An Open-Source R Package for Detection of Adverse Events Under-Reporting in Clinical Trials: Implementation and Validation by the IMPALA (Inter coMPany quALity Analytics) Consortium.

Accurate and timely reporting of adverse events (AEs) in clinical trials is crucial to ensuring data integrity and patient safety. However, AE under-reporting remains a challenge, often highlighted in Good Clinical Practice (GCP) audits and inspections. Traditional detection methods, such as on-site investigator audits via manual source data verification (SDV), have limitations. Addressing this, the open-source R package {simaerep} was developed to facilitate rapid, comprehensive, and near-real-time detection of AE under-reporting at each clinical trial site. This package leverages patient-level AE and visit data for its analyses. To validate its efficacy, three member companies from the Inter coMPany quALity Analytics (IMPALA) consortium independently assessed the package. Results showed that {simaerep} consistently and effectively identified AE under-reporting across all three companies, particularly when there were significant differences in AE rates between compliant and non-compliant sites. Furthermore, {simaerep}'s detection rates surpassed heuristic methods, and it identified 50% of all detectable sites as early as 25% into the designated study duration. The open-source package can be embedded into audits to enable fast, holistic, and repeatable quality oversight of clinical trials.

Comparison of retention of monolithic zirconia crowns with alumina airborne-particle abraded and nonabraded intaglio using three different cements: A clinical simulation.

STATEMENT OF PROBLEM: The necessity of roughening the intaglio surface of zirconia crowns to achieve adequate retention is unclear. PURPOSE: The purpose of this clinical simulation study was to evaluate the retention of airborne-particle-abraded and nonabraded monolithic zirconia crowns using 3 different cement types. MATERIAL AND METHODS: Extracted human molars were used and prepared with a 10-degree taper. Impressions were made of the prepared teeth with a polyvinyl siloxane (PVS) material, and dies were made with Type 4 gypsum. Each die was scanned with a NobelProcera 1G Scanner, and the standard tessellation language (STL) files were transferred electronically to the Nobel Biocare production site, where a bar was added virtually on top of each crown and parameters were set for milling. Seventy-two Procera zirconia crowns were generated, of which half were airborne-particle abraded on the intaglio surface with 50-µm alumina particles at 400 to 500 kPa for 15 seconds. The other 36 received no intaglio treatment other than cleaning. Both groups of 36 crowns were divided into 3 subgroups of 12 specimens. The area of each preparation was calculated using a computer-aided design software program. The specimens were distributed to attain similar mean surface areas among the cementation groups. The crowns were cemented onto the specimen with a controlled force of 196 N. The 3 cements used were self-adhesive, modified resin RelyX Unicem Aplicap, resin-modified glass ionomer RelyX Luting, and a composite resin, Panavia F2.0 with ED Primer A & B. All specimens were thermocycled (5 °C to 55 °C) for 5000 cycles and then removed axially with a universal testing machine (Instron Model 5585H) at a crosshead speed of 0.5 mm/min. The removal force was recorded, and stress of dislodgement was calculated for each crown. A 2-way analysis of variance was used for statistical analyses. The type of failure was analyzed with the chi-squared test of association for independent samples (α=.05 for all tests). RESULTS: The mean dislodging force for crowns with airborne-particle abraded intaglio was 5.4 MPa, which was statistically greater than the mean of 3.2 MPa for nonabraded specimens (P<.001). No significant differences related to the dislodging stresses were detected among the 3 cements (P=.109). The mode of failure was similar whether abraded or not, with 50% of specimens retaining cement in the crown after separation. CONCLUSIONS: Alumina airborne-particle abrasion of the intaglio of zirconia to create surface roughness is beneficial in retaining the crowns, regardless of the cement type. The nonabraded crowns demonstrated significantly lower retentive stress with crown removal. The principal mode of failure was similar whether the zirconia intaglio was airborne-particle abraded or not. The most common mode of failure (>50% of specimens) was at least three-fourths of the cement remaining within the crown.

Lipases and carboxylesterases affect moth sex pheromone compounds involved in interspecific mate recognition.

