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The purpose of this study is to characterize the ocular surface microbiota of patients with an anophthalmic cavity. An eNAT with 1 mL of Liquid Amies Medium was used to collect samples. Microbial DNA from anophthalmic socket and healthy fellow control eye samples was isolated and sequenced. Raw reads were analyzed with GAIA (v 2.02). The richness and Shannon alpha diversity metrics, as well as Bray-Curtis beta diversity and Wilcoxon signed-rank test values, were computed with R packages such as phyloseq, mia, or DESeq2 to allow for microbiome analysis. Principal coordinate analysis (PCoA) was performed using the function plotReducedDim from the R package scater. The different taxonomic profiles were described under the concept of eye community state type (ECST). The microbiomes of both eyes from 25 patients with an anophthalmic cavity were analyzed in this study. While the microbial communities of paired eyes from the same patients showed notable dissimilarity, no consistent patterns emerged when comparing healthy eyes to anophthalmic sockets. Alpha diversity values did not significantly differ between healthy eyes and anophthalmic socket samples, though there was considerable variability within each group. Notably, anophthalmic socket samples generally exhibited lower abundances of genera such as Staphylococcus , Enterococcus , Paenibacillus , and Sediminibacterium compared to their healthy counterparts. Microbial variability between healthy eyes and anophthalmic sockets may be due to anatomical differences. Further research is needed to determine whether patients without anophthalmic sockets exhibit similar microbiome patterns in both eyes.

Rhamnolipids (RLs) and Fengycins (FGs) are biosurfactants with very promising antifungal properties proposed to reduce the use of synthetic pesticides in crops. They are amphiphilic molecules, both known to target the plasma membrane. They act differently on Botrytis cinerea and Sclerotinia sclerotiorum, two close Sclerotiniaceae phytopathogenic fungi. RLs are more efficient at permeabilizing S. sclerotiorum, and FGs are more efficient at permeabilizing B. cinerea mycelial cells. To study the link between the lipid membrane composition and the activity of RLs and FGs, we analyzed the lipid profiles of B. cinerea and S. sclerotiorum. We determined that unsaturated or saturated C18 and saturated C16 fatty acids are predominant in both fungi. We also showed that phosphatidylethanolamine (PE), phosphatidic acid (PA), and phosphatidylcholine (PC) are the main phospholipids (in this order) in both fungi, with more PA and less PC in S. sclerotiorum. The results were used to build biomimetic lipid membrane models of B. cinerea and S. sclerotiorum for all-atom molecular dynamic simulations and solid-state NMR experiments to more deeply study the interactions between RLs or FGs with different compositions of lipid bilayers. Distinctive effects are exerted by both compounds. RLs completely insert in all the studied model membranes with a fluidification effect. FGs tend to form aggregates out of the bilayer and insert individually more easily into the models representative of B. cinerea than those of S. sclerotiorum, with a higher fluidification effect. These results provide new insights into the lipid composition of closely related fungi and its impact on the mode of action of very promising membranotropic antifungal molecules for agricultural applications., 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 © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Excess sedentary behaviour (SB) and insufficient physical activity have been identified as risk factors for cardiometabolic diseases in adolescents, and some factors may affect how much time they spend on these activities. This study sought to compare the SB and PA patterns as well as compliance with PA recommendations by sex, geographical location, and time of the week in Mexican adolescents. Methods: In a cross-sectional design, we objectively assessed SB and PA in 106 adolescents (15 to 18 y) through waist-worn accelerometers for one week. The time spent in SB and in PA at different intensities was compared by sex, geographical location and time of the week with two-way and three-way repeated measures MANOVAs, while the compliance with physical activity recommendations (i.e., ≥60 min/day) was compared using chi-squared and McNemar tests. Results : Male participants spent more time in moderate, vigorous, and moderate to vigorous PA than females both during the whole week and on weekdays (all p < 0.05). There was no significant difference in SB nor PA by geographical location (i.e., metropolitan vs. non-metropolitan areas). Moreover, all participants spent more time on moderate, vigorous, and moderate to vigorous PA on weekdays than on weekends ( p < 0.05). Compliance with international PA recommendations also showed a sex difference (males > females) and change between weekdays and weekends with no difference by geographical location. Conclusions: While geographical location does not seem to be a relevant factor, sex and time of the week appear to influence the SB and PA patterns in Mexican adolescents.

The evolution and rapid expansion of online hate speech perpetration (OHSP) behaviors among adolescents toward different groups contrast with the lack of theory-based and empirically evaluated programs targeting this phenomenon. This study, developed by the Spanish Volunteering Platform, contributes to reversing this situation by investigating the impact of a service-learning program to prevent OHSP among students in secondary education. To do so, a cluster-randomized research design was adopted with a sample of secondary school students ( n  = 60) from two public schools. After the random assignment of each class group to either the intervention or control condition, the service-learning program previously designed was implemented for 3 months. Regression results in model 7 with all predictors and controls yield a significant effect on the variable experimental group = 0.803, p  < .05, and gender = 0.987, p  < .05, explaining 45.9% of the variance. The effect size for this intervention was 0.42. From a theoretical perspective, participants are moving in the right direction to reduce and/or prevent OHSP behaviors, which demonstrates the theoretical utility of the theory of planned behavior in hate speech research. Finally, several recommendations are made to improve the impact of future replications or adaptations of this program., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interests with respect to the authorship and/or publication of this article.

This study reported a case of an arachnoid cyst of the sphenoid bone causing orbital signs and symptoms in a 58-year-old man with progressive proptosis and nonspecific discomfort in the OS. Orbital MRI showed a 3-cm homogeneous cyst within the left greater wing of the sphenoid bone. To the best of our knowledge, this is the first report of an intradiploic arachnoid cyst in the sphenoid bone with atypical radiological features, causing clinical symptoms, and managed through an eyelid approach, achieving a complete resolution with no complications., Competing Interests: The authors have no financial or conflicts of interest to disclose., (Copyright © 2024 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.)

Periodontitis and peri-implantitis are inflammatory diseases of infectious etiology that lead to the destruction of the supporting tissues located around teeth or implants. Although both pathologies share several characteristics, it is also known that they show important differences which could be due to the release of particles and metal ions from the implant surface. The activation of the inflammasome pathway is one of the main triggers of the inflammatory process. The inflammatory process in patients who suffer periodontitis or peri-implantitis has been mainly studied on cells of the immune system; however, it is also important to consider other cell types with high relevance in the regulation of the inflammatory response. In that context, mesenchymal stromal cells (MSCs) play an essential role in the regulation of inflammation due to their ability to modulate the immune response. This study shows that the induction of NLRP3 and absent in melanoma 2 (AIM2) inflammasome pathways mediated by bacterial components increases the secretion of active IL-1β and the pyroptotic process on human alveolar bone-derived mesenchymal stromal cells (hABSCs). Interestingly, when bacterial components are combined with titanium ions, NLRP3 expression is further increased while AIM2 expression is reduced. Furthermore, decrease of NLRP3 or AIM2 expression in hABSCs partially reverses the negative effect observed on the progression of the inflammatory process as well as on cell survival. In summary, our data suggest that the progression of the inflammatory process in peri-implantitis could be more acute due to the combined action of organic and inorganic components., (© The Author(s) 2024. Published by Oxford University Press.)

