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Abstract Introduction Data on real-world clinical practice and outcomes of patients with pulmonary arterial hypertension (PAH) associated with congenital heart disease (CHD) are scarce. The OPUS/OrPHeUS studies enrolled patients with PAH newly initiating macitentan, including those with PAH associated with CHD (CHD-PAH). Methods OPUS was a prospective, United States, multicenter, long-term, observational drug registry (April 2014–June 2020). OrPHeUS was a retrospective, United States, multicenter medical chart review (October 2013–March 2017). The characteristics, treatment patterns, safety, and outcomes during macitentan treatment of patients with CHD-PAH and the subgroups Eisenmenger syndrome, left-to-right shunts and small/coincidental CHD were descriptively compared. Results The combined OPUS/OrPHeUS population included 272 (6.1%) patients with CHD-PAH (80 patients with Eisenmenger syndrome; 82 patients with left-to-right shunts and 92 patients with small/coincidental defects). Most patients across the CHD-PAH subgroups were in World Health Organization Functional Class II/III (82.9–94.6%). Macitentan was initiated as combination therapy in 65.0% of patients with CHD-PAH. During follow-up, 81.4% of patients experienced ≥ 1 adverse event (AE), the most common being dyspnea (23.5%), nausea (13.7%), dizziness (12.7%), headache (12.7%) and edema (10.8%). The 1- and 2-year Kaplan–Meier (95% confidence limits) estimates of patients with CHD-PAH being free from hospitalization were 64.5% (57.9, 70.4) and 49.3% (41.9, 56.3); for survival, the 1- and 2-year Kaplan–Meier estimates were 93.5% (89.3, 96.1) and 90.2% (84.9, 93.7). Conclusions Macitentan was used in clinical practice in patients with CHD-PAH and its subgroups, including as combination therapy in the majority of patients. Safety in this population was consistent with the known profile of macitentan. Trial Registration OPsumit® Users Registry (OPUS): NCT02126943; Opsumit® Historical Users cohort (OrPHeUS): NCT03197688; URL www.clinicaltrials.gov .

Background: Cardiac rehabilitation programs provide a valuable opportunity to promote the adoption of healthy lifestyle behaviors in patients with atherosclerotic cardiovascular diseases (ASCVDs) and metabolic comorbidities, including metabolic syndrome and prediabetes. However, strategies to reverse these conditions remain to be explored. The DIABEPIC-1 study aimed to assess the feasibility of an enhanced 6-month cardiac rehabilitation program for patients with ASCVD while investigating prediabetes and metabolic syndrome remission. Methods: The study combined exercise training with a comprehensive nutritional intervention, emphasizing reduction in intake of ultraprocessed foods, adoption of a Mediterranean diet, and implementation of time-restricted eating. Baseline, 3-month, and 6-month assessments included segmental body-composition measurements, blood analysis, maximal exercise testing, nutritional diaries recorded with the Keenoa AI app, and lifestyle questionnaires. Remission criteria included a return to an HbA1c level of < 5.7%, and < 3 National Cholesterol Education Program Adult Treatment Panel III (NCEP/ATP-III) criteria for prediabetes and metabolic syndrome, respectively. Results: A total of 36 participants were recruited. The study demonstrated completion rates of 94.4% at 3 months, and 88.9% at 6 months, and a mean compliance rate of 92.5% for planned clinical appointments. Significant reductions in waist circumference (–9.2 cm, P < 0.001) and weight (–8.0 kg, P < 0.001) were observed. Improvement in glycemic and lipid profiles, insulin-resistance marker levels, and liver health were noted. Participants enhanced their cardiorespiratory fitness, reduced their consumption of ultraprocessed food, and increased their adherence to the Mediterranean diet and time-restricted eating. Notably, 50% achieved prediabetes remission, and 70% with metabolic syndrome at baseline achieved remission. Conclusions: The study demonstrates the possibility of enhancing cardiac rehabilitation with an intensive nutritional intervention, yielding clinically significant outcomes, including remission of key risk factors in a substantial number of ASCVD patients. Clinical Trial Registration: ClinicalTrials.gov, NCT05459987. Résumé: Contexte: Les programmes de réadaptation cardiaque offrent une occasion précieuse de promouvoir l'adoption d'un mode de vie sain chez les patients atteints de maladies cardiovasculaires athéroscléreuses (MCVA) et de comorbidités métaboliques, notamment le syndrome métabolique et le prédiabète. Cependant, les stratégies visant à inverser ces conditions restent à explorer. L'étude DIABEPIC-1 visait à évaluer la faisabilité d'un programme de réadaptation cardiaque renforcé de 6 mois pour les patients atteints de MCVA tout en examinant la rémission du prédiabète et du syndrome métabolique. Méthodes: L'étude a combiné un entraînement physique avec une intervention nutritionnelle complète, mettant l'accent sur la réduction de la consommation d'aliments ultra-transformés, l'adoption d'un régime méditerranéen et la mise en œuvre d'une alimentation restreinte dans le temps. Les évaluations de base, à 3 mois et à 6 mois, comprenaient des mesures de la composition corporelle par segments, des analyses sanguines, des tests d'exercice maximal, la tenue de journaux nutritionnels enregistrés avec l'application Keenoa AI et des questionnaires sur le mode de vie. Les critères de rémission comprenaient un retour à un niveau d'hémoglobine glyquée HbA1c < 5,7 %, et < 3 critères de la table du « National Cholesterol Education Program Adult Treatment Panel III » (NCEP/ATP-III) pour le prédiabète et le syndrome métabolique, respectivement. Résultats: Au total, 36 participants ont été recrutés. L'étude a montré des taux d'achèvement de 94,4 % à 3 mois et de 88,9 % à 6 mois, ainsi qu'un taux de conformité moyen de 92,5 % pour les rendez-vous cliniques planifiés. Des réductions significatives du tour de taille (-9,2 cm, p < 0,001) et du poids (-8,0 kg, p < 0,001) ont été observées. Une amélioration des profils glycémiques et lipidiques, des niveaux de marqueurs de résistance à l'insuline et de la santé hépatique a été constatée. Les participants ont amélioré leur condition cardiorespiratoire, réduit leur consommation d'aliments ultra-transformés et augmenté leur adhésion au régime méditerranéen et à l'alimentation restreinte dans le temps. Notamment, 50 % des participants ont obtenu une rémission du prédiabète et 70 % des participants atteints du syndrome métabolique au début de l'étude ont atteint la rémission. Conclusions: L'étude démontre la possibilité d'améliorer la réadaptation cardiaque par une intervention nutritionnelle intensive, produisant des résultats cliniquement significatifs, y compris la rémission des principaux facteurs de risque chez un nombre substantiel de patients atteints de MCVA. Enregistrement de l'essai clinique: ClinicalTrials.gov, NCT05459987.

Abstract Key Message Understanding the impact of extreme drought on the canopy fuel moisture content (CFMC) is crucial to anticipate the effects of climate change on wildfires. Our study demonstrates that foliage mortality, caused by leaf embolism, can substantially diminish CFMC during drought on Pinus halepensis Mill. and Quercus ilex L. It emphasizes the importance of considering plant hydraulics to improve wildfire predictions. Context Canopy fuel moisture content (CFMC), which represents the water-to-dry mass ratio in leaves and fine twigs within the canopy, is a major factor of fire danger across ecosystems worldwide. CFMC results from the fuel moisture content of living foliage (live fuel moisture content, LFMC) and dead foliage (dead fuel moisture content, DFMC) weighted by the proportion of foliage mortality in the canopy (α Dead ). Understanding how LFMC, α Dead , and ultimately CFMC are affected during extreme drought is essential for effective wildfire planning. Aims We aimed to understand how plant hydraulics affect CFMC for different levels of soil water deficit, examining its influence on both LFMC and α Dead . Methods We conducted a drought experiment on seedlings of two Mediterranean species: Aleppo pine (Pinus halepensis Mill.) and Holm oak (Quercus ilex L.). Throughout the drought experiment and after rewatering, we monitored CFMC, LFMC, and α Dead along with other ecophysiological variables. Results LFMC exhibited a significant decrease during drought, and as leaf water potentials reached low levels, α Dead increased in both species, thereby reducing CFMC. Distinct water use strategies resulted in species-specific variations in dehydration dynamics. Conclusion Our findings demonstrate that as drought conditions intensify, foliage mortality might become a critical physiological factor driving the decline in CFMC.

