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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.

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 Hospital-associated functional decline affects nearly one-third of the hospitalized older adults. The aim of this trial is to investigate the effect of a cognitive stimulation intervention provided via immersive virtual reality (IVR), with or without a multicomponent physical exercise intervention (ME) in hospitalized patients aged 75 or older with severe functional dependency at admission (Barthel Index

Abstract Background The progressive aging of the population has meant the increase in elderly patients requiring an urgent surgery. Older adults, especially those with frailty, have a higher risk for complications, functional and cognitive decline after urgent surgery. These patients have their functional and physiological reserve reduced which makes them more vulnerable to the effects of being bedridden. The consequences are at multiple levels emphasizing the functional loss or cognitive impairment, longer stays, mortality and institutionalization, delirium, poor quality of life and increased use of resources related to health. We aim to determine whether postoperative physical rehabilitation can prevent functional and cognitive decline and modify the posterior trajectory. Methods/design This study is a randomized clinical trial, simple blinded, conducted in the Department of Surgery of a tertiary public hospital in Navarra (Hospital Universitario de Navarra), Spain. Patients > = 70 years old undergoing urgent abdominal surgery who meet inclusion criteria will be randomly assigned to the intervention or control group. The intervention will consist of a multicomponent physical training programme, which will include progressive and supervised endurance, resistance and balance training for 4 weeks, twice weekly sessions with a total of 8 sessions, and the group control will receive the usual care. The primary outcome measure is the change in functional (SPPB) and cognitive status (Mini-Mental State Examination) and the change of quality of life (EuroQol-5D-VAS) during the study period. The secondary outcomes are postoperative complications, length of stay, delirium, mortality, use of health resources, functional status (Barthel Index and handgrip strength tests), cost per quality-adjusted life year and mininutritional assessment. The data for both the intervention group and the control group will be obtained at four different times: the initial visit during hospital admission and at months 1, 3 and 6 months after hospital discharge. Discussion If our hypothesis is correct, this project could show that individualized and progressive exercise programme provides effective therapy for improving the functional capacity and achieve a better functional, cognitive and quality of life recovery. This measure, without entailing a significant expense for the administration, probably has an important repercussion both in the short- and long-term recovery, improving care and functional parameters and could determine a lower subsequent need for health resources. To verify this, we will carry out a cost-effectiveness study. The clinical impact of this trial can be significant if we help to modify the traditional management of the elderly patients from an illness model to a more person-centred and functionally oriented perspective. Moreover, the prescription of individualized exercise can be routinely included in the clinical practice of these patients. Trial registration ClinicalTrials.gov Identifier: NCT05290532. Version 1. Registered on March 13, 2022.

Abstract Despite the development of novel therapies for acute myeloid leukemia, outcomes remain poor for most patients, and therapeutic improvements are an urgent unmet need. Although treatment regimens promoting differentiation have succeeded in the treatment of acute promyelocytic leukemia, their role in other acute myeloid leukemia subtypes needs to be explored. Here we identify and characterize two lysine deacetylase inhibitors, CM-444 and CM-1758, exhibiting the capacity to promote myeloid differentiation in all acute myeloid leukemia subtypes at low non-cytotoxic doses, unlike other commercial histone deacetylase inhibitors. Analyzing the acetylome after CM-444 and CM-1758 treatment reveals modulation of non-histone proteins involved in the enhancer–promoter chromatin regulatory complex, including bromodomain proteins. This acetylation is essential for enhancing the expression of key transcription factors directly involved in the differentiation therapy induced by CM-444/CM-1758 in acute myeloid leukemia. In summary, these compounds may represent effective differentiation-based therapeutic agents across acute myeloid leukemia subtypes with a potential mechanism for the treatment of acute myeloid leukemia.