Although chimeric antigen receptor (CAR) T cell therapy has revolutionized type B cancer treatment, efficacy remains limited in various lymphomas and solid tumors. Reinforcing conventional CAR-T cells to release cytokines can improve their efficacy but also increase safety concerns. Several strategies have been developed to regulate their secretion using minimal promoters that are controlled by chimeric proteins harboring transactivators. However, these chimeric proteins can disrupt the normal physiology of T cells. Here, we present the first transactivator-free anti-CD19 CAR-T cells able to control IL-18 expression (iTRUCK19.18) under ultra-low doses of doxycycline and without altering cellular fitness. Interestingly, IL-18 secretion requires T cell activation in addition to doxycycline, allowing the external regulation of CAR-T cell potency. This effect was translated into an increased CAR-T cell antitumor activity against aggressive hematologic and solid tumor models. In a clinically relevant context, we generated patient-derived iTRUCK19.18 cells capable of eradicating primary B cells tumors in a doxycycline-dependent manner. Furthermore, IL-18-releasing CAR-T cells polarized pro-tumoral macrophages toward an antitumoral phenotype, suggesting potential for modulating the tumor microenvironment. In summary, we showed that our platform can generate exogenously controlled CAR-T cells with enhanced potency and in the absence of transactivators., Competing Interests: F.M. and P.M. are inventors of the patents entitled “Lent-on-plus system for conditional expression in human stem cells” (PCT/EP2017/078246) and “Insulator to improve gene transfer vectors” (PCT/EP2014/055027). F.M., M.T.-M., and J.A.M. are partners of LentiStem Biotech. P.J.-L., M.T.-M., and C.B.-J. are contractually associated with LentiStem Biotech, a spin-off company that holds the license of the above-mentioned patents., (© 2024 The Authors. Published by Elsevier Inc. on behalf of The American Society of Gene and Cell Therapy.)

Polygalacturonases (PGs) can modulate chemistry and mechanical properties of the plant cell wall through the degradation of pectins, one of its major constituents. PGs are largely used in food, beverage, textile, and paper industries to increase processes' performances. To improve the use of PGs, knowledge of their biochemical, structural and functional features is of prime importance. Our study aims at characterizing SmoPG1, a polygalacturonase from Selaginella moellendorffii, that belongs to the lycophytes. Transcription data showed that SmoPG1 was mainly expressed in S. moellendorffii shoots while phylogenetic analyses suggested that SmoPG1 is an exo-PG, which was confirmed by the biochemical characterization following its expression in heterologous system. Indeed, LC-MS/MS oligoprofiling using various pectic substrates identified galacturonic acid (GalA) as the main hydrolysis product. We found that SmoPG1 was most active on polygalacturonic acid (PGA) at pH 5, and that its activity could be modulated by different cations (Ca 2+ , Cu 2+ , Fe 2+ , Mg 2+ , Mn 2+ , Na 2+ , Zn 2+ ). In addition, SmoPG1 was inhibited by green tea catechins, including (-)-epigallocatechin-3-gallate (EGCG). Docking analyses and MD simulations showed in detail amino acids responsible for the SmoPG1-EGCG interaction. Considering its expression yield and activity, SmoPG1 appears as a prime candidate for the industrial production of GalA., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest associated with this work., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background and Objectives: There are few scales with prospective validation for the assessment of the upper gastrointestinal mucosal cleanliness during an esophagogastroduodenoscopy (EGD). The aim of this study was to develop a valid and reproducible cleanliness scale for use during an EGD., Methods: We developed a cleanliness scale (Barcelona scale) with a score (0-2 points) of five segments of the upper gastrointestinal tract with thorough cleaning techniques (esophagus, fundus, body, antrum, and duodenum). First, 125 photos (25 of each area) were assessed, and a score was assigned to each image by consensus among 7 experts endoscopists. Subsequently, 100 of the 125 images were selected and the inter- and intra-observer variability of 15 previously trained endoscopists was evaluated using the same images at two different times., Results: In total, 1500 assessments were performed. In 1336/1500 observations (89%) there was agreement with the consensus score, with a mean kappa value of 0.83 (0.45-0.96). In the second evaluation, in 1330/1500 observations (89%) there was agreement with the consensus score, with a mean kappa value of 0.82 (0.45-0.93). The intra-observer variability was 0.89 (0.76-0.99)., Conclusions: The Barcelona cleanliness scale is a valid measure and reproducible with minimal training. Its application in clinical practice is a significant step to standardize the quality of the EGD., (Copyright © 2023 Elsevier España, S.L.U. All rights reserved.)

Context: Little is known about whether parity is associated with elevated early-pregnancy insulin resistance (IR), or whether overweight/obesity contributes to increasing the possible effect., Objective: We determined the associations between parity and glucose metabolism parameters in the first trimester of pregnancy in a Mediterranean pregnant population, and whether these associations are affected by overweight/obesity., Methods: A cross-sectional study was conducted of 264 healthy pregnant women from the ECLIPSES study who were recruited at 12 weeks of gestation. At baseline, details on socioeconomic status, obstetric history (including parity, ie, number of births), lifestyle factors, anthropometry, and blood samples were collected. Fasting serum glucose, insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) index were assessed in the first trimester. Elevated IR was defined as the upper HOMA-IR tertile (≥1.58). Multivariable linear regression and Cox regression model with constant time were performed., Results: Parity ranged from 0 to 4. After multivariable adjustment, the insulin levels (β [% change]: 20.92; 95% CI, 4.08-37.71) and HOMA-IR index (β [% change]: 19.72; 95% CI, 2.43-40.49) were positively associated with parity. Additionally, multiparous women, as compared to nulliparous, were more likely to have higher HOMA-IR levels (primiparous [1 birth], β [% change[: 16.88; 95% CI, -1.00 to 37.99; multiparous [≥2 births), β [% change]: 32.18; 95% CI, 3.56-68.71), and an increased relative risk (RR) of an elevated IR (primiparous [1 birth], RR: 1.55; 95% CI, 1.03-2.36; multiparous (≥2 births), RR: 1.72; 95% CI, 1.05-2.83). The combination of multiparity and overweight/obesity conferred a 3.04-fold increase in the RR of elevated IR, which increased proportionally to the number of parities., Conclusion: This study demonstrates that parity may have a negative effect on early-pregnancy IR and that maternal overweight/obesity appears to further aggravate this relationship., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: To assess the photic phenomena (PP) and positive dysphotopsia in candidates for presbyopia or cataract surgery and to evaluate their relationship with cataract grading systems., Design: Retrospective observational., Methods: Monocular data for 82 subjects measured during the preoperative screening were retrospectively retrieved from our database. The evaluated variables consisted of two methods for PP measurement: light distortion index (LDI) and parameters obtained from a simulator, both of which were combined with subjective bother related to PP. The cutoff for LDI that better predicted patients passing from slightly to moderately bothersome was estimated. The relationships between LDI and the following objective cataract grading methods were also assessed: objective scatter index (OSI), dysfunctional lens index (DLI), and Pentacam Nucleus Staging (PNS)., Results: LDI was the best method for measuring PP, which showed a significant correlation with the bothersome question (rho = 0.34, P = 0.002) and also with OSI (rho = 0.67, P < 0.0005), DLI (rho = -0.29, P = 0.007), and PNS (rho = 0.48, P < 0.0005). The number/percentage of patients who found it bothersome was as follows: "Not at all" (18/22%), "Slightly" (41/50%), "Moderately" (15/18.3%), and "Very" (8/9.7%). The cutoff value that predicted the transition from slightly to moderately bothersome was ≥15.20% according to LDI, which could be estimated with the following values for grading: ≥2.8 for OSI, ≤7.6 for DLI, and ≥2 for PNS., Conclusions: Patients reporting moderately or higher bothersome levels in the preoperative period and with LDI <15.20%, <2.8 for OSI, >7.6 for DLI, and <2 for PNS might deserve special attention in the multifocal intraocular lens selection., (Copyright © 2024 Copyright: © 2024 Indian Journal of Ophthalmology.)