Moth sex pheromones are a classical model for studying sexual selection. Females typically produce a species-specific pheromone blend that attracts males. Revealing the enzymes involved in the interspecific variation in blend composition is key for understanding the evolution of these sexual communication systems. The nature of the enzymes involved in the variation of acetate esters, which are prominent compounds in moth pheromone blends, remains unclear. We identify enzymes involved in acetate degradation using two closely related moth species: Heliothis (Chloridea) subflexa and H. (C.) virescens, which have different quantities of acetate esters in their sex pheromone. Through comparative transcriptomic analyses and CRISPR/Cas9 knockouts, we show that two lipases and two esterases from H. virescens reduce the levels of pheromone acetate esters when expressed in H. subflexa females. Together, our results show that lipases and carboxylesterases are involved in tuning Lepidoptera pheromones composition.

Cross-company collaboration to leverage analytics for clinical quality and accelerate drug development: The IMPALA industry group.

Quality functions from pharmaceutical sponsor companies aim to increase the use of analytics in their oversight of Good Clinical Practices and Pharmacovigilance activities. To leverage and accelerate progress, several companies decided to establish a collaborative model. The goals of this collaboration span the sharing of knowledge and ideas, the sharing of analytics methods, discussion of talent upskilling and technology adoption strategies, and collaborative discussion on these potential changes with global Health Authorities.

Within-population variability in a moth sex pheromone blend: genetic basis and behavioural consequences.

Evolutionary diversification of sexual communication systems in moths is perplexing because signal and response are under stabilizing selection in many species, and this is expected to constrain evolutionary change. In the moth Heliothis virescens, we consistently found high phenotypic variability in the female sex pheromone blend within each of four geographically distant populations. Here, we assess the heritability, genetic basis and behavioural consequences of this variation. Artificial selection with field-collected moths dramatically increased the relative amount of the saturated compound 16:Ald and decreased its unsaturated counterpart Z11-16:Ald, the major sex pheromone component (high line). In a cross between the high- and low-selected lines, one quantitative trait locus (QTL) explained 11-21% of the phenotypic variance in the 16:Ald/Z11-16:Ald ratio. Because changes in activity of desaturase enzymes could affect this ratio, we measured their expression levels in pheromone glands and mapped desaturase genes onto our linkage map. A delta-11-desaturase had lower expression in females producing less Z11-16:Ald; however, this gene mapped to a different chromosome than the QTL. A model in which the QTL is a trans-acting repressor of delta-11 desaturase expression explains many features of the data. Selection favouring heterozygotes which produce more unsaturated components could maintain a polymorphism at this locus.

Sexual isolation of male moths explained by a single pheromone response QTL containing four receptor genes.

Long distance sexual communication in moths has fascinated biologists because of the complex, precise female pheromone signals and the extreme sensitivity of males to specific pheromone molecules. Progress has been made in identifying some genes involved in female pheromone production and in male response. However, we have lacked information on the genetic changes involved in evolutionary diversification of these mate-finding mechanisms that is critical to understanding speciation in moths and other taxa. We used a combined quantitative trait locus (QTL) and candidate gene approach to determine the genetic architecture of sexual isolation in males of two congeneric moths, Heliothis subflexa and Heliothis virescens. We report behavioral and neurophysiological evidence that differential male responses to three female-produced chemicals (Z9-14:Ald, Z9-16:Ald, Z11-16:OAc) that maintain sexual isolation of these species are all controlled by a single QTL containing at least four odorant receptor genes. It is not surprising that pheromone receptor differences could control H. subflexa and H. virescens responses to Z9-16:Ald and Z9-14:Ald, respectively. However, central rather than peripheral level control over the positive and negative responses of H. subflexa and H. virescens to Z11-16:OAc had been expected. Tight linkage of these receptor genes indicates that mutations altering male response to complex blends could be maintained in linkage disequilibrium and could affect the speciation process. Other candidate genes such as those coding for pheromone binding proteins did not map to this QTL, but there was some genetic evidence of a QTL for response to Z11-16:OH associated with a sensory neuron membrane protein gene.