Conflict of interest: No Introduction and Objectives: Transjugular intrahepatic portosystemic shunt (TIPS) is a procedure that diverts portal blood flow to the hepatic vein with the aim of reducing portal hypertension, being an alternative for managing its complications, such as variceal gastrointestinal bleeding and ascites, in both cirrhotic and non-cirrhotic patients. Objetives: To characterize patients who underwent TIPS between January 2007 and July 2024 at the Hospital Clínico De la Universidad de Chile Patients / Materials and Methods: Observational, retrospective cohort study. 39 patients medical records who underwent the procedure during the specified period were reviewed. Results and Discussion: 39 patients were analyzed, 53.8% of whom were men, with an average age of 60.7 years. The procedure was performed in 51% (20/39) of the patients within a period of just 4 years (2019 to 2024). The main indication was secondary to variceal gastrointestinal bleeding (59%), followed by refractory ascites (36%). Additionally, 33.3% presented some degree of portal vein thrombosis, and 33.3% had reported hepatic encephalopathy episodes before the procedure. The average MELD Na score was 15.4. Only three patients experienced hemorrhagic complications related to the procedure, with one resulting in death. 53.8% reported some degree of hepatic encephalopathy after the procedure. One-year survival was analyzed, showing 47.4% in patients whose procedure was performed before 2019 versus 76.9% in the period between 2020 and 2023 (p 0.095). Four patients underwent transplants after TIPS, without complications. Conclusions: We have observed a progressive increase in the indication for TIPS over time at our center, with half of the cases concentrated in the last four years. In addition, survival outcomes appear to be better, probably due to improved patient selection and more timely indications. The procedure was safe, with a low rate of acute complications and an incidence of encephalopathy similar to that reported in the literature. Longer-term follow-up will allow us to verify its effectiveness in our population

Background Gingivitis, i.e. inflammation of the gums, is often induced by dental plaque. However, its exact link to the oral microbiota remains unclear.Methods In a case-control study involving 120 participants, comprising 60 cases and 60 controls (mean age (SD) 36.6 (7.6) years; 50% males), nested within a prospective multicentre cohort study, we examined the oral microbiome composition of gingivitis patients and their controls using shotgun metagenomic sequencing of saliva samples. Participants underwent clinical and radiographic oral health examinations, including bleeding on probing (BOP), at six tooth sites. BOP ≥33% was considered ‘generalized gingivitis/initial periodontitis’(GG/IP), and BOP

Background: Sex-based differences in the clinical presentation and outcomes are well-established in patients hospitalized for geriatric syndromes. We aimed to investigate sex differences in response to in-hospital exercise on function, strength, cognition, and quality of life in acute care admissions. Methods: 570 patients (mean age 87 years, 298 females [52.3%]) admitted to acute care for elderly units were randomized to multicomponent exercise emphasizing progressive resistance training or usual care. Functional assessments included Short Physical Performance Battery (SPPB), grip strength, Mini-Mental State Examination (MMSE), and health-related quality of life (EQ-VAS). Results: Exercising females showed more significant SPPB improvements than males (between-group difference 1.48 points, p = 0.027), exceeding the minimal clinically significant difference. While female participants significantly increased handgrip strength and male patients improved cognition after in-hospital exercise compared to the control group (all p

Climate change and other environmental consequences of socio-economic activities require a more sustainable and circular growth. At the same time, the limitation of the earth resource demands industries to improve resource efficiency and increase the rate of recycling of materials. There are several sustainable and circular alternatives that the industries may adopt. However, the question is that among these alternatives, which one should be selected for implementation for the highest sustainable and circular benefits. This study introduces a novel tool for assessing the sustainability and circularity of biomass-based energy supply chains, integrating multi-criteria decision-making methods with life cycle thinking approach. It evaluates five alternatives using a sustainability and circularity indicators, offering new insights into the deloyment of circular business models at companies in biomass-based energy supply chain. The tool is also applied to a specific rice straw supply chain in Italy, to assess the sustainability and circularity of five alternatives and outrank them. The results indicated that not all the alternatives are better in terms of supporting sustainable development and circular economy, compared to the baseline business model. In this supply chain, the extended lifetime for digestate from the aerobic digestion plant is the most ‘sustainable and circular’ alternative, while the capture of carbon dioxide from the same plant and its use for microalgae cultivation is the least ‘sustainable and circular’ alternative. A sensitivity analysis was conducted on different weighting sets during the assessment. It indicated that the priority of the decision makers can slightly change the outrank of the alternatives and the magnitude of the outranks.