Evidence of effectiveness and safety in combined therapies is scarce and based on case reports and small case series. We report a case of dual biologic therapy with ustekinumab and dupilumab in a patient with severe Crohn disease and atopic dermatitis. There was no interference between these drugs after a 7-month follow-up., (© 2023 The Australasian College of Dermatologists.)

The objective of the present study is to evaluate the psychometric properties of the Scale of Attitudes toward Gender Equality in Football in the Context of Schools (SAGEFS) in the international context. This sample was formed by N = 6,101 students. The study was conducted by applying the SAGEFS. The model of the three factors correlated in the complete sample and for each country was correlated using AFC. The structural model was appraised by employing eight indices: the relative Chi-squared index; the goodness of fit index and its adjusted formula; the normal fit index; the comparative fit index; the standardized Quadratic Mean; and the Quadratic Mean Error of Approximation. To conclude, the results evidence the presence of psychometric properties that are indispensable for the measurement of attitudes toward gender equality in the context of schools., 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 © 2024 Méndez-Hinojosa, Gil-Madrona, Zamorano-García, Simón-Piqueras, Padierna-Cardona, Flores-Ferro, González-Villalobos, Pavlovic, Maureira-Cid, Gómez-Santos, Morales-Calvo and Cárdenas-Rodríguez.)

Introduction: The Mexican Report Card on Physical Activity for Children and Adolescents aims to assess the prevalence of movement behaviors and opportunities to perform them., Methods: Data on 11 indicators were obtained from national health surveys, census data, government documents, websites, and published studies. Data were compared against established benchmarks, and a grade between 0 and 10 was assigned to each indicator., Results: For Daily Behaviors, we found 34.5% of Mexican children and adolescents meet Physical Activity recommendations (Grade 3), 48.4% participate in Organized Sports (Grade 5), 35-75.8% engage in Active Play outdoors (Grade 4), 54.1% use Active Transportation (Grade 5), 43.6% spend <2 h in Sedentary Behavior per day (Grade 4), and 65-91% meet Sleep recommendations (Grade 7). Girls have lower physical activity levels and sports participation than boys of the same age. For Physical Fitness, we found 56.2-61.8% of children and adolescents have an adequate body mass index for their age (Grade 6). For Sources of Influence, we found 65-67% of parents engage in physical activity or sports in a week (Grade 7), 32.2-53.3% of basic education schools have a physical education teacher (Grade 6), and 37% of neighborhoods in Mexico have sidewalks with trees (Grade 4). Regarding Government, several policies and programs aimed at improving children physical activity were launched but their impact and allocated implementation budget are unknown (Grade 6)., Discussion: Mexican children and adolescents engage in low levels of movement behaviors and have limited opportunities to perform such behaviors. The grades and recommendations provided here should be considered to improve such opportunities., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Argumedo, López y Taylor, Ortiz Brunel, Gaytán-González, González-Casanova, González Villalobos, Jáuregui, Jáuregui Ulloa, Medina, Pacheco Miranda, Pérez Rodríguez, Retano Pelayo, Rodríguez Martínez and Galaviz.)

Purpose: The purpose of this study was to check the efficacy and safety of a novel tear substitute containing hyaluronic acid and low-dose hydrocortisone in the treatment of moderate dry eye disease. Methods: In this prospective randomized study, 38 patients with moderate dry eye disease were divided into two treatment groups: Group 1 received one drop of 0.2% sodium hyaluronate and 0.001% hydrocortisone four times daily for 3 months, while Group 2 received 0.15% sodium hyaluronate and 3% trehalose at the same dosage. OSDI and SANDE questionnaires, Non-Invasive Break-Up time (NIBUT), Tear Meniscus Height (TMH), meibography, Lipid Layer Thickness (LLT), Tear Break-Up Time (TBUT), Corneal Staining Score (CFS), and Intraocular Pressure (IOP) were evaluated at baseline and after 1, 2, and 3 months of treatment. Results: During the treatment period, Group 1 showed statistically significant improvement in OSDI score ( p = 0.002), SANDE score ( p = 0.01), NIBUT ( p < 0.0001), LLT ( p < 0.0001), TBUT ( p = 0.01), and CFS ( p = 0.02). In Group 2, significant improvement was observed only in the TBUT score ( p < 0.05). Comparison of the two groups showed that NIBUT and LLT were significantly different at the end of treatment ( p = 0.001 for both comparisons), with more favorable results for sodium hyaluronate and hydrocortisone than for sodium hyaluronate and trehalose. No significant variations in intraocular pressure were observed in either group during the treatment period ( p > 0.05). Conclusions : The study confirms that a 3-months treatment with hyaluronic acid 0.2% in combination with low-dose hydrocortisone 0.001% improves the signs and symptoms of moderate DED and that a low-dosage 0.001% hydrocortisone can be helpful in preventing the progression to chronic stages of DED.

Navigating robots with precision in complex environments remains a significant challenge. In this article, we present an innovative approach to enhance robot localization in dynamic and intricate spaces like homes and offices. We leverage Visual Question Answering (VQA) techniques to integrate semantic insights into traditional mapping methods, formulating a novel position hypothesis generation to assist localization methods, while also addressing challenges related to mapping accuracy and localization reliability. Our methodology combines a probabilistic approach with the latest advances in Monte Carlo Localization methods and Visual Language models. The integration of our hypothesis generation mechanism results in more robust robot localization compared to existing approaches. Experimental validation demonstrates the effectiveness of our approach, surpassing state-of-the-art multi-hypothesis algorithms in both position estimation and particle quality. This highlights the potential for accurate self-localization, even in symmetric environments with large corridor spaces. Furthermore, our approach exhibits a high recovery rate from deliberate position alterations, showcasing its robustness. By merging visual sensing, semantic mapping, and advanced localization techniques, we open new horizons for robot navigation. Our work bridges the gap between visual perception, semantic understanding, and traditional mapping, enabling robots to interact with their environment through questions and enrich their map with valuable insights. The code for this project is available on GitHub https://github.com/juandpenan/topology&#95;nav&#95;ros2., 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 Peña-Narvaez, Martín, Guerrero and Pérez-Rodríguez.)

