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Abstract Polyphasic approach has become a generally accepted method for the classification of cyanobacteria. In this study, we present a detailed characterisation of two strains, KUCC C1 and KUCC C2, isolated from the Curonian Lagoon and classified to the Aphanizomenon genus. Despite phylogenetic similarity, the strains differ with respect to morphology, ultrastructure characteristics, and the metabolite profile. In the KUCC C1 extract, three unknown peptides and eight anabaenopeptins were detected, while KUCC C2 produced one unknown peptide and one aeruginosin. In both strains, a total of eleven pigments were detected. The production of myxoxantophyll, chlorophyll-a, chlorophylide-a, and zeaxanthin was higher in KUCC C2 than in KUCC C1. Extracts from both strains of Aphanizomenon also had different effects in antibacterial, anticancer and enzyme inhibition assays. Comprehensive analyses of Aphanizomenon strains performed in this study showed significant diversity between the isolates from the same bloom sample. These differences should be considered when exploring the ecological significance and biotechnological potential of a given population.

Abstract Low drug adherence is a major obstacle to the benefits of pharmacotherapies and it is therefore important to identify factors associated with discontinuing or being poorly adherent to a prescribed treatment regimen. Using high-quality nationwide health registry data and genome-wide genotyping, we evaluate the impact of socio-demographic and genetic risk factors on adherence and persistence for 5 common medication classes that require long-term, regular therapy (N = 1,814,591 individuals from Finnish nationwide registries, 217,005 with genetic data from Finland and Estonia). Need for social assistance and immigration status show a notable negative effect on persistence and adherence across the examined medications (odd ratios between 0.48 and 0.82 for persistence and between 1.1% to 4.3% decrease in adherence) while demographic and health factors show comparably modest or inconsistent effects. A genome-wide scan does not identify genetic variants associated with the two phenotypes, while some pharmacogenes (i.e. CYP2C9 and SLCO1B1) are modestly associated with persistence, but not with adherence. We observe significant genetic correlations between medication adherence and participation in research studies. Overall, our findings suggest that socio-economically disadvantaged groups would benefit from targeted interventions to improve the dispensing and uptake of pharmacological treatments.

Abstract Background The obligate intracellular bacterial family Chlamydiaceae comprises a number of different species that cause disease in various vertebrate hosts including humans. Chlamydia suis, primarily found in the gastrointestinal tract of pigs, is the only species of the Chlamydiaceae family to have naturally gained tetracycline resistance (TetR), through a genomic island (Tet-island), integrated into the middle of chromosomal invasin-like gene inv. Previous studies have hypothesised that the uptake of the Tet-island from a host outside the Chlamydiaceae family was a unique event, followed by spread among C. suis through homologous recombination. In vitro recombination studies have shown that Tet-island exchange between C. suis strains is possible. Our aim in this study was to gain a deeper understanding of the interclade recombination of the Tet-island, among currently circulating C. suis field strains compared to in vitro-generated recombinants, using published whole genome sequences of C. suis field strains (n = 35) and in vitro-generated recombinants (n = 63). Results We found that the phylogeny of inv better reflected the phylogeny of the Tet-island than that of the whole genome, supporting recombination rather than site-specific insertion as the means of transfer. There were considerable differences between the distribution of recombinations within in vitro-generated strains compared to that within the field strains. These differences are likely because in vitro-generated recombinants were selected for a tetracycline and rifamycin/rifampicin resistant background, leading to the largest peak of recombination across the Tet-island. Finally, we found that interclade recombinations across the Tet-island were more variable in length downstream of the Tet-island than upstream. Conclusions Our study supports the hypothesis that the occurrence of TetR strains in both clades of C. suis came about through interclade recombination after a single ancestral horizontal gene transfer event.

Abstract Background Paediatric palliative and hospice care aims to improve the quality of life of children with life-limiting and life-threatening conditions and their families. The number of these patients has risen significantly in recent years, resulting in an increased need for palliative care for this population. Although the need for paediatric palliative and hospice care is growing, meaningful outcome evaluation to demonstrate its effectiveness as a complex healthcare intervention is in its early stages. For complex interventions (programmes), theory-based evaluations have grown in prominence in recent years. They seek to understand how and why an intervention works by uncovering its underlying mechanisms by means of programme theory. To support both outcome evaluation in paediatric palliative care and a reflective practice of programme theorizing, we aimed to describe the construction of a programme theory for a specialist paediatric palliative and hospice care programme in Austria and to offer a reflective account of its development process. Methods We drew on a combination of theory-based evaluation frameworks to construct a programme theory consisting of an action and a change component. Through multiple iterations, incorporating different stakeholders’ perspectives and drawing on different sources of knowledge and theory, we theorized how and why the programme likely achieves its intended outcomes. Results The programme theory outlines the proposed chains of events, causal mechanisms and outcomes of a specialist paediatric palliative and hospice care programme for children and families in several areas corresponding to its main conceptual tenets. Through a range of activities and interventions, the programme triggers coping and adaptation mechanisms that ultimately contribute to family and child wellbeing in physical, psychological, social, and spiritual dimensions. Established trust and partnership between children/families and healthcare professionals as well as a person-centered and family-centered approach were identified as enabling factors. Conclusions Our findings provide insights into how a specialized paediatric palliative and hospice care programme works to achieve its intended outcomes for children and families. This helps demonstrate its impact, contributing to meaningful outcome evaluation and service improvement.

Compressed Natural Gas (CNG) is cleaner than diesel for powering heavy duty trucks. A framework for establishing mobile on-site CNG refueling at truck yards is proposed and evaluated for the Greater Toronto and Hamilton Area (GTHA), Canada. The locations for potential CNG hubs where mobile trailers obtain CNG to fuel parked trucks at yards were determined. Also, the demand representing parked CNG trucks was estimated across the GTHA. With 15 potential CNG hubs, location-allocation modeling suggests that one CNG hub located in the Peel region can cover 88% of the demand within a 30-minute driving window across the study area.

Abstract Objective Cell‐based outer vocal fold replacement (COVR) offers a potential treatment for severe vocal fold scarring or cancer reconstruction. Previous work in rabbits using human adipose‐derived stem cells (ASC) in fibrin suggested that a hybrid structure emerged within 2 months, containing both implanted and host cells. This project uses immunocytochemistry to better define the phenotypic fate of implanted cells and features of the extracellular environment. Methods Immunocytochemistry was performed on sections collected from rabbits 2 months after COVR implantation or scar surgery. Cellular targets included human leukocyte antigen (HLA), CD31, and smooth muscle actin (SMA). Results HLA was present in all implanted sections and was used to identify human cells. In adjacent sections, HLA‐positive cells were identified expressing CD31. SMA was not identified in the same cells as HLA. These markers were also present in injured vocal folds not receiving COVR. SMA protein content did not differ according to treatment. Conclusions Implanted human ASC persist in rabbit vocal folds. Some appear to express CD31, an endothelial marker. Smooth muscle actin, a marker of myofibroblast phenotype, was present in all sections regardless of treatment, and was not identified in hASC. Host cells also infiltrate the structure, producing a hybrid host‐graft vocal fold.

Hydrangea serrata, also knowen as the Japanese tea hortensia, is known for its sweet taste and health properties of bevarages produced from this plant. The H. serrata 3,4-dihydroisocoumarins, hydrangenol and phyllodulcin harbour a variety of biological activities and pharmacological properties. Therefore, a detailed understanding of dihydroisocoumarin biosynthesis in H. serrata is of major interest. Their biosynthesis is assumed to be enhanced by elicitors and mediated by polyketide synthases like in cases of phenylpropanoid derived phytoalexins. A de-novo transcriptome assembly of leaves and roots from the aluminium chloride treatment group versus the control group alongside with annotation was generated. Secondary plant metabolites were analysed by LC-MS. It revealed that a terpene synthase and a triterpenoid synthase gene as well as lignin biosynthesis encoding genes were upregulated in roots. Many genes for transporters, glycosyl, and other transferases as well as glycosylases were found to be differentially expressed in both organs. As no differentially expressed polyketide synthase gene homolog was found, the relative leaf and root 3,4-dihydroisocoumarin content was analysed by LC-MS measurement. Although Hydrangea species are known for their aluminium detoxification using phenylpropanoid-derived compounds, the levels of 3,4- dihydroisocoumarins were not enhanced. In this metabolite analysis, an organ- specific accumulation profile of hydrangenol, phyllodulcin, hydrangeic acid and their mono- and di-glycosides was figured out.

