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Eduardo Tuta-Quintero,1 Alirio R Bastidas,1 Kamil Faizal-Gómez,1 Sergio Guillermo Torres-Riveros,2 Diego Alejandro Rodríguez-Barajas,2 Jonathan Alexander Guezguan,1 Laura D Muñoz,1 Ana Carolina Rojas,1 Katherine Hernández Calderón,1 Natalia Valentina Ardila Velasco,1 Paula Prieto,1 Juliana Cuestas,1 Julian Camacho-Osorio,1 Gabriela Bonilla,1 Estefania Collazos Bahamon,1 María Alejandra Guardiola,1 David Luna Salazar,1 Lina Paola Fajardo,1 Johan Rincón-Hernández1 1Facultad de Medicina, Universidad de La Sabana, Chía, Colombia; 2Residente de Medicina Interna, Facultad de Medicina, Universidad de La Sabana, Chía, ColombiaCorrespondence: Alirio R Bastidas, School of Medicine, Universidad de La Sabana, Km 7, Autonorte de Bogota, Chía, Cundinamarca, 250001, Colombia, Email alirio.bastidas@unisabana.edu.coBackground: Survival in patients with sleep apnoea (SA) can be reduced by variables such as age, sex, and comorbidities. However, survival data in patients with SA in Colombia remains scarce.Methods: This is a retrospective cohort study of patients diagnosed with SA between 2005 and 2022. Five-year survival was assessed using the Kaplan-Meier method, and survival curves were stratified by age, sex, and cardiovascular disease. Risk factors associated with survival were evaluated using Hazard Ratio (HR) by adjusting for confounding variables with a Cox regression model. A minimum sample size of 1537 patients were estimated to be necessary to estimate a survival incidence rate with a 5% precision.Results: The five-year survival rate in the general population was 94.6%, with lower survival in patients over 65 years (88.5% vs 97.9%; p < 0.001) and in patients with cardiovascular disease (89% vs 95.2%; p < 0.001) compared to the control group. In the Cox regression, age showed an HR of 1.05 (95% CI: 1.02– 1.07; p < 0.001). Male sex had an HR of 2.31 (95% CI: 1.25– 4.25; p = 0.007), congestive heart failure an HR of 4.00 (95% CI: 2.31– 6.94; p < 0.001), chronic obstructive pulmonary disease (COPD) an HR of 1.75 (95% CI: 1.04– 2.96; p = 0.035), chronic kidney disease (CKD) an HR of 2.23 (95% CI: 1.31– 3.78; p = 0.003), and metastatic cancer an HR of 4.96 (95% CI: 1.95– 12.60; p = 0.001).Conclusion: The study showed a high five-year survival rate in patients with SA. The risk factors associated with decreased overall five-year survival were age, male sex, cardiovascular disease, COPD, CKD, and metastatic cancer.Keywords: sleep apnoea, survival, risk factors

Purpose: This study aims to assess the effectiveness of active teaching methodologies, namely, problem-oriented learning and the case method, to develop sustainability competencies. It also analyses the advantages and challenges for teachers when implementing the sustainable development goals (SDGs) in eight undergraduate and postgraduate degrees within the framework of a cross-departmental collaboration. Design/methodology/approach: A mixed research methodology was used: a quantitative study to assess the levels of acquisition of sustainability and research competencies and the potential correlation between them, as well as a mixed study of the advantages and challenges for the teachers participating in the cross-departmental initiative. Curriculum content linked to the SDGs was worked on. Active teaching methodologies and a competency assessment rubric were used as curriculum implementation strategies in the eight courses involved. Findings: Active teaching methodologies are suitable to implement the SDGs in university teaching and to develop both sustainability and research competencies. A synergic effect is observed between them. Coordinated work between teachers of different subjects in several degrees contributes to developing a culture of sustainability at the university. Research limitations/implications: Although the collaboration between teachers from different disciplines was successful, this study did not promote interdisciplinary projects among students from different degrees. This promises to be highly valuable for future research. Practical implications Students can become present and future leaders in achieving the SDGs. This approach can be replicated in other educational institutions. Social implications: This study bridges the gap between theoretical recommendations and the practical implementation of the SDGs in undergraduate and postgraduate degrees. Originality/value: Coordinated work between teachers of different subjects in different degrees contributes to the development of a culture of sustainability at the university.

