Infigratinib in children with achondroplasia:the PROPEL and PROPEL 2 studies

BACKGROUND: Achondroplasia is the most common short-limbed skeletal dysplasia resulting from gain-of-function pathogenic variants in fibroblast growth factor receptor 3 (FGFR3) gene, a negative regulator of endochondral bone formation. Most treatment options are symptomatic, targeting medical complications. Infigratinib is an orally bioavailable, FGFR1–3 selective tyrosine kinase inhibitor being investigated as a direct therapeutic strategy to counteract FGFR3 overactivity in achondroplasia. OBJECTIVES: The main objective of PROPEL is to collect baseline data of children with achondroplasia being considered for future enrollment in interventional studies sponsored by QED Therapeutics. The objectives of PROPEL 2 are to obtain preliminary evidence of safety and efficacy of oral infigratinib in children with achondroplasia, to identify the infigratinib dose to be explored in future studies, and to characterize the pharmacokinetic (PK) profile of infigratinib and major metabolites. DESIGN: PROPEL (NCT04035811) is a prospective, noninterventional clinical study designed to characterize the natural history and collect baseline data of children with achondroplasia over 6−24 months. PROPEL 2 (NCT04265651), a prospective, phase II, open-label study of infigratinib in children with achondroplasia, consists of a dose-escalation, dose-finding, and dose-expansion phase to confirm the selected dose, and a PK substudy. METHODS AND ANALYSIS: Children aged 3−11 years with achondroplasia who completed ⩾6 months in PROPEL are eligible for PROPEL 2. Primary endpoints include treatment-emergent adverse events and change from baseline in annualized height velocity. Four cohorts at ascending dose levels are planned for dose escalation. The selected dose will be confirmed in the dose-expansion phase. ETHICS: PROPEL and PROPEL 2 are being conducted in accordance with the International Conference on Harmonization Good Clinical Practice guidelines, principles of the Declaration of Helsinki, and relevant human clinical research and data privacy regulations. Protocols have been approved by local health authorities, ethics committees, and institutions as applicable. Parents/legally authorized representatives are required to provide signed informed consent; signed informed assent by the child is also required, where applicable. DISCUSSION: PROPEL and PROPEL 2 will provide preliminary evidence of the safety and efficacy of infigratinib as precision treatment of children with achondroplasia and will inform the design of future studies of FGFR-targeted agents in achondroplasia. REGISTRATION: ClinicalTrials.gov: NCT04035811; NCT04265651

TRY plant trait database – enhanced coverage and open access

Plant traits - the morphological, anatomical, physiological, biochemical and phenological characteristics of plants - determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait‐based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits - almost complete coverage for ‘plant growth form’. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait–environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives

Phenology of vegetation light-use efficiency and reflectance: experiment over two boreal ecosystems

Understanding phenological changes in vegetation through spectral data needs further exploration in order to maximize the contribution that remote sensing technologies make to environmental studies. Analyzing temporal trends in reflectance and associated eddy-covariance estimations would allow not only for understanding the seasonality of their relationship, but also for the determination of optimal time frames for airborne / satellite image collection. This research investigates the temporal trends of several vegetation indices and computed vegetation light-use efficiency (LUE) for two major boreal ecosystems (a black spruce forest, and a peatland), in the vicinity of the Eastmain-1 reservoir, James Bay, Northern Quebec. Ground data were collected hourly from August 3rd, 2012 through to September 22nd, 2012 with three representative time classes (9AM, 1PM, 5PM) analyzed in this thesis. The research further investigates the applicability of ground based models of land cover using previously collected Compact Airborne Spectrographic Imager (CASI) data. No statistically significant relationships were found at the black spruce forest site between reflectance and vegetation LUE. However, significant relationships occurred in the mid-morning between the vegetation reflectance indices PRI (photochemical reflectance index), PSRI (plant senescence reflectance index), RVSI (red-edge vegetation stress index) and LUE at the peatland site allowing for vegetation LUE estimations at the landscape level using previously acquired CASI hyperspectral imagery. For both sites, vegetation LUE increases over the data collection period, which is attributed to species' efficiency in more diffuse sunlight from changing sun angle geometry. At both sites, statistically significant seasonal trends in reflectance for the most part, occurred in the morning time class (9AM). Similar results were found with vegetation LUE. This highlights the importance of determining optimal time frames for imagery collection (with the goal of landscape estimations in environmental studies), which in the case of this study, points to the mid-morning.Comprendre les changements phénologiques de la végétation à partir de données spectrales a besoin de plus d'exploration afin de maximiser la contribution que les technologies de télédétection apportent aux études environnementales. L'analyse temporelle des tendances de la réflectance du sol ainsi que des estimations conjointes de données dérivées de la covariance des turbulences, permettrait non seulement de comprendre la saisonnalité de leur relation, mais aussi de déterminer les délais optimaux pour la collecte d'imagerie aérienne / satellite. Cette étude examine les tendances temporelles de plusieurs indices de la végétation et des données de l'efficacité lumineuse de la végétation dans deux écosystèmes boréaux (une forêt d'épinettes noires et une tourbière), situés dans les environs du réservoir de Eastmain- 1 de la baie James, dans le Nord du Québec. Les données au sol ont été recueillies toutes les heures du 3 Août 2012 au 22 Septembre 2012, avec trois classes de temps représentatives (9hrs, 13hrs, et 17hrs) analysées dans cette thèse. Cette étude enquête également l'applicabilité des modèles au sol sur la couverture terrestre en utilisant des données de l'imageur spectrographique compact aéroporté (CASI) recueillie précédemment. Aucune relation statistiquement significative n'a été trouvée pour le site de la forêt entre la réflectance du sol et l'efficacité lumineuse de la végétation. Il y a par contre une bonne relation statistique entre l'indice de réflectance photochimique (PRI), le PSRI (sénescence de la plante), le RVSI (indice de stress dans le rouge 'red edge'), et l'efficacité de la végétation à la tourbière. Cela permet les estimations de l'efficacité lumineuse de la végétation sur le paysage en utilisant l'imagerie hyperspectrale CASI préalablement acquise. Pour les deux sites, l'efficacité lumineuse de la végétation augmente au cours de la période de collecte de données, ce qui est attribué à l'efficacité des espèces végétales sous une lumière plus diffuse causée par les changements de la géométrie solaire. Pour les deux sites, les tendances saisonnières de réflectance statistiquement significatives ont eu lieu vers 9 heures du matin. Des résultats similaires ont été trouvés entre l'efficacité lumineuse et la réflectance. Cela souligne l'importance de la détermination des délais optimaux pour la collecte d'images (dans le but d'estimations spatiales dans les études environnementales), qui dans le cas de cette étude, pointe à la matinée