Introduction: Central nervous system tuberculosis (CNS TB), the most serious form of TB, is usually associated with an intense neuroinflammatory response and severe sequels, and it is often accompanied by human immunodeficiency virus (HIV) coinfection. Few works have studied mental functioning sequels in this population. Objective: The aim of this study was to characterize long-term neuropsychiatric sequels in central nervous system tuberculosis (CNS TB) patients and CNS TB/Human Immunodeficiency Virus (HIV) co-infected patients, and to describe some associated factors.Methods: Retrospective cohort study in CNS TB patients admitted from 2008 to 2018 in a Mexican neurological center in which sociodemographic, clinical, neuroimaging, cognitive, and neuropsychiatric data were collected. Cognitive sequel data were obtained from a screening tool that has been standardized and normalized for the Hispanic population. Neuropsychiatric data were obtained from the Neuropsychiatric Inventory Questionnaire and from medical records.Results: A total of 86 subjects were included, 23 had CNSTB and HIV. The mean age was 40.4 years, and 23% of patients had a history of pulmonary TB. The main symptoms were headache, fever, and cranial nerve palsy. Executive functions, visuospatial, and memory impairment were the most common neurocognitive se-quels, while the most frequent neuropsychiatric sequels were depression, irritability, and anxiety. There was a correlation between immunity (CD4+ T cell count) and executive functions.Conclusions: This is the first report in Mexican patients evaluating long-term neurocognitive sequels in CNS TB. Some clinical and sociodemographic traits seem to be neuroprotective factors against long-term neuropsychiatric sequels.

Abstract Background Video consultations between hospital-based neurologists and Emergency Medical Services (EMS) have potential to increase precision of decisions regarding stroke patient assessment, management and transport. In this study we explored the use of real-time video streaming for neurologist–EMS consultation from the ambulance, using highly realistic full-scale prehospital simulations including role-play between on-scene EMS teams, simulated patients (actors), and neurologists specialized in stroke and reperfusion located at the remote regional stroke center. Methods Video streams from three angles were used for collaborative assessment of stroke using the National Institutes of Health Stroke Scale (NIHSS) to assess symptoms affecting patient’s legs, arms, language, and facial expressions. The aim of the assessment was to determine appropriate management and transport destination based on the combination of geographical location and severity of stroke symptoms. Two realistic patient scenarios were created, with severe and moderate stroke symptoms, respectively. Each scenario was simulated using a neurologist acting as stroke patient and an ambulance team performing patient assessment. Four ambulance teams with two nurses each all performed both scenarios, for a total of eight cases. All scenarios were video recorded using handheld and fixed cameras. The audio from the video consultations was transcribed. Each team participated in a semi-structured interview, and neurologists and actors were also interviewed. Interviews were audio recorded and transcribed. Results Analysis of video-recordings and post-interviews (n = 7) show a more thorough prehospital patient assessment, but longer total on-scene time, compared to a baseline scenario not using video consultation. Both ambulance nurses and neurologists deem that video consultation has potential to provide improved precision of assessment of stroke patients. Interviews verify the system design effectiveness and suggest minor modifications. Conclusions The results indicate potential patient benefit based on a more effective assessment of the patient’s condition, which could lead to increased precision in decisions and more patients receiving optimal care. The findings outline requirements for pilot implementation and future clinical tests.

Abstract Background Errors of omissions affect the quality of nursing care in hospitals. The Missed Nursing Care Model explains that the reasons for missed care are linked with 1) demand for patient care, 2) labor resource allocation, 3) material resource allocation, and 4) relationship and communication factors. Scientific evidence points to a lack of adequate nursing staffing as the most important factor triggering missed care. However, it remains unclear how the different theoretical reasons for missed care are interlinked with reports on missed care from the perspective of nurses in acute care settings. The aim of this study was to explore non-trivial configurations of reasons for missed care that are associated with missed care interventions from the perspective of nurses working in general units in Austrian hospitals. Methods A cross-sectional study was conducted. Data collection was performed using the revised MISSCARE-Austria questionnaire. Our sample consisted of 401 nurses who provided complete data. Data were analyzed using qualitative comparative analysis. Configurational models of contextual factors, reasons for missed care, and missed nursing interventions were analyzed. Results In our study contextual factors were not consistent precursors of the reasons for missed care. Missed care was consistently present when the demand for patient care was high. A lack of labor resources, in combination with the other known reasons for missed care, was consistently observed when missed care occurred. Different configurations of reasons were found to be non-trivially associated with different types and frequencies of missed care. Conclusions To understand the complexity of the causal mechanisms of missed care, complexity theory may be necessary. Accordingly, a theoretical framework that acknowledges that complex systems, such as missed care, are composed of multiple interacting causal components must be further developed to guide new methodical approaches to enlighten its causal mechanisms.

Bladder cancer encapsulates a wide spectrum of disease severities, with non-muscle invasive bladder cancer (NMIBC) representing an entirely different entity from muscle-invasive disease. Bacillus Calmette-Guérin (BCG) is one of the most successful intravesical treatment methods for patients diagnosed. However, a considerable proportion of patients fail to respond to BCG treatment. Given the propensity for recurrence in patients with high-risk bladder cancer, these patients present with surgical dilemmas. There is currently no gold standard for salvage treatment post-BCG failure or unified definition as to what that means. In this review, we discuss the mechanisms of action and pathophysiology of BCG, potential theories behind BCG failure, and the scope of novel treatments for this surgical conundrum.

Purpose – This study aims to explore the effect of Problem-Based Learning Model (PBL) on the learning outcomes of students in grade XI of SMAN 4 Medan in writing an explanatory text in Indonesian language subject. By focusing on the effectiveness of PBL in improving students' writing skills, this study provides theoretical contributions to the development of learning theories as well as practical benefits for teachers and schools in improving the quality of learning. Method – The study used a quasi-experimental design with an experimental group and a control group. The approach was Problem Based Learning (PBL) Model. The research was conducted at SMAN 4 Medan involving students of grade XI. Data were collected through an explanatory text writing test conducted before (pretest) and after (posttest) the application of PBL. The analysis was conducted by comparing the posttest results between the experimental group using PBL and the control group using conventional learning methods. The results were analyzed to assess the effectiveness of PBL in improving students' writing ability. Findings – The results showed that the Problem-Based Learning Model (PBL) significantly improved students' learning outcomes in writing explanatory texts. Proven by the average value of posttest in the experimental group which is higher than the control group, which proves the effectiveness of PBL in the context of Indonesian language learning in class XI SMAN 4 Medan. Research Implications – The Problem-Based Learning (PBL) model enhances students' writing skills in explanatory texts at the senior high school level. This study, limited to one school, does not reflect broader educational variations in Indonesia. It focused solely on PBL's impact on writing skills without a thorough exploration of other influencing factors. Future research should expand the sample size and include diverse contextual elements to more robustly verify these results.

This research investigates into the significant role of financial and credit regulations in promoting investments within Ukraine's tourism sector, with a specific emphasis on the hotel and restaurant industry. By integrating mathematical modelling and empirical data analysis, the study uncovers how regulatory environments and credit accessibility jointly influence investment decisions. The development of a differential equation model quantitatively reveals that measures aimed at regulatory simplification and enhancing credit conditions are closely linked with increased investment levels. It identifies critical thresholds for regulatory simplification and credit availability, where indices exceeding 0.45 and 0.55, respectively, are associated with substantial growth in investment rates. This assertion is substantiated by empirical evidence from a survey of 250 industry stakeholders, highlighting the significant positive effects of these regulatory and financial adjustments on investment intentions. The findings highlight the necessity of precise financial and credit regulatory reforms to improve Ukraine's tourism investment climate. The practical significance of this research lies in its potential to guide policy formulation aimed at unlocking the investment potential of Ukraine's tourism sector, ensuring its growth and sustainability in the global context.

