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Purpose: Despite high clinical need, there are no biomarkers that accurately predict the response of patients with metastatic melanoma to anti-PD-1 therapy., Experimental Design: In this multicenter study, we applied protein depletion and enrichment methods prior to various proteomic techniques to analyze a serum discovery cohort (n = 56) and three independent serum validation cohorts (n = 80, n = 12, n = 17). Further validation analyses by literature and survival analysis followed., Results: We identified several significantly regulated proteins as well as biological processes such as neutrophil degranulation, cell-substrate adhesion, and extracellular matrix organization. Analysis of the three independent serum validation cohorts confirmed the significant differences between responders (R) and nonresponders (NR) observed in the initial discovery cohort. In addition, literature-based validation highlighted 30 markers overlapping with previously published signatures. Survival analysis using the TCGA database showed that overexpression of 17 of the markers we identified correlated with lower overall survival in patients with melanoma., Conclusions: Ultimately, this multilayered serum analysis led to a potential marker signature with 10 key markers significantly altered in at least two independent serum cohorts: CRP, LYVE1, SAA2, C1RL, CFHR3, LBP, LDHB, S100A8, S100A9, and SAA1, which will serve as the basis for further investigation. In addition to patient serum, we analyzed primary melanoma tumor cells from NR and found a potential marker signature with four key markers: LAMC1, PXDN, SERPINE1, and VCAN., (©2023 American Association for Cancer Research.)

Background: Electroanatomical mapping is an essential tool in the ablation of typical AFL., Objectives: To identify the existence of voltage patterns in the CTI voltage maps and their relevance for typical AFL ablation., Methods: A voltage map of the CTI was made prior to ablation, identifying the areas of maximum voltage and their location along the CTI, allowing classification into patterns according to their distribution. A stepwise ablation approach targeting the areas of maximum voltage was conducted. The ablation characteristics were compared based on the pattern obtained., Results: Two voltage patterns were identified, with differences in ablation time to bidirectional CTI block. No complications occurred., Conclusions: Voltage mapping identifies patterns in the CTI with implications for typical AFL ablation., Competing Interests: The authors declare no conflict of interest., (© 2024 The Authors. Journal of Arrhythmia published by John Wiley & Sons Australia, Ltd on behalf of Japanese Heart Rhythm Society.)

Background: Aberrant vascular architecture and angiogenesis are hallmarks of glioblastoma IDH-wildtype, suggesting that these tumors are suitable for antiangiogenic therapy. Bevacizumab was FDA-approved in 2009 following promising results in two clinical trials. However, its use for recurrent glioblastomas remains a subject of debate, as it does not universally improve patient survival., Purposes: In this study, we aimed to analyze the influence of tumor vascularity on the benefit provided by BVZ and propose preoperative rCBVmax at the high angiogenic tumor habitat as a predictive biomarker to select patients who can benefit the most., Methods: Clinical and MRI data from 106 patients with glioblastoma IDH-wildtype have been analyzed. Thirty-nine of them received BVZ, and the remaining sixty-seven did not receive a second-line treatment. The ONCOhabitats method was used to automatically calculate rCBV., Results: We found a median survival from progression of 305 days longer for patients with moderate vascular tumors who received BVZ than those who did not receive any second-line treatment. This contrasts with patients with high-vascular tumors who only presented a median survival of 173 days longer when receiving BVZ. Furthermore, better responses to BVZ were found for the moderate-vascular group with a higher proportion of patients alive at 6, 12, 18, and 24 months after progression., Conclusions: We propose rCBVmax as a potential biomarker to select patients who can benefit more from BVZ after tumor progression. In addition, we propose a threshold of 7.5 to stratify patients into moderate- and high-vascular groups to select the optimal second-line treatment.

Chronic wounds, especially those that are hard-to-heal, constitute a serious public-health problem. Although progress has been made in the development of wound dressings for healing, there is little high-quality evidence of their efficacy, with no evidence of superiority in the use of one hydrogel over another. To evaluate the superiority of a hydrogel (EHO-85), containing Olea europaea leaf extract (OELE), over a standard hydrogel (SH), the promotion and/or improvement of healing of difficult-to-heal wounds was compared in a prospective, parallel-group multicenter, randomized, observer-blinded, controlled trial ("MACAON"). Non-hospitalized patients with pressure, venous or diabetic foot-ulcers difficult-to-heal were recruited and treated with standard care, and EHO-85 (n = 35) or VariHesive (n = 34) as SH. Wound-area reduction (WAR; percentage) and healing rate (HR; mm 2 /day) were measured. EHO-85 showed a statistically significant superior effect over VariHesive. At the end of the follow-up period, the relative WAR decreased by 51.6% vs. 18.9% ( p < 0.001), with a HR mean of 10.5 ± 5.7 vs. 1.0 ± 7.5 mm 2 /day ( p = 0.036). EHO-85 superiority is probably based on its optimal ability to balance the ulcer bed, by modulating pH and oxidative stress. That complements the wetting and barrier functions, characteristics of conventional hydrogels. These results support the use of EHO-85 dressing, for treatment of hard-to-heal ulcers. Trial Registration AEMPS:PS/CR623/17/CE.

Background and Objective: Reusing Electronic Health Records (EHRs) for Machine Learning (ML) leads on many occasions to extremely incomplete and sparse tabular datasets, which can hinder the model development processes and limit their performance and generalization. In this study, we aimed to characterize the most effective data imputation techniques and ML models for dealing with highly missing numerical data in EHRs, in the case where only a very limited number of data are complete, as opposed to the usual case of having a reduced number of missing values., Methods: We used a case study including full blood count laboratory data, demographic and survival data in the context of COVID-19 hospital admissions and evaluated 30 processing pipelines combining imputation methods with ML classifiers. The imputation methods included missing mask, translation and encoding, mean imputation, k-nearest neighbors' imputation, Bayesian ridge regression imputation and generative adversarial imputation networks. The classifiers included k-nearest neighbors, logistic regression, random forest, gradient boosting and deep multilayer perceptron., Results: Our results suggest that in the presence of highly missing data, combining translation and encoding imputation-which considers informative missingness-with tree ensemble classifiers-random forest and gradient boosting-is a sensible choice when aiming to maximize performance, in terms of area under curve., Conclusions: Based on our findings, we recommend the consideration of this imputer-classifier configuration when constructing models in the presence of extremely incomplete numerical data in EHR., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Obesity is a weight-related disorder characterized by excessive adipose tissue growth and dysfunction which leads to the onset of a systemic chronic low-grade inflammatory state. Likewise, inflammation is considered a classic cancer hallmark affecting several steps of carcinogenesis and tumor progression. In this regard, novel molecular complexes termed inflammasomes have been identified which are able to react to a wide spectrum of insults, impacting several metabolic-related disorders, but their contribution to cancer biology remains unclear. In this context, prostate cancer (PCa) has a markedly inflammatory component, and patients frequently are elderly individuals who exhibit weight-related disorders, being obesity the most prevalent condition. Therefore, inflammation, and specifically, inflammasome complexes, could be crucial players in the interplay between PCa and metabolic disorders. In this review, we will: 1) discuss the potential role of each inflammasome component (sensor, molecular adaptor, and targets) in PCa pathophysiology, placing special emphasis on IL-1β/NF-kB pathway and ROS and hypoxia influence; 2) explore the association between inflammasomes and obesity, and how these molecular complexes could act as the cornerstone between the obesity and PCa; and, 3) compile current clinical trials regarding inflammasome targeting, providing some insights about their potential use in the clinical practice., (© 2023. The Author(s).)

Plant-based materials are an important source of bioactive compounds (BC) with interesting industrial applications. Therefore, adequate experimental strategies for maximizing their recovery yield are required. Among all procedures for extracting BC (maceration, Soxhlet, hydro-distillation, pulsed-electric field, enzyme, microwave, high hydrostatic pressure, and supercritical fluids), the ultrasound-assisted extraction (UAE) highlighted as an advanced, cost-efficient, eco-friendly, and sustainable alternative for recovering BC (polyphenols, flavonoids, anthocyanins, and carotenoids) from plant sources with higher yields. However, the UAE efficiency is influenced by several factors, including operational variables and extraction process (frequency, amplitude, ultrasonic power, pulse cycle, type of solvent, extraction time, solvent-to-solid ratio, pH, particle size, and temperature) that exert an impact on the molecular structures of targeted molecules, leading to variations in their biological properties. In this context, a diverse design of experiments (DOEs), including full or fractional factorial, Plackett-Burman, Box-Behnken, Central composite, Taguchi, Mixture, D-optimal, and Doehlert have been investigated alone and in combination to optimize the UAE of BC from plant-based materials, using the response surface methodology and mathematical models in a simple or multi-factorial/multi-response approach. The present review summarizes the advantages and limitations of the most common DOEs investigated to optimize the UAE of bioactive compounds from plant-based materials.

