BACKGROUND:Standard modifiable cardiovascular risk factors (SMuRF) have been identified for coronary artery disease (CAD) and targeted in primary prevention efforts, resulting in significantly improved outcomes. However, an increasing proportion of individuals present with ST elevation myocardial infarction (STEMI) in the absence of conventionally elevated levels of modifiable risk factors ("SMuRFless"), with significantly worse short-term outcomes. Culprit lesions of the left anterior descending artery (LAD) are more frequently implicated in SMuRFless STEMI patients than those with at least one risk factor. Differences in segmental-level coronary disease burden outside the acute setting in SMuRFless individuals are largely unknown. OBJECTIVES:To characterise vessel-level coronary calcification, comparing SMuRFless to SMuRF≥1 participants. METHODS:Secondary analysis of the Multi-Ethnic Study of Atherosclerosis (MESA) was completed. Coronary artery calcium score (CACS) was measured at baseline and follow-up (median 6.3 years). RESULTS:6792 participants were included, with 20.6 ​% classified as SMuRFless. Among participants with detectable coronary calcification at baseline, SMuRFless participants had a significantly higher proportion of their total coronary calcium localised to the LAD, compared to SMuRF≥1 participants (74.2 ​% vs. 58.9 ​%, p ​< ​0.0001). This difference was most pronounced in individuals with higher baseline total CACS (CACS 100-400 Agatston units [AU] and CACS 401+), but attenuated after multivariable adjustment and was not statistically significant in best-subsets modelling. LAD CACS progressed in both groups during follow-up; however, annualised progression rates were similar between SMuRFless and SMuRF≥1 participants after adjustment for total coronary calcium progression and follow-up duration. CONCLUSION:SMuRFless MESA participants had a higher unadjusted proportion of coronary calcification in the LAD compared SMuRF≥1 participants; however, this associated attenuated after multivariable adjustment. Further research is warranted to better understand the development of atherosclerotic CAD in SMuRFless individuals, and biological relevance and potentially different susceptibility at the epicardial segment level.

BACKGROUND:Homologous recombination (HR) deficiency (HRD) from germline BRCA1/2 mutations (gBRCAm) sensitizes high-grade serous ovarian cancer (HGSOC) and triple-negative breast cancer (TNBC) to PARP inhibitors (PARPi), as may promoter methylation of BRCA1 (meBRCA1) or RAD51C (meRAD51C) or mutation of non-BRCA HR genes. This trial evaluated olaparib in platinum-sensitive, relapsed HGSOC (PSROC) and metastatic TNBC (mTNBC) with non-gBRCA HRD. METHODS:Single-arm phase 2 trial of olaparib 300 mg orally twice daily. Tumour meBRCA1/meRAD51C determined by methylation-sensitive, high-resolution melting PCR and targeted sequencing. Unmethylated cases underwent HR gene mutation testing. PRIMARY OUTCOME:objective tumour response rate (OTRR) at 6 months(m). SECONDARY OUTCOMES:progression-free survival (PFS), OTRR according to HR gene aberration, and safety. RESULTS:Total 22 enrolled: promoter methylation detected in 8/15 HGSOC and 5/7 TNBC, and pathogenic variants (PV) in non-BRCA HR genes. OTRR at 6 m was 40% HGSOC and 0% TNBC. OTRR was 38% in methylated cases vs 43% for other HRD. 6 m/12 m PFS were 53% / 25% (HGSOC), and 17% / 0% (TNBC). CONCLUSIONS:Olaparib demonstrated activity in HGSOC beyond gBRCAm, including with meBRCA1 or gRAD51C PV. Olaparib had limited activity in pre-treated TNBC. Effects of prior chemotherapy on meBRCA1/meRAD51C require exploration to improve patient selection for PARPi. CLINICAL TRIALS REGISTRATION:Australian New Zealand Clinical Trials Registry Registration number ACTRN 12617000855325.