Transparent ZnMn 2 O 4 thin films on indium tin oxide (ITO) were prepared through spray pyrolysis and implemented as electrodes in symmetric supercapacitors (SSCs). A specific capacitance value of 752 F g -1 at 0.5 A g -1 and a 70% retention over 3000 galvanostatic charge-discharge (GCD) cycles were reached with a 1.0 M Na 2 SO 4 electrolyte in a three-electrode electrochemical cell. Analysis of the cycled electrodes with 1.0 M Na 2 SO 4 revealed a local loss of electrode material; this loss increases when electrodes are used in SCCs. To avoid this drawback, solid polyvinylpyrrolidone-LiClO 4 (PVP-LiClO 4 ) and quasi-solid polyvinylpyrrolidone-ionic liquid (PVP-ionic liquid) electrolytes were tested in SSCs as substitutes for aqueous Na 2 SO 4 . An improvement in capacitance retention without a loss of electrode material was observed for the PVP-ionic liquid and PVP-LiClO 4 electrolytes. With these non-aqueous electrolytes, the tetragonal structure of the ZnMn 2 O 4 spinel was maintained throughout the cyclic voltammetry (CV) cycles, although changes occurred in the stoichiometry from ZnMn 2 O 4 to Mn-rich Zn 1-x Mn 3-x O 4 . In the case of the electrolyte 1.0 M Na 2 SO 4 , the loss of Zn 2+ led to the formation of MnO 2 via Zn 1-x M 3-x O 4 . The location of the three SCCs in the Ragone plot shows supercapacitor behavior. The electrochemical results prove that the pseudocapacitance is the major contributor to the electrode capacitance, and the SCCs can therefore be considered as pseudocapacitors.

Protective immunity against pathogens or cancer is mediated by the activation and clonal expansion of antigen-specific naive T cells into effector T cells. To sustain their rapid proliferation and effector functions, naive T cells switch their quiescent metabolism to an anabolic metabolism through increased levels of aerobic glycolysis, but also through mitochondrial metabolism and oxidative phosphorylation, generating energy and signalling molecules 1-3 . However, how that metabolic rewiring drives and defines the differentiation of T cells remains unclear. Here we show that proliferating effector CD8 + T cells reductively carboxylate glutamine through the mitochondrial enzyme isocitrate dehydrogenase 2 (IDH2). Notably, deletion of the gene encoding IDH2 does not impair the proliferation of T cells nor their effector function, but promotes the differentiation of memory CD8 + T cells. Accordingly, inhibiting IDH2 during ex vivo manufacturing of chimeric antigen receptor (CAR) T cells induces features of memory T cells and enhances antitumour activity in melanoma, leukaemia and multiple myeloma. Mechanistically, inhibition of IDH2 activates compensating metabolic pathways that cause a disequilibrium in metabolites regulating histone-modifying enzymes, and this maintains chromatin accessibility at genes that are required for the differentiation of memory T cells. These findings show that reductive carboxylation in CD8 + T cells is dispensable for their effector response and proliferation, but that it mainly produces a pattern of metabolites that epigenetically locks CD8 + T cells into a terminal effector differentiation program. Blocking this metabolic route allows the increased formation of memory T cells, which could be exploited to optimize the therapeutic efficacy of CAR T cells., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: We are currently undergoing a profound process of digital transformation that has favoured the development and use of apps in multiple facets of people's daily lives. In the fitness industry, this situation has facilitated the control of exercise and the maintenance of healthier lifestyles. However, it is not known how the perceived quality and importance of fitness apps vary for users based on gender and age, which is the objective of this study conducted among users of fitness centres., Methods: By means of a convenience sample, 321 users from different centres of the boutique fitness chain Sano Centre (238 females and 83 males) took part in the study. They answered the 16 items of the MARS scale, distributed in four dimensions, in terms of importance and perceived quality. The existence of significant differences was analysed using non-parametrical statistics such as the U-Mann-Whitney (gender) and the H-Kruskal-Wallis (age). In addition, a cluster analysis, combining hierarchical and non-hierarchical methods, was analysed considering as a dependent variable the level of recommendation of fitness apps., Results: Considering gender, in importance-performance analysis (IPA), credibility was the most important attribute for females and quality of information for males. In the case of age, credibility was the most important attribute in all the ranges. The cluster analysis established two groups (high and low recommendations of the fitness app). In importance, the first group scored better on all factors except entertainment and interest. In valuation, the scores were lower than on importance, especially in the low recommendation group., Conclusion: Regarding usage behaviour, credibility is the factor to which users attach the highest importance and rating, regardless of gender and age. The main demand focuses on improving the gestural design and visual appeal, which will facilitate a better user experience., 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 Martín, García-Fernández, Valcarce-Torrente, Bernal-García, Gálvez-Ruiz and Angosto-Sánchez.)

Purpose of Review: Urinary pH is an important factor related to renal stone disease, and it plays an essential role in stone prevention. Monitoring of urinary pH by patients at home provides information that can help to assess the treatment needed by each patient. We conducted a systematic review is to assess the available evidence concerning urinary pH monitoring methods along with their accuracy, cost, and usefulness by patients with urolithiasis., Recent Findings: A total of 9 articles were included (1886 urinary pH measurements). They reported information about urinary dipsticks, portable electronic pH meters and electronic strip readers, amongst other methods. Accuracy was compared with a laboratory pH meter (gold standard). Urinary dipsticks were found to be not accurate enough to guide clinical decision making and portable electronic pH meters showed promising results. Urinary dipsticks are neither precise nor accurate enough. Portable electronic pH meters seem to be more accurate, easy to use, and cost-effective. They are a reliable source for patients to use at home in order to prevent future episodes of nephrolithiasis., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: To evaluate the microbiota of culture negative Corneal Impression Membrane (CIM) microbial keratitis samples with the use of shotgun metagenomics analysis., Methods: DNA of microbial keratitis samples were collected with CIM and extracted using the MasterPure™ Complete DNA and RNA Purification Kit (Epicentre). DNA was fragmented by sonication into fragments of 300 to 400 base pairs (bp) using Bioruptor® (Diagenode, Belgium) and then used as a template for library preparation. DNA libraries were sequenced on Illumina® HiSeq2500. The resulting reads were quality controlled, trimmed and mapped against the human reference genome. The unmapped reads were taxonomically classified using the Kraken software., Results: 18 microbial keratitis samples were included in the study. Brevundimonas diminuta was found in 5 samples while 6 samples showed the presence of viral infections. Cutibacterium acnes , Staphylococcus aureus , Moraxella lacunata and Pseudomonas alcaligenes were also identified as the presumed putative cause of the infection in 7 samples., Conclusions: Shotgun sequencing can be used as a diagnostic tool in microbial keratitis samples. This diagnostic method expands the available tests to diagnose eye infections and could be clinically significant in culture negative samples.