In this work, the new energy demand and greenhouse gas emissions that would be associated with heavy truck electrification in Ontario is evaluated. A new equation is derived to calculate the pollution-producing electricity generation based on the breakdown of the Ontario generation mosaic. Using this as a basis, for 4 scenarios of 5 %, 25 %, 50 % and 75 % of heavy-duty truck electrification, the Marginal Emission Factor (MEF) is calculated. This evaluation suggests that Ontario's peak demand in 2040 for the least and the most heavy-duty truck electrification scenarios can be up to 27.5 GW and 30.4 GW, respectively, compared to a baseline of 26.8 GW when assuming no heavy truck electrification condition. It is also forecasted that if the extra demand for electric trucks is supplied by clean renewable resources, the GHG emission reduction for 2040 can be as high as 0.9 MT, 4.3 MT, 8.6 MT and 12.9 MT GHG, respectively.

Abstract Background Flavonoids are plant specialised metabolites, which derive from phenylalanine and acetate metabolism. They possess a variety of beneficial characteristics for plants and humans. Several modification steps in the synthesis of tricyclic flavonoids cause for the amazing diversity of flavonoids in plants. The 2-oxoglutarate-dependent dioxygenases (2-ODDs) flavanone 3-hydroxylase (F3H, synonym FHT), flavonol synthase (FLS) and anthocyanidin synthase (ANS, synonym leucoanthocyanidin dioxygenase (LDOX)), catalyse oxidative modifications to the central C ring. They are highly similar and have been shown to catalyse, at least in part, each other’s reactions. FLS and ANS have been identified as bifunctional enzymes in many species, including Arabidopsis thaliana, stressing the capability of plants to bypass missing or mutated reaction steps on the way to flavonoid production. However, little is known about such bypass reactions and the flavonoid composition of plants lacking all three central flavonoid 2-ODDs. Results To address this issue, we generated a f3h/fls1/ans mutant, as well as the corresponding double mutants and investigated the flavonoid composition of this mutant collection. The f3h/fls1/ans mutant was further characterised at the genomic level by analysis of a nanopore DNA sequencing generated genome sequence assembly and at the transcriptomic level by RNA-Seq analysis. The mutant collection established, including the novel double mutants f3h/fls1 and f3h/ans, was used to validate and analyse the multifunctionalities of F3H, FLS1, and ANS in planta. Metabolite analyses revealed the accumulation of eriodictyol and additional glycosylated derivatives in mutants carrying the f3h mutant allele, resulting from the conversion of naringenin to eriodictyol by flavonoid 3’-hydroxylase (F3’H) activity. Conclusions We describe the in planta multifunctionality of the three central flavonoid 2-ODDs from A. thaliana and identify a bypass in the f3h/fls1/ans triple mutant that leads to the formation of eriodictyol derivatives. As (homo-)eriodictyols are known as bitter taste maskers, the annotated eriodictyol (derivatives) and in particular the observations made on their in planta production, could provide valuable insights for the creation of novel food supplements.

Abstract Background To identify subjects with rupture-prone atherosclerotic plaques before thrombotic events occur is an unmet clinical need. Thus, this proof-of-concept study aims to determine which rupture-prone plaque features can be detected using clinically available photon-counting computed tomography (PCCT). Methods In this retrospective study, advanced atherosclerotic plaques (ex vivo, paraffin-embedded) from the Carotid Plaque Imaging Project were scanned by PCCT with reconstructed energy levels (45, 70, 120, 190 keV). Density in HU was measured in 97 regions of interest (ROIs) representing rupture-prone plaque features as demonstrated by histopathology (thrombus, lipid core, necrosis, fibrosis, intraplaque haemorrhage, calcium). The relationship between HU and energy was then assessed using a mixed-effects model for each plaque feature. Results Plaques from five men (age 79 ± 8 [mean ± standard deviation]) were included in the study. Comparing differences in coefficients (b 1diff) of matched ROIs on plaque images obtained by PCCT and histology confirmed that calcium was distinguishable from all other analysed features. Of greater novelty, additional rupture-prone plaque features proved discernible from each other, particularly when comparing haemorrhage with fibrous cap (p = 0.017), lipids (p = 0.003) and necrosis (p = 0.004) and thrombus compared to fibrosis (p = 0.048), fibrous cap (p = 0.028), lipids (p = 0.015) and necrosis (p = 0.017). Conclusions Clinically available PCCT detects not only calcification, but also other rupture-prone features of human carotid plaques ex vivo. Relevance statement Improved atherosclerotic plaque characterisation by photon-counting CT provides the ability to distinguish not only calcium, but also rupture-prone plaque features such as haemorrhage and thrombus. This may potentially improve monitoring and risk stratification of atherosclerotic patients in order to prevent strokes. Key points • CT of atherosclerotic plaques mainly detects calcium. • Many components, such as intra-plaque haemorrhage and lipids, determine increased plaque rupture risk. • Ex vivo carotid plaque photon-counting CT distinguishes haemorrhage and thrombus. • Improved plaque photon-counting CT evaluation may refine risk stratification accuracy to prevent strokes. Graphical Abstract

Abstract Background Combining multimodal lifestyle interventions and disease-modifying drugs (novel or repurposed) could provide novel precision approaches to prevent cognitive impairment. Metformin is a promising candidate in view of the well-established link between type 2 diabetes (T2D) and Alzheimer’s Disease and emerging evidence of its potential neuro-protective effects (e.g. vascular, metabolic, anti-senescence). MET-FINGER aims to test a FINGER 2.0 multimodal intervention, combining an updated FINGER multidomain lifestyle intervention with metformin, where appropriate, in an APOE ε4-enriched population of older adults (60–79 years) at increased risk of dementia. Methods MET-FINGER is an international randomised, controlled, parallel-group, phase-IIb proof-of-concept clinical trial, where metformin is included through a trial-within-trial design. 600 participants will be recruited at three sites (UK, Finland, Sweden). Participants at increased risk of dementia based on vascular risk factors and cognitive screening, will be first randomised to the FINGER 2.0 intervention (lifestyle + metformin if eligible; active arm) or to receive regular health advice (control arm). Participants allocated to the FINGER 2.0 intervention group at risk indicators of T2D will be additionally randomised to receive metformin (2000 mg/day or 1000 mg/day) or placebo. The study duration is 2 years. The changes in global cognition (primary outcome, using a Neuropsychological Test Battery), memory, executive function, and processing speed cognitive domains; functional status; lifestyle, vascular, metabolic, and other dementia-related risk factors (secondary outcomes), will be compared between the FINGER 2.0 intervention and the control arm. The feasibility, potential interaction (between-groups differences in healthy lifestyle changes), and disease-modifying effects of the lifestyle-metformin combination will be exploratory outcomes. The lifestyle intervention is adapted from the original FINGER trial (diet, physical activity, cognitive training, monitoring of cardiovascular/metabolic risk factors, social interaction) to be consistently delivered in three countries. Metformin is administered as Glucophage®XR/SR 500, (500 mg oral tablets). The metformin/placebo treatment will be double blinded. Conclusion MET-FINGER is the first trial combining a multimodal lifestyle intervention with a putative repurposed disease-modifying drug for cognitive impairment prevention. Although preliminary, its findings will provide crucial information for innovative precision prevention strategies and form the basis for a larger phase-III trial design and future research in this field. Trial registration ClinicalTrials.gov (NCT05109169).

