 95% CI: 1.05 to 1.41). A possible decreased risk was observed for SHBG (RR: 0.83, 95% CI: 0.66 to 1.05). Conclusion: Progesterone, estrogens and androgens likely increase postmenopausal ER-positive breast cancer risk, whereas SHBG may decrease risk. These findings strengthen the causal evidence surrounding the sex hormone-driven nature of postmenopausal breast cancer.

Study protocol for TARGET protein: The effect of augmented administration of enteral protein to critically ill adults on clinical outcomes: A cluster randomised, cross-sectional, double cross-over, clinical trial.

Background: It is unknown whether increasing dietary protein to 1.2-2.0 g/kg/day as recommended in international guidelines compared to current practice improves outcomes in intensive care unit (ICU) patients. The TARGET Protein trial will evaluate this. Objective: To describe the study protocol for the TARGET Protein trial. Design setting and participants: TARGET Protein is a cluster randomised, cross-sectional, double cross-over, pragmatic clinical trial undertaken in eight ICUs in Australia and New Zealand. Each ICU will be randomised to use one of two trial enteral formulae for three months before crossing over to the other formula, which is then repeated, with enrolment continuing at each ICU for 12 months. All patients aged ≥16 years in their index ICU admission commencing enteral nutrition will be eligible for inclusion. Eligible patients will receive the trial enteral formula to which their ICU is allocated. The two trial enteral formulae are isocaloric with a difference in protein dose: intervention 100g/1000 ml and comparator 63g/1000 ml. Staggered recruitment commenced in May 2022. Main outcomes measures: The primary outcome is days free of the index hospital and alive at day 90. Secondary outcomes include days free of the index hospital at day 90 in survivors, alive at day 90, duration of invasive ventilation, ICU and hospital length of stay, incidence of tracheostomy insertion, renal replacement therapy, and discharge destination. Conclusion: TARGET Protein aims to determine whether augmented enteral protein delivery reduces days free of the index hospital and alive at day 90. Trial registration: Australian New Zealand Clinical Trials Registry (ACTRN12621001484831).

The effect of time before diagnosis and treatment on colorectal cancer outcomes: systematic review and dose-response meta-analysis.

BACKGROUND: This systematic review and meta-analysis aimed to evaluate existing evidence on the relationship between diagnostic and treatment intervals and outcomes for colorectal cancer. METHODS: Four databases were searched for English language articles assessing the role of time before initial treatment in colorectal cancer on any outcome, including stage and survival. Two reviewers independently screened articles for inclusion and data were synthesised narratively. A dose-response meta-analysis was performed to examine the association between treatment interval and survival. RESULTS: One hundred and thirty papers were included in the systematic review, eight were included in the meta-analysis. Forty-five different intervals were considered in the time from first symptom to treatment. The most common finding was of no association between the length of intervals on any outcome. The dose-response meta-analysis showed a U-shaped association between the treatment interval and overall survival with the nadir at 45 days. CONCLUSION: The review found inconsistent, but mostly a lack of, association between interval length and colorectal cancer outcomes, but study design and quality were heterogeneous. Meta-analysis suggests survival becomes increasingly poorer for those commencing treatment more than 45 days after diagnosis. REGISTRATION: This review was registered, and the protocol is available, in PROSPERO, the international database of systematic reviews, with the registration ID CRD42021255864.

Benefits and harms of breast cancer screening: Cohort study of breast cancer mortality and overdiagnosis.

