Intrauterine levonorgestrel (LNG-IUD) is used to treat patients with endometrial adenocarcinoma (EAC) and endometrial hyperplasia with atypia (EHA) but limited evidence is available on its ...effectiveness. The study determined the extent to which LNG-IUD with or without metformin (M) or weight loss (WL) achieves a pathological complete response (pCR) in patients with EAC or EHA.
This phase II randomized controlled clinical trial enrolled patients with histologically confirmed, clinically stage 1 FIGO grade 1 EAC or EHA; a body mass index > 30 kg/m2; a depth of myometrial invasion of less than 50% on MRI; a serum CA125 ≤ 30 U/mL. All patients received LNG-IUD and were randomized to observation (OBS), M (500 mg orally twice daily), or WL (pooled analysis). The primary outcome measure was the proportion of patients developing a pCR (defined as absence of any evidence of EAC or EHA) after 6 months.
From December 2012 to October 2019, 165 patients were enrolled and 154 completed the 6-months follow up. Women had a mean age of 53 years, and a mean BMI of 48 kg/m2. Ninety-six patients were diagnosed with EAC (58%) and 69 patients with EHA (42%). Thirty-five participants were randomized to OBS, 36 to WL and 47 to M (10 patients were withdrawn). After 6 months the rate of pCR was 61% (95% CI 42% to 77%) for OBS, 67% (95% CI 48% to 82%) for WL and 57% (95% CI 41% to 72%) for M. Across the three treatment groups, the pCR was 82% and 43% for EHA and EAC, respectively.
Complete response rates at 6 months were encouraging for patients with EAC and EHA across the three groups.
U.S. National Library of Medicine, NCT01686126.
•LNG-IUD is commonly used to treat patients with EHA or EAC.•Complete response rates were 43% and 82%, for EAC and EHA, respectively.•Pathological complete response was 61% for LNG-IUD alone.•Pathological complete response was 67% for LNG-IUD plus weight loss.•Pathological complete response was 57% for LNG-IUD plus metformin.
Objective To determine whether delayed cord clamping improves systemic blood flow compared with immediate cord clamping in very preterm infants in the first 24 hours. Study design Women delivering at ...<30 weeks' gestation at 5 tertiary centers were randomized to receive immediate cord clamping (<10 seconds) or delayed cord clamping (≥60 seconds). Echocardiography and cardiorespiratory data were collected at 3, 9, and 24 hours after birth. The primary outcome was mean lowest superior vena cava (SVC) flow. Results Of 266 infants enrolled, 133 were randomized to immediate cord clamping and 133 to delayed cord clamping. The 2 groups were similar at baseline, including mean gestation (immediate cord clamping 28 weeks vs delayed cord clamping 28 weeks) and birth weight (immediate cord clamping 1003 g vs delayed cord clamping 1044 g). There was no significant difference between groups in the primary outcome of mean lowest SVC flow (immediate cord clamping 71.4 mL/kg/min SD 28.1 vs delayed cord clamping 70.2 mL/kg/min SD 26.9; P = .7). For secondary outcomes, hemoglobin increased by 0.9 g/dL at 6 hours in the group with delayed cord clamping (95% CI 3.9, 14.4; P = .0005, adjusted for baseline). The group with delayed cord clamping had lower right ventricular output (−21.9 mL/kg/min, 95% CI −39.0, −4.7; P = .01). Rates of treated hypotension, ductus arteriosus size and shunt direction, and treatment of the ductus arteriosus were similar. Conclusions Delayed cord clamping had no effect on systemic blood flow measured as mean lowest SVC flow in the first 24 hours in infants <30 weeks' gestation. Trial registration Australia New Zealand Clinical Trials Registry: ACTRN12610000633088.
In patients with diabetes mellitus presenting with ST elevation myocardial infarction (STEMI) the degree to which cardiac death rates may be attributed to an increased burden of coronary artery ...disease is not clear.
This prospective observational study examines rates of cardiac death between those with and without diabetes at long term follow up, stratified by presence of multivessel disease (MVD), in consecutive STEMI patients from 5 Australian hospitals.
Amongst 2083 patients, 393 patients had diabetes (18.8%), and 810 (38.8%) had MVD. Patients with diabetes were more likely to have MVD 48.6% (191/393) than patients without diabetes 36.6% (619/1690; p < .001). At final follow up (median 3.6 years IQR 2.4–5.4) cardiac death occurred in 37/393 diabetic patients and 92/1690 nondiabetic patients (adjusted HR1.67, 95% CI 1.10–2.52). In those with MVD cardiac death occurred in 27/191 diabetic patients, and 54/619 non-diabetic patients (adjusted HR 1.94; 95% CI 1.17–3.23). In single vessel disease (SVD) cardiac death occurred in 10/202 diabetic patients, and 38/1071 non-diabetic patients (adjusted HR 1.37; 95% CI 0.65–2.89). Both diabetes and MVD were independently associated with cardiac death.
STEMI patients with diabetes are more likely to have MVD, with an absolute difference in MVD rates of 12%, and higher rates of cardiac death. Randomized trials studying these high risk patients are needed to reduce cardiac mortality in patients with diabetes, MVD and STEMI.
