A systematic review of techniques and interventions for improving adherence to inclusion and exclusion criteria during enrolment into randomised controlled trials

<p>Abstract</p> <p>Background</p> <p>Enrolment of patients into a randomised controlled trial (RCT) in violation of key inclusion or exclusion criteria, may lead to excess avoidable harm. The purpose of this paper was to systematically identify and review techniques and interventions proven to prevent or avoid inappropriate enrolment of patients into RCTs.</p> <p>Methods</p> <p>EMBASE, MEDLINE, Cochrane Database of Systematic Reviews, Cochrane Methodology Register, online abstract repositories, and conference websites were searched. Experts were contacted and bibliographies of retrieved papers hand-searched. The search cut-off date was 31 August 2009.</p> <p>Results</p> <p>No primary publications were found. We identified one study in the grey literature (conference abstracts and presentations) reporting the results of an evaluation of the effectiveness of an intervention designed to prevent or avoid inappropriate enrolment of patients into an RCT. In the context of a multicentre trial, use of a dummy enrolment run-in phase was shown to reduce enrolment errors significantly (<it>P </it>< 0.001), from 16.1% during the run-in phase to < 1% after trial initiation.</p> <p>Conclusions</p> <p>Our systematic search yielded only one technique or intervention shown to improve adherence to eligibility criteria during enrolment into RCTs. Given the potential harm involved in recruiting patients into a clinical trial in violation of key eligibility criteria, future research is needed to better inform those conducting clinical trials of how best to prevent enrolment errors</p

Treatment of squamous cell carcinoma of the uterine cervix with radiation therapy alone: long-term survival, late complications, and incidence of second cancers

The objective of this retrospective study was to determine the survival rate, incidence of late complications, and incidence of second cancers when radiation therapy alone is used for carcinoma of the uterine cervix. Between 1971 and 1995, 1495 patients with squamous cell carcinoma of the uterine cervix (stages I–IV) were treated with radiation therapy alone in our hospital. Radiation therapy consisted of a combination of high-dose-rate intracavitary brachytherapy and external beam radiotherapy. The cumulative 5-year survival rates for stages Ib, II, and III/IVa carcinoma were 93.5, 77.0, and 60.3%, respectively, and the 10-year survival rates were 90.9, 74.5, and 56.1%, respectively. Local control rates for stages Ib, II, and III/IVa carcinoma were 92.0, 79.4 and 64.2%, respectively. Eighty-two (5.5%) patients suffered grade III/IV or V (fatal) complications. A second cancer developed in 13 (0.87%) patients. Second cancers were observed most frequently in the rectum (five cases), colon (three cases), and uterine body (two cases). Long-term follow-up data revealed that our method of radiation therapy alone for locally advanced carcinoma of the uterine cervix is effective, with low incidences of late complications and second cancers

Regional Environmental Breadth Predicts Geographic Range and Longevity in Fossil Marine Genera

Geographic range is a good indicator of extinction susceptibility in fossil marine species and higher taxa. The widely-recognized positive correlation between geographic range and taxonomic duration is typically attributed to either accumulating geographic range with age or an extinction buffering effect, whereby cosmopolitan taxa persist longer because they are reintroduced by dispersal from remote source populations after local extinction. The former hypothesis predicts that all taxa within a region should have equal probabilities of extinction regardless of global distributions while the latter predicts that cosmopolitan genera will have greater survivorship within a region than endemics within the same region. Here we test the assumption that all taxa within a region have equal likelihoods of extinction.We use North American and European occurrences of marine genera from the Paleobiology Database and the areal extent of marine sedimentary cover in North America to show that endemic and cosmopolitan fossil marine genera have significantly different range-duration relationships and that broad geographic range and longevity are both predicted by regional environmental breadth. Specifically, genera that occur outside of the focal region are significantly longer lived and have larger geographic ranges and environmental breadths within the focal region than do their endemic counterparts, even after controlling for differences in sampling intensity. Analyses of the number of paleoenvironmental zones occupied by endemic and cosmopolitan genera suggest that the number of paleoenvironmental zones occupied is a key factor of geographic range that promotes genus survivorship.Wide environmental tolerances within a single region predict both broad geographic range and increased longevity in marine genera over evolutionary time. This result provides a specific driving mechanism for the spatial and temporal distributions of marine genera at regional and global scales and is consistent with the niche-breadth hypothesis operating on macroevolutionary timescales