Abstract Background Women with vulvar neoplasia continue to experience uncertainty up to six months post-surgery. Uncertainty in illness is considered a significant psychosocial stressor, that negatively influences symptom distress, self-management strategies and quality of life. According to the Reconceptualized Uncertainty in Illness Theory, the appraisal of uncertainty changes positively over time in chronic illness. We aimed at exploring whether and how the experience of uncertainty develops in women with vulvar neoplasia. Methods We selected a purposive sample of seven women diagnosed with vulvar neoplasia in four Swiss and one Austrian women’s clinic. By means of a qualitative longitudinal study, we conducted 30 individual interviews at five points of time during one year after diagnosis. We applied Saldaña’s analytical questions for longitudinal qualitative research. Results First, participants experienced uncertainty as an existential threat, then an inherent part of their illness, and finally a certainty. Women initially associated the existential threat with a high risk for suffering from severe health deteriorations. Participants that could reduce their individually assessed risk by adopting health promoting behaviors, accepted the remaining uncertainty. From now on they reframed uncertainty into a certainty. This new mindset was based on a belief of promoting recovery and reducing the risk of recurrence. Conclusions The long-lasting and oscillating nature of uncertainty should receive attention in supportive oncology care. Uncertainty concerning existential issues is of special importance since it can inhibit a positive development of uncertainty experience.

Hematogenous metastasis limits the survival of colorectal cancer (CRC) patients. Here, we illuminated the roles of CD44 isoforms in this process. Isoforms 3 and 4 were predominantly expressed in CRC patients. CD44 isoform 4 indicated poor outcome and correlated with epithelial–mesenchymal transition (EMT) and decreased oxidative phosphorylation (OxPhos) in patients; opposite associations were found for isoform 3. Pan‐CD44 knockdown (kd) independently impaired primary tumor formation and abrogated distant metastasis in CRC xenografts. The xenograft tumors mainly expressed the clinically relevant CD44 isoforms 3 and 4. Both isoforms were enhanced in the paranecrotic, hypoxic tumor regions but were generally absent in lung metastases. Upon CD44 kd, tumor angiogenesis was increased in the paranecrotic areas, accompanied by reduced hypoxia‐inducible factor‐1α and CEACAM5 but increased E‐cadherin expression. Mitochondrial genes and proteins were induced upon pan‐CD44 kd, as were OxPhos genes. Hypoxia increased VEGF release from tumor spheres, particularly upon CD44 kd. Genes affected upon CD44 kd in xenografts specifically overlapped concordantly with genes correlating with CD44 isoform 4 (but not isoform 3) in patients, validating the clinical relevance of the used model and highlighting the metastasis‐promoting role of CD44 isoform 4.

Abstract The most common complications related to the treatment of childhood acute lymphoblastic leukemia (ALL) are infections. The aim of the study was to analyze the incidence and mortality rates among pediatric patients with ALL who were treated in 17 Polish pediatric hematology centers in 2020–2021 during the pandemic. Additionally, we compared these results with those of our previous study, which we conducted in the years 2012–2017. The retrospective analysis included 460 patients aged 1–18 years with newly diagnosed ALL. In our study, 361/460 (78.5%) children were reported to have microbiologically documented bacterial infections during chemotherapy. Ten patients (2.8%) died due to sepsis. Fungal infections were reported in 99 children (21.5%), of whom five (5.1%) died due to the infection. We especially observed an increase in bacterial infections during the pandemic period compared to the previous study. The directions of our actions should be to consider antibiotic prophylaxis, shorten the duration of hospitalization, and educate parents and medical staff about complications (mainly infections) during anticancer therapy. It is necessary to continue clinical studies evaluating infection prophylaxis to improve outcomes in childhood ALL patients.

Background. The macroscopic evaluation of the color and consistency of cow uterine-vaginal mucus (UVM) samples revealed that during days 1–3 of the estrous cycle, 45.4 % of the animals in the studied sample (n = 11) had a clear-glassy color, 27.3 % had blood impurities, 18.2 %, and 9.1 % – altered coloring. Additionally, 36.4 % of the samples had thick-viscous, liquid consistency, while 63.6 % had liquid texture. Materials and methods. Mucus was collected from experimental animals at 7–8 a.m. on days 1–3 of the estrous cycle. The volume (cm3) was measured and the color and consistency of the secretion were evaluated. Indicators of mass (g) and content (%) of water (H2O), organic substances (OS), and inorganic substances (IS) were determined gravimetrically. Results. The analysis of the volume and mass indicators of native UVM samples indicates a high (˃95 %) error rate in the registered changes of H2O. However, the error in the sum of the masses OS and IS samples of dry residue (DR) components is completely different. This indicator tends to change on days 1 and 2 (Р ˂0.05), but its stable probability is detected on days 2 and 3, as well as 1 and 3 (Р ˂0.001). Stable changes in the mass OS were detected on days 2 and 3 (Р ˂0.01), while the masses of IS changed on days 1 and 2 (P ˂0.01) and 2 and 3 (P ˂0.001). In all other cases, the error exceeds 95 %. The mass percentages of H2O, OS, and IS indicate a tendency (Р ˂0.05) for changes in H2O and OS content on days 1 and 3; IS content changes on days 1 and 2, as well as 2 and 3, but the changes on days 1 and 3 are highly stable (Р ˂0.001). Stable changes in the mass of DR components were only observed on days 2 and 3. The analysis of homeostasis changes in the mass of native samples indicates that the limit of mean values of UVM:Н2О (1.02–1.04:1) ˂ Н2О:OS (67–77:1) ˂ Н2О:IS (82–439:1), but the OS:IS ratios (1.2–5.5:1) of UVM sample align with the OS:IS ratios (1.2–5.5:1) of DR samples. The limit of Сv for UVM:Н2О, Н2О:OS, Н2О:IS ratio is 0.8–5.3; 19–27; 46–93 % respectively. The OS:IS ratios of native UVM and its DR samples are the same (49; 63; 31 %). The indicators of UVM:Н2О, Н2О:IS, and OS:IS ratios suggest a tendency for change (Р ˂0.05) on days 1 and 3. Their stable changes (Р ˂0.01–0.001) were observed on days 1 and 2, as well as 2 and 3 for Н2О:IS and OS:IS ratios. Conclusion. Given the above, there is a need for further thorough investigation of the characteristics of the imbalance in the components’ mass of UVM during days 1–3 of the estrous cycle, as well as the response of secretory cells of the mucous membrane of the reproductive organs to the effects of pathological factors. This research will be applied in the development of new methods of prevention, diagnosis, and treatment of reproductive tract diseases in female animals.

Porcine circovirus 3 (PCV-3) has emerged as a significant pathogen affecting global swine populations, yet its epidemiology and clinical implications remain incompletely understood. This retrospective study aimed to investigate the prevalence and histopathological features of PCV-3 infection in pigs from Switzerland, focusing on archival cases of suckling and weaner piglets presenting with suggestive lesions. An in-house qPCR assay was developed for detecting PCV-3 in frozen and formalin-fixed paraffin-embedded tissues, enhancing the national diagnostic capabilities. Histopathological reassessment identified PCV-3 systemic disease (PCV-3-SD) compatible lesions in 19 (6%) of archival cases, with 47% testing positive by qPCR across various organs. Notably, vascular lesions predominated, particularly in mesenteric arteries, heart, and kidneys. The study confirms the presence of PCV-3 in Switzerland since at least 2020, marking the first documented cases within the Swiss swine population. Despite challenges in in situ hybridization validation due to prolonged formalin fixation, the findings indicate viral systemic dissemination. These results contribute to the understanding of PCV-3 epidemiology in Swiss pigs, emphasizing the need for continued surveillance and further research on its clinical implications and interaction with host factors. Our study underscores the utility and limitations of molecular techniques in confirming PCV-3 infections.

The objective of this study was to assess consumer behaviour towards tilapia and tilapia products and provide information linking production with consumption patterns and preferences as well as to predict factors that influence consumer preference, purchase behaviour, and willingness to patronize tilapia fillets using classification and regression trees. A total of 960 responses were obtained using convenient sampling. The findings of this survey indicate that tilapia is eaten mainly because of its taste. Regarding the various cooked tilapia options available in Ghana, 58.5 % preferred charcoal-grilled tilapia while sixty-six per cent (66 %) preferred to purchase their tilapia in the fresh state. Furthermore, sixty-five per cent (65 %) of the participants revealed that they consume tilapia at least once a month, indicating a link between production and consumption, as well as a continuous market for tilapia fish farmers. Most respondents (85 %) would prefer an easier way to prepare tilapia. The availability of tilapia in a fillet form appealed to about 50.8 % of respondents with 78 % indicating that they would purchase tilapia fillets if they were available on the market. For the parts of tilapia consumed, 70 % indicated that the head of tilapia was important to them and only 49 % of respondents indicated they would buy fillets without the head. The top three preferred fillet options in increasing order were chilled, frozen, and spiced. From the study of associations, income was the most important factor determining whether a consumer would purchase tilapia fillets or not. However, with regards to preference of head or tail region, age was the most important determining factor. Thus, consideration of all these factors would serve as a guide to businesspeople and actors within the tilapia value chain in Ghana and beyond.

