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Translational medicine has been a buzzword for over two decades. The concept was intended to be lofty, to reflect a new bench-to-bedside approach to basic and clinical research that would bridge fields, close gaps, accelerate innovation, and shorten the time and effort it takes to bring novel technologies from basic discovery to clinical application. Has this approach been successful and lived up to its promise? Despite incredible scientific advances and innovations developed within academia, successful clinical translation into real-world solutions has been difficult. This has been particularly challenging within the pulmonary field, because there have been fewer U.S. Food and Drug Administration-approved drugs and higher failure rates for pulmonary therapies than with other common disease areas. The American Thoracic Society convened a working group with the goal of identifying major challenges related to the commercialization of technologies within the pulmonary space and opportunities to enhance this process. A survey was developed and administered to 164 participants within the pulmonary arena. This report provides a summary of these survey results. Importantly, this report identifies a number of poorly recognized challenges that exist in pulmonary academic settings, which likely contribute to diminished efficiency of commercialization efforts, ultimately hindering the rate of successful clinical translation. Because many innovations are initially developed in academic settings, this is a global public health issue that impacts the entire American Thoracic Society community. This report also summarizes key resources and opportunities and provides recommendations to enhance successful commercialization of pulmonary technologies.

Abstract The treatment of non-small cell lung cancer (NSCLC) patients has significantly improved with recent therapeutic strategies; however, many patients still do not benefit from them. As a result, new treatment approaches are urgently needed. In this study, we evaluated the antitumor efficacy of co-targeting G9a and DNMT1 enzymes and its potential as a cancer drug sensitizer. We observed co-expression and overexpression of G9a and DNMT1 in NSCLC, which were associated with poor prognosis. Co-targeting G9a/DNMT1 with the drug CM-272 reduced proliferation and induced cell death in a panel of human and murine NSCLC cell lines. Additionally, the transcriptomes of these cells were reprogrammed to become highly responsive to chemotherapy (cisplatin), targeted therapy (trametinib), and epigenetic therapy (vorinostat). In vivo, CM-272 reduced tumor volume in human and murine cell-derived cancer models, and this effect was synergistically enhanced by cisplatin. The expression of SCARA5 and AOX1 was induced by CM-272, and both proteins were found to be essential for the antiproliferative response, as gene silencing decreased cytotoxicity. Furthermore, the expression of SCARA5 and AOX1 was positively correlated with each other and inversely correlated with G9a and DNMT1 expression in NSCLC patients. SCARA5 and AOX1 DNA promoters were hypermethylated in NSCLC, and SCARA5 methylation was identified as an epigenetic biomarker in tumors and liquid biopsies from NSCLC patients. Thus, we demonstrate that co-targeting G9a/DNMT1 is a promising strategy to enhance the efficacy of cancer drugs, and SCARA5 methylation could serve as a non-invasive biomarker to monitor tumor progression.

Abstract Rhizobia are alpha- and beta- Proteobacteria that, through the establishment of symbiotic interactions with leguminous plants, are able to fix atmospheric nitrogen as ammonium. The successful establishment of a symbiotic interaction is highly dependent on the availability of nitrogen sources in the soil, and on the specific rhizobia strain. Insertion sequences (ISs) are simple transposable genetic elements that can move to different locations within the host genome and are known to play an important evolutionary role, contributing to genome plasticity by acting as recombination hot-spots, and disrupting coding and regulatory sequences. Disruption of coding sequences may have occurred either in a common ancestor of the species or more recently. By means of ISComapare, we identified Differentially Located ISs (DLISs) in nearly related rhizobial strains of the genera Bradyrhizobium, Mesorhizobium, Rhizobium and Sinorhizobium. Our results revealed that recent IS transposition could have a role in adaptation by enabling the activation and inactivation of genes that could dynamically affect the competition and survival of rhizobia in the rhizosphere. Graphical Abstract

Objective/context: The objective pursued by this research is to analyse the possible existence of a social and political fracture around the figure of former President Rafael Correa and his political legacy, the Citizen Revolution, which would act as a kind of polarizing division of Ecuadorian society: correismo/anti-correismo axis. A division that, born of politics, would have been established within society, allowing the existence of two opposing sides that feel, perceive and act in politics in a very different way. Methodology: To this end, a study has been drawn up with a quantitative methodological approach based on an analysis of the data contained in the Study of Politics and Emotions in Ecuador, March 2021 (SPEE), carried out by the EIP-USC after the first round of the 2021 presidential elections. Conclusions: The results of this first approach (descriptive and multivariate) allow us to affirm the existence of important differences between supporters and detractors of correismo, especially as regards political and emotional issues, but not so regarding sociodemographic issues. Originality: The influence that the emotional factor expressed towards the different political leaders would have in the construction of this fracture is especially relevant; providing a novel vision to the literature on the influence of Rafael Correa and his project in the Ecuadorian political system

