Sonothrombolysis before and after percutaneous coronary intervention provides the largest myocardial salvage in ST-segment Elevation Myocardial Infarction.

BACKGROUND: Sonothrombolysis is a therapeutic application of ultrasound with ultrasound contrast for patients with ST elevation Myocardial Infarction (STEMI). Recent trials demonstrated that sonothrombolysis, delivered before and after primary percutaneous coronary intervention (pPCI), increase infarct vessel patency, improve microvascular flow, reduce infarct size, and improve ejection fraction. However, it is unclear whether pre-pPCI sonothrombolysis is essential for therapeutic benefit. We designed a parallel three-arm sham-controlled randomised controlled trial to address this. METHODS: Patients presenting with first STEMI undergoing pPCI within six hours of symptom onset were randomised 1:1:1 into three arms: sonothrombolysis pre/post pPCI (Group 1), Sham pre & sonothrombolysis post pPCI (Group 2), and Sham pre/post pPCI (Group 3). Our primary endpoint was infarct size (% LV mass) assessed by Cardiac MRI at day 4±2. Secondary endpoints included myocardial salvage index (MSI) and echocardiographic parameters at Day 4±2 and six months. RESULTS: Our trial was ceased early due to the COVID pandemic. From 122 patients screened between September 2020 and June 2021, 51 patients (Age 60, male 82%) were included post randomisation. Median sonothrombolysis took 5 minutes pre pPCI and 15 minutes post, without significant door-to-balloon delay. There was a trend towards reduction in median infarct size between Group 1 (8%[IQR 4,11]), Group 2 (11%[7,19]) or Group 3 (15%[9,22]). Similarly there was a trend towards improved MSI in Group 1 (79%[64,85]) compared to Groups 2 (51%[45,70]) and 3 (48%[37,73]) No major adverse cardiac events occurred during hospitalization. CONCLUSION: Pre-pPCI sonothrombolysis may be key to improving MSI in STEMI. Multicentre trials and health economic analyses are required before clinical translation.

Protocol for a systematic review with prospective individual patient data meta-analysis in EGFR-mutant NSCLC with brain metastases to assess the effect of SRS+osimertinib compared to osimertinib alone: the STARLET Collaboration.

BACKGROUND: Patients with advanced non-small-cell lung cancer (NSCLC) with activating mutations in the epidermal growth factor receptor (EGFR) gene are a heterogeneous population who often develop brain metastases (BM). The optimal management of patients with asymptomatic brain metastases is unclear given the activity of newer-generation targeted therapies in the central nervous system. We present a protocol for an individual patient data (IPD) prospective meta-analysis to evaluate whether the addition of stereotactic radiosurgery (SRS) before osimertinib treatment will lead to better control of intracranial metastatic disease. This is a clinically relevant question that will inform practice. METHODS: Randomised controlled trials will be eligible if they include participants with BM arising from EGFR-mutant NSCLC and suitable to receive osimertinib both in the first-line and second-line settings (P); comparisons of SRS followed by osimertinib versus osimertinib alone (I, C) and intracranial disease control included as an endpoint (O). Systematic searches of Medline (Ovid), Embase (Ovid), Cochrane Central Register of Controlled Trials (CENTRAL), CINAHL (EBSCO), PsychInfo, ClinicalTrials.gov and the WHO's International Clinical Trials Registry Platform's Search Portal will be undertaken. An IPD meta-analysis will be performed using methodologies recommended by the Cochrane Collaboration. The primary outcome is intracranial progression-free survival, as determined by response assessment in neuro-oncology-BM criteria. Secondary outcomes include overall survival, time to whole brain radiotherapy, quality of life, and adverse events of special interest. Effect differences will be explored among prespecified subgroups. ETHICS AND DISSEMINATION: Approved by each trial's ethics committee. Results will be relevant to clinicians, researchers, policymakers and patients, and will be disseminated via publications, presentations and media releases. PROSPERO REGISTRATION: CRD42022330532.

Restoring microvascular circulation with diagnostic ultrasound and contrast agent: Rationale and Design of the REDUCE trial.

