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Dentin Sialoprotein (DSP) and phosphophoryn (PP) are two most dominant non-collagenous proteins in dentin, which are the cleavage products of the DSPP (dentin sialophosphoprotein) precursor protein. The absence of the DSPP gene in DSPP knock-out (KO) mice results in characteristics that are consistent with dentinogenesis imperfecta type III in humans. Symptoms include thin dentin, bigger pulp chamber with frequent pulp exposure as well as abnormal epithelial-mesenchymal interactions, and the appearance of chondrocyte-like cells in dental pulp. To better understand how DSPP influences tooth development and dentin formation, we used a bacterial artificial chromosome transgene construct (BAC-DSPP) that contained the complete DSPP gene and promoter to generate BAC-DSPP transgenic mice directly in a mouse DSPP KO background. Two BAC-DSPP transgenic mouse strains were generated and characterized. DSPP mRNA expression in BAC-DSPP Strain A incisors was similar to that from wild-type (wt) mice. DSPP mRNA expression in BAC-DSPP Strain B animals was only 10% that of wt mice. PP protein content in Strain A incisors was 25% of that found in wt mice, which was sufficient to completely rescue the DSPP KO defect in mineral density, since microCT dentin mineral density analysis in 21-day postnatal animal molars showed essentially identical mineral density in both strain A and wt mice. Strain B mouse incisors, with 5% PP expression, only partially rescued the DSPP KO defect in mineral density, as microCT scans of 21-day postnatal animal molars indicated a reduced dentin mineral density compared to wt mice, though the mineral density was still increased over that of DSPP KO. Furthermore, our findings showed that DSPP dosage in Strain A was sufficient to rescue the DSPP KO defect in terms of epithelial-mesenchymal interactions, odontoblast lineage maintenance, along with normal dentin thickness and normal mineral density while DSPP gene dosage in Strain B only partially rescued the aforementioned DSPP KO defect.

BACKGROUND:Insight in hospitalizations in long-term childhood cancer survivors (CCS) is useful to understand the impact of long-term morbidity. We aimed to investigate hospitalization rates and underlying types of diagnoses in CCS compared to matched controls, and to investigate the determinants. METHODS:We linked 5,650 five-year CCS from the Dutch nationwide Dutch LATER cohort and 109,605 age- and sex-matched controls to the Dutch Hospital Discharge register, which contained detailed information on inpatient hospitalizations from 1995-2016. Relative hospitalization rates (RHRs) were calculated using a Poisson regression model. Adjusting for multiple hospitalizations per person via a Poisson model for generalized estimated equations, we investigated determinants for hospitalizations for all types of underlying diagnoses among CCS. RESULTS:CCS were twice as likely to be hospitalized as reference persons (hospitalization rate 178 and 78 per 1,000 person-years respectively; RHR 2.0, 95% confidence interval (CI) 1.9-2.2). Although CCS had more hospitalizations for 17 types of underlying diagnoses, they were especially more likely to be hospitalized for endocrine conditions (RHR: 6.0, 95% CI 4.6-7.7), subsequent neoplasms (RHR: 5.6, 95% CI 4.6-6.7) and symptoms without underlying diagnoses (RHR: 5.2, 95% CI 4.6-5.8). For those types of underlying diagnoses, female sex and radiotherapy were determinants. CONCLUSION:This study provides new insights in the high risk of hospitalizations for many types of underlying diagnoses in CCS and treatment related determinants. CCS are especially at high risk for hospitalizations for endocrine conditions, subsequent neoplasms and symptoms without an underlying diagnosis. This new knowledge is important for survivorship care and to identify possible preventable hospitalizations among CCS.

ObjectivesCurrent evidence on fecal microbiota transplantation for inflammatory bowel disease is inconclusive. We conducted a systematic review to gather evidence on the efficacy and safety of fecal microbiota transplantation for inflammatory bowel disease.MethodsSystematic searches were conducted in PubMed, Scopus, and Web of Science. Clinical remission was considered as the primary endpoint. Pairwise meta-analyses were performed for the randomized controlled studies (Mantel Haenszel, random effects model). Proportion meta-analyses, accounting for weighted pooled rates reported in the interventional studies, were conducted using the mixed effects model. Subgroup analyses considering the type of stool, donor type, and disease subtype were also performed. Cumulative meta-analyses to assess further needs of evidence were conducted.ResultsSixty studies were included, from which 36 could be synthesized in the quantitative analyses. Pairwise meta-analyses of six controlled trials showed significant differences in favor of fecal microbiota transplantation compared with placebo (clinical remission: RR 1.70 [95% CI 1.12, 2.56]; clinical response: RR 1.68 [95% CI 1.04, 2.72]). An overall clinical remission of 37%, overall clinical response of 54%, and a prevalence of 29% of adverse events were found for the interventional studies. Frozen fecal material and universal donors were related to better efficacy outcomes. In addition, Crohn's disease patients seemed to benefit more from the procedure.ConclusionsThe comparative analyses demonstrated that frozen fecal material from universal donors may be related to a higher rate of clinical remission, especially for Crohn's disease.

BackgroundThe conduction and report of network meta-analysis (NMA), including the presentation of the network-plot, should be transparent. We aimed to propose metrics adapted from graph theory and social network-analysis literature to numerically describe NMA geometry.MethodsA previous systematic review of NMAs of pharmacological interventions was performed. Data on the graph's presentation were collected. Network-plots were reproduced using Gephi 0.9.1. Eleven geometric metrics were tested. The Spearman test for non-parametric correlation analyses and the Bland-Altman and Lin's Concordance tests were performed (IBM SPSS Statistics 24.0).ResultsFrom the 477 identified NMAs only 167 graphs could be reproduced because they provided enough information on the plot characteristics. The median nodes and edges were 8 (IQR 6-11) and 10 (IQR 6-16), respectively, with 22 included studies (IQR 13-35). Metrics such as density (median 0.39, ranged 0.07-1.00), median thickness (2.0, IQR 1.0-3.0), percentages of common comparators (median 68%), and strong edges (median 53%) were found to contribute to the description of NMA geometry. Mean thickness, average weighted degree and average path length produced similar results than other metrics, but they can lead to misleading conclusions.ConclusionsWe suggest the incorporation of seven simple metrics to report NMA geometry. Editors and peer-reviews should ensure that guidelines for NMA report are strictly followed before publication.

Network meta-analysis (NMA) is a new tool developed to overcome some limitations of pairwise meta-analyses. NMAs provide evidence on more than two comparators simultaneously. This study aimed to map the characteristics of the published NMAs on drug therapy comparisons.A systematic review of NMAs comparing pharmacological interventions was performed. Searches in Medline (PubMed) and Scopus along with manual searches were conducted. The main characteristics of NMAs were systematically collected: publication metadata, criteria for drug inclusion, statistical methods used, and elements reported. A methodological quality score with 25 key elements was created and applied to the included NMAs. To identify potential trends, the median of the publication year distribution was used as a cut-off.The study identified 365 NMAs published from 2003 to 2016 in more than 30 countries. Randomised controlled trials were the primary source of data, with only 5% including observational studies, and 230 NMAs used a placebo as a comparator. Less than 15% of NMAs were registered in PROSPERO or a similar system. One third of studies followed PRISMA and less than 9% Cochrane recommendations. Around 30% presented full-search strategies of the systematic review, and 146 NMAs stated the selection criteria for drug inclusion. Over 75% of NMAs presented network plots, but only half described their geometry. Statistical parameters (model fit, inconsistency, convergence) were properly reported by one third of NMAs. Although 216 studies exhibited supplemental material, no data set of primary studies was available. The methodological quality score (mean 13·9; SD 3·8) presented a slightly positive trend over the years.The map of the published NMAs emphasises the potential of this tool to gather evidence in healthcare, but it also identified some weaknesses, especially in the report, which limits its transparency and reproducibility.