BackgroundThe inotropic drug levosimendan is often used off-label perioperatively in cardiac surgery patients with cardiopulmonary bypass (CPB). Data regarding serum concentrations of levosimendan and its metabolites within this context is lacking.MethodsTotal serum concentrations (TSC) and unbound fractions (UF) of levosimendan and its metabolites OR-1896 and OR-1855 in cardiac surgery patients with CPB were retrospectively measured using LC-ESI-MS/MS. Simulation of expected levosimendan TSC was performed using Pharkin 4.0. Serum NT-proBNP was assessed with ELISA.ResultsAfter prolonged levosimendan infusion (1.25 mg or 2.5 mg, respectively) after induction of anaesthesia, a median TSC of 1.9 ng/ml and 10.4 ng/ml was determined in samples taken directly after surgery (T1). Median TSC of 7.6 ng/ml and 22.0 ng/ml, respectively, were simulated at T1. Whereas 1.1 ng/ml and 1.6 ng/ml TSC of OR-1896, respectively, was quantified the day after surgery (T2), TSC of the intermediate metabolite OR-1855 was mostly below the lower limit of quantification (LLOQ). The UF was 0.5% and 1.1% for levosimendan and 64.1% and 52.1% for OR-1896, respectively, with over half the samples being below LLOQ. No difference in NT-proBNP concentrations before surgery and T2 was detected.DiscussionThe low TSC, UF and unchanged NT-proBNP levels suggest a need for dose adjustments of levosimendan in this off-label range. In addition, the differences between the measured and estimated concentrations may suggest a possible influence of a CPB on levosimendan serum concentrations. Due to high variation of serum levels between patients, an optimized dosing regimen combined with therapeutic drug monitoring may be advisable.

ObjectiveWe investigated the longitudinal associations of cumulative motor fitness, muscular strength, and cardiorespiratory fitness (CRF) from childhood to adolescence with cortical excitability and inhibition in adolescence. The other objective was to determine cross-sectional associations of motor fitness and muscular strength with brain function in adolescence.MethodsIn 45 healthy adolescents (25 girls and 20 boys) aged 16–19 years, we assessed cortical excitability and inhibition by navigated transcranial magnetic stimulation (nTMS), and motor fitness by 50-m shuttle run test and Box and block test, and muscular strength by standing long jump test. These measures of physical fitness and CRF by maximal exercise were assessed also at the ages 7–9, 9–11, and 15–17 years. Cumulative measures of physical measures were computed by summing up sample-specific z-scores at ages 7–9, 9–11, and 15–17 years.ResultsHigher cumulative motor fitness performance from childhood to adolescence was associated with lower right hemisphere resting motor threshold (rMT), lower silent period threshold (SPt), and lower motor evoked potential (MEP) amplitude in boys. Better childhood-to-adolescence cumulative CRF was also associated with longer silent period (SP) duration in boys and higher MEP amplitude in girls. Cross-sectionally in adolescence, better motor fitness and better muscular strength were associated with lower left and right rMT among boys and better motor fitness was associated with higher MEP amplitude and better muscular strength with lower SPt among girls.ConclusionPhysical fitness from childhood to adolescence modifies cortical excitability and inhibition in adolescence. Motor fitness and muscular strength were associated with motor cortical excitability and inhibition. The associations were selective for specific TMS indices and findings were sex-dependent.

This article provides an overview of the challenges faced at the intersection of philosophy and translation studies. The interdisciplinary scope under consideration covers philosophical contributions to theoretical investigation of translation, which are substantively grounded in the experiences of practicing translators, amongst whom are philosophers. Furthermore, the paper emphasizes the prominent role of philosophy in establishing the fundamental conditions and concepts of translation, and addresses the numerous philosophical approaches contributing to the interdisciplinary discourse on the nature of translation. Considerable attention is given to metaphysical and epistemological points that seem to play a significant role in conceptualising translation issues and establishing the theoretical foundations of translation studies, as well as in providing a deeper insight into the translation process. On the whole, the philosophisation of the translation phenomenon contributes to the substantial growth of both philosophical thought and translation studies.

Climate change has increased the frequency, duration and intensity of heatwaves in Europe. These extreme events result in alterations of physical, chemical, and biological properties of lakes that may synergistically promote cyanobacterial dominance. In our study we focused on cyanobacterial blooms in lakes distributed over a longitudinal gradient in Central Europe during one of the “top ten European heat waves” in summer 2015. 92 lakes were included in the study, located across three climatic subregions: cool northern lakes, situated in Lithuania, temperate northern lakes in Poland, and warm northern lakes in Croatia. The objective of the study was to determine if cyanobacterial biomass, predominant species, and cyanotoxin concentration differed, across the south-north gradient, as a function of water temperature, total phosphorus, and total nitrogen. Statistical significance of observed patterns was tested using the Kruskal-Wallis rank sum test and the generalized linear model. We found the lowest average epilimnion temperature, but the highest average cyanobacterial biomass in the northern, ‘cool’ lakes while the highest average temperature with the lowest average cyanobacterial biomass in the southern, ‘warm’ lakes. The concentration of cyanotoxins was also the highest in the ‘cool’ lakes. Total phosphorus and total nitrogen correlated significantly with cyanobacterial biomass, cyanotoxins concentration and biomass of some cyanobacterial species (mainly Planktothrix agardhii), regardless of the latitude. Only in the ‘cool’ lakes concentration of cyanotoxins (microcystins and anatoxin-a) correlated significantly with cyanobacterial biomass and the biomass of some dominant cyanobacterial species (P. agardhii). Our results emphasized the differences of heat weaves impact on lakes of various latitudes, with the strongest increase in toxic cyanobacterial blooms in northern ‘cool’ lakes, situated in high latitudes. On the other hand, nutrients directly enhanced blooms across all the studied latitudes of Central Europe. The cyanobacteria species dominating in blooms might be recognized as ecological indicators of climate change, especially in the north-eastern part of Europe.

Se describieron los principales hallazgos actuales relacionados con el proceso del envejecimiento. Para ello se realizó una revisión de artículos actualizados que abordan la temática. para valorar la necesidad de la educación en torno a esta etapa de la vida, desde la neuropsicología, en donde se enfatiza la importancia de un manejo integral, ya que se observa al individuo dentro de un contexto sociocultural que impacta en su funcionamiento cerebral. Conocer el desarrollo en el envejecimiento normal proporciona pautas para el abordaje integral del adulto mayor.

Abstract Background Patients with type 2 diabetes have an increased risk of death and cardiovascular events and people with diabetes or prediabetes have been found to have increased atherosclerotic burden in the coronary and carotid arteries. This study will estimate the cross-sectional prevalence of atherosclerosis in the coronary and carotid arteries in individuals with prediabetes and diabetes, compared with normoglycaemic individuals in a large population-based cohort. Methods The 30,154 study participants, 50–64 years, were categorized according to their fasting glycaemic status or self-reported data as normoglycaemic, prediabetes, and previously undetected or known diabetes. Prevalence of affected coronary artery segments, severity of stenosis and coronary artery calcium score (CACS) were determined by coronary computed tomography angiography. Total atherosclerotic burden was assessed in the 11 clinically most relevant segments using the Segment Involvement Score and as the presence of any coronary atherosclerosis. The presence of atherosclerotic plaque in the carotid arteries was determined by ultrasound examination. Results Study participants with prediabetes (n = 4804, 16.0%) or diabetes (n = 2282, 7.6%) had greater coronary artery plaque burden, more coronary stenosis and higher CACS than normoglycaemic participants (all, p

The rising demand for plant-based alternatives to traditional meat products has led to the development of plant-based sausages (PBSs) that closely mimic the texture and taste of their meat counterparts. This study investigates the rheological and textural properties, as well as proton molecular dynamics, of hot dog-type PBSs and batters used in their production. Various formulations were analyzed to understand how different ingredients and processing methods affect the characteristics of the final products. Our findings reveal that the incorporation of specific plant proteins and hydrocolloids significantly influences the rheological behavior and texture profile of sausages. The hardness of the samples ranged from 4.33 to 5.09 N/mm and was generally higher for the products with inorganic iron sources. Regarding the viscoelastic properties, all the samples showed larger values of the storage modulus than the loss modulus, which indicates their solid-like behavior. Additionally, the study utilized advanced proton nuclear magnetic resonance (NMR) techniques to elucidate the molecular dynamics within plant-based matrices, providing insights into water distribution and mobility. Key findings highlight the impact of different plant proteins and additives on the texture and stability of sausage analogs.