OBJECTIVES: This study aims to evaluate the efficacy and cost-effectiveness of sonothrombolysis delivered pre and post primary percutaneous coronary intervention (pPCI) on infarct size assessed by cardiac MRI, in patients presenting with STEMI, when compared against sham procedure. BACKGROUND: More than a half of patients with successful pPCI have significant microvascular obstruction and residual infarction. Sonothrombolysis is a therapeutic use of ultrasound with contrast enhancement that may improve microcirculation and infarct size. The benefits and real time physiological effects of sonothrombolysis in a multicentre setting are unclear. METHODS: The REDUCE (Restoring microvascular circulation with diagnostic ultrasound and contrast agent) trial is a prospective, multicentre, patient and outcome blinded, sham-controlled trial. Patients presenting with STEMI will be randomized to one of two treatment arms, to receive either sonothrombolysis treatment or sham echocardiography before and after pPCI. This tailored design is based on preliminary pilot data from our centre, showing that sonothrombolysis can be safely delivered, without prolonging door to balloon time. Our primary endpoint will be infarct size assessed on day 4±2 on Cardiac Magnetic Resonance (CMR). Patients will be followed up for six months post pPCI to assess secondary endpoints. Sample size calculations indicate we will need 150 patients recruited in total. CONCLUSIONS: This multicentre trial will test whether sonothrombolysis delivered pre and post primary PCI can improve patient outcomes and is cost-effective, when compared with sham ultrasound delivered with primary PCI. The results from this trial may provide evidence for the utilization of sonothrombolysis as an adjunct therapy to pPCI to improve cardiovascular outcomes in STEMI. ANZ Clinical Trial Registration number: ACTRN 12620000807954.

LACC Trial: Final Analysis on Overall Survival Comparing Open Versus Minimally Invasive Radical Hysterectomy for Early-Stage Cervical Cancer.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The aim of this study was to compare overall survival between open and minimally invasive radical hysterectomy with participants followed for 4.5 years. The primary objective was to evaluate whether minimally invasive surgery was noninferior in disease-free survival (DFS) to abdominal radical hysterectomy. Secondary outcomes included overall survival. Sample size was based on DFS of 90% at 4.5 years and 7.2% noninferiority margin for minimally invasive surgery. A total of 631 patients were enrolled: 319 assigned to minimally invasive and 312 to open surgery. Of these, 289 (90.6%) patients underwent minimally invasive surgery and 274 (87.8%) patients open surgery. At 4.5 years, DFS was 85.0% in the minimally invasive group and 96% in the open group (difference of -11.1; 95% CI, -15.8 to -6.3; P = .95 for noninferiority). Minimally invasive surgery was associated with lower rate of DFS compared with open surgery (hazard ratio [HR], 3.91 [95% CI, 2.02 to 7.58]; P < .001). Rate of overall survival at 4.5 years was 90.6% versus 96.2% for the minimally invasive and open surgery groups, respectively (HR for death of any cause = 2.71 [95% CI, 1.32 to 5.59]; P = .007). Given higher recurrence rate and worse overall survival with minimally invasive surgery, an open approach should be standard of care.

Cost-effectiveness of Accepting Kidneys From Deceased Donors With Common Cancers-A Modeling Study.

BACKGROUND: The disparity between the demand for and supply of kidney transplants has resulted in prolonged waiting times for patients with kidney failure. A potential approach to address this shortage is to consider kidneys from donors with a history of common cancers, such as breast, prostate, and colorectal cancers. METHODS: We used a patient-level Markov model to evaluate the outcomes of accepting kidneys from deceased donors with a perceived history of breast, prostate, or colorectal cancer characterized by minimal to intermediate transmission risk. Data from the Australian transplant registry were used in this analysis. The study compared the costs and quality-adjusted life years (QALYs) from the perspective of the Australian healthcare system between the proposed practice of accepting these donors and the conservative practice of declining them. The model simulated outcomes for 1500 individuals waitlisted for a deceased donor kidney transplant for a 25-y horizon. RESULTS: Under the proposed practice, when an additional 15 donors with minimal to intermediate cancer transmission risk were accepted, QALY gains ranged from 7.32 to 20.12. This translates to an approximate increase of 7 to 20 additional years of perfect health. The shift in practice also led to substantial cost savings, ranging between $1.06 and $2.3 million. CONCLUSIONS: The proposed practice of accepting kidneys from deceased donors with a history of common cancers with minimal to intermediate transmission risk offers a promising solution to bridge the gap between demand and supply. This approach likely results in QALY gains for recipients and significant cost savings for the health system.

Testosterone Treatment, Weight Loss, and Health-related Quality of Life and Psychosocial Function in Men: A 2-year Randomized Controlled Trial.