BACKGROUND: Quantifying the benefits and harms of breast cancer screening accurately is important for planning and evaluating screening programs and for enabling women to make informed decisions about participation. However, few cohort studies have attempted to estimate benefit and harm simultaneously. AIMS: We aimed to quantify the impact of mammographic screening on breast cancer mortality and overdiagnosis using a cohort of women invited to attend Australia's national screening program, BreastScreen. METHODS: In a cohort of 41,330 women without prior breast cancer diagnosis, screening, or diagnostic procedures invited to attend BreastScreen Western Australia in 1994-1995, we estimated the cumulative risk of breast cancer mortality and breast cancer incidence (invasive and ductal carcinoma in situ) from age 50 to 85 years for attenders and non-attenders. Data were obtained by linking population-based state and national health registries. Breast cancer mortality risks were estimated from a survival analysis that accounted for competing risk of death from other causes. Breast cancer risk for unscreened women was estimated by survival analysis, while accounting for competing causes of death. For screened women, breast cancer risk was the sum of risk of being diagnosed at first screen, estimated using logistic regression, and risk of diagnosis following a negative first screen estimated from a survival analysis. RESULTS: For every 1,000 women 50 years old at first invitation to attend BreastScreen, there were 20 (95% CI 12-30) fewer breast cancer deaths and 25 (95% CI 15-35) more breast cancers diagnosed for women who attended than for non-attendees by age 85. Of the breast cancers diagnosed in screened women, 21% (95% CI 13%-27%) could be attributed to screening. DISCUSSION: The estimated ratio of benefit to harm was consistent with, but slightly less favourable to screening than most other estimates from cohort studies. CONCLUSION: Women who participate in organised screening for breast cancer in Australia have substantially lower breast cancer mortality, while some screen-detected cancers may be overdiagnosed.

Adiposity and breast, endometrial, and colorectal cancer risk in postmenopausal women: Quantification of the mediating effects of leptin, C-reactive protein, fasting insulin, and estradiol.

BACKGROUND: Mechanisms underlying the adiposity-cancer relationship are incompletely understood. We quantified the mediating roles of C-reactive protein (CRP), leptin, fasting insulin, and estradiol in the effect of adiposity on estrogen receptor (ER)-positive breast, endometrial, and colorectal cancer risk in postmenopausal women. METHODS: We used a case-cohort study within the Women's Health Initiative Observational Study, analyzed as a cumulative sampling case-control study. The study included 188 breast cancer cases, 98 endometrial cancer cases, 193 colorectal cancer cases, and 285 controls. Interventional indirect and direct effects on the risk ratio (RR) scale were estimated using causal mediation analysis. RESULTS: For breast cancer, the total effect RR for BMI ≥30 versus ≥18.5-<25 kg/m2 was 1.87 (95%CI,1.11-3.13). The indirect effect RRs were 1.38 (0.79-2.33) through leptin and CRP, 1.58 (1.17-2.43) through insulin, and 1.11 (0.98-1.30) through estradiol. The direct effect RR was 0.82 (0.39-1.68). For endometrial cancer, the total effect RR was 2.12 (1.12-4.00). The indirect effect RRs were 1.72 (0.85-3.98) through leptin and CRP, 1.42 (0.96-2.26) through insulin, and 1.24 (1.03-1.65) through estradiol. The direct effect RR was 0.70 (0.23-2.04). For colorectal cancer, the total effect RR was 1.70 (1.03-2.79). The indirect effect RRs were 1.04 (0.61-1.72) through leptin and CRP, 1.36 (1.00-1.88) through insulin, and 1.02 (0.88-1.17) through estradiol. The direct effect RR was 1.16 (0.58-2.43). CONCLUSION: Leptin, CRP, fasting insulin, and estradiol appear to mediate the effect of high BMI on cancer risk to different extents, with likely varying degrees of importance between cancers. These insights might be important in developing interventions to modify obesity-associated cancer risk in postmenopausal women.

The relationship between markers of antenatal iron stores and birth outcomes differs by malaria prevention regimen-a prospective cohort study.

