Search

Divergent reproductive strategies of tree species generate differences in the dynamics of seed production and dispersion. The spatial and temporal variability in seed rain abundance and viability was monitored during the period 2000-2007 in four boreal stands in Quebec, Canada. The aim was to compare the inter- and intra-annual patterns of seed dispersal between species with diverging adaptive characteristics and reproductive strategies by testing the hypothesis that sympatric species can exhibit different patterns of seed dispersal according to specific ecological adaptations. The coefficient of variation (CV), representing the inter-annual variability in seed rain, was close to or higher than 1 in balsam fir (Abies balsamea [L.] P. Mill.) and white birch (Betula papyrifera Marsh.) and confirmed the mast seeding habit of the two species. In contrast, CV in black spruce (Picea mariana [Mill.] BSP) ranged between 0.24 and 0.54, indicating a more homogeneous inter-annual amount of seed dispersal because of its semiserotinous cones that preserve seeds for an indefinite period of time. The species showed divergent intra-annual patterns of seed dispersal. Most seed dispersal of the companion species was observed in September-November, while black spruce concentrated seed rain in spring, when the proportion of germinated seeds was higher. Boreal stands experience annual seed rains constituted by a gradual dispersal of seeds of different ages and originating from cones belonging to multiple cohorts. However, asynchronous seed rains in terms of quantity and quality can occur if companion species are associated to the dominant black spruce.

In the event of a criticality accident, not only the maximal doses received by the victims must be determined but it is also crucial to evaluate the doses to the different organs. With a neutron component, morphology is a key parameter in the organ dose calculation. As the simulation tools can be time consuming to proceed, especially if morphology is taken into account, for all the victims, it may be very useful to have a database of conversion coefficients that allow to obtain the organ doses from the dose measured in the dosemeter for different kinds of morphology. In this paper, we present a study performed to evaluate such conversion coefficients using voxelized anthropomorphic phantoms. These coefficients take into account two crucial parameters having an impact on the dose at the organs: the orientation of the victim in the radiation field and the morphology, that is to say the body mass index of the different victims. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Microscopy is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Forestry Chronicle is the property of Canadian Institute of Forestry and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Nitrogen (N) is a major growth-limiting factor in boreal forest ecosystems. Increases of temperature and atmospheric N deposition are expected to affect forest growth directly and indirectly by increasing N availability due to higher rates of N mineralization. In order to understand the potential impacts of these changes, a mature balsam fir stand in Québec, Canada, was subjected during three consecutive growing seasons (2009-2011) to (i) experimentally increased soil temperature (4 °C) and earlier snowmelt (2-3 weeks) as well as (ii) increased inorganic N concentration in artificial precipitation (3xcurrent N concentrations using 15NH4- 15NO3). Soil inorganic N was measured using buried ionexchange membranes (PRS™ probes) and standard soil extractions. Dendrometers were used to monitor the variations in diameter growth and needles were analyzed annually for N to assess the nutritional response of trees. Results from the second (2010) and third (2011) year of treatment are reported. After three years of treatment, there was no significant increase in soil nitrate (NO3) or ammonium (NH4) availability either in the organic or in the mineral soil as measured with standard soil extractions. Similar results were obtained with ion-exchange membranes, except for NH4 in the forest floor, which increased by an average of 54% over the two years. No effect of treatments were observed on needle N or diameter growth, but an 8-day earlier peak in diameter growth was measured in heated plots in 2010. We attributed the limited effects of our treatments to the acute soil competition for available N at the site. As a result, the projected modifications of the forest N cycle and concomitant increased forest growth due to an earlier snowmelt, increased soil temperature and N deposition should be considered with caution in similar cold N-poor ecosystems. [ABSTRACT FROM AUTHOR]

Nitrogen (N) is a major growth-limiting factor in boreal forest ecosystems. Increases of temperature and atmospheric N deposition are expected to affect forest growth directly and indirectly, by increasing N availability due to higher rates of N mineralization. In order to understand the potential impacts of these changes, a mature balsam fir stand in Québec, Canada, was subjected to (i) experimentally increased soil temperature (4 °C) and earlier snowmelt (2-3 weeks) as well as (ii) increased inorganic N concentration in artificial precipitation (3x current N concentrations using 15NH4-15 NO3). Soil inorganic N was measured using buried ion exchange membranes (PRS™-probes) and standard soil extractions. Dendrometers were used to monitor the variations in diameter growth and needles were analyzed annually for N to assess the nutritional response of trees. After three years of treatment, there was no significant increase in soil nitrate (NO3) or ammonium (NH4) availability either in the organic or in the mineral soil as measured with standard soil extractions. Similar results were obtained with ion exchange membranes, except for an average 54% increase in the forest floor available NH4. No effect of treatments were observed on needle N or diameter growth, but an eight-day earlier peak in diameter growth was measured in heated plots in 2010. We attributed the limited effects of our treatments to the acute soil competition for available N at the site. As a result, the projected modifications of the forest N cycle and concomitant increased forest growth due to an earlier snowmelt, increased soil temperature and N deposition should be considered with caution in similar cold N-poor ecosystems. [ABSTRACT FROM AUTHOR]