OBJECTIVE: To determine the effect of testosterone vs placebo treatment on health-related quality of life (HR-QOL) and psychosocial function in men without pathologic hypogonadism in the context of a lifestyle intervention. DESIGN, SETTING, PARTICIPANTS: Secondary analysis of a 2-year randomized controlled testosterone therapy trial for prevention or reversal of newly diagnosed type 2 diabetes, enrolling men ≥ 50 years at high risk for type 2 diabetes from 6 Australian centers. INTERVENTIONS: Injectable testosterone undecanoate or matching placebo on the background of a community-based lifestyle program. MAIN OUTCOMES: Self-reported measures of HR-QOL/psychosocial function. RESULTS: Of 1007 participants randomized into the Testosterone for Type 2 Diabetes Mellitus (T4DM) trial, 648 (64%) had complete data available for all HR-QOL/psychosocial function assessments at baseline and 2 years. Over 24 months, while most measures were not different between treatment arms, testosterone treatment, compared with placebo, improved subjective social status and sense of coherence. Baseline HR-QOL/psychosocial function measures did not predict the effect of testosterone treatment on glycemic outcomes, primary endpoints of T4DM. Irrespective of treatment allocation, larger decreases in body weight were associated with improved mental quality of life, mastery, and subjective social status. Men with better baseline physical function, greater sense of coherence, and fewer depressive symptoms experienced greater associated decreases in body weight, with similar effects on waist circumference. CONCLUSION: In this diabetes prevention trial, weight loss induced by a lifestyle intervention improved HR-QOL and psychosocial function in more domains than testosterone treatment. The magnitude of weight and waist circumference reduction were predicted by baseline physical function, depressive symptomology, and sense of coherence.

To guide future practice, perinatal trials should be much larger, simpler and less fragile with close to 100% ascertainment of mortality and other key outcomes.

The Australian Placental Transfusion Study (APTS) randomised 1,634 fetuses to delayed (≥60 s) versus immediate (≤10 s) clamping of the umbilical cord. Systematic reviews with meta-analyses, including this and similar trials, show that delaying clamping in preterm infants reduces mortality and need for blood transfusions. Amongst 1,531 infants in APTS followed up at two years, aiming to delay clamping for 60 s or more reduced the relative risk of the primary composite outcome of death or disability by 17% (p = 0.01). However, this result is fragile because nominal statistical significance (p < 0.05) would be abolished by only 2 patients switching from a non-event to an event, and the primary composite outcome was missing in 112 patients (7%). To achieve more robust evidence, any future trials should emulate the large, simple trials co-ordinated from Oxford which reliably identified moderate, incremental improvements in mortality in tens of thousands of participants, with <1% missing data. Those who fund, regulate, and conduct trials that aim to change practice should repay the trust of those who consent to participate by doing everything possible to minimise missing data for key outcomes.

Sex Differences in Outcome and Prescribing Practice in ST-elevation MI Patients with Multivessel Disease and Incomplete Revascularisation.

Objective: To investigate the extent to which multivessel disease, incomplete revascularisation and prescribing differences contribute to sex-based outcome disparities in patients with ST-elevation MI (STEMI) and establish whether differences in cardiac death and MI (CDMI) rates persist at long-term follow-up. Methods and results: This observational study evaluates sex-based outcome differences (median follow-up 3.6 years; IQR [2.4-5.4]) in a consecutive cohort of patients (n=2,083) presenting with STEMI undergoing percutaneous coronary intervention). Of the studied patients 20.3% (423/2,083) were women and 38.3% (810/2,083) had multivessel disease (MVD). Incomplete revascularisation was common. The median residual SYNTAX score (rSS) was 5.0 (IQR [0-9]) in women and 5.0 (IQR [1-11]) in men (p=0.369), and in patients with MVD it was 9 (IQR [6-17]) in women and 10 (IQR [6-15]) in men (p=0.838). The primary endpoint CDMI occurred in 20.3% of women (86/423) and in 13.2% of men (219/1,660) (p=0.028). Differences persisted following multivariable risk adjustment: female sex was independently associated with CDMI (aHR 1.33; IQR [1.02-1.74]). Women with MVD had CDMI more often than all other groups (p<0.001 for all). Significant sex-based prescribing differences were evident: women were less likely to receive guideline-recommended potent P2Y12 inhibitors than men (31% versus 43%; p=0.012), and differences were particularly evident in patients with MVD (25% in women versus 45% in men, p=0.011). Conclusion: Sex-based differences in STEMI patient outcome persist at long-term follow-up. Poor outcomes were disproportionately found in women with MVD and those with rSS>8. Observed differences in P2Y12 prescribing practices may contribute to poor outcomes for women with MVD and incomplete revascularisation.

Mediation analysis of the testosterone treatment effect to prevent type 2 diabetes in the Testosterone for Prevention of Type 2 Diabetes Mellitus trial.