Dentin sialoprotein (DSP) and phosphophoryn (PP), acidic proteins critical to dentin mineralization, are translated from a single transcript as a DSP-PP precursor that undergoes specific proteolytic processing to generate DSP and PP. The cleavage mechanism continues to be controversial, in part because of the difficulty of obtaining DSP-PP from mammalian cells and dentin matrix. We have infected Sf9 cells with a recombinant baculovirus to produce large amounts of secreted DSP-PP(240), a variant form of rat DSP-PP. Mass spectrometric analysis shows that DSP-PP(240) secreted by Sf9 cells undergoes specific cleavage at the site predicted from the N-terminal sequence of PP extracted from dentin matrix: SMQG(447)↓D(448)DPN. DSP-PP(240) is cleaved after secretion by a zinc-dependent activity secreted by Sf9 cells, generating DSP(430) and PP(240) products that are stable in the medium. DSP-PP processing activity is constitutively secreted by Sf9 cells, but secretion is diminished 3 days after infection. Using primers corresponding to the highly conserved catalytic domain of Drosophila melanogaster tolloid (a mammalian BMP1 homolog), we isolated a partial cDNA for a Spodopotera frugiperda tolloid-related-1 protein (TLR1) that is 78% identical to Drosophila TLR1 but only 65% identical to Drosophila tolloid. Tlr1 mRNA decreased rapidly in Sf9 cells after baculovirus infection and was undetectable 4d after infection, paralleling the observed decrease in secretion of the DSP-PP(240) processing activity after infection. Human BMP1 is more similar to Sf9 and Drosophila TLR1 than to tolloid, and Sf9 TLR1 is more similar to BMP1 than to other mammalian homologs. Recombinant human BMP1 correctly processed baculovirus-expressed DSP-PP(240) in a dose-dependent manner. Together, these data suggest that the physiologically accurate cleavage of mammalian DSP-PP(240) in the Sf9 cell system represents the action of a conserved processing enzyme and support the proposed role of BMP1 in processing DSP-PP in dentin matrix.

Background: Insight in hospitalizations in long-term childhood cancer survivors (CCS) is useful to understand the impact of long-term morbidity. We aimed to investigate hospitalization rates and underlying types of diagnoses in CCS compared to matched controls, and to investigate the determinants. Methods: We linked 5,650 five-year CCS from the Dutch nationwide Dutch LATER cohort and 109,605 age- and sex-matched controls to the Dutch Hospital Discharge register, which contained detailed information on inpatient hospitalizations from 1995–2016. Relative hospitalization rates (RHRs) were calculated using a Poisson regression model. Adjusting for multiple hospitalizations per person via a Poisson model for generalized estimated equations, we investigated determinants for hospitalizations for all types of underlying diagnoses among CCS. Results: CCS were twice as likely to be hospitalized as reference persons (hospitalization rate 178 and 78 per 1,000 person-years respectively; RHR 2.0, 95% confidence interval (CI) 1.9–2.2). Although CCS had more hospitalizations for 17 types of underlying diagnoses, they were especially more likely to be hospitalized for endocrine conditions (RHR: 6.0, 95% CI 4.6–7.7), subsequent neoplasms (RHR: 5.6, 95% CI 4.6–6.7) and symptoms without underlying diagnoses (RHR: 5.2, 95% CI 4.6–5.8). For those types of underlying diagnoses, female sex and radiotherapy were determinants. Conclusion: This study provides new insights in the high risk of hospitalizations for many types of underlying diagnoses in CCS and treatment related determinants. CCS are especially at high risk for hospitalizations for endocrine conditions, subsequent neoplasms and symptoms without an underlying diagnosis. This new knowledge is important for survivorship care and to identify possible preventable hospitalizations among CCS. [ABSTRACT FROM AUTHOR]

Several cities are facing water emergencies related to urbanization impact and amplified by climate change. Most of the cities have responded to these crises through short-term measures. However, some cities have incorporated a watershed approach to water management in seeking more sustainable solutions. Although the importance of a watershed approach in land management is generally acknowledged, studies on this topic have typically focused on theoretical models, water management in rural areas or single case-studies of cities or countries. In this research, a scoping review of the literature was performed, based on the PRISMA 2020 statement, in three databases: Web of Science, Google Scholar and SciELO. Forty-one studies were identified analyzing 17 city cases implementing urban actions from a watershed approach in water management. These cities were from the Global North and Asian rising world powers. The lack of results of cities from the Global South, based on the research undertaken, was the main limitation and bias identified. Most of the Global South results identified in this research were theoretical models, scenarios and cases of rural areas instead of urban contexts. The results obtained indicate that the main motivations for cities to implement a watershed approach were water scarcity, floods and contamination of water bodies. The implemented actions focused on the shift from gray to green and blue infrastructure and on conservation measures. Lastly, the challenges to introduce those actions were mainly the lack of economic investment, insufficient experience, stakeholder opposition, and regulatory obstacles. Urban water management could be seen as an opportunity to change the way we relate to urban territory. Incorporating a watershed approach into urban planning and water management could promote more sustainable cities., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Canteiro et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Aims: The aim of the present study was to estimate the evolution of binge drinking since the pre-pandemic period, and throughout the pandemic period with the application and lifting of the restrictions in adolescents aged 12 to 19 years old in school in Central Catalonia., Methodology: Quasi-experimental time series study with two samples of adolescents. The first sample (1st wave of survey, pre-pandemic period) was obtained between the months of September 2019 to March 2020 (n = 6621) and the second sample (2nd wave of survey, pandemic period) between the months of October 2021 and March 2022 (n = 7576). The dependent variable was monthly binge drinking. The main independent variable was the period of data collection (1st and 2nd wave), and gender and grade were also included. Twenty-one time slices were performed by fortnight and the binge drinking prevalence of the previous month was extracted in each of them. Interrupted time series analysis was performed and Poisson regression models with robust variance were estimated., Results: The data indicated a significant increase in the prevalence of binge drinking in certain periods in girls [easing of measures in October, aPR: 2.25 (1.03-4.89); and total lifting of restrictions in February, aPR: 3.29 (1.57-6.89)] and a reduction in consumption in periods of tightening of restrictions. After the upturn before the return to the pre-pandemic situation binge drinking followed a decreasing trend in both sexes [aPR boys: 0.73 (95%CI: 0.66-0.81); aPR girls: 0.78 (95%CI: 0.71-0.86)]., Conclusions: Periods of community interventions aimed at protecting people's health have had an impact on other health behaviors or aspects of health such as binge drinking, and differentially across groups and communities., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Rogés et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Infective endocarditis (IE) is a rare but severe infectious disease. Patients with IE are treated for weeks in the hospital and have profound impairments to their health. New treatment modalities increase options for outpatient care. Little is known about how patients perceive their disease and hospitalisation. We aimed to explore the needs of patients with IE during hospitalisation and the first few months after discharge., Methods: In this qualitative study, 20 patients (45-86 years of age) hospitalised due to IE in Swedish hospitals were interviewed a median of 112 (67-221) days after hospitalisation. Data were analysed with qualitative content analysis, identifying eight subcategories, two categories, and an overall theme., Results: The overall theme illuminated a spectrum of needs of patients suffering from IE, between treating the disease and meeting the person with the illness. The needs encompassed eight axes with dual focus on both medical excellence and person-centred care. Medical excellence was needed to optimally treat, supervise, and offer follow-up on this rare and severe disease; patients longed to come home, and there were issues of reliability in the healthcare system. Person-centred care was requested, including individualised information leading to knowledge, reorientation, the beginning of health restoration, and being met as a unique person. Symptoms of fatigue, wasting, and cognitive and mental distress were often neglected by the caregiver., Conclusions: This explorative study shows the patient's needs as important areas in a spectrum between medical excellence and person-centred care. Care in specialised units secure quality. Early discharge is requested by patients. Multiprofessional individualizing outpatient care needs to develop with preserved safety and medical excellence. The disease trajectory after discharge progresses slowly, and the possibility of mitigating its progress is still unclear. Person-centred care, screening for delayed restoration and rehabilitation after endocarditis are important fields for future studies., Competing Interests: The authors have declared that no competing interests exists., (Copyright: © 2024 Lindberg et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: To identify childhood cancer survivors (CCSs) at risk of premature ovarian insufficiency (POI) and impaired fertility is important given its impact on quality of life. The aim of this study was to assess ovarian markers and fertility outcomes in adult female CCSs. We used the Swedish and the PanCareLIFE classifications for infertility risk grouping., Methods: 167 CCSs, at median age 34.6 years (19.3-57.8) with a median follow-up time of 25.4 years (11.6-41.3), and 164 healthy matched controls were included in this cross-sectional study. We assessed anti-Müllerian hormone (AMH) levels, antral follicle count (AFC), ovarian volume (OV), and fertility outcomes. Based on gonadotoxic treatments given, CCSs were categorized into infertility risk groups., Results: The median levels of AMH, AFC and OV were lower in CCSs (1.9 vs. 2.1 ng/ml, 12.0 vs. 13.0, 6.8 vs. 8.0 cm3) compared with controls, although statistically significant only for OV (p = 0.021). AMH levels in CCSs <40 years were lower for those classified as high-risk (p = 0.034) and very high-risk (p<0.001) for infertility, based on the Swedish risk classification. Similarly, AFC was reduced in the high-risk (p<0.001) and the very high-risk groups (p = 0.003). CCSs of all ages showed a trend towards impaired fertility, especially in the very high-risk group. POI was diagnosed in 22/167 CCSs, of whom 14 were in the high- and very high-risk groups. The results according to the PanCareLIFE classification were similar., Conclusion: Both the Swedish and the PanCareLIFE infertility risk classifications are reliable tools for identifying those at risk of reduced ovarian markers and fertility, as well as POI. We recommend fertility preservation counselling for patients receiving highly gonadotoxic treatments (i.e., Cyclophosphamide Equivalent Dose ≥6 g/m2, radiotherapy exposure to ovaries or stem cell transplantation) with follow-up at a young reproductive age due to the risk of a shortened reproductive window., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Nyström et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Parkinson's Disease (PD) affects movement and cognition, and physiotherapy, particularly treadmill gait training, has potential in addressing movement dysfunctions in PD. However, treadmill training falls short in addressing cognitive aspects and adherence. Virtual reality (VR) and gamification can enhance motor and cognitive retraining and improve adherence. People with Parkinson's Disease (PWPD) have decreased motor skill learning efficiency, but tDCS can improve motor and cognitive learning., Methods: 78 participants with PD will be randomly allocated in a 1:1:1 ratio to one of three groups: (1) treadmill + Gamified Virtual Reality Environment (GVRE) + tDCS training group; (2) treadmill + GVRE training group or (3) treadmill training group. Participants will follow a 6-week, 12-session treadmill gait training plan, gradually increasing session duration from 20 to 45 minutes. Participants in (1) and (2) will undergo a GVRE training protocol, with (1) also receiving tDCS for the first 20 minutes of each session. Assessments will occur at baseline, post-intervention, and at a 6-week follow-up. The primary outcome measure will be gait speed during single and dual-task performance. Secondary measures will include additional gait parameters, executive tests for cognitive performance, and clinical outcomes for disease stage, cognitive status, and physical condition., Discussion: This randomized clinical trial presents an innovative neurorehabilitation protocol that aims to improve gait and cognition in PWPD. The study also examines how tDCS can enhance motor and cognitive training. Results could contribute to enhancing the motor and cognitive state of PWPD through a GVRE and tDCS-based neurorehabilitation protocol., Trial Registration: NCT05243394. 28/02/2024 -v3.2., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Bosch-Barceló et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Currently, there are few treatment-predictive and prognostic biomarkers in triple-negative breast cancer (TNBC). Caveolin-1 (CAV1) is linked to chemoresistance and several important processes involved in tumor progression and metastasis, such as epithelial-mesenchymal transition (EMT). Herein, we report that high CAV1 gene expression is an independent factor of poor prognosis in TNBC., Methods: CAV1 gene expression was compared across different molecular features (e.g., PAM50 subtypes). CAV1 expression was assessed in relation to clinical outcomes using Cox regression adjusted for clinicopathological predictors. Differential gene expression and gene set enrichment analyses were applied to compare high- and low-expressing CAV1 tumors. Tumor microenvironment composition of high- and low-expressing CAV1 tumors was estimated using ECOTYPER. Tumor tissue microarrays were used to evaluate CAV1 protein levels in stromal and malignant cells., Results: In the SCAN-B (n = 525) and GSE31519 (n = 327) cohorts, patients with CAV1-high tumors had an increased incidence of early recurrence adjusted HR 1.78 (95% CI 1.12-2.81) and 2.20 (95% CI 1.39-3.47), respectively. In further analysis, high CAV1 gene expression was associated with a molecular profile indicating altered metabolism, neovascularization, chemoresistance, EMT, suppressed immune response, and active tumor microenvironment. Protein levels of CAV1 in malignant and stromal cells were not correlated with CAV1 gene expression., Conclusion: CAV1 gene expression in TNBC is a biomarker that merits further investigation in clinical trials and as a therapeutic target., Competing Interests: Ana Bosch has received institutional honoraria from Pfizer, Roche and Lilly for consultation and lectures. She has participated in Advisory Board meetings for Pfizer and Novartis. Co-founder and chair of the board for SACRA therapeutics. Karolin Isaksson has received speaker honorarium from Pierre Fabre. The other authors declare no conflict of interest., (Copyright: © 2024 Godina et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

People experiencing homelessness are more likely to utilize emergency departments than their non-homeless counterparts. However, obtaining a bed in a homeless shelter for patients can be complex. To better understand the challenges of finding a safe discharge plan for homeless patients in the emergency department, our team conducted interviews with emergency department social workers and homeless shelter case managers in the Boston area. We identified and mapped the stages in the processes performed by both parties, identifying challenges with successful placement into a shelter. Furthermore, we assembled a data dictionary of key factors considered when assessing a patient's fit for a homeless shelter. By identifying bottlenecks and areas of opportunity, this study serves as a first step in enabling homeless individuals to receive the post-discharge assistance they require., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Marcus et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: The All4Children project addresses the urgent need to transition from institutionalization to family-based care for out-of-home children in Portugal. Despite evidence highlighting the detrimental effects of institutionalization, only a small percentage of children (less than 4%) are currently placed in family foster care in the country. In response to European directives for deinstitutionalization, Portuguese legislation now prioritizes non-kinship family foster care as the preferred alternative for young children in need of care. To facilitate this transition, the Integrated Model of Family Foster Care (MIAF) was developed, offering a comprehensive framework covering the entire spectrum of family foster care., Objective: This research aims to investigate the initial implementation stage of the MIAF to promote high-quality family foster care in Portugal., Method: The study will conduct a mixed-method and longitudinal research project in family foster care agencies across different regions of Portugal, focusing on evaluating the implementation and outcomes of the MIAF model using a multi-informant and multi-method approach. The participants will include caseworkers, children aged 0-9 years entering foster care, and their respective foster families enrolled in the MIAF program. Process evaluation will assess fidelity, feasibility, appropriateness, and acceptability of MIAF modules, while outcome evaluation will examine child safety, stability, well-being, as well as foster family well-being and quality of relational care., Outcomes: The insights gained from this research initiative will serve as a foundation for the ongoing enhancement of MIAF. Consequently, this project has the capacity to advance evidence-based child welfare practices by refining processes and strategies to better serve vulnerable children and youth., Conclusion: Facilitated by a multidisciplinary team, this project will contribute to advancing research in the field, enhancing practice, and informing policy during a pivotal stage of deinstitutionalization in Portugal., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Baptista et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Climate change can have direct and indirect effects on human health. Direct effects can include an increase in extreme weather events, such as heatwaves and floods, as well as an increase in the spread of vector-borne and infectious diseases, which may lead to a set of health problems and diseases. Indirect effects can include changes in air quality, water availability, and food production and distribution. These changes can lead to an increase in respiratory problems, malnutrition, and increased food insecurity. There is a perceived need to investigate the extent to which Higher Education Institutions (HEIs) are engaged in efforts to foster a greater understanding of the connections between climate change and health. In this context, this preliminary investigation offers an overview of the relationships between climate change and health. By means of a survey among teaching staff and researchers at HEIs