The accurate prediction of solute transport through soils is a necessity to counter the worldwide degradation of aquifers. Dye tracers are widely used to visualize active flow paths in cross-sections of soil, but methods previously proposed to map concentrations have been very costly, demanding, or of coarse resolution and not always applicable in dark allophanic soils. We have developed a cheap and fairly easy experimental procedure and used multiple regression to map dye concentrations in two dimensions. We tested the method using the fluorescent dye, pyranine, in intact cores of an allophanic soil. The method requires a calibration step, which we made using eight dye concentrations. The main difficulty was to mix the soil homogeneously with the dye and to pack it evenly before acquisition of the images. The pyranine was infiltrated in soil cores under unsaturated conditions: its distribution on the vertical core faces was highly heterogeneous with fingered penetration. The maps of dye concentration obtained from each core section achieved fine spatial resolution (e.g. 0.25 mm2 per pixel) and satisfactory dye concentration localization and estimation. We could achieve better spatial resolution by sectioning the soil cores at finer intervals, and estimate the dye concentration more accurately by improving the correction for illumination variations. Quantification d’un traceur fluorescent dans des sols allophaniques Résumé Pouvoir prédire avec précision le transport des solutés à travers les sols est essentiel pour contrecarrer la dégradation mondiale des aquifères. Les colorants sont communément utilisés comme traceur pour visualiser les chemins de flux préférentiels dans des profils de sol, mais les méthodes proposées antérieurement pour obtenir la carte des concentrations étaient soit onéreuses, complexes ou de faible résolution, et pas toujours applicables à des sols allophaniques de couleur sombre. Nous développons ici une expérience peu coûteuse et facile à mettre en œuvre, et nous utilisons la régression multiple pour obtenir les cartes de concentrations du colorant. Nous testons la méthode proposée à l’aide du colorant fluorescent, la pyranine, dans des monolithes intacts d’un sol allophanique. Nous avons premièrement procédéà une calibration, en utilisant huit concentrations. La principale difficulté a été de mélanger le sol avec le colorant de façon homogène puis de le compacter avant l’acquisition des images. La pyranine a été infiltrée dans les monolithes de sol sous conditions non saturées: la distribution du colorant sur les faces verticales du monolithe est très hétérogène, avec un front d’infiltration « en doigts ». Les cartes de concentrations de colorant obtenues pour chaque section du monolithe présentent une bonne résolution spatiale (0.25 mm2 par pixel) ainsi qu’une localisation et quantification des concentrations satisfaisantes. Une meilleure résolution spatiale pourrait être obtenue en sectionnant les monolithes plus finement, et l’estimation des concentrations pourrait être plus précise en améliorant la correction des inhomogénéités d’éclairage. [ABSTRACT FROM AUTHOR]

The aim of this study is to evaluate the contribution of texture information to high spatial and spectral resolution for zonal mapping in urban areas. The airborne data used were acquired over the Montreal Urban Community (Montreal, Canada) by the Multi-detector Electro-optical Imaging Scanner (MEIS-II) of the Canada Centre for Remote Sensing. Spectral analysis of the divergence between classes has shown that bands 3 (847-901 nm), 4 (622-659nm), and 7 (433-463mm) offer the optimal combination for discriminating between the urban classes we have defined. Textural features derived from three different order histograms were calculated from band 4 and evaluated in terms of their ability to discriminate between urban classes. We then extracted the best feature from each of the histograms. The integration of these three textural features with the three spectral bands has shown that textural information permits an improvement in class separability resulting in an increase in the rate of correct classification in the order of 12%. This increase is however dependent on the type of class and varies from 4.5% for forest and parks to 16.8% for urban areas with low vegetation density. Classification by maximum likelihood of these spectral-textural data and the visual analysis of results also show that textural information, in conjunction with high spatial and spectral resolution, provides appropriate zonal mapping of urban areas. L'objectif de cette etude est d'evaluer l'apport de la texture en terme d'information additionnelle a la resolution spatiale et spectrale pour la cartographie des zones urbaines. Les donnees aeroportees utilisees ont ete acquises au dessus de la Communaute-urbaine de Montreal (Montreal, Canada) a l'aide du detecteur Multi-detector Electro-optical Imaging Scanner (MEIS-II) du Centre canadien de teledetection. L'analyse spectrale du point de vue de la divergence entre classes a montre que les bandes 3 (847-901nm), 4 (622-659nm) et 7 (433-463nm) offrent la combinaison optimale pour la discrimination entre les classes urbaines qu'on s'est definies. Des parametres de texture issues de trois differents ordres d'histogrammes ont ete calcules sur la bande 4 et evalues du point de vue de leur discrimination entre les classes urbaines. On a ensuite extrait le meilleur parametre de chacun de ces trois histogrammes. L'integration de ces trois parametres texturaux avec les trois bandes spectrales a montre que l'information texturale permet une amelioration de la separabilite des classes entrainant une augmentation du taux de classification correcte de l'ordre de 12%. Cette augmentation est cependant dependante du type de classes et varie de 4,5% pour la foret et parcs a 16,8% pour l'urbain possedant une faible densite vegetale. La classification par maximum de vraisemblance de ces donnees spectro-texturales et l'analyse visuelle des resultats montrent aussi que l'information texturale, de concert avec la haute resolution spatiale et spectrale, permet une cartographie zonale appropriee du milieu urbain. [ABSTRACT FROM AUTHOR]

Intra-annual variations of carbon stable isotope ratios (δ13C) in different tree compartments could represent valuable indicators of plant carbon source-sink dynamics, at weekly time scale. Despite this significance, the absence of a methodological framework for tracking δ13C values in tree rings persists due to the complexity of tree ring development. To fill this knowledge gap, we developed a method to monitor weekly variability of δ13C in the cambium-xylem continuum of black spruce species [Picea mariana (Mill.) BSP.] during the growing season. We collected and isolated the weekly incremental growth of the cambial region and the developing tree ring from five mature spruce trees over three consecutive growing seasons (2019-21) in Simoncouche and two growing seasons (2020-21) in Bernatchez, both located in the boreal forest of Quebec, Canada. Our method allowed for the creation of intra-annual δ13C series for both the growing cambium (δ13Ccam) and developing xylem cellulose (δ13Cxc) in these two sites. Strong positive correlations were observed between δ13Ccam and δ13Cxc series in almost all study years. These findings suggest that a constant supply of fresh assimilates to the cambium-xylem continuum may be the dominant process feeding secondary growth in the two study sites. On the other hand, rates of carbon isotopic fractionation appeared to be poorly affected by climate variability, at an inter-weekly time scale. Hence, increasing δ13Ccam and δ13Cxc trends highlighted here possibly indicate shifts in carbon allocation strategies, likely fostering frost resistance and reducing water uptake in the late growth season. Additionally, these trends may be related to the black spruce trees' responses to the seasonal decrease in photosynthetically active radiation. Our findings provide new insights into the seasonal carbon dynamics and growth constraints of black spruce in boreal forest ecosystems, offering a novel methodological approach for studying carbon allocation at fine temporal scales., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

As major terrestrial carbon sinks, forests play an important role in mitigating climate change. The relationship between the seasonal uptake of carbon and its allocation to woody biomass remains poorly understood, leaving a significant gap in our capacity to predict carbon sequestration by forests. Here, we compare the intra-annual dynamics of carbon fluxes and wood formation across the Northern hemisphere, from carbon assimilation and the formation of non-structural carbon compounds to their incorporation in woody tissues. We show temporally coupled seasonal peaks of carbon assimilation (GPP) and wood cell differentiation, while the two processes are substantially decoupled during off-peak periods. Peaks of cambial activity occur substantially earlier compared to GPP, suggesting the buffer role of non-structural carbohydrates between the processes of carbon assimilation and allocation to wood. Our findings suggest that high-resolution seasonal data of ecosystem carbon fluxes, wood formation and the associated physiological processes may reduce uncertainties in carbon source-sink relationships at different spatial scales, from stand to ecosystem levels., (© 2024. The Author(s).)