OBJECTIVE: To determine if testosterone treatment effect on glycaemia is mediated through changes in total fat mass, abdominal fat mass, skeletal muscle mass, non-dominant hand-grip, oestradiol (E2), and sex hormone-binding globulin (SHBG). DESIGN: Mediation analysis of a randomised placebo-controlled trial of testosterone. METHODS: Six Australian tertiary care centres recruited 1007 males, aged 50-74 years, with waist circumference ≥95 cm, serum total testosterone ≤14 nmol/L (immunoassay), and either impaired glucose tolerance or newly diagnosed type 2 diabetes on an oral glucose tolerance test (OGTT). Participants were enrolled in a lifestyle programme and randomised 1:1 to 3 monthly injections of 1000 mg testosterone undecanoate or placebo for 2 years. Complete data were available for 709 participants (70%). Mediation analyses for the primary outcomes of type 2 diabetes at 2 years (OGTT ≥ 11.1 mmol/L and change in 2-h glucose from baseline), incorporating potential mediators: changes in fat mass, % abdominal fat, skeletal muscle mass, non-dominant hand-grip strength, E2, and SHBG, were performed. RESULTS: For type 2 diabetes at 2 years, the unadjusted OR for treatment was 0.53 (95% CI:.35-.79), which became 0.48 (95% CI:.30-.76) after adjustment for covariates. Including potential mediators attenuated the treatment effect (OR 0.77; 95% CI:.44-1.35; direct effect) with 65% mediated. Only fat mass remained prognostic in the full model (OR: 1.23; 95% CI: 1.09-1.39; P < .001). CONCLUSION: At least part of the testosterone treatment effect was found to be mediated by changes in fat mass, abdominal fat, skeletal muscle mass, grip strength, SHBG, and E2, but predominantly by changes in fat mass.

Protocol for a Nested, Retrospective Study of the Australian Placental Transfusion Study Cohort.

Background Neonates, particularly if born preterm or with congenital anomalies, are among the pediatric patients most likely to need blood transfusion. However, they are also particularly vulnerable to adverse consequences of blood transfusion. Aiming to clamp the umbilical cord for at least a minute after birth is a simple safe procedure that is being increasingly adopted worldwide, although may be associated with increased rates of polycythemia and jaundice. It may also reduce the proportion of preterm babies who need a blood transfusion. The mechanisms for this are not fully understood. Potential mechanisms could include an increased volume of blood transfusion from the placenta to the baby after birth, and an overall reduction in the severity of illness in the first weeks after birth, which could lead to fewer blood tests and greater tolerance of anemia, or enhanced erythropoiesis. Objectives To investigate the mechanism behind the reduced need for blood transfusions after deferral of cord clamping. Methodology This protocol outlines the methods and data analysis plan for a study using nested retrospective data from a large randomized trial combined with additional data collected from patient medical and pathology records. The additional data items to be collected all relate to the receipt of transfusion and the factors that affect the risk for transfusion in preterm babies. The analysis will include all randomized babies from Australia and New Zealand for whom data are available. Causal mediation analysis is planned to estimate the effects of mediators on the relationship between the timing of cord clamping and the need for blood transfusion. The analysis is designed to discern whether initial severity of illness or the magnitude of placental transfusion mediates red blood cell transfusion dependence. Anticipated outcomes and dissemination We expect the study will identify potential strategies for reducing blood transfusions and associated negative outcomes in preterm infants. This will be relevant to researchers, clinicians, and parents. The results will be disseminated through publications, presentations, and inclusion in evidence-based guidelines.

Maternal diabetes independent of BMI is associated with altered accretion of adipose tissue in large for gestational age fetuses.

AIM: To analyse the effects of maternal diabetes mellitus (DM) and body mass Index (BMI) on central and peripheral fat accretion of large for gestational age (LGA) offspring. METHODS: This retrospective study included LGA fetuses (n = 595) with ultrasound scans at early (19.23 ± 0.68 weeks), mid (28.98 ± 1.62 weeks) and late (36.20 ± 1.59 weeks) stages of adipogenesis and measured abdominal (AFT) and mid-thigh (TFT) fat as surrogates for central and peripheral adiposity. Women were categorised according to BMI and DM status [pre-gestational (P-DM; n = 59), insulin managed (I-GDM; n = 132) and diet managed gestational diabetes (D-GDM; n = 29)]. Analysis of variance and linear regressions were applied. RESULTS: AFT and TFT did not differ significantly between BMI categories (normal, overweight and obese). In contrast, AFT was significantly higher in pregnancies affected by D-GDM compared to non-DM pregnancies from mid stage (0.44 mm difference, p = 0.002) and for all DM categories in late stage of adipogenesis (≥ 0.49 mm difference, p < 0.008). Late stage TFT accretion was higher than controls for P-DM and I-GDM but not for D-GDM (0.67 mm difference, p < 0.001; 0.49 mm difference, p = 0.001, 0.56 mm difference, p = 0.22 respectively). In comparison to the early non-DM group with an AFT to TFT ratio of 1.07, the I-GDM group ratio was 1.25 (p < 0.001), which normalised by 28 weeks becoming similar to control ratios. CONCLUSIONS: DM, independent of BMI, was associated with higher abdominal and mid-thigh fat accretion in fetuses. Use of insulin improved central to peripheral fat ratios in fetuses of GDM mothers.

