A systematic review on reporting outcomes and outcome measures in trials on synthetic mesh procedures for pelvic organ prolapse: Urgent action is needed to improve quality of research.

The use of synthetic mesh in pelvic organ prolapse surgery is being closely scrutinized because of serious concerns regarding life-changing complications such as erosion, pain, infection, bleeding, dyspareunia, organ perforation, and urinary problems. Randomized trials and their syntheses in meta-analysis offer a unique opportunity to assess efficacy and safety. However, outcomes and outcome measures need to be consistently selected, collected, and reported across randomized trials to be effectively combined in systematic reviews. AIMS: We evaluated outcome and outcome measure reporting across randomized controlled trials on surgical interventions using synthetic mesh for pelvic organ prolapse. METHODS: Systematic review of randomized controlled trials using synthetic mesh for the treatment of pelvic organ prolapse. The selected studies were evaluated using Jadad and MOMENT criteria. Outcomes and outcome measures were systematically identified and categorized. RESULTS: Seventy-one randomized trials were included. Twenty-four different types of mesh were identified. Included trials reported 110 different outcomes and 60 outcome measures. Erosion (40 trials, 78%), pain (29 trials, 56%), bleeding (31 trials, 61%), and dyspareunia (25 trials, 49%) were the most frequently reported outcomes. The longest follow up was 74 months. CONCLUSIONS: Most randomized trials evaluating surgical interventions using synthetic mesh for pelvic organ prolapse failed to report on clinically important outcomes and to evaluate efficacy and safety over the medium- and long-term. Developing and implementing a minimum data set, known as a core outcome set, in future vaginal prolapse trials could help address these issues

Quality assessment of outcome reporting, publication characteristics and overall methodological quality in trials on synthetic mesh procedures for the treatment of pelvic organ prolapse for development of core outcome sets.

INTRODUCTION AND HYPOTHESIS: Variations in outcome measures and reporting of outcomes in trials on surgery for pelvic organ prolapse (POP) using synthetic mesh have been evaluated and reported. However, the quality of outcome reporting, methodology of trials and their publication parameters are important considerations in the process of development of Core Outcome Sets. We aimed to evaluate these characteristics in randomized controlled trials on surgery for POP using mesh. METHODS: Secondary analysis of randomized controlled trials on surgical treatments using synthetic mesh for POP previously included in a systematic review developing an inventory of reported outcomes and outcome measures. The methodological quality was investigated with the modified Jadad criteria. Outcome reporting quality was evaluated with the MOMENT criteria. Publication parameters included publishing journal, impact factor and year of publication. RESULTS: Of the 71 previously reviewed studies published from 2000 to 2017, the mean JADAD score was 3.59 and the mean MOMENT score was 4.63. Quality of outcomes (MOMENT) was related to methodological quality (JADAD) (rho = 0.662; p = 0.000) and to year of publication (rho = 0.262; p = 0.028). CONCLUSIONS: Methodological quality and outcome reporting quality appear correlated. However, publication characteristics do not have strong associations with the methodological quality of the studies. Evaluation of the quality of outcomes, methodology and publication characteristics are all an indispensable part of a staged process for the development of Core Outcome and Outcome Measure Sets

A Dominant-Negative Approach That Prevents Diphthamide Formation Confers Resistance to Pseudomonas Exotoxin A and Diphtheria Toxin

Diphtheria toxin (DT), Pseudomonas aeruginosa Exotoxin A (ETA) and cholix toxin from Vibrio cholerae share the same mechanism of toxicity; these enzymes ADP-rybosylate elongation factor-2 (EF-2) on a modified histidine residue called diphthamide, leading to a block in protein synthesis. Mutant Chinese hamster ovary cells that are defective in the formation of diphthamide have no distinct phenotype except their resistance to DT and ETA. These observations led us to predict that a strategy that prevents the formation of diphthamide to confer DT and ETA resistance is likely to be safe. It is well documented that Dph1 and Dph2 are involved in the first biochemical step of diphthamide formation and that these two proteins interact with each other. We hypothesized that we could block diphthamide formation with a dominant negative mutant of either Dph1 or Dph2. We report in this study the first cellular-targeted strategy that protects against DT and ETA toxicity. We have generated Dph2(C-), a dominant-negative mutant of Dph2, that could block very efficiently the formation of diphthamide. Cells expressing Dph2(C-) were 1000-fold more resistant to DT than parental cells, and a similar protection against Pseudomonas exotoxin A was also obtained. The targeting of a cellular component with this approach should have a reduced risk of generating resistance as it is commonly seen with antibiotic treatments

