Explore the vast range of titles available.

In this prospective randomized trial, minimally invasive radical hysterectomy resulted in lower rates of disease-free survival and overall survival than open abdominal radical hysterectomy among women with early-stage cervical cancer. A prospective randomized trial and an epidemiologic study that used large cancer databases (National Cancer Database and SEER) both showed that minimally invasive radical hysterectomy was associated with shorter survival in early cervical cancer than open abdominal radical hysterectomy.

ObjectiveTo conduct a methodological systematic review of multicentre trials of premature infants to (1) determine if and how multiple births have been considered in the design, analysis and reporting of recent trials and (2) assess whether there has been an improvement since the last review was conducted 10 years ago.DesignA systematic search was conducted in PubMed on 28 June 2023 for articles published between June 2018 and June 2023. Articles were eligible for inclusion if they were a multicentre randomised trial of infants born preterm and reported the results of a primary outcome that was measured on an infant or could be attributed to an infant.ResultsWe reviewed 62/74 trials (80%), after determining it was unclear if multiple births were present in the other 20%. 87% of trials (54/62) did not account for multiple births in their sample size calculations and 48% (30/62) did not account for clustering due to multiple births in their analyses. Problems were not limited to lower-ranked journals. No trials reported the intraclass correlation coefficient for any outcomes, indicating the degree of clustering present.ConclusionsPersistent problems remain with the design and analysis of multicentre trials of premature infants due to ignoring the complexity that comes with the inclusion of multiple births, despite methods available to address this. Trialists should consider the impact of multiple births in their trial design and analysis. Readers of neonatal trials should be aware of these issues, particularly those who peer review papers.

In the phase 3 LACC trial and a subsequent population-level review, minimally invasive radical hysterectomy was shown to be associated with worse disease-free survival and higher recurrence rates than was open radical hysterectomy in patients with early stage cervical cancer. Here, we report the results of a secondary endpoint, quality of life, of the LACC trial. The LACC trial was a randomised, open-label, phase 3, non-inferiority trial done in 33 centres worldwide. Eligible participants were women aged 18 years or older with International Federation of Gynaecology and Obstetrics (FIGO) stage IA1 with lymphovascular space invasion, IA2, or IB1 adenocarcinoma, squamous cell carcinoma, or adenosquamous carcinoma of the cervix, with an Eastern Cooperative Oncology Group performance status of 0 or 1, who were scheduled to have a type 2 or 3 radical hysterectomy. Participants were randomly assigned (1:1) to receive open or minimally invasive radical hysterectomy. Randomisation was done centrally using a computerised minimisation program, stratified by centre, disease stage according to FIGO guidelines, and age. Neither participants nor investigators were masked to treatment allocation. The primary endpoint of the LACC trial was disease-free survival at 4·5 years, and quality of life was a secondary endpoint. Eligible patients completed validated quality-of-life and symptom assessments (12-item Short Form Health Survey [SF-12], Functional Assessment of Cancer Therapy–Cervical [FACT-Cx], EuroQoL-5D [EQ-5D], and MD Anderson Symptom Inventory [MDASI]) before surgery and at 1 and 6 weeks and 3 and 6 months after surgery (FACT-Cx was also completed at additional timepoints up to 54 months after surgery). Differences in quality of life over time between treatment groups were assessed in the modified intention-to-treat population, which included all patients who had surgery and completed at least one baseline (pretreatment) and one follow-up (at any timepoint after surgery) questionnaire, using generalised estimating equations. The LACC trial is registered with ClinicalTrials.gov, NCT00614211. Between Jan 31, 2008, and June 22, 2017, 631 patients were enrolled; 312 assigned to the open surgery group and 319 assigned to the minimally invasive surgery group. 496 (79%) of 631 patients had surgery completed at least one baseline and one follow-up quality-of-life survey and were included in the modified intention-to-treat analysis (244 [78%] of 312 patients in the open surgery group and 252 [79%] of 319 participants in the minimally invasive surgery group). Median follow-up was 3·0 years (IQR 1·7–4·5). At baseline, no differences in the mean FACT-Cx total score were identified between the open surgery (129·3 [SD 18·8]) and minimally invasive surgery groups (129·8 [19·8]). No differences in mean FACT-Cx total scores were identified between the groups 6 weeks after surgery (128·7 [SD 19·9] in the open surgery group vs 130·0 [19·8] in the minimally invasive surgery group) or 3 months after surgery (132·0 [21·7] vs 133·0 [22·1]). Since recurrence rates are higher and disease-free survival is lower for minimally invasive radical hysterectomy than for open surgery, and postoperative quality of life is similar between the treatment groups, gynaecological oncologists should recommend open radical hysterectomy for patients with early stage cervical cancer. MD Anderson Cancer Center and Medtronic.