An individual participant data meta-analysis of breast cancer detection and recall rates for digital breast tomosynthesis versus digital mammography population screening.

BACKGROUND: Although digital breast tomosynthesis (DBT) improves breast cancer screen-detection compared to digital mammography (DM), there is less evidence on comparative screening outcomes by age and breast density, and inconsistent evidence on its effect on recall rate. METHOD: We performed an individual participant data (IPD) meta-analysis from DBT screening studies (identified to November, 30 2019) that contributed to the study protocol. We estimated and compared cancer detection rate (CDR), recall rate, and positive predictive value (PPV) for recall for DBT and DM screening. Two-stage random-effects meta-analyses of detection outcomes adjusted for study and age, and were estimated in age and density subgroups. Screen-detected cancer characteristics were summarized descriptively within studies and screening-groups. RESULTS: Four prospective studies, from European population-based programs, contributed IPD for 66,451 DBT-screened participants and 170,764 DM-screened participants. Age-adjusted pooled CDR difference between DBT and DM was 25.49 of 10,000 (95% CI:6.73-44.25). There was suggestive evidence of a higher CDR for DBT compared to DM in the high-density (35.19 of 10,000; 95% CI:17.82-56.56) compared to low-density (17.4 of 10,000; 95% CI:7.62-27.18) group (P = .08). Pooled CDR difference between DBT and DM did not differ across age-groups (P = .71). Age-adjusted recall rate difference was 0.18% (95% CI:-0.80-1.17), indicating no difference between DBT and DM- this finding did not differ across age-groups (P = .96). Recall PPV was higher for DBT than DM with an estimated rate ratio of 1.31 (95% CI:1.07-1.61). DISCUSSION: DBT improved CDR compared to DM in all age and density groups. DBT also had higher recall PPV than DM, although further research is needed to explore the heterogeneity in recall rates across studies.

Distributional regression in clinical trials: treatment effects on parameters other than the mean.

BACKGROUND: The classical linear model is widely used in the analysis of clinical trials with continuous outcomes. However, required model assumptions are frequently not met, resulting in estimates of treatment effect that can be inefficient and biased. In addition, traditional models assess treatment effect only on the mean response, and not on other aspects of the response, such as the variance. Distributional regression modelling overcomes these limitations. The purpose of this paper is to demonstrate its usefulness for the analysis of clinical trials, and superior performance to that of traditional models. METHODS: Distributional regression models are demonstrated, and contrasted with normal linear models, on data from the LIPID randomized controlled trial, which compared the effects of pravastatin with placebo in patients with coronary heart disease. Systolic blood pressure (SBP) and the biomarker midregional pro-adrenomedullin (MR-proADM) were analysed. Treatment effect was estimated in models that used response distributions more appropriate than the normal (Box-Cox-t and Johnson's Su for MR-proADM and SBP, respectively), applied censoring below the detection limit of MR-proADM, estimated treatment effect on distributional parameters other than the mean, and included random effects for longitudinal observations. A simulation study was conducted to compare the performance of distributional regression models with normal linear regression, under conditions mimicking the LIPID study. The R package gamlss (Generalized Additive Models for Location, Scale and Shape), which implements maximum likelihood estimation for distributional regression modelling, was used throughout. RESULTS: In all cases the distributional regression models fit the data well, in contrast to poor fits obtained for traditional models; for MR-proADM a small but significant treatment effect on the mean was detected by the distributional regression model and not the normal model; and for SBP a beneficial treatment effect on the variance was demonstrated. In the simulation study distributional models strongly outperformed normal models when the response variable was non-normal and heterogeneous; and there was no disadvantage introduced by the use of distributional regression modelling when the response satisfied the normal linear model assumptions. CONCLUSIONS: Distributional regression models are a rich framework, largely untapped in the clinical trials world. We have demonstrated a sample of the capabilities of these models for the analysis of trials. If interest lies in accurate estimation of treatment effect on the mean, or other distributional features such as variance, the use of distributional regression modelling will yield superior estimates to traditional normal models, and is strongly recommended. TRIAL REGISTRATION: The LIPID trial was retrospectively registered on ANZCTR on 27/04/2016, registration number ACTRN12616000535471 .