Gene expression analysis is essential for understanding the mechanisms involved in plant development. Here, we developed M2WISH, a protocol based on MicroWave treatment for Wholemount mRNA In Situ Hybridization in Arabidopsis. By permeabilizing tissues without damaging cellular organization this protocol results in high and homogeneous hybridization yields that enable systematic analysis of gene expression dynamics. Moreover, when combined with cellular histochemical staining, M2WISH successfully provides a cellular resolution of gene expression. Thus, we demonstrate the robustness of M2WISH with 10 genes on roots, aerial meristems, leaves, and embryos in the seed. We applied M2WISH to study the spatial dynamics of WUSCHEL (WUS) and CLAVATA3 (CLV3) expression during in vitro meristematic conversion of roots into shoot apical meristems. Thus, we showed that shoot apical meristems could arise from two different types of root structures that differed by their CLV3 gene expression patterns. We constructed 3D cellular representations of WUS and CLV3 gene co-expression pattern and stressed the variability inherent to meristem conversion. Thus, this protocol generates a large amount of data on the localization of gene expression, which can be used to model complex systems., (© 2024 Society for Experimental Biology and John Wiley & Sons Ltd.)

Wood growth is key to understanding the feedback of forest ecosystems to the ongoing climate warming. An increase in spatial synchrony (i.e., coincident changes in distant populations) of spring phenology is one of the most prominent climate responses of forest trees. However, whether temperature variability contributes to an increase in the spatial synchrony of spring phenology and its underlying mechanisms remains largely unknown. Here, we analyzed an extensive dataset of xylem phenology observations of 20 conifer species from 75 sites over the Northern Hemisphere. Along the gradient of increase in temperature variability in the 75 sites, we observed a convergence in the onset of cell enlargement roughly toward the 5 th of June, with a convergence in the onset of cell wall thickening toward the summer solstice. The increase in rainfall since the 5 th of June is favorable for cell division and expansion, and as the most hours of sunlight are received around the summer solstice, it allows the optimization of carbon assimilation for cell wall thickening. Hence, the convergences can be considered as the result of matching xylem phenological activities to favorable conditions in regions with high temperature variability. Yet, forest trees relying on such consistent seasonal cues for xylem growth could constrain their ability to respond to climate warming, with consequences for the potential growing season length and, ultimately, forest productivity and survival in the future., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Ricca assays allow the direct introduction of compounds extracted from plants or the organisms that attack them into the leaf vasculature. Using chromatographic fractionation of Arabidopsis (Arabidopsis thaliana) leaf extracts, we found glutamate was the most active low mass elicitor of membrane depolarization. However, other known elicitors of membrane depolarization are generated in the wound response. These include unstable aglycones generated by glucosinolate (GSL) breakdown. None of the aglycone-derived GSL-breakdown products, including nitriles and isothiocyanates, that we tested using Ricca assays triggered electrical activity. Instead, we found that glutathione and the GSL-derived compound sulforaphane glutathione triggered membrane depolarizations. These findings identify a potential link between GSL breakdown and glutathione in the generation of membrane depolarizing signals. Noting that the chromatographic fractionation of plant extracts can dilute or exchange ions, we found that Cl- caused glutamate receptor-like3.3-dependent membrane depolarizations. In summary, we show that, in addition to glutamate, glutathione derivatives as well as chloride ions will need to be considered as potential elicitors of wound-response membrane potential change. Finally, by introducing aphid (Brevicoryne brassicae) extracts or the flagellin-derived peptide flg22 into the leaf vasculature we extend the use of Ricca assays for the exploration of insect/plant and bacteria/plant interactions., Competing Interests: Conflict of interest statement. None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Society of Plant Biologists.)

Purpose: Evaluation of the effectiveness of pneumatic vitreolysis in disrupting vitreomacular traction in our own cohort of patients., Methodology: Prospective follow-up of 21 eyes of 18 patients with focal VMT (adhesion width < 1500 µm) who underwent intravitreal injection of 0.3 ml of 100% perfluoropropane between January 2015 and December 2020. The patients were observed for 90 days., Results: Release of VMT was achieved on the 28th day of observation in 15 out of 21 eyes (71.4%), and by the 90th day in 19 out of 21 eyes (90.5%). The average width of adhesion in our patients was 382 µm (±212 µm). Average best corrected visual acuity in our cohort was initially 0.77 (±0.21), after 28 days 0.74 (±0.30), and after 3 months 0.82 (±0.21). At the end of the follow-up period, we did not observe a statistically significant improvement in vision. Macular holes developed in two eyes, but spontaneously closed within 1 month of observation, and no more complications were observed in the cohort., Conclusion: Pneumatic vitreolysis by intravitreal injection of C3F8 gas is an effective and inexpensive option for the management of symptomatic vitreomacular traction. The incidence of serious adverse events in our follow-up was significantly lower than in recently published series. The method of management should be selected individually according to the parameters of adhesion, macular hole and associated ocular pathologies.

Purpose: The aim of this study was to investigate whether there is any association between the levels of the angiogenic growth factors and the vascular oxygen saturation in eyes with diabetic retinopathy., Methods: The study was designed as a prospective trial. The cohort consisted of 29 diabetic patients with scheduled vitreous procedures (intravitreal injection or pars plana vitrectomy). The control group included 30 patients scheduled for macular surgery (macular hole or epiretinal membrane). Nine patients (four from the diabetic maculopathy [DM] group and five from the control group) were excluded from the study because of unsuccessful vitreous samples. Retinal oximetry was performed several hours before the vitreous procedure was performed, and vitreous samples were obtained during the procedure. The concentrations of VEGF, Serpin F1/pigment epithelium-derived factor (PEDF), and placental growth factor (PlGF) were measured by ELISA., Results: A negative correlation between level of VEGF and arteriovenous (AV) saturation difference was determined in the DM group (Pearson correlation coefficient r = -0.607; two-tailed test, P = 0.002). Also a negative correlation between level of PlGF and AV saturation difference was determined in the DM group (Pearson correlation coefficient r = -0.521; two-tailed test, P = 0.011) A positive correlation between PlGF level and the vein saturation was not statistically significant (Pearson correlation coefficient r = 0.325; two-tailed test, P = 0.130). We did not find any correlation between vitreous level of PEDF and vascular saturation within the DM group., Conclusions: Our findings in diabetic patients suggests a correlation between the intravitreal level of proangiogenic factors and the AV difference measured by retinal oximetry.