from 42 countries across all continents working on the connection between climate change and health. The study has investigated the extent to which current provisions for education and training on the connection between climate change and health are being considered and how current needs in terms of policy development, research, and training are being met. A series of case studies illustrate how universities worldwide are actively developing strategies and implementing measures to address climate change and health. The study concludes by providing specific recommendations aimed at facilitating the handling of issues related to climate change and health in a higher education context., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Leal Filho et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Childhood, adolescent and young adult (CAYA) cancer survivors are vulnerable to adverse late-effects. For CAYA cancer survivors, tobacco smoking is the most important preventable cause of ill-health and early death. Yet, effective strategies to support smoking cessation in this group are lacking. The PRISM study aims to undertake multi-method formative research to explore the need for, and if appropriate, inform the future development of an evidence-based and theory-informed tobacco smoking cessation intervention for CAYA cancer survivors., Materials and Methods: PRISM involves three phases of: 1) an environmental scan using multiple strategies to identify and examine a) smoking cessation interventions for CAYA cancer survivors that are published in the international literature and b) current smoking cessation services in England that may be available to, or tailorable to, CAYA cancer survivors; 2) a qualitative study involving semi-structured interviews with CAYA cancer survivors (aged 16-29 years and who are current or recent ex-smokers and/or current vapers) to explore their views and experiences of smoking, smoking cessation and vaping; and 3) stakeholder workshops with survivors, healthcare professionals and other stakeholders to consider the potential for a smoking cessation intervention for CAYA cancer survivors and what such an intervention would need to target and change. Findings will be disseminated to patient groups, healthcare professionals and researchers, through conference presentations, journal papers, plain English summaries and social media., Discussion: PRISM will explore current delivery of, perceived need for, and barriers and facilitators to, smoking cessation advice and support to CAYA cancer survivors from the perspective of both survivors and healthcare professionals. A key strength of PRISM is the user involvement throughout the study and the additional exploration of survivors' views on vaping, a behaviour which often co-occurs with smoking. PRISM is the first step in the development of a person-centred, evidence- and theory-based smoking cessation intervention for CAYA cancer survivors who smoke, which if effective, will reduce morbidity and mortality in the CAYA cancer survivor population., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Brown et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Despite the high prevalence of mental health difficulties in children and young people with long-term health conditions (LTCs), these difficulties and experiences are often overlooked and untreated. Previous research demonstrated the effectiveness of psychological support provided via a drop-in mental health centre located in a paediatric hospital. The aim of this prospective non-randomised single-arm multi-centre interventional study is to determine the clinical effectiveness of drop-in mental health services when implemented at paediatric hospitals in England., Methods: It is hypothesised that families who receive psychological interventions through the drop-in services will show improved emotional and behavioural symptoms. Outcomes will be measured at baseline and at 6-month follow-up. The primary outcome is the difference in the total difficulties score on the Strengths and Difficulties Questionnaire (SDQ) reported by parent or child at 6 months. Secondary outcomes include self and parent reported Paediatric Quality of Life Inventory (PedsQL), self-reported depression (PHQ-9) and anxiety measures (GAD-7) and family satisfaction (CSQ-8)., Discussion: This trial aims to determine the clinical effectiveness of providing psychological support in the context of LTCs through drop-in mental health services at paediatric hospitals in England. These findings will contribute to policies and practice addressing mental health needs in children and young people with other long-term health conditions., Trial Registration: ISRCTN15063954, Registered on 9 December 2022., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Roach et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

With the growing popularity of clear aligners, more patients have chosen to use them instead of traditional orthodontic braces to correct their malocclusions. Clear aligners offer distinct advantages over conventional fixed braces, such as limited aesthetic impact, the convenience of easily removing them for meals, improved accessibility for brushing and flossing, and a treatment approach that avoids the use of metal, minimizing potential irritation to the cheeks and gums. Manufacturers point out a disadvantage that can be administered in this type of treatment. Still, to our knowledge, a comprehensive review of the published literature assessing the adverse/negative effects of clear aligners has not yet been conducted. A systematic review, with or without meta-analysis, will be performed. The inclusion criteria will be studies involving individuals using clear aligners and reporting potential adverse/negative effects during or after treatment. No restrictions about time or language will be applied. The studies screening will be conducted in two stages. Two independent reviewers will initially evaluate the title and abstract under the eligibility criteria. Subsequently, the same two reviewers will examine the articles' full text in-depth. The results will be synthesized in the form of a narrative description and incorporate a meta-analysis if justified. Furthermore, we will present details regarding the sample characteristics, intervention, study objectives, methodologies employed, and primary findings. This study aims to investigate the potential adverse effects and their frequency among orthodontic patients wearing clear aligners. Moreover, the outcomes of this review have the potential to illuminate specific inherent limitations of aligner therapy as a comprehensive orthodontic approach., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Ronchi Lemos et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Climate change and rapid population ageing pose challenges for communities and public policies. This systematic review aims to gather data from studies that present health indicators establishing the connection between climate change and the physical and mental health of the older population (≥ 65 years), who experience a heightened vulnerability to the impacts of climate change when compared to other age cohorts. This review was conducted according to the PICO strategy and following Cochrane and PRISMA guidelines. Three databases (PubMed, Scopus and Greenfile) were searched for articles from 2015 to 2022. After applying inclusion and exclusion criteria,nineteen studies were included. The findings indicated that various climate change phenomena are associated with an elevated risk of mortality and morbidity outcomes in older adults. These included cardiovascular, respiratory, renal, and mental diseases, along with physical injuries. Notably, the impact of climate change was influenced by gender, socioeconomic status, education level, and age-vulnerability factors. Climate change directly affected the health of older adults through ambient temperature variability, extreme and abnormal temperatures, strong winds, sea temperature variability, extreme El Niño-southern Oscillation (ENSO) conditions and droughts, and indirectly by air pollution resulting from wildfires. This review presents further evidence confirming that climate change significantly impacts the health and well-being of older adults. It highlights the urgency for implementing effective strategies to facilitate adaptation and mitigation, enhancing the overall quality of life for all individuals., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Figueiredo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Noise exposure during pregnancy may affect a child's auditory system, which may disturb fetal learning and language development. We examined the impact of occupational noise exposure during pregnancy on children's language acquisition at the age of one., Methods: A cohort study was conducted among women working in the food industry, as kindergarten teachers, musicians, dental nurses, or pharmacists who had a child aged <1 year. The analyses covered 408 mother-child pairs. Language acquisition was measured using the Infant-Toddler Checklist. An occupational hygienist assessed noise exposure individually as no (N = 180), low (70-78 dB; N = 108) or moderate/high exposure (>79 dB; N = 120)., Results: Among the boys, the adjusted mean differences in language acquisition scores were -0.4 (95% CI -2.5, 1.8) for low, and -0.7 (95% CI -2.9, 1.4) for moderate/high exposure compared to no exposure. Among the girls the respective scores were +0.1 (95% CI -2.2, 2.5) and -0.1 (95% CI -2.3, 2.2). Among the children of kindergarten teachers, who were mainly exposed to human noise, low or moderate exposure was associated with lower language acquisition scores. The adjusted mean differences were -3.8 (95% CI -7.2, -0.4) for low and -4.9 (95% CI -8.6, -1.2) for moderate exposure., Conclusions: In general, we did not detect an association between maternal noise exposure and children's language acquisition among one-year-old children. However, the children of kindergarten teachers exposed to human noise had lower language acquisition scores than the children of the non-exposed participants. These suggestive findings merit further investigation by level and type of exposure., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Jungewelter et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