Background and Purpose We compared the outcomes of endovascular therapy (EVT) in an extended time window in patients with large-vessel occlusion (LVO) between patients with and without pre-stroke disability. Methods In this prespecified analysis of the multinational CT for Late Endovascular Reperfusion study (66 participating sites, 10 countries between 2014 and 2022), we analyzed data from patients with acute ischemic stroke with a pre-stroke modified Rankin Scale (mRS) score of 0–4 and LVO who underwent EVT 6–24 hours from the time last seen well. The primary outcome was the composite of functional independence (FI; mRS score 0–2) or return to the pre-stroke mRS score (return of Rankin, RoR) at 90 days. Outcomes were compared between patients with pre-stroke disability (pre-stroke mRS score 2–4) and those without (mRS score 0–1). Results A total of 2,231 patients (median age, 72 years; median National Institutes of Health Stroke Scale score, 16) were included in the present analysis. Of these, 564 (25%) had pre-stroke disability. The primary outcome (FI or RoR) was observed in 30.7% of patients with pre-stroke disability (FI, 16.5%; RoR, 30.7%) compared to 44.1% of patients without (FI, 44.1%; RoR, 13.0%) (P

Objective Cryoballoon ablation for pulmonary vein isolation is a time-efficient procedure that can alleviate stress on electrophysiology lab resources. This analysis modeled the impact of cryoballoon ablation on electrophysiology lab operation using data from Latin America. Methods Data from centers in Argentina, Mexico, Colombia, and Chile of the Cryo Global Registry were used as inputs for an electrophysiology lab efficiency simulation model. The model used the assumption that either two (today’s electrophysiology lab operations) or three (including electrophysiology lab operational changes) cryoballoon ablation procedures could be performed per day. The endpoints were the percentage of days that resulted in 1) overtime and 2) time left for an extra non-ablation electrophysiology procedure. Results Data from a total of 232 procedures from six Latin American centers were included in the analysis. The average electrophysiology lab occupancy time for all procedures in Latin America was 132 ± 62 minutes. In the Current Scenario (two procedures per day), 7.4% of simulated days resulted in overtime, and 81.4% had enough time for an extra electrophysiology procedure. In the Enhanced Productivity Scenario (three procedures per day), 16.4% of days used overtime, while 67.4% allowed time for an extra non-ablation electrophysiology procedure. Conclusions Using real-world, Latin American-specific data, we found that with operational changes, three ablation procedures could feasibly be performed daily, leaving time for an extra electrophysiology procedure on more than half of days. Thus, use of cryoballoon ablation is an effective tool to enhance electrophysiology lab efficiency in resource-constrained regions such as Latin America.

In the face of escalating emission reduction demands and heightened public awareness, the imperative for transparent assessments is fundamental to responsible and sustainable development. The use of life cycle assessment (LCA) is instrumental in identifying environmental hotspots in intricate systems and guiding the design and selection of environmentally conscious production methods. However, LCA's comprehensive approach demands substantial data, fundamentally material and energy flows for individual materials or processes, consolidated within a life cycle inventory (LCI). The amount of time, resources, and expertise required to compile an accurate LCI dataset are among the greatest concerns for LCA practitioners. During the early design phase for industrial-scale production, process simulation is a useful tool for estimating LCI data; however, first-principle models can sometimes be unfeasible. This has prompted researchers and engineers to advocate for simplified or surrogate versions of these intricate models in some particular cases. In contrast to first-principle models, machine learning (ML) models efficiently manage extensive datasets and complex systems without rigorous model equations. This work assesses the current state of ML-LCA integration through literature and bibliometric analysis, categorizing works into three clusters and identifying publication trends. Furthermore, this analysis yielded three frameworks aimed at facilitating the integration of ML techniques into LCA workflows, enhancing precision and efficiency in environmental impact assessment. The first framework revealed the interest in abstracting a complete process into a surrogate ML model for fast LCI predictions. Conversely, the second one focused on substituting a complex part of the process for an ML surrogate model based on data from experiments or literature. Finally, in the third framework, LCA performance was directly correlated with a system characteristic, enabling direct and fast predictions of LCIs or LCA performance indicators, and optimization in not yet designed systems.