Purpose: To report a case of achromatopsia with a new mutation in the PDE6C gene which has not been previously described., Methods: Case report., Patients: A single patient., Results: A 35-year-old woman with poor vision and impaired color vision. Fundus examination of both eyes (OU) revealed small optic discs. Optical coherence tomography (OCT) showed photoreceptor segment defects and a disruption of the ellipsoid layer in the foveal region, with intact overlying outer limiting membrane and underlying RPE bands. The electroretinogram (ERG) showed scotopic responses: DA 0.01: normal amplitude, b-wave latency at upper limit of normal / slightly increased. DA 3 and DA 10: slightly increased b-wave latency, asymmetry in b amplitude, being lower in the left eye. Oscillatory potentials: no responses are obtained. Photopic responses: LA-3: greatly increased latencies, decreased amplitude. Subsequently, a case of incomplete achromatopsia was suspected. Therefore, a genetic study was carried out showing the homozygous presence of the undescribed pathogenic variant c.660&#95;661del (p.Ser221Tyrfs * 15) in exon 3 of the PDE6C gene., Conclusion: Achromatopsia is an autosomal-recessive genetic disease characterized by decreased visual acuity, color blindness, photophobia, and nystagmus. Due to the variability of genetic mutations in achromatopsia, genetic characterization is mandatory in order to improve the efficiency in molecular diagnosis. This data may be useful in future therapeutic strategies. We present a previously undescribed mutation in the PDE6C gene in a patient with incomplete achromatopsia.

Background: New intraocular lenses (IOLs) have emerged since the originally coined monofocal and multifocal IOLs. The extended depth of focus (EDoF) and enhanced monofocal IOLs (mono-EDoF) that have appeared in the last decade have caused some confusion in their classification. The aim of this review was to summarize the outcomes provided by mono-EDOF IOLs and to determine which of the endpoints, described by the American National Standard (ANSI) for EDoF IOLs, are fulfilled., Methods: The MEDLINE, EMBASE, and WEB OF SCIENCE databases were searched. Two independent reviewers screened the studies for inclusion and data extraction. The search strategy was limited to studies published between 2020 and 2022, but not by language. The results are presented as a narrative summary accompanied by tables, in alignment with the objectives of this scoping review. Compliance with the endpoints for clinical outcomes described in the American National Standard Z80.35-2018 (ANSI) for EDoF lenses was checked and additional endpoints were defined., Results: Two systematic reviews, 13 laboratory, 21 clinical, and two mixed studies were included. Tecnis Eyhance was the mono-EDOF with the highest volume of evidence to date. Although laboratory studies included other IOLs, clinical evidence for them is still scarce, with only one study of IsoPure compared to a standard monofocal IOL. Evidence in comparison to EDoF lenses is also scarce, even for Tecnis Eyhance, with only three studies including this lens in comparison to an EDoF lens. After evaluation of the ANSI criteria, agreement was found in the failure for the increase in depth of field equal to or greater than 0.5 D for a visual acuity (VA) level of 0.2 logMAR and none of the studies supported that the median monocular VA at intermediate distance was at least 0.2 logMAR., Conclusions: Additional clinical evidence is required for other mono-EDOF IOLs beyond Tecnis Eyhance. Until the arrival of a standard classification, mono-EDOF should be better still classified as monofocal because the ANSI standards were not fully met., (© 2023. The Author(s).)

The 2021 guidelines on the prevention of vascular disease (VD) in clinical practice published by the European Society of Cardiology (ESC) and supported by 13 other European scientific societies recognize the key role of screening for chronic kidney disease (CKD) in the prevention of VD. Vascular risk in CKD is categorized based on measurements of estimated glomerular filtration rate (eGFR) and urine albumin to creatinine ratio (ACR). Thus, moderate CKD is associated with a high vascular risk and severe CKD with a very high vascular risk requiring therapeutic action, and there is no need to apply other vascular risk scores when vascular risk is already very high due to CKD. Moreover, the ESC indicates that vascular risk assessment and the subsequent decision algorithm should start with measurement of eGFR and ACR. To optimize the implementation of the ESC 2021 guidelines on the prevention of CVD in Spain, we consider that: 1) Urine testing for albuminuria using ACR should be part of the clinical routine at the same level as blood glucose, cholesterolemia, and GFR estimation when these are used to make decisions on CVD risk. 2) Spanish public and private health services should have the necessary means and resources to optimally implement the ESC 2021 guidelines for the prevention of CVD in Spain, including ACR testing., (Copyright © 2023 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.)

Background: SAAP-148 is an antimicrobial peptide derived from LL-37. It exhibits excellent activity against drug-resistant bacteria and biofilms while resisting degradation in physiological conditions. Despite its optimal pharmacological properties, its mechanism of action at the molecular level has not been explored., Methods: The structural properties of SAAP-148 and its interaction with phospholipid membranes mimicking mammalian and bacterial cells were studied using liquid and solid-state NMR spectroscopy as well as molecular dynamics simulations., Results: SAAP-148 is partially structured in solution and stabilizes its helical conformation when interacting with DPC micelles. The orientation of the helix within the micelles was defined by paramagnetic relaxation enhancements and found similar to that obtained using solid-state NMR, where the tilt and pitch angles were determined based on 15 N chemical shift in oriented models of bacterial membranes (POPE/POPG). Molecular dynamic simulations revealed that SAAP-148 approaches the bacterial membrane by forming salt bridges between lysine and arginine residues and lipid phosphate groups while interacting minimally with mammalian models containing POPC and cholesterol., Conclusions: SAAP-148 stabilizes its helical fold onto bacterial-like membranes, placing its helix axis almost perpendicular to the surface normal, thus probably acting by a carpet-like mechanism on the bacterial membrane rather than forming well-defined pores.

Introduction: Rhamnolipids (RLs) are secondary metabolites naturally produced by bacteria of the genera Pseudomonas and Burkholderia with biosurfactant properties. A specific interest raised from their potential as biocontrol agents for crop culture protection in regard to direct antifungal and elicitor activities. As for other amphiphilic compounds, a direct interaction with membrane lipids has been suggested as the key feature for the perception and subsequent activity of RLs. Methods: Molecular Dynamics (MD) simulations are used in this work to provide an atomistic description of their interactions with different membranous lipids and focusing on their antifungal properties. Results and discussion: Our results suggest the insertion of RLs into the modelled bilayers just below the plane drawn by lipid phosphate groups, a placement that is effective in promoting significant membrane fluidification of the hydrophobic core. This localization is promoted by the formation of ionic bonds between the carboxylate group of RLs and the amino group of the phosphatidylethanolamine (PE) or phosphatidylserine (PS) headgroups. Moreover, RL acyl chains adhere to the ergosterol structure, forming a significantly higher number of van der Waals contact with respect to what is observed for phospholipid acyl chains. All these interactions might be essential for the membranotropic-driven biological actions of RLs., 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 Rodríguez-Moraga, Ramos-Martín, Buchoux, Rippa, D’Amelio and Sarazin.)

Introduction: Extracorporeal wave lithotripsy (ESWL) is considered a first-line treatment for renal and ureteral stones up to 10-20 mm in diameter. Complications are uncommon, with a reported rate of 0-6% in the literature. Bowel perforation has only been described in a few case reports but requires rapid diagnosis and treatment., Methods: A review of the literature from PubMed/Medline, Embase, Cochrane, and Web of Science databases was performed including studies reporting bowel perforation secondary to ESWL between January 1990 and June 2022., Results: We found 16 case reports of intestinal perforation in the literature. Although some patients had previously undergone abdominal surgery or had inflammatory intestinal disease, others were without comorbidities that could lead to complications. Abdominal pain was the main symptom and imaging was required to confirm the diagnosis, which usually necessitated a surgical intervention. As regards the ESWL technique, it appears that the combination of a high energy level and the prone position constitutes a risk factor for these rare complications. At the authors' centre, only one case has been reported among 24,000 ESWL procedures over 20 years: A 59-year-old female who underwent ESWL for a distal right ureteral stone presented acute abdominal pain and free intraperitoneal pelvic fluid on ultrasound. A CT scan revealed a small bowel perforation requiring open laparotomy with primary closure., Conclusions: In conclusion, although bowel perforation after ESWL is rare, progressive abdominal pain with tenderness at physical examination requires proper imaging evaluation to exclude bowel perforation and prompt intervention if required.

