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Outdoor education fosters student well-being, development and learning. However, many schools restrict outdoor experience to their own playground, and to times considered recess. This case study, which examined student and teacher perceptions about the outdoor experience on traditional playgrounds, was conducted in an urban school in the Basque Country with an asphalt playground whose only resources were related to sports. We conducted five focal studies with 40 students, and administered a questionnaire to 78 teachers in Primary and Secondary Education. The results obtained made clear the dissatisfaction of both students and teachers with the use of the playground and with the opportunities it offered. However, they also identified areas for improvement and suggested future lines of work. It is essential to promote a dynamic of reflection on outdoor spaces that includes student participation as well as training teachers and raising their awareness.

The aim of this exploratory sequential mixed methods study was to examine the beliefs of Early Childhood Education teachers regarding the enculturation process of children. Eleven 2-year-old classroom teachers (M[subscript age]= 40.64; DT = 7.43; 81.81% female) participated in the qualitative phase, and 256 teachers (M[subscript age] = 42.25; DT = 9.78; 90.3% female) participated in the quantitative one. Based on interviews, four main themes were identified: Routines and habits, Values, Models of behavior, and Knowledge. Based on the qualitative results, an instrument was created to measure the teachers' beliefs regarding enculturation in Early Childhood Education and Care. High convergence was obtained between the qualitative and quantitative results, supporting the idea that teachers are active agents of enculturation and social role models for children. We conclude that enculturation should be a curricular objective and that it deserves a greater presence in professional development programs for Early Childhood Education teachers.

Collaborative governance is a broad concept that includes many forms of collaborative arrangements among various actors that differ in their nature, objectives, and types of interactions. This article empirically illustrates how, despite being understudied in the literature on collaborative governance, the “place” dimension (used here to refer to territory as a collective subject) can serve as a backbone that provides a distinctive logic and dynamic, bringing about a specific collaborative governance model — one that is especially relevant in the context of collaborative initiatives by regional governments. We describe a series of necessary features for place-based dynamics to emerge. The article seeks to share a conceptual framework that distinguishes between government-centred and place-based approaches to collaborative governance which can be used as a reflective tool for facilitators of collaborative governance. The framework relies on two empirical cases employed to illustrate its application.

Xabier Aizpurua-Arruti,1,2 Shalom Charlie I Benrimoj,3 Estibaliz Goyenechea,1 Arantxa Isla,2,4 Ainhoa Oñatibia-Astibia,1 Amaia Malet-Larrea,1 Miguel Ángel Gastelurrutia,1,3 Olatz Cuevas,1 Julen Rodríguez-Castejón,2,4 Saioa Domingo-Echaburu,5 María Ángeles Solinís,2,4 Montserrat García,6 Ana del Pozo-Rodríguez2,4 1Official Pharmacist Association of Gipuzkoa, Donostia / San Sebastián, Spain; 2Pharmacy Practice Research Group, PharmaNanoGene Group, Faculty of Pharmacy, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain; 3Pharmaceutical Care Research Group, Faculty of Pharmacy, University of Granada, Granada, Spain; 4Bioaraba, Microbiology, Infectious Disease, Antimicrobial Agents, and Gene Therapy, Vitoria-Gasteiz, Spain; 5Osakidetza Basque Health Service, Debagoiena Integrated Health Organisation, Pharmacy Service, Arrasate, Spain; 6Basque Country Pharmacovigilance Unit, Osakidetza Basque Health Service, Galdakao-Usansolo Hospital, Galdakao, SpainCorrespondence: Ana del Pozo-Rodríguez, Pharmacy Practice Research Group, PharmaNanoGene Group, Faculty of Pharmacy, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain, Email ana.delpozo@ehu.eusPurpose: Additional monitoring (AM) medicines include (i) medicines containing a new active substance; (ii) biological medicines; (iii) medicines with conditional approval or authorized in special situations; (iv) medicines which require further studies; (v) medicines that have specific requirements regarding the reporting of suspected adverse drug reactions (ADRs). When AM medicines are marketed, their most common ADRs are known, but safety information is limited because relatively rare ADRs are often not detected in clinical trials. Their AM status warrants real-world studies to identify other safety issues; however, such studies are lacking. Correct use and adherence to dosage regimen by patients are key factors for the evaluation of the safety and efficacy of medicines. The objective of this work was assessing the impact on safety, adherence, use and knowledge (U&K) about medicines and patient’s quality of life (QOL), of community pharmacist (CP)-led interventions in a new service focused on AM medicines targeted at three prevalent chronic diseases: diabetes mellitus type 2, chronic obstructive pulmonary disease and cardiovascular disease.Patients and Methods: A prospective interventional cohort study was conducted with a 6-month follow-up in 27 community pharmacies (145 patients). Safety, adherence to treatment, patient U&K and QOL were assessed at follow-up visits (months 0, 3 and 6).Results: The number of detected ADRs was 163 with 41 patients referred to the doctor. At baseline, 24.1% of the patients were non-adherent, mainly due to unintentional causes. After six months and 130 interventions by CPs on adherence, a significant reduction to lower than 5.8% was achieved. The inadequate U&K of medicines also decreased, from 47.6% to 7.9% after 182 interventions. Also, the patient’s QOL improved.Conclusion: A new patient-centered pharmacy service provides some evidence on the important role of CP in assisting the proper and safe use of AM medicines, improving patient health outcomes. Keywords: community pharmacy, medicines under additional monitoring, safety, adherence, use and knowledge, pharmaceutical care