Unpacking the behavioural components and delivery features of early childhood obesity prevention interventions in the TOPCHILD Collaboration: a systematic review and intervention coding protocol.

INTRODUCTION: Little is known about how early (eg, commencing antenatally or in the first 12 months after birth) obesity prevention interventions seek to change behaviour and which components are or are not effective. This study aims to (1) characterise early obesity prevention interventions in terms of target behaviours, delivery features and behaviour change techniques (BCTs), (2) explore similarities and differences in BCTs used to target behaviours and (3) explore effectiveness of intervention components in preventing childhood obesity. METHODS AND ANALYSIS: Annual comprehensive systematic searches will be performed in Epub Ahead of Print/MEDLINE, Embase, Cochrane (CENTRAL), CINAHL, PsycINFO, as well as clinical trial registries. Eligible randomised controlled trials of behavioural interventions to prevent childhood obesity commencing antenatally or in the first year after birth will be invited to join the Transforming Obesity in CHILDren Collaboration. Standard ontologies will be used to code target behaviours, delivery features and BCTs in both published and unpublished intervention materials provided by trialists. Narrative syntheses will be performed to summarise intervention components and compare applied BCTs by types of target behaviours. Exploratory analyses will be undertaken to assess effectiveness of intervention components. ETHICS AND DISSEMINATION: The study has been approved by The University of Sydney Human Research Ethics Committee (project no. 2020/273) and Flinders University Social and Behavioural Research Ethics Committee (project no. HREC CIA2133-1). The study's findings will be disseminated through peer-reviewed publications, conference presentations and targeted communication with key stakeholders. PROSPERO REGISTRATION NUMBER: CRD42020177408.

Transforming Obesity Prevention for CHILDren (TOPCHILD) Collaboration: protocol for a systematic review with individual participant data meta-analysis of behavioural interventions for the prevention of early childhood obesity.

INTRODUCTION: Behavioural interventions in early life appear to show some effect in reducing childhood overweight and obesity. However, uncertainty remains regarding their overall effectiveness, and whether effectiveness differs among key subgroups. These evidence gaps have prompted an increase in very early childhood obesity prevention trials worldwide. Combining the individual participant data (IPD) from these trials will enhance statistical power to determine overall effectiveness and enable examination of individual and trial-level subgroups. We present a protocol for a systematic review with IPD meta-analysis to evaluate the effectiveness of obesity prevention interventions commencing antenatally or in the first year after birth, and to explore whether there are differential effects among key subgroups. METHODS AND ANALYSIS: Systematic searches of Medline, Embase, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycInfo and trial registries for all ongoing and completed randomised controlled trials evaluating behavioural interventions for the prevention of early childhood obesity have been completed up to March 2021 and will be updated annually to include additional trials. Eligible trialists will be asked to share their IPD; if unavailable, aggregate data will be used where possible. An IPD meta-analysis and a nested prospective meta-analysis will be performed using methodologies recommended by the Cochrane Collaboration. The primary outcome will be body mass index z-score at age 24±6 months using WHO Growth Standards, and effect differences will be explored among prespecified individual and trial-level subgroups. Secondary outcomes include other child weight-related measures, infant feeding, dietary intake, physical activity, sedentary behaviours, sleep, parenting measures and adverse events. ETHICS AND DISSEMINATION: Approved by The University of Sydney Human Research Ethics Committee (2020/273) and Flinders University Social and Behavioural Research Ethics Committee (HREC CIA2133-1). Results will be relevant to clinicians, child health services, researchers, policy-makers and families, and will be disseminated via publications, presentations and media releases. PROSPERO REGISTRATION NUMBER: CRD42020177408.

Rapid Adaptation of Cancer Education in Response to the COVID-19 Pandemic: Evaluation of a Live Virtual Statistics and Research Skills Workshop for Oncology Trainees.

Due to COVID-19, an annual interactive statistics and research methodology workshop for radiation oncology trainees was adapted at short notice into a live virtual format. This study aimed to evaluate trainee opinions around the educational value of the workshop, logistical aspects and impact on interactivity. A post-course on-line survey was completed by 26/42 trainee attendees (response rate 62%). For five pre-specified learning outcomes (LO), 58 to 69% of trainees agreed that the LO was completely or largely met (Likert scores 6 and 7 on a scale 1 = not met at all; 7 = completely met). All trainees felt that logistical aspects of the workshop including organisation, accessibility to the platform and sound/image quality were good or excellent. With regard to opportunities for interaction and suitability for small-group 'break-out' sessions, the majority felt that interaction could be adequately maintained whilst just under a quarter felt the delivery method was not fit for the purpose. Networking/social engagement with peers and teachers was the factor most impaired using the live virtual delivery format. Over three-quarters of trainees replied they would favour the current event or other educational sessions being offered (at least as an option) in a virtual format in the future. Cost and convenience were given as the major non-COVID-19-related benefits of virtual on-line learning. These preliminary findings provide valuable feedback to help adapt or develop further on-line educational and training initiatives that will be necessary in the COVID-19 pandemic period and beyond.