Background: Electrical isolation of pulmonary veins (PV) with high-power short-duration (HPSD) radiofrequency application (RFa) may reduce the duration of atrial fibrillation (AF) ablation, without compromising the procedural efficacy and safety in comparison with the conventional approach. This hypothesis has been generated in several observational studies; the POWER FAST III will test it in a randomized multicenter clinical trial., Methods: It is a multicenter randomized, open-label and non-inferiority clinical trial with two parallel groups. AF ablation using 70 W and 9-10 s RFa is compared with the conventional technique using 25-40 W RFa guided by numerical lesion indexes. The main efficacy objective is the incidence of atrial arrhythmia recurrences electrocardiographically documented during 1-year follow-up. The main safety objective is the incidence of endoscopically detected esophageal thermal lesions (EDEL). This trial includes a substudy of incidence of asymptomatic cerebral lesions detected by magnetic resonance imaging (MRI) after ablation., Results: A randomized clinical trial compares for the first time high-power short-duration and conventional ablation in order to obtain data about the efficacy and safety of the high-power technique in an adequate methodological context., Conclusions: The results of the POWER FAST III could support the use of the high-power short-duration ablation in clinical practice., Registration: ClinicalTrials.gov: NTC04153747., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: Although the knowledge base regarding the financial exploitation of older adults is expanding, work to understand the subpopulations of older adult financial exploitation victims and their experiences is greatly needed. This study uses betrayal trauma theory (BTT) as the foundation for conceptualizing the harm that arises from elder family financial exploitation., Methods: The study uses a cross-sectional design to investigate group differences among a total sample of 95 community-dwelling older adults, 32 of the participants (33.7%) were older adult victims of family financial exploitation and the remaining 63 (66.3%) were victims of financial exploitation perpetrated by strangers., Results: The group of older adults who were victims of elder family financial exploitation had significantly lower functional ability scores, higher stress and financial exploitation vulnerability scores and lost more money on average than those victimized by strangers., Conclusion: The present study provides support that BTT provides a valuable framework for understanding why older adult family financial exploitation victims are more vulnerable than victims of exploitation committed by strangers. Attention to this subgroup of financially exploited older adults will provide improved understanding of the unique challenges these victims face and inform prevention and intervention services.

Global agreement in central nervous system (CNS) tumor classification is essential for predicting patient prognosis and determining the correct course of treatment, as well as for stratifying patients for clinical trials at international level. The last update by the World Health Organization of CNS tumor classification and grading in 2021 considered, for the first time, IDH-wildtype glioblastoma and astrocytoma IDH-mutant grade 4 as different tumors. Mutations in the genes isocitrate dehydrogenase (IDH) 1 and 2 occur early and, importantly, contribute to gliomagenesis. IDH mutation produces a metabolic reprogramming of tumor cells, thus affecting the processes of hypoxia and vascularity, resulting in a clear advantage for those patients who present with IDH-mutated astrocytomas. Despite the clinical relevance of IDH mutation, current protocols do not include full sequencing for every patient. Alternative biomarkers could be useful and complementary to obtain a more reliable classification. In this sense, magnetic resonance imaging (MRI)-perfusion biomarkers, such as relative cerebral blood volume and flow, could be useful from the moment of presurgery, without incurring additional financial costs or requiring extra effort. The main purpose of this work is to analyze the vascular and hemodynamic differences between IDH-wildtype glioblastoma and IDH-mutant astrocytoma. To achieve this, we evaluate and validate the association between dynamic susceptibility contrast-MRI perfusion biomarkers and IDH mutation status. In addition, to gain a deeper understanding of the vascular differences in astrocytomas depending on the IDH mutation, we analyze the transcriptomic bases of the vascular differences., (© 2023 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.)

Obesity (OB) is a metabolic disorder characterized by adipose tissue dysfunction that has emerged as a health problem of epidemic proportions in recent decades. OB is associated with multiple comorbidities, including some types of cancers. Specifically, prostate cancer (PCa) has been postulated as one of the tumors that could have a causal relationship with OB. Particularly, a specialized adipose tissue (AT) depot known as periprostatic adipose tissue (PPAT) has gained increasing attention over the last few years as it could be a key player in the pathophysiological interaction between PCa and OB. However, to date, no studies have defined the most appropriate internal reference genes (IRGs) to be used in gene expression studies in this AT depot. In this work, two independent cohorts of PPAT samples ( n = 20/ n = 48) were used to assess the validity of a battery of 15 literature-selected IRGs using two widely used techniques (reverse transcription quantitative PCR [RT-qPCR] and microfluidic-based qPCR array). For this purpose, ΔCt method, GeNorm (v3.5), BestKeeper (v1.0), NormFinder (v.20.0), and RefFinder software were employed to assess the overall trends of our analyses. LRP10 , PGK1 , and RPLP0 were identified as the best IRGs to be used for gene expression studies in human PPATs, specifically when considering PCa and OB conditions.

Background: Obesity (OB) is a chronic metabolic disease with important associated comorbidities and mortality. Vitamin D supplementation is frequently administered after bariatric surgery (BS), so as to reduce OB-related complications, maybe including chronic inflammation., Aim: This study aimed to explore relations between vitamin D metabolites and components of the inflammasome machinery in OB before and after BS and their relations with the improvement of metabolic comorbidities., Patients and Methods: Epidemiological/clinical/anthropometric/biochemical evaluation was performed in patients with OB at baseline and 6 months after BS. Evaluation of i) vitamin-D metabolites in plasma and ii) components of the inflammasome machinery and inflammatory-associated factors [NOD-like-receptors (NLRs), inflammasome-activation-components, cytokines and inflammation/apoptosis-related components, and cell-cycle and DNA-damage regulators] in peripheral blood mononuclear cells (PBMCs) was performed at baseline and 6 months after BS. Clinical and molecular correlations/associations were analyzed., Results: Significant correlations between vitamin D metabolites and inflammasome-machinery components were observed at baseline, and these correlations were significantly reduced 6 months after BS in parallel to a decrease in inflammation markers, fat mass, and body weight. Treatment with calcifediol remarkably increased 25OHD levels, despite 24,25(OH) 2 D 3 remained stable after BS. Several inflammasome-machinery components were associated with improvement in metabolic comorbidities, especially hypertension and dyslipidemia., Conclusion: The beneficial effects of vitamin D on OB-related comorbidities after BS patients are associated with significant changes in the molecular expression of key inflammasome-machinery components. The expression profile of these inflammasome components can be dynamically modulated in PBMCs after BS and vitamin D supplementation, suggesting that this profile could likely serve as a sensor and early predictor of the reversal of OB-related complications after BS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Herrera-Martínez, Castillo-Peinado, Molina-Puerta, Calañas-Continente, Membrives, Castilla, Camacho Cardenosa, Casado-Díaz, Gálvez-Moreno, Gahete, Quesada Gómez, Bouillon, Priego-Capote and Luque.)