Isabel Ortiz de Solorzano,1,2,* Laura Uson,1,2,* Ane Larrea,1,2,* Mario Miana,3 Victor Sebastian,1,2 Manuel Arruebo1,2 1Department of Chemical Engineering and Environmental Technologies, Institute of Nanoscience of Aragon (INA), University of Zaragoza, 2CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Centro de Investigación Biomédica en Red, Madrid, 3ITAINNOVA, Instituto Tecnológico de Aragón, Materials & Components, Zaragoza, Spain *These authors contributed equally to this work Abstract: By using interdigital microfluidic reactors, monodisperse poly(d,l lactic-co-glycolic acid) nanoparticles (NPs) can be produced in a continuous manner and at a large scale (~10 g/h). An optimized synthesis protocol was obtained by selecting the appropriated passive mixer and fluid flow conditions to produce monodisperse NPs. A reduced NP polydispersity was obtained when using the microfluidic platform compared with the one obtained with NPs produced in a conventional discontinuous batch reactor. Cyclosporin, an immunosuppressant drug, was used as a model to validate the efficiency of the microfluidic platform to produce drug-loaded monodisperse poly(d,l lactic-co-glycolic acid) NPs. The influence of the mixer geometries and temperatures were analyzed, and the experimental results were corroborated by using computational fluid dynamic three-dimensional simulations. Flow patterns, mixing times, and mixing efficiencies were calculated, and the model supported with experimental results. The progress of mixing in the interdigital mixer was quantified by using the volume fractions of the organic and aqueous phases used during the emulsification–evaporation process. The developed model and methods were applied to determine the required time for achieving a complete mixing in each microreactor at different fluid flow conditions, temperatures, and mixing rates. Keywords: microchannel emulsification, high-throughput synthesis, drug-loaded polymer nanoparticles, passive mixing, numerical modeling

Traumatic brain injury (TBI) can lead to neurodegenerative diseases such as Alzheimer's disease (AD) through mechanisms that remain incompletely characterized. Similar to AD, TBI models present with cellular metabolic alterations and modulated cleavage of amyloid precursor protein (APP). Specifically, AD and TBI tissues display increases in amyloid-β as well as its precursor, the APP C-terminal fragment of 99 a.a. (C99). Our recent data in cell models of AD indicate that C99, due to its affinity for cholesterol, induces the formation of transient lipid raft domains in the ER known as mitochondria-associated endoplasmic reticulum (ER) membranes ("MAM" domains). The formation of these domains recruits and activates specific lipid metabolic enzymes that regulate cellular cholesterol trafficking and sphingolipid turnover. Increased C99 levels in AD cell models promote MAM formation and significantly modulate cellular lipid homeostasis. Here, these phenotypes were recapitulated in the controlled cortical impact (CCI) model of TBI in adult mice. Specifically, the injured cortex and hippocampus displayed significant increases in C99 and MAM activity, as measured by phospholipid synthesis, sphingomyelinase activity and cholesterol turnover. In addition, our cell type-specific lipidomics analyses revealed significant changes in microglial lipid composition that are consistent with the observed alterations in MAM-resident enzymes. Altogether, we propose that alterations in the regulation of MAM and relevant lipid metabolic pathways could contribute to the epidemiological connection between TBI and AD.