The links between wound-response electrical signalling and the activation of jasmonate synthesis are unknown. We investigated damage-response remodelling of jasmonate precursor pools in the Arabidopsis thaliana leaf vasculature. Galactolipids and jasmonate precursors in primary veins from undamaged and wounded plants were analysed using MS-based metabolomics and NMR. In parallel, DAD1-LIKE LIPASEs (DALLs), which control the levels of jasmonate precursors in veins, were identified. A novel galactolipid containing the jasmonate precursor 12-oxo-phytodienoic acid (OPDA) was identified in veins: sn-2-O-(cis-12-oxo-phytodienoyl)-sn-3-O-(β-galactopyranosyl) glyceride (sn-2-OPDA-MGMG). Lower levels of sn-1-OPDA-MGMG were also detected. Vascular OPDA-MGMGs, sn-2-18:3-MGMG and free OPDA pools were reduced rapidly in response to damage-activated electrical signals. Reduced function dall2 mutants failed to build resting vascular sn-2-OPDA-MGMG and OPDA pools and, upon wounding, dall2 produced less jasmonoyl-isoleucine (JA-Ile) than the wild-type. DALL3 acted to suppress excess JA-Ile production after wounding, whereas dall2 dall3 double mutants strongly reduce jasmonate signalling in leaves distal to wounds. LOX6 and DALL2 function to produce OPDA and the non-bilayer-forming lipid sn-2-OPDA-MGMG in the primary vasculature. Membrane depolarizations trigger rapid depletion of these molecules. We suggest that electrical signal-dependent lipid phase changes help to initiate vascular jasmonate synthesis in wounded leaves., (© 2023 The Authors. New Phytologist © 2023 New Phytologist Foundation.)