Background: Brain activity governing cognition and behaviour depends on the fine-tuned microenvironment provided by a tightly controlled blood-brain barrier (BBB). Brain endothelium dysfunction is a hallmark of BBB breakdown in most neurodegenerative/neuroinflammatory disorders. Therefore, the identification of new endogenous molecules involved in endothelial cell disruption is essential to better understand BBB dynamics. Cortistatin is a neuroimmune mediator with anti-inflammatory and neuroprotective properties that exerts beneficial effects on the peripheral endothelium. However, its role in the healthy and injured brain endothelium remains to be evaluated. Herein, this study aimed to investigate the potential function of endogenous and therapeutic cortistatin in regulating brain endothelium dysfunction in a neuroinflammatory/neurodegenerative environment., Methods: Wild-type and cortistatin-deficient murine brain endothelium and human cells were used for an in vitro barrier model, where a simulated ischemia-like environment was mimicked. Endothelial permeability, junction integrity, and immune response in the presence and absence of cortistatin were evaluated using different size tracers, immunofluorescence labelling, qPCR, and ELISA. Cortistatin molecular mechanisms underlying brain endothelium dynamics were assessed by RNA-sequencing analysis. Cortistatin role in BBB leakage was evaluated in adult mice injected with LPS., Results: The endogenous lack of cortistatin predisposes endothelium weakening with increased permeability, tight-junctions breakdown, and dysregulated immune activity. We demonstrated that both damaged and uninjured brain endothelial cells isolated from cortistatin-deficient mice, present a dysregulated and/or deactivated genetic programming. These pathways, related to basic physiology but also crucial for the repair after damage (e.g., extracellular matrix remodelling, angiogenesis, response to oxygen, signalling, and metabolites transport), are dysfunctional and make brain endothelial barrier lacking cortistatin non-responsive to any further injury. Treatment with cortistatin reversed in vitro hyperpermeability, tight-junctions disruption, inflammatory response, and reduced in vivo BBB leakage., Conclusions: The neuropeptide cortistatin has a key role in the physiology of the cerebral microvasculature and its presence is crucial to develop a canonical balanced response to damage. The reparative effects of cortistatin in the brain endothelium were accompanied by the modulation of the immune function and the rescue of barrier integrity. Cortistatin-based therapies could emerge as a novel pleiotropic strategy to ameliorate neuroinflammatory/neurodegenerative disorders with disrupted BBB., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Same-sex sexual behaviour has attracted the attention of many scientists working in disparate areas, from sociology and psychology to behavioural and evolutionary biology. Since it does not contribute directly to reproduction, same-sex sexual behaviour is considered an evolutionary conundrum. Here, using phylogenetic analyses, we explore the evolution of same-sex sexual behaviour in mammals. According to currently available data, this behaviour is not randomly distributed across mammal lineages, but tends to be particularly prevalent in some clades, especially primates. Ancestral reconstruction suggests that same-sex sexual behaviour may have evolved multiple times, with its appearance being a recent phenomenon in most mammalian lineages. Our phylogenetically informed analyses testing for associations between same-sex sexual behaviour and other species characteristics suggest that it may play an adaptive role in maintaining social relationships and mitigating conflict., (© 2023. Springer Nature Limited.)

Vascular calcification (VC) is a common complication in patients with chronic kidney disease which increases their mortality. Although oxidative stress is involved in the onset and progression of this disorder, the specific role of some of the main redox regulators, such as catalase, the main scavenger of H 2 O 2 , remains unclear. In the present study, epigastric arteries of kidney transplant recipients, a rat model of VC, and an in vitro model of VC exhibiting catalase (Cts) overexpression were analysed. Pericalcified areas of human epigastric arteries had increased levels of catalase and cytoplasmic, rather than nuclear runt-related transcription factor 2 (RUNX2). In the rat model, advanced aortic VC concurred with lower levels of the H 2 O 2 -scavenger glutathione peroxidase 3 compared to controls. In an early model of calcification using vascular smooth muscle cells (VSMCs), Cts VSMCs showed the expected increase in total levels of RUNX2. However, Cts VMSCs also exhibited a lower percentage of the nucleus stained for RUNX2 in response to calcifying media. In this early model of VC, we did not observe a dysregulation of the mitochondrial redox state; instead, an increase in the general redox state was observed in the cytoplasm. These results highlight the complex role of antioxidant enzymes as catalase by regulation of RUNX2 subcellular location delaying the onset of VC.

Probiotic supplementation in dairy cattle has achieved several beneficial effects (improved growth rate, immune response, and adequate ruminal microbiota). This study assessed the effects on the growth parameters and gut microbiota of newborn dairy calves supplemented with two Lactobacillus -based probiotics, individually (6BZ or 6BY) or their combination (6BZ + 6BY), administrated with the same concentration (1 × 10 9 CFU/kg weight) at three times, between days 5 and 19 after birth. The control group consisted of probiotic-unsupplemented calves. Growth parameters were recorded weekly until eight weeks and at the calves' ages of three, four, and five months. Fecal microbiota was described by high-throughput sequencing and bioinformatics. Although no significant effects were observed regarding daily weight and height gain among probiotic-supplemented and non-supplemented calves, correlation analysis showed that growth rate was maintained until month 5 through probiotic supplementation, mainly when the two-strain probiotics were supplied. Modulation effects on microbiota were observed in probiotic-supplemented calves, improving the Bacteroidota: Firmicutes and the Proteobacteria ratios. Functional prediction by PICRUSt also showed an increment in several pathways when the two-strain probiotic was supplemented. Therefore, using the three-administration scheme, the two-strain probiotic improved the growth rate and gut microbiota profile in newborn dairy calves. However, positive effects could be reached by applying more administrations of the probiotic during the first 20 days of a calf's life.

Background: Long-distance migratory birds spend most of their annual cycle in non-breeding areas. During this period birds must meet their daily nutritional needs and acquire additional energy intake to deal with future events of the annual cycle. Therefore, patterns of space use and movement may emerge as an efficient strategy to maintain a trade-off between acquisition and conservation of energy during the non-breeding season. However, there is still a paucity of research addressing this issue, especially in trans-hemispheric migratory birds., Methods: Using GPS-tracking data and a recently developed continuous-time stochastic process modeling framework, we analyzed fine-scale movements in a non-breeding population of Hudsonian godwits (Limosa haemastica), a gregarious long-distance migratory shorebird. Specifically, we evaluated if these extreme migrants exhibit restricted, shared, and periodic patterns of space use on one of their main non-breeding grounds in southern South America. Finally, via a generalized additive model, we tested if the observed patterns were consistent within a circadian cycle., Results: Overall, godwits showed finely-tuned range-residence and periodic movements (each 24-72 h), being similar between day and night. Remarkably, range-resident individuals segregated spatially into three groups. In contrast, a smaller fraction of godwits displayed unpredictable and irregular movements, adding functional connectivity within the population., Conclusions: In coastal non-breeding areas where resource availability is highly predictable due to tidal cycles, range-resident strategies during both the day and night are the common pattern in a long-distance shorebird population. Alternative patterns exhibited by a fraction of non-resident godwits provide functional connectivity and suggest that the exploratory tendency may be essential for information acquisition and associated with individual traits. The methodological approach we have used contributes to elucidate how the composition of movement phases operates during the non-breeding season in migratory species and can be replicated in non-migratory species as well. Finally, our results highlight the importance of considering movement as a continuum within the annual cycle., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Plasticity-mediated changes in interaction dynamics and structure may scale up and affect the ecological network in which the plastic species are embedded. Despite their potential relevance for understanding the effects of plasticity on ecological communities, these effects have seldom been analysed. We argue here that, by boosting the magnitude of intra-individual phenotypic variation, plasticity may have three possible direct effects on the interactions that the plastic species maintains with other species in the community: may expand the interaction niche, may cause a shift from one interaction niche to another or may even cause the colonization of a new niche. The combined action of these three factors can scale to the community level and eventually expresses itself as a modification in the topology and functionality of the entire ecological network. We propose that this causal pathway can be more widespread than previously thought and may explain how interaction niches evolve quickly in response to rapid changes in environmental conditions. The implication of this idea is not solely eco-evolutionary but may also help to understand how ecological interactions rewire and evolve in response to global change., (© 2023 The Authors. Ecology Letters published by John Wiley & Sons Ltd.)

Olive tree ( Olea europaea ) leaf extract (OELE) has important antioxidant and anti-inflammatory properties, supporting its use in human clinical practice. We recently designed an amorphous hydrogel called EHO-85 (EHO indicates olive leaf extract in Spanish) containing OELE for skin ulcer treatments. Yet, its effectiveness has not been previously compared with other products used in routine clinical practice. This is necessary to evaluate its potential translation to the human clinic. Thus, in this study, the effect of EHO-85 on healing was evaluated in comparison with treatments containing Indian/Asiatic pennywort ( Centella asiatica ), hyaluronic acid, or dexpanthenol in a rat model. The speed of wound closure and histological parameters after seven and 14 days were analyzed. All treatments accelerated wound closure, but there were differences between them. Dexpanthenol after seven days produced the highest epithelialization and the lowest inflammation and vascularization. EHO-85 also promoted epithelialization and reduced vascularization. After 14 days, wounds treated with EHO-85 showed less inflammation and higher levels of collagen in the extracellular matrix. This indicates a higher degree of maturity in the regenerated tissue. In conclusion, the effect of EHO-85 on healing was equal to or superior to that of other treatments routinely used in human clinical practice. Therefore, these results, together with previous data on the effects of this hydrogel on ulcer healing in humans, indicate that EHO-85 is a suitable, low-cost, and efficient therapeutic option for wound healing.

