Best practice for analysis of shared clinical trial data

BACKGROUND: Greater transparency, including sharing of patient-level data for further research, is an increasingly important topic for organisations who sponsor, fund and conduct clinical trials. This is a major paradigm shift with the aim of maximising the value of patient-level data from clinical trials for the benefit of future patients and society. We consider the analysis of shared clinical trial data in three broad categories: (1) reanalysis - further investigation of the efficacy and safety of the randomized 3 intervention, (2) meta-analysis, and (3) supplemental analysis for a research question that is not directly assessing the randomized intervention. DISCUSSION: In order to support appropriate interpretation and limit the risk of misleading findings, analysis of shared clinical trial data should have a pre-specified analysis plan. However, it is not generally possible to limit bias and control multiplicity to the extent that is possible in the original trial design, conduct and analysis, and this should be acknowledged and taken into account when interpreting results. We highlight a number of areas where specific considerations arise in planning, conducting, interpreting and reporting analyses of shared clinical trial data. A key issue is that that these analyses essentially share many of the limitations of any post hoc analyses beyond the original specified analyses. The use of individual patient data in meta-analysis can provide increased precision and reduce bias. Supplemental analyses are subject to many of the same issues that arise in broader epidemiological analyses. Specific discussion topics are addressed within each of these areas. SUMMARY: Increased provision of patient-level data from industry and academic-led clinical trials for secondary research can benefit future patients and society. Responsible data sharing, including transparency of the research objectives, analysis plans and of the results will support appropriate interpretation and help to address the risk of misleading results and avoid unfounded health scares

Incisional hernia after upper abdominal surgery: A randomised controlled trial of midline versus transverse incision

Objectives: To determine whether a transverse incision is an alternative to a midline incision in terms of incisional hern

Components Separation Technique Combined with a Double-Mesh Repair for Large Midline Incisional Hernia Repair

Background The surgical treatment of large midline incisional hernias remains a challenge. The aim of this report is to present the results of a new technique for large midline incisional hernia repair which combines the components- separation technique with a double-prostheticmesh repair. Methods The records of all consecutive patients who received a double-mesh combined with the componentsseparation technique for ventral hernia repair were reviewed. The clinical, surgical, and follow-up data were analyzed. Results Nine patients [3 women, 6 men; median age = 62 years (range = 26-77)] were included in the study. Median transverse defect size was 20 cm (range = 15-25). The median duration of hospital stay was 8 days (range = 5-17). Postoperative complications occurred in 66% (6/9). Follow-up [median = 13 months (range = 3-49)] showed no recurrent hernias, but one patient had a small hernia after a relaparotomy for colon carcinoma recurrence. The overall occurrence of wound infections was 44% (4/9). There was no mortality. Conclusion The components-separation technique in combination with a double-mesh has shown a low recurrence rate in the short-term follow-up. However, there is a considerable occurrence of postoperative wound infections. Long-term results of the hernia recurrence rate have to be awaited

Molecular analysis of human endometrium: short-term tibolone signaling differs significantly from estrogen and estrogen + progestagen signaling

Tibolone, a tissue-selective compound with a combination of estrogenic, progestagenic, and androgenic properties, is used as an alternative for estrogen or estrogen plus progesterone hormone therapy for the treatment of symptoms associated with menopause and osteoporosis. The current study compares the endometrial gene expression profiles after short-term (21 days) treatment with tibolone to the profiles after treatment with estradiol-only (E2) and E2 + medroxyprogesterone acetate (E2 + MPA) in healthy postmenopausal women undergoing hysterectomy for endometrial prolapse. The impact of E2 treatment on endometrial gene expression (799 genes) was much higher than the effect of tibolone (173 genes) or E2 + MPA treatment (174 genes). Furthermore, endometrial gene expression profiles after tibolone treatment show a weak similarity to the profiles after E2 treatment (overlap 72 genes) and even less profile similarity to E2 + MPA treatment (overlap 17 genes). Interestingly, 95 tibolone-specific genes were identified. Translation of profile similarity into biological processes and pathways showed that ER-mediated downstream processes, such as cell cycle and cell proliferation, are not affected by E2 + MPA, slightly by tibolone, but are significantly affected by E2. In conclusion, tibolone treatment results in a tibolone-specific gene expression profile in the human endometrium, which shares only limited resemblance to E2 and even less resemblance to E2 + MPA induced profiles