Sex determination evolved to control the development of unisexual flowers. In agriculture, it conditions how plants are cultivated and bred. We investigated how female flowers develop in monoecious cucurbits. We discovered in melon, Cucumis melo, a mechanism in which ethylene produced in the carpel is perceived in the stamen primordia through spatially differentially expressed ethylene receptors. Subsequently, the CmEIN3/CmEIL1 ethylene signalling module, in stamen primordia, activates the expression of CmHB40, a transcription factor that downregulates genes required for stamen development and upregulates genes associated with organ senescence. Investigation of melon genetic biodiversity revealed a haplotype, originating in Africa, altered in EIN3/EIL1 binding to CmHB40 promoter and associated with bisexual flower development. In contrast to other bisexual mutants in cucurbits, CmHB40 mutations do not alter fruit shape. By disentangling fruit shape and sex-determination pathways, our work opens up new avenues in plant breeding., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: There is a clinical need for therapeutics for COVID-19 patients with acute hypoxemic respiratory failure whose 60-day mortality remains at 30-50%. Aviptadil, a lung-protective neuropeptide, and remdesivir, a nucleotide prodrug of an adenosine analog, were compared with placebo among patients with COVID-19 acute hypoxaemic respiratory failure., Methods: TESICO was a randomised trial of aviptadil and remdesivir versus placebo at 28 sites in the USA. Hospitalised adult patients were eligible for the study if they had acute hypoxaemic respiratory failure due to confirmed SARS-CoV-2 infection and were within 4 days of the onset of respiratory failure. Participants could be randomly assigned to both study treatments in a 2 × 2 factorial design or to just one of the agents. Participants were randomly assigned with a web-based application. For each site, randomisation was stratified by disease severity (high-flow nasal oxygen or non-invasive ventilation vs invasive mechanical ventilation or extracorporeal membrane oxygenation [ECMO]), and four strata were defined by remdesivir and aviptadil eligibility, as follows: (1) eligible for randomisation to aviptadil and remdesivir in the 2 × 2 factorial design; participants were equally randomly assigned (1:1:1:1) to intravenous aviptadil plus remdesivir, aviptadil plus remdesivir matched placebo, aviptadil matched placebo plus remdesvir, or aviptadil placebo plus remdesivir placebo; (2) eligible for randomisation to aviptadil only because remdesivir was started before randomisation; (3) eligible for randomisation to aviptadil only because remdesivir was contraindicated; and (4) eligible for randomisation to remdesivir only because aviptadil was contraindicated. For participants in strata 2-4, randomisation was 1:1 to the active agent or matched placebo. Aviptadil was administered as a daily 12-h infusion for 3 days, targeting 600 pmol/kg on infusion day 1, 1200 pmol/kg on day 2, and 1800 pmol/kg on day 3. Remdesivir was administered as a 200 mg loading dose, followed by 100 mg daily maintenance doses for up to a 10-day total course. For participants assigned to placebo for either agent, matched saline placebo was administered in identical volumes. For both treatment comparisons, the primary outcome, assessed at day 90, was a six-category ordinal outcome: (1) at home (defined as the type of residence before hospitalisation) and off oxygen (recovered) for at least 77 days, (2) at home and off oxygen for 49-76 days, (3) at home and off oxygen for 1-48 days, (4) not hospitalised but either on supplemental oxygen or not at home, (5) hospitalised or in hospice care, or (6) dead. Mortality up to day 90 was a key secondary outcome. The independent data and safety monitoring board recommended stopping the aviptadil trial on May 25, 2022, for futility. On June 9, 2022, the sponsor stopped the trial of remdesivir due to slow enrolment. The trial is registered with ClinicalTrials.gov, NCT04843761., Findings: Between April 21, 2021, and May 24, 2022, we enrolled 473 participants in the study. For the aviptadil comparison, 471 participants were randomly assigned to aviptadil or matched placebo. The modified intention-to-treat population comprised 461 participants who received at least a partial infusion of aviptadil (231 participants) or aviptadil matched placebo (230 participants). For the remdesivir comparison, 87 participants were randomly assigned to remdesivir or matched placebo and all received some infusion of remdesivir (44 participants) or remdesivir matched placebo (43 participants). 85 participants were included in the modified intention-to-treat analyses for both agents (ie, those enrolled in the 2 x 2 factorial). For the aviptadil versus placebo comparison, the median age was 57 years (IQR 46-66), 178 (39%) of 461 participants were female, and 246 (53%) were Black, Hispanic, Asian or other (vs 215 [47%] White participants). 431 (94%) of 461 participants were in an intensive care unit at baseline, with 271 (59%) receiving high-flow nasal oxygen or non-invasive ventiliation, 185 (40%) receiving invasive mechanical ventilation, and five (1%) receiving ECMO. The odds ratio (OR) for being in a better category of the primary efficacy endpoint for aviptadil versus placebo at day 90, from a model stratified by baseline disease severity, was 1·11 (95% CI 0·80-1·55; p=0·54). Up to day 90, 86 participants in the aviptadil group and 83 in the placebo group died. The cumulative percentage who died up to day 90 was 38% in the aviptadil group and 36% in the placebo group (hazard ratio 1·04, 95% CI 0·77-1·41; p=0·78). The primary safety outcome of death, serious adverse events, organ failure, serious infection, or grade 3 or 4 adverse events up to day 5 occurred in 146 (63%) of 231 patients in the aviptadil group compared with 129 (56%) of 230 participants in the placebo group (OR 1·40, 95% CI 0·94-2·08; p=0·10)., Interpretation: Among patients with COVID-19-associated acute hypoxaemic respiratory failure, aviptadil did not significantly improve clinical outcomes up to day 90 when compared with placebo. The smaller than planned sample size for the remdesivir trial did not permit definitive conclusions regarding safety or efficacy., Funding: National Institutes of Health., Competing Interests: Declaration of interests SMB reports funding from the National Institutes of Health during the conduct of the study and chairing a Data and Safety Monitoring Board (DSMB) for Hamilton Ventilators, outside of the study. CEB reports funding from the National Institutes of Health (NIH) for the Aviptadil study, during the conduct of the study. BG reports grants from the NIH, during the conduct of the study. SS reports a grant from the NIH, during the conduct of the study. ANP reports grants from the Wellcome Trust, the National Institute for Health and Care Research, UK Research and Innovation (UKRI), and the Bill & Melinda Gates Foundation, and consulting fees from the Bill & Melinda Gates Foundation, outside of the submitted work. IDP reports funding from NIH and the National Institute of General Medical Sciences, during the conduct of the study, a grant from Janssen for a study of influenza patient reported outcomes, and a contract with Regeneron for a COVID-19 therapy trial, outside of the submitted work. JRB reports a grant from the NIH, during the conduct of the study, grants from the NIH, Quantum Leap Healthcare Collaborative, and Sedana Medical, consulting fees from Sedana Medical, Biomarck, and Global Blood Therapeutics, and compensation from Hamilton Medical for participation as a medical monitor, outside of the submitted work. ESHa reports study materials from NeuroRx and Gilead through a National Heart, Lung, and Blood Institute (NHLBI) subcontract, during the conduct of the study, subcontracts with Bristol Meyers Squibb (BMS), Allergan, Gilead, and Janssen for the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV-1) clinical trial, subcontracts with AstraZeneca, Brii Biosciences, Vir Biotechnology, and Eli Lilly for the Therapeutics for Inpatients with COVID-19 (TICO) clinical trial, and additional subcontracts with Rigel, APEIRON Biologics, and Trevena for the Novel Experimental COVID-19 Therapies Affecting Host Response (NECTAR) clinical trial, outside of the submitted work. EAM reports study materials from NeuroRx and Gilead through an NHLBI subcontract, during the conduct of the study, subcontracts with BMS, Allergan, Gilead, and Janssen for the ACTIV-1 clinical trial, subcontracts with AstraZeneca, Brii Biosciences, Vir Biotechnology, and Eli Lilly for the TICO clinical trial, and additional subcontracts with Rigel, APEIRON Biologics, and Trevena for the NECTAR clinical trial, outside of the submitted work. MAGB reports study materials from NeuroRx and Gilead through an NHLBI subcontract, during the conduct of the study, subcontracts with BMS, Allergan, Gilead, and Janssen for the ACTIV-1 clinical trial, subcontracts with AstraZeneca, Brii Biosciences, Vir Biotechnology, and Eli Lilly for the TICO clinical trial, and subcontracts with Rigel, APEIRON Biologics, and Trevena for the NECTAR clinical trial, outside of the submitted work. KSM reports grants and contracts from NIH, NHLBI, and the Society for Critical Care Medicine, participation as a steering committee member for Roivant-Kinevant Sciences, and employment as a clinical research physician at Chiesi USA, outside of submitted work. JM reports receiving study materials and funding from the Albert Einstein College of Medicine for the study protocol, during the conduct of the study. CH reports funding from the National Institute of Allergy and Infectious Diseases (NIAID) in the form of per-patient payments for A Multicenter, Adaptive, Randomized, Blinded Controlled Trial of the Safety and Efficacy of Investigational Therapeutics for Hospitalized Patients with Acute Respiratory Distress Syndrome Associated with COVID-19, during the conduct of the study. AK reports grants from Eli Lilly, AstraZeneca, 4D Medical, United Therapeutics, Regeneron Pharmaceuticals, and Dompe Pharmaceuticals and consulting fees from Dompe Pharmaceuticals for clinical trial design, outside of the submitted work. AD reports grants from NHLBI Prevention and Early Treatment of Acute Lung Injury network and the US Centers for Disease Control and Prevention (CDC) and data safety monitoring board (DSMB) or advisory board participation for Alung Technologies, outside of the submitted work. SD reports a grant from Chest Sonosite Ultrasound to study the incidence of deep vein thrombosis in patients with COVID-19, during the conduct of the study. AJG reports payment from Sound Pharmaceuticals for participation as a medical monitor for a COVID therapeutic trial, outside of the submitted work. USS reports consulting fees from Shionogi, Paratek, and ViiV Healthcare for participation on advisory boards and speaking fees from Shionogi and Paratek, outside of the submitted work. NJJ reports grants from the CDC, the US Department of Defense (DOD), and NIH and participation on a DSMB for the Legacy Health System, outside of the submitted work. MAM reports grants from NIH and NIAID, during the conduct of the study. NRA reports funding from NIH, during the conduct of the study. JDC reports grants from NIH and DOD, outside of the submitted work. DDM reports funding from the Danish National Research Foundation (DNRF126), during the conduct of study. AAG reports funding from NIH, during the conduct of the study, grants or contracts from NIH, DOD, CDC, Faron Pharmaceuticals, and Abbvie, and participation on a DSMB or advisory board for NIH, outside of the submitted work. WHS reports funding from NIH and NIAID, during the conduct of the study. CFO reports contracts with NIH and NHLBI, outside of the submitted work. BTT reports a grant from NHLBI, consulting fees from Bayer, Genetec, and Novartis, and participation on a DSMB or advisory board for Aperion, outside of the submitted work. During a portion of this research, BTT had a financial interest in Direct Biologics, a developer and manufacturer of regenerative biologic products, including an investigational treatment of COVID-19-associated ARDS. BTT's interests were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict of interest policies, and had no relationship to the agents studied. VK reports subcontracts with University of Minnesota, NIAID, and NIH for the TICO and Therapeutics for Severely Ill Inpatients with COVID-19 platform trials, outside of the submitted work. AGB reports a grant from University of Minnesota, during the conduct of the study, grants from the Medical Reserve Corps and UKRI, payment from NIAID for participation on a COVID-19 Vaccines DSMB, and participation on the WHO Trial Data and Safety Monitoring Committee, outside of the submitted work. JDN reports grants from NIAID, NIH, and Leidos Biomedical, outside of the submitted work. HCL reports employment from NIAID, during the conduct of the study. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Androgen receptor (AR) inhibition remains the primary strategy to combat the progression of prostate cancer (PC). However, all clinically used AR inhibitors target the ligand-binding domain (LBD), which is highly susceptible to truncations through splicing or mutations that confer drug resistance. Thus, there exists an urgent need for AR inhibitors with novel modes of action. We thus launched a virtual screening of an ultra-large chemical library to find novel inhibitors of the AR DNA-binding domain (DBD) at two sites: protein-DNA interface (P-box) and dimerization site (D-box). The compounds selected through vigorous computational filtering were then experimentally validated. We identified several novel chemotypes that effectively suppress transcriptional activity of AR and its splice variant V7. The identified compounds represent previously unexplored chemical scaffolds with a mechanism of action that evades the conventional drug resistance manifested through LBD mutations. Additionally, we describe the binding features required to inhibit AR DBD at both P-box and D-box target sites., (© 2023 The Authors. Molecular Informatics published by Wiley-VCH GmbH.)