OBJECTIVE:Multiple births are common in randomised trials targeting preterm populations. Clustering due to multiple births is often overlooked in individual trials and may impact the results of meta-analyses that pool their results. We aimed to assess how multiple births have been handled in the reporting and meta-analyses of recent systematic reviews. DESIGN:We conducted a methodological systematic review of Cochrane and non-Cochrane systematic reviews. The search was conducted on 10 September 2024 in the Cochrane Database of Systematic Reviews and PubMed for articles published in the previous 12 months. Reviews were eligible if they involved randomised trials of interventions delivered in pregnancy or infancy, included multiple births and reported results of at least one aggregate data meta-analysis for an infant outcome. RESULTS:After screening 222 articles, 39 had unclear eligibility due to making no mention of multiple births and nine met the eligibility criteria (five Cochrane and four non-Cochrane reviews). Multiple births were inconsistently handled across included reviews. The degree of clustering due to multiple births was poorly described and meta-analyses accounting for clustering were rarely reported (2/9 reviews; 22%). CIs around pooled treatment effect estimates were wider after accounting for clustering. CONCLUSIONS:Clustering due to multiple births is a poorly recognised issue in systematic reviews and meta-analyses. Given the potential for this clustering to alter conclusions about the effectiveness of interventions, we recommend accounting for clustering due to multiple births in future meta-analyses.

Variance regression is used to model heteroscedasticity in terms of covariates. Algorithms already exist but they may face computational instability due to the required parameter constraints. Therefore, having a suite of tools based on a variety of computational methods is essential. Here we present VarReg, an R package that fits variance regression models using a stable expectation-maximisation approach, which can incorporate flexible splines. VarReg accommodates censored and skewed data and allows regression models for shape parameters as well as location and scale. VarReg’s functions are demonstrated with real-world examples, illustrating a valuable, stable package for fitting these complex regression models.

Introduction:Glomerular diseases are rare but associated with substantial morbidity. Existing studies focus mainly on kidney failure and mortality, often overlooking multisystem complications. This first Australian population-based study uses linked routinely collected health data to estimate incidence, prevalence, and long-term outcomes, capturing cardiovascular, thrombotic, infectious, and healthcare burdens. Methods:We conducted a population-based cohort study of adults ≥45 years in New South Wales, Australia (2005-2009, n = 267,357), using the 45 and Up Study with probabilistic data linkage via CHeReL and the Sax Institute. Glomerular disease was identified using nephrology specialist reviews, ICD-10-AM codes, kidney biopsy procedure codes, and the Australian and New Zealand Dialysis and Transplant (ANZDATA) registry. Age-standardised glomerular disease prevalence and incidence were estimated. Kaplan-Meier curves and Cox regression models evaluated all-cause mortality, major cardiovascular events (MACE; composite of acute myocardial infarction [AMI], stroke, and all-cause mortality), venous thromboembolism (VTE), and any hospitalised infection. Sub-distribution hazard models assessed kidney replacement therapy (KRT) risk, accounting for the competing risk of death. Results:We identified 365 participants with glomerular disease (n = 195 prevalent, n = 170 incident; 67% male, mean age 65 years). The age-standardised prevalence and incidence of glomerular disease was 89/100,000 persons and 12/100,000 person-years-at-risk, respectively. After a median follow-up of 6 years, prevalent disease participants had a higher adjusted risk (HR; 95% CI; all p values <0.001) of all-cause mortality (2.18; 1.60-2.99), KRT (31.3; 12.7-77.2), MACE (2.17; 1.59-2.96), AMI (3.84; 2.05-7.20), stroke (3.58; 1.69-7.56), VTE (2.93; 1.76-4.89), and any hospitalised infection (2.92; 2.42-3.54). The 5-year risk of complications was comparable between prevalent and incident cases. Hospitalisation burden was also significantly higher among glomerular disease participants (p < 0.001). Conclusions:Using linked data, this study reveals the substantial multisystem burden of glomerular diseases, including kidney failure, death, cardiovascular events, infections, and hospitalisations in adults aged 45 and over.