Obese women are more likely to experience pregnancy complications. The distribution of fat, and more particularly the rise in visceral fat, is well established to be more closely linked to the onset of cardiovascular disease and metabolic syndrome than obesity itself. We aim to examine the relationship between maternal visceral fat assessment in the first trimester and the appearance of adverse pregnancy outcomes. A prospective cohort study including 416 pregnant women was conducted. During the first trimester scan (11-13 + 6 weeks), all individuals had their visceral fat and subcutaneous thicknesses measured by ultrasonography. Blood samples were obtained, and maternal demographics and clinical information were documented. After delivery, the obstetric outcomes were evaluated. We contrasted two groups: one with healthy pregnancies and the other with adverse pregnancy outcomes (APO), defined as the development of at least one of the following complications: gestational diabetes mellitus, hypertensive disorders of pregnancy, abnormal fetal growth, preterm delivery or preterm premature rupture of membranes. Median maternal age was 33 and 34 years old for the uncomplicated and adverse pregnancy outcomes groups, respectively. We found that women with adverse pregnancy outcomes had higher VFT (median 30 vs. 26.5 mm, p = 0.001) and SFT (median 18.9 vs. 17.1 mm, p = 0.03). However, the visceral/subcutaneous fat ratio was not statistically different between groups. Finally, we performed a subanalysis for metabolic and placental vascular dysfunction complications. After performing a multivariate logistic regression analysis adjusted for maternal age, smoking, and mean arterial pressure, both the VFT (aOR 1.03, p < 0.001) and the ratio of visceral/subcutaneous fat (aOR 1.37, p = 0.04) were significantly associated with the development of adverse pregnancy outcomes; however, the associations of VFT and the VFT-to-SFT ratio were higher for the occurrence of gestational diabetes (aOR 1.07, p < 0.001; aOR 2.09, p = 0.001; respectively) and showed no relationships with placental complications. When conducting a first-trimester ultrasound assessment, sonographers may measure VFT without additional time or cost involved. Identification of pregnant women with increased VFT (>37 mm) may benefit from a close follow-up, especially for the development of gestational diabetes, independent of BMI.

Introduction: The health emergency caused by COVID-19 has led to substantial changes in the usual working system of primary healthcare centers and in relations with users. The Catalan Society of Family and Community Medicine designed a survey that aimed to collect the opinions and facilitate the participation of its partners on what the future work model of general practitioners (GPs) should look like post-COVID-19. Methodology: Online survey of Family and Community Medicine members consisting of filiation data, 22 Likert-type multiple-choice questions grouped in five thematic axes, and a free text question. Results: The number of respondents to the questionnaire was 1051 (22.6% of all members): 83.2% said they spent excessive time on bureaucratic tasks; 91.8% were against call center systems; 66% believed that home care is the responsibility of every family doctor; 77.5% supported continuity of care as a fundamental value of patient-centered care; and >90% defended the contracting of complementary tests and first hospital visits from primary healthcare (PHC). Conclusions: The survey responses describe a strong consensus on the identity and competencies of the GP and on the needs of and the threats to the PHC system. The demand for an increase in health resources, greater professional leadership, elimination of bureaucracy, an increase in the number of health professionals, and greater management autonomy, are the axes towards which a new era in PHC should be directed.

The Arabidopsis PROSCOOP genes belong to a family predicted to encode secreted pro-peptides, which undergo maturation steps to produce peptides named SCOOP. Some of them are involved in defence signalling through their perception by a receptor complex including MIK2, BAK1 and BKK1. Here, we focused on the PROSCOOP10 gene, which is highly and constitutively expressed in aerial organs. The MS/MS analyses of leaf apoplastic fluids allowed the identification of two distinct peptides (named SCOOP10#1 and SCOOP10#2) covering two different regions of PROSCOOP10. They both possess the canonical S-X-S family motif and have hydroxylated prolines. This identification in apoplastic fluids confirms the biological reality of SCOOP peptides for the first time. NMR and molecular dynamics studies showed that the SCOOP10 peptides, although largely unstructured in solution, tend to assume a hairpin-like fold, exposing the two serine residues previously identified as essential for the peptide activity. Furthermore, PROSCOOP10 mutations led to an early-flowering phenotype and increased expression of the floral integrators SOC1 and LEAFY , consistent with the de-regulated transcription of PROSCOOP10 in several other mutants displaying early- or late-flowering phenotypes. These results suggest a role for PROSCOOP10 in flowering time, highlighting the functional diversity within the PROSCOOP family.

Biomembranes constitute the first lines of defense of cells. While small molecules can often permeate cell walls in bacteria and plants, they are generally unable to penetrate the barrier constituted by the double layer of phospholipids, unless specific receptors or channels are present. Antimicrobial or cell-penetrating peptides are in fact highly specialized molecules able to bypass this barrier and even discriminate among different cell types. This capacity is made possible by the intrinsic properties of its phospholipids, their distribution between the internal and external leaflet, and their ability to mutually interact, modulating the membrane fluidity and the exposition of key headgroups. Although common phospholipids can be found in the membranes of most organisms, some are characteristic of specific cell types. Here, we review the properties of the most common lipids and describe how they interact with each other in biomembranes. We then discuss how their assembly in bilayers determines some key physical-chemical properties such as permeability, potential and phase status. Finally, we describe how the exposition of specific phospholipids determines the recognition of cell types by membrane-targeting molecules., Competing Interests: Declaration of competing interest The authors have declared no conflict of interest whatsoever. All authors have read and approved the final article., (Copyright © 2022 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

Sesquin is a wide spectrum antimicrobial peptide displaying a remarkable activity on fungi. Contrarily to most antimicrobial peptides, it presents an overall negative charge. In the present study, we elucidate the molecular basis of its mode of action towards biomimetic membranes by NMR and MD experiments. While a specific recognition of phosphatidylethanolamine (PE) might explain its activity in a variety of different organisms (including bacteria), a further interaction with ergosterol accounts for its strong antifungal activity. NMR data reveal a charge gradient along its amide protons allowing the peptide to reach the membrane phosphate groups despite its negative charge. Subsequently, the peptide gets structured inside the bilayer, reducing its order. MD simulations predict that its activity is retained in conditions commonly used for food preservation: low temperatures, high pressure, or the presence of electric field pulses, making Sesquin a good candidate as food preservative., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2022 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