Introduction: Traumatic Brain Injury (TBI) is a significant public health concern that causes death, disability, and economic burden. Its repercussions affect physical, cognitive, emotional, and behavioral aspects of long-term care needs. Despite improvements in communication among multidisciplinary teams, the management of TBI remains fragmented. Objective: This study aimed to assess patients and caregivers’ experiences through sentiment analysis. Materials and methods: A qualitative cross-sectional study utilized structured topic modeling (STM) to analyze in-depth interview data. The study involved 29 patients with TBI and 27 caregivers in Madrid (Spain), using a survey design. The interviews were conducted, transcribed, and coded independently over 5 months. Sentiments such as anticipation, fear, and emotional concerns were analyzed using three dictionaries. The STM analysis identified four key concepts: desire for independence, potential improvement, need for injury information, and psychological consequences. STM diagnostic graphs were used to determine the number of topics relevant to the evaluation of patient and caregiver concerns. Furthermore, an analysis was conducted across four topics. Results: The average age of the patients was 44.2 ± 14.9 years (69 % males). Regarding TBI severity, 59 % of patients had severe TBI, whereas the remaining 41 % had experienced moderate TBI. Among the caregivers, the majority were parents (30 %), partners (24 %), or siblings (24 % each). Among the 51 participants, sentiments were analyzed using three dictionaries. While there were no significant age differences (Z = 0.24, p = 0.815), the STM model was adjusted for significant sex differences (p = 0.017) between patients and relatives. Anticipation and fear prevailed in both groups, highlighting the shared emotional patterns. Discussion: The analysis of diagnostic graphs indicated the optimal number of topics for evaluation, emphasizing key concerns across different phases of TBI. Patients' main worries shifted from physical symptoms to limitations in daily life and independence. Caregivers highlighted the importance of staff interactions, misinformation challenges, and the need for psychological care. Conclusion: Key patient concerns, including dependency on daily activities, limitations in autonomy, and caregiver burden, emphasize crucial areas for enhancement in multidisciplinary treatment. Moreover, the lack of long-term psychological support is a significant barrier to optimal patient and caregiver well-being.

ABSTRACT Objective: The aim of this study was to describe the epidemiological characteristics of pediatric patients with sickle cell disease (SCD) and evaluate the use of medicinal plants in these patients concomitantly with their drug treatment. Methods: This is a review of the medical records of pediatric patients at a public institution with tertiary care. The selection criterion was to be a child or adolescent with SCD undergoing pediatric follow-up at this outpatient clinic. In the medical records of the patients selected, records of the use of plants for medicinal purposes were sought. Results: In total, 154 records (100% of total active patients followed in this clinic) were reviewed: 99 children and 55 adolescents. The predominant genotype was SS (58.4%), followed by SC (29.2%). The use of at least one medication for SCD was reported in 95.5% of the medical records. The use of medicinal plants was reported by 70.1% of patients, with 276 citations in the medical records referring to 64 different types of plants. Six plants were used for the treatment of SCD, the main one being Lemonvine/Ora-pro-nóbis (Pereskia aculeata). The use of medicinal plants was reported for flu-like symptoms and/or COVID-19 (both for prevention and treatment) by 60.5% of the citations, with 35 different plants reported for this use, exclusively or not. This use was followed by pain symptoms (14.2% of citations). Conclusions: The majority of patients in this study use both conventional and traditional/complementary/alternative medicine, highlighting the need for more studies in the area, with a special focus on patient safety.