The ability to communicate effectively is a crucial aspect of education. For college students, learning how to speak in public is essential for their academic and professional future. However, many students report fear of speaking in public, the so-called Public Speaking Anxiety (PSA). This study aims to implement a training program using Virtual Reality (VR) with distractors to reduce the college students' anxiety. Anxiety was measured with two methods: electrodermal activity and self-report. We also analyze gender differences. There were an experimental and a control group. Both groups had to deliver the same speech twice: pre-test (before training); and post-test (after the training program) while participants' electrodermal activity was measured. Only the experimental group was trained with VR. Students also completed the Public Speaking Anxiety Scale and a survey to examine their experience. The results showed that the VR training reduced the anxiety levels significantly in the experimental group, but there were no significant differences in the control group. The data also revealed a higher level of anxiety in male than in female students. Finally, participants reported a positive impression of the VR training. These results showed the effectiveness of Virtual Reality software with distractors to reduce public speaking anxiety.

Abstract Inherited and developmental eye diseases are quite diverse and numerous, and determining their genetic cause is challenging due to their high allelic and locus heterogeneity. New molecular approaches, such as whole exome sequencing (WES), have proven to be powerful molecular tools for addressing these cases. The present study used WES to identify the genetic etiology in ten unrelated Mexican pediatric patients with complex ocular anomalies and other systemic alterations of unknown etiology. The WES approach allowed us to identify five clinically relevant variants in the GZF1, NFIX, TRRAP, FGFR2 and PAX2 genes associated with Larsen, Malan, developmental delay with or without dysmorphic facies and autism, LADD1 and papillorenal syndromes. Mutations located in GZF1 and NFIX were classified as pathogenic, those in TRRAP and FGFR2 were classified as likely pathogenic variants, and those in PAX2 were classified as variants of unknown significance. Protein modeling of the two missense FGFR2 p.(Arg210Gln) and PAX2 p.(Met3Thr) variants showed that these changes could induce potential structural alterations in important functional regions of the proteins. Notably, four out of the five variants were not previously reported, except for the TRRAP gene. Consequently, WES enabled the identification of the genetic cause in 40% of the cases reported. All the syndromes reported herein are very rare, with phenotypes that may overlap with other genetic entities.

Abstract Genetic mutations causing primary mitochondrial disease (i.e those compromising oxidative phosphorylation [OxPhos]) resulting in reduced bioenergetic output display great variability in their clinical features, but the reason for this is unknown. We hypothesized that disruption of the communication between endoplasmic reticulum (ER) and mitochondria at mitochondria-associated ER membranes (MAM) might play a role in this variability. To test this, we assayed MAM function and ER-mitochondrial communication in OxPhos-deficient cells, including cybrids from patients with selected pathogenic mtDNA mutations. Our results show that each of the various mutations studied indeed altered MAM functions, but notably, each disorder presented with a different MAM “signature”. We also found that mitochondrial membrane potential is a key driver of ER-mitochondrial connectivity. Moreover, our findings demonstrate that disruption in ER-mitochondrial communication has consequences for cell survivability that go well beyond that of reduced ATP output. The findings of a “MAM-OxPhos” axis, the role of mitochondrial membrane potential in controlling this process, and the contribution of MAM dysfunction to cell death, reveal a new relationship between mitochondria and the rest of the cell, as well as providing new insights into the diagnosis and treatment of these devastating disorders.