Pinna nobilis is undergoing one of the most dramatic events suffered by an endangered species. An emerging disease has relegated its populations to coastal lagoons or estuaries with salinities beyond the 36.5-39.7 psu range. The Mar Menor is one of two such locations on the Spanish coastline. Poor environmental conditions and eutrophication and anoxia events, that became critical in 2016, 2019 and 2021, have reduced its population in >99 %. In this work, the spatial distribution of the species within the lagoon and the factors determining its survival along the successive crises of eutrophication are studied using a two-stage (presence/absence estimation and density modelling) Species Distribution Model. A potential area of 200.97 ha and an average density of 1.05 ind.100 m 2 is estimated for 2020. The viability of the Mar Menor population depends on management actions designed both for the species and to improve the lagoon environmental state., 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 © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The experience of the COVID-19 pandemic and the horizon of expectations in relation to climate change reminds us that it is a collective responsibility to anticipate to the best of our ability and knowledge the risks of foreseeable disasters and their potential impacts on vulnerable communities. The article will examine the meaning and status of moral duties regarding disaster preparedness by adopting a disaster ethics approach which draws on the interrelationship of bioethics with public health ethics and looks at the full cycle of disaster management and the corresponding cycle of protection of victims and professionals. After discussing some normative controversies accompanying well-known classifications of disasters and characterizing the ethical turn to preparedness in disaster management, it will be argued that preparedness duties include obligations relating to planning, anticipation, and prevention of disasters and that they are derivative and positive duties involving a series of prospective, shared and institutionally mediated responsibilities., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Cecropin D is an antimicrobial peptide from Bombyx mori displaying anticancer and pro-apoptotic activities and, together with Cecropin XJ and Cecropin A, one of the very few peptides targeting esophageal cancer. Cecropin D displays poor similarity to other cecropins but a remarkable similarity in the structure and activity spectrum with Cecropin A and Cecropin XJ, offering the possibility to highlight key motifs at the base of the biological activity. In this work we show by NMR and MD simulations that Cecropin D is partially structured in solution and stabilizes its two-helix folding upon interaction with biomimetic membranes. Simulations show that Cecropin D strongly interacts with the surface of cancer cell biomimetic bilayers where it recognises the phosphatidylserine headgroup often exposed in the outer leaflet of cancerous cells by means of specific salt bridges. Cecropin D is also able to penetrate deeply in bilayers containing cardiolipin, a phospholipid found in mitochondria, causing significant destabilization in the lipid packing which might account for its pro-apoptotic activity. In bacterial membranes, phosphatidylglycerol and phosphatidylethanolamine act synergically by electrostatically attracting cecropin D and providing access to the membrane core, respectively., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Pseudopterygium is a non-progressive conjunctival adhesion to the peripheral cornea secondary to a corneal-limbus damage. According to the literature, the main etiology is a previous eye trauma. Nevertheless, this could be biased by the existence of other underdiagnosed causes of pseudopterygium, some of which may have severe consequences for the integrity of the eye and patient's life. This comprehensive literature review was performed based on a search on the PubMed and Google Scholar databases of relevant pseudopterygium published papers according to our current knowledge and seeks to gather the existing evidence about its diverse etiologies and clinical features, as well as to propose a diagnostic algorithm to simplify its correct approach.

In patients with trastuzumab-resistant HER2-positive breast cancer, the combination of everolimus (mTORC1 inhibitor) with trastuzumab failed to show a clinically significant benefit. However, the combination of mTOR inhibition and the antibody-drug conjugate (ADC) trastuzumab-emtansine (T-DM1) remains unexplored. We tested T-DM1 plus everolimus in a broad panel of HER2-positive breast cancer cell lines. The combination was superior to T-DM1 alone in four cell lines (HCC1954, SKBR3, EFM192A, and MDA-MB-36) and in two cultures from primary tumor cells derived from HER2-positive patient-derived xenografts (PDX), but not in BT474 cells. In the trastuzumab-resistant HCC1954 cell line, we characterized the effects of the combination using TAK-228 (mTORC1 and -2 inhibitor) and knockdown of the different mTOR complex components. T-DM1 did not affect mTOR downstream signaling nor induct autophagy. Importantly, mTOR inhibition increased intracellular T-DM1 levels, leading to increased lysosomal accumulation of the compound. The increased efficacy of mTOR inhibition plus T-DM1 was abrogated by lysosome inhibitors (chloroquine and bafilomycin A1). Our experiments suggest that BT474 are less sensitive to T-DM1 due to lack of optimal lysosomal processing and intrinsic resistance to the DM1 moiety. Finally, we performed several in vivo experiments that corroborated the superior activity of T-DM1 and everolimus in HCC1954 and PDX-derived mouse models. In summary, everolimus in combination with T-DM1 showed strong antitumor effects in HER2-positive breast cancer, both in vitro and in vivo. This effect might be related, at least partially, to mTOR-dependent lysosomal processing of T-DM1, a finding that might apply to other ADCs that require lysosomal processing., Implications: Inhibition of mTOR increases the antitumor activity of T-DM1, supporting that the combination of mTOR inhibitors and antibody-drug conjugates warrants clinical evaluation in patients with HER2-positive breast cancer., (©2022 American Association for Cancer Research.)

Lower eyelid retraction occurring as a complication of lower eyelid blepharoplasty may give rise to symptoms of exposure keratitis as well as cosmetic considerations. This retrospective longitudinal study describes our clinical experience with 74 patients with bilateral lower eyelid retraction postblepharoplasty (148 eyes) undergoing a transconjunctival subperiosteal midface lift with the implantation of a hard palate spacer graft over the period 2002 to 2019. All patients had a forced-up traction test result of less than or equal to 2 mm, indicating a significant fibrosis of the middle lamellae. Margin reflex distances (MRD2) were examined at follow-up visits scheduled for 2 weeks, 1 month, and 1, 3, 6, 9, and 12 years. Mean follow-up duration was ± 102 months (range 6 to 144 months). In all patients, MRD2 varied up until 1-year postsurgery and stabilized thereafter. Last follow-up MRD2 values indicated retraction improvements of 1.4, 2.4, and 3.2 mm, respectively, for those with mild: MRD2 6.3 mm [5.5 - 6.6], moderate: 7.0 mm [6.7 - 7.8], and severe retraction: 8.5 mm [7.9 - 9]. This improvement was statistically significant in patients with severe baseline retraction (p = 0.04). This approach proved to be safe and functional, and cosmetic results were excellent and remained stable over time., (Copyright © 2022 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Autophagy is a highly conserved process that mediates the targeting and degradation of intracellular components to lysosomes, contributing to the maintenance of cellular homeostasis and to obtaining energy, which ensures viability under stress conditions. Therefore, autophagy defects are common to different neurodegenerative disorders. Rnd3 belongs to the family of Rho GTPases, involved in the regulation of actin cytoskeleton dynamics and important in the modulation of cellular processes such as migration and proliferation. Murine models have shown that Rnd3 is relevant for the correct development and function of the Central Nervous System and lack of its expression produces several motor alterations and neural development impairment. However, little is known about the molecular events through which Rnd3 produces these phenotypes. Interestingly we have observed that Rnd3 deficiency correlates with the appearance of autophagy impairment profiles and irregular mitochondria. In this work, we have explored the impact of Rnd3 loss of expression in mitochondrial function and autophagy, using a Rnd3 KO CRISPR cell model. Rnd3 deficient cells show no alterations in autophagy and mitochondria turnover is not impaired. However, Rnd3 KO cells have an altered mitochondria oxidative metabolism, resembling the effect caused by oxidative stress. In fact, lack of Rnd3 expression makes these cells strictly dependent on glycolysis to obtain energy. Altogether, our results demonstrate that Rnd3 is relevant to maintain mitochondria function, suggesting a possible relationship with neurodegenerative diseases., 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 © 2022 Cueto-Ureña, Mocholí, Escrivá-Fernández, González-Granero, Sánchez-Hernández, Solana-Orts, Ballester-Lurbe, Benabdellah, Guasch, García-Verdugo, Martín, Coffer, Pérez-Roger and Poch.)