Summary: Background: The inflammatory response in patients with traumatic brain injury (TBI) offers opportunities for stratification and intervention. Previous unselected approaches to immunomodulation in patients with TBI have not improved patient outcomes. Methods: Serum and plasma samples from two prospective, multi-centre observational studies of patients with TBI were used to discover (Collaborative European NeuroTrauma Effectiveness Research [CENTER-TBI], Europe) and validate (Transforming Research and Clinical Knowledge in Traumatic Brain Injury [TRACK-TBI] Pilot, USA) individual variations in the immune response using a multiplex panel of 30 inflammatory mediators. Mediators that were associated with unfavourable outcomes (Glasgow outcome score-extended [GOS-E] ≤ 4) were used for hierarchical clustering to identify patients with similar signatures. Findings: Two clusters were identified in both the discovery and validation cohorts, termed early-inflammatory and pauci-inflammatory. The early-inflammatory phenotype had higher concentrations of interleukin-6 (IL-6), IL-15, and monocyte chemoattractant protein 1 (MCP1). Patients with the early-inflammatory phenotype were older and more likely to have an unfavourable GOS-E at 6 months. There were no differences in the baseline injury severity scores between patients in each phenotype. A combined IL-15 and MCP1 signature identified patients with the early-inflammatory phenotype in both cohorts. Inflammatory processes mediated outcomes in older patients with moderate-severe TBI. Interpretation: Our findings offer a precision medicine approach for future clinical trials of immunomodulation in patients with TBI, by using inflammatory signatures to stratify patients. Funding: CENTER-TBI study was supported by the European Union 7th Framework Programme. TRACK-TBI is supported by the National Institute of Neurological Disorders and Stroke.

We introduce Aquila-LCS, GPU and CPU optimized object-oriented, in-house codes for volumetric particle advection and 3D Finite-Time Lyapunov Exponent (FTLE) and Finite-Size Lyapunov Exponent (FSLE) computations. The purpose is to analyze 3D Lagrangian Coherent Structures (LCS) in large Direct Numerical Simulation (DNS) data. Our technique uses advanced search strategies for quick cell identification and efficient storage techniques. This solver scales effectively on both GPUs (up to 62 NVIDIA V100 GPUs) and multi-core CPUs (up to 32,768 CPU-cores), tracking up to 8-billion particles. We apply our approach to turbulent boundary layers at different flow regimes and Reynolds numbers.

Summary: Background: Traumatic brain injury is conventionally categorised as mild, moderate, or severe on the Glasgow Coma Scale (GCS). Recently developed biomarkers can provide more objective and nuanced measures of the extent of brain injury. Methods: Exposure–response relationships were investigated in 2479 patients aged ≥16 enrolled in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) prospective observational cohort study. Neurofilament protein-light (NFL), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and glial fibrillary acidic protein (GFAP) were assayed from serum sampled in the first 24 h; concentrations were divided into quintiles within GCS severity groups. Relationships with the Glasgow Outcome Scale-Extended were examined using modified Poisson regression including age, sex, major extracranial injury, time to sample, and log biomarker concentration as covariates. Findings: Within severity groups there were associations between biomarkers and outcomes after adjustment for covariates: GCS 13–15 and negative CT imaging (relative risks [RRs] from 1.28 to 3.72), GCS 13–15 and positive CT (1.21–2.81), GCS 9–12 (1.16–2.02), GCS 3–8 (1.09–1.94). RRs were associated with clinically important differences in expectations of prognosis. In patients with GCS 3 (RRs 1.51–1.80) percentages of unfavourable outcome were 37–51% in the lowest quintiles of biomarker levels and reached 90–94% in the highest quintiles. Similarly, for GCS 15 (RRs 1.83–3.79), the percentages were 2–4% and 19–28% in the lowest and highest biomarker quintiles, respectively. Interpretation: Conventional TBI severity classification is inadequate and underestimates heterogeneity of brain injury and associated outcomes. The adoption of circulating biomarkers can add to clinical assessment of injury severity. Funding: European Union 7th Framework program (EC grant 602150), Hannelore Kohl Stiftung, One Mind, Integra LifeSciences, Neuro-Trauma Sciences, NIHR Rosetrees Trust.

Abstract In the three-dimensional $$\mathcal{N}$$ = 6 Chern-Simons matter (ABJM) theory, the integrand for the logarithm of the scattering amplitude admits a decomposition in terms of negative geometries, which implies that all the infrared divergences concentrate in the last loop integration. We compute the infrared-finite functions that arise from performing a three-loop integration over the four-loop integrand for the logarithm of the four-point amplitude, for which we use the method of differential equations. Our results provide a direct computation of the four-loop cusp anomalous dimension of the theory, in agreement with the current all-loop integrability-based proposal. We find an apparent simplicity in the leading singularities of the integrated results, provided one works in the frame in which the unintegrated loop variable goes to infinity. Finally, our results suggest an alternating sign pattern for the integrated negative geometries in the Euclidean region.