•STEMI patients with diabetes have more MVD than non-diabetic patients, with an absolute difference in rates of MVD of 12%•Cardiac death rates in MVD & STEMI are higher in diabetic patients than non-diabetic patients (aHR 1.94; 95% CI 1.17–3.23)•Differences in cardiac death rates between DM and non-DM patients are evident early & extend years into late follow-up
Variance regression allows for heterogeneous variance, or heteroscedasticity, by incorporating a regression model into the variance. This paper uses a variant of the expectation–maximisation ...algorithm to develop a new method for fitting additive variance regression models that allow for regression in both the mean and the variance. The algorithm is easily extended to allow for B-spline bases, thus allowing for the incorporation of a semi-parametric model in both the mean and variance. Although there are existing methods to fit these types of models, this new algorithm provides a reliable alternative approach that is not susceptible to numerical instability that can arise in this constrained estimation context. We utilise the developed algorithm with a series of simulation studies and analyse illustrative data. Various simulation studies show that the algorithm can recover the true model for a variety of scenarios. We also study automatic selection of model complexity based on information-based criteria, and show that the Akaike information criterion is useful for choosing the optimal number of knots in a B-spline model. An R package is available for implementing these methods.
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.
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.
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.
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
•We use individual participant data two-stage meta-analyses•Detection and recalls were compared for tomosynthesis (DBT) and mammography (DM)•DBT had higher cancer detection rate than DM across all ...age and density subgroups•DBT screen-recall had higher positive predictive value than DM recall•Recall rates were heterogenous across studies
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.
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.
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).
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.
We use individual participant data two-stage meta-analyses. Detection and recalls were compared for tomosynthesis (DBT) and mammography (DM). DBT had a higher cancer detection rate than DM across all age and density subgroups. DBT screen-recall had higher positive predictive value than DM recall. Recall rates were heterogenous across studies.
Abstract 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.
Women and patients with incomplete revascularization (IR) have a worse prognosis after ST elevation myocardial infarction (STEMI). However, the extent to which IR affects outcomes for women with ...STEMI compared with men is not well characterized. Thus, we examined late outcomes of 589 consecutive STEMI patients who received percutaneous coronary intervention and assessed SYNTAX scores (SS), both at baseline and after all procedures (residual SS). A residual SS >8 defined IR. The primary end point was cardiac death or myocardial infarction (MI), with median follow-up of 3.6 years interquartile range IQR 2.6 to 4.7. Women (n = 123) had lower baseline SSs 15.0 IQR 9 to 20, than men (n = 466), 16.0 IQR 9 to 20; p = 0.02. After all planned procedures, the residual SS was 5.0 IQR 0 to 9 in women and 5.0 (IQR 1 to 11 in men, p = 0.37. Cardiac death or MI occurred in (97/589) patients (16%), 24% (30/123) in women and 14% (67/466) in men (hazard ratio HR 1.75; 95% confidence intervals CI 1.14 to 2.69; p = 0.01). In patients with residual SYNTAX score (rSS) >8 cardiac death or MI occurred in 43% (15/35) of women and 23% 36/158 men (HR 2.14; 95% CI 1.17 to 3.91; p = 0.01). In patients with rSS = 0 to 8 cardiac death or MI occurred in 17% (15/88) of women and 10% of men (31/308) (HR 1.68; 95% CI 0.91 to 3.12; p = 0.10; interaction p value 0.58). Multivariate analysis found women were 1.77 times more likely than men to experience cardiac death or MI (95% CI 1.13 to 2.77; p = 0.01). In conclusion, we found despite a lower burden of disease at presentation and no difference in rates of IR between men and women, outcome differences were substantial. Women with rSS >8 were twice as likely as men with the same rSS to experience cardiac death or MI post-STEMI. Differences remained significant postrisk adjustment.
Effective interventions are required to prevent the current rapid increase in the prevalence of Type 2 diabetes. Clinical trials of large-scale interventions to prevent Type 2 diabetes are essential ...but recruitment is challenging and expensive, and there are limited data regarding the most cost-effective and efficient approaches to recruitment. This paper aims to evaluate the cost and effectiveness of a range of promotional strategies used to recruit men to a large Type 2 diabetes prevention trial.
An observational study was conducted nested within the Testosterone for the Prevention of Type 2 Diabetes (T4DM) study, a large, multi-centre randomised controlled trial (RCT) of testosterone treatment for the prevention of Type 2 diabetes in men aged 50-74 years at high risk of developing diabetes. Study participation was promoted via mainstream media-television, newspaper and radio; direct marketing using mass mail-outs, publicly displayed posters and attendance at local events; digital platforms, including Facebook and Google; and online promotions by community organisations and businesses. For each strategy, the resulting number of participants and the direct cost involved were recorded. The staff effort required for each strategy was estimated based on feedback from staff.
Of 19,022 men screened for the study, 1007 (5%) were enrolled. The most effective recruitment strategies were targeted radio advertising (accounting for 42% of participants), television news coverage (20%) and mass mail-outs (17%). Other strategies, including radio news, publicly displayed posters, attendance at local events, newspaper advertising, online promotions and Google and Facebook advertising, each accounted for no more than 4% of enrolled participants. Recruitment promotions cost an average of AU$594 per randomised participant. The most cost-effective paid strategy was mass mail-outs by a government health agency (AU$745 per participant). Other paid strategies were more expensive: mail-out by general practitioners (GPs) (AU$1104 per participant), radio advertising (AU$1081) and newspaper advertising (AU$1941).
Radio advertising, television news coverage and mass mail-outs by a government health agency were the most effective recruitment strategies. Close monitoring of recruitment outcomes and ongoing enhancement of recruitment activities played a central role in recruitment to this RCT.
ANZCTR, ID: ACTRN12612000287831 . Registered on 12 March 2012.
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