Molecular pathways involved in the synergistic interaction of the PKCβ inhibitor enzastaurin with the antifolate pemetrexed in non-small cell lung cancer cells

Conventional regimens have limited impact against non-small cell lung cancer (NSCLC). Current research is focusing on multiple pathways as potential targets, and this study investigated molecular mechanisms underlying the combination of the PKCβ inhibitor enzastaurin with the multitargeted antifolate pemetrexed in the NSCLC cells SW1573 and A549. Pharmacologic interaction was studied using the combination-index method, while cell cycle, apoptosis induction, VEGF secretion and ERK1/2 and Akt phosphorylation were studied by flow cytometry and ELISAs. Reverse transcription–PCR, western blot and activity assays were performed to assess whether enzastaurin influenced thymidylate synthase (TS) and the expression of multiple targets involved in cancer signaling and cell cycle distribution. Enzastaurin-pemetrexed combination was highly synergistic and significantly increased apoptosis. Enzastaurin reduced both phosphoCdc25C, resulting in G2/M checkpoint abrogation and apoptosis induction in pemetrexed-damaged cells, and GSK3β and Akt phosphorylation, which was additionally reduced by drug combination (−58% in A549). Enzastaurin also significantly reduced pemetrexed-induced upregulation of TS expression, possibly through E2F-1 reduction, whereas the combination decreased TS in situ activity (>50% in both cell lines) and VEGF secretion. The effects of enzastaurin on signaling pathways involved in cell cycle control, apoptosis and angiogenesis, as well as on the expression of genes involved in pemetrexed activity provide a strong experimental basis to their evaluation as pharmacodynamic markers in clinical trials of enzastaurin-pemetrexed combination in NSCLC patients

Flow-to-fracture transition and pattern formation in a discontinuous shear thickening fluid

Recent theoretical and experimental work suggests a frictionless-frictional transition with increasing inter-particle pressure explains the extreme solid-like response of discontinuous shear thickening suspensions. However, analysis of macroscopic discontinuous shear thickening flow in geometries other than the standard rheometry tools remain scarce. Here we use a Hele-Shaw cell geometry to visualise gas-driven invasion patterns in discontinuous shear thickening cornstarch suspensions. We plot quantitative results from pattern analysis in a volume fraction-pressure phase diagram and explain them in context of rheological measurements. We observe three distinct pattern morphologies: viscous fingering, dendritic fracturing, and system-wide fracturing, which correspond to the same packing fraction ranges as weak shear thickening, discontinuous shear thickening, and shear-jammed regimes

Shape Self-Regulation in Early Lung Morphogenesis

The arborescent architecture of mammalian conductive airways results from the repeated branching of lung endoderm into surrounding mesoderm. Subsequent lung’s striking geometrical features have long raised the question of developmental mechanisms involved in morphogenesis. Many molecular actors have been identified, and several studies demonstrated the central role of Fgf10 and Shh in growth and branching. However, the actual branching mechanism and the way branching events are organized at the organ scale to achieve a self-avoiding tree remain to be understood through a model compatible with evidenced signaling. In this paper we show that the mere diffusion of FGF10 from distal mesenchyme involves differential epithelial proliferation that spontaneously leads to branching. Modeling FGF10 diffusion from sub-mesothelial mesenchyme where Fgf10 is known to be expressed and computing epithelial and mesenchymal growth in a coupled manner, we found that the resulting laplacian dynamics precisely accounts for the patterning of FGF10-induced genes, and that it spontaneously involves differential proliferation leading to a self-avoiding and space-filling tree, through mechanisms that we detail. The tree’s fine morphological features depend on the epithelial growth response to FGF10, underlain by the lung’s complex regulatory network. Notably, our results suggest that no branching information has to be encoded and that no master routine is required to organize branching events at the organ scale. Despite its simplicity, this model identifies key mechanisms of lung development, from branching to organ-scale organization, and could prove relevant to the development of other branched organs relying on similar pathways

Does the Potential for Chaos Constrain the Embryonic Cell-Cycle Oscillator?