Abstract Glioblastoma (GB) is a devastating tumor of the central nervous system characterized by a poor prognosis. One of the best-established predictive biomarker in IDH-wildtype GB is O6-methylguanine-DNA methyltransferase (MGMT) methylation (mMGMT), which is associated with improved treatment response and survival. However, current efforts to monitor GB patients through mMGMT detection have proven unsuccessful. Small extracellular vesicles (sEVs) hold potential as a key element that could revolutionize clinical practice by offering new possibilities for liquid biopsy. This study aimed to determine the utility of sEV-based liquid biopsy as a predictive biomarker and disease monitoring tool in patients with IDH-wildtype GB. Our findings show consistent results with tissue-based analysis, achieving a remarkable sensitivity of 85.7% for detecting mMGMT in liquid biopsy, the highest reported to date. Moreover, we suggested that liquid biopsy assessment of sEV-DNA could be a powerful tool for monitoring disease progression in IDH-wildtype GB patients. This study highlights the critical significance of overcoming molecular underdetection, which can lead to missed treatment opportunities and misdiagnoses, possibly resulting in ineffective therapies. The outcomes of our research significantly contribute to the field of sEV-DNA-based liquid biopsy, providing valuable insights into tumor tissue heterogeneity and establishing it as a promising tool for detecting GB biomarkers. These results have substantial implications for advancing predictive and therapeutic approaches in the context of GB and warrant further exploration and validation in clinical settings.

Bisphenol A alternatives are manufactured as potentially less harmful substitutes of bisphenol A (BPA) that offer similar functionality. These alternatives are already in the market, entering the environment and thus raising ecological concerns. However, it can be expected that levels of BPA alternatives will dominate in the future, they are limited information on their environmental safety. The EU PARC project highlights BPA alternatives as priority chemicals and consolidates information on BPA alternatives, with a focus on environmental relevance and on the identification of the research gaps. The review highlighted aspects and future perspectives. In brief, an extension of environmental monitoring is crucial, extending it to cover BPA alternatives to track their levels and facilitate the timely implementation of mitigation measures. The biological activity has been studied for BPA alternatives, but in a non-systematic way and prioritized a limited number of chemicals. For several BPA alternatives, the data has already provided substantial evidence regarding their potential harm to the environment. We stress the importance of conducting more comprehensive assessments that go beyond the traditional reproductive studies and focus on overlooked relevant endpoints. Future research should also consider mixture effects, realistic environmental concentrations, and the long-term consequences on biota and ecosystems.

Abstract Background The early management of polytrauma patients with traumatic spinal cord injury (tSCI) is a major challenge. Sparse data is available to provide optimal care in this scenario and worldwide variability in clinical practice has been documented in recent studies. Methods A multidisciplinary consensus panel of physicians selected for their established clinical and scientific expertise in the acute management of tSCI polytrauma patients with different specializations was established. The World Society of Emergency Surgery (WSES) and the European Association of Neurosurgical Societies (EANS) endorsed the consensus, and a modified Delphi approach was adopted. Results A total of 17 statements were proposed and discussed. A consensus was reached generating 17 recommendations (16 strong and 1 weak). Conclusions This consensus provides practical recommendations to support a clinician’s decision making in the management of tSCI polytrauma patients.

En comparar les dinàmiques normatives del portuguès i l’espanyol, s’observa que existeixen diferències significatives en el desenvolupament històric dels seus espais lingüístics i dels seus models de gestió de la norma estàndard. Les empreses de comunicació fan servir el concepte d’espanyol neutre com a estratègia per ampliar mercats, i institucions internacionals com ara l’Associació d’Acadèmies de la Llengua Espanyola (ASALE) elaboren instruments la finalitat dels quals és descriure un espanyol total. No obstant, les condicions històriques que van impulsar la creació, a Portugal i el Brasil, de dos grans centres normatius del portuguès fan que concebre un “portuguès neutre” sembli una tasca impossible. En el cas del portuguès, a l’absència d’una política de gestió lingüística ampliada per part de Portugal se suma un mercat lingüístic internacional precari, amb una circulació desigual de béns culturals entre els principals centres normatius. Si es comparen les dues dinàmiques, és possible comprendre les condicions materials que justifiquen, en el cas de l’espanyol, una ideologia d’unió lingüística i, en el del portuguès, una ideologia de divisió de la llengua.

Innovative tools suitable for chemical risk assessment are being developed in numerous domains, such as non-target chemical analysis, omics, and computational approaches. These methods will also be critical components in an efficient early warning system (EWS) for the identification of potentially hazardous chemicals. Much knowledge is missing for current use chemicals and thus computational methodologies complemented with fast screening techniques will be critical. This paper reviews current computational tools, emphasizing those that are accessible and suitable for the screening of new and emerging risk chemicals (NERCs). The initial step in a computational EWS is an automatic and systematic search for NERCs in literature and database sources including grey literature, patents, experimental data, and various inventories. This step aims at reaching curated molecular structure data along with existing exposure and hazard data. Next, a parallel assessment of exposure and effects will be performed, which will input information into the weighting of an overall hazard score and, finally, the identification of a potential NERC. Several challenges are identified and discussed, such as the integration and scoring of several types of hazard data, ranging from chemical fate and distribution to subtle impacts in specific species and tissues. To conclude, there are many computational systems, and these can be used as a basis for an integrated computational EWS workflow that identifies NERCs automatically.