Compounds derived from natural sources pave the way for novel drug development. Cyanobacteria is an ubiquitous phylum found in various habitats. The fitness of those microorganisms, within different biotopes, is partially dependent on secondary metabolite production. Their enhanced production under biotic/abiotic stress factors accounts for better survival rates of cells, and thereby cyanobacteria are as an enticing source of bioactive compounds. Previous studies have shown the potent activity of extracts and fractions from Pseudanabaena galeata (Böcher 1949) strain CCNP1313 against cancer cells and viruses. However, active agents remain unknown, as the selected peptides had no effect on the tested cell lines. Here, we present a bottom-up approach, pinpointing key structures involved in secondary metabolite production. Consisting of six replicons, a complete genome sequence of P. galeata strain CCNP1313 was found to carry genes for non-ribosomal peptide/polyketide synthetases embedded within chromosome spans (4.9 Mbp) and for a ribosomally synthesized peptide located on one of the plasmids (0.2 Mbp). Elucidation of metabolite synthesis pathways led to prediction of their structure. While none of the synthesis-predicted products were found in mass spectrometry analysis, unexplored synthetases are characterized by structural similarities to those producing potent bioactive compounds.

Abstract Introduction Inappropriate ventilator settings, non-adherence to a lung-protective ventilation strategy, and inadequate patient monitoring during mechanical ventilation can potentially expose critically ill children to additional risks. We set out to improve team theoretical knowledge and practical skills regarding pediatric mechanical ventilation and to increase compliance with treatment goals. Methods An educational initiative was conducted from August 2019 to July 2021 in a neonatal and pediatric intensive care unit of the University Children’s Hospital, Hamburg-Eppendorf, Germany. We tested baseline theoretical knowledge using a multiple choice theory test (TT) and practical skills using a practical skill test (PST), consisting of four sequential Objective Structured Clinical Examinations of physicians and nurses. We then implemented an educational bundle that included video self-training, checklists, pocket cards, and reevaluated team performance. Ventilators and monitor settings were randomly checked in all ventilated patients. We used a process control chart and a mixed-effects model to analyze the primary outcome. Results A total of 47 nurses and 20 physicians underwent assessment both before and after the implementation of the initiative using TT. Additionally, 34 nurses and 20 physicians were evaluated using the PST component of the initiative. The findings revealed a significant improvement in staff performance for both TT and PST (TT: 80% [confidence interval (CI): 77.2–82.9] vs. 86% [CI: 83.1–88.0]; PST: 73% [CI: 69.7–75.5] vs. 95% [CI: 93.8–97.1]). Additionally, there was a notable increase in self-confidence among participants, and compliance with mechanical ventilation treatment goals also saw a substantial rise, increasing from 87.8% to 94.5%. Discussion Implementing a pediatric mechanical ventilation education bundle improved theoretical knowledge and practical skills among interprofessional pediatric intensive care staff and increased treatment goal compliance in ventilated children.

Abstract Dairy systems, which are the main pillars of rural livelihoods in north-eastern Europe encounter ecological, economic, and political changes in their operating environments which threaten their capacity to provide dairy supply. As uncertainty increases, there is a need to increase understanding and identify concrete tools to help food system actors manage resilience. We defined ‘dairy systems’ as a social-ecological system in which milk supply is the primary function, and humans and ecosystems endogenous factors. We conducted a qualitative empirical study to develop, enrich, and validate a theoretical framework, acknowledging social, economic, and ecological perspectives affecting the resilience. This paper identifies critical changes affecting the systems and key determinants of dairy system resilience, especially means actors can manage, in two socially and ecologically contrasting regions, Finland and Russia. The data consist of 26 qualitative in-depth interviews conducted in Finland and the surroundings of St Petersburg in the Leningrad Oblast. The critical changes confronting dairy system actors in both regions were especially related to prices and economics, policies, and epidemics. In Finland, possible cuts to agricultural subsidies, as well as an increasing workload, were perceived as a significant threat, whereas risks related to investors and resource adequacy were highlighted in Leningrad Oblast. Despite the socioeconomic distinctions between the countries, the determinants were similar and included ecological, economic, and social issues. However, the form of farm ownership proved decisive: for family farms in Finland, social well-being determinants were more important than economic ones; for investor-owned businesses in Leningrad Oblast, the opposite was the case. The results can be used by dairy systems actors, as well as administrators and policymakers, as a tool for understanding, assessing, and managing resilience.

Abstract Aim To explore nursing assistants' (NAs') experiences of developing communication skills while participating in an educational intervention on person‐centred communication. Design A descriptive qualitative study was conducted. Methods Data were collected from interviews and written assignments before, during and after an educational intervention on person‐centred communication targeting NAs in home care services. The data were analysed using a phenomenological approach. A total of 25 NAs participated in the study. Results The findings describe NAs' experiences concerning the communication skills needed for building relationships with older persons and handling emotionally challenging situations. The educational intervention increased their knowledge and awareness of the importance of communication skills and how such skills are developed and refined.

Conclusion: The prevalence of mental distress among women who experienced GBV and attended the courts of the Hadiya Zone was high. Place of residence, concern about food insecurity, family history of mental illness, ever khat use, and having a husband who marries another wife were found to have statistically significant associations with mental distress among women who experienced GBV and attended the courts of the Hadiya Zone. Women need to be assessed regularly for GBV during health care visits. Regular counseling, facilitating, and adhering to different GBV coping mechanisms during the waiting time is imperative to overcome this problem.

ABSTRACT Chlamydia, comprising several human and zoonotic pathogens, is a genus of the conserved bacterial phylum Chlamydiota. Their obligate intracellular niche serves as a barrier for natural genetic exchange via horizontal gene transfer (HGT), and further limits the development and application of genetic tools. To date, the only example for recent inter-phylum HGT among the Chlamydiota is tetracycline resistance in the potentially zoonotic species Chlamydia suis, a close phylogenetic relative of human C. trachomatis, which causes bacterial sexually transmitted infections and ocular trachoma. Tetracycline resistance in porcine C. suis strains has been described worldwide and is always part of a genomic island dividing invasin (inv), located within a chromosomal region between the rRNA operon (rrn) and the nqrF reductase. Here, we aimed to expand the still modest number of available genetic manipulation systems for Chlamydia by generating allele-replacement and integration vectors for C. suis. These vectors comprised homologous C. suis sequences of the chromosomal region of interest, an E. coli origin of replication (ori) and selection markers but lacked the native chlamydial plasmids or its ori. We first recovered allele-replacement mutants using a vector that targets the tryptophan (trp) operon of C. suis. The vector was further successfully maintained as a free plasmid in C. trachomatis without allele replacement, suggesting complex plasmid dynamics in the absence of a chlamydial ori. Moreover, we showed that the hypervariable rrn-nqrF intergenic region of C. suis is highly susceptible to transformation, resulting in complete vector integration upstream of nqrF without interruption of the targeted inv gene. IMPORTANCE The obligate intracellular Chlamydia genus contains many pathogens with a negative impact on global health and economy. Despite recent progress, there is still a lack of genetic tools limiting our understanding of these complex bacteria. This study provides new insights into genetic manipulation of Chlamydia with the opportunistic porcine pathogen Chlamydia suis, the only chlamydial species naturally harboring an antibiotic resistance gene, originally obtained by horizontal gene transfer. C. suis is transmissible to humans, posing a potential public health concern. We report that C. suis can take up vectors that lack the native plasmid, a requirement for most chlamydial transformation systems described to date. Additionally, we show that C. trachomatis, the most common cause for bacterial sexually transmitted infections and infectious blindness worldwide, can be transformed with C. suis vectors. Finally, the chromosomal region that harbors the resistance gene of C. suis is highly susceptible to complete vector integration.