Although many of the core components of the embryonic cell-cycle network have been elucidated, the question of how embryos achieve robust, synchronous cellular divisions post-fertilization remains unexplored. What are the different schemes that could be implemented by the embryo to achieve synchronization? By extending a cell-cycle model previously developed for embryos of the frog Xenopus laevis to include the spatial dimensions of the embryo, we establish a novel role for the rapid, fertilization-initiated calcium wave that triggers cell-cycle oscillations. Specifically, in our simulations a fast calcium wave results in synchronized cell cycles, while a slow wave results in full-blown spatio-temporal chaos. We show that such chaos would ultimately lead to an unpredictable patchwork of cell divisions across the embryo. Given this potential for chaos, our results indicate a novel design principle whereby the fast calcium-wave trigger following embryo fertilization synchronizes cell divisions

Avoiding or Reversing Hartmann’s Procedure Provides Improved Quality of Life After Perforated Diverticulitis

# 2010 The Author(s). This article is published with open access at Springerlink.com Introduction The existing literature regarding acute perforated diverticulitis only reports about short-term outcome; longterm following outcomes have not been assessed before. The aim of this study was to assess long-term quality of life (QOL) after emergency surgery for perforated diverticulitis. Patients and Methods Validated QOL questionnaires (EQ-VAS, EQ-5D index, QLQ-C30, and QLQ-CR38) were sent to all eligible patients who had undergone emergency surgery for perforated diverticulitis in five teaching hospitals between 199

Influence of a montmorency cherry juice blend on indices of exercise-induced stress and upper respiratory tract symptoms following marathon running—a pilot investigation

Background: Prolonged exercise, such as marathon running, has been associated with an increase in respiratory mucosal inflammation. The aim of this pilot study was to examine the effects of Montmorency cherry juice on markers of stress, immunity and inflammation following a Marathon. Methods: Twenty recreational Marathon runners consumed either cherry juice (CJ) or placebo (PL) before and after a Marathon race. Markers of mucosal immunity secretory immunoglobulin A (sIgA), immunoglobulin G (IgG), salivary cortisol, inflammation (CRP) and self-reported incidence and severity of upper respiratory tract symptoms (URTS) were measured before and following the race. Results: All variables except secretory IgA and IgG concentrations in saliva showed a significant time effect (P < 0.01). Serum CRP showed a significant interaction and treatment effect (P < 0.01). The CRP increase at 24 and 48 h post-Marathon was lower (P < 0.01) in the CJ group compared to PL group. Mucosal immunity and salivary cortisol showed no interaction effect or treatment effect. The incidence and severity of URTS was significantly greater than baseline at 24 h and 48 h following the race in the PL group and was also greater than the CJ group (P < 0.05). No URTS were reported in the CJ group whereas 50 % of runners in the PL group reported URTS at 24 h and 48 h post-Marathon. Conclusions: This is the first study that provides encouraging evidence of the potential role of Montmorency cherries in reducing the development of URTS post-Marathon possibly caused by exercise-induced hyperventilation trauma, and/or other infectious and non-infectious factors

The Evolution of Compact Binary Star Systems

We review the formation and evolution of compact binary stars consisting of white dwarfs (WDs), neutron stars (NSs), and black holes (BHs). Binary NSs and BHs are thought to be the primary astrophysical sources of gravitational waves (GWs) within the frequency band of ground-based detectors, while compact binaries of WDs are important sources of GWs at lower frequencies to be covered by space interferometers (LISA). Major uncertainties in the current understanding of properties of NSs and BHs most relevant to the GW studies are discussed, including the treatment of the natal kicks which compact stellar remnants acquire during the core collapse of massive stars and the common envelope phase of binary evolution. We discuss the coalescence rates of binary NSs and BHs and prospects for their detections, the formation and evolution of binary WDs and their observational manifestations. Special attention is given to AM CVn-stars -- compact binaries in which the Roche lobe is filled by another WD or a low-mass partially degenerate helium-star, as these stars are thought to be the best LISA verification binary GW sources.Comment: 105 pages, 18 figure