The Wait a Minute or More (WAMM) trial is a pragmatic stepped-wedge cluster randomised implementation trial designed to increase the proportion of preterm infants receiving delayed cord clamping for at least 60 seconds (DCC60) across Australian maternity hospitals. This statistical analysis plan prespecifies primary, secondary, and exploratory analyses prior to accessing outcome data. The primary analysis will use mixed-effects modelling to estimate the effect of a locally adapted quality improvement programme and accurate data sharing, on achieving DCC60, accounting for clustering and secular trends. By detailing our approach, this SAP ensures transparency, reproducibility, and rigorous evaluation of the WAMM intervention.

OBJECTIVE:The feMMe phase 2 randomized trial demonstrated that approximately 60% of participants with endometrial hyperplasia with atypia or clinical stage 1, International Federation of Gynecology and Obstetrics grade 1 endometrioid adenocarcinoma had a pathological complete response after 6 months of treatment with the levonorgestrel intra-uterine device (NCT01686126). The objective of this study was to determine the long-term oncological and reproductive outcomes of a sub-group of feMMe trial participants in Queensland. METHODS:A total of 96 feMMe trial participants from 6 sites in Queensland were contacted to participate in this study, and 52 (54%) consented. Medical records were retrieved for 51 participants, and 44 participants completed questionnaires. RESULTS:Median follow-up time after trial completion was 18.9 months (range; 0.2-45.1). Of the 33 participants who had a pathological complete response at trial completion, 21 of 33 (64%) had a sustained complete response throughout follow-up (range; 6.7-43.5). Recurrence developed in 8 of 33 participants (24%). The probability of recurrence-free survival was 93% (95% confidence interval 84% to 100%) at 12 months and 74% (95% confidence interval 59% to 93%) at 24 months. Four of 33 participants (12%) did not have endometrial sampling beyond trial completion. Of the 19 participants who did not have a pathological complete response at trial completion, 4 of 19 (21%) went on to achieve a complete response. Persistent disease occurred in 5 of 19 participants (26%), and 10 of 19 participants (53%) did not have endometrial sampling beyond trial completion. Overall, 21 of 52 participants (40%) had a hysterectomy. Diagnostic concordance between the latest biopsy and the hysterectomy specimen was 62% (13 of 21; κ = 0.44). Four participants attempted to conceive, and the live birth rate was 50%. CONCLUSIONS:Long-term follow-up of feMMe trial participants demonstrated that most participants who developed a pathological complete response at trial completion were likely to sustain this response, while those who did not respond at trial completion were likely to require a hysterectomy for disease control.

BACKGROUND:Lower testosterone concentrations in older men are associated with poorer health outcomes. OBJECTIVE:We examined whether, on a background of lifestyle intervention, testosterone treatment modulates leucocyte telomere length, a postulated marker of biological ageing, in overweight men with impaired glucose tolerance (IGT) or newly diagnosed type 2 diabetes (T2D). PARTICIPANTS AND METHODS:We conducted a secondary analysis of a randomised, placebo-controlled trial in 50- to 74-year-old men with waist circumference ≥ 95 cm and dysglycaemia (ACTRN12612000287831). All men received a background lifestyle program, and were randomised to 2 years treatment with intramuscular testosterone undecanoate (1000 mg) every 3 months or placebo. Leucocyte telomere length was assayed by multiplex quantitative polymerase chain reaction and expressed as relative telomere length (rTL), a ratio of telomeric DNA to β-globin, a single-copy control gene (T/S ratio). RESULTS:There were 720 participants, aged 60 ± 6 years (mean ± SD), 38% had BMI 30-34.99 kg/m2 and 44% ≥ 35 kg/m2. Mean rTL at baseline was 1.63 ± 0.27 in testosterone-treated men (N = 375) and 1.61 ± 0.28 in placebo-treated men (N = 345). At 2 years, mean rTL was 1.61 ± 0.28 and 1.58 ± 0.29, respectively. Change in rTL after 2 years treatment was -0.02 ± 0.15 in testosterone-treated and -0.03 ± 0.12 in placebo-treated men. Adjusting for baseline values there was no effect of testosterone treatment on rTL at 2 years (mean difference 0.01 [95% CI, -0.01 to 0.03], p = 0.24). Results were similar for rTL change at 2 years from baseline. CONCLUSIONS:There was no effect of testosterone treatment on telomere length in this group of men. Larger studies with longer treatment durations are merited.