Despite growing interest in predicting plant phenological shifts, advanced spring phenology by global climate change remains debated. Evidence documenting either small or large advancement of spring phenology to rising temperature over the spatio-temporal scales implies a potential existence of a thermal threshold in the responses of forests to global warming. We collected a unique data set of xylem cell-wall-thickening onset dates in 20 coniferous species covering a broad mean annual temperature (MAT) gradient (-3.05 to 22.9°C) across the Northern Hemisphere (latitudes 23°-66° N). Along the MAT gradient, we identified a threshold temperature (using segmented regression) of 4.9 ± 1.1°C, above which the response of xylem phenology to rising temperatures significantly decline. This threshold separates the Northern Hemisphere conifers into cold and warm thermal niches, with MAT and spring forcing being the primary drivers for the onset dates (estimated by linear and Bayesian mixed-effect models), respectively. The identified thermal threshold should be integrated into the Earth-System-Models for a better understanding of spring phenology in response to global warming and an improved prediction of global climate-carbon feedbacks., (© 2022 John Wiley & Sons Ltd.)

Numerous cancers, including prostate cancer (PCa), are addicted to transcription programs driven by specific genomic regions known as super-enhancers (SEs). The robust transcription of genes at such SEs is enabled by the formation of phase-separated condensates by transcription factors and coactivators with intrinsically disordered regions. The androgen receptor (AR), the main oncogenic driver in PCa, contains large disordered regions and is co-recruited with the transcriptional coactivator mediator complex subunit 1 (MED1) to SEs in androgen-dependent PCa cells, thereby promoting oncogenic transcriptional programs. In this work, we reveal that full-length AR forms foci with liquid-like properties in different PCa models. We demonstrate that foci formation correlates with AR transcriptional activity, as this activity can be modulated by changing cellular foci content chemically or by silencing MED1. AR ability to phase separate was also validated in vitro by using recombinant full-length AR protein. We also demonstrate that AR antagonists, which suppress transcriptional activity by targeting key regions for homotypic or heterotypic interactions of this receptor, hinder foci formation in PCa cells and phase separation in vitro. Our results suggest that enhanced compartmentalization of AR and coactivators may play an important role in the activation of oncogenic transcription programs in androgen-dependent PCa., (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Male and female unisexual flowers evolved from hermaphroditic ancestors, and control of flower sex is useful for plant breeding. We isolated a female-to-male sex transition mutant in melon and identified the causal gene as the carpel identity gene <i>CRABS CLAW (CRC)</i>. We show that the master regulator of sex determination in cucurbits, the transcription factor <i>WIP1</i> whose expression orchestrates male flower development, recruits the corepressor TOPLESS to the <i>CRC</i> promoter to suppress its expression through histone deacetylation. Impairing TOPLESS-WIP1 physical interaction leads to <i>CRC</i> expression, carpel determination, and consequently the expression of the stamina inhibitor, the aminocyclopropane-1-carboxylic acid synthase 7 (<i>CmACS7</i>), leading to female flower development. Our findings suggest that sex genes evolved to interfere with flower meristematic function, leading to unisexual flower development.

Flower morphologies shape the accessibility to nectar and pollen, two major traits that determine plant-pollinator interactions and reproductive success. Melon is an economically important crop whose reproduction is completely pollinator-dependent and, as such, is a valuable model for studying crop-ecological functions. High-resolution imaging techniques, such as micro-computed tomography (micro-CT), have recently become popular for phenotyping in plant science. Here, we implemented micro-CT to study floral morphology and honey bees in the context of nectar-related traits without a sample preparation to improve the phenotyping precision and quality. We generated high-quality 3D models of melon male and female flowers and compared the geometric measures. Micro-CT allowed for a relatively easy and rapid generation of 3D volumetric data on nectar, nectary, flower, and honey bee body sizes. A comparative analysis of male and female flowers showed a strong positive correlation between the nectar gland volume and the volume of the secreted nectar. We modeled the nectar level inside the flower and reconstructed a 3D model of the accessibility by honey bees. By combining data on flower morphology, the honey bee size and nectar volume, this protocol can be used to assess the flower accessibility to pollinators in a high resolution, and can readily carry out genotypes comparative analysis to identify nectar-pollination-related traits.