Conserving soil carbon is one of many actions to take in limiting global warming. However, carbon dense peatlands are still being drained or excavated. Infrastructure development is one of the major current threats to boral peatlands in Fennoscandia, but few tools are available for calculations of carbon stocks in peatland areas, necessary for decision makers planning development projects. Thus, we compiled a reference database of key peat characteristics from main boreal peatland types sampled in Norway and tested “best practice” peat depth sampling methods and peat volume interpolations. We implemented our findings in CarbonViewer, a tool and easy-to-use app that reliably calculates carbon stocks of delimited peatlands. Tool and method presented, estimates carbon stocks to assess potential soil carbon loss in planned infrastructure development on peatlands and will give decision makers the necessary knowledge base to limit emissions from soil carbon.

The aim of this study is to present the pathological lesions observed in a skeleton (male, about 35–38 years old) from Radom (Poland), dated to the 18th–19th century. Bone changes were observed in both femurs and both pelvic bones. The head of the femur is enlarged and deformed, described as “mushroom-shaped”, with areas of smooth cortex and cavities, or possible cystic residues. The neck of femur is short and thick. The bone shaft and distal epiphysis do not show any changes. The changes were also observed in both acetabularies of the hip joint (marginal bone formation, subchondral bone remodelling). Radiographic images show bilateral necrosis of the femoral head. There is a significant sclerotization of the femoral head, with a discrete visible crescent sign. These macroscopic and radiological changes match the symptoms associated with Legg-Calvé-Perthes disease. This is the first case of the disease described in bioarchaeological materials from Poland.

Objective: The study objective was to determine what proportion of asymptomatic patients had resectable lung cancer detected through lung cancer screening versus incidentally. Methods: We performed a retrospective study of patients who underwent resection for lung cancer between January 2015 and December 2020. We then assessed whether asymptomatic patients with incidentally found lung cancers were eligible for lung cancer screening using the National Comprehensive Cancer Network, United States Preventive Services Task Force, Centers for Medicare & Medicaid Services, American College of Chest Physicians, American Cancer Society, and American Society of Clinical Oncology guidelines. Results: Of 539 patients who underwent resection for primary lung cancer, 437 (81%) were asymptomatic and 355 (66%) of these patients had lung cancer found discovered incidentally. Of the 355 patients with incidentally detected lung cancer, 10 were excluded for insufficient data. Of the remaining 345 patients, 110 (32%) would have been eligible for screening using National Comprehensive Cancer Network guidelines, 65 (19%) using 2021 United States Preventive Services Task Force guidelines, 53 (15%) using 2013 United States Preventive Services Task Force guidelines, 64 (19%) using 2022 Centers for Medicare & Medicaid Services guidelines, 52 (15%) using 2015 Centers for Medicare & Medicaid Services/American College of Chest Physicians guidelines, and 45 (13%) using American Cancer Society/American Society of Clinical Oncology guidelines. Of the 280 patients who were screen ineligible by 2021 United States Preventive Services Task Force criteria, 143 patients (51%) never smoked, 112 patients (40%) quit smoking more than 15 years ago, 89 patients (32%) did not smoke at least 20 pack-years, and 44 patients (16%) were ineligible due to age. Conclusions: The majority of asymptomatic patients with resectable lung cancers had lung cancer identified incidentally and not through lung cancer screening. Most of these patients were not eligible for screening under current guidelines. This study suggests a need for improved lung cancer screening implementation and further investigation in the identification and assessment of risk factors for lung cancer.

Abstract Background The immunological composition of the tumor microenvironment has a decisive influence on the biological course of cancer and is therefore of profound clinical relevance. In this study, we analyzed the cooperative effects of integrin β4 (ITGB4) on tumor cells and E-/P-selectin on endothelial cells within the tumor stroma for regulating tumor growth by shaping the local and systemic immune environment. Methods We used several preclinical mouse models for different solid human cancer types (xenograft and syngeneic) to explore the role of ITGB4 (shRNA-mediated knockdown in tumor cells) and E-/P-selectins (knockout in mice) for tumor growth; effects on apoptosis, proliferation and intratumoral signaling pathways were determined by histological and biochemical methods and 3D in vitro experiments; changes in the intratumoral and systemic immune cell composition were determined by flow cytometry and immunohistochemistry; chemokine levels and their attracting potential were measured by ELISA and 3D invasion assays. Results We observed a very robust synergism between ITGB4 and E-/P-selectin for the regulation of tumor growth, accompanied by an increased recruitment of CD11b+ Gr-1Hi cells with low granularity (i.e., myeloid-derived suppressor cells, MDSCs) specifically into ITGB4-depleted tumors. ITGB4-depleted tumors undergo apoptosis and actively attract MDSCs, well-known to promote tumor growth in several cancers, via increased secretion of different chemokines. MDSC trafficking into tumors crucially depends on E-/P-selectin expression. Analyses of clinical samples confirmed an inverse relationship between ITGB4 expression in tumors and number of tumor-infiltrating leukocytes. Conclusions These findings suggest a distinct vulnerability of ITGB4Lo tumors for MDSC-directed immunotherapies. Graphical Abstract

Abstract Background The risk of older adults being injured or killed in a bicycle accident increases significantly due to the age-related decline of physical function. Therefore, targeted interventions for older adults to improve safe cycling competence (CC) are urgently needed. Methods The “Safer Cycling in Older Age” (SiFAr) randomized controlled trial investigated if a progressive multi-component training program related to cycling improves CC of older adults. Between June 2020 and May 2022, 127 community-dwelling persons living in the area Nürnberg-Fürth-Erlangen, Germany aged 65 years and older were recruited, who are either (1) beginners with the e-bike or (2) feeling self-reported unsteadiness when cycling or (3) uptaking cycling after a longer break. Participants were either randomized 1:1 to an intervention group (IG; cycling exercise program, 8 sessions within 3 months) or an active control group (aCG; health recommendations). The CC as primary outcome was tested not blinded in a standardized cycle course prior and after the intervention period and after 6–9 months, which consists of variant tasks requiring skills related to daily traffic situations. Regression analyses with difference of errors in the cycling course as dependent variable and group as independent variable adjusted for covariates (gender, number of errors at baseline, bicycle type, age and cycled distance) were performed. Results 96 participants (73.4 ± 5.1 years; 59.4% female) were analyzed for primary outcome. Compared to the aCG (n = 49), the IG (n = 47) made an average of 2.37 fewer errors in the cycle course after the 3 months intervention period (p = 0.004). People with more errors at baseline had higher potential for improvement (B=-0.38; p

Abstract Aim The aim was to generate a framework for dementia care in acute hospitals. Design Framework development with logic modelling. Methods In phase one, we identified relevant elements of the framework by analysing several sources and by critically discussing them within the research team. We created the framework with logic modelling. In phase two, we adapted the framework in expert workshops and by reanalysing the included sources. We used the first stage of CReDECI 2 checklist for reporting. Results The framework describes necessary activities within four main bundles of measures: “developing structures and processes,” “developing competences and attitudes,” “building relationships” and “ensuring a social environment and adequate stimulation.” The overarching outcome is a person‐centred hospital culture, manifesting itself on different levels. The framework illustrates the necessity of an organization‐wide person‐centred culture for achieving positive outcomes for people with dementia, their relatives and health professionals.

