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Estimates of the spectrum and frequency of pathogenic variants in Parkinsons disease (PD) in different populations are currently limited and biased. Furthermore, although therapeutic modification of several genetic targets has reached the clinical trial stage, a major obstacle in conducting these trials is that PD patients are largely unaware of their genetic status and, therefore, cannot be recruited. Expanding the number of investigated PD-related genes and including genes related to disorders with overlapping clinical features in large, well-phenotyped PD patient groups is a prerequisite for capturing the full variant spectrum underlying PD and for stratifying and prioritizing patients for gene-targeted clinical trials. The Rostock Parkinsons disease (ROPAD) study is an observational clinical study aiming to determine the frequency and spectrum of genetic variants contributing to PD in a large international cohort. We investigated variants in 50 genes with either an established relevance for PD or possible phenotypic overlap in a group of 12 580 PD patients from 16 countries [62.3% male; 92.0% White; 27.0% positive family history (FH+), median age at onset (AAO) 59 years] using a next-generation sequencing panel. Altogether, in 1864 (14.8%) ROPAD participants (58.1% male; 91.0% White, 35.5% FH+, median AAO 55 years), a PD-relevant genetic test (PDGT) was positive based on GBA1 risk variants (10.4%) or pathogenic/likely pathogenic variants in LRRK2 (2.9%), PRKN (0.9%), SNCA (0.2%) or PINK1 (0.1%) or a combination of two genetic findings in two genes (∼0.2%). Of note, the adjusted positive PDGT fraction, i.e. the fraction of positive PDGTs per country weighted by the fraction of the population of the world that they represent, was 14.5%. Positive PDGTs were identified in 19.9% of patients with an AAO ≤ 50 years, in 19.5% of patients with FH+ and in 26.9% with an AAO ≤ 50 years and FH+. In comparison to the idiopathic PD group (6846 patients with benign variants), the positive PDGT group had a significantly lower AAO (4 years, P = 9 × 10-34). The probability of a positive PDGT decreased by 3% with every additional AAO year (P = 1 × 10-35). Female patients were 22% more likely to have a positive PDGT (P = 3 × 10-4), and for individuals with FH+ this likelihood was 55% higher (P = 1 × 10-14). About 0.8% of the ROPAD participants had positive genetic testing findings in parkinsonism-, dystonia/dyskinesia- or dementia-related genes. In the emerging era of gene-targeted PD clinical trials, our finding that ∼15% of patients harbour potentially actionable genetic variants offers an important prospect to affected individuals and their families and underlines the need for genetic testing in PD patients. Thus, the insights from the ROPAD study allow for data-driven, differential genetic counselling across the spectrum of different AAOs and family histories and promote a possible policy change in the application of genetic testing as a routine part of patient evaluation and care in PD.

To make it easier for students to learn the contents of physics and increase their motivation to learn, physics teachers need to apply different teaching strategies. With this study we aimed to examine the impact of the modified Know-Want-Learn (mKWL) strategy in physics teaching on elementary school students' metacognition. The pedagogical experiment with parallel groups was applied to determine whether the mKWL strategy affected students' metacognition. The students in the experimental group were taught by applying the mKWL strategy with a specific chart. The chart consisted of columns: T -- What I think and what I know, Q -- What questions I have, H -- How can I find out, L -- What I Learned (TQHL chart). The students in the control group were taught (the same physics curriculum) by using the traditional teaching model, without this TQHL chart. A questionnaire on metacognition was used for the evaluation of sixth-grade students' metacognition. The statistical analysis of data included descriptive statistics, as well as paired sample t-tests and independent sample t-tests. Research results, based on the scores obtained using the questionnaire on metacognition, imply that the use of the proposed mKWL strategy increases students' metacognition. Considering the positive effect of this teaching strategy on students' metacognition, its further application in other teaching subjects is planned as well as the training of a large number of elementary school teachers for its application.

This paper studies the problem of coordination and supervision of virtual teams and their capabilities. The goal is to develop a model suitable for managing virtual student teams specialized in the development of smart environments. The developed model is based on SAFe and DevOps, which when combined provide us with a framework for the evaluation of team capabilities in an academic environment. Additionally, DevOps principles can be more efficiently leveraged through an agile methodology to provide students with a better understanding of continuous value delivery. Through the application of the proposed model, virtual student teams gained practical experience in self-organization and virtual team management while being efficiently monitored and guided through the project lifecycle. Virtual student teams were likewise encouraged to be more agile, as this change in mindset is imperative in business, and as such must also be adopted in academic environments. By incorporating best practices of the corporate environments into the existing curriculum, we have proven that by adopting the proposed model these changes can be feasibly incorporated to the satisfaction of both the students and their future employers.