Multi-omics profiling by CITE-seq bridges the RNA-protein gap in single-cell analysis but has been largely applied to liquid biopsies. Applying CITE-seq to clinically relevant solid biopsies to characterize healthy tissue and the tumor microenvironment is an essential next step in single-cell translational studies. In this study, gating of cell populations based on their transcriptome signatures for use in cell type-specific ridge plots allowed identification of positive antibody signals and setting of manual thresholds. Next, we compare five skin dissociation protocols by taking into account dissociation efficiency, captured cell type heterogeneity and recovered surface proteome. To assess the effect of enzymatic digestion on transcriptome and epitope expression in immune cell populations, we analyze peripheral blood mononuclear cells (PBMCs) with and without dissociation. To further assess the RNA-protein gap, RNA-protein we perform codetection and correlation analyses on thresholded protein values. Finally, in a proof-of-concept study, using protein abundance analysis on selected surface markers in a cohort of healthy skin, primary, and metastatic melanoma we identify CD56 surface marker expression on metastatic melanoma cells, which was further confirmed by multiplex immunohistochemistry. This work provides practical guidelines for processing and analysis of clinically relevant solid tissue biopsies for biomarker discovery., (© 2023. Springer Nature Limited.)

Background: Cardiac resynchronization therapy (CRT) via permanent His bundle pacing (pHBP) has gained acceptance globally, but robust studies comparing pHBP-CRT with classic CRT are lacking. In this study, we aimed to compare the improvement in left ventricular ejection fraction (LVEF) after pHBP-CRT versus classic CRT., Methods: This was a single-center study comparing a prospective series of pHBP-CRT with a historical series of CRT via classic biventricular pacing (BVP). Patients with non-ischemic cardiomyopathy, baseline LVEF < 35%, left bundle branch block (LBBB), and CRT indications were selected., Results: Fifty-one patients underwent classic CRT and 52 patients underwent pHBP-CRT. In the classic CRT group, the median (interquartile range) basal LVEF was 30% (IQR, 29-35%) before implantation and 40% (35-48%) at follow-up. In the pHBP-CRT group, the median basal LVEF was 30% (28-34%) before implantation and 55% (45-60%) at follow-up, with significant differences between both modalities at follow-up (p = 0.001). The median long term His recruitment threshold with LBBB correction was 1.25 (1-2.5) V at 0.4 ms in cases of pHBP-CRT, compared to a left ventricular coronary sinus threshold of 1.25 (1-1.75) V in cases of classic CRT (p = 0.48). After CRT, the median paced QRS was 135 (120-145) ms for pHBP-CRT versus 140 (130-150) ms for BVP-CRT (p = 0.586)., Conclusions: The improvement in LVEF was superior with pHBP-CRT than with classic CRT. The thresholds at follow-up were similar in both groups., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Although the prevalence of community-acquired respiratory bacterial coinfection upon hospital admission in patients with coronavirus disease 2019 (COVID-19) has been reported to be < 5%, almost three-quarters of patients received antibiotics. We aim to investigate whether procalcitonin (PCT) or C-reactive protein (CRP) upon admission could be helpful biomarkers to identify bacterial coinfection among patients with COVID-19 pneumonia., Methods: We carried out a multicentre, observational cohort study including consecutive COVID-19 patients admitted to 55 Spanish intensive care units (ICUs). The primary outcome was to explore whether PCT or CRP serum levels upon hospital admission could predict bacterial coinfection among patients with COVID-19 pneumonia. The secondary outcome was the evaluation of their association with mortality. We also conducted subgroups analyses in higher risk profile populations., Results: Between 5 February 2020 and 21 December 2021, 4076 patients were included, 133 (3%) of whom presented bacterial coinfection. PCT and CRP had low area under curve (AUC) scores at the receiver operating characteristic (ROC) curve analysis [0.57 (95% confidence interval (CI) 0.51-0.61) and 0.6 (95% CI, 0.55-0.64), respectively], but high negative predictive values (NPV) [97.5% (95% CI 96.5-98.5) and 98.2% (95% CI 97.5-98.9) for PCT and CRP, respectively]. CRP alone was associated with bacterial coinfection (OR 2, 95% CI 1.25-3.19; p = 0.004). The overall 15, 30 and 90 days mortality had a higher trend in the bacterial coinfection group, but without significant difference. PCT ≥ 0.12 ng/mL was associated with higher 90 days mortality., Conclusion: Our study suggests that measurements of PCT and CRP, alone and at a single time point, are not useful for ruling in or out bacterial coinfection in viral pneumonia by COVID-19., (© 2023. The Author(s).)

DPP4 may play a relevant role in MSC differentiation into osteoblasts or adipocytes. Dipeptidyl peptidase 4 (DPP4) inhibitors (DPP4i), such as sitagliptin and vildagliptin, are used as antidiabetic drugs. However, vildagliptin is not a specific DPP4i and also inhibits DPP8/9, which is involved in energy metabolism and immune regulation. The aim of this study is to evaluate how sitagliptin, vildagliptin or 1G244 (a DPP8/9 specific inhibitor) may influence cell viability, as well as osteogenic and adipogenic differentiation in human mesenchymal stem cells (MSC). Viability, apoptosis, osteoblastogenesis and adipogenesis markers, as well as protein synthesis of β-catenin, were studied in MSC cultures induced to differentiate into osteoblasts or adipocytes in the presence or absence of sitagliptin, vildagliptin or 1G244. The two tested DPP4i did not affect MSC viability, but 1G244 significantly decreased it in MSC and osteoblast-induced cells. Additionally, 1G244 and vildagliptin inhibited osteogenesis and adipogenesis, unlike sitagliptin. Therefore, inhibition of DPP4 did not affect MSC viability and differentiation, whereas inhibition of DPP8/9 negatively affected MSC. To the best of our knowledge, these results show for the first time that DPP8/9 have an important role in the viability and differentiation of human MSC. This data can be considered for human clinical use of drugs affecting DPP8/9 activity.

Many advanced wound healing dressings exist, but there is little high-quality evidence to support them. To determine the performance of a novel amorphous hydrogel (EHO-85) in relation to its application, we compared its rheological properties with those of other standard hydrogels (SH), and we assessed the induction of acceleration of the early stages of wound healing as a secondary objective of a prospective, multicenter, randomized, observer-blinded, controlled trial. The patients were recruited if they had pressure, venous, or diabetic foot ulcers and were treated with EHO-85 ( n = 103) or VariHesive ® (SH) ( n = 92), and their response was assessed by intention-to-treat as wound area reduction (WAR (%)) and healing rate (HR mm 2 /day) in the second and fourth weeks of treatment. Results: EHO-85 had the highest shear thinning and G'/G″ ratio, the lowest viscous modulus, G″, and relatively low cohesive energy; EHO-85 had a significantly superior effect over SH in WAR and HR, accelerating wound healing in the second and fourth weeks of application ( p : 0.002). This superiority is likely based on its optimal moisturizing capacity and excellent pH-lowering and antioxidant properties. In addition, the distinct shear thinning of EHO-85 facilitates spreading by gentle hand pressure, making it easier to apply to wounds. These rheological properties contribute to its improved performance.