BACKGROUND: Iron deficiency (ID) has been associated with adverse pregnancy outcomes, maternal anaemia, and altered susceptibility to infection. In Papua New Guinea (PNG), monthly treatment with sulphadoxine-pyrimethamine plus azithromycin (SPAZ) prevented low birthweight (LBW; <2500 g) through a combination of anti-malarial and non-malarial effects when compared to a single treatment with SP plus chloroquine (SPCQ) at first antenatal visit. We assessed the relationship between ID and adverse birth outcomes in women receiving SPAZ or SPCQ, and the mediating effects of malaria infection and haemoglobin levels during pregnancy. METHODS: Plasma ferritin levels measured at antenatal enrolment in a cohort of 1892 women were adjusted for concomitant inflammation using C-reactive protein and α-1-acid glycoprotein. Associations of ID (defined as ferritin <15 µg/L) or ferritin levels with birth outcomes (birthweight, LBW, preterm birth, small-for-gestational-age birthweight [SGA]) were determined using linear or logistic regression analysis, as appropriate. Mediation analysis assessed the degree of mediation of ID-birth outcome relationships by malaria infection or haemoglobin levels. RESULTS: At first antenatal visit (median gestational age, 22 weeks), 1256 women (66.4%) had ID. Overall, ID or ferritin levels at first antenatal visit were not associated with birth outcomes. There was effect modification by treatment arm. Amongst SPCQ recipients, ID was associated with a 81-g higher mean birthweight (95% confidence interval [CI] 10, 152; P = 0.025), and a twofold increase in ferritin levels was associated with increased odds of SGA (adjusted odds ratio [aOR] 1.25; 95% CI 1.06, 1.46; P = 0.007). By contrast, amongst SPAZ recipients, a twofold increase in ferritin was associated with reduced odds of LBW (aOR 0.80; 95% CI 0.67, 0.94; P = 0.009). Mediation analyses suggested that malaria infection or haemoglobin levels during pregnancy do not substantially mediate the association of ID with birth outcomes amongst SPCQ recipients. CONCLUSIONS: Improved antenatal iron stores do not confer a benefit for the prevention of adverse birth outcomes in the context of malaria chemoprevention strategies that lack the non-malarial properties of monthly SPAZ. Research to determine the mechanisms by which ID protects from suboptimal foetal growth is needed to guide the design of new malaria prevention strategies and to inform iron supplementation policy in malaria-endemic settings. TRIAL REGISTRATION: ClinicalTrials.gov NCT01136850 .

Adiposity and Endometrial Cancer Risk in Postmenopausal Women: A Sequential Causal Mediation Analysis.

BACKGROUND: Adiposity increases endometrial cancer risk, possibly through inflammation, hyperinsulinemia, and increasing estrogens. We aimed to quantify the mediating effects of adiponectin (anti-inflammatory adipocytokine); IL6, IL1-receptor antagonist, TNF receptor 1 and 2, and C-reactive protein (inflammatory status biomarkers); C-peptide (hyperinsulinemia biomarker); and free estradiol and estrone (estrogen biomarkers) in the adiposity-endometrial cancer link in postmenopausal women. METHODS: We used data from a case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC). Eligible women did not have cancer, hysterectomy, and diabetes; did not use oral contraceptives or hormone therapy; and were postmenopausal at recruitment. Mediating pathways from adiposity to endometrial cancer were investigated by estimating natural indirect (NIE) and direct (NDE) effects using sequential mediation analysis. RESULTS: The study included 163 cases and 306 controls. The adjusted OR for endometrial cancer for body mass index (BMI) ≥30 versus ≥18.5-<25 kg/m2 was 2.51 (95% confidence interval, 1.26-5.02). The ORsNIE were 1.95 (1.01-3.74) through all biomarkers [72% proportion mediated (PM)] decomposed as: 1.35 (1.06-1.73) through pathways originating with adiponectin (33% PM); 1.13 (0.71-1.80) through inflammation beyond (the potential influence of) adiponectin (13% PM); 1.05 (0.88-1.24) through C-peptide beyond adiponectin and inflammation (5% PM); and 1.22 (0.89-1.67) through estrogens beyond preceding biomarkers (21% PM). The ORNDE not through biomarkers was 1.29 (0.54-3.09). Waist circumference gave similar results. CONCLUSIONS: Reduced adiponectin and increased inflammatory biomarkers, C-peptide, and estrogens mediated approximately 70% of increased odds of endometrial cancer in women with obesity versus normal weight. IMPACT: If replicated, these results could have implications for identifying targets for intervention to reduce endometrial cancer risk in women with obesity.

Latent Class Trajectory Modeling of Adult Body Mass Index and Risk of Obesity-Related Cancer: Findings from the Melbourne Collaborative Cohort Study.