Abstract Microgravity is associated with immunological dysfunction, though the mechanisms are poorly understood. Here, using single-cell analysis of human peripheral blood mononuclear cells (PBMCs) exposed to short term (25 hours) simulated microgravity, we characterize altered genes and pathways at basal and stimulated states with a Toll-like Receptor-7/8 agonist. We validate single-cell analysis by RNA sequencing and super-resolution microscopy, and against data from the Inspiration-4 (I4) mission, JAXA (Cell-Free Epigenome) mission, Twins study, and spleens from mice on the International Space Station. Overall, microgravity alters specific pathways for optimal immunity, including the cytoskeleton, interferon signaling, pyroptosis, temperature-shock, innate inflammation (e.g., Coronavirus pathogenesis pathway and IL-6 signaling), nuclear receptors, and sirtuin signaling. Microgravity directs monocyte inflammatory parameters, and impairs T cell and NK cell functionality. Using machine learning, we identify numerous compounds linking microgravity to immune cell transcription, and demonstrate that the flavonol, quercetin, can reverse most abnormal pathways. These results define immune cell alterations in microgravity, and provide opportunities for countermeasures to maintain normal immunity in space.

Abstract Introduction Portopulmonary hypertension (PoPH) carries a worse prognosis than other forms of pulmonary arterial hypertension (PAH). Data regarding use of PAH-specific therapies in patients with PoPH are sparse as they are usually excluded from clinical trials. This analysis describes patient characteristics, treatment patterns, outcomes, and safety profiles in patients with PoPH newly initiating macitentan in the USA using the OPUS/OrPHeUS combined dataset. Methods OPUS was a prospective, US, multicenter, observational drug registry (April 2014–June 2020); OrPHeUS was a retrospective, US, multicenter chart review (October 2013–March 2017). Additional information regarding patients’ liver disease was retrospectively collected for patients with PoPH in OPUS. Results The OPUS/OrPHeUS dataset included 206 patients with PoPH (median age 58 years; 52.4% female), with baseline cirrhosis and liver test abnormalities reported in 72.8% and 31.6% of patients respectively. Macitentan was initiated as combination therapy in 74.8% of patients and median (Q1, Q3) exposure to macitentan was 11.9 (3.1, 26.0) months. One-year Kaplan–Meier estimates (95% confidence limit, CL) of patients free from all-cause hospitalization and survival were 48.6% (40.7, 56.0) and 82.2% (75.1, 87.4). Of the 96 patients with PoPH in OPUS, 29.2% were classified as in need of liver transplant due to underlying liver disease during the study; transplant waitlist registration was precluded because of PAH severity for 32.1% and 17.9% were transplanted. Hepatic adverse events (HAE) were experienced by 49.0% of patients; the most common being increased bilirubin (16.0%), ascites (7.3%), and hepatic encephalopathy (5.8%); 1.5% and 21.8% of patients discontinued macitentan as a result of HAE and non-hepatic adverse events. Conclusion There were no unexpected safety findings in patients with PoPH treated with macitentan. These data add to the evidence supporting the safety and tolerability of macitentan in patients with PoPH. A graphical abstract is available with this article. Trial Registration OPsumit® Users Registry (OPUS): NCT02126943; OPsumit® Historical Users cohort (OrPHeUS): NCT03197688; www.clinicaltrials.gov . Graphical Abstract

Abstract Introduction The aim of this sub-study was to evaluate the relationship between echocardiography (echo) and cardiac magnetic resonance imaging (cMRI) variables and to utilize echo to assess the effect of macitentan on right ventricle (RV) structure and function. Methods REPAIR (NCT02310672) was a prospective, multicenter, single-arm, open-label, 52-week, phase 4 study in pulmonary arterial hypertension (PAH) patients, which investigated the effect of macitentan 10 mg as monotherapy, or in combination with a phosphodiesterase 5 inhibitor, on RV structure, function, and hemodynamics using cMRI and right heart catheterization. In this sub-study, patients were also assessed by echo at screening and at weeks 26 and/or 52. Post hoc correlation analyses between echo and cMRI variables were performed using Pearson’s correlation coefficient, Spearman's correlation coefficient, and Bland–Altman analyses. Results The Echo sub-study included 45 patients. Improvements in echo-assessed RV stroke volume (RVSV), left ventricular SV (LVSV), LV end-diastolic volume (LVEDV), RV fractional area change (RVFAC), tricuspid annular plane systolic excursion (TAPSE), and in 2D global longitudinal RV strain (2D GLRVS) were observed at weeks 26 and 52 compared to baseline. There was a strong correlation between echo (LVSV, 2D GLRVS, and LVEDV) and cMRI variables, with a moderate correlation for RVSV. Bland–Altman analyses showed a good agreement for LVSV measured by echo versus cMRI, whereas an overestimation in echo-assessed RVSV was observed compared to cMRI (bias of − 15 mL). Hemodynamic and functional variables, as well as safety, were comparable between the Echo sub-study and REPAIR. Conclusions A good relationship between relevant echo and cMRI parameters was shown. Improvements in RV structure and function with macitentan treatment was observed by echo, consistent with results observed by cMRI in the primary analysis of the REPAIR study. Echo is a valuable complementary method to cMRI, with the potential to non-invasively monitor treatment response at follow-up. Trial registration number REPAIR NCT02310672. Graphical Abstract

Background: Research has demonstrated that the loss of one or more natural teeth can be an emotionally traumatic experience that mirrors processes associated with bereavement. There remains scant literature examining the role of emotions in dental encounters. One such exception is the literature on the idea of the ‘treatment alliance’ in dental encounters. The aim of this paper is to explore the role of the ‘treatment alliance’ in dentist–patient encounters. Methods: Data were collected from clinical observations, semi-structured interviews and focus groups exploring the experience of tooth loss and how the treatment alliance shaped the patient journey. Data analysis was conducted using the grounded theory method influenced by phenomenology. Coding was conducted using NVIVO and the unit of analysis was the treatment alliance. Results: Twenty participants took part in the interviews (eleven male; nine female; 22–86 years; mean age = 58.9 years). Observations were carried out with a further fourteen participants (seven male; seven female; 50–101 years; mean age = 62.2 years). The paper draws on four cases taken from the observational data to illustrate important dynamics underpinning how the treatment alliance varied. These case studies are then used as the basis for a critical discussion of the importance of the treatment alliance in dentistry. Conclusions: The treatment alliance acted as an important moderator in the clinical encounter, helping to influence successful outcomes. An important foundational component of the treatment alliance was the degree of emotional work the dental team conducted when ‘getting to know’ unfamiliar patients. Whilst emotions were an important factor in dental encounters, their acknowledgement and management were not essential to all successful outcomes. Much more research is therefore needed into the role of emotional labour in dental encounters.