Addressing the patterns of variation in thermal traits is crucial to better predict the potential effects of climate change on organisms. Here, we assessed seasonal (winter vs summer) adjustments in key thermoregulatory traits in eight Mediterranean-resident songbirds. Overall, songbirds increased whole-animal (by 8%) and mass-adjusted (by 9%) basal metabolic rate and decreased (by 56%) thermal conductance below the thermoneutral zone during winter. The magnitude of these changes was within the lower values found in songbirds from northern temperate areas. Moreover, songbirds increased (by 11%) evaporative water loss within the thermoneutral zone during summer, while its rate of increase above the inflection point of evaporative water loss (i.e., the slope of evaporative water loss versus temperature) decreased by 35% during summer - a value well above that reported for other temperate and tropical songbirds. Finally, body mass increased by 5% during winter, a pattern similar to that found in many northern temperate species. Our findings support the idea that physiological adjustments might enhance the resilience of Mediterranean songbirds to environmental changes, with short-term benefits by saving energy and water under thermally stressful conditions. Nevertheless, not all species showed the same patterns, suggesting different strategies in their thermoregulatory adaptations to seasonal environments., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to declare., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: This paper examines the relationships between the reported accidents of workers in construction firms and the probability of those firms' survival., Method: Between 2004 and 2010, a sample of 344 Spanish construction firms from Majorca were selected. The study built panel data with the reported official accidents from the Labor Authority records and the firm survival or mortality from the Bureau van Dijḱs Iberian Balance Sheet Analysis System database. The hypothesis is that a higher number of accidents directly affects the probability of the company surviving in the sector. By using a probit regression model with panel data, the relationship between these two variables were explored to test the hypothesis., Results: The study found evidence that an increment in accidents decreases the probability of the company continuing to operate, or worse, going bankrupt. The results can be useful to highlight the importance of defining policies to control those accidents effectively, since this may be a key factor in the sustainability, competitiveness, and growth of the construction sector for the economy of a region., Competing Interests: Declaration of interest statement The authors declare that they have not any conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Anti-CD19 chimeric antigen receptor T cells (CART) has rapidly been adopted as the standard third-line therapy to treat aggressive B-cell lymphomas (ABCL) after failure of second-line therapy despite the lack of direct comparisons with allogeneic hematopoietic cell transplantation (alloHCT)-based strategies. Using the Grupo Español de Trasplante y Terapia Celular (GETH-TC) registry, we selected patients with the following characteristics: CART or alloHCT performed between 2016 and 2021; ≥18 years old; ABCL diagnosis; ≥2 lines of therapy; and either anti-CD19 CART or alloHCT as therapy at relapse. The analysis included a total of 316 (CART = 215, alloHCT = 101) patients. Median follow-up was 15 and 36 months for the CART and alloHCT cohorts, respectively. In the multivariate analysis, CART was confirmed to be similar to alloHCT for the primary study endpoint (progression-free survival) (hazard ratio [HR] 0.92, CI95%:0.56-1.51, p = 0.75). Furthermore, when the analysis was limited to only patients with chemo-sensitive diseases (complete and partial response) at infusion (CART = 26, alloHCT=93), no differences were reported (progression-free survival at month +18: 65% versus 55%, p = 0.59). However, CART had lower non-relapse mortality (HR 0.34, 95% CI: 0.13-0.85, p = 0.02). Given the lower toxicity and similar survival outcomes, these results suggest the use of CART before alloHCT., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Aim of the present study is to investigate whether preoperative neurocognitive status is prognostically associated with overall survival (OS) in newly diagnosed glioblastoma (GBM) patients., Methods: Ninety patients with dominant-hemisphere IDH-wild-type GBM were assessed by Mini Mental Status Exam (MMSE), Trail Making Test (TMT) A and B parts, and Control Word Association Test (COWAT) phonemic and semantic subtests. Demographics, Karnofsky Performance Scale, tumor parameters, type of surgery, and adjuvant therapy data were available for patients., Results: According to Cox proportional hazards model the neurocognitive variables of TMT B ( P < .01), COWAT semantic subset ( P < .05), and the MMSE ( P < .01) were found significantly associated with survival prediction. From all other factors, only tumor volume and operation type (debulking vs biopsy) showed a statistical association ( P < .05) with survival prediction. Kaplan Meier Long rank test showed statistical significance ( P < .01) between unimpaired and impaired groups for TMT B, with median survival for the unimpaired group 26 months and 10 months for the impaired group, for COWAT semantic ( P < .01) with median survival 23 months and 12 months, respectively and for MMSE ( P < .01) with medial survival 19 and 12 months respectively., Conclusions: Our study demonstrates that neurocognitive status at baseline-prior to treatment-is an independent prognostic factor for OS in wild-type GBM patients, adding another prognostic tool to assist physicians in selecting the best treatment plan., Competing Interests: The authors have no relevant financial or nonfinancial interests to disclose., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Background: Secukinumab is a biologic disease-modifying antirheumatic drug (bDMARD) that has demonstrated efficacy in the treatment of axial spondyloarthritis (axSpA, i.e., ankylosing spondylitis and non-radiographic axSpA) across various clinical trials. However, data of secukinumab in clinical practice is still limited. Here, we aimed to provide real-world data on secukinumab use, effectiveness, and persistence in axSpA., Patients and Methods: Retrospective, multicenter study of patients with a diagnosis of axSpA treated with secukinumab at 12 centers up to June 2021 in the Valencian Community (Spain). Information was gathered on BASDAI measurement, pain, patient and physician global assessment (ptGA, phGA) using a 100-mm visual analog scale (VAS), persistence and other secondary variables by treatment line (first, second, and ≥ third) for up to 24 months., Results: 221 patients were included (69% men; mean age [standard deviation, SD]: 46.7 [12.1] years old). Secukinumab was used as a first-line bDMARD in 38% of patients, as a second-line in 34% and as a ≥ hird-line in 28%. The percentage of patients achieving low disease activity (BASDAI<4) increased from 9% at baseline to 48% at month 6 and was maintained (49%) up to month 24. The greatest improvement in BASDAI was observed in naïve patients (month 6: -2.6; month 24: -3.7), followed by second-line (month 6: -1.9; month 24: -3.1) and ≥ third-line (month 6: -1.3; month 24: -2.3) patients. Reductions in mean pain VAS (-23.3; -31.9), ptGA (-25.1; -31.9) and phGA (-25.1; -31) were also observed at 6 and 24 months. Secukinumab showed an overall 12-months persistence rate of 70% (95% confidence interval [CI]: 63-77%) and a 24-months persistence rate of 58% (95% CI, 51-66%). Patients receiving first-line secukinumab had the highest 24-months persistence rate ( p  = 0.05)., Conclusion: Secukinumab improved disease activity in axSpA patients, especially in naive, and second-line patients, which was accompanied by high persistence rates up to 24 months., Competing Interests: FS received honoraria as a consultant from AbbVie, Pfizer, Astra Zeneca. Grant/Research support from AbbVie, Novartis, Eli Lilly, Roche, BMS. JMSG reports personal fees and non-financial support from Abbvie, non-financial support from BMS, personal fees from Celgene, personal fees from Janssen, non-financial support from Lilly, non-financial support from MSD, personal fees from Novartis, non-financial support from Pfizer, non-financial support from Roche, non-financial support from UCB, outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Sivera, Núñez-Monje, Campos-Fernández, Balaguer-Trull, Robustillo-Villarino, Aguilar-Zamora, Garijo-Bufort, López-Gómez, Peña-González, de la Morena, Bedoya-Sanchís, Yankova-Komsalova, Conesa-Mateos, Martínez-Cristóbal, Navarro-Blasco, Senabre-Gallego and Alegre-Sancho.)

Bladder cancer is the most common malignancy of the urinary tract worldwide. The therapeutic options to tackle this disease comprise surgery, intravesical or systemic chemotherapy, and immunotherapy. Unfortunately, a wide number of patients ultimately become resistant to these treatments and develop aggressive metastatic disease, presenting a poor prognosis. Therefore, the identification of novel therapeutic approaches to tackle this devastating pathology is urgently needed. However, a significant limitation is that the progression and drug response of bladder cancer is strongly associated with its intrinsic molecular heterogeneity. In this sense, RNA splicing is recently gaining importance as a critical hallmark of cancer since can have a significant clinical value. In fact, a profound dysregulation of the splicing process has been reported in bladder cancer, especially in the expression of certain key splicing variants and circular RNAs with a potential clinical value as diagnostic/prognostic biomarkers or therapeutic targets in this pathology. Indeed, some authors have already evidenced a profound antitumor effect by targeting some splicing factors (e.g., PTBP1), mRNA splicing variants (e.g., PKM2, HYAL4-v1), and circular RNAs (e.g., circITCH, circMYLK), which illustrates new possibilities to significantly improve the management of this pathology. This review represents the first detailed overview of the splicing process and its alterations in bladder cancer, and highlights opportunities for the development of novel diagnostic/prognostic biomarkers and their clinical potential for the treatment of this devastating cancer type. This article is categorized under: RNA Processing > Splicing Regulation/Alternative Splicing RNA in Disease and Development > RNA in Disease., (© 2022 The Authors. WIREs RNA published by Wiley Periodicals LLC.)

Bacteria have been used to increase crop yields. For their application on crops, bacteria are provided in inoculant formulations that are continuously changing, with liquid- and solid-based products. Bacteria for inoculants are mainly selected from natural isolates. In nature, microorganisms that favor plants exhibit various strategies to succeed and prevail in the rhizosphere, such as biological nitrogen fixation, phosphorus solubilization, and siderophore production. On the other hand, plants have strategies to maintain beneficial microorganisms, such as the exudation of chemoattractanst for specific microorganisms and signaling pathways that regulate plant-bacteria interactions. Transcriptomic approaches are helpful in attempting to elucidate plant-microorganism interactions. Here, we present a review of these issues.

