A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Purpose Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock

Improved tear resistance by low environmental impact coupling of plasma reactive and additive treatment of a TPU/PET coated fabric

International audienceAn environmentally friendly approach, which consists in coupling a dielectric barrier discharge (DBD) based atmospheric plasma treatment with a coating of an aqueous phase polyurethane dispersion (PUD) containing blocked polyisocyanates, is proposed to improve the adhesion of a thermoplastic polyurethane (TPU) film onto a poly-(ethylene terephthalate) (PET) textile fabric. In this study, a screening digital design of experiment plan (DOE) was developed to determine the influence of process parameters on the adhesion between film and fabric and to evaluate the best possible adhesion value. The process parameters considered are: the dielectric barrier discharge power, the speed of the fabric undergoing the treatment, the concentration of polyisocyanates (NCO) in the PUD and the air gap. The adhesion was measured by a peeling test and further scanning electron microscope observations were carried out. Results showed that an increase of both the processing power and the NCO content in PUD, as well as the decrease in the DBD speed, had a positive effect on the adhesion. In addition, X-ray photoelectron spectroscopy and contact angle measurements demonstrated an increase in the oxygen/carbon atomic percentage ratio between the reference fabric and the treated fabric. Thus, the calibrated oxidation of the PET treated with DBD plasma treatment leads to a greater chemical and physical interaction with the TPU film, which results in better film-fabric adhesion

Comparative Evaluation of Urinary PCA3 and TMPRSS2: ERG Scores and Serum PHI in Predicting Prostate Cancer Aggressiveness

It has been suggested that urinary PCA3 and TMPRSS2:ERG fusion tests and serum PHI correlate to cancer aggressiveness-related pathological criteria at prostatectomy. To evaluate and compare their ability in predicting prostate cancer aggressiveness, PHI and urinary PCA3 and TMPRSS2:ERG (T2) scores were assessed in 154 patients who underwent radical prostatectomy for biopsy-proven prostate cancer. Univariate and multivariate analyses using logistic regression and decision curve analyses were performed. All three markers were predictors of a tumor volume ≥0.5 mL. Only PHI predicted Gleason score ≥7. T2 score and PHI were both independent predictors of extracapsular extension (≥pT3), while multifocality was only predicted by PCA3 score. Moreover, when compared to a base model (age, digital rectal examination, serum PSA, and Gleason sum at biopsy), the addition of both PCA3 score and PHI to the base model induced a significant increase (+12%) when predicting tumor volume >0.5 mL. PHI and urinary PCA3 and T2 scores can be considered as complementary predictors of cancer aggressiveness at prostatectomy

A natural experiment to assess how urban interventions in lower socioeconomic areas influence health behaviors: the UrbASanté study

International audienceBackgroundMechanisms underlying the associations between changes in the urban environment and changes in health-related outcomes are complex and their study requires specific approaches. We describe the protocol of the interdisciplinary UrbASanté study, which aims to explore how urban interventions can modify environmental exposures (built, social, and food environments; air quality; noise), health-related behaviors, and self-reported health using a natural experiment approach. MethodsThe study is based on a natural experiment design using a before/after protocol with a control group to assess changes in environmental exposures, health-risk behaviors, and self-reported health outcomes of a resident adult population before and after the implementation of a time series of urban interventions in four contiguous neighborhoods in Paris (France). The changes in environmental exposures, health-related behaviors, and self-reported health outcomes of a resident adult population will be concurrently monitored in both intervention and control areas. We will develop a mixed-method framework combining substantial fieldwork with quantitative and qualitative analytical approaches. This study will make use of (i) data relating to exposures and health-related outcomes among all participants and in subsamples and (ii) interviews with residents regarding their perceptions of their neighborhoods and with key stakeholders regarding the urban change processing, and (iii) existing geodatabases and field observations to characterize the built, social, and food environments. The data collected will be analyzed with a focus on interrelationships between environmental exposures and health-related outcomes using appropriate approaches (e.g., interrupted time series, difference–in-differences method). DiscussionRelying on a natural experiment approach, the research will provide new insights regarding issues such as close collaboration with urban/local stakeholders, recruitment and follow-up of participants, identification of control and intervention areas, timing of the planned urban interventions, and comparison of subjective and objective measurements. Through the collaborative work of a consortium ensuring complementarity between researchers from different disciplines and stakeholders, the UrbASanté study will provide evidence-based guidance for designing future urban planning and public health policies. Trial registrationThis research was registered at the ClinicalTrial.gov (NCT05743257