Background: The aim of this study was to compare postoperative outcomes following liver resection between patients with prolonged cumulative ischemia time (CIT) which exceeded 60 min and patients with CIT less than 60 min. Methods: Between March 2020 and October 2022, 164 consecutive patients underwent liver resection at the Unit for hepato-bilio-pancreatic surgery, University Clinic for Digestive Surgery in Belgrade, Serbia. Intermittent Pringle maneuver was routinely applied. Depending on CIT during transection, patients were divided into two groups: group 1 (CIT

The differences related to gender are evident in physics education from the early age of the students. Thus, it is important that the teaching strategies that are implemented in mixed-gender physics classrooms are appropriate for both boys and girls. This research examined physics achievement and metacognitive awareness of students in lower secondary education in relation to gender when the modified Know-Want-Learn (mKWL) strategy is implemented. During the study, the students were divided into the control group (where direct teaching was implemented) and the experimental group (where the mKWL strategy was implemented in physics teaching). Students' physics achievement (estimated with knowledge tests) and metacognitive awareness (estimated with a questionnaire) before and after the pedagogical experiment, and also the students' comments on the mKWL strategy (provided through an informal conversation) were analyzed. It was shown that the students' achievement did not differ in relation to gender while girls showed higher metacognitive awareness in comparison with boys, and the mKWL strategy increased physics achievement and metacognitive awareness of both boys and girls. Furthermore, the students' comments on the strategy were discussed. The proposed strategy is shown to be appropriate for both genders, and its implementation in physics classrooms can be recommended.

Physics teaching should facilitate students to acquire knowledge, increase metacognitive awareness and motivation for learning physics. The implementation of cooperative learning could be useful for improving teaching. The aim of this research was to examine the effect of cooperative learning (specifically the jigsaw technique) on students' achievement in physics, metacognitive awareness, and motivation. An experiment with parallel groups (experimental and control) was carried out with 92 seventh-grade students (in lower secondary education). Jigsaw technique was implemented in the experimental group, while the control group was taught using teacher-directed teaching method. Students' physics achievement, metacognitive awareness and motivation were measured using knowledge tests and questionnaires (before and after the experiment). Statistical analysis included calculations of Cronbach's Alpha coefficient, performance of the Shapiro-Wilk test, Mann-Whitney U test and the Wilcoxon Signed Ranks Test. The research results showed that the implementation of jigsaw technique in physics classes significantly improved students' physics achievement, metacognitive awareness, and motivation. Therefore, it can be suggested that this technique is beneficial in lower secondary physics education, and it can be recommended to implement the jigsaw technique in everyday school practice.

Skates are cartilaginous fish whose body plan features enlarged wing-like pectoral fins, enabling them to thrive in benthic environments1,2. However, the molecular underpinnings of this unique trait remain unclear. Here we investigate the origin of this phenotypic innovation by developing the little skate Leucoraja erinacea as a genomically enabled model. Analysis of a high-quality chromosome-scale genome sequence for the little skate shows that it preserves many ancestral jawed vertebrate features compared with other sequenced genomes, including numerous ancient microchromosomes. Combining genome comparisons with extensive regulatory datasets in developing fins-including gene expression, chromatin occupancy and three-dimensional conformation-we find skate-specific genomic rearrangements that alter the three-dimensional regulatory landscape of genes that are involved in the planar cell polarity pathway. Functional inhibition of planar cell polarity signalling resulted in a reduction in anterior fin size, confirming that this pathway is a major contributor to batoid fin morphology. We also identified a fin-specific enhancer that interacts with several hoxa genes, consistent with the redeployment of hox gene expression in anterior pectoral fins, and confirmed its potential to activate transcription in the anterior fin using zebrafish reporter assays. Our findings underscore the central role of genome reorganization and regulatory variation in the evolution of phenotypes, shedding light on the molecular origin of an enigmatic trait.

Abstract Objective To provide an assessment of the cost burden of obesity across a spectrum of obesity-related comorbidities (ORCs) for four countries in South-Eastern Europe (SEE). Methods A micro-costing analysis from the public payer perspective was conducted to estimate direct healthcare costs associated with ten obesity-related comorbidities (ORCs) in Czech Republic, Greece, Hungary, and Romania. A survey was administered to obtain healthcare resource use and unit cost data. Cost estimates were validated by local steering committees which comprised at least one public sector clinician and a panel of independent industry experts. Results Chronic kidney disease and cardiovascular diseases were the costliest ORCs across all 4 countries, where annual cost burden per ORC exceeded 1,500 USD per patient per year. In general, costs were driven by the tertiary care resources allocated to address treatment-related adverse events, disease complications, and associated inpatient procedures. Conclusions Our findings confirm that the high prevalence of obesity and its comorbidities result in substantial financial burden to all 4 SEE public payers. By quantifying the burden of obesity from a public healthcare perspective, our study aims to support policy efforts that promote health education and promotion in combating obesity in the region.