Abstract Aim To explore the feasibility of evaluating a novel educational intervention on person‐centered communication for nursing assistants (NAs) in home care. Design A feasibility study with pre‐ and post‐assessments. Methods Feasibility was assessed pre‐ and post‐intervention, including evaluation of data collection procedures, completion rates and missing data in two questionnaires: Self‐efficacy Questionnaire measuring communication skills and Measure of Job Satisfaction, analysed descriptively and statistically. Results The questionnaires were feasible and acceptable for the NAs to complete and understand. The pre‐ and post‐assessments showed 83% and 61% completion rates, respectively, and a low proportion of missing data. Barriers for not participating in data collection were stress caused by staff shortages and high workload. Preliminary analysis of the questionnaires showed no significant difference pre‐ and post‐intervention, even though an overall tendency of increased communication self‐efficacy was observed. The NAs' self‐efficacy ratings also revealed a ceiling effect.

The pyoverdine siderophore is produced by Pseudomonas aeruginosa to access iron. Its synthesis involves the complex coordination of four nonribosomal peptide synthetases (NRPSs), which are responsible for assembling the pyoverdine peptide backbone. The precise cellular organization of these NRPSs and their mechanisms of interaction remain unclear. Here, we used a combination of several single-molecule microscopy techniques to elucidate the spatial arrangement of NRPSs within pyoverdine-producing cells. Our findings reveal that PvdL differs from the three other NRPSs in terms of localization and mobility patterns. PvdL is predominantly located in the inner membrane, while the others also explore the cytoplasmic compartment. Leveraging the power of multicolor single-molecule localization, we further reveal co-localization between PvdL and the other NRPSs, suggesting a pivotal role for PvdL in orchestrating the intricate biosynthetic pathway. Our observations strongly indicates that PvdL serves as a central orchestrator in the assembly of NRPSs involved in pyoverdine biosynthesis, assuming a critical regulatory function.

Periodontal defects’ localization affects wound healing and bone remodeling, with faster healing in the upper jaw compared to the lower jaw. While differences in blood supply, innervation, and odontogenesis contribute, cell-intrinsic variances may exist. Few studies explored cell signaling in periodontal ligament stem cells (PDLSC), overlooking mandible-maxilla disparitiesUsing kinomics technology, we investigated molecular variances in PDLSC. Characterization involved stem cell surface markers, proliferation, and differentiation capacities. Kinase activity was analyzed via multiplex kinase profiling, mapping differential activity in known gene regulatory networks. Upstream kinase analysis identified stronger EphA receptor expression in the mandible, potentially inhibiting osteogenic differentiation. The PI3K-Akt pathway showed higher activity in lower-jaw PDLSC. PDLSC from the upper jaw exhibit superior proliferation and differentiation capabilities. Differential activation of gene regulatory pathways in upper vs. lower-jaw PDLSC suggests implications for regenerative therapies.

Introduction The increase of young and middle-aged adult patients with multimorbid and/or complex chronic conditions has created new challenges for healthcare systems and services. Advanced Practice Nurses (APNs) play an essential role in treating these patients because of their expertise and advanced nursing skills. Little is known about competencies, scope of practice and impact of APNs within APN-led care models for young and middle-aged adult patients with multimorbidity and/or complex chronic conditions in hospital settings. The objective of this scoping review is to describe the impact, scope of practice and competencies of APNs within APN-led care models for young and middle-aged adult patients in hospital settings.Methods and analysis This scoping review will be conducted using the methodological framework proffered by Arksey and O'Malley, incorporating the methodological enhancement of Levac et al. It will comply with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) for Scoping Reviews’ guidelines of Tricco et al. Systematic research will be conducted in the databases MEDLINE (PubMed), CINAHL (EBSCO), EMBASE (Ovid), CENTRAL and PsycINFO (Ovid) using all recognised keywords, index terms and search strings. Grey literature will be scanned. Bibliography of all selected studies will be hand searched. Studies will be selected based on defined inclusion and exclusion criteria, screened by title and abstracts. Data from full-text articles meeting the inclusion criteria will be extracted independently by two authors. Disagreements in evaluation will be discussed and resolved by consensus. Results will be reported in the form of descriptive tables. Narrative summery is used to present the results of the review in the context of the study’s objectives and questions.Ethics and dissemination This scoping review does not require ethics approval. The review will be handed in as part of a doctoral thesis and published in a peer-reviewed journal.Trial registration number OSF 4PM38.

BackgroundThis study relates to emerging concepts of appropriate trial designs to evaluate effects of intervention on the accumulation of irreversible disability in multiple sclerosis (MS). Major starting points of our study are the known limitations of current definitions of disability progression by rater-based clinical assessment and the high relevance of gait and balance dysfunctions in MS. The study aims to explore a novel definition of disease progression using repeated instrumental assessment of relevant motor functions performed by patients in their home setting.MethodsThe study is a prospective single-center observational cohort study with the primary outcome acquired by participants themselves, a home-based assessment of motor functions based on an RGB-Depth (RGB-D) camera, a camera that provides both depth (D) and color (RGB) data. Participants are instructed to perform and record a set of simple motor tasks twice a day over a one-week period every 6 months. Assessments are complemented by a set of questionnaires. Annual research grade assessments are acquired at dedicated study visits and include clinical ratings as well as structural imaging (MRI and optical coherence tomography). In addition, clinical data from routine visits is provided semiannually by treating neurologists. The observation period is 24 months for the primary endpoint with an additional clinical assessment at 27 month to confirm progression defined by the Expanded Disability Status Scale (EDSS). Secondary analyses aim to explore the time course of changes in motor parameters and performance of the novel definition against different alternative definitions of progression in MS. The study was registered at Deutsches Register für Klinische Studien (DRKS00027042).DiscussionThe study design presented here investigates disease progression defined by marker-less home-based assessment of motor functions against 3-month confirmed disease progression (3 m-CDP) defined by the EDSS. The technical approach was chosen due to previous experience in lab-based settings. The observation time per participant of 24, respectively, 27 months is commonly conceived as the lower limit needed to study disability progression. Defining a valid digital motor outcome for disease progression in MS may help to reduce observation times in clinical trials and add confidence to the detection of progression events in MS.

This paper examines a PBL project module “Sustainable Urban Transformation” in an Urban Design master’s education. The module combines urban design and hydrology engineering. Within the module, students are supported by lectures and study circles on various dimensions of sustainability, especially vis-a-vis climate change. However, they are left with the freedom to choose how they balance between design and engineering approaches when they give a physical form for sustainability in the site transformation projects with which they work through the semester. This paper discusses the development of their skills building on three Aristotelean concepts: techne (engineering), poiesis (aesthetic form-giving), and phronesis (making of ethical judgments). The last two concepts, the paper argues, are especially important when at issue is design education. Based on an analysis of the student projects in Fall 2022, the paper examines whether and how the students manage to find a balance between engineering skills, on the one hand, and aesthetic creativity and ethical judgement, on the other hand, in their project work.

Introduction Gestational diabetes mellitus (GDM) is associated with increased risk for type 2 diabetes in the mother and cardiometabolic diseases in the child. The preconception period is an optimal window to adapt the lifestyle for improved outcomes for both mother and child. Our aim is to determine the effect of a lifestyle intervention, initiated before and continued throughout pregnancy, on maternal glucose tolerance and other maternal and infant cardiometabolic outcomes.Methods and analysis This ongoing randomised controlled trial has included 167 females aged 18–39 years old at increased risk for GDM who are contemplating pregnancy. The participants were randomly allocated 1:1 to an intervention or control group. The intervention consists of exercise (volume is set by a heart rate-based app and corresponds to ≥ 1 hour of weekly exercise at ≥ 80% of individual heart rate maximum), and time-restricted eating (≤ 10 hours/day window of energy intake). The primary outcome measure is glucose tolerance in gestational week 28. Maternal and offspring outcomes are measured before and during pregnancy, at delivery, and at 6–8 weeks post partum. Primary and secondary continuous outcome measures will be compared between groups based on the ‘intention to treat’ principle using linear mixed models.Ethics and dissemination The Regional Committees for Medical and Health Research Ethics in Norway has approved the study (REK 143756). The anonymised results will be submitted for publication and posted in a publicly accessible database of clinical study results.Trial registration number Clinical trial gov NCT04585581.