Spectral Reflectance of Polar Bear and Other Large Arctic Mammal Pelts; Potential Applications to Remote Sensing Surveys

Spectral reflectance within the 350–2500 nm range was measured for 17 pelts of arctic mammals (polar bear, caribou, muskox, and ringed, harp and bearded seals) in relation to snow. Reflectance of all pelts was very low at the ultraviolet (UV) end of the spectrum (<10%), increased through the visual and near infrared, peaking at 40%–60% between 1100 and 1400 nm and then gradually dropped, though remaining above 20% until at least 1800 nm. In contrast, reflectance of snow was very high in the UV range (>90%), gradually dropped to near zero at 1500 nm, and then fluctuated between zero and 20% up to 2500 nm. All pelts could be distinguished from clean snow at many wavelengths. The polar bear pelts had higher and more uniform averaged reflectance from about 600–1100 nm than most other pelts, but discrimination was challenging due to variation in pelt color and intensity among individuals within each species. Results suggest promising approaches for using remote sensing tools with a broad spectral range to discriminate polar bears and other mammals from clean snow. Further data from live animals in their natural environment are needed to develop functions to discriminate among species of mammals and to determine whether other environmental elements may have similar reflectance

Videographic Analysis of Eriophorum Vaginatum Spatial Coverage in an Ombotrophic Bog

The use of Remotely Piloted Aircraft Systems (RPAS) as well as newer automated unmanned aerial vehicles is becoming a standard method in remote sensing studies requiring high spatial resolution (<1 m) and very precise temporal data to capture phenological events. In this study we use a low cost rotorcraft to map Eriophorum vaginatum at Mer Bleue, an ombrotrophic bog located east of Ottawa, ON, Canada. We focus on E. vaginatum because this sedge plays an important role in methane (CH4) gas exchange in peatlands. Using the remote controlled rotorcraft we were able to record, process, and mosaic 11.1 hectares of 4.5 cm spatial resolution imagery extracted from individual frames of video recordings (post georegistration RMSE 4.90 ± 4.95 cm). Our results, based on a supervised classification (96% accuracy) of the red, green, blue image planes, indicate a total tussock cover of 2,417 m2. Because the basal area of the plant is more relevant for calculating its contribution to the CH4 flux, the tussock area was related to the basal area from field data (R2 = 0.88, p < 0.0001). Our final results indicate a total basal area of 1,786 ± 62.8 m2. Based on temporal measurements of CH4 flux from the peatland as a whole that vary over the growing season, we estimate the E. vaginatum contribution to range from 3.0% to 17.3% of that total. Overall, our low cost approach was an effective non-destructive way to derive E. vaginatum coverage and estimate CH4 exchange over the growing season

Videographic Analysis of Eriophorum Vaginatum Spatial Coverage in an Ombotrophic Bog