While extensive research on traditional model species has significantly advanced the biological sciences, the ongoing search for new model organisms is essential to tackle contemporary challenges such as human diseases or climate change, and fundamental phenomena including adaptation or speciation. Recent methodological advances such as next-generation sequencing, gene editing, and imaging are widely applicable and have simplified the selection of species with specific traits from the wild. However, a critical milestone in this endeavor remains the successful cultivation of selected species. A historically overlooked but increasingly recognized group of non-model organisms are cave dwellers. These unique animals offer invaluable insights into the genetic basis of human diseases like eye degeneration, metabolic and neurological disorders, and basic evolutionary principles and the origin of adaptive phenotypes. However, to take advantage of the beneficial traits of cave-dwelling animals, laboratory cultures must be established-a practice that remains extremely rare except for the cavefish Astyanax mexicanus. For most cave-dwelling organisms, there are no published culturing protocols. In this study, we present the results of our multi-year effort to establish laboratory cultures for a variety of invertebrate groups. We have developed comprehensive protocols for housing, feeding, and husbandry of cave dwellers and their surface relatives. Our recommendations are versatile and can be applied to a wide range of species. Hopefully our efforts will facilitate the establishment of new laboratory animal facilities for cave-dwelling organisms and encourage their greater use in experimental biology., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Lukić et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

A comprehensive analysis of outdoor weathering and soil burial of cork during 1-year experiments was carried out with measurements of CIELAB color parameters, cellular observations by scanning electron microscopy, and surface chemical features analysed by ATR-FTIR and wet chemical analysis. Cork applied in outdoor conditions above and below ground retained its physical structure and integrity without signs of deterioration or fracturing. The cellular structure was maintained with some small changes at the one-cell layer at the surface, featuring cellular expansion and minute cell wall fractures. Surface color and chemistry showed distinct results for outdoor exposure and soil burial. The weathered cork surfaces acquired a lighter color while the soil buried cork surfaces became darker. With outdoor weathering, the cork polar solubles increased (13.0% vs. 7.6% o.d. mass) while a substantial decrease of lignin occurred (about 28% of the original lignin was removed) leading to a suberin-enriched cork surface. The chemical impact on lignin is therefore responsible for the surface change towards lighter colors. Soil-burial induced hydrolysis of ester bonds of suberin and xylan, and the lignin-enriched cork surface displayed a dark brown color. FTIR and wet chemical results were consistent. Overall cork showed a considerable structural and physical stability that allows its application in outdoor conditions, namely for building façades or other surfacing applications. Architects and designers should take into account the color dynamics of the cork surfaces., Competing Interests: The authors have declared that no competing interests exist, (Copyright: © 2024 Miranda et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Acute otitis media (AOM) is a common childhood disease frequently caused by Streptococcus pneumoniae. Pneumococcal conjugate vaccines (PCV7, PCV10, PCV13) can reduce the risk of AOM but may also shift AOM etiology and serotype distribution. The aim of this study was to review estimates from published literature of the burden of AOM in Europe after widespread use of PCVs over the past 10 years, focusing on incidence, etiology, serotype distribution and antibiotic resistance of Streptococcus pneumoniae, and economic burden., Methods: This systematic review included published literature from 31 European countries, for children aged ≤5 years, published after 2011. Searches were conducted using PubMed, Embase, Google, and three disease conference websites. Risk of bias was assessed with ISPOR-AMCP-NPC, ECOBIAS or ROBIS, depending on the type of study., Results: In total, 107 relevant records were identified, which revealed wide variation in study methodology and reporting, thus limiting comparisons across outcomes. No homogenous trends were identified in incidence rates across countries, or in detection of S. pneumoniae as a cause of AOM over time. There were indications of a reduction in hospitalization rates (decreases between 24.5-38.8% points, depending on country, PCV type and time since PCV introduction) and antibiotic resistance (decreases between 14-24%, depending on country), following the widespread use of PCVs over time. The last two trends imply a potential decrease in economic burden, though this was not possible to confirm with the identified cost data. There was also evidence of an increase in serotype distributions towards non-vaccine serotypes in all of the countries where non-PCV serotype data were available, as well as limited data of increased antibiotic resistance within non-vaccine serotypes., Conclusions: Though some factors point to a reduction in AOM burden in Europe, the burden still remains high, residual burden from uncovered serotypes is present and it is difficult to provide comprehensive, accurate and up-to-date estimates of said burden from the published literature. This could be improved by standardised methodology, reporting and wider use of surveillance systems., Competing Interests: ET and GB are employees of MSD. HRC, HS and NN are employees of Quantify Research, which received consulting fees from MSD to support the preparation and development of the manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The authors report no other conflicts of interest in this work., (Copyright: © 2024 Ricci Conesa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Radon springs, characterized by their high concentrations of radon gas (Rn222), are extreme environments with unique physicochemical conditions distinct from conventional aquatic ecosystems. Our research aimed to investigate microbial life in radon springs, focusing on isolating extremophilic bacteria and assessing their resistance to adverse conditions. Our study revealed the prevalence of Actinomycetia species in the radon spring environment. We conducted various tests to evaluate the resistance of these isolates to oxidative stress, irradiation, desiccation, and metal ion content. These extremophilic bacteria showed overall higher resistance to these stresses compared to control strains. Lipidomic analysis was also employed to provide insights into the adaptive mechanisms of these bacteria which were found mainly in the correlations among individual clusters and changes in content of fatty acids (FA) as well as differences between content and type of FAs of environmental isolates and type strains., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Timkina et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: The queen bee phenomenon (QBP) describes the behavioural response that occurs when women achieve success in a male-dominated environment, and in this position of authority, treat their female subordinates more critically. It has been demonstrated in business, academia, the military, and police force. The goal of this study was to determine whether the QBP occurs in surgical specialties. We hypothesized that female surgeons, fellows, and senior surgical residents would be more critical in their assessment of junior female residents than their male counterparts., Methods: A scenario-based survey was distributed via email to all Canadian surgical programs between February and March 2021. Scenarios were designed to assess either female or male learners. Centers distributed surveys to attending surgeons, surgical fellows, resident physicians, and affiliate surgeons. Respondents average Likert score for female-based and male-based questions were calculated. Subgroup analyses were performed based on gender, age, seniority, and surgical specialty., Results: 716 survey responses were collected, with 387 respondents identifying as male (54%) and 321 identifying as female (45%). 