The mutation-driven transformation of clinical anti-androgen drugs into agonists of the human androgen receptor (AR) represents a major challenge for the treatment of prostate cancer patients. To address this challenge, we have developed a novel class of inhibitors targeting the DNA-binding domain (DBD) of the receptor, which is distanced from the androgen binding site (ABS) targeted by all conventional anti-AR drugs and prone to resistant mutations. While many members of the developed 4-(4-phenylthiazol-2-yl)morpholine series of AR-DBD inhibitors demonstrated the effective suppression of wild-type AR, a few represented by 4-(4-(3-fluoro-2-methoxyphenyl)thiazol-2-yl)morpholine (VPC14368) exhibited a partial agonistic effect toward the mutated T878A form of the receptor, implying their cross-interaction with the AR ABS. To study the molecular basis of the observed cross-reactivity, we co-crystallized the T878A mutated form of the AR ligand binding domain (LBD) with a bound VPC14368 molecule. Computational modelling revealed that helix 12 of AR undergoes a characteristic shift upon VPC14368 binding causing the agonistic behaviour. Based on the obtained structural data we then designed derivatives of VPC14368 to successfully eliminate the cross-reactivity towards the AR ABS, while maintaining significant anti-AR DBD potency.

Background: American Academy of Pediatrics guidelines recommend 400 IU of vitamin D supplementation daily for certain infants <1 year of age. We aimed to increase the proportion of reported appropriate vitamin D supplementation for infants born at our institution and those who followed up in our resident clinic through 6 months from 49% to 80% over 24 months., Methods: Our interdisciplinary quality improvement effort included vitamin D medication delivery before nursery discharge and family and staff education. The process measure was the percentage of families discharged from birth hospitalization with vitamin D and teaching. The outcome measure was the percentage of families reporting appropriate vitamin D supplementation at 2-, 4-, and 6-month well child visits. The balancing measure was the percentage of infants discharged from the nursery by 2 pm. Data were displayed on Statistical Process Control p charts and established rules for detecting special causes were applied., Results: Baseline and improvement data were collected for 587 hospital discharges and 220 outpatient encounters. The percentage of families discharged with vitamin D increased from 24.8% to 98% from 2016 to 2018. Percent of families reporting appropriate vitamin D supplementation at well child visits increased from 49% to 89% from 2016 to 2018. Overall, the percentage of discharges by 2 pm remained stable at 60%., Conclusion: Bedside medication delivery and education in the newborn nursery improved reported vitamin D supplementation rates in the first 6 months of life. The intervention did not delay newborn hospital discharge., (Copyright © 2022 by the American Academy of Pediatrics.)

Shapes of vegetables and fruits are the result of adaptive evolution and human selection. Modules controlling organ shape have been identified. However, little is known about signals coordinating organ development and shape. Here, we describe the characterization of a melon mutation rf1, leading to round fruit. Histological analysis of rf1 flower and fruits revealed fruit shape is determined at flower stage 8, after sex determination and before flower fertilization. Using positional cloning, we identified the causal gene as the monoecy sex determination gene CmACS7, and survey of melon germplasms showed strong association between fruit shape and sexual types. We show that CmACS7-mediated ethylene production in carpel primordia enhances cell expansion and represses cell division, leading to elongated fruit. Cell size is known to rise as a result of endoreduplication. At stage 8 and anthesis, we found no variation in ploidy levels between female and hermaphrodite flowers, ruling out endoreduplication as a factor in fruit shape determination. To pinpoint the gene networks controlling elongated versus round fruit phenotype, we analyzed the transcriptomes of laser capture microdissected carpels of wild-type and rf1 mutant. These high-resolution spatiotemporal gene expression dynamics revealed the implication of two regulatory modules. The first module implicates E2F-DP transcription factors, controlling cell elongation versus cell division. The second module implicates OVATE- and TRM5-related proteins, controlling cell division patterns. Our finding highlights the dual role of ethylene in the inhibition of the stamina development and the elongation of ovary and fruit in cucurbits., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Plant somatic embryogenesis (SE) is a natural process of vegetative propagation. It can be induced in tissue cultures to investigate developmental transitions, to create transgenic or edited lines, or to multiply valuable crops. We studied the induction of SE in the scutellum of monocots with Brachypodium distachyon as a model system. Towards the in-depth analysis of SE initiation, we determined the earliest stages at which somatic scutellar cells acquired an embryogenic fate, then switched to a morphogenetic mode in a regeneration sequence involving treatments with exogenous hormones: first an auxin (2,4-D) then a cytokinin (kinetin). Our observations indicated that secondary somatic embryos could already develop in the proliferative calli derived from immature zygotic embryo tissues within one week from the start of in vitro culture. Cell states and tissue identity were deduced from detailed histological examination, and in situ hybridization was performed to map the expression of key developmental genes. The fast SE induction method we describe here facilitates the mechanistic study of the processes involved and may significantly shorten the production of transgenic or gene-edited plants.

Background: Despite the importance of adequate hospital nurse staffing, California is the only state with minimum nurse-to-patient ratio mandates. The health care workforce is historically "countercyclical"-exhibiting growth during economic recessions when employment in other sectors is shrinking., Purpose: This study was to examine how staffing mandates impact hospital nurse staffing during economic recessions., Method: We compared hospital nurse staffing in California and in other states over 20 years to examine differences before and after the California mandate and, within the postmandate period, before, during, and after the Great Recession of 2008., Findings: Staffing differences increased during the postmandate period due to faster growth in California staffing compared to other states, except during the Great Recession, when staffing remained stable in California but declined in other states., Discussion: State legislators deliberating staffing mandates should consider the protective factor such policies provide during economic recessions and the implications for the quality and safety of care., (Copyright © 2021. Published by Elsevier Inc.)

The Myc family of transcription factors are involved in the development and progression of numerous cancers, including prostate cancer (PCa). Under the pressure of androgen receptor (AR)-directed therapies resistance can occur, leading to the lethal form of PCa known as neuroendocrine prostate cancer (NEPC), characterized among other features by N-Myc overexpression. There are no clinically approved treatments for NEPC, translating into poor patient prognosis and survival. Therefore, there is a pressing need to develop novel therapeutic avenues to treat NEPC patients. In this study, we investigate the N-Myc-Max DNA binding domain (DBD) as a potential target for small molecule inhibitors and utilize computer-aided drug design (CADD) approaches to discover prospective hits. Through further exploration and optimization, a compound, VPC-70619, was identified with notable anti-N-Myc potency and strong antiproliferative activity against numerous N-Myc expressing cell lines, including those representing NEPC.