BACKGROUND: Obesity increases the risk of 13 cancer types. Given the long process of carcinogenesis, it is important to determine the impact of patterns of body mass over time. METHODS: Using data from 30,377 participants in the Melbourne Collaborative Cohort Study, we identified body mass index (BMI) trajectories across adulthood and examined their association with the risk of obesity-related cancer. Participants completed interviews and questionnaires at baseline (1990-1994, age 40-69 years), follow-up 1 (1995-1998), and follow-up 2 (2003-2005). Body mass was recalled for age 18 to 21 years, measured at baseline, self-reported at follow-up 1, and measured at follow-up 2. Height was measured at baseline. Cancer diagnoses were ascertained from the Victorian Cancer Registry and the Australian Cancer Database. A latent class trajectory model was used to identify BMI trajectories that were not defined a priori. Cox regression was used to estimate HRs and 95% confidence intervals (CI) of obesity-related cancer risks by BMI trajectory. RESULTS: Six distinct BMI trajectories were identified. Compared with people who maintained lower normal BMI, higher risks of developing obesity-related cancer were observed for participants who transitioned from normal to overweight (HR, 1.29; 95% CI, 1.13-1.47), normal to class I obesity (HR, 1.50; 95% CI, 1.28-1.75), or from overweight to class II obesity (HR, 1.66; 95% CI, 1.32-2.08). CONCLUSIONS: Our findings suggest that maintaining a healthy BMI across the adult lifespan is important for cancer prevention. IMPACT: Categorization of BMI by trajectory allowed us to identify specific risk groups to target with public health interventions.

Explaining the link between adiposity and colorectal cancer risk in men and postmenopausal women in the UK Biobank: A sequential causal mediation analysis.

Mechanisms underlying adiposity-colorectal cancer (CRC) association are incompletely understood. Using UK Biobank data, we investigated the role of C-reactive protein (CRP), hemoglobin-A1c (HbA1c) and (jointly) sex hormone-binding globulin (SHBG) and testosterone, in explaining this association. Total effect of obesity versus normal-weight (based on waist circumference, body mass index, waist-hip ratio) on CRC risk was decomposed into natural direct (NDE) and indirect (NIE) effects using sequential mediation analysis. After a median follow-up of 7.1 years, 2070 incident CRC cases (men = 1,280; postmenopausal women = 790) were recorded. For men, the adjusted risk ratio (RR) for waist circumference (≥102 vs. ≤94 cm) was 1.37 (95% confidence interval [CI], 1.19-1.58). The RRsNIE were 1.08 (95% CI: 1.01-1.16) through all biomarkers, 1.06 (95% CI: 1.01-1.11) through pathways influenced by CRP, 0.99 (95% CI: 0.97-1.01) through HbA1c beyond (the potential influence of) CRP and 1.03 (95% CI: 0.99-1.08) through SHBG and testosterone combined beyond CRP and HbA1c. The RRNDE was 1.26 (95% CI: 1.09-1.47). For women, the RR for waist circumference (≥88 vs. ≤80 cm) was 1.27 (95% CI: 1.07-1.50). The RRsNIE were 1.08 (95% CI: 0.94-1.22) through all biomarkers, 1.08 (95% CI: 0.99-1.17) through CRP, 1.00 (95% CI: 0.98-1.02) through HbA1c beyond CRP and 1.00 (95% CI: 0.92-1.09) through SHBG and testosterone combined beyond CRP and HbA1c. The RRNDE was 1.18 (95% CI: 0.96-1.45). For men and women, pathways influenced by CRP explained a small proportion of the adiposity-CRC association. Testosterone and SHBG also explained a small proportion of this association in men. These results suggest that pathways marked by these obesity-related factors may not explain a large proportion of the adiposity-CRC association.

Adiposity and estrogen receptor-positive, postmenopausal breast cancer risk: Quantification of the mediating effects of fasting insulin and free estradiol.

Adiposity increases estrogen receptor (ER)-positive postmenopausal breast cancer risk. While mechanisms underlying this relationship are uncertain, dysregulated sex-steroid hormone production and insulin signaling are likely pathways. Our aim was to quantify mediating effects of fasting insulin and free estradiol in the adiposity and ER-positive postmenopausal breast cancer association. We used data from a case-cohort study of sex hormones and insulin signaling nested within the Melbourne Collaborative Cohort Study. Eligible women, at baseline, were not diagnosed with cancer, were postmenopausal, did not use hormone therapy and had no history of diabetes or diabetes medication use. Women with ER-negative disease or breast cancer diagnosis within the first follow-up year were excluded. We analyzed the study as a cumulative sampling case-control study with 149 cases and 1,029 controls. Missing values for insulin and free estradiol were multiply imputed with chained equations. Interventional direct (IDE) and indirect (IIE) effects were estimated using regression-based multiple-mediator approach. For women with body mass index (BMI) >30 kg/m2 compared to women with BMI 18.5-25 kg/m2 , the risk ratio (RR) of breast cancer was 1.75 (95% confidence interval [CI] 1.05-2.91). The estimated IDE (RR) not through the mediators was 1.03 (95% CI 0.43-2.48). Percentage mediated effect through free estradiol was 72% (IIE-RR 1.56; 95% CI 1.11-2.19). There was no evidence for an indirect effect through insulin (IIE-RR 1.12; 95% CI 0.68-1.84; 28% mediated). Our results suggest that circulating free estradiol plays an important mediating role in the adiposity-breast cancer relationship but does not explain all of the association.