Usually, after an abnormal level of serum prostate-specific antigen (PSA) or digital rectal exam, men undergo a prostate needle biopsy. However, the traditional sextant technique misses 15-46% of cancers. At present, there are problems regarding disease diagnosis/prognosis, especially in patients' classification, because the information to be handled is complex and challenging to process. Matrix metalloproteases (MMPs) have high expression by prostate cancer (PCa) compared with benign prostate tissues. To assess the possible contribution to the diagnosis of PCa, we evaluated the expression of several MMPs in prostate tissues before and after PCa diagnosis using machine learning, classifiers, and supervised algorithms. A retrospective study was conducted on 29 patients diagnosed with PCa with previous benign needle biopsies, 45 patients with benign prostatic hyperplasia (BHP), and 18 patients with high-grade prostatic intraepithelial neoplasia (HGPIN). An immunohistochemical study was performed on tissue samples from tumor and non-tumor areas using specific antibodies against MMP -2, 9, 11, and 13, and the tissue inhibitor of MMPs -3 (TIMP-3), and the protein expression by different cell types was analyzed to which several automatic learning techniques have been applied. Compared with BHP or HGPIN specimens, epithelial cells (ECs) and fibroblasts from benign prostate biopsies before the diagnosis of PCa showed a significantly higher expression of MMPs and TIMP-3. Machine learning techniques provide a differentiable classification between these patients, with greater than 95% accuracy, considering ECs, being slightly lower when considering fibroblasts. In addition, evolutionary changes were found in paired tissues from benign biopsy to prostatectomy specimens in the same patient. Thus, ECs from the tumor zone from prostatectomy showed higher expressions of MMPs and TIMP-3 compared to ECs of the corresponding zone from the benign biopsy. Similar differences were found for expressions of MMP-9 and TIMP-3, between fibroblasts from these zones. The classifiers have determined that patients with benign prostate biopsies before the diagnosis of PCa showed a high MMPs/TIMP-3 expression by ECs, so in the zone without future cancer development as in the zone with future tumor, compared with biopsy samples from patients with BPH or HGPIN. Expression of MMP -2, 9, 11, and 13, and TIMP-3 phenotypically define ECs associated with future tumor development. Also, the results suggest that MMPs/TIMPs expression in biopsy tissues may reflect evolutionary changes from prostate benign tissues to PCa. Thus, these findings in combination with other parameters might contribute to improving the suspicion of PCa diagnosis.

Background: Glioblastoma is one of the most devastating and incurable cancers due to its aggressive behaviour and lack of available therapies, being its overall-survival from diagnosis ∼14-months. Thus, identification of new therapeutic tools is urgently needed. Interestingly, metabolism-related drugs (e.g., metformin/statins) are emerging as efficient antitumour agents for several cancers. Herein, we evaluated the in vitro/in vivo effects of metformin and/or statins on key clinical/functional/molecular/signalling parameters in glioblastoma patients/cells., Methods: An exploratory-observational-randomized retrospective glioblastoma patient cohort (n = 85), human glioblastoma/non-tumour brain human cells (cell lines/patient-derived cell cultures), mouse astrocytes progenitor cell cultures, and a preclinical xenograft glioblastoma mouse model were used to measure key functional parameters, signalling-pathways and/or antitumour progression in response to metformin and/or simvastatin., Findings: Metformin and simvastatin exerted strong antitumour actions in glioblastoma cell cultures (i.e., proliferation/migration/tumoursphere/colony-formation/VEGF-secretion inhibition and apoptosis/senescence induction). Notably, their combination additively altered these functional parameters vs. individual treatments. These actions were mediated by the modulation of key oncogenic signalling-pathways (i.e., AKT/JAK-STAT/NF-κB/TGFβ-pathways). Interestingly, an enrichment analysis uncovered a TGFβ-pathway activation, together with AKT inactivation, in response to metformin + simvastatin combination, which might be linked to an induction of the senescence-state, the associated secretory-phenotype, and to the dysregulation of spliceosome components. Remarkably, the antitumour actions of metformin + simvastatin combination were also observed in vivo [i.e., association with longer overall-survival in human, and reduction in tumour-progression in a mouse model (reduced tumour-size/weight/mitosis-number, and increased apoptosis)]., Interpretation: Altogether, metformin and simvastatin reduce aggressiveness features in glioblastomas, being this effect significantly more effective (in vitro/in vivo) when both drugs are combined, offering a clinically relevant opportunity that should be tested for their use in humans., Funding: Spanish Ministry of Science, Innovation and Universities; Junta de Andalucía; CIBERobn (CIBER is an initiative of Instituto de Salud Carlos III, Spanish Ministry of Health, Social Services and Equality)., Competing Interests: Declaration of interests The authors declare that no-competing financial and/or non-financial interests concerning the work exist., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: The scholarship of teaching and learning (SoTL) should promote diversity, equity, inclusion, and social justice for the next generation of psychologists., Statement of the Problem: I worry that the SoTL propagates an exclusionary field that becomes increasingly irrelevant in our diverse society given that graduate curricula largely exclude scholarship on structural inequality., Literature Review: I detail the process of graduate curricular changes in my current department, with a focus on my new required graduate course, Diversity, Systems, and Inequality. I utilize scholarship from law, sociology, philosophy, women and gender studies, education, and psychology., Teaching Implications: I provide the structure and content of the course-including syllabi and lecture slides-as well as modes of assessment that promote inclusivity and critical thinking. I detail how current faculty can learn to incorporate the content of this work into their own teaching and scholarship through weekly journal clubs., Conclusion: SoTL outlets can publish transdisciplinary, inclusive course materials regarding structural inequality, thus mainstreaming and amplifying such work for the benefit of the field and our world., Competing Interests: Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The outcome of many ecological interactions lies somewhere along a continuum between pure positive and pure negative effects. Although the popularity of this idea has notoriously risen in the last decades, with the occurrence of continua in interaction outcomes invoked for a wide variety of interactions, the absence of a precise theoretical treatment has led to considerable inaccuracy and ambiguity in its treatment. We develop here a consumer-resource model to explore the occurrence of continua. This model is based on the assumption that the distribution of individual interaction events includes both negative and positive immediate outcomes, with variable frequencies, for at least one of the interacting species. Our study shows that continua in interaction outcomes happen just by varying the sign and impact of individual events. The exact shape of the continua depends on the proportion of positive versus negative events and the relative magnitude of per-capita interaction strengths. Our model shows that continua in interaction outcomes are a key property of most pairwise interactions and are originated from the variable roles played by the interacting partners. It constitutes a step forward in the paradigm change from discrete categorization of ecological interactions to a new perspective over a continuous space., (© 2023 The Authors. Ecology published by Wiley Periodicals LLC on behalf of The Ecological Society of America.)

Donor lung preservation at 10 °C appears to be an innovative and promising method that may improve transplant logistics by extending the cold ischemia time with excellent outcomes. We report the case of two lung transplants from two different donors involving the use of two different preservation methods, highlighting the benefits of using 10 °C lung storage., (Copyright © 2022. Published by Elsevier España, S.L.U.)

Vitamin D plays a major role in bone health and probably also in multiple extraskeletal acute and chronic diseases. Although supplementation with calcifediol, a vitamin D metabolite, has demonstrated efficacy and safety in short-term clinical trials, its effects after long-term monthly administration have been studied less extensively. This report describes the results of a 1-year, phase III-IV, double-blind, randomized, controlled, parallel, multicenter superiority clinical trial to assess the efficacy and safety of monthly calcifediol 0.266 mg versus cholecalciferol 25,000 IU (0.625 mg) in postmenopausal women with vitamin D deficiency (25(OH)D < 20 ng/mL). A total of 303 women were randomized and 298 evaluated. Patients were randomized 1:1:1 to calcifediol 0.266 mg/month for 12 months (Group A1), calcifediol 0.266 mg/month for 4 months followed by placebo for 8 months (Group A2), and cholecalciferol 25,000 IU/month (0.625 mg/month) for 12 months (Group B). By month 4, stable 25(OH)D levels were documented with both calcifediol and cholecalciferol (intention-to-treat population): 26.8 ± 8.5 ng/mL (Group A1) and 23.1 ± 5.4 ng/mL (Group B). By month 12, 25(OH)D levels were 23.9 ± 8.0 ng/mL (Group A1) and 22.4 ± 5.5 ng/mL (Group B). When calcifediol treatment was withdrawn in Group A2, 25(OH)D levels decreased to baseline levels (28.5 ± 8.7 ng/mL at month 4 versus 14.4 ± 6.0 ng/mL at month 12). No relevant treatment-related safety issues were reported in any of the groups. The results confirm that long-term treatment with monthly calcifediol in vitamin D-deficient patients is effective and safe. The withdrawal of treatment leads to a pronounced decrease of 25(OH)D levels. Calcifediol presented a faster onset of action compared to monthly cholecalciferol. Long-term treatment produces stable and sustained 25(OH)D concentrations with no associated safety concerns. © 2023 Faes Farma SA. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)., (© 2023 Faes Farma SA. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).)