Ground calibration of the Ariel space telescope: optical ground support equipment design and description

This paper describes the Optical Ground Support Equipment (OGSE) that is being developed for the payload level testing of the Ariel Space Telescope. Ariel has been adopted as ESA’s “M4” mission in its Cosmic Visions Programme and will launch in 2029 to the second Earth-Sun Lagrange point. During four years of operation the Ariel payload (PL – the cryogenic payload module plus warm units) will perform precise transit spectroscopy of approximately 1000 known exoplanetary atmospheres using a 1.1 m × 0.7 m telescope coupled to two instruments: the Fine Guidance Sensor (FGS) and the Ariel Infrared Spectrometer (AIRS). These instruments provide three spectrometric channels that cover 1.0 to 7.8 μm wavelength range and three photometric channels between 0.5 and 1.1 μm. The Ariel OGSE will verify the optical and radiometric performance of the integrated Ariel PL under vacuum and cryogenic (<40 K) test conditions within the limitations of operation under Earth’s gravity and vibration environments. To achieve these verification requirements the OGSE is integrated with the main Ariel ground test 5 m thermal vacuum chamber. The test chamber contains a cryogenic enclosure (the Cryogenic Test Rig) that surrounds the PL and the OGSE itself comprises of four subsystems. (1) A cryogenic vacuum chamber and integrating sphere illumination module that is fed by visible, near infrared and thermal infrared sources. The illumination module is mounted external to the Ariel test chamber and coupled via a vacuum feedthrough that relays a 22 mm diameter test beam into the Cryogenic Test Rig. The test beam is then relayed using (2) an injection module that steers the beam to maintain alignment during cool-down and scan the Ariel telescope field of view. The beam is then expanded to partially illuminate the Ariel telescope primary mirror using an (3) ~0.3 m diameter target projector collimating mirror. The final optical component of the OGSE is a (4) beam expander placed on the Ariel common optical bench to compensate for the sub-aperture illumination of the primary and to ensure that the spectrometer modules provide illumination with correct cone angles during ground testing. It is planned to use the OGSE in 2026 for a full range of calibration and verification tests of the end-to-end telescope and instrument performance, including detectors, field of view and alignment. These tests will then ensure that Ariel meets it challenging photometric and spectral performance requirements

Alternative PDGFD rearrangements in dermatofibrosarcomas protuberans without PDGFB fusions

International audienceDermatofibrosarcoma protuberans is underlined by recurrent collagen type I alpha 1 chain-platelet-derived growth factor B chain (COL1A1-PDGFB) fusions but ~ 4% of typical dermatofibrosarcoma protuberans remain negative for this translocation in routine molecular screening. We investigated a series of 21 cases not associated with the pathognomonic COL1A1-PDGFB fusion on routine fluorescence in situ hybridization (FISH) testing. All cases displayed morphological and clinical features consistent with the diagnosis of dermatofibrosarcoma protuberans. RNA-sequencing analysis was successful in 20 cases. The classical COL1A1-PDGFB fusion was present in 40% of cases (n = 8/20), and subsequently confirmed with a COL1A1 break-apart FISH probe in all but one case (n = 7/8). 55% of cases (n = 11/20) displayed novel PDGFD rearrangements; PDGFD being fused either to the 5' part of COL6A3 (2q37.3) (n = 9/11) or EMILIN2 (18p11) (n = 2/11). All rearrangements led to in-frame fusion transcripts and were confirmed at genomic level by FISH and/or array-comparative genomic hybridization. PDGFD-rearranged dermatofibrosarcoma protuberans presented clinical outcomes similar to typical dermatofibrosarcoma protuberans. Notably, the two EMILIN2-PDGFD cases displayed fibrosarcomatous transformation and homozygous deletions of CDKN2A at genomic level. We report the first recurrent molecular variant of dermatofibrosarcoma protuberans involving PDGFD, which functionally mimic bona fide COL1A1-PDGFB fusions, leading presumably to a similar autocrine loop-stimulating PDGFRB. This study also emphasizes that COL1A1-PDGFB fusions can be cytogenetically cryptic on FISH testing in a subset of cases, thereby representing a diagnostic pitfall that pathologists should be aware of