Pompe disease (PD) is a rare disorder caused by mutations in the acid alpha-glucosidase (GAA) gene. Most gene therapies (GT) partially rely on the cross-correction of unmodified cells through the uptake of the GAA enzyme secreted by corrected cells. In the present study, we generated isogenic murine GAA-KO cell lines resembling severe mutations from Pompe patients. All of the generated GAA-KO cells lacked GAA activity and presented an increased autophagy and increased glycogen content by means of myotube differentiation as well as the downregulation of mannose 6-phosphate receptors (CI-MPRs), validating them as models for PD. Additionally, different chimeric murine GAA proteins (IFG, IFLG and 2G) were designed with the aim to improve their therapeutic activity. Phenotypic rescue analyses using lentiviral vectors point to IFG chimera as the best candidate in restoring GAA activity, normalising the autophagic marker p62 and surface levels of CI-MPRs. Interestingly, in vivo administration of liver-directed AAVs expressing the chimeras further confirmed the good behaviour of IFG, achieving cross-correction in heart tissue. In summary, we generated different isogenic murine muscle cell lines mimicking the severe PD phenotype, as well as validating their applicability as preclinical models in order to reduce animal experimentation.

(1) Background: New pulse modulation (PM) technologies in Holmium:YAG lasers are available for urinary stone treatment, but little is known about them. We aim to systematically evaluate the published evidence in terms of their lithotripsy performance. (2) Methods: A systematic electronic search was performed (MEDLINE, Scopus, and Cochrane databases). We included all relevant publications, including randomized controlled trials, non-randomized comparative and non-comparative studies, and in-vitro studies investigating Holmium:YAG lithotripsy performance employing any new PM. (3) Results: Initial search yielded 203 studies; 24 studies were included after selection: 15 in-vitro, 9 in-vivo. 10 In-vitro compared Moses with regular PM, 1 compared Quanta's, 1 Dornier MedTech's, 2 Moses with super Thulium Fiber Laser, and 1 compared Moses with Quanta PMs. Six out of seven comparative studies found a statistically significant difference in favor of new-generation PM technologies in terms of operative time and five out of six in fragmentation time; two studies evaluated retropulsion, both in favor of new-generation PM. There were no statistically significant differences regarding stone-free rate, lasing and operative time, and complications between Moses and regular PM when data were meta-analyzed. (4) Conclusions: Moses PM seems to have better lithotripsy performance than regular modes in in-vitro studies, but there are still some doubts about its in-vivo results. Little is known about the other PMs. Although some results favor Quanta PMs, further studies are needed.

Background: Health-related quality of life (HRQoL) allows knowing the subject’s feelings in distress and well-being, as well as perception of current and future health. Objective: To assess associations between health-related quality of life, fitness status, and adherence to the Mediterranean diet in Spanish children and adolescents. Methods: A cross-sectional study was carried out in a sample of 305 (47.2% women) children and adolescents aged between 8 and 16 years, in the primary and secondary schools of the province of Ávila (central Spain) (NCT05380674). Subjects were classified according to their quality of life: group 1 (highest quality of life) > group 2 (medium quality of life) > group 3 (lowest quality of life). Results: More participants in group 1 showed higher adherence to Mediterranean diet (70.8%) than other groups (group 2: 55.0%; group 3: 43.4%). It was less likely to find optimal levels of muscle strength as quality of life decreased (OR; 95% CI: group 2: 0.535; 0.303−0.955; and group 3: 0.424; 0.234−0.768). Similar trends were found for speed and agility, but only group 3 showed significant results (OR; 95% CI: group 3: 0.297; 0.162−0.545). Flexibility was also the worst in groups 2 and 3 (OR; 95% CI: G2: 0.403; 0.213−0.762; and group 3: 0.520; 0.282−0.958). Conclusion: High fitness status and adherence to the Mediterranean diet were associated with improved health-related quality of life in schoolchildren of central Spain.

Despite the remarkable similarity in amino acid composition, many anticancer peptides (ACPs) display significant differences in terms of activity. This strongly suggests that particular relative dispositions of amino acids (motifs) play a role in the interaction with their biological target, which is often the cell membrane. To better verify this hypothesis, we intentionally modify HB43, an ACP active against a wide variety of cancers. Sequence alignment of related ACPs by ADAPTABLE web server highlighted the conserved motifs that could be at the origin of the activity. In this study, we show that changing the order of amino acids in such motifs results in a significant loss of activity against colon and breast cancer cell lines. On the contrary, amino acid substitution in key motifs may reinforce or weaken the activity, even when the alteration does not perturb the amphipathicity of the helix formed by HB43 on liposomes mimicking their surface. NMR and MD simulations with different membrane models (micelles, bicelles, and vesicles) indicate that the activity reflects the insertion capability in cancer-mimicking serine-exposing membranes, supported by the insertion of N-terminal phenylalanine in the FAK motif and the anchoring to the carboxylate of phosphatidylserine by means of arginine side chains.

Glycolysis, including both lactate fermentation and pyruvate oxidation, orchestrates CD8 + T cell differentiation. However, how mitochondrial pyruvate metabolism and uptake controlled by the mitochondrial pyruvate carrier (MPC) impact T cell function and fate remains elusive. We found that genetic deletion of MPC drives CD8 + T cell differentiation toward a memory phenotype. Metabolic flexibility induced by MPC inhibition facilitated acetyl-coenzyme-A production by glutamine and fatty acid oxidation that results in enhanced histone acetylation and chromatin accessibility on pro-memory genes. However, in the tumor microenvironment, MPC is essential for sustaining lactate oxidation to support CD8 + T cell antitumor function. We further revealed that chimeric antigen receptor (CAR) T cell manufacturing with an MPC inhibitor imprinted a memory phenotype and demonstrated that infusing MPC inhibitor-conditioned CAR T cells resulted in superior and long-lasting antitumor activity. Altogether, we uncover that mitochondrial pyruvate uptake instructs metabolic flexibility for guiding T cell differentiation and antitumor responses., Competing Interests: Declaration of interests M.W. and P.R. are inventors on a patent application related to these findings and have research collaborations with MPC Therapeutics, with P.R. being a member of the advisory board. D.M. is an inventor on patents related to CAR T cell therapy, filed by the University of Pennsylvania and the University of Geneva, and is a consultant for Limula Therapeutics and MPC Therapeutics. P.-C.H. is scientific advisory for Elixiron Immunotherapeutics, Acepodia, and Novartis. P.-C.H. also receives research support from Elixiron Immunotherapeutics. S.Y.L. is a consultant to Senda Biosciences., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)