Purpose Because of atypical response imaging patterns in patients with metastatic non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICPIs), new biomarkers are needed for a better monitoring of treatment efficacy. The aim of this prospective study was to evaluate the prognostic value of volume-derived positron-emission tomography (PET) parameters on baseline and follow-up 18F-fluoro-deoxy-glucose PET (18F-FDG-PET) scans and compare it with the conventional PET Response Criteria in Solid Tumors (PERCIST).Methods Patients with metastatic NSCLC were included in two different single-center prospective trials. 18F-FDG-PET studies were performed before the start of immunotherapy (PETbaseline), after 6–8 weeks (PETinterim1) and after 12–16 weeks (PETinterim2) of treatment, using PERCIST criteria for tumor response assessment. Different metabolic parameters were evaluated: absolute values of maximum standardized uptake value (SUVmax) of the most intense lesion, total metabolic tumor volume (TMTV), total lesion glycolysis (TLG), but also their percentage changes between PET studies (ΔSUVmax, ΔTMTV and ΔTLG). The median follow-up of patients was 31 (7.3–31.8) months. Prognostic values and optimal thresholds of PET parameters were estimated by ROC (Receiver Operating Characteristic) curve analysis of 12-month overall survival (12M-OS) and 6-month progression-free survival (6M-PFS). Tumor progression needed to be confirmed by a multidisciplinary tumor board, considering atypical response patterns on imaging.Results 110 patients were prospectively included. On PETbaseline, TMTV was predictive of 12M-OS [AUC (Area Under Curve) =0.64; 95% CI: 0.61 to 0.66] whereas SUVmax and TLG were not. On PETinterim1 and PETinterim2, all metabolic parameters were predictive for 12M-OS and 6M-PFS, the residual TMTV on PETinterim1 (TMTV1) being the strongest prognostic biomarker (AUC=0.83 and 0.82; 95% CI: 0.74 to 0.91, for 12M-OS and 6M-PFS, respectively). Using the optimal threshold by ROC curve to classify patients into three TMTV1 subgroups (0 cm3; 0–57 cm3; >57 cm3), TMTV1 prognostic stratification was independent of PERCIST criteria on both PFS and OS, and significantly outperformed them. Subgroup analysis demonstrated that TMTV1 remained a strong prognostic biomarker of 12M-OS for non-responding patients (p=0.0003) according to PERCIST criteria. In the specific group of patients with PERCIST progression on PETinterim1, low residual tumor volume (

This research introduces a novel framework for enhancing soybean cultivation in North America by categorizing growing environments into distinct ecological and maturity-based zones. Using an integrated analysis of long-term climatic data and records of soybean varietal trials, this research generates a zonal environmental characterization which captures major components of the growing environment which affect the range of adaptation of soybean varieties. These findings have immediate applications for optimizing multi-environment soybean trials. This characterization allows breeders to assess the environmental representation of a multi-environmental trial of soybean varieties, and to strategize the distribution of testing and the placement of test sites accordingly. This application is demonstrated with a historical scenario of a soybean multi-environment trial, using two resource allocation models: one targeted towards improving the general adaptation of soybean varieties, which focuses on widely cultivated areas, and one targeted towards specific adaptation, which captures diverse environmental conditions. Ultimately, the study aims to improve the efficiency and impact of soybean breeding programs, leading to the development of cultivars resilient to variable and changing climates.

Background. Portopulmonary hypertension (PoPH) occurs in patients with advanced liver disease and can be a contraindication to liver transplant (LT). Improvement of hemodynamic parameters with pulmonary arterial hypertension (PAH) therapies (including endothelin receptor antagonists [ERAs]) may help some patients to become eligible for LT. Methods. We conducted a retrospective secondary data analysis to describe the clinical course and management of PoPH in patients on a US registry LT waitlist and outcomes in patients receiving an ERA. Results. At the time of LT waitlist entry (1996–2019), patient characteristics and disease severity were similar in the 685 patients with PoPH enrolled overall (LT waitlist data set) and the 420 of them who underwent LT (LT data set). Most patients (92.0%) had a model for end-stage liver disease exception granted before entering the LT waitlist. Patients spent a median of 8.9 mo (interquartile range, 3.7–19.7) on the LT waitlist before undergoing LT. Overall, 77.1% of patients received PAH treatment at LT waitlist entry (ERAs, 30.1%). Hemodynamic parameters improved in ≥95% of patients between the first assessment versus the second (median interval, 9 mo) and last assessments (median interval, 14 mo). At the first assessment, 49.6% of patients had mean pulmonary arterial pressure ≥45 mm Hg versus 2.6% and 1.8% of patients at the second and last assessments, respectively; 47.5% of patients had pulmonary vascular resistance >450 dynes·s/cm5 versus 0.9% and 0.2% of patients at the second and last assessments. One-year survival was 90.6% (95% confidence interval [CI], 87.6-92.9) following LT waitlist entry and was 86.4% (95% CI, 82.6-89.5) after LT; 5-y survival was 67.4% (95% CI, 60.0-73.8) while on the LT waitlist (before LT) and was 75.6% (95% CI, 70.4-80.0) following LT. Conclusions. This large US study of patients with PoPH on an LT waitlist confirms that effective PAH treatments can help patients achieve acceptable hemodynamics, providing the opportunity to undergo LT.

Abstract Background Animal models are essential to understand the physiopathology of human diseases but also to evaluate new therapies. However, for several diseases there is no appropriate animal model, which complicates the development of effective therapies. HPV infections, responsible for carcinoma cancers, are among these. So far, the lack of relevant animal models has hampered the development of therapeutic vaccines. In this study, we used a candidate therapeutic vaccine named C216, similar to the ProCervix candidate therapeutic vaccine, to validate new mouse and dog HPV preclinical models. ProCervix has shown promising results with classical subcutaneous murine TC-1 cell tumor isografts but has failed in a phase II study. Results We first generated E7/HPV16 syngeneic transgenic mice in which the expression of the E7 antigen could be switched on through the use of Cre–lox recombination. Non-integrative LentiFlash® viral particles were used to locally deliver Cre mRNA, resulting in E7/HPV16 expression and GFP reporter fluorescence. The expression of E7/HPV16 was monitored by in vivo fluorescence using Cellvizio imaging and by local mRNA expression quantification. In the experimental conditions used, we observed no differences in E7 expression between C216 vaccinated and control groups. To mimic the MHC diversity of humans, E7/HPV16 transgenes were locally delivered by injection of lentiviral particles in the muscle of dogs. Vaccination with C216, tested with two different adjuvants, induced a strong immune response in dogs. However, we detected no relationship between the level of cellular response against E7/HPV16 and the elimination of E7-expressing cells, either by fluorescence or by RT-ddPCR analysis. Conclusions In this study, we have developed two animal models, with a genetic design that is easily transposable to different antigens, to validate the efficacy of candidate vaccines. Our results indicate that, despite being immunogenic, the C216 candidate vaccine did not induce a sufficiently strong immune response to eliminate infected cells. Our results are in line with the failure of the ProCervix vaccine that was observed at the end of the phase II clinical trial, reinforcing the relevance of appropriate animal models.

Abstract Modern cells are complex chemical compartments tightly regulated by an underlying DNA-encoded program. Achieving a form of coupling between molecular content, chemical reactions, and chassis in synthetic compartments represents a key step to the assembly of evolvable protocells but remains challenging. Here, we design coacervate droplets that promote non-enzymatic oligonucleotide polymerization and that restructure as a result of the reaction dynamics. More specifically, we rationally exploit complexation between end-reactive oligonucleotides able to stack into long physical polymers and a cationic azobenzene photoswitch to produce three different phases—soft solids, liquid crystalline or isotropic coacervates droplets—each of them having a different impact on the reaction efficiency. Dynamical modulation of coacervate assembly and dissolution via trans-cis azobenzene photo-isomerization is used to demonstrate cycles of light-actuated oligonucleotide ligation. Remarkably, changes in the population of polynucleotides during polymerization induce phase transitions due to length-based DNA self-sorting to produce multiphase coacervates. Overall, by combining a tight reaction-structure coupling and environmental responsiveness, our reactive coacervates provide a general route to the non-enzymatic synthesis of polynucleotides and pave the way to the emergence of a primitive compartment-content coupling in membrane-free protocells.