Introduction: Critical COVID-19 survivors have a high risk of respiratory sequelae. Therefore, we aimed to identify key factors associated with altered lung function and CT scan abnormalities at a follow-up visit in a cohort of critical COVID-19 survivors., Methods: Multicenter ambispective observational study in 52 Spanish intensive care units. Up to 1327 PCR-confirmed critical COVID-19 patients had sociodemographic, anthropometric, comorbidity and lifestyle characteristics collected at hospital admission; clinical and biological parameters throughout hospital stay; and, lung function and CT scan at a follow-up visit., Results: The median [p 25 -p 75 ] time from discharge to follow-up was 3.57 [2.77-4.92] months. Median age was 60 [53-67] years, 27.8% women. The mean (SD) percentage of predicted diffusing lung capacity for carbon monoxide (D LCO ) at follow-up was 72.02 (18.33)% predicted, with 66% of patients having D LCO <80% and 24% having D LCO <60%. CT scan showed persistent pulmonary infiltrates, fibrotic lesions, and emphysema in 33%, 25% and 6% of patients, respectively. Key variables associated with D LCO <60% were chronic lung disease (CLD) (OR: 1.86 (1.18-2.92)), duration of invasive mechanical ventilation (IMV) (OR: 1.56 (1.37-1.77)), age (OR [per-1-SD] (95%CI): 1.39 (1.18-1.63)), urea (OR: 1.16 (0.97-1.39)) and estimated glomerular filtration rate at ICU admission (OR: 0.88 (0.73-1.06)). Bacterial pneumonia (1.62 (1.11-2.35)) and duration of ventilation (NIMV (1.23 (1.06-1.42), IMV (1.21 (1.01-1.45)) and prone positioning (1.17 (0.98-1.39)) were associated with fibrotic lesions., Conclusion: Age and CLD, reflecting patients' baseline vulnerability, and markers of COVID-19 severity, such as duration of IMV and renal failure, were key factors associated with impaired D LCO and CT abnormalities., (Published by Elsevier España, S.L.U.)

Background: The primary aim of our study was to investigate the association between intubation timing and hospital mortality in critically ill patients with coronavirus disease 2019 (COVID-19)-associated respiratory failure. We also analysed both the impact of such timing throughout the first four pandemic waves and the influence of prior noninvasive respiratory support on outcomes., Methods: This is a secondary analysis of a multicentre, observational and prospective cohort study that included all consecutive patients undergoing invasive mechanical ventilation due to COVID-19 from across 58 Spanish intensive care units (ICUs) participating in the CIBERESUCICOVID project. The study period was between 29 February 2020 and 31 August 2021. Early intubation was defined as that occurring within the first 24 h of ICU admission. Propensity score matching was used to achieve a balance across baseline variables between the early intubation cohort and those patients who were intubated after the first 24 h of ICU admission. Differences in outcomes between early and delayed intubation were also assessed. We performed sensitivity analyses to consider a different time-point (48 h from ICU admission) for early and delayed intubation., Results: Of the 2725 patients who received invasive mechanical ventilation, a total of 614 matched patients were included in the analysis (307 for each group). In the unmatched population, there were no differences in mortality between the early and delayed groups. After propensity score matching, patients with delayed intubation presented higher hospital mortality (27.3% versus 37.1%; p=0.01), ICU mortality (25.7% versus 36.1%; p=0.007) and 90-day mortality (30.9% versus 40.2%; p=0.02) compared with the early intubation group. Very similar findings were observed when we used a 48-h time-point for early or delayed intubation. The use of early intubation decreased after the first wave of the pandemic (72%, 49%, 46% and 45% in the first, second, third and fourth waves, respectively; first versus second, third and fourth waves p<0.001). In both the main and sensitivity analyses, hospital mortality was lower in patients receiving high-flow nasal cannula (HFNC) (n=294) who were intubated earlier. The subgroup of patients undergoing noninvasive ventilation (n=214) before intubation showed higher mortality when delayed intubation was set as that occurring after 48 h from ICU admission, but not when after 24 h., Conclusions: In patients with COVID-19 requiring invasive mechanical ventilation, delayed intubation was associated with a higher risk of hospital mortality. The use of early intubation significantly decreased throughout the course of the pandemic. Benefits of such an approach occurred more notably in patients who had received HFNC., Competing Interests: Conflicts of interest: O. Roca discloses a research grant from Hamilton Medical AG; speaker fees from Hamilton Medical AG, Ambu, Fisher & Paykel Ltd and Aerogen Ltd; and nonfinancial research support from Timpel and Masimo. R. Mellado-Artigas reports speaker fees from Medtronic and Fisher & Paykel, all outside the submitted work. The remaining authors declare no conflicts of interest., (Copyright ©The authors 2023.)

The development of new strategies based on the use of Tr1 cells has taken relevance to induce long-term tolerance, especially in the context of allogeneic stem cell transplantation. Although Tr1 cells are currently identified by the co-expression of CD49b and LAG-3 and high production of interleukin 10 (IL-10), recent studies have shown the need for a more exhaustive characterization, including co-inhibitory and chemokines receptors expression, to ensure bona fide Tr1 cells to be used as cell therapy in solid organ transplantation. Moreover, the proinflammatory environment induced by the allograft could affect the suppressive function of Treg cells, therefore stability of Tr1 cells needs to be further investigated. Here, we establish a new protocol that allows long-term in vitro expansion of highly purified expanded allospecific Tr1 ( Exp-allo Tr1). Our expanded Tr1 cell population becomes highly enriched in IL-10 producers (> 90%) and maintains high expression of CD49b and LAG-3, as well as the co-inhibitory receptors PD-1, CTLA-4, TIM-3, TIGIT and CD39. Most importantly, high dimensional analysis of Exp-allo Tr1 demonstrated a specific expression profile that distinguishes them from activated conventional T cells (T conv), showing overexpression of IL-10, CD39, CTLA-4 and LAG-3. On the other hand, Exp-allo Tr1 expressed a chemokine receptor profile relevant for allograft homing and tolerance induction including CCR2, CCR4, CCR5 and CXCR3, but lower levels of CCR7. Interestingly, Exp-allo Tr1 efficiently suppressed allospecific but not third-party T cell responses even after being expanded in the presence of proinflammatory cytokines for two extra weeks, supporting their functional stability. In summary, we demonstrate for the first time that highly purified allospecific Tr1 ( Allo Tr1) cells can be efficiently expanded maintaining a stable phenotype and suppressive function with homing potential to the allograft, so they may be considered as promising therapeutic tools for solid organ transplantation., Competing Interests: CA-S was employed by Accellix. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2023 Arteaga-Cruz, Cortés-Hernández, Alvarez-Salazar, Rosas-Cortina, Aguilera-Sandoval, Morales-Buenrostro, Alberú-Gómez and Soldevila.)

A construction site has specific risks and organizational conditions requiring on-site safety inspections. Paperwork inspections have important limitations that can be overcome by substituting paper records with digital registers and using new information and communication technologies. Although academic literature has provided several tools to carry out on-site safety inspections adopting new technologies, most construction sites are not currently ready to adopt them. This paper covers this need of on-site control by providing an application that uses a simple technology accessible to most construction companies. The main objective and contribution of this paper is to design, develop, and implement a mobile device application (App), named "RisGES". It is based on the model of risk that grounds the Construction Site Risk Assessment Tool (CONSRAT) and on the related models that connect risk with specific organizational and safety resources. This proposed application is aimed to assess the on-site risk and organizational structure by using new technologies and considering all relevant resources and material safety conditions. The paper includes practical examples of how to use RisGES in real settings. Evidence for the discriminant validity of CONSRAT is also provided. The RisGES tool is at once preventive and predictive since it yields a specific set of criteria for interventions intended to decrease the levels of risks on-site, as well as to detect improvement needs in the site structure and resources for increasing the safety levels.