El proyecto se ejecutó en el corregimiento de Leticia, una de las zonas más importantes de Montería en la producción de leche y que se caracteriza por sus malos indicadores, generando esto brechas tecnológicas en comparación con otros sistemas ganaderos. Con la implementación de las escuelas de campo, estrategia de educación no formal, se generó un ambiente de aprendizaje entre productores y técnicos. El objetivo fue determinar el efecto de dicha intervención educativa en buenas prácticas de ordeño, sobre la salud de la ubre y la calidad microbiológica de la leche en fincas de pequeños productores de Montería, Córdoba, Colombia. La recolección de la información de campo se desarrolló en tres fases: pretest, donde se hizo una encuesta y una primera toma de muestras; intervención, donde se efectuó una capacitación mediante escuelas de campo en diferentes protocolos y postest, donde se hizo una evaluación final mediante una encuesta y una segunda toma de muestras para valorar la sanidad de las ubres y la calidad microbiológica; todas estas mediciones se analizaron en un laboratorio certificado. Mediante un estudio analítico, se recolectaron 144 encuestas y 144 muestras de leche cruda en el pretest, de igual manera sucedió en el postest, y los datos fueron procesados mediante estadística descriptiva e inferencial en el software Infostat. Como resultado, las variables células somáticas y mesófilos fueron menores en el postest. El acompañamiento técnico permitió implementar buenas prácticas de ordeño y vincular a pequeños productores con mercados formales de la cadena láctea.

Background With the expanding eligibility for endovascular therapy (EVT) of patients presenting in the late window (6–24 hours after last known well), we aimed to derive a score to predict favorable outcomes associated with EVT versus best medical management. Methods and Results A multinational observational cohort of patients from the CLEAR (Computed Tomography for Late Endovascular Reperfusion) study with proximal intracranial occlusion (2014–2022) was queried (n=58 sites). Logistic regression analyses were used to derive a 9‐point score for predicting good functional outcome (modified Rankin Scale score 0–2 or return to premorbid modified Rankin Scale score) at 90 days, with sensitivity analyses for prespecified subgroups conducted using bootstrapped random forest regressions. Secondary outcomes included 90‐day functional independence (modified Rankin Scale score 0–2), poor outcome (modified Rankin Scale score 5–6), and 90‐day survival. The score was externally validated with a single‐center cohort (2014–2023). Of the 3231 included patients (n=2499 EVT), a 9‐point score included age, early computed tomography ischemic changes, and stroke severity, with higher points indicating a higher probability of a good functional outcome. The areas under the curve for the primary outcome among EVT and best medical management subgroups were 0.72 (95% CI, 0.70–0.74) and 0.87 (95% CI, 0.84–0.90), respectively, with similar performance in the external validation cohort (area under the curve, 0.71 [95% CI, 0.66–0.76]). There was a significant interaction between the score and EVT for good functional outcome, functional independence, and poor outcome (all Pinteraction

Primary hyperaldosteronism (PAH) is an important cause of secondary hypertension (HTN). The study of the same requires a high clinical suspicion in addition to a hormonal study that confirms hormonal hypersecretion. It is important to start the appropriate treatment once the diagnosis is confirmed, and for this is necessary to demonstrate whether the hormonal hypersecretion is unilateral (patients who could be candidates for surgical treatment) or bilateral (patients who are candidates for pharmacological treatment only).At the Hospital del Mar since 2016 there has been a multidisciplinary work team in which Nephrologists, Endocrinologists, Radiologists and Surgeons participate to evaluate cases with suspected hyperaldosteronism and agree on the best diagnostic-therapeutic approach for these patients, including the need for adrenal vein sampling, which is a technique that in recent years has become the gold standard for the study of PAH.In the present study we collect the experience of our centre in performing AVC and its usefulness for the management of these patients. Resumen: El hiperaldosteronismo primario (HAP) es una causa importante de hipertensión arterial (HTA) secundaria. El estudio del mismo precisa de una alta sospecha clínica además de un estudio hormonal que confirme la hipersecreción hormonal. Es importante iniciar el tratamiento adecuado una vez se confirma el diagnóstico y para ello es preciso demostrar si la hipersecreción hormonal es unilateral (pacientes que podrían ser tributarios a tratamiento quirúrgico) o bilateral (pacientes que son tributarios a tratamiento únicamente farmacológico).En el Hospital del Mar desde el año 2016 existe un equipo de trabajo multidisciplinar en el que participan Nefrólogos, Endocrinólogos, Radiólogos y Cirujanos para evaluar los casos con sospecha de hiperaldosteronismo y consensuar el mejor abordaje diagnóstico-terapéutico de estos pacientes, incluyendo la necesidad de cateterismo venoso adrenal que es una técnica que en los últimos años se ha erigido como gold standard para el estudio de HAP.En el presente estudio recogemos la experiencia de nuestro centro en la realización de CVA y en la utilidad de este para el manejo de estos pacientes.