Plain Language Summary Psoriatic arthritis (PsA) is a type of arthritis associated with inflammation that occurs in almost one-third of patients with the inflammatory skin condition psoriasis. PsA can vary between individuals, and typically causes joint pain, swelling and stiffness, affecting both physical and social well-being. Over the past decade, several new PsA treatments have become available. However, there is currently a lack of agreement about the best treatment options. As PsA is a chronic (long-term) disease, the duration of time a patient continues taking a prescribed treatment (termed “treatment persistence”) is important. The randomised clinical trials used to determine if a treatment works use strict rules to select patients. Therefore, large studies from everyday practice are needed to better understand the effectiveness and safety of these PsA treatments for a wider range of patients. PsABIOnd is a real-life study that will compare guselkumab (an interleukin-23 inhibitor) and interleukin-17 inhibitors, which are two relatively new types of PsA treatments. The study will provide information about how long patients remain on these treatments and how effectively and safely they work over a 3-year period. PsABIOnd will also explore the impact of PsA on participants’ lives by collecting information about their quality of life, disease activity and treatment satisfaction. In addition, participants also taking part in the eDaily by PsABIOnd substudy will wear a watch-like device and use a smartphone-based app to record measurements including activity, sleep, pain and well-being to give a detailed picture of PsA and its impact on patients’ daily lives.

We present ∼300 stellar metallicity measurements in two faint M31 dwarf galaxies, Andromeda XVI ( M _V = −7.5) and Andromeda XXVIII ( M _V = –8.8), derived using metallicity-sensitive calcium H and K narrowband Hubble Space Telescope imaging. These are the first individual stellar metallicities in And XVI (95 stars). Our And XXVIII sample (191 stars) is a factor of ∼15 increase over literature metallicities. For And XVI, we measure $\langle {\rm{[Fe/H]}}\rangle =-{2.17}_{-0.05}^{+0.05}$ , ${\sigma }_{{\rm{[Fe/H]}}}={0.33}_{-0.07}^{+0.07}$ , and ∇ _[Fe/H] = −0.23 ± 0.15 dex ${R}_{e}^{-1}$ . We find that And XVI is more metal-rich than Milky Way ultrafaint dwarf galaxies of similar luminosity, which may be a result of its unusually extended star formation history. For And XXVIII, we measure $\langle {\rm{[Fe/H]}}\rangle =-{1.95}_{-0.04}^{+0.04}$ , ${\sigma }_{{\rm{[Fe/H]}}}\,=\,{0.34}_{-0.05}^{+0.05}$ , and ∇ _[Fe/H] = −0.46 ± 0.10 dex ${R}_{e}^{-1}$ , placing it on the dwarf galaxy mass–metallicity relation. Neither galaxy has a metallicity distribution function (MDF) with an abrupt metal-rich truncation, suggesting that star formation fell off gradually. The stellar metallicity gradient measurements are among the first for faint ( L ≲ 10 ^6 L _⊙ ) galaxies outside the Milky Way halo. Both galaxies’ gradients are consistent with predictions from the FIRE simulations, where an age–gradient strength relationship is the observational consequence of stellar feedback that produces dark matter cores. We include a catalog for community spectroscopic follow-up, including 19 extremely metal-poor ([Fe/H] < –3.0) star candidates, which make up 7% of And XVI’s MDF and 6% of And XXVIII’s.

We measure the metallicities of 374 red giant branch (RGB) stars in the isolated, quenched dwarf galaxy Tucana using Hubble Space Telescope narrowband (F395N) calcium H and K imaging. Our sample is a factor of ∼7 larger than what is available from previous studies. Our main findings are as follows. (i) A global metallicity distribution function (MDF) with $\langle {\rm{[Fe/H]}}\rangle =-{1.55}_{-0.04}^{+0.04}$ and ${\sigma }_{{\rm{[Fe/H]}}}={0.54}_{-0.03}^{+0.03}$ . (ii) A metallicity gradient of −0.54 ± 0.07 dex ${R}_{e}^{-1}$ (−2.1 ± 0.3 dex kpc ^−1 ) over the extent of our imaging (∼2.5 R _e ), which is steeper than literature measurements. Our finding is consistent with predicted gradients from the publicly available FIRE-2 simulations, in which bursty star formation creates stellar population gradients and dark matter cores. (iii) Tucana’s bifurcated RGB has distinct metallicities: a blue RGB with $\langle {\rm{[Fe/H]}}\rangle =-{1.78}_{-0.06}^{+0.06}$ and ${\sigma }_{{\rm{[Fe/H]}}}={0.44}_{-0.06}^{+0.07}$ and a red RGB with $\langle {\rm{[Fe/H]}}\rangle =-{1.08}_{-0.07}^{+0.07}$ and ${\sigma }_{{\rm{[Fe/H]}}}={0.42}_{-0.06}^{+0.06}$ . (iv) At fixed stellar mass, Tucana is more metal-rich than Milky Way satellites by ∼0.4 dex, but its blue RGB is chemically comparable to the satellites. Tucana’s MDF appears consistent with star-forming isolated dwarfs, though MDFs of the latter are not as well populated. (v) About 2% of Tucana’s stars have [Fe/H] < −3% and 20% have [Fe/H] > −1. We provide a catalog for community spectroscopic follow-up.

We present the discovery of Ursa Major III/UNIONS 1, the least luminous known satellite of the Milky Way, which is estimated to have an absolute V -band magnitude of $+{2.2}_{-0.3}^{+0.4}$ mag, equivalent to a total stellar mass of ${16}_{-5}^{+6}$ M _⊙ . Ursa Major III/UNIONS 1 was uncovered in the deep, wide-field Ultraviolet Near Infrared Optical Northern Survey (UNIONS) and is consistent with an old ( τ > 11 Gyr), metal-poor ([Fe/H] ∼ −2.2) stellar population at a heliocentric distance of ∼10 kpc. Despite its being compact ( r _h = 3 ± 1 pc) and composed of few stars, we confirm the reality of Ursa Major III/UNIONS 1 with Keck II/DEIMOS follow-up spectroscopy and identify 11 radial velocity members, eight of which have full astrometric data from Gaia and are co-moving based on their proper motions. Based on these 11 radial velocity members, we derive an intrinsic velocity dispersion of ${3.7}_{-1.0}^{+1.4}$ km s ^−1 but some caveats preclude this value from being interpreted as a direct indicator of the underlying gravitational potential at this time. Primarily, the exclusion of the largest velocity outlier from the member list drops the velocity dispersion to ${1.9}_{-1.1}^{+1.4}$ km s ^−1 , and the subsequent removal of an additional outlier star produces an unresolved velocity dispersion. While the presence of binary stars may be inflating the measurement, the possibility of a significant velocity dispersion makes Ursa Major III/UNIONS 1 a high-priority candidate for multi-epoch spectroscopic follow-ups to deduce the true nature of this incredibly faint satellite.