Distinguishing endometrial hyperplasia from endometrial adenocarcinoma remains a histopathologic challenge. Several retrospective studies have reported high interobserver variability when assessing the progestin-naive endometrium, while only one study has assessed interobserver variability of postprogestin endometrial biopsies. This study quantified the interobserver variability between trial site pathologists and central pathology review of endometrial specimens taken before treatment with the levonorgestrel intrauterine device (LNG-IUD), 3 months and 6 months post-treatment as part of the feMMe phase 2 randomized clinical trial (NCT01686126). Interobserver agreement was 73% (105/143, κ=0.50) at baseline, 80% (107/134, κ=0.72) at 3 months and 77% (98/127, κ=0.64) at 6 months post-LNG-IUD treatment. Overall, 42% (45/107) site-reported diagnoses of endometrial hyperplasia and 13% (21/161) site-reported diagnoses of endometrial adenocarcinoma were discordant. Site-reported diagnoses were upgraded to higher risk pathology on central review for 77% (72/94) discordant cases. This study confirms the high rate of interobserver variability when diagnosing endometrial hyperplasia or endometrial adenocarcinoma both before and after progestin treatment in specimens collected as part of a clinical trial. It emphasizes the value of confirming diagnosis by a gynecologic pathologist and comparing specimens from the progestin-treated endometrium with the pretreatment biopsy. This study highlights the importance of central pathology review for clinical trial reporting and when deciding on treatment options and assessing response, particularly in the context of progestin treatment.

Introduction Delayed cord clamping (DCC) is an evidence-based intervention that reduces mortality, anaemia and disability in infants born <37 weeks’ gestation who do not require immediate resuscitation. However, it is neither reliably recorded nor routinely implemented in Australia. The Wait a Minute or More (WAMM) study aims to reduce this gap between the evidence and practice by integrating timely sharing of cord clamping data with Evidence-based Practice for Improving Quality methods to increase the proportion of preterm infants receiving DCC for 60 s or longer (DCC60). Methods The WAMM study is a pragmatic stepped wedge cluster randomised trial (SW-CRT), informed by the Integrated-Promoting Action on Research Implementation in Health Services (i-PARIHS) framework. Up to 20 Australian maternity hospitals will participate in this pragmatic SW-CRT to evaluate if in ( Population ) infants <37 weeks’ gestation who do not need resuscitation, does ( Intervention ) the WAMM intervention (sharing of anonymised data on DCC60, together with a locally adapted quality improvement (QI) programme), compared with ( Control ) sharing of anonymised data on DCC60 alone, increase ( primary Outcome ) the proportion of infants receiving DCC60? At the end of 72 weeks, all sites will complete an 8-week period without the WAMM intervention to evaluate if implementation of DCC is sustained. Alongside the SW-CRT, an embedded process evaluation will assess the fidelity, acceptability, mechanisms of action and contextual barriers and enablers of the WAMM intervention. Discussion Using the stepped wedged design and guided by an explicit implementation framework (i-PARIHS), WAMM will provide information on the effectiveness and transferability of a locally adapted QI method to improve DCC60. If proven effective, ultimately scaling up the WAMM intervention globally will greatly improve childhood anaemia, death, disability and long-term costs. Trial registration number ACTRN12624000035527.