A gummy smile, defined as excessive gingival exposure while smiling, is an esthetic and functional condition affecting an individual’s quality of life. Despite its prevalence and impact, the classification and treatment of the gummy smile remain challenging in clinical practice. The problem lies in (1) the fact that the etiology of this pathology is multifactorial, and these factors sometimes go unnoticed, (2) the lack of consensus on the classification criteria, which, together, create (3) challenges in designing an optimal treatment plan for each patient. This article reviews the etiologic factors of this condition as the main basis for understanding the existing classifications of the gummy smile. It highlights the importance of muscle dynamics in the genesis and treatment of this clinical condition. We present a new, treatment-oriented classification that integrates the muscle hyperactivity present within the classification criteria and explore the implication of this interaction in the design of effective treatments. The ultimate goal of this present work is to improve the clinical understanding of the gingival smile and offer more personalized treatment strategies, through a more complete classification.

A gummy smile is the visualization of more than 3 mm of gingiva above the maxillary incisors. This study aimed to evaluate the long-term effects on aesthetics and patient satisfaction of a new hyaluronic acid infiltration technique in reducing the gummy smile. Fifty patients with gummy smiles were treated using hyaluronic acid infiltration points by applying 0.1 mL per injection at specific points. Post-treatment evaluations were performed one week, one month, three months, six months, and 12 months later. A questionnaire assessed patient satisfaction, willingness to recommend the treatment, and side effects (pain and bruising during and after treatment). An average reduction of 2.5 mm in gingival exposure during smiling was observed. After one week, the reduction was constant. At six months, 40% of the original gingival exposure was recovered, and recovery was complete at 12 months. Patient satisfaction was 82.1%, and 100% of patients would recommend the treatment. Bruising, swelling, and pain decreased to 0% from the first month. In conclusion, this technique is a safe and effective option to improve the smile’s appearance with minimal complications.

Background: Numerous studies in the literature have aimed to evaluate the difficulty level of removing third molars. However, most of these studies have focused on the lower third molars, which can lead to complications. There is a lack of a method to determine the complexity of upper third molar extraction. Therefore, this study’s objective was to develop an equation using multiple linear regression to estimate the extraction time of an upper third molar based on its complexity. Methods: This study involved patients enrolled in the Master of Oral Surgery program at the University of Seville. To determine their relationship with surgical time, the researchers analyzed various factors, such as depth, root morphology, and the need for odontosection. They then validated their findings by studying patients treated at Palmaplanas Hospital in Mallorca. Results: The cohort analysis from the University of Seville revealed significant associations between surgical time and the identified factors. A regression equation design was performed to predict the total duration of surgical intervention for wisdom teeth extraction. This equation incorporates several independent variables, represented by Xi, together with a constant term, C, and the corresponding coefficients, Bi, which weight the impact of each variable on the intervention time. The results are as follows: −0.312 (spatial relationship), 0.651 (depth), −0.443 (bone and mucosa integrity), 0.214 (roots), −0.745 (ostectomy), 0.713 (odontosection), and −0.426 (suture). Upon application of the statistical methodology to the Palmaplanas Hospital cohort, a regression coefficient of 0.770 was determined. This indicates a strong correlation between the input data and the estimated surgical time. Conclusions: In conclusion, the proposed formula demonstrates notable validity in predicting the surgical time required to extract upper third molars.

This article explores the determinants of the transition from higher education to work, analysing the time it takes college graduates to obtain their first job in Spain. To estimate the exit rate to employment of university graduates, we use parametric and nonparametric analysis of duration models. We have incorporated unobserved heterogeneity using frailty models to account for misspecification or omitted covariates. The results show that after graduation, men are more likely to obtain employment than women. Our results also show that graduates of private universities gain their first jobs sooner than graduates of public universities. Furthermore, we found that those graduates who have previous work experience and those who start looking for a job before the end of their degree programme are likely to obtain a job sooner. In addition, Arts and Humanities graduates have the greatest difficulty in finding work. Finally, the results suggest that graduates who have international experience and those with expert knowledge of communication are more likely to obtain employment.