Abstract Background The application of CRISPR/Cas9 technology in human induced pluripotent stem cells (hiPSC) holds tremendous potential for basic research and cell-based gene therapy. However, the fulfillment of these promises relies on the capacity to efficiently deliver exogenous nucleic acids and harness the repair mechanisms induced by the nuclease activity in order to knock-out or repair targeted genes. Moreover, transient delivery should be preferred to avoid persistent nuclease activity and to decrease the risk of off-target events. We recently developed bacteriophage-chimeric retrovirus-like particles that exploit the properties of bacteriophage coat proteins to package exogenous RNA, and the benefits of lentiviral transduction to achieve highly efficient, non-integrative RNA delivery in human cells. Here, we investigated the potential of bacteriophage-chimeric retrovirus-like particles for the non-integrative delivery of RNA molecules in hiPSC for CRISPR/Cas9 applications. Results We found that these particles efficiently convey RNA molecules for transient expression in hiPSC, with minimal toxicity and without affecting the cell pluripotency and subsequent differentiation. We then used this system to transiently deliver in a single step the CRISPR-Cas9 components (Cas9 mRNA and sgRNA) to generate gene knockout with high indel rate (up to 85%) at multiple loci. Strikingly, when using an allele-specific sgRNA at a locus harboring compound heterozygous mutations, the targeted allele was not altered by NHEJ/MMEJ, but was repaired at high frequency using the homologous wild type allele, i.e., by interallelic gene conversion. Conclusions Our results highlight the potential of bacteriophage-chimeric retrovirus-like particles to efficiently and safely deliver RNA molecules in hiPSC, and describe for the first time genome engineering by gene conversion in hiPSC. Harnessing this DNA repair mechanism could facilitate the therapeutic correction of human genetic disorders in hiPSC.

Objectives: To investigate, by an in vitro study, the fracture strength of root-filled teeth restored with polyetheretherketone (PEEK) full-coverage crowns. Materials and Methods: Two single-rooted maxillary second premolar Typodont teeth were prepared according to the standardized preparation guidelines for two different full-coverage crown restorations: computer-aided design/computer-aided manufacturing monolithic lithium disilicate crowns (E.max) for the control samples and machine pressed monolithic PEEK crowns for the test samples. Teeth were duplicated in a polyurethane-based resin, with properties analogous to human dentin; n = 5 for each category. Replicas were embedded in polyurethane-based resin material using a retaining copper ring, with a simulated 200-μ periodontal ligament. Subsequently, all samples received orthograde root canal treatment using standardized preparation and obturation techniques. Crowns were cemented with resin-modified glass ionomer cement using a standardized cementation force. All teeth were subjected to a monotonic, axial static load of 2500 N to the point of fracture. Results: All control group samples displayed failure as a combined crown/tooth fracture. The crowns in the test group samples (PEEK) did not fracture under the experimental loads. Under the maximum loads, the crowns exhibited plastic deformation visible as an indentation created on the occlusal surface. Subsurface cohesive damage of the interface cement was noted. T-test showed that the resistance to fracture of the test group compared to the control group was highly significant (P < 0.001). Conclusions: Within the limitations of this study, PEEK crowns help preserve the remaining tooth structure and provide more predictable protection when compared to E.max crowns. They demonstrate failure by surface deformation and subsurface cohesive damage to the interface cement layer. It is unknown if this failure mode would occur under normal masticatory loads.

Abstract Background Atrial fibrillation (AF) is the most documented arrhythmia in COVID-19 pneumonia. Left atrial (LA) strain (LAS) analysis, a marker of LA contractility, have been associated with the development of AF in several clinical situations. We aimed to assess the diagnostic ability of LA strain parameters to predict AF in patients with severe hypoxemic COVID-19 pneumonia. We conducted a prospective single center study in Amiens University Hospital intensive care unit (ICU) (France). Adult patients with severe or critical COVID-19 pneumonia according to the World Health Organization definition and in sinus rhythm were included. Transthoracic echocardiography was performed within 48 h of ICU admission. LA strain analysis was performed by an automated software. The following LA strain parameters were recorded: LA strain during reservoir phase (LASr), LA strain during conduit phase (LAScd) and LA strain during contraction phase (LASct). The primary endpoint was the occurrence of AF during ICU stay. Results From March 2020 to February of 2021, 79 patients were included. Sixteen patients (20%) developed AF in ICU. Patients of the AF group were significantly older with a higher SAPS II score than those without AF. LAScd and LASr were significantly more impaired in the AF group compared to the other group (− 8.1 [− 6.3; − 10.9] vs. − 17.2 [− 5.0; − 10.2] %; P − 11% and 8 ± 4% with LAScd ≤ − 11% (log rank test P value

BackgroundIt is known that acute cor pulmonale (ACP) worsens the prognosis of non-coronavirus disease 2019 (COVID-19) acute respiratory distress syndrome (NC-ARDS). The ACP risk score evaluates the risk of ACP occurrence in mechanically ventilated patients with NC-ARDS. There is less data on the risk factors and prognosis of ACP induced by COVID-19-related pneumonia.ObjectiveThe objective of this study was to evaluate the prognostic value of ACP, assessed by transthoracic echocardiography (TTE) and clinical factors associated with ACP in a cohort of patients with COVID-19-related pneumonia.Materials and methodsBetween February 2020 and June 2021, patients admitted to intensive care unit (ICU) at Amiens University Hospital for COVID-19-related pneumonia were assessed by TTE within 48 h of admission. ACP was defined as a right ventricle/left ventricle area ratio of >0.6 associated with septal dyskinesia. The primary outcome was mortality at 30 days.ResultsAmong 146 patients included, 36% (n = 52/156) developed ACP of which 38% (n = 20/52) were non-intubated patients. The classical risk factors of ACP (found in NC-ARDS) such as PaCO2 >48 mmHg, driving pressure >18 mmHg, and PaO2/FiO2 < 150 mmHg were not associated with ACP (all P-values > 0.1). The primary outcome occurred in 32 (22%) patients. More patients died in the ACP group (n = 20/52 (38%) vs. n = 12/94 (13%), P = 0.001). ACP [hazards ratio (HR) = 3.35, 95%CI [1.56–7.18], P = 0.002] and age >65 years (HR = 2.92, 95%CI [1.50–5.66], P = 0.002) were independent risk factors of 30-day mortality.ConclusionACP was a frequent complication in ICU patients admitted for COVID-19-related pneumonia. The 30-day-mortality was 38% in these patients. In COVID-19-related pneumonia, the classical risk factors of ACP did not seem relevant. These results need confirmation in further studies.

Aquatic environments have been found to be contaminated with a variety of inorganic and organic UV filters. This includes novel nano-sized titanium dioxide (TiO2) composite particles, which have been increasingly developed and incorporated into commercial sunscreens in recent years. So far, relatively little is known about the effects of this novel class of UV filters on aquatic life. Therefore, this study aimed to determine and compare the toxicity of three such nanoparticulate TiO2 UV filters with different surface coatings, namely Eusolex® T-Avo (SiO2-coated), T-Lite™ SF (Al(OH)3/PDMS-coated), and Eusolex® T-S (Al2O3/stearic acid-coated) either alone, or in the presence of selected organic UV filters (octinoxate, avobenzone, octocrylene), toward fish using RTgill-W1 cell cultures as an in vitro experimental model. Besides standard exposure protocols, alternative approaches (i.e., exposure to water accommodated fractions (WAFs), hanging-drop exposure) were explored to account for nanoparticle (NP)-specific fate in the medium and obtain additional/complementary information on their toxicity in different conditions. The AlamarBlue, CFDA-AM and Neutral Red Retention (NR) assays were used to measure effects on different cellular endpoints. Transmission electron microscopy (TEM) was used to examine NP uptake. Our results showed that none of the TiO2 NP UV filters were cytotoxic at the concentrations tested (0.1–10 µg/mL; 24 h) but there were differences in their uptake by the cells. Thus, only the hydrophilic T-AVO was detected inside cells, but the hydrophobic T-Lite SF and T-S were not. In addition, our results show that the presence of NPs (or the used dispersant) tended to decrease organic UV filter toxicity. The level of combination effect depended on both NP-type (surface chemistry) and concentration, suggesting that the reduced toxicity resulted from reduced availability of the organic UV filters due to their adsorption to the NP surface. Thus, mixtures of TiO2 NP UV filters and organic UV filters may have a different toxicological profile compared to the single substances, but probably do not pose an increased hazard.