Bone is a very complex tissue that is constantly changing throughout the lifespan. The precise mechanism of bone regeneration remains poorly understood. Large bone defects can be caused by gunshot injury, trauma, accidents, congenital anomalies and tissue resection due to cancer. Therefore, understanding bone homeostasis and regeneration has considerable clinical and scientific importance in the development of bone therapy. Macrophages are well known innate immune cells secreting different combinations of cytokines and their role in bone regeneration during bone healing is essential. Here, we present a method to identify mRNA transcripts in cryosections of non-decalcified rat bone using in situ hybridization and hybridization chain reaction to explore gene expression in situ for better understanding the gene expression of the bone tissues.

Objectives: Depression and anxiety are common in children with asthma, and asthma hospitalization is an underused opportunity to identify mental health concerns. We assessed depression and anxiety symptoms during asthma hospitalization and 1 to 2 months post discharge., Methods: This prospective cohort study included children aged 7 to 17 years who were hospitalized for asthma exacerbation. Participants completed the self-report PROMIS (Patient-Reported Outcomes Measurement Information System) depression and anxiety symptom scales (T score mean = 50, SD = 10) during hospitalization and 1 to 2 months after discharge. Higher scores indicate more symptoms and/or greater severity. We compared patients' scores during hospitalization and at follow-up using paired t tests and examined individual patients' depression and anxiety symptom trajectories using a Sankey diagram., Results: Among 96 participants who completed the study, 53% had elevated symptoms of depression, anxiety, or both either during hospitalization or after discharge. During hospitalization, 38% had elevated depression symptoms and 45% had elevated anxiety symptoms. At postdischarge follow-up, 18% had elevated depression symptoms and 20% had elevated anxiety symptoms. We observed all possible symptom trajectories: symptoms during hospitalization that persisted (especially if both depression and anxiety symptoms were present), symptoms that resolved, and symptoms that were present at follow-up only., Conclusions: Just more than half of youth hospitalized for asthma exacerbation experienced depression and/or anxiety symptoms during hospitalization or at follow-up. Patients who had both depression and anxiety symptoms during hospitalization were the most likely to have persistent symptoms at follow-up. Screening at both time points may be useful to identify mental health symptoms., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2021 by the American Academy of Pediatrics.)

Background: The standardized management of anticoagulation during the cardiopulmonary bypass seems inaccurate because of patients and surgeries variability. This study evaluates if an individualized management of heparin and protamine guided by the HMS Plus system during cardiopulmonary bypass could reduce postoperative blood loss., Methods: We conducted a prospective, controlled, unblinded, single-center study. One-hundred and eighthy-eight patients operated for cardiac surgery were included. Patients were divided in ACT Plus group (standardized approach) and HMS Plus group (individualized approach). The primary outcome was blood-loss volume during the first 24 postoperative hours. The main secondary outcomes were the need for allogeneic blood transfusions and the final protamine/heparin ratio., Results: There was no difference between the two groups for baseline characteristics. Medium blood-loss volume in the ACT Plus group was 522±260 mL vs. 527±255 mL in the HMS Plus group (P=0.58). The final protamine/heparin ratio in the ACT Plus group was 0.94±0.1 vs. 0.58±0.1 in the HMS Plus group (P<0.0001). The transfusion rate during surgery in the ACT Plus group was 25% vs. 14% in the HMS Plus group (P=0.09)., Conclusions: HMS Plus did not reduce the mean blood-loss volume during the first 24 postoperative hours compared with ACT Plus. Its utility for potential transfusion rate reduction remains to be proven.

Prostate cancer (PCa) patients undergoing androgen deprivation therapy almost invariably develop castration-resistant prostate cancer (CRPC). Targeting the androgen receptor (AR) Binding Function-3 (BF3) site offers a promising option to treat CRPC. However, BF3 inhibitors have been limited by poor potency or inadequate metabolic stability. Through extensive medicinal chemistry, molecular modeling, and biochemistry, we identified 2-(5,6,7-trifluoro-1 H -Indol-3-yl)-quinoline-5-carboxamide (VPC-13789), a potent AR BF3 antagonist with markedly improved pharmacokinetic properties. We demonstrate that VPC-13789 suppresses AR-mediated transcription, chromatin binding, and recruitment of coregulatory proteins. This novel AR antagonist selectively reduces the growth of both androgen-dependent and enzalutamide-resistant PCa cell lines. Having demonstrated in vitro efficacy, we developed an orally bioavailable prodrug that reduced PSA production and tumor volume in animal models of CRPC with no observed toxicity. VPC-13789 is a potent, selective, and orally bioavailable antiandrogen with a distinct mode of action that has a potential as novel CRPC therapeutics.

Objectives: The carotid approach for transcatheter aortic valve replacement (TAVR) has been shown to be feasible and safe. The goal of this study was to compare the 30-day outcomes of trans-carotid (TC) and transfemoral (TF) TAVR., Methods: This retrospective study enrolled 500 consecutive patients treated by TC-TAVR (n = 100) or TF-TAVR (n = 400) with percutaneous closure between January 2018 and January 2020 at the Nantes University Hospital. The primary end-point was the occurrence of cardiovascular death and cerebrovascular events at 30 days., Results: The mean age was 79.9 ± 8.1 in the TC group and 81.3 ± 6.9 (P = 0.069) in the TF group. The TC group had more men (69% vs 50.5%; P = 0.001) and more patients with peripheral vascular disease (86% vs 14.8%; P < 0.0001). Cardiac characteristics were similar between the groups, and the EuroSCORE II was 3.8 ± 2.6% vs 4.6 ± 6.0%, respectively (P = 0.443). The 30-day mortality was 2% in the TC group versus 1% in the TF group (P = 0.345). TC-TAVR was not associated with an increased risk of stroke (2% vs 2.5%; P = 0.999) or major vascular complications (2% vs 4%; P = 0.548). More permanent pacemakers were implanted in the TF group (14.9% vs 5.6%; P = 0.015), and no moderate or severe aortic regurgitation was observed in the TC group (0 vs 3.3%; P = 0.08). TC-TAVR was not associated with an increased risk of mortality or stroke at 30 days (odds ratio 1.32; 95% confidence interval 0.42-4.21; P = 0.63) in the multivariable analysis., Conclusions: No statistically significant differences between TC-TAVR and TF-TAVR were observed; therefore, TC-TAVR should be the first alternative in patients with anatomical contraindications to the femoral route., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)