Abstract Introduction Personalised prevention aims to delay or avoid disease occurrence, progression, and recurrence of disease through the adoption of targeted interventions that consider the individual biological, including genetic data, environmental and behavioural characteristics, as well as the socio-cultural context. This protocol summarises the main features of a rapid scoping review to show the research landscape on biomarkers or a combination of biomarkers that may help to better identify subgroups of individuals with different risks of developing specific diseases in which specific preventive strategies could have an impact on clinical outcomes. This review is part of the “Personalised Prevention Roadmap for the future HEalThcare” (PROPHET) project, which seeks to highlight the gaps in current personalised preventive approaches, in order to develop a Strategic Research and Innovation Agenda for the European Union. Objective To systematically map and review the evidence of biomarkers that are available or under development in cancer, cardiovascular and neurodegenerative diseases that are or can be used for personalised prevention in the general population, in clinical or public health settings. Methods Three rapid scoping reviews are being conducted in parallel (February–June 2023), based on a common framework with some adjustments to suit each specific condition (cancer, cardiovascular or neurodegenerative diseases). Medline and Embase will be searched to identify publications between 2020 and 2023. To shorten the time frames, 10% of the papers will undergo screening by two reviewers and only English-language papers will be considered. The following information will be extracted by two reviewers from all the publications selected for inclusion: source type, citation details, country, inclusion/exclusion criteria (population, concept, context, type of evidence source), study methods, and key findings relevant to the review question/s. The selection criteria and the extraction sheet will be pre-tested. Relevant biomarkers for risk prediction and stratification will be recorded. Results will be presented graphically using an evidence map. Inclusion criteria Population: general adult populations or adults from specific pre-defined high-risk subgroups; concept: all studies focusing on molecular, cellular, physiological, or imaging biomarkers used for individualised primary or secondary prevention of the diseases of interest; context: clinical or public health settings. Systematic review registration https://doi.org/10.17605/OSF.IO/7JRWD (OSF registration DOI).

Abstract The first-order phase transition between the liquid and gaseous phases ends at a critical point. Critical opalescence occurs at this singularity. Discovered in 1822, it is known to be driven by diverging fluctuations in the density. During the past two decades, boundaries between the gas-like and liquid-like regimes have been theoretically proposed and experimentally explored. Here, we show that fast cooling of near-critical sulfur hexafluoride (SF6), in presence of Earth’s gravity, favors dark opalescence, where visible photons are not merely scattered, but also absorbed. When the isochore fluid is quenched across the critical point, its optical transmittance drops by more than three orders of magnitude in the whole visible range, a feature which does not occur during slow cooling. We show that transmittance shows a dip at 2eV near the critical point, and the system can host excitons with binding energies ranging from 0.5 to 4 eV. The spinodal decomposition of the liquid-gas mixture, by inducing a periodical modulation of the fluid density, can provide a scenario to explain the emergence of this platform for coupling between light and matter. The possible formation of excitons and polaritons points to the irruption of quantum effects in a quintessentially classical context.

IntroductionOver 6.8 million fractures occur annually in the US, with 10% experiencing delayed- or non-union. Anabolic therapeutics like PTH analogs stimulate fracture repair, and small molecule salt inducible kinase (SIK) inhibitors mimic PTH action. This study tests whether the SIK inhibitor YKL-05-099 accelerates fracture callus osteogenesis.Methods126 female mice underwent femoral shaft pinning and midshaft fracture, receiving daily injections of PBS, YKL-05-099, or PTH. Callus tissues were analyzed via RT-qPCR, histology, single-cell RNA-seq, and μCT imaging. Biomechanical testing evaluated tissue rigidity. A hydrogel-based delivery system for PTH and siRNAs targeting SIK2/SIK3 was developed and tested.ResultsYKL-05-099 and PTH-treated mice showed higher mineralized callus volume fraction and improved structural rigidity. RNA-seq indicated YKL-05-099 increased osteoblast subsets and reduced chondrocyte precursors. Hydrogel-released siRNAs maintained target knockdown, accelerating callus mineralization.DiscussionYKL-05-099 enhances fracture repair, supporting selective SIK inhibitors’ development for clinical use. Hydrogel-based siRNA delivery offers targeted localized treatment at fracture sites.

Summary: Abdominal and thoracic aortic aneurysms (AAAs, TAAs) remain a major cause of deaths worldwide, in part due to the lack of reliable prognostic markers or early warning signs. Sox6 has been found to regulate renin controlling blood pressure. We hypothesized that Sox6 may serve as an important regulator of the mechanisms contributing to hypertension-induced aortic aneurysms. Phenotype and laboratory-wide association scans in a clinical cohort found that SOX6 gene expression is associated with aortic aneurysm in subjects of European ancestry. Sox6 and tumor necrosis factor alpha (TNF-α) expression were upregulated in aortic tissues from patients affected by either AAA or TAA. In Sox6 knockout mice with angiotensin-II-induced AAA, we found that Sox6 plays critical role in the development and progression of AAA. Our data support a regulatory role of SOX6 in the development of hypertension-induced AAA, suggesting that Sox6 may be a therapeutic target for the treatment of aortic aneurysms.