Abstract Background The criteria for antiphospholipid syndrome (APS) include severe preeclampsia and/or placental insufficiency leading to preterm delivery before 34 weeks of gestation, but this APS manifestation has been rarely studied. Thus, we report a series of severe preeclampsia occurred in patients with APS. Methods We retrospectively analysed data of women with APS (Sydney criteria) who experienced severe preeclampsia with delivery before 34 weeks’ gestation between 2000 and 2017 at five French internal medicine departments and one Italian rheumatology unit. Results The 40 women had a mean age of 30.5 ± 4.6 years at their first episode of preeclampsia; 21 were nulligravid (52.5%), 12 (30%) had already been diagnosed with APS, and 21 (52.5%) had a triple-positive antiphospholipid (aPL) antibody test. Preeclampsia occurred at a median gestational age of 25.5 weeks (IQR 23-29). It was associated with HELLP in 18 cases (45%), eclampsia in 6 (15%), placental abruption in 3 (7.5%), catastrophic APS in 3 (7.5%), and foetal and neonatal death in 11 and 15 cases. Overall, 14 (35%) children survived, born at a median gestational age of 31 weeks. Among other APS criteria, 16 women (40%) experienced at least one thrombosis, 17 (42.5%) an intrauterine foetal death, and 19 (47.5%) at least one episode of HELLP during follow-up (median 5 years, IQR = 2-8). None had three or more consecutive miscarriages. Notably, 12 women (30%) had systemic lupus erythematosus. Conclusions Severe preeclampsia led to high mortality in the offspring. Almost half of these women experienced other APS features, but not three consecutive miscarriages.

Abstract Even though sleep modification is a hallmark of the aging process, age-related changes in functional connectivity using functional Magnetic Resonance Imaging (fMRI) during sleep, remain unknown. Here, we combined electroencephalography and fMRI to examine functional connectivity differences between wakefulness and light sleep stages (N1 and N2 stages) in 16 young (23.1 ± 3.3y; 7 women), and 14 older individuals (59.6 ± 5.7y; 8 women). Results revealed extended, distributed (inter-between) and local (intra-within) decreases in network connectivity during sleep both in young and older individuals. However, compared to the young participants, older individuals showed lower decreases in connectivity or even increases in connectivity between thalamus/basal ganglia and several cerebral regions as well as between frontal regions of various networks. These findings reflect a reduced ability of the older brain to disconnect during sleep that may impede optimal disengagement for loss of responsiveness, enhanced lighter and fragmented sleep, and contribute to age effects on sleep-dependent brain plasticity.

OBJECTIVE: Diffuse large B-cell lymphoma can complicate the course of B-cell primary immunodeficiencies or induce lowering of total gamma globulin levels, whose clinical status as an effective secondary immunodeficiency remains unspecified. This study aimed to assess the frequency, and clinical and prognostic relevance of the low total gamma-globulin levels discovered at diagnosis of diffuse large B-cell lymphoma. RESULTS: In a 2-year monocentric retrospective study, 96 patients diagnosed with diffuse large B-cell lymphoma who had a serum electrophoresis were included. Patients were divided into those with lower (L-TGL and higher (H-TGL) total gamma-globulin levels (total gamma-globulin levels ≤5.5 g/l and >5.5 g/l) and compared for outcomes, including fatal infectious events. Twelve (12.5%; 8 males; age median 68 years, range 55—82 years) exhibited L-TGL. There was no difference between the both groups regarding demographics, Ann Arbor lymphoma stage, inflammatory parameters or chemotherapy regimen. However, overall death rates (10/12, 83.3% versus 22/96, 26.2%; p = 0.03) and infection-related death rates (10/12, 83% versus 6/96, 6.2%; p

In the past decade, the focus of bottom-up synthetic biology has shifted from the design of complex artificial cell architectures to the design of interactions between artificial cells mediated by physical and chemical cues. Engineering communication between artificial cells is crucial for the realization of coordinated dynamic behaviours in artificial cell populations, which would have implications for biotechnology, advanced colloidal materials and regenerative medicine. In this review, we focus our discussion on molecular communication between artificial cells. We cover basic concepts such as the importance of compartmentalization, the metabolic machinery driving signaling across cell boundaries and the different modes of communication used. The various studies in artificial cell signaling have been classified based on the distance between sender and receiver cells, just like in biology into autocrine, juxtacrine, paracrine and endocrine signaling. Emerging tools available for the design of dynamic and adaptive signaling are highlighted and some recent advances of signaling-enabled collective behaviours, such as quorum sensing, travelling pulses and predator-prey behaviour, are also discussed.

We present uniformly measured stellar metallicities of 463 stars in 13 Milky Way (MW) ultra-faint dwarf galaxies (UFDs; M _V = −7.1 to −0.8) using narrowband CaHK (F395N) imaging taken with the Hubble Space Telescope. This represents the largest homogeneous set of stellar metallicities in UFDs, increasing the number of metallicities in these 13 galaxies by a factor of 5 and doubling the number of metallicities in all known MW UFDs. We provide the first well-populated MDFs for all galaxies in this sample, with 〈[Fe/H]〉 ranging from −3.0 to −2.0 dex, and σ _[Fe/H] ranging from 0.3–0.7 dex. We find a nearly constant [Fe/H]∼ −2.6 over 3 decades in luminosity (∼10 ^2 –10 ^5 L _⊙ ), suggesting that the mass–metallicity relationship does not hold for such faint systems. We find a larger fraction (24%) of extremely metal-poor ([Fe/H]< −3) stars across our sample compared to the literature (14%), but note that uncertainties in our most metal-poor measurements make this an upper limit. We find 19% of stars in our UFD sample to be metal-rich ([Fe/H] > −2), consistent with the sum of literature spectroscopic studies. MW UFDs are known to be predominantly >13 Gyr old, meaning that all stars in our sample are truly ancient, unlike metal-poor stars in the MW, which have a range of possible ages. Our UFD metallicities are not well matched to known streams in the MW, providing further evidence that known MW substructures are not related to UFDs. We include a catalog of our stars to encourage community follow-up studies, including priority targets for ELT-era observations.

We present the lifetime star formation histories (SFHs) for six ultrafaint dwarf (UFD; M _V > − 7.0, $4.9\lt {\mathrm{log}}_{10}({M}_{* }(z=0)/{M}_{\odot })\lt 5.5$ ) satellite galaxies of M31 based on deep color–magnitude diagrams constructed from Hubble Space Telescope imaging. These are the first SFHs obtained from the oldest main-sequence turnoff of UFDs outside the halo of the Milky Way (MW). We find that five UFDs formed at least 50% of their stellar mass by z = 5 (12.6 Gyr ago), similar to known UFDs around the MW, but that 10%–40% of their stellar mass formed at later times. We uncover one remarkable UFD, And xiii , which formed only 10% of its stellar mass by z = 5, and 75% in a rapid burst at z ∼ 2–3, a result that is robust to choices of underlying stellar model and is consistent with its predominantly red horizontal branch. This “young” UFD is the first of its kind and indicates that not all UFDs are necessarily quenched by reionization, which is consistent with predictions from several cosmological simulations of faint dwarf galaxies. SFHs of the combined MW and M31 samples suggest reionization did not homogeneously quench UFDs. We find that the least-massive MW UFDs ( M _* ( z = 5) ≲ 5 × 10 ^4 M _⊙ ) are likely quenched by reionization, whereas more-massive M31 UFDs ( M _* ( z = 5) ≳ 10 ^5 M _⊙ ) may only have their star formation suppressed by reionization and quench at a later time. We discuss these findings in the context of the evolution and quenching of UFDs.