Abstract Background Carboplatin and paclitaxel (CP) have been the standard of care for advanced/recurrent endometrial cancer (EC) for many years. However, this chemotherapy combination shows limited efficacy and recurrences often occur in less than 12 months. ABTL0812 is a novel drug that selectively kill cancer cells by cytotoxic autophagy and has shown anticancer efficacy in preclinical models of EC in combination with CP. Methods ENDOLUNG was an open-label, phase 1/2 clinical trial designed to determine the safety and efficacy of Ibrilatazar (ABTL0812) with CP in patients with advanced/recurrent EC and non-irradiable stage III and IV squamous non-small cell lung cancer (sq-NSCLC). The phase 1 part consisted of a 3 + 3 de-escalation design followed by an expansion cohort with 12 patients. The primary endpoint was safety. ABTL0812 starting dose was 1300 mg tid combined with carboplatin at area under the curve (AUC) 5 and paclitaxel at 175 mg/m2 both administered every 21 days for up to 8 cycles. The phase 2 part included a total of 51 patients. The primary endpoint was overall response rate (ORR) and the secondary endpoints included duration of response (DOR), progression-free survival (PFS) and overall survival (OS). Results During the phase 1 only one dose limiting toxicity (DLT), a grade 4 neutropenia, was observed in 1 out of 6 patients, thus no de-escalation was applied. One additional DLT, a grade 3 febrile neutropenia, was observed in the expansion cohort, thus the recommended phase 2 dose (RP2D) for ABTL0812 was established at 1300 mg tid. Most frequent hematological adverse events (AE) of the combination were neutropenia (52.9%), anemia (37.3%) and thrombocytopenia (19.6%). Nausea (66.7%), asthenia (66.7%), diarrhea (54.9%) and vomiting (54.9%) were the most frequent non-hematological adverse events (AEs). The combination of ABTL0812 plus CP showed an ORR of 65.8% (13.2% complete response and 52.6% partial response) with a median DOR of 7.4 months (95% CI: 6.3–10.8 months). Median PFS was 9.8 months (95% CI: 6.6–10.6) and median OS 23.6 months (95% CI 6.4-ND). Pharmacokinetic parameters were compatible with target engagement observed in preclinical studies, and blood pharmacodynamic biomarkers indicated sustained target regulation during, at least, 28 days after starting the treatment. Conclusions This study suggests that the combination of ABTL0812 with CP is safe and feasible with an encouraging activity in patients with advanced/recurrent EC. Our data warrant further confirmation in prospective randomized trials. Trial registration EU Clinical Trial Register, EudraCT number 2016-001352-21 and National Clinical Trials Number, NCT03366480. Registration on 19 September 2016.

Abstract Background Classical mutagenesis is a powerful tool that has allowed researchers to elucidate the molecular and genetic basis of a plethora of processes in many model species. The integration of these methods with modern massively parallel sequencing techniques, initially in model species but currently also in many crop species, is accelerating the identification of genes underlying a wide range of traits of agronomic interest. Results We have developed MAPtools, an open-source Python3 application designed specifically for the analysis of genomic data from bulked segregant analysis experiments, including mapping-by-sequencing (MBS) and quantitative trait locus sequencing (QTL-seq) experiments. We have extensively tested MAPtools using datasets published in recent literature. Conclusions MAPtools gives users the flexibility to customize their bioinformatics pipeline with various commands for calculating allele count-based statistics, generating plots to pinpoint candidate regions, and annotating the effects of SNP and indel mutations. While extensively tested with plants, the program is versatile and applicable to any species for which a mapping population can be generated and a sequenced genome is available. Availability and implementation MAPtools is available under GPL v3.0 license and documented as a Python3 package at https://github.com/hcandela/MAPtools .