Abstract DNA methylation (5mC) is a repressive gene regulatory mark widespread in vertebrate genomes, yet the developmental dynamics in which 5mC patterns are established vary across species. While mammals undergo two rounds of global 5mC erasure, teleosts, for example, exhibit localized maternal-to-paternal 5mC remodeling. Here, we studied 5mC dynamics during the embryonic development of sea lamprey, a jawless vertebrate which occupies a critical phylogenetic position as the sister group of the jawed vertebrates. We employed 5mC quantification in lamprey embryos and tissues, and discovered large-scale maternal-to-paternal epigenome remodeling that affects ~30% of the embryonic genome and is predominantly associated with partially methylated domains. We further demonstrate that sequences eliminated during programmed genome rearrangement (PGR), are hypermethylated in sperm prior to the onset of PGR. Our study thus unveils important insights into the evolutionary origins of vertebrate 5mC reprogramming, and how this process might participate in diverse developmental strategies.

IntroductionListeria monocytogenes is an ubiquitous foodborne pathogen that represents a serious threat to public health and the food industry.MethodsIn this study Whole Genome Sequencing (WGS) was used to characterize 160 L. monocytogenes isolates obtained from 22,593 different food sources in Montenegro during the years 2014–2022.ResultsIsolates belonged to 21 different clonal complexes (CCs), 22 sequence types (STs) and 73 core genome multilocus sequence types (cgMLST) revealing a high diversity. The most prevalent STs were ST8 (n = 29), ST9 (n = 31), ST121 (n = 19) and ST155 (n = 20). All isolates carried virulence genes (VGs), 111 isolates carried mobile genetic elements (MGEs) (ranging from 1 to 7 MGEs) and 101 isolates carried plasmids (ranging from 1 to 3 plasmids). All isolates carried the intrinsic resistance genes fosX and lin. None of the isolates carried acquired antimicrobial resistance genes (ARGs).Discussion/conclusionContinuous monitoring and surveillance of L. monocytogenes is needed for improving and ameliorating the public health.

Abstract In recent decades, the role of tumor biomechanics on cancer cell behavior at the primary site has been increasingly appreciated. However, the effect of primary tumor biomechanics on the latter stages of the metastatic cascade, such as metastatic seeding of secondary sites and outgrowth remains underappreciated. This work sought to address this in the context of triple negative breast cancer (TNBC), a cancer type known to aggressively disseminate at all stages of disease progression. Using mechanically tuneable model systems, mimicking the range of stiffness's typically found within breast tumors, it is found that, contrary to expectations, cancer cells exposed to softer microenvironments are more able to colonize secondary tissues. It is shown that heightened cell survival is driven by enhanced metabolism of fatty acids within TNBC cells exposed to softer microenvironments. It is demonstrated that uncoupling cellular mechanosensing through integrin β1 blocking antibody effectively causes stiff primed TNBC cells to behave like their soft counterparts, both in vitro and in vivo. This work is the first to show that softer tumor microenvironments may be contributing to changes in disease outcome by imprinting on TNBC cells a greater metabolic flexibility and conferring discrete cell survival advantages.

Summary: Background & Aims: Diarrhea is very common in patients receiving enteral nutrition. The principle of diarrhea treatment involves implementing dietary modifications, such as reduction of the fatty component, oral and probiotic supplementations, and increase of the fiber intake, aimed at mitigating the frequency and intensity of symptoms. In this context, partially hydrolyzed guar gum (PHGG) has emerged as a potential soluble fiber maximizing the effect against GI symptoms, particularly diarrhea. Among PHGG, NOVASOURCE® GI Control is an enteral nutrition formula indicated to improve the nutritional status and intestinal symptoms in patients with (risk of) malnutrition and intestinal barrier dysfunction, or intolerance to enteral nutrition. The objective of this economic analysis was to compare costs and effects of PHGG diet (taken with NOVASOURCE® GI Control) vs standard diet (SD, without fibers), in patients who are in need of enteral nutrition, in Italy. Methods: Two different analyses were conducted to reflect the most typical settings where enteral nutrition is relevant: i) critically-ill patients admitted to the hospital for an acute, life-threatening condition; ii) medical or (post)surgical patients. A simple decision-tree analysis was developed, with some minor differences depending on the setting. Hospital perspective was used to evaluate PHGG cost-opportunity in the hospital for critically-ill patients setting, while the Italian National Health Service (NHS) to assess the product for medical or surgical patients, assuming they were predominantly treated in an outpatient setting. Health outcomes and costs of critically-ill hospitalized patients and medical or surgical patients treated in a healthcare facility were estimated over a time horizon of 20 (PHGG group) to 27 (SD arm) days and over 24 days, respectively. Results: In the critically-ill setting, the use of PHGG diet prevented ∼12 cases of diarrhea every N=100 cases treated (relative reduction: -35%). The higher acquisition costs needed for PHGG diet (+€2,992) were more than offset by savings in all the other cost items, such as costs of hospital stay, medical therapy, costs of consumables, and cost of professional care to manage diarrhea (total saving -€1,186,330). Similarly, in medical or surgical patients, the use of PHGG was found cost-saving vs SD (-€6,040), and also reduced the number of diarrhea cases (relative reduction: -60%). Conclusions: The conducted economic analysis provides confidence that PHGG is a valuable and economically sustainable asset. Its utilization ensures not only adequate nutrition but also proves effective in mitigating diarrhea, thereby improving quality of life and limiting complication costs.