We present the discovery of Boötes V, a new ultra-faint dwarf galaxy (UFD) candidate. This satellite is detected as a resolved overdensity of stars during an ongoing search for new Local Group dwarf galaxy candidates in the UNIONS photometric data set. It has a physical half-light radius of ${26.9}_{-5.4}^{+7.5}$ pc, a V -band magnitude of −4.5 ± 0.4 mag, and resides at a heliocentric distance of approximately 100 kpc. We use Gaia DR3 astrometry to identify member stars, characterize the systemic proper motion, and confirm the reality of this faint stellar system. The brightest star in this system was followed up using Gemini GMOS-N long-slit spectroscopy and is measured to have a metallicity of [Fe/H] = −2.85 ± 0.10 dex and a heliocentric radial velocity of v _r = 5.1 ± 13.4 km s ^−1 . Boötes V is larger (in terms of scale radius), more distant, and more metal-poor than the vast majority of globular clusters. It is likely that Boötes V is an UFD, though future spectroscopic studies will be necessary to definitively classify this object.

Little is known about the impact of giant cell arteritis (GCA) and its treatment on patient-reported physical, mental, and psychic quality of life (QoL). In this monocentric study, a questionnaire was sent to the 100 last patients diagnosed with GCA and followed-up in a single tertiary center. Their physical, mental and psychic status were self-assessed via close-ended questions, the 12-item short form survey (SF-12) and the 15-item geriatric depression scale (GDS). We aimed to identify parameters that were significantly associated with moderate-to-severe disability in both physical and mental domains. Ninety patients were analyzable. Moderate to severe physical disability was found in 41 (46%) patients. In multivariate analysis, walking difficulties (OR, 95% CI 8.42 [2.98–26.82], p 80 (OR, 95% CI 4.21 [1.44–13.61], p = 0.008) were independent findings associated with moderate to severe physical disability. Moderate to severe mental disability was found in 30 (33%) patients. In multivariate analysis, depressive mood (OR, 95% CI 11.05 [3.78–37.11], p < 0.0001), felt adverse events attributable to glucocorticoids (OR, 95% CI 10.54 [1.65–213.1], p = 0.01) and use of immune-suppressants (OR, 95% CI 3.50 [1.14–11.87], p = 0.03) were independent findings associated with moderate to severe mental disability. There was a statistically significant negative correlation between GDS and the physical and/or mental disability scores (GDS and PCS-12: r = −0.33, p = 0.0013; GDS and MCS-12: r = −0.36, p = 0.0005). In conclusion, this study identified via a self-assessment of patients with GCA some medical and modifiable findings that significantly affect their physical and mental quality of life. A better knowledge of these factors may help improve the care of GCA patients.

Mesoscopic shear elasticity has been revealed in ordinary liquids both experimentally by reinforcing the liquid/surface interfacial energy and theoretically by nonextensive models. The elastic effects are here examined in the frame of small molecules with strong electrostatic interactions such as room temperature ionic liquids [emim][Tf2N] and nitrate solutions exhibiting paramagnetic properties. We first show that these charged fluids also exhibit a nonzero low-frequency shear elasticity at the submillimeter scale, highlighting their resistance to shear stress. A neutron scattering study completes the dynamic mechanical analysis of the paramagnetic nitrate solution, evidencing that the magnetic properties do not induce the formation of a structure in the solution. We conclude that the elastic correlations contained in liquids usually considered as viscous away from any phase transition contribute in an effective way to collective effects under external stress whether mechanical or magnetic fields.

SnO2 thin films were prepared by conventional and Glancing Angle Deposition reactive sputtering, and their gas sensing properties were investigated. The porosity of the as-prepared films was widely assessed using optical methods, and the sensing performances of these active layers were correlated with the evolution of surface and film porosity as a function of deposition conditions and annealing treatment. The sensor made of inclined columns grown at high sputtering pressure (6 × 10−3 mbar) and annealed at 500 °C in air exhibited the best response to benzene, with a limit of detection of 30 ppb. In addition, successful BTEX (i.e., benzene, toluene, ethylbenzene, and xylenes) discrimination was achieved by combining the sensing signals of four nanostructured tin-oxide-based gas sensors.

Poultry and swine farming are large contributors to environmental impacts, such as climate change, eutrophication, acidification, and air and water pollution. Feed production and manure management are identified as the main sources of these impacts. Reducing dietary crude protein levels is a nutritional strategy recognized to both decrease the use of high-impact feed ingredients and alter manure composition, reducing emissions of harmful components. For a successful implementation of this technique, feed-grade amino acid supplementation is crucial to maintaining animal performance. Reducing crude protein lowers nitrogen excretion, especially excess nitrogen excreted in urea or uric acid form, improving nitrogen efficiency. At the feed-gate, low–crude protein diets can reduce the carbon footprint of feed production through changes in raw material inclusion. The magnitude of this reduction mainly depends on the climate change impact of soybean meal and its land-use change on the feed-grade amino acids used. Reducing dietary crude protein also lowers the environmental impact of manure management in housing, storage, and at spreading: nitrogen emissions from manure (ammonia, nitrates, nitrous oxide) are reduced through reduction of nitrogen excretion. Moreover, synergetic effects exist with nitrogen form, water excretion, and manure pH, further reducing emissions. Volatilization of nitrogen is more reduced in poultry than in pigs, but emissions are more studied and better understood for pig slurry than poultry litter. Ammonia emissions are also more documented than other N-compounds. Low–crude protein diets supplemented with amino acids is a strategy reducing environmental impact at different stages of animal production, making life cycle assessment the best-suited tool to quantify reduction of environmental impacts. Recent studies report an efficient reduction of environmental impacts with low–crude protein diets. However, more standardization of limits and methods used is necessary to compare results. This review summarizes the current knowledge on mitigation of environmental impacts with low–crude protein diets supplemented with amino acids in poultry and swine, its quantification, and the biological mechanisms involved. A comparison between pigs and poultry is also included. It provides concrete information based on quantified research for decision making for the livestock industry and policy makers.

Background: This study aimed to develop a tooth wear classification system that combined the extent, severity, and aesthetic impact of tooth wear and correlated them with the most appropriate clinical management strategy. Methods: Three hundred photographs were used to develop a classification tool that contained four levels of severity and aesthetic impact (0, 1, 2, and 3) in three age groups of patients. Ten examiners assessed and classified the cases using validated forms. Additionally, they selected the recommended treatment modality for each level. The analysis was conducted using a coefficient correlation test. Results: The coefficient correlation for the severity was 0.81, 0.82 in the upper anterior and posterior segments, and 0.85 and 0.77 for the lower anterior and posterior segments, respectively. The aesthetic impact correlation coefficient was 0.84. Examiners had agreed that minor cases required monitoring or simple restorative interventions. The moderate-level cases had variety in the recommended management options depending on the aim of treatment. The severe level cases often required rehabilitation at an increased occlusal vertical dimension. Conclusion: Within the limitations of this preliminary study, a good agreement between the examiners was found using the provided tools. More strict criteria in the classification part of the tool can further improve the examiners’ agreement.

In this article, we will ask to what extent a genetic approach, which postulates that “text doesn’t exist”, implying the necessity of going upstream, to before the text is printed, wouldn’t actually go against this literature of the Congo River which, on the contrary, postulates, through the image of a continuous, dynamic, and irreversible flux which “defenestrates itself in the Ocean”, that the draft or the “avant-text” does not need be. In fact, through serendipitous encounters with texts, terrains, and artists of both shores of the Congo, we realize that this inextricable tension between the poetic katabasis and genetic anabasis over-determines the undisciplined and multiforme “river-like” dynamic carried through all artistic practices, from writing to the visual arts, living or performance art, and this, according to the global model of “l’Art salvateur” with no origin and no end.