Abstract The present study aims to develop and characterize a controlled-release delivery system for protein therapeutics in skeletal muscle regeneration following an acute injury. The therapeutic protein, a membrane-GPI anchored protein called Cripto, was immobilized in an injectable hydrogel delivery vehicle for local administration and sustained release. The hydrogel was made of poly(ethylene glycol)-fibrinogen (PEG-Fibrinogen, PF), in the form of injectable microspheres. The PF microspheres exhibited a spherical morphology with an average diameter of approximately 100 micrometers, and the Cripto protein was uniformly entrapped within them. The release rate of Cripto from the PF microspheres was controlled by tuning the crosslinking density of the hydrogel, which was varied by changing the concentration of poly(ethylene glycol) diacrylate (PEG-DA) crosslinker. In vitro experiments confirmed a sustained-release profile of Cripto from the PF microspheres for up to 27 days. The released Cripto was biologically active and promoted the in vitro proliferation of mouse myoblasts. The therapeutic effect of PF-mediated delivery of Cripto in vivo was tested in a cardiotoxin (CTX)-induced muscle injury model in mice. The Cripto caused an increase in the in vivo expression of the myogenic markers Pax7, the differentiation makers eMHC and Desmin, higher numbers of centro-nucleated myofibers and greater areas of regenerated muscle tissue. Collectively, these results establish the PF microspheres as a potential delivery system for the localized, sustained release of therapeutic proteins toward the accelerated repair of damaged muscle tissue following acute injuries.

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is the most lethal cancer with an aggressive metastatic phenotype and very poor clinical prognosis. Interestingly, a lower occurrence of PDAC has been described in individuals with severe and long-standing asthma. Here we explored the potential link between PDAC and the glucocorticoid (GC) budesonide, a first-line therapy to treat asthma. Methods We tested the effect of budesonide and the classical GCs on the morphology, proliferation, migration and invasiveness of patient-derived PDAC cells and pancreatic cancer cell lines, using 2D and 3D cultures in vitro. Furthermore, a xenograft model was used to investigate the effect of budesonide on PDAC tumor growth in vivo. Finally, we combined genome-wide transcriptome analysis with genetic and pharmacological approaches to explore the mechanisms underlying budesonide activities in the different environmental conditions. Results We found that in 2D culture settings, high micromolar concentrations of budesonide reduced the mesenchymal invasive/migrating features of PDAC cells, without affecting proliferation or survival. This activity was specific and independent of the Glucocorticoid Receptor (GR). Conversely, in a more physiological 3D environment, low nanomolar concentrations of budesonide strongly reduced PDAC cell proliferation in a GR-dependent manner. Accordingly, we found that budesonide reduced PDAC tumor growth in vivo. Mechanistically, we demonstrated that the 3D environment drives the cells towards a general metabolic reprogramming involving protein, lipid, and energy metabolism (e.g., increased glycolysis dependency). This metabolic change sensitizes PDAC cells to the anti-proliferative effect of budesonide, which instead induces opposite changes (e.g., increased mitochondrial oxidative phosphorylation). Finally, we provide evidence that budesonide inhibits PDAC growth, at least in part, through the tumor suppressor CDKN1C/p57Kip2. Conclusions Collectively, our study reveals that the microenvironment influences the susceptibility of PDAC cells to GCs and provides unprecedented evidence for the anti-proliferative activity of budesonide on PDAC cells in 3D conditions, in vitro and in vivo. Our findings may explain, at least in part, the reason for the lower occurrence of pancreatic cancer in asthmatic patients and suggest a potential suitability of budesonide for clinical trials as a therapeutic approach to fight pancreatic cancer.

The pig sector has shown sustained growth in the last thirteen years in Latin America, which is why it is of special importance for these economies. This article explores trends in research on internationalization and production chains in the pig sector. For this purpose, a network analysis of keyword co-occurrences was developed, which allowed visualizing the state of development of research in the field. Four clusters or thematic groups were identified that summarize the areas addressed in the research on internationalization and production chains in the pig sector: pig industry market, supply chain management and animal welfare, sustainable development in the pig industry and human welfare in the pig industry.