A quantitative bias analysis to estimate measurement error-related attenuation of the association between self-reported physical activity and colorectal cancer risk.

BACKGROUND: Self-reported physical activity is inaccurate, yet few investigators attempt to adjust for measurement error when estimating risks for health outcomes. We estimated what the association between self-reported physical activity and colorectal cancer risk would be if physical activity had been assessed using accelerometry instead. METHODS: We conducted a validation study in which 235 Australian adults completed a telephone-administered International Physical Activity Questionnaire (IPAQ), and wore an accelerometer (Actigraph GT3X+) for 7 days. Using accelerometer-assessed physical activity as the criterion measure, we calculated validity coefficients and attenuation factors using a structural equation model adjusted for age, sex, education and body mass index. We then used a regression calibration approach to apply the attenuation factors to data from the Melbourne Collaborative Cohort Study (MCCS) to compute bias-adjusted hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: Average daily minutes of physical activity from the short form of the International Physical Activity Questionnaire (IPAQ-short) were substantially higher than accelerometer-measured duration (55 versus 32 min). The validity coefficient (0.32; 95% CI: 0.20, 0.43) and attenuation factor (0.20; 95% CI: 0.12, 0.28) were low. The HRs for colorectal cancer risk for high (75th percentile; 411 min/week) versus low (25th percentile; 62 min/week) levels of self-reported physical activity were 0.95 (95% CI: 0.87, 1.05) before and 0.78 (95% CI: 0.47, 1.28) after bias adjustment. CONCLUSIONS: Over-estimation of physical activity by the IPAQ-short substantially attenuates the association between physical activity and colorectal cancer risk, suggesting that the protective effect of physical activity has been previously underestimated.

Trajectories of body mass index in adulthood and all-cause and cause-specific mortality in the Melbourne Collaborative Cohort Study.

OBJECTIVE: Limited research has assessed the association between patterns of body mass index (BMI) change across adulthood and mortality. We aimed to identify groups of individuals who followed specific group-based BMI trajectories across adulthood, using weight collected on three occasions and recalled data from early adulthood, and to examine associations with all-cause and cause-specific mortality. DESIGN: Prospective cohort study. SETTING: Melbourne, Australia. PARTICIPANTS: Adults (n=29 881) enrolled in the Melbourne Collaborative Cohort Study, who were aged from 40 to 70 years between 1990 and 1994, and had BMI data for at least three time points. OUTCOME: Deaths from any cause before 31 March 2017 and deaths from obesity-related cancers, cardiovascular diseases (CVDs) and other causes before 31 December 2013. RESULTS: We identified six group-based BMI trajectories: lower-normal stable (TR1), higher-normal stable (TR2), normal to overweight (TR3), chronic borderline obesity (TR4), normal to class I obesity (TR5) and overweight to class II obesity (TR6). Generally, compared with maintaining lower-normal BMI throughout adulthood, the lowest mortality was experienced by participants who maintained higher-normal BMI (HR 0.90; 95% CI 0.84 to 0.97); obesity during midlife was associated with higher all-cause mortality even when BMI was normal in early adulthood (HR 1.09; 95% CI 0.98 to 1.21) and prolonged borderline obesity from early adulthood was also associated with elevated mortality (HR 1.16; 95% CI 1.01 to 1.33). These associations were stronger for never-smokers and for death due to obesity-related cancers. Being overweight in early adulthood and becoming class II obese was associated with higher CVD mortality relative to maintaining lower-normal BMI (HR 2.27; 95% CI 1.34 to 3.87). CONCLUSION: Our findings highlight the importance of weight management throughout adulthood to reduce mortality.

Intermittent screening and treatment with dihydroartemisinin-piperaquine and intermittent preventive therapy with sulfadoxine-pyrimethamine have similar effects on malaria antibody in pregnant Malawian women.