Objectives: Adherence to healthy lifestyle recommendations has been reported to improve health-related quality of life (HRQL) in breast cancer (BC) patients, but the influence of long-term behavioral changes remains unknown. We evaluated the association between adherence to the 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) cancer prevention recommendations and HRQL both, at BC diagnosis and the change 7−12 years later. Design: Prospective cohort study. Settings and participants: A total of 406 breast cancer survivors, from the EpiGEICAM study, were recruited in 16 Spanish hospitals. Measurements: Epidemiological, clinical, dietary, physical activity and HRQL information was collected both at recruitment and 7−12 years later. A 7-item score to measure compliance with recommendations was assessed according to the 2018 WCRF/AICR scoring criteria. HRQL was evaluated using SF-36 questionnaire. Linear mixed models for longitudinal data were used to assess the cross-sectional and longitudinal association between adherence score and the physical and mental component summary scores. Results: At diagnosis, for each unit increase in WCRF/AICR score adherence, the HRQL physical domain increased 0.78 points (95%CI: −0.04 to 1.60; P trend:0.06). The mean change in physical HRQL from diagnosis to follow-up per unit increase in within-subject adherence score was 0.73 points (95%CI: −0.18 to 1.65; P trend: 0.12). For the mental domain, no association was observed with compliance with the recommendations at diagnosis, nor with changes in adherence over time. Conclusions: Our results suggest that Increased adherence to WCRF/AICR cancer prevention recommendations over time could contribute to slightly improved long-term physical HRQoL in BC survivors.

Abstract Recommendations regarding the best time to start treatment in patients with relapsed/refractory multiple myeloma (RRMM) after biological relapse/progression (BR) are unclear. This observational, prospective, multicenter registry aimed to evaluate the impact on time to progression (TTP) of treatment initiation at BR versus at symptomatic clinical relapse (ClinR) based on the Spanish routine practice in adult patients with RRMM. Patients had two or less previous treatment lines and at least one previous partial response. Baseline characteristics and treatment outcomes were recorded, and survival was analyzed. Of 225 patients, 110 were treated at BR (TxBR group) and 115 at ClinR (TxClinR group) according to the investigators' criteria. The proportion of patients with higher ECOG, previous noncomplete remission (CR), and second relapse were significantly higher in the TxBR group compared to the TxClinR group. TheTxClinR group showed improved outcomes, including TTP, compared to the TxBR group. Progression‐free survival increased in the TxClinR group (56.2 months) compared to the TxBR group (32.5 months) (p = 0.0137), and median overall survival also increased (p = 0.0897). Median TTP was significantly longer in patients relapsing from a CR (50.4 months) and in their first relapse (38.7 months) compared to those relapsing from a non‐CR response (32.9 months) and in their second relapse (25.2 months). Physicians seemed to start treatment earlier in RRMM patients with poor prognosis features. Previous responses to anti‐MM treatment and the number of prior treatment lines were identified as prognosis factors, whereby relapse from CR and first relapse were associated with a longer time to progression.

Abstract In this work, a new method of multi‐material printing in one‐go using a commercially available 3D printer is presented. The approach is simple and versatile, allowing the manufacturing of multi‐material layered or multi‐material printing in the same layer. To the best of the knowledge, it is the first time that 3D printed Poly(3,4‐ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) micro‐patterns combining different materials are reported, overcoming mechanical stability issues. Moreover, the conducting ink is engineered to obtain stable in‐time materials while retaining sub‐100 µm resolution. Micro‐structured bio‐shaped protuberances are designed and 3D printed as electrodes for electrophysiology. Moreover, these microstructures are combined with polymerizable deep eutectic solvents (polyDES) as functional additives, gaining adhesion and ionic conductivity. As a result of the novel electrodes, low skin impedance values showed suitable performance for electromyography recording on the forearm. Finally, this concluded that the use of polyDES conferred stability over time, allowing the usability of the electrode 90 days after fabrication without losing its performance. All in all, this demonstrated a very easy‐to‐make procedure that allows printing PEDOT:PSS on soft, hard, and/or flexible functional substrates, opening up a new paradigm in the manufacturing of conducting multi‐functional materials for the field of bioelectronics and wearables.