385 attending surgeons (54%), 66 fellows (9%), and 263 residents (37%) responded. The mean Likert scores for female respondents assessing female learners was significantly lower than male learners (p = 0·008, CI = 95%). During subgroup analysis, some specialties demonstrated significant scoring differences., Discussion: The QBP was shown to be present among surgical specialties. Female respondents assessed female learners more critically than their male counterparts., Conclusion: These findings highlight the importance of tackling organizational biases to create more equitable educational and work environment in surgery., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Goff et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Autologous haematopoietic stem cell transplantation (AHSCT) is increasingly used as a treatment for aggressive multiple sclerosis (MS) and has the potential to induce long-term remission and resolution of disease activity. Despite the extensive research on treatment outcome after AHSCT, the experience of living with MS after AHSCT has not been previously described in the scientific literature. The aim of this study was to explore long-term lived experience of people with MS treated with AHSCT., Methods and Findings: To exclude selection bias, all persons treated with AHSCT for MS at Uppsala University Hospital, Sweden, between 2004 and 2007 (n = 10), were asked to participate in the study, and all accepted. Open-ended interviews were conducted, digitally recorded, transcribed verbatim, and then subjected to qualitative content analysis with an inductive approach. Five main themes emerged from the interviews: (I) being diagnosed with MS-an unpredictable existence; (II) a new treatment-a possibility for a new life; (III) AHSCT-a transition; (IV) reclaiming life; and (V) a bright future accompanied by insecurity. AHSCT was described by the participants in terms of a second chance and an opportunity for a new life. The treatment became a transition from a state of illness to a state of health, enabling a previous profound uncertainty to wane and normality to be restored. Although participants of different age and sex were included, the main limitation of this study is the relatively small number of participants. Also, the inclusion of persons from one centre alone could restrict transferability of the results., Conclusions: The results give a first insight into lived experience following a highly effective induction treatment for MS, and the experience of not having MS anymore. Underpinned by previously described outcome following AHSCT, the results of this study challenge the current view on MS as a chronic disease with no possible cure., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Tolf et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Anakinra and tocilizumab are used for severe Covid-19, but only one previous randomized controlled trial (RCT) has studied both. We performed a multi-center RCT comparing anakinra or tocilizumab versus usual care (UC) for adults at high risk of deterioration., Methods: The study was conducted June 2020 to March 2021. Eligibility required ≥ 5 liters/minute of Oxygen to maintain peripheral oxygen saturation at ≥ 93%, CRP > 70 mg/L, ferritin > 500 μg/L and at least two points where one point was awarded for lymphocytes < 1x 109/L; D-dimer ≥ 0.5 mg/L and; lactate dehydrogenase ≥ 8 microkatal/L. Patients were randomly assigned 1:1:1 to receive either a single dose of tocilizumab (8 mg/kg) or anakinra 100 mg IV QID for seven days or UC alone. The primary outcome was time to recovery., Results: Recruitment was ended prematurely when tocilizumab became part of usual care. Out of a planned 195 patients, 77 had been randomized, 27 to UC, 28 to anakinra and 22 to tocilizumab. Median time to recovery was 15, 15 and 11 days. Rate ratio for recovery for UC vs anakinra was 0.91, 0.47 to 1.78, 95% [CI], p = 0.8 and for UC vs tocilizumab 1.13, 0.55 to 2.30; p = 0.7. There were non-significant trends favoring tocilizumab (and to limited degree anakinra) vs UC for some secondary outcomes. Safety profiles did not differ significantly., Conclusion: Premature closure of trial precludes firm conclusions. Anakinra or tocilizumab did not significantly shorten time to clinical recovery compared to usual care. (IMMCoVA, NCT04412291, EudraCT: 2020-00174824)., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Sundén-Cullberg et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Musculoskeletal conditions are a major source of disability worldwide, and its burden have been rising in the last decades. Rural areas, in particular, are associated with higher prevalence of these conditions as well as higher levels of disability, which is likely related to other determinants that affect these communities. Although digital health has been identified as a potential solution to mitigate the impact of these determinants, it is also known that these populations may face barriers that limit the implementation of these interventions. Therefore, the aim of this scoping review is to comprehensively map the evidence regarding the implementation of digital health interventions in rural populations with chronic musculoskeletal conditions. We will include studies published from the year 2000; that report the use of digital interventions that promote prevention, treatment or monitoring of any chronic musculoskeletal condition or chronic pain from musculoskeletal origin, in patients that live in rural areas. This protocol follows the methodological framework for scoping reviews proposed by Arksey and O'Malley, as well as the Joana Briggs Institute (JBI) approach. We will conduct the search on Medline (PubMed), EMBASE, Web of Science and Scopus, as well as grey literature databases. Two independent reviewers will screen titles and abstracts followed by a full-text review to assess the eligibility of the articles. Data extracted will include the identification of the digital interventions used, barriers and enablers identified by the patients or healthcare providers, the patient-level outcomes measured, and the implementation strategies and outcomes reported. By mapping the evidence on the implementation of digital health interventions in rural communities with musculoskeletal conditions, this scoping review will enhance our understanding of their applicability in real-world settings., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Campos et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Founder variants in sarcomere protein genes account for a significant proportion of disease-causing variants in patients with hypertrophic cardiomyopathy (HCM). However, information on founder variants in non-sarcomeric protein genes, such as FHOD3, which have only recently been associated with HCM, remains scarce. In this study, we conducted a retrospective analysis of exome sequencing data of 134 probands with HCM for recurrent pathogenic variants. We discovered a novel likely pathogenic variant c.1646+2T>C in FHOD3 in heterozygous state in eight probands with HCM and confirmed its presence in seven additional relatives. Individuals with this variant had a wide range of ages at onset of the disease (4-63 years). No adverse cardiac events were observed. Haplotype analysis revealed that the individuals with this variant shared a genomic region of approximately 5 Mbp surrounding the variant, confirming the founder effect of the variant. FHOD3 c.1646+2T>C is estimated to have arisen 58 generations ago (95% CI: 45-81) in a common ancestor living on the Balkans. A founder FHOD3 c.1646+2T>C variant is the second most common genetic variant in our cohort of patients with HCM, occurring in 16% of probands with a known genetic cause of HCM, which represents a substantially higher proportion than the currently estimated 0.5-2% for causal FHOD3 variants. Our study broadens the understanding of the genetic causes of HCM and may improve the diagnosis of this condition, particularly in patients from the Balkans., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Vodnjov et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Peroxisomes are membrane-enclosed organelles with important roles in fatty acid breakdown, bile acid synthesis and biosynthesis of sterols and ether lipids. Defects in peroxisomes result in severe genetic diseases, such as Zellweger syndrome and neonatal adrenoleukodystrophy. However, many aspects of peroxisomal biogenesis are not well understood. Here we investigated delivery of tail-anchored (TA) proteins to peroxisomes in mammalian cells. Using glycosylation assays we showed that peroxisomal TA proteins do not enter the endoplasmic reticulum (ER) in both wild type (WT) and peroxisome-lacking cells. We observed that in cells lacking the essential peroxisome biogenesis factor, PEX19, peroxisomal TA proteins localize mainly to mitochondria. Finally, to investigate peroxisomal TA protein targeting in cells with fully functional peroxisomes we used a proximity biotinylation approach. We showed that while ER-targeted TA construct was exclusively inserted into the ER, peroxisome-targeted TA construct was inserted to both peroxisomes and mitochondria. Thus, in contrast to previous studies, our data suggest that some peroxisomal TA proteins do not insert to the ER prior to their delivery to peroxisomes, instead, mitochondria can be involved., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Somborac et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Activation of Map kinase/Erk signalling downstream of fibroblast growth factor (Fgf) tyrosine kinase receptors regulates gene expression required for mesoderm induction and patterning of the anteroposterior axis during Xenopus development. We have proposed that a subset of Fgf target genes are activated in the embyo in response to inhibition of a transcriptional repressor. Here we investigate the hypothesis that Cic (Capicua), which was originally identified as a transcriptional repressor negatively regulated by receptor tyrosine kinase/Erk signalling in Drosophila, is involved in regulating Fgf target gene expression in Xenopus. We characterise Xenopus Cic and show that it is widely expressed in the embryo. Fgf overexpression or ectodermal wounding, both of which potently activate Erk, reduce Cic protein levels in embryonic cells. In keeping with our hypothesis, we show that Cic knockdown and Fgf overexpression have overlapping effects on embryo development and gene expression. Transcriptomic analysis identifies a cohort of genes that are up-regulated by Fgf overexpression and Cic knockdown. We investigate two of these genes as putative targets of the proposed Fgf/Erk/Cic axis: fos and rasl11b, which encode a leucine zipper transcription factor and a ras family GTPase, respectively. We identify Cic consensus binding sites in a highly conserved region of intron 1 in the fos gene and Cic sites in the upstream regions of several other Fgf/Cic co-regulated genes, including rasl11b. We show that expression of fos and rasl11b is blocked in the early mesoderm when Fgf and Erk signalling is inhibited. In addition, we show that fos and rasl11b expression is associated with the Fgf independent activation of Erk at the site of ectodermal wounding. Our data support a role for a Fgf/Erk/Cic axis in regulating a subset of Fgf target genes during gastrulation and