Beyond Gross-Pitaevskii Mean Field Theory

A large number of effects related to the phenomenon of Bose-Einstein Condensation (BEC) can be understood in terms of lowest order mean field theory, whereby the entire system is assumed to be condensed, with thermal and quantum fluctuations completely ignored. Such a treatment leads to the Gross-Pitaevskii Equation (GPE) used extensively throughout this book. Although this theory works remarkably well for a broad range of experimental parameters, a more complete treatment is required for understanding various experiments, including experiments with solitons and vortices. Such treatments should include the dynamical coupling of the condensate to the thermal cloud, the effect of dimensionality, the role of quantum fluctuations, and should also describe the critical regime, including the process of condensate formation. The aim of this Chapter is to give a brief but insightful overview of various recent theories, which extend beyond the GPE. To keep the discussion brief, only the main notions and conclusions will be presented. This Chapter generalizes the presentation of Chapter 1, by explicitly maintaining fluctuations around the condensate order parameter. While the theoretical arguments outlined here are generic, the emphasis is on approaches suitable for describing single weakly-interacting atomic Bose gases in harmonic traps. Interesting effects arising when condensates are trapped in double-well potentials and optical lattices, as well as the cases of spinor condensates, and atomic-molecular coupling, along with the modified or alternative theories needed to describe them, will not be covered here.Comment: Review Article (19 Pages) - To appear in 'Emergent Nonlinear Phenomena in Bose-Einstein Condensates: Theory and Experiment', Edited by P.G. Kevrekidis, D.J. Frantzeskakis and R. Carretero-Gonzalez (Springer Verlag

A randomised controlled trial to evaluate and optimize the use of antiplatelet agents in the perioperative management in patients undergoing general and abdominal surgery- the APAP trial (ISRCTN45810007)

<p>Abstract</p> <p>Background</p> <p>Due to the increase of cardiovascular diseases acetylsalicylic acid (ASA) has become one of the most frequently prescribed drugs these days. Despite the rising number of patients with ASA medication presenting for elective general and abdominal surgery and the potentially increased risk of hemorrhage in these patients, there are no clear, evidence-based guidelines for the perioperative use of antiplatelet agents. The present randomised controlled trial was designed to evaluate the safety and optimize the use of ASA in the perioperative management of patients undergoing general and abdominal surgery.</p> <p>Methods/Design</p> <p>This is a two-arm, monocenter randomised controlled trial. Patients scheduled for elective surgical treatment (i.e. inguinal hernia repair, cholecystectomy and colorectal resections) with ASA as a permanent medication are randomised equally to perioperative continuation or discontinuation of ASA. Patients who are randomised in the discontinuation group stop the administration of ASA five days prior to surgical treatment and start intake of ASA on postoperative day 5. Fifty-two patients will be enrolled in this trial. The primary outcome is the incidence of postoperative bleeding and cardiovascular events at 30 days after surgery. In addition a set of general as well as surgical variables are analysed.</p> <p>Discussion</p> <p>This is a randomised controlled two-group parallel trial designed to assess the safety and optimize the use of ASA in the perioperative management of patients undergoing general and abdominal surgery. The results of this pilot study build the basis for a confirmative randomised controlled trial that may help to clarify the use and potential risk/benefits of perioperative ASA medication in patients undergoing elective surgery.</p> <p>Trial registration</p> <p>The trial is registered with Current Controlled Trials <a href="http://www.controlled-trials.com/ISRCTN45810007">ISRCTN45810007</a>.</p

Age and sex influence marmot antipredator behavior during periods of heightened risk

Animals adjust their antipredator behavior according to environmental variation in risk, and to account for their ability to respond to threats. Intrinsic factors that influence an animal’s ability to respond to predators (e.g., age, body condition) should explain variation in antipredator behavior. For example, a juvenile might allocate more time to vigilance than an adult because mortality as a result of predation is often high for this age class; however, the relationship between age/vulnerability and antipredator behavior is not always clear or as predicted. We explored the influence of intrinsic factors on yellow-bellied marmot (Marmota flaviventris) antipredator behavior using data pooled from 4 years of experiments. We hypothesized that inherently vulnerable animals (e.g., young, males, and individuals in poor condition) would exhibit more antipredator behavior prior to and immediately following conspecific alarm calls. As expected, males and yearlings suppressed foraging more than females and adults following alarm call playbacks. In contrast to predictions, animals in better condition respond more than animals in below average condition. Interestingly, these intrinsic properties did not influence baseline time budgets; animals of all ages, sexes, and condition levels devoted comparable amounts of time to foraging prior to alarm calls. Our results support the hypothesis that inherent differences in vulnerability influence antipredator behavior; furthermore, it appears that a crucial, but poorly acknowledged, interaction exists between risk and state-dependence. Elevated risk may be required to reveal the workings of state-dependent behavior, and studies of antipredator behavior in a single context may draw incomplete conclusions about age- or sex-specific strategies