Resumen: El hiperaldosteronismo primario (HAP) es una causa importante de hipertensión arterial (HTA) secundaria. El estudio del mismo precisa de una alta sospecha clínica, además de un estudio hormonal que confirme la hipersecreción hormonal. Es importante iniciar el tratamiento adecuado una vez se confirma el diagnóstico, y para ello es preciso demostrar si la hipersecreción hormonal es unilateral (pacientes que podrían ser tributarios a tratamiento quirúrgico) o bilateral (pacientes que son tributarios a tratamiento únicamente farmacológico).En el Hospital del Mar desde el año 2016 existe un equipo de trabajo multidisciplinar en el que participan nefrólogos, endocrinólogos, radiólogos y cirujanos para evaluar los casos con sospecha de hiperaldosteronismo y consensuar el mejor abordaje diagnóstico-terapéutico de estos pacientes, incluyendo la necesidad de cateterismo venoso adrenal, que es una técnica que en los últimos años se ha erigido como gold standard para el estudio del HAP.En el presente estudio recogemos la experiencia de nuestro centro en la realización de cateterismo venoso adrenal y en la utilidad de este para el manejo de tales pacientes. Abstract: Primary hyperaldosteronism (PAH) is an important cause of secondary hypertension (HTN). The study of the same requires a high clinical suspicion in addition to a hormonal study that confirms hormonal hypersecretion. It is important to start the appropriate treatment once the diagnosis is confirmed, and for this is necessary to demonstrate whether the hormonal hypersecretion is unilateral (patients who could be candidates for surgical treatment) or bilateral (patients who are candidates for pharmacological treatment only).At the Hospital del Mar since 2016 there has been a multidisciplinary work team in which Nephrologists, Endocrinologists, Radiologists and Surgeons participate to evaluate cases with suspected hyperaldosteronism and agree on the best diagnostic-therapeutic approach for these patients, including the need for adrenal vein sampling, which is a technique that in recent years has become the gold standard for the study of PAH.In the present study we collect the experience of our center in performing adrenal vein catheterization and its usefulness for the management of these patients.

The development of motor competence is thought to be a crucial precursor to raising the trajectory of PA throughout a person’s life. The objectives of this study are to determine motor competence and the daily time of moderate and vigorous physical activity of students in 5th and 6th grade elementary in Chile, and to establish whether there are differences in motor competence according to sex and compliance with physical activity recommendations. 368 schoolchildren (M = 11.10 years; 54.3% girls) participated. To assess motor competence, the MOBAK 5–6 test was used. Physical activity was measured using ActiGraph wGT3X-BT® accelerometers. Boys (M = 3.65, SD = 2.14) showed better performance than girls (M = 2.39, SD = 1.80) in Object Control (p ≤ 0.001, PS = 0.67). For Self-Movement, the girls (M = 2.72, SD = 2.14) performed better than the boys (M = 2.40, SD = 1.86); however, there were no significant differences between the two sexes (p = 0.257). Boys (M = 48.4, SD = 22.8) presented more daily minutes of moderate and vigorous physical activity than girls (M = 35.9, SD = 16.9), with statistically significant differences (p ≤ 0.001, PS = 0.67). About MC according to compliance with the physical activity recommendations, only in Object Control there is a statistically significant difference (p ≤ 0.001; PS = 0.29) between the students who comply with the recommendations (M = 4.28, SD = 2.12) and those who do not achieve the recommended minutes (M = 2.67, SD = 1.29). By contrast, an analysis of Self-Movement found no significant difference (complies: M = 2.73, SD = 1.97; does not comply: M = 2.54, SD = 2.04; p = 0.408) between the two groups. It is necessary to generate instances that develop motor competence in all its dimensions to promote higher levels of moderate to vigorous physical activity.