Clinical Trial Protocol for HyNOVA: Hyperthermic and Normothermic intraperitoneal chemotherapy following interval cytoreductive surgery for stage III epithelial OVArian, fallopian tube and primary peritoneal cancer (ANZGOG1901/2020).

BACKGROUND: Ovarian cancer is the most lethal gynecological cancer, causing over 200,000 deaths worldwide in 2020. Initial standard treatment for primary ovarian cancer is optimal cytoreductive surgery (CRS) preceded and/or followed by intravenous platinum-based chemotherapy. However, most women develop recurrence within the peritoneal cavity and die of disease. Results of the OVIHIPEC 1 trial (2018) showed improved survival of 34% when hyperthermic intraperitoneal chemotherapy (HIPEC) was given immediately following interval-CRS in women with stage III disease. However, it is unknown if the effect of HIPEC is due to hyperthermia, one extra cycle of intraperitoneal (IP) chemotherapy, or other factors. There is also concern that hyperthermia might be associated with an increase in adverse events (AEs) due to a heightened systemic inflammatory response. HyNOVA is a seamless, multi-stage randomized study that attempts to answer these questions by comparing HIPEC to normothermic intraperitoneal chemotherapy (NIPEC), focusing on safety (stage 1), then assessing activity (stage 2) and effectiveness (stage 3). In this initial study, we hypothesize that NIPEC will result in a lower rate of severe AEs compared to HIPEC. METHODS: This initial stage of HyNOVA is a phase II study of 80 women with International Federation of Gynaecology and Obstetrics stage III epithelial ovarian cancer, with at least stable disease following 3-4 cycles of neoadjuvant chemotherapy, achieving interval-CRS to <2.5 mm residual disease. Participants are randomized 1:1 to receive IP cisplatin 100 mg/m² for 90 minutes either as HIPEC, heated to 42°C (41.5°C-42.5°C), or NIPEC, at 37°C (36.5°C-37.5°C). The primary outcome is the proportion of AEs ≥ grade 3 occurring within 90 days. Secondary outcomes are AE of interest, surgical morbidity, patient reported outcomes, resource allocation, feasibility, progression-free survival and overall survival. AEs are measured using both CTCAE v5.0 and Clavien-Dindo classification, particularly infection, pain, bowel dysfunction, and anemia. Tertiary outcomes are potential predictive biomarkers measured before and after HIPEC/NIPEC including circulating cell-free tumor DNA, tissue factors, and systemic inflammatory markers. There are 4 participating Australian sites with experience in CRS and HIPEC for peritoneal malignancy. HyNOVA is funded by an MRFF grant (APP1199155). TRIAL REGISTRATION: ANZCTR Identifier: ACTRN12621000269831.

A consensus-based core feature set for surgical complexity at laparoscopic hysterectomy.

BACKGROUND: There are no current standardized and accepted methods to characterize the surgical complexity of a laparoscopic hysterectomy. This leads to challenges when trying to understand the relationship between the patient and the surgical features and outcomes. The development of core feature sets for laparoscopic hysterectomy studies would enable future trials to measure the similar meaningful variables that can contribute to surgical complexity and outcomes. OBJECTIVE: The purpose of this study was to develop a core feature set for the surgical complexity of a laparoscopic hysterectomy. STUDY DESIGN: This was an international Delphi consensus study. A comprehensive literature review was conducted to identify the features that were reported in studies on laparoscopic hysterectomy complexity. All the features were presented for evaluation and prioritization to key experts in 3 rounds of online surveys. A priori consensus criteria were used to reach agreement on the final outcomes for inclusion in the core feature set. RESULTS: Experts represented North America, South America, Europe, Africa, Asia, and Oceania. Most of them had fellowship training in minimally invasive gynecologic surgery. Sixty-four potential features were entered into round 1. Experts reached a consensus on 7 features to be included in the core feature set. These features were grouped under the following domains: 1) patient features, 2) uterine features, and 3) nonuterine pelvic features. The patient features include obesity and other nonobesity comorbidities that alter or limit the ability of a surgeon to perform the basic or routine steps in a laparoscopic hysterectomy. The uterine features include the size and presence of fibroids. The nonuterine pelvic features include endometriosis, ovarian cysts, and adhesions (bladder-to-uterus, rectouterine pouch, and other adhesions). CONCLUSION: Using robust consensus science methods, an international consortium of experts has developed a core feature set that should be assessed and reported in all future studies that aim to assess the relationship between the patient features and surgical outcomes of laparoscopic hysterectomy.