Seeds are essential for plant reproduction, survival, and dispersal. Germination ability and successful establishment of young seedlings strongly depend on seed quality and on environmental factors such as nutrient availability. In tomato (Solanum lycopersicum) and many other species, seed quality and seedling establishment characteristics are determined by genetic variation, as well as the maternal environment in which the seeds develop and mature. The genetic contribution to variation in seed and seedling quality traits and environmental responsiveness can be estimated at transcriptome level in the dry seed by mapping genomic loci that affect gene expression (expression QTLs) in contrasting maternal environments. In this study, we applied RNA-sequencing to construct a linkage map and measure gene expression of seeds of a tomato recombinant inbred line (RIL) population derived from a cross between S. lycopersicum (cv. Moneymaker) and S. pimpinellifolium (G1.1554). The seeds matured on plants cultivated under different nutritional environments, i.e., on high phosphorus or low nitrogen. The obtained single-nucleotide polymorphisms (SNPs) were subsequently used to construct a genetic map. We show how the genetic landscape of plasticity in gene regulation in dry seeds is affected by the maternal nutrient environment. The combined information on natural genetic variation mediating (variation in) responsiveness to the environment may contribute to knowledge-based breeding programs aiming to develop crop cultivars that are resilient to stressful environments., (© 2023. The Author(s).)

Background and Aims: Hybridization is a common and important force in plant evolution. One of its outcomes is introgression - the transfer of small genomic regions from one taxon to another by hybridization and repeated backcrossing. This process is believed to be common in glacial refugia, where range expansions and contractions can lead to cycles of sympatry and isolation, creating conditions for extensive hybridization and introgression. Polyploidization is another genome-wide process with a major influence on plant evolution. Both hybridization and polyploidization can have complex effects on plant evolution. However, these effects are often difficult to understand in recently evolved species complexes., Methods: We combined flow cytometry, analyses of transcriptomic sequences and pollen tube growth assays to investigate the consequences of polyploidization, hybridization and introgression on the recent evolution of several Erysimum (Brassicaceae) species from the South of the Iberian Peninsula, a well-known glacial refugium. This species complex differentiated in the last 2 million years, and its evolution has been hypothesized to be determined mainly by polyploidization, interspecific hybridization and introgression., Key Results: Our results support a scenario of widespread hybridization involving both extant and 'ghost' taxa. Several taxa studied here, most notably those with purple corollas, are polyploids, probably of allopolyploid origin. Moreover, hybridization in this group might be an ongoing phenomenon, as pre-zygotic barriers appeared weak in many cases., Conclusions: The evolution of Erysimum spp. has been determined by hybridization to a large extent. Species with purple (polyploids) and yellow flowers (mostly diploid) exhibit a strong signature of introgression in their genomes, indicating that hybridization occurred regardless of colour and across ploidy levels. Although the adaptive value of such genomic exchanges remains unclear, our results demonstrate the significance of hybridization for plant diversification, which should be taken into account when studying plant evolution., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Annals of Botany Company. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Implantable cardioverter defibrillators (ICD) are effective as a primary prevention measure of ventricular tachyarrhythmias in patients with ST-segment elevation myocardial infarction (STEMI) and depressed left ventricular ejection fraction (LVEF). The implications of using cardiac magnetic resonance (CMR) instead of echocardiography (Echo) to assess LVEF prior to the indication of ICD in this setting are unknown., Materials and Methods: We evaluated 52 STEMI patients (56.6 ± 11 years, 88.5% male) treated with ICD in primary prevention who underwent echocardiography and CMR prior to ICD implantation. ICD implantation was indicated based on the presence of heart failure and depressed LVEF (≤ 35%) by echocardiography, CMR, or both. Prediction of ICD therapies (ICD-T) during follow-up by echocardiography and CMR before ICD implantation was assessed., Results: Compared to echocardiography, LVEF was lower by cardiac CMR (30.2 ± 9% vs. 37.4 ± 7.6%, p < 0.001). LVEF ≤ 35% was detected in 24 patients (46.2%) by Echo and in 42 (80.7%) by CMR. During a mean follow-up of 6.1 ± 4.2 years, 10 patients received appropriate ICD-T (3.16 ICD-T per 100 person-years): 5 direct shocks to treat very fast ventricular tachycardia or ventricular fibrillation, 3 effective antitachycardia pacing (ATP) for treatment of ventricular tachycardia, and 2 ineffective ATP followed by shock to treat ventricular tachycardia. Echo-LVEF ≤ 35% correctly predicted ICD-T in 4/10 (40%) patients and CMR-LVEF ≤ 35% in 10/10 (100%) patients. CMR-LVEF improved on Echo-LVEF for predicting ICD-T (area under the curve: 0.76 vs. 0.48, p = 0.04)., Conclusion: In STEMI patients treated with ICD, assessment of LVEF by CMR outperforms Echo-LVEF to predict the subsequent use of appropriate ICD therapies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Marcos-Garcés, Perez, Gavara, Lopez-Lereu, Monmeneu, Rios-Navarro, de Dios, Merenciano-González, Gabaldon-Pérez, Ferrero-De-Loma-Osorio, Martínez-Brotons, Bondanza, Sánchez-Gómez, Albiach, Nunez, Bayés-Genís, Chorro, Ruiz-Granell and Bodi.)

Experts typically define vitamin D deficiency levels by the determination of a circulating 25-hydroxyvitamin D 3 -calcifediol prohormone. A large part of the population is characterized by deficient vitamin D levels (calcifediol < 20 ng mL -1 ) despite individuals not being affected by any disorder. Cholecalciferol (vitamin D 3 ) and/or calcifediol supplementation is a common practice for vitamin D-deficient individuals as recommended by international scientific societies and official agencies. In the last few years, several studies have reported the presence of conjugated vitamin D 3 metabolites, mainly glucuronidation and sulfation derivatives, although simultaneous quantitative measurements involving phase I and II vitamin D metabolites have not been carried out. A quantitative method based on tandem mass spectrometry detection is proposed here for the combined determination of phase I and phase II vitamin D 3 metabolites in human serum. As phase I and phase II metabolites are preferentially ionized in different modes, a switching polarity mode was adopted to determine both groups of compounds in serum at high sensitivity levels (pg mL -1 ). The validation of this proposal was successfully accomplished by following the Center for Drug Evaluation and Research (CDER) guidelines. Its applicability was tested in a cohort of volunteers with mostly deficient baseline levels. Considering the sulfated form of calcifediol, the sum of its concentrations showed sufficient baseline vitamin D levels in all individuals, suggesting that this could be a novel strategy for vitamin D deficiency definition. Therefore, phase II metabolites are proposed to be included when evaluating the vitamin D status since they provide more information about the overall status of the vitamin D endocrine system. Nevertheless, further studies are required to confirm the biological activity of these conjugated metabolites and the suitability of this strategy for the description of vitamin D deficiency.

COVID-19, caused by the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), originated a global health crisis, causing over 2 million casualties and altering human daily life all over the world. This pandemic emergency revealed the limitations of current diagnostic tests, highlighting the urgency to develop faster, more precise and sensitive sensors. Graphene field effect transistors (GFET) are analytical platforms that enclose all these requirements. However, the design of a sensitive and robust GFET is not a straightforward objective. In this work, we report a GFET array biosensor for the detection of SARS-CoV-2 spike protein using the human membrane protein involved in the virus internalisation: angiotensin-converting enzyme 2 (ACE2). By finely controlling the graphene functionalisation, by tuning the Debye length, and by deeply characterising the ACE2-spike protein interactions, we have been able to detect the target protein with an extremely low limit of detection (2.94 aM). This work set the basis for a new class of analytical platforms, based on human membrane proteins, with the potential to detect a broad variety of pathogens, even before their isolation, being a powerful tool in the fight against future pandemics.

Objective: Although clinical decision support systems (CDSS) have many benefits for clinical practice, they also have several barriers to their acceptance by professionals. Our objective in this study was to design and validate The Aleph palliative care (PC) CDSS through a user-centred method, considering the predictions of the artificial intelligence (AI) core, usability and user experience (UX)., Methods: We performed two rounds of individual evaluation sessions with potential users. Each session included a model evaluation, a task test and a usability and UX assessment., Results: The machine learning (ML) predictive models outperformed the participants in the three predictive tasks. System Usability Scale (SUS) reported 62.7  ±  14.1 and 65  ±  26.2 on a 100-point rating scale for both rounds, respectively, while User Experience Questionnaire - Short Version (UEQ-S) scores were 1.42 and 1.5 on the -3 to 3 scale., Conclusions: The think-aloud method and including the UX dimension helped us to identify most of the workflow implementation issues. The system has good UX hedonic qualities; participants were interested in the tool and responded positively to it. Performance regarding usability was modest but acceptable., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)