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Abstract Background Type 2 diabetes (T2D) is one of the most prevalent chronic diseases worldwide and a leading cause of cardiorenal disease and mortality. Only one-third of individuals with T2D receive care as recommended by the American Diabetes Association’s clinical practice guidelines. Effective strategies are needed to accelerate the implementation of guideline concordant T2D care. Methods The Michigan Collaborative for Type 2 Diabetes (MCT2D) is a statewide population health collaborative quality initiative (CQI) developed to improve the care of all people with T2D in Michigan. MCT2D has developed a learning health system with physician organizations and their constituent practices to support quality improvement initiatives focused on (1) improving use of guideline-directed pharmacotherapy to improve cardiorenal outcomes, (2) increasing evidence-based use of continuous glucose monitoring, and (3) supporting use of lower carbohydrate eating patterns. Results Between 2021 and 2022, MCT2D recruited 28 of the 40 Michigan-based physician organizations participating in Blue Cross’ Physician Group Incentive Program with 336 constituent practices and 1357 physicians in primary care (304), endocrinology (21) and nephrology (11). In January 2022, baseline data included a sample of 96,140 unique individuals with T2D. The baseline HbA1c was ≤ 7.0% for 66.3% of patients (n = 32,787), while 14.9% of patients had a most recent HbA1c ≥ 8.0% (n = 7,393). The most recent body mass index (BMI) was ≥ 30.0 for 64.8% of patients (n = 38,516). Discussion MCT2D has organized a statewide collaborative to recruit and engage a diverse and large set of physician organizations and their constituent practices. This is a promising opportunity to accelerate adoption of guideline-concordant care for people with T2D and may be a model for other state or regional collaboratives. Future directions include specific evidence-based interventions targeted at reducing diabetes-linked comorbidities and associated healthcare costs as well as strategies focused on T2D prevention among at-risk populations.

Abstract Replacing petrochemicals with compounds from bio-based manufacturing processes remains an important part of the global effort to move towards a sustainable future. However, achieving economic viability requires both optimized cell factories and innovative processes. Here, we address this challenge by developing a fermentation platform, which enables two concurrent fermentations in one bioreactor. We first construct a xylitol producing Escherichia coli strain in which CRISPRi-mediated gene silencing is used to switch the metabolism from aerobic to anaerobic, even when the bacteria are under oxic conditions. The switch also decouples growth from production, which further increases the yield. The strain produces acetate as a byproduct, which is subsequently metabolized under oxic conditions by a secondary E. coli strain. Through constraint-based metabolic modelling this strain is designed to co-valorize glucose and the excreted acetate to a secondary product. This unique syntrophic consortium concept facilitates the implementation of “two fermentations in one go”, where the concurrent fermentation displays similar titers and productivities as compared to two separate single strain fermentations.

With the advent of modern Medicine, the connections between emotions and medical conditions have primarily been described through observational studies, where conclusions are drawn from correlations of observations rather than experimental research. Psychoanalytical theory has often been used to explain many common illnesses. This approach remains prevalent today. Interestingly, despite the wealth of information now available on the influence of emotions on health, the current divide between neurology and psychiatry, as well as the separation between mental health services and primary care, combined with the time constraints and physicians’ workload, have led to a fragmented approach to many disorders. In these cases, psychological and emotional factors play an important role but are often inadequately addressed. The objective of this paper is to analyse the existing evidence on the relationship between anger and health through a narrative review. The evidence and data presented point to the need for analytical studies based on scientific methodology to explore the relationship between anger and health, and particularly to adopt an integral health approach taking into account social determinants and the role of empathy among the healthcare professionals and clinical and social care. The prevention and treatment of problems related to the high prevalence and intensity of anger are particularly relevant, given the potential negative impact this emotion can have on patients’ physical and mental health, as well as their social adjustment and relationships.

Abstract Here, we examined the potential role of mitochondrial DNA (mtDNA) levels in conveying aggressive phenotypes in cancer cells, using two widely-used breast cell lines as model systems (MCF7[ER+] and MDA-MB-231[ER-]). These human breast cancer cell lines were fractionated into mtDNA-high and mtDNA-low cell sub-populations by flow cytometry, using SYBR Gold as a vital probe to stain mitochondrial nucleoids in living cells. Enrichment of mtDNA-high and mtDNA-low cell sub-populations was independently validated, using a specific DNA-binding mAb probe (AC-30-10), and mitochondrial-based functional assays. As predicted, mtDNA-high MCF7 cells showed significant increases in mitochondrial mass, membrane potential, and superoxide production, as well as increased mitochondrial respiration and ATP production. Moreover, mtDNA-high MCF7 cells demonstrated increases in stemness features, such as anchorage-independent growth and CD44 levels, as well as drug-resistance to Gemcitabine and Tamoxifen. Proliferation rates were also significantly increased, with a dramatic shift towards the S- and G2/M-phases of the cell cycle; this was indeed confirmed by RNA-Seq analysis. Complementary results were obtained with MDA-MB-231 cells. More specifically, mtDNA-high MDA-MB-231 cells showed increases in stemness features and ATP production, as well as rapid cell cycle progression. Moreover, mtDNA-high MDA-MB-231 cells also exhibited increases in both cell migration and invasion, suggesting a role for mtDNA in distant metastasis. To test this hypothesis more directly, a preclinical in vivo model was utilized. For this purpose, MDA-MB-231 tumour cell grafts were treated with an established mtDNA synthesis inhibitor, namely Alovudine (3’-deoxy-3’-fluorothymidine). As expected, drug-induced depletion of mtDNA led to a shift from mitochondrial to glycolytic metabolism. Interestingly, Alovudine very effectively reduced the formation of spontaneous metastases by nearly 70%, but minimally inhibited tumour growth by approximately 20%. Taken together, these data suggest that high mtDNA content is a key driver of stemness, proliferation, and migration, as well as cancer cell metastasis.

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

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).

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.

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.