The use of Remotely Piloted Aircraft Systems (RPAS) as well as newer automated unmanned aerial vehicles is becoming a standard method in remote sensing studies requiring high spatial resolution (<1 m) and very precise temporal data to capture phenological events. In this study we use a low cost rotorcraft to map Eriophorum vaginatum at Mer Bleue, an ombrotrophic bog located east of Ottawa, ON, Canada. We focus on E. vaginatum because this sedge plays an important role in methane (CH₄) gas exchange in peatlands. Using the remote controlled rotorcraft we were able to record, process, and mosaic 11.1 hectares of 4.5 cm spatial resolution imagery extracted from individual frames of video recordings (post georegistration RMSE 4.90 ± 4.95 cm). Our results, based on a supervised classification (96% accuracy) of the red, green, blue image planes, indicate a total tussock cover of 2,417 m². Because the basal area of the plant is more relevant for calculating its contribution to the CH₄ flux, the tussock area was related to the basal area from field data (R² = 0.88, p < 0.0001). Our final results indicate a total basal area of 1,786 ± 62.8 m². Based on temporal measurements of CH₄ flux from the peatland as a whole that vary over the growing season, we estimate the E. vaginatum contribution to range from 3.0% to 17.3% of that total. Overall, our low cost approach was an effective non-destructive way to derive E. vaginatum coverage and estimate CH₄ exchange over the growing season

Infigratinib in children with achondroplasia: the PROPEL and PROPEL 2 studies.

BackgroundAchondroplasia is the most common short-limbed skeletal dysplasia resulting from gain-of-function pathogenic variants in fibroblast growth factor receptor 3 (FGFR3) gene, a negative regulator of endochondral bone formation. Most treatment options are symptomatic, targeting medical complications. Infigratinib is an orally bioavailable, FGFR1-3 selective tyrosine kinase inhibitor being investigated as a direct therapeutic strategy to counteract FGFR3 overactivity in achondroplasia.ObjectivesThe main objective of PROPEL is to collect baseline data of children with achondroplasia being considered for future enrollment in interventional studies sponsored by QED Therapeutics. The objectives of PROPEL 2 are to obtain preliminary evidence of safety and efficacy of oral infigratinib in children with achondroplasia, to identify the infigratinib dose to be explored in future studies, and to characterize the pharmacokinetic (PK) profile of infigratinib and major metabolites.DesignPROPEL (NCT04035811) is a prospective, noninterventional clinical study designed to characterize the natural history and collect baseline data of children with achondroplasia over 6-24 months. PROPEL 2 (NCT04265651), a prospective, phase II, open-label study of infigratinib in children with achondroplasia, consists of a dose-escalation, dose-finding, and dose-expansion phase to confirm the selected dose, and a PK substudy.Methods and analysisChildren aged 3-11 years with achondroplasia who completed ⩾6 months in PROPEL are eligible for PROPEL 2. Primary endpoints include treatment-emergent adverse events and change from baseline in annualized height velocity. Four cohorts at ascending dose levels are planned for dose escalation. The selected dose will be confirmed in the dose-expansion phase.EthicsPROPEL and PROPEL 2 are being conducted in accordance with the International Conference on Harmonization Good Clinical Practice guidelines, principles of the Declaration of Helsinki, and relevant human clinical research and data privacy regulations. Protocols have been approved by local health authorities, ethics committees, and institutions as applicable. Parents/legally authorized representatives are required to provide signed informed consent; signed informed assent by the child is also required, where applicable.DiscussionPROPEL and PROPEL 2 will provide preliminary evidence of the safety and efficacy of infigratinib as precision treatment of children with achondroplasia and will inform the design of future studies of FGFR-targeted agents in achondroplasia.RegistrationClinicalTrials.gov: NCT04035811; NCT04265651

POU3F3-related disorder:Defining the phenotype and expanding the molecular spectrum

POU3F3 variants cause developmental delay, behavioral problems, hypotonia and dysmorphic features. We investigated the phenotypic and genetic landscape, and genotype–phenotype correlations in individuals with POU3F3-related disorders. We recruited unpublished individuals with POU3F3 variants through international collaborations and obtained updated clinical data on previously published individuals. Trio exome sequencing or single exome sequencing followed by segregation analysis were performed in the novel cohort. Functional effects of missense variants were investigated with 3D protein modeling. We included 28 individuals (5 previously published) from 26 families carrying POU3F3 variants; 23 de novo and one inherited from an affected parent. Median age at study inclusion was 7.4 years. All had developmental delay mainly affecting speech, behavioral difficulties, psychiatric comorbidities and dysmorphisms. Additional features included gastrointestinal comorbidities, hearing loss, ophthalmological anomalies, epilepsy, sleep disturbances and joint hypermobility. Autism, hearing and eye comorbidities, dysmorphisms were more common in individuals with truncating variants, whereas epilepsy was only associated with missense variants. In silico structural modeling predicted that all (likely) pathogenic variants destabilize the DNA-binding region of POU3F3. Our study refined the phenotypic and genetic landscape of POU3F3-related disorders, it reports the functional properties of the identified pathogenic variants, and delineates some genotype–phenotype correlations.</p