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 S u 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 .

Abstract Context Testosterone treatment increases bone mineral density (BMD) in hypogonadal men. Effects on bone microarchitecture, a determinant of fracture risk, are unknown. Objective We aimed to determine the effect of testosterone treatment on bone microarchitecture using high resolution–peripheral quantitative computed tomography (HR-pQCT). Methods Men ≥ 50 years of age were recruited from 6 Australian centers and were randomized to receive injectable testosterone undecanoate or placebo over 2 years on the background of a community-based lifestyle program. The primary endpoint was cortical volumetric BMD (vBMD) at the distal tibia, measured using HR-pQCT in 177 men (1 center). Secondary endpoints included other HR-pQCT parameters and bone remodeling markers. Areal BMD (aBMD) was measured by dual-energy x-ray absorptiometry (DXA) in 601 men (5 centers). Using a linear mixed model for repeated measures, the mean adjusted differences (95% CI) at 12 and 24 months between groups are reported as treatment effect. Results Over 24 months, testosterone treatment, versus placebo, increased tibial cortical vBMD, 9.33 mg hydroxyapatite (HA)/cm3) (3.96, 14.71), P < 0.001 or 3.1% (1.2, 5.0); radial cortical vBMD, 8.96 mg HA/cm3 (3.30, 14.62), P = 0.005 or 2.9% (1.0, 4.9); total tibial vBMD, 4.16 mg HA/cm3 (2.14, 6.19), P < 0.001 or 1.3% (0.6, 1.9); and total radial vBMD, 4.42 mg HA/cm3 (1.67, 7.16), P = 0.002 or 1.8% (0.4, 2.0). Testosterone also significantly increased cortical area and thickness at both sites. Effects on trabecular architecture were minor. Testosterone reduced bone remodeling markers CTX, −48.1 ng/L [−81.1, −15.1], P < 0.001 and P1NP, −6.8 μg/L[−10.9, −2.7], P < 0.001. Testosterone significantly increased aBMD at the lumbar spine, 0.04 g/cm2 (0.03, 0.05), P < 0.001 and the total hip, 0.01 g/cm2 (0.01, 0.02), P < 0.001. Conclusion In men ≥ 50 years of age, testosterone treatment for 2 years increased volumetric bone density, predominantly via effects on cortical bone. Implications for fracture risk reduction require further study.

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. 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. 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. 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.

While normal pelvic organ support has been defined for women with intact uterus, this is not the case for post- hysterectomy vault descent. A recent systematic review found that definitions of apical prolapse are highly variable. To investigate the relationship between prolapse symptoms and apical POP-Q measurements and establish cutoffs for 'significant apical descent using receiver-operator characteristics (ROC) statistics. Retrospective analysis of patients seen at a tertiary urogynecological unit. Evaluation included a standardized interview and clinical assessment using the Pelvic Organ Prolapse Quantification (POP-Q) system. ROC curves were prepared for the relationship between prolapse symptoms and POP-Q measure \"C\". The records of 3010 women were available for analysis. Prolapse symptoms were reported by 52.3% (n = 1573), with a mean bother of 5.9 (SD 3.0, range 0-10). POP-Q point \"C\" was associated with symptoms of prolapse (p <0.0001) and prolapse bother (p <0.0001) on both univariate and multivariate analysis. ROC curves for women with and without uterus were similar, although the relationship between apical descent and symptoms of prolapse was stronger for women with uterus (AUC 0.728 versus 0.678). After controlling for multi-compartment prolapse, the models improved, resulting in AUCs of 0.782 and 0.720. For prediction of prolapse symptoms, cutoffs were set at C = -5 (sensitivity 0.73, specificity 0.67 with uterus in situ, sensitivity 0.59, specificity, 0.73 after hysterectomy). A cut- off for 'significant central compartment descent' of 5 cm above the hymen on Valsalva seems valid regardless of previous hysterectomy.