Effects of delayed versus immediate umbilical cord clamping in reducing death or major disability at 2 years corrected age among very preterm infants (APTS): a multicentre, randomised clinical trial.

BACKGROUND: Very preterm infants are at increased risk of adverse outcomes in early childhood. We assessed whether delayed clamping of the umbilical cord reduces mortality or major disability at 2 years in the APTS Childhood Follow Up Study. METHODS: In this long-term follow-up analysis of the multicentre, randomised APTS trial in 25 centres in seven countries, infants (<30 weeks gestation) were randomly assigned before birth (1:1) to have clinicians aim to delay clamping for 60 s or more or clamp within 10 s of birth, both without cord milking. The primary outcome was death or major disability (cerebral palsy, severe visual loss, deafness requiring a hearing aid or cochlear implants, major language or speech problems, or cognitive delay) at 2 years corrected age, analysed in the intention-to-treat population. This trial is registered with the Australian and New Zealand Clinical Trials Registry (ACTRN12610000633088). FINDINGS: Between Oct 21, 2009, and Jan 6, 2017, consent was obtained for follow-up for 1531 infants, of whom 767 were randomly assigned to delayed clamping and 764 to immediate clamping. 384 (25%) of 1531 infants were multiple births, 862 (56%) infants were male, and 505 (33%) were born before 27 weeks gestation. 564 (74%) of 767 infants assigned to delayed clamping and 726 (96%) of 764 infants assigned to immediate clamping received treatment that fully adhered to the protocol. Death or major disability was determined in 1419 (93%) infants and occurred in 204 (29%) of 709 infants who were assigned to delayed clamping versus 240 (34%) of 710 assigned to immediate clamping, (relative risk [RR]) 0·83, 95% CI 0·72-0·95; p=0·010). 60 (8%) of 725 infants in the delayed clamping group and 81 (11%) of 720 infants in the immediate clamping group died by 2 years of age (RR 0·70, 95% CI 0·52-0·95); among those who survived, major disability at 2 years occurred in 23% (144/627) versus 26% (159/603) of infants, respectively (RR 0·88, 0·74-1·04). INTERPRETATION: Clamping the umbilical cord at least 60 s after birth reduced the risk of death or major disability at 2 years by 17%, reflecting a 30% reduction in relative mortality with no difference in major disability. FUNDING: Australian National Health and Medical Research Council.

Results of PD-L1 Analysis of Women Treated with Durvalumab in Advanced Endometrial Carcinoma (PHAEDRA).

Women with advanced endometrial carcinoma (EC) with mismatch repair (MMR) deficiency have improved outcomes when treated with immune checkpoint inhibitors; however, additional biomarkers are needed to identify women most likely to respond. Scores for programmed death ligand 1 (PD-L1), immunohistochemical staining of tumor (TC+), immune cells (IC+) and presence of tumor-associated immune cells (ICP) on MMR deficient (n = 34) and proficient (n = 33) EC from women treated with durvalumab in the PHAEDRA trial (ANZGOG1601/CTC0144) (trial registration number ACTRN12617000106336, prospectively registered 19 January 2017) are reported and correlated with outcome. Receiver operating characteristic (ROC) analyses and area under the ROC curve were used to determine optimal cutpoints. Performance was compared with median cutpoints and two algorithms; a novel algorithm derived from optimal cutpoints (TC+ ≥ 1 or ICP ≥ 10 or IC+ ≥ 35) and the Ventana urothelial carcinoma (UC) algorithm (either TC+ ≥ 25, ICP > 1 and IC+ ≥ 25 or ICP = 1 and IC+ = 100). The cutpoint ICP ≥ 10 had highest sensitivity (53%) and specificity (82%), being prognostic for progression-free survival (PFS) (p = 0.01), while the optimal cutpoints algorithm was associated with overall survival (p = 0.02); these results were not significant after adjusting for MMR status. The optimal cutpoints algorithm identified non-responders (p = 0.02) with high sensitivity (88%) and negative predictive value (92%), remaining significant after adjustment for MMR. Although MMR status had the strongest association with response, further work to determine the significance of ICP ≥ 10 and the novel optimal cutpoint algorithm is needed.