OBJECTIVE:To investigate the interobserver agreement of the International Ovarian Tumour Analysis (IOTA) ultrasound-based simple rules risk (SRRisk) score, the logistic regression model 2 (LR2), the Assessment of Different NEoplasias in the adneXa (ADNEX) model and the Ovarian-Adnexal Reporting and Data System (O-RADS) in an Australian, population-based context. METHODS:A retrospective multi-centre study was performed between January 2020 and January 2021. The study included 198 women with adnexal masses examined with transvaginal grey scale and power Doppler ultrasound. Participants were recruited from the multidisciplinary oncology meetings (MDT) of two tertiary cancer centres. Two independent radiologists described the adnexal masses according to the SRR, LR2 scores, ADNEX model, and O-RADS. Values > 30 units different were considered differential and > 50 units were considered highly differential. RESULTS:From 198 patients, 128 were diagnosed with benign ovarian masses, 53 with malignant and 17 patients with borderline tumours. There was strong agreement (Cohen's kappa 0.8) for intra-tumour blood flow, number of cysts locules, and presence of blood flow within solid projections. Interobserver agreement was moderate (Cohen's kappa 0.60-0.79) for the presence of free pelvic fluid/ascites, solid components, unilocular cysts and acoustic shadows. Of the 198 cases, 10 (5%) cases were highly differential and (38/198) 19% were differential for SRRisk, (20/198) 10% highly differential and (36/198) 18% differential for LR2, and (10/198) 5% and (24/198) 12% for ADNEXA model, respectively. Comparison of O-RADS scores between the two observers showed a moderate agreement with a kappa of 0.65. In 7/198 (4%) cases, the difference between observers was for 2 or more categories when using the O-RADS score. CONCLUSIONS:Our results suggested that interobserver variation was present in evaluating adnexal masses using well established ultrasonographic diagnostic models. Implementation of sonographic ovarian cancer risk prediction models will need to consider this issue and ensure examiners have adequate training in the technique, and standard operating procedures are in place to reduce interobserver variability.

BACKGROUND:Childhood obesity is a global public health issue, which has prompted governments to invest in prevention programmes. We aimed to investigate the effectiveness of parent-focused early childhood obesity prevention interventions globally. METHODS:We did a systematic review and individual participant data meta-analysis. We searched databases and trial registries (MEDLINE, Embase, CENTRAL, CINAHL, PsycInfo, ClinicalTrials.gov, and WHO International Clinical Trials Registry Platform) from inception until Sept 30, 2024, for randomised controlled trials commencing before 12 months of age examining parent-focused behavioural interventions to prevent obesity in children, compared with usual care, no intervention, or attention control. Individual participant data were checked, harmonised, and assessed for integrity and risk of bias. We excluded trials that were quasi-randomised, investigated pregnancy-only interventions, or did not collect any child weight-related outcomes. The primary outcome was BMI Z score at age 24 months (±6 months). We did an intention-to-treat, two-stage, random effects meta-analysis to examine effects overall and for prespecified subgroups. We assessed certainty of evidence using Grading of Recommendations Assessment, Development, and Evaluation. This study is registered with PROSPERO, CRD42020177408. FINDINGS:Of 19 990 identified records, 47 (0·24%) trials were completed and eligible. Of these, 18 (38%) assessed our primary outcome, BMI Z score. We obtained individual participant data for 17 (94%; n=9128) of these 18 trials (n=9383), representing 97% of eligible participants. Of these 9128 participants, 4549 (50%) were boys, 4415 (48%) were girls, and 164 (2%) had unknown sex. We found no evidence of an effect of interventions on BMI Z score at age 24 months (±6 months; mean difference -0·01 [95% CI -0·08 to 0·05]; high certainty evidence, τ2=0·01; n=6505; 2623 missing). Findings were robust to prespecified sensitivity analyses (eg, different analysis methods and missing data), and we found no evidence of differential intervention effects for prespecified subgroups including priority populations and trial-level factors. INTERPRETATION:These findings indicate that examined parent-focused behavioural interventions are insufficient to prevent obesity at age 24 months (±6 months). This evidence highlights a need to re-think childhood obesity prevention approaches. FUNDING:Australian National Health and Medical Research Council.