ObjectiveLarge-scale mortality trials require reliable secondary assessments of impairment. We compared the Ages and Stages Questionnaire (ASQ-3), a screening tool self-administered by parents, in classifying impairment using the ‘gold standard’ Bayley Scales of Infant Development (Bayley-III), a diagnostic tool administered by trained assessors.DesignAnalysis of 405 children around 2 years corrected age from the Australian Placental Transfusion Study, a trial conducted over 8 years.SettingSecondary analysis of international, open-label, multicentre randomised trial.PatientsChildren born <30 weeks gestation.InterventionsImmediate (<10 s) versus delayed (60 s+) cord clamping.Main outcomesASQ-3 and Bayley-III assessments around 2 years corrected age. Impairment (or developmental delay) was defined as <2 SD below the mean (<70) for Bayley-III domains.ResultsThe area under the receiver operating curve for ASQ-3 domains predicting delay was 0.75–0.99. Sensitivity for predicting delay was 57%–100%, while specificity was 88%–90%.We modelled the cost and sample size using a less expensive, though less precise, screening assessment for impairment compared with a more costly diagnostic assessment. For detecting a 25% reduction in the relative risk of delay, using ASQ-3 rather than Bayley-III could require double the sample size (15 000 to 30 000), but outcome assessment cost savings would be US$13M (EUR$12M). However, assessment cost savings may be outweighed by upscaling.ConclusionsWhen measuring developmental outcomes in a large-scale clinical trial, using a more precise diagnostic tool may be financially prohibitive, so increasing the sample size and using a less precise but appropriately calibrated tool may be more affordable.Trial registration numberACTRN12610000633088.

Background Randomisation forms the foundation of clinical trials, but its implementation can be prone to error. Often randomisation errors affect few participants and do not seriously compromise the integrity of the trial. However, in some cases randomisation errors can have widespread consequences and call into question the validity of trial conclusions. Published articles may be retracted as a result. Valuable insight can be gained from studying past errors to minimise the risk of similar errors and their disastrous consequences impacting future trials. The aims of this article are to (i) describe examples of major failures of randomisation, and (ii) provide guidance on how to avoid them in practice. Methods Major failures of randomisation were defined as inadvertent errors that affected many trial participants and occurred during the process of designing the randomisation scheme, generating the randomisation schedule, allocating participants to treatment groups, or providing the assigned treatment. Examples of major failures of randomisation were drawn from author experience and through a review of the published literature, which included a systematic search of the Retraction Watch Database for serious randomisation problems that led to the retraction of a published article. Practice points to avoid such errors were developed by consensus among the authors. Results Examples are provided of seven broad types of major failures of randomisation: randomisation schedule followed incorrectly, randomisation schedule sorted incorrectly, randomisation schedule too short, clusters handled incorrectly, incorrect or unknown treatment provided at randomisation, poorly designed randomisation scheme, and programming errors in adaptive randomisation schemes. Practice points for avoiding such errors are presented, including suggestions for written documentation, staff training, and thorough testing of the randomisation process prior to trial commencement. Conclusions Randomisation is of fundamental importance in clinical trials. Greater consideration should be given to the potential for major failures of randomisation and strategies to avoid them. When major failures of randomisation do occur, greater transparency in reporting is needed.