Summary: Here, we present a protocol for investigating the non-genetic heterogeneity of membrane proteins expression within murine muscle stem cell (MuSC) population isolated from injured skeletal muscles. We describe a protocol that employs flow cytometry technology to detect variations in membrane CRIPTO protein levels and ensure measurements standardization. We detail steps for muscle digestion, bulk muscle cell staining, and phenotypic analysis. This approach allows for the identification of MuSC fractions with distinct phenotypic and functional properties.For complete details on the use and execution of this protocol, please refer to Guardiola et al.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

IntroductionResearch data show the impact of the endocannabinoid system on psychosis through its neurotransmission homeostatic functions. However, the effect of the endocannabinoid system genetic variability on the relationship between cannabis use and psychosis has been unexplored, even less in first-episode patients. Here, through a case-only design, we investigated the effect of cannabis use and the genetic variability of endocannabinoid receptors on clinical and cognitive outcomes in first-episode psychosis (FEP) patients.MethodsThe sample comprised 50 FEP patients of European ancestry (mean age (sd) = 26.14 (6.55) years, 76% males), classified as cannabis users (58%) or cannabis non-users. Two Single Nucleotide Polymorphisms (SNP) were genotyped at the cannabinoid receptor type 1 gene (CNR1 rs1049353) and cannabinoid receptor type 2 gene (CNR2 rs2501431). Clinical (PANSS, GAF) and neuropsychological (WAIS, WMS, BADS) assessments were conducted. By means of linear regression models, we tested the main effect of cannabis use and its interaction with the polymorphic variants on the clinical and cognitive outcomes.ResultsFirst, as regards cannabis effects, our data showed a trend towards more severe positive symptoms (PANSS, p = 0.05) and better performance in manipulative abilities (matrix test-WAIS, p = 0.041) among cannabis users compared to non-users. Second, concerning the genotypic effects, the T allele carriers of the CNR1 rs1049353 presented higher PANSS disorganization scores than CC homozygotes (p = 0.014). Third, we detected that the observed association between cannabis and manipulative abilities is modified by the CNR2 polymorphism (p = 0.022): cannabis users carrying the G allele displayed better manipulative abilities than AA genotype carriers, while the cannabis non-users presented the opposite genotype-performance pattern. Such gene–environment interaction significantly improved the overall fit of the cannabis-only model (Δ-R2 = 8.4%, p = 0.019).DiscussionDespite the preliminary nature of the sample, our findings point towards the role of genetic variants at CNR1 and CNR2 genes in the severity of the disorganized symptoms of first-episode psychosis and modulating cognitive performance conditional to cannabis use. This highlights the need for further characterization of the combined role of endocannabinoid system genetic variability and cannabis use in the understanding of the pathophysiology of psychosis.

Methods Four-step process: (1) creation of a governance model, a web platform and reporting forms for a PSRLS in Catalonia (SNiSP Cat); (2) SNiSP Cat roll out; (3) embed SNiSP Cat information in the accreditation model for HCO and the PS scorecard; (4) Development of SNiSP Cat within the QPSS Plan Cat 2023–2027.Results The SNiSP Cat is in use by 63/64 acute care hospital (ACH), 376/376 primary healthcare teams (PCT) and 17/98 long-term care facilities (LTCF). 1335/109 273 professionals were trained. Until 2022, 127 051 incidents have been migrated and reported (2013–2022). The system has generated three comprehensive risk maps for HCO: one for ACH, including patients’ falls, medication, clinical process and procedures; second for PCT, including clinical process and procedures, clinical administration and medication; and a third for LTCF, included patients’ falls, medication, digital/analogical documentation. SNiSP Cat provided information to support 53 standards out of 1312 of the ACH accreditation model and 14 standards out of 379 of PCT one. Regarding the MHC patient safety scorecard, 14 indicators out of 147 of ACH and 4 out of 41 of PCT are supported by SNiSP Cat data.Conclusions The availability of a territorial PSRLS (SNiSP Cat) allows MHC leads the Q&PS policy with direct information, risk maps and data support to the standards for the Catalan accreditation models and PS scorecard linked to incentivisation, turning the SNiSP Cat into a driven tool to implement the Quality and Patient Safety Strategic Plan of Catalonia 2023–2027.

An abdominal aortic aneurysm (AAA) in children is a rare clinical condition, with idiopathic AAAs even more atypical. We report a case of a 19-month-old girl with incidental findings of an infrarenal AAA and right common iliac artery aneurysm during workup for heart failure. Extensive genetic testing was unremarkable for connective tissue disorders. An aortic bi-iliac artery bypass with a Dacron graft from the infrarenal aorta to the right external iliac artery and left common iliac artery was performed. The patient achieved complete recovery and only required one oral hypertensive medication at 30 days of follow-up. Wide patency of the graft was observed on the 3-month follow-up computed tomography angiogram.