The evidence base for circulating tumour DNA blood-based biomarkers for the early detection of cancer: a systematic mapping review

Background: The presence of circulating cell-free DNA from tumours in blood (ctDNA) is of major importance to those interested in early cancer detection, as well as to those wishing to monitor tumour progression or diagnose the presence of activating mutations to guide treatment. In 2014, the UK Early Cancer Detection Consortium undertook a systematic mapping review of the literature to identify blood-based biomarkers with potential for the development of a non-invasive blood test for cancer screening, and which identified this as a major area of interest. This review builds on the mapping review to expand the ctDNA dataset to examine the best options for the detection of multiple cancer types. Methods: The original mapping review was based on comprehensive searches of the electronic databases Medline, Embase, CINAHL, the Cochrane library, and Biosis to obtain relevant literature on blood-based biomarkers for cancer detection in humans (PROSPERO no. CRD42014010827). The abstracts for each paper were reviewed to determine whether validation data were reported, and then examined in full. Publications concentrating on monitoring of disease burden or mutations were excluded. Results: The search identified 94 ctDNA studies meeting the criteria for review. All but 5 studies examined one cancer type, with breast, colorectal and lung cancers representing 60% of studies. The size and design of the studies varied widely. Controls were included in 77% of publications. The largest study included 640 patients, but the median study size was 65 cases and 35 controls, and the bulk of studies (71%) included less than 100 patients. Studies either estimated cfDNA levels non-specifically or tested for cancer-specific mutations or methylation changes (the majority using PCR-based methods). Conclusion: We have systematically reviewed ctDNA blood biomarkers for the early detection of cancer. Pre-analytical, analytical, and post-analytical considerations were identified which need to be addressed before such biomarkers enter clinical practice. The value of small studies with no comparison between methods, or even the inclusion of controls is highly questionable, and larger validation studies will be required before such methods can be considered for early cancer detection

Chromosome evolution in Cophomantini (Amphibia, Anura, Hylinae)

The hylid tribe Cophomantini is a diverse clade of Neotropical treefrogs composed of the genera Aplastodiscus, Boana, Bokermannohyla, Hyloscirtus, and Myersiohyla. The phylogenetic relationships of Cophomantini have been comprehensively reviewed in the literature, providing a suitable framework for the study of chromosome evolution. Employing different banding techniques, we studied the chromosomes of 25 species of Boana and 3 of Hyloscirtus; thus providing, for the first time, data for Hyloscirtus and for 15 species of Boana. Most species showed karyotypes with 2n = 2x = 24 chromosomes; some species of the B. albopunctata group have 2n = 2x = 22, and H. alytolylax has 2n = 2x = 20. Karyotypes are all bi-armed in most species presented, with the exception of H. larinopygion (FN = 46) and H. alytolylax (FN = 38), with karyotypes that have a single pair of small telocentric chromosomes. In most species of Boana, NORs are observed in a single pair of chromosomes, mostly in the small chromosomes, although in some species of the B. albopunctata, B. pulchella, and B. semilineata groups, this marker occurs on the larger pairs 8, 1, and 7, respectively. In Hyloscirtus, NOR position differs in the three studied species: H. alytolylax (4p), H. palmeri (4q), and H. larinopygion (1p). Heterochromatin is a variable marker that could provide valuable evidence, but it would be necesserary to understand the molecular composition of the C-bands that are observed in different species in order to test its putative homology. In H. alytolylax, a centromeric DAPI+ band was observed on one homologue of chromosome pair 2. The band was present in males but absent in females, providing evidence for an XX/XY sex determining system in this species. We review and discuss the importance of the different chromosome markers (NOR position, C-bands, and DAPI/CMA3 patterns) for their impact on the taxonomy and karyotype evolution in Cophomantini