Risk-proportionate clinical trial monitoring: an example approach from a non-commercial trials unit

Background Some level of monitoring is usually required during a clinical trial to protect the rights and safety of trial participants and to safeguard the quality and reliability of trial results. Although there is increasing support for the use of risk-proportionate approaches to achieve these aims, the variety of methods and lack of an empirical evidence base can present challenges for clinical trial practitioners. Methods This paper describes the monitoring methods and procedures that are utilised by a noncommercial clinical trials unit which coordinates a range of clinical trials across a variety of clinical areas with different associated risks. Results Monitoring activities and approaches should be selected to be proportionate to the risks identified within a trial. A risk-proportionate approach to monitoring is described giving details of methods that may be considered by clinical trial practitioners during the development of a trial monitoring plan. An example risk assessment and corresponding monitoring plan for a low risk (type A in the Medicines and Healthcare Products Regulatory Agency (MHRA) classification system) pediatric trial is provided for illustration. Conclusion We present ideas for developing a monitoring plan for a clinical trial of an investigational medicinal product based on our experience. Alternative approaches may be relevant or preferable in other settings based on inherent risk

The sterlet sturgeon genome sequence and the mechanisms of segmental rediploidization.

Sturgeons seem to be frozen in time. The archaic characteristics of this ancient fish lineage place it in a key phylogenetic position at the base of the ~30,000 modern teleost fish species. Moreover, sturgeons are notoriously polyploid, providing unique opportunities to investigate the evolution of polyploid genomes. We assembled a high-quality chromosome-level reference genome for the sterlet, Acipenser ruthenus. Our analysis revealed a very low protein evolution rate that is at least as slow as in other deep branches of the vertebrate tree, such as that of the coelacanth. We uncovered a whole-genome duplication that occurred in the Jurassic, early in the evolution of the entire sturgeon lineage. Following this polyploidization, the rediploidization of the genome included the loss of whole chromosomes in a segmental deduplication process. While known adaptive processes helped conserve a high degree of structural and functional tetraploidy over more than 180 million years, the reduction of redundancy of the polyploid genome seems to have been remarkably random

Modulation of defense signal transduction by flagellin-induced WRKY41 transcription factor in Arabidopsis thaliana

Flagellin, a component of the flagellar filament of Pseudomonas syringae pv. tabaci 6605 (Pta), induces hypersensitive reaction in its non-host Arabidopsis thaliana. We identified the WRKY41 gene, which belongs to a multigene family encoding WRKY plant-specific transcription factors, as one of the flagellin-inducible genes in A. thaliana. Expression of WRKY41 is induced by inoculation with the incompatible pathogen P. syringae pv. tomato DC3000 (Pto) possessing AvrRpt2 and the non-host pathogens Pta within 6-h after inoculation, but not by inoculation with the compatible Pto. Expression of WRKY41 was also induced by inoculation of A. thaliana with an hrp-type three secretion system (T3SS)-defective mutant of Pto, indicating that effectors produced by T3SS in the Pto wild-type suppress the activation of WRKY41. Arabidopsis overexpressing WRKY41 showed enhanced resistance to the Pto wild-type but increased susceptibility to Erwinia carotovora EC1. WRKY41-overexpressing Arabidopsis constitutively expresses the PR5 gene, but suppresses the methyl jasmonate-induced PDF1.2 gene expression. These results demonstrate that WRKY41 may be a key regulator in the cross talk of salicylic acid and jasmonic acid pathways.</p

The 'PUCE CAFE' Project: the First 15K Coffee Microarray, a New Tool for Discovering Candidate Genes correlated to Agronomic and Quality Traits

Background: Understanding the genetic elements that contribute to key aspects of coffee biology will have an impact on future agronomical improvements for this economically important tree. During the past years, EST collections were generated in Coffee, opening the possibility to create new tools for functional genomics. Results: The "PUCE CAFE" Project, organized by the scientific consortium NESTLE/IRD/CIRAD, has developed an oligo-based microarray using 15,721 unigenes derived from published coffee EST sequences mostly obtained from different stages of fruit development and leaves in Coffea Canephora (Robusta). Hybridizations for two independent experiments served to compare global gene expression profiles in three types of tissue matter (mature beans, leaves and flowers) in C. canephora as well as in the leaves of three different coffee species (C. canephora, C. eugenoides and C. arabica). Microarray construction, statistical analyses and validation by Q-PCR analysis are presented in this study. Conclusion: We have generated the first 15 K coffee array during this PUCE CAFE project, granted by Genoplante (the French consortium for plant genomics). This new tool will help study functional genomics in a wide range of experiments on various plant tissues, such as analyzing bean maturation or resistance to pathogens or drought. Furthermore, the use of this array has proven to be valid in different coffee species (diploid or tetraploid), drastically enlarging its impact for high-throughput gene expression in the community of coffee research

Identification of Potential Pharmacological Targets by Analysis of the Comprehensive G Protein-Coupled Receptor Repertoire in the Four Cardiac Chambers

International audienc

Trop Med Int Health

Objective To evaluate the effectiveness of the prevention of mother‐to‐child transmission (PMTCT) Option B+ programme in two provinces with high human immunodeficiency virus (HIV) burden in Mozambique over the first four years of programme implementation. Methods We assessed the PMTCT cascade in antenatal care (ANC) from July 2013 to December 2017 using facility‐level data and performed a retrospective cohort analysis with patient‐level data. We compared the 12‐month antiretroviral therapy (ART) retention rates between women with HIV infection who initiated ART under Option B+ (‘B+ pregnant’) and those who initiated ART for their own health (‘own health’). Results A total of 916 280 pregnant women enrolled in ANC. The proportion of women with a documented HIV status increased from 93% in 2013 to 96% in 2017. The proportion of those tested HIV‐positive decreased from 8% to 6% while that of those HIV‐positive on ART increased from 42% to 95%. Of the 44 377 HIV‐positive women included in the analysis, 35% were lost to care. ‘B+ pregnant’ women initiating ART in 2015 were less likely to have no follow‐up (NFU) compared with ‘own health’ women starting ART during the same period (adjusted odds ratio: 0.77, 95% confidence interval [CI]: 0.64–0.94, P = 0.01). There was no statistical difference between the two groups during the other years in which ART was initiated. Of those returning for care after their first visit (N = 39 801), the ‘B+ pregnant’ women showed a higher risk of non‐retention than the other group (adjusted hazard ratio: 1.14, 95% CI: 1.03–1.25) when ART was initiated in 2013. The risk decreased during the subsequent years, with no difference observed between the groups. Conclusion PMTCT Option B+ programme scale‐up has yielded positive results, including the maintenance of high HIV testing and ART initiation rates in ANC. Challenges still remain, however, in improving immediate engagement in care and long‐term retention. Seeking alternative service delivery models to support existing health systems and prevent defaulters is required to achieve the UNAIDS 95‐95‐95 targets for PMTCT in Mozambique