Abstract Background Early childhood obesity prevention interventions that aim to change parent/caregiver practices related to infant (milk) feeding, food provision and parent feeding, movement (including activity, sedentary behaviour) and/or sleep health (i.e. target parental behaviour domains) are diverse and heterogeneously reported. We aimed to 1) systematically characterise the target behaviours, delivery features, and Behaviour Change Techniques (BCTs) used in interventions in the international Transforming Obesity Prevention for CHILDren (TOPCHILD) Collaboration, and 2) explore similarities and differences in BCTs used in interventions by target behaviour domains. Methods Annual systematic searches were performed in MEDLINE, Embase, Cochrane (CENTRAL), CINAHL, PsycINFO, and two clinical trial registries, from inception to February 2023. Trialists from eligible randomised controlled trials of parent-focused, behavioural early obesity prevention interventions shared unpublished intervention materials. Standardised approaches were used to code target behaviours, delivery features and BCTs in both published and unpublished intervention materials. Validation meetings confirmed coding with trialists. Narrative syntheses were performed. Results Thirty-two trials reporting 37 active intervention arms were included. Interventions targeted a range of behaviours. The most frequent combination was targeting all parental behaviour domains (infant [milk] feeding, food provision and parent feeding, movement, sleep health; n[intervention arms] = 15/37). Delivery features varied considerably. Most interventions were delivered by a health professional (n = 26/36), included facilitator training (n = 31/36), and were interactive (n = 28/36). Overall, 49 of 93 unique BCTs were coded to at least one target behaviour domain. The most frequently coded BCTs were: Instruction on how to perform a behaviour (n[intervention arms, separated by domain] = 102), Behavioural practice and rehearsal (n = 85), Information about health consequences (n = 85), Social support (unspecified) (n = 84), and Credible source (n = 77). Similar BCTs were often used for each target behaviour domain. Conclusions Our study provides the most comprehensive description of the behaviour change content of complex interventions targeting early childhood obesity prevention available to date. Our analysis revealed that interventions targeted multiple behaviour domains, with significant variation in delivery features. Despite the diverse range of BCTs coded, five BCTs were consistently identified across domains, though certain BCTs were more prevalent in specific domains. These findings can be used to examine effectiveness of components and inform intervention development and evaluation in future trials. Trial registration PROSPERO registration no. CRD42020177408.

Introduction Delayed cord clamping (DCC) is an evidence-based intervention that reduces mortality, anaemia and disability in infants born <37 weeks’ gestation who do not require immediate resuscitation. However, it is neither reliably recorded nor routinely implemented in Australia. The Wait a Minute or More (WAMM) study aims to reduce this gap between the evidence and practice by integrating timely sharing of cord clamping data with Evidence-based Practice for Improving Quality methods to increase the proportion of preterm infants receiving DCC for 60 s or longer (DCC60).Methods The WAMM study is a pragmatic stepped wedge cluster randomised trial (SW-CRT), informed by the Integrated-Promoting Action on Research Implementation in Health Services (i-PARIHS) framework. Up to 20 Australian maternity hospitals will participate in this pragmatic SW-CRT to evaluate if in (Population) infants <37 weeks’ gestation who do not need resuscitation, does (Intervention) the WAMM intervention (sharing of anonymised data on DCC60, together with a locally adapted quality improvement (QI) programme), compared with (Control) sharing of anonymised data on DCC60 alone, increase (primary Outcome) the proportion of infants receiving DCC60? At the end of 72 weeks, all sites will complete an 8-week period without the WAMM intervention to evaluate if implementation of DCC is sustained. Alongside the SW-CRT, an embedded process evaluation will assess the fidelity, acceptability, mechanisms of action and contextual barriers and enablers of the WAMM intervention.Discussion Using the stepped wedged design and guided by an explicit implementation framework (i-PARIHS), WAMM will provide information on the effectiveness and transferability of a locally adapted QI method to improve DCC60. If proven effective, ultimately scaling up the WAMM intervention globally will greatly improve childhood anaemia, death, disability and long-term costs.Trial registration number ACTRN12624000035527.