In a randomised trial comparing intermittent screening and treatment (IST) with dihydroartemisinin-piperaquine (DP) and intermittent preventive therapy against malaria in pregnancy (IPT) with sulfadoxine-pyrimethamine (SP) in Malawi, the impacts of IST-DP and IPT-SP on the development and maintenance of malaria antibody immunity were compared. Pregnant Malawian women were randomised to receive IST-DP or IPT-SP. In a nested study, paired enrolment and delivery plasma samples from 681 women were assayed for antibodies against recombinant antigens and for IgG and opsonising antibodies to antigens found on infected erythrocytes (IEs). At delivery, antibody responses did not differ between study arms. Between enrolment and delivery, antibodies to recombinant antigens decreased, whereas antibodies to IEs including opsonising antibodies remained stable. Overall, changes in antibody responses over pregnancy did not differ by treatment arm. Stratifying by gravidity, antibody to schizont extract decreased more in multigravidae receiving IST-DP than IPT-SP. There was minimal impact of treatment arm on the development and maintenance of malaria immunity. While antibodies to recombinant antigens declined between enrolment and delivery, antibodies directed against IEs tended to be more stable, suggesting longer-lasting protection.Clinical trial registration: Pa n African Clinical Trials Registry (PACTR201103000280319) 14/03/2011. URL: http://www.isrctn.com/ISRCTN69800930 .

Domain-specific physical activity and the risk of colorectal cancer: results from the Melbourne Collaborative Cohort Study.

BACKGROUND: Physical activity reduces the risk of colorectal cancer (CRC), but the relevant evidence derives primarily from self-reported recreational and occupational activity. Less is known about the contribution of other domains of physical activity, such as transport and household. We examined associations between domain-specific physical activities and CRC risk within the Melbourne Collaborative Cohort Study. METHODS: Analyses included 23,586 participants who were free from invasive colorectal cancer and had completed the International Physical Activity Questionnaire-Long Form at follow-up 2 (2003-2007). Cox regression, with age as the time metric, was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for ordinal categories of each physical activity domain. RESULTS: Adjusted HRs for the highest versus the lowest categories of physical activity were 0.71 (95% CI: 0.51-0.98; ptrend = 0.03) for recreational activity; 0.80 (95% CI: 0.49-1.28; ptrend = 0.38) for occupational activity; 0.90 (95% CI: 0.68-1.19; ptrend = 0.20) for transport activity; and 1.07 (95% CI: 0.82-1.40; ptrend = 0.46) for household activity. CONCLUSIONS: Recreational activity was associated with reduced CRC risk. A non-significant, inverse association was observed for occupational activity, whereas no association was found for transport or household domains.

Prospective analysis of 30-day mortality following palliative chemotherapy at a tertiary cancer centre.

BACKGROUND: Thirty-day mortality after chemotherapy has been suggested as a marker of quality in oncology care. Retrospective audits worldwide have put this figure at between 8.1% and 43%, with previous retrospective Australian audits putting this figure at between 3.4% and 18%. To date, there has not been a prospective cohort study of patients receiving palliative intent chemotherapy at an Australian chemotherapy day unit. AIM: The aim of the study is to benchmark 30-day mortality for patients receiving palliative intent chemotherapy and identify associated factors at an Australian tertiary cancer centre. METHODS AND RESULTS: A prospective cohort study of all patients with a diagnosis of malignancy referred for palliative intent intravenous chemotherapy to the Sunshine Hospital Chemotherapy Day Unit over a 12-month period. The primary outcome was death within 30 days of receiving palliative intent chemotherapy. Other outcome measures included place of death and whether the patient received an outpatient palliative care referral. A total of 314 patients were enrolled in the study, and 98 patients died within the audit period. Of these, 21 (6.6%) died within 30 days of commencing palliative intent chemotherapy, and 60 (18.8%) died more than 30 days after receiving chemotherapy. Of the 34 patients that were referred, but did not start chemotherapy, 18 (52%) died. Multivariable logistic regression found that patients who received an outpatient palliative care referral and received chemotherapy were more likely to die within 30 days, although these did not reach statistical significance. CONCLUSION(S): This prospective cohort study demonstrated that 6.6% of patients died within 30 days of the administration of palliative intent chemotherapy; however, none of the prespecified factors were found to be statistically significantly associated with 30-day mortality.