IntroductionUnderstanding how socioeconomic markers interact could inform future policies aimed at increasing adherence to a healthy diet.MethodsThis cross-sectional study included 437,860 participants from the UK Biobank. Dietary intake was self-reported. Were used as measures socioeconomic education level, income and Townsend deprivation index. A healthy diet score was defined using current dietary recommendations for nine food items and one point was assigned for meeting the recommendation for each. Good adherence to a healthy diet was defined as the top 75th percentile, while poor adherence was defined as the lowest 25th percentile. Poisson regression was used to investigate adherence to dietary recommendations.ResultsThere were significant trends whereby diet scores tended to be less healthy as deprivation markers increased. The diet score trends were greater for education compared to area deprivation and income. Compared to participants with the highest level of education, those with the lowest education were found to be 48% less likely to adhere to a healthy diet (95% Confidence Interval [CI]: 0.60–0.64). Additionally, participants with the lowest income level were 33% less likely to maintain a healthy diet (95% CI: 0.73–0.81), and those in the most deprived areas were 13% less likely (95% CI: 0.84–0.91).Discussion/conclussionAmong the three measured proxies of socioeconomic status – education, income, and area deprivation – low education emerged as the strongest factor associated with lower adherence to a healthy diet.

The objective of this research was to assess and quantify the potential vitamin A losses that occur during the manufacturing of pet feed and premix, as well as during their extended storage periods. This trial was conducted at a commercial feeder mill that utilized a standard commercial dog feed along with a corresponding vitamin-mineral premix. The calculated amount of vitamin A supplemented in the feed, in addition to the endogenous vitamins present in the ingredients, was adjusted to 18,000 IU/kg of feed. Five 500 g feed samples were collected at each of the predefined critical points throughout the manufacturing process (after mixing, milling, preconditioner, and extrusion/drying processes) to verify the stability of vitamin A during feed production. Additionally, various samples were collected at regular intervals of 30, 60, 90, 120, and 180 days during the storage of the premix to assess the stability of vitamin A. Vitamin A analyses in the samples were performed using high-performance liquid chromatography. The variables were assessed for normality using the Shapiro–Wilk test, followed by analysis of variance (ANOVA) and Tukey’s test to compare the differences between the manufacturing process and premix shelf life. The statistical significance was set at 95%. The vitamin losses during the pre-conditioning process were 26%, and during the extrusion-drying processes, the losses were 34% when compared to the initial analyzed value. However, no differences were observed in other processes. There were no significant differences observed in recovered vitamin levels in the premix during its shelf-life (p = 0.484). The study indicated that the primary vitamin A losses in pet feed manufacturing processes occur during the pre-conditioning and drying/extrusion steps. However, it is worth noting that no significant losses of vitamin A were found during the premix storage phase.

Regardless of their age, adult patients with Wiskott-Aldrich syndrome should be considered for hematopoietic stem cell transplantation if clinically indicated.

Deep optical emission-line images are presented for nine known plus three new Galactic supernova remnants (SNRs), all but one having at least one angular dimension >1°. Wide-field images taken in H α and [O iii ] λ 5007 reveal many new and surprising remnant structures including large remnant shock extensions and “breakout” features not seen in published optical or radio data. These images represent over 12,000 individual images totaling more than 1000 hr of exposure time taken over the last 2 yr mainly using small aperture telescopes, which detected fainter nebular line emissions than published emission-line images. During the course of this imaging program, we discovered three new SNRs, namely G107.5-5.1 (the Nereides Nebula), G209.9-8.2, and G210.5+1.3, two of which have diameters >1.°5. In addition to offering greater structural detail on the nine already known SNRs, a key finding of this study is the importance of [O iii ] emission-line imaging for mapping the complete shock emissions of Galactic SNRs.