Background Reliable predictive and prognostic markers are still lacking for patients treated with programmed death receptor 1 (PD1) inhibitors for non-small cell lung cancer (NSCLC). The purpose of this study was to investigate the prognostic and predictive values of different baseline metabolic parameters, including metabolic tumor volume (MTV), from 18F-fluorodeoxyglucose positron emission tomography–computed tomography (18F-FDG PET/CT) scans in patients with NSCLC treated with PD1 inhibitors.Methods Maximum and peak standardized uptake values, MTV and total lesion glycolysis (TLG), as well as clinical and biological parameters, were recorded in 75 prospectively included patients with NSCLC treated with PD1 inhibitors. Associations between these parameters and overall survival (OS) were evaluated as well as their accuracy to predict early treatment discontinuation (ETD).Results A high MTV and a high TLG were significantly associated with a lower OS (p

Abstract Objective Although one of the three obstetric manifestations of antiphospholipid syndrome (APS) is intrauterine fetal death (IUFD), little is known about it in this context. We report the first large series of patients with APS and IUFD. Methods We retrospectively analyzed the history and clinical data of women at four French hospitals. All had (1) APS diagnosis (Sydney criteria) and (2) IUFD at or after 10 weeks of gestation (weeks) between 2000 and 2016. Results The study included 65 women. Their median age at the index IUFD was 29 years (IQR 26–33); 38 (58%) were primigravidas. The index IUFD was the first APS clinical manifestation in 48 women (74%). Overall, 35% had a triple-positive antibody profile. IUFD occurred at a median gestational age of 24 weeks (IQR 18–27) and was associated with maternal obstetric complications in 16 women (25%), namely, preeclampsia (n = 12), hemolysis, elevated liver enzymes, and low platelet syndrome (HELLP) (n = 6), and/or placental abruption (n = 5). Half of the 50 women with available data had a small-for-gestational-age fetus. Overall, including during the follow-up period of 4 years (IQR 2–9), 28 women (43%) had at least one thrombosis, and 29% were diagnosed with systemic lupus erythematosus (SLE). Ultimately, 54 women (83%) had at least one live birth. Only one woman had three consecutive early miscarriages. Conclusion IUFD was most often the inaugural sign of APS. Of the APS classification criteria, IUFD, preeclampsia, and thromboses were common in this cohort, while the “3 consecutive early miscarriages” criterion was met only once. With treatment, most of the women successfully had at least one live birth.

Multi-compartmentalised soft micro-systems are used as models of synthetic protocells. Here, the authors developed nested host–guest protocell constructs capable of self-reconfiguration in response to changes in pH generated by antagonistic modes of enzyme-mediated coupling.

The effect of a restored machined hybrid dental ceramic crown–tooth complex is not well understood. This study was conducted to determine the effect of the stress state of the machined hybrid dental ceramic crown using three-dimensional finite element analysis. Human premolars were prepared to receive full coverage crowns and restored with machined hybrid dental ceramic crowns using the resin cement. Then, the teeth were digitized using micro-computed tomography and the teeth were scanned with an optical intraoral scanner using an intraoral scanner. Three-dimensional digital models were generated using an interactive image processing software for the restored tooth complex. The generated models were imported into a finite element analysis software with all degrees of freedom concentrated on the outer surface of the root of the crown–tooth complex. To simulate average occlusal load subjected on a premolar a total load of 300 N was applied, 150 N at a buccal incline of the palatal cusp, and palatal incline of the buccal cusp. The von Mises stresses were calculated for the crown–tooth complex under simulated load application was determined. Three-dimensional finite element analysis showed that the stress distribution was more in the dentine and least in the cement. For the cement layer, the stresses were more concentrated on the buccal cusp tip. In dentine, stress was more on the cusp tips and coronal 1/3 of the root surface. The conventional crown preparation is a suitable option for machined polymer crowns with less stress distribution within the crown–tooth complex and can be a good aesthetic replacement in the posterior region. Enamic crowns are a good viable option in the posterior region.

Isolated droplets can be used as micro-reactors, yet it is challenging to operate them functionally in solution and observe chemical exchanges between droplets. Here, Tian et al. use an acoustic trap to assemble water-based micro-droplets into periodic arrays, spontaneously separated from solution media.

Soybean maturity is a trait of critical importance for the development of new soybean cultivars, nevertheless, its characterization based on visual ratings has many challenges. Unmanned aerial vehicles (UAVs) imagery-based high-throughput phenotyping methodologies have been proposed as an alternative to the traditional visual ratings of pod senescence. However, the lack of scalable and accurate methods to extract the desired information from the images remains a significant bottleneck in breeding programs. The objective of this study was to develop an image-based high-throughput phenotyping system for evaluating soybean maturity in breeding programs. Images were acquired twice a week, starting when the earlier lines began maturation until the latest ones were mature. Two complementary convolutional neural networks (CNN) were developed to predict the maturity date. The first using a single date and the second using the five best image dates identified by the first model. The proposed CNN architecture was validated using more than 15,000 ground truth observations from five trials, including data from three growing seasons and two countries. The trained model showed good generalization capability with a root mean squared error lower than two days in four out of five trials. Four methods of estimating prediction uncertainty showed potential at identifying different sources of errors in the maturity date predictions. The architecture developed solves limitations of previous research and can be used at scale in commercial breeding programs.

Tungsten films were prepared by DC magnetron sputtering using glancing angle deposition with a constant deposition angle α = 80°. A first series of films was obtained at a constant pressure of 4.0 × 10−3 mbar with the films’ thickness increasing from 50 to 1000 nm. A second series was produced with a constant thickness of 400 nm, whereas the pressure was gradually changed from 2.5 × 10−3 to 15 × 10−3 mbar. The A15 β phase exhibiting a poor crystallinity was favored at high pressure and for the thinner films, whereas the bcc α phase prevailed at low pressure and for the thicker ones. The tilt angle of the columnar microstructure and fanning of their cross-section were tuned as a function of the pressure and film thickness. Electrical resistivity and surface elastic wave velocity exhibited the highest anisotropic behaviors for the thickest films and the lowest pressure. These asymmetric electrical and elastic properties were directly connected to the anisotropic structural characteristics of tungsten films. They became particularly significant for thicknesses higher than 450 nm and when sputtered particles were mainly ballistic (low pressures). Electronic transport properties, as well as elastic wave propagation, are discussed considering the porous architecture changes vs. film thickness and pressure.

« Le fleuve commence ici » is a patchwork of texts by authors from both sides of the river Congo, evoking their personal representation of their river, often against the current of conradian influence. This anthology is not exhaustive. It is a work in progress, its aim is to propose texts recommended by readers.

Objectives. In Erdheim-Chester disease (ECD), the empirical single dose (SD, 100 mg/day) anakinra sometimes induces only partial responses. Since SD is usually well tolerated, doubling the dose might improve response while maintaining an acceptable safety profile. Methods. A retrospective analysis was performed of outcomes under double-dose (DD) of anakinra in 4 ECD patients who did not exhibit a complete response (CR) under SD treatment. Bone, retroperitoneal, neurologic/orbital, peritoneal, pericardial, right atrium, and pleural involvements were recorded. CR, partial response (PR), stable disease, progressive disease (PD) and tolerance of DD were assessed. Results. SD treatment was a second or third line treatment in three patients after interferon-therapy failure. Two patients, including one with a BRAF mutation, achieved a CR and one patient with a NRAS mutation achieved a PR with DD treatment. The fourth patient, wild-type for both genes, did not respond to a first DD treatment, but then achieved CR under SD associated with a reduced dose of vemurafenib (960 mg/d). Bone and retroperitoneal lesions partially improved on imaging with SD in all patients, but were further improved under DD with two patients achieving CR. With SD treatment, two patients with right atrial masses showed sustained CR. Under DD treatment, two patients with massive serositis refractory to SD, showed PR. Conclusion. DD improved the response to anakinra and lead to two CRs and a PR in three out of four ECD patients, with minor and comparable side-effects to those of SD, while failures were essentially related to massive serositis.