is suggestive that Erk signalling is involved in regulating Cic target genes at the site of ectodermal wounding., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Cowell et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Young adults entering the workforce have an almost 40% greater risk of work-related mental health problems than other working age groups. Common mental disorders (CMDs) constitute the majority of such mental health problems. Managers are crucial in promoting a good psychosocial work environment and preventing sick leave. The study aims to explore managers' experience of 1) causes of sick leave in the personal and work-life of young employees with CMDs, and 2) prevention of such sick leave. A gender perspective is applied to examine managers' experience of causes and prevention of sick leave in relation to male and female employees and male and female-dominated occupations., Material and Methods: A qualitative design was applied and 23 semi-structured interviews were conducted with Swedish managers experienced in supervising young employees with CMDs. The interviews were analysed with conventional content analysis and the managers' experience of similarities and differences between young female and male employees and occupations were explored through reflective notes., Results: Four main categories and eight subcategories describe the managers' experience of the causes of sick leave due to CMD among young employees. The main categories are: 1) entering work life when already worn-out, 2) struggling with too high expectations at work, 3) having a challenging personal life, and 4) being unable to manage specific occupational challenges and demands. Gender differences were found in six subcategories regarding, e.g., work demands and problems in personal relationships. One main category and three subcategories describe how this type of sick leave might be prevented, with managers emphasizing the need to ease the transition into work life. Gender differences in the prevention of sick leave were found in one subcategory regarding communication about workers' health and problems at work., Conclusion: Our findings show that gender norms and the expectations of young men and women are factors of importance in managers' experience of the development and prevention of CMDs. These results can inform their preventive work and their supervision and introduction of newly-employed young adults., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Tinnerholm Ljungberg et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: Common mental disorder (CMD) is the most common reason for sick leave among young employees in Sweden, with young women having a higher prevalence. There is a lack of studies focusing on young employees' own perceptions of sick leave. The aim was twofold: to investigate 1) perceived causes of sick leave due to CMD among young employees, and 2) differences and similarities among women and men., Methods: Using a qualitative design with an applied gender perspective enabled us to capture young employees' gendered experiences and consider cultural and social aspects of their situations. We interviewed 13 women and 12 men (aged 20-29) with experience of being on sick leave and applied a conventional inductive content analysis., Results: Six categories were identified: a) Being new to the labour market and the workplace; b) Want to prove themselves; c) To be exposed to poor working conditions; d) Relations at work; e) Being vulnerable; and f) Additional private life burdens., Conclusion: This study adds to the understanding of young employees' perceived causes of sick leave due to CMD, by letting them share their experiences of events prior to sick leave connected to work and private life. Similarities and differences in women's and men's experiences were revealed. Overall, both young men and women describe a more pressured work situation for young women compared to their male counterparts, that young women take more social responsibility in private life and at work whereas men on the other hand find it harder to disclose mental health problems., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Olsson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Breast cancer therapy improved significantly, allowing for different surgical approaches for the same disease stage, therefore offering patients different aesthetic outcomes with similar locoregional control. The purpose of the CINDERELLA trial is to evaluate an artificial-intelligence (AI) cloud-based platform (CINDERELLA platform) vs the standard approach for patient education prior to therapy., Methods: A prospective randomized international multicentre trial comparing two methods for patient education prior to therapy. After institutional ethics approval and a written informed consent, patients planned for locoregional treatment will be randomized to the intervention (CINDERELLA platform) or controls. The patients in the intervention arm will use the newly designed web-application (CINDERELLA platform, CINDERELLA APProach) to access the information related to surgery and/or radiotherapy. Using an AI system, the platform will provide the patient with a picture of her own aesthetic outcome resulting from the surgical procedure she chooses, and an objective evaluation of this aesthetic outcome (e.g., good/fair). The control group will have access to the standard approach. The primary objectives of the trial will be i) to examine the differences between the treatment arms with regards to patients' pre-treatment expectations and the final aesthetic outcomes and ii) in the experimental arm only, the agreement of the pre-treatment AI-evaluation (output) and patient's post-therapy self-evaluation., Discussion: The project aims to develop an easy-to-use cost-effective AI-powered tool that improves shared decision-making processes. We assume that the CINDERELLA APProach will lead to higher satisfaction, better psychosocial status, and wellbeing of breast cancer patients, and reduce the need for additional surgeries to improve aesthetic outcome., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Kaidar-Person et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: Maraviroc may reduce hepatic inflammation in people with HIV and non-alcoholic fatty liver disease (HIV-NAFLD) through CCR5-receptor antagonism, which warrants further exploration., Methods: We performed an open-label 96-week randomised-controlled feasibility trial of maraviroc plus optimised background therapy (OBT) versus OBT alone, in a 1:1 ratio, for people with virologically-suppressed HIV-1 and NAFLD without cirrhosis. Dosing followed recommendations for HIV therapy in the Summary of Product Characteristics for maraviroc. The primary outcomes were safety, recruitment and retention rates, adherence and data completeness. Secondary outcomes included the change in Fibroscan-assessed liver stiffness measurements (LSM), controlled attenuation parameter (CAP) and Enhanced Liver Fibrosis (ELF) scores., Results: Fifty-three participants (53/60, 88% of target) were recruited; 23 received maraviroc plus OBT; 89% were male; 19% had type 2 diabetes mellitus. The median baseline LSM, CAP & ELF scores were 6.2 (IQR 4.6-7.8) kPa, 325 (IQR 279-351) dB/m and 9.1 (IQR 8.6-9.6) respectively. Primary outcomes: all individuals eligible after screening were randomised; there was 92% (SD 6.6%) adherence to maraviroc [target >90%]; 83% (95%CI 70%-92%) participant retention [target >65%]; 5.5% of data were missing [target <20%]. There were noo Serious Adverse Reactions; mild-moderate intensity Adverse Reactions were reported by five participants (5/23, 22% (95%CI 5%-49%)) [target <10%]. All Adverse Reactions resolved. Secondary outcomes: no important differences were seen by treatment group for the change from baseline in LSM, CAP or ELF scores., Conclusions: This feasibility study provides preliminary evidence of maraviroc safety amongst people with HIV-NAFLD, and acceptable recruitment, retention, and adherence rates. These data support a definitive randomised-controlled trial assessing maraviroc impact on hepatic steatosis and fibrosis., Trial Registration: Clinical trial registry: ISCRTN, registration number 31461655., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: DB: research grant from Gilead Sciences. SV: speaker fees, consultancy and research grants from Gilead Sciences and speaker fees from Abbvie and Dr Falk. YG: honoraria for educational meeting development and delivery, advisory board attendance and conference sponsorship from ViiV and Gilead. MN: travel expenses, grants and advisory board membership for Gilead, ViiV and GSK. CO: research grants from Viiv, Gilead, MSD, Astra Zeneca, Janssen and honoraria, travel scholarships and lecture fees from Viiv, Gilead, MSD, Janssen. AF: paid advisory work for Gilead, ViiV and Tibotec. EC: principal investigator for trials funded by ViiV and GSK; expert panel member for ViiV; funding received for educational talks from Gilead and ViiV. DC: research grant from Gilead Sciences. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Bradshaw et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Flow-mediated slowing (FMS) is a non-invasive measure of endothelial function measured through reactive hyperemia-induced changes in pulse wave velocity (PWV). FMS is suggested to mitigate known pitfalls of flow-mediated dilation (FMD) including suboptimal repeatability and high-operator dependency. However, the few single-rater studies that examined FMS repeatability have shown controversial results and used only regional measurements of PWV, which might not reflect local brachial artery stiffness responses to reactive hyperemia. We assessed the inter- and intra-rater repeatability of ultrasound-based changes in local PWV (FMS) and diameter (FMD). Twenty-four healthy male participants aged 23-75 yr, were examined on two separate days. Reactive hyperemia-induced changes in PWV were calculated using a tailored R-script. The inter- and intra-rater repeatability were tested with the intraclass correlation coefficient (ICC), coefficient of variation (CV), and the Bland-Altman plot estimates. The inter-rater repeatability of FMS (bias: -0.08%; ICC: 0.85; 95% CI: 0.65 to 0.93; CV: 11%) and FMD (bias: -0.02%; ICC: 0.98; 95% CI: 0.97 to 0.99; CV: 7%) showed overall good repeatability over different days. The intra-rater repeatability of FMD (1st rater: bias: 0.27%; ICC: 0.90; 95% CI: 0.78 to 0.96; CV: 14%; 2nd rater: bias: 0.60%; ICC: 0.85; 95% CI: 0.64 to 0.94; CV: 18%) was better than FMS (1st rater: bias: -1.03%; ICC: 0.76; 95% CI: 0.44 to 0.91; CV: 21%; 2nd rater: bias:-0.49%; ICC: 0.70; 95% CI: 0.34 to 0.80; CV: 23%) but not different between raters. Ultrasound-based local measurements of PWV deceleration reactive hyperemia were repeatable among the raters., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Marôco et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The importance of the muscle-tendon complex in sport and for activities of everyday living is well recognised. The free oscillation technique is frequently used to determine the musculo-articular "apparent" stiffness (obtained from vertical ground reaction force) and other parameters. However, an in-depth understanding of the muscle-tendon complex can be gained by separating the muscle (soleus) and the tendon (Achilles tendon) components and studying the "true" stiffness for each of these components (by considering the ankle joint moment arms), which can be valuable in improving our understanding of training, injury prevention, and recovery programs. Hence, this study aimed to investigate if muscle and tendon stiffness (i.e., "true" stiffness) are similarly affected by different impulse magnitudes when using the free-oscillation technique. Three impulse magnitudes (impulse 1, 2 and 3), corresponding to peak forces of 100, 150 and 200 N, were used to estimate the stiffness of the ankle joint in 27 males, using multiple loads (10, 15, 20, 25, 30, 35, and 40 kg). A significant decrease (p < 0.0005) was found in musculo-articular "apparent" stiffness (29224 ± 5087 N.m-1; 27839 ± 4914 N.m-1; 26835 ± 4880 N.m-1) between impulses 1, 2 and 3 respectively, when loads were collapsed across groups. However, significant differences (p < 0.001) were only found between the median (Mdn) of impulse 1 (Mdn = 564.31 (kN/m)/kN) and 2 (Mdn = 468.88 (kN/m)/kN) and between impulse 1 (Mdn = 564.31 (kN/m)/kN) and 3 (Mdn = 422.19 (kN/m)/kN), for "true" muscle stiffness, but not for "true" tendon stiffness (Mdn = 197.35 kN/m; Mdn = 210.26 kN/m; Mdn = 201.60 kN/m). The results suggest that the musculo-articular "apparent" stiffness around the ankle joint is influenced by the magnitude of the impulse applied. Interestingly, this is driven by muscle stiffness, whereas tendon stiffness appears to be unaffected., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Faria et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Cognitive styles are commonly studied constructs in cognitive psychology. The theory of field dependence-independence was one of the most important cognitive styles. Yet in the past, its measurement had significant shortcomings in validity and reliability. The theory of analytic and holistic cognitive styles attempted to extend this theory and overcome its shortcomings. Unfortunately, the psychometric properties of its measurement methods were not properly verified. Furthermore, new statistical approaches, such as analysis of reaction times, have been overlooked by current research. The aim of this pre-registered study was to verify the psychometric properties (i.e., factor structure, split-half reliability, test-retest reliability, discriminant validity with intelligence and personality, and divergent, concurrent and predictive validity) of several methods routinely applied in the field. We developed/adapted six methods based on self-report questionnaires, rod-and-frame principles, embedded figures, and hierarchical figures. The analysis was conducted on 392 Czech participants, with two data collection waves. The results indicate that the use of methods based on the rod-and-frame principle may be unreliable, demonstrating no absence of association with intelligence. The use of embedded and hierarchical figures is recommended. The self-report questionnaire used in this study showed an unsatisfactory factor structure and also cannot be recommended without futher validation on independent samples. The findings also did not correspond with the original two-dimensional theory., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Lacko et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: During the COVID-19 pandemic, changes in working life occurred, even in Sweden, where there was no general lockdown. The aim of this study was to examine how the COVID-19 pandemic was perceived as affecting the hindering and enabling factors among young employees with CMD to remain at or return to work, here as investigated from the perspective of young employees and managers., Material and Methods: A qualitative design was applied with semistructured interviews with 23 managers and 25 young employees (20-29 years old). The interviews were recorded and transcribed verbatim, and the parts of the interviews related to the aim of this article were analysed using conventional content analysis., Results: The hindering factors were changed working conditions, decreased well-being when spending more time at home, and uncertainty. The enabling factors were decreased demands, increased balance, and well-functioning work processes. For managers it is important to be aware of warning signals indicating blurred boundaries between work and private life, to create and maintain well-functioning communication, and leave room for recovery., Conclusion: The hindering and enabling factors can be described as two sides of the same coin. Changes in the working conditions during the pandemic led to difficulties for both young employees and managers when the margins of maneuver were insufficient., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Wallberg et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Data about long-term prognosis after hospitalisation of elderly multimorbid patients remains scarce., Objectives: Evaluate medium and long-term prognosis in hospitalised patients older than 75 years of age with multimorbidity. Explore the impact of gender, age, frailty, physical dependence, and chronic diseases on mortality over a seven-year period., Methods: We included prospectively all patients hospitalised for medical reasons over 75 years of age with two or more chronic illnesses in a specialised ward. Data on chronic diseases were collected using the Charlson comorbidity index and a questionnaire for disorders not included in this index. Demographic characteristics, Clinical Frailty Scale, Barthel index, and complications during hospitalisation were collected., Results: 514 patients (46% males) with a mean age of 85 (± 5) years were included. The median follow-up was 755 days (interquartile range 25-75%: 76-1,342). Mortality ranged from 44% to 68%, 82% and 91% at one, three, five, and seven years. At inclusion, men were slightly younger and with lower levels of physical impairment. Nevertheless, in the multivariate analysis, men had higher mortality (p<0.001; H.R.:1.43; 95% C.I.95%:1.16-1.75). Age, Clinical Frailty Scale, Barthel, and Charlson indexes were significant predictors in the univariate and multivariate analysis (all p<0.001). Dementia and neoplastic diseases were statistically significant in the unadjusted but not the adjusted model. In a cluster analysis, three patterns of patients were identified, with increasing significant mortality differences between them (p<0.001; H.R.:1.67; 95% CI: 1.49-1.88)., Conclusions: In our cohort, individual diseases had a limited predictive prognostic capacity, while the combination of chronic illness, frailty, and physical dependence were independent predictors of survival., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Molina et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: People with kidney failure require renal replacement therapy in the form of dialysis or a kidney transplant for survival. Many facets of their life, both within and outside the dialysis unit, are impacted by the management of this disease. It is important to comprehend the experiences of people undergoing hemodialysis in order to improve the care provided to them. Therefore, this study aimed to explore the experiences of patients undergoing maintenance hemodialysis in Ethiopia., Methods: A qualitative descriptive study was conducted at two healthcare facilities in Ethiopia. Individual interviews with 15 participants (men and women aged 19-63), undergoing hemodialysis in Ethiopia, were analyzed using reflexive thematic analysis., Results: The analysis resulted in five themes: Feeling grateful, Facing a restricted life, a Supportive environment, Dreaming of a transplant, and Leading a hassled life. The subthemes include Trust in treatment, Faith in God, Challenging fluid and dietary restrictions, Being too fatigued to socialize, Being stigmatized, Family and social support, Supportive healthcare, Lacking a donor and sponsor, COVID-19 as a barrier, Financial constraints, Inaccessibility to care and transport and Access line implantation. Despite being dependent on a machine and having to deal with food and fluid restrictions as well as financial challenges, participants were hopeful and dreamed of a transplant., Conclusion: From the study's participants, it was discovered that the experiences of people with kidney failure undergoing hemodialysis were generally, considerably negative narratives. Based on the results we recommend development of multidisciplinary teams to better meet patients' physical, emotional, and social needs while undergoing hemodialysis. Such a team should also involve the patient's family members when caring for patients on hemodialysis., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Gebrie et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)