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Abstract Despite extensive research, the molecular role of AGR2 in the progression and metastasis of colorectal cancer (CRC) has not been fully characterized. We used quantitative mass spectrometry (SWATH MS) to identify differentially expressed proteins in paired CRC cell models of the SW480 and SW620 cell lines in response to AGR2 protein level manipulation. Relying on the results from SWATH MS and subsequent immunochemical validation, we selected NMP3 as the top candidate protein associated with AGR2 in CRC tumour cells in our screen. RT‒qPCR and immunochemical analysis confirmed the involvement of AGR2-mediated regulation of NPM3 at the transcriptional and posttranscriptional levels. Since PD-L1 is a constituent of the NPM3 regulatory axis, we aimed to correlate the changes in PD-L1 to the differential expression of AGR2 in our cell models. We found that AGR2 positively regulates PD-L1 levels in both SW480 and SW620 cell lines; additionally, several different CRC patient transcriptome cohorts confirmed the association of AGR2 with PD-L1. Our work reveals a new AGR2-NPM3 regulatory axis and the involvement of AGR2 in the regulation of PD-L1, which paves the way for the association of AGR2 with immune evasion in CRC cells.

Aim. Patients with multiple brain metastases (BM) benefit from hippocampal-avoiding whole brain radiotherapy (HA-WBRT), the challenging and less available form of WBRT. This study explores potential of pre-radiotherapy (pre-RT) hippocampal magnetic resonance spectroscopy (MRS) measuring hippocampal neuronal density as an imaging surrogate and predictive tool for assessing neurocognitive functions (NCF). Methods. 43 BM patients underwent pre-RT hippocampal MRS. N-acetyl aspartate (NAA) concentration, a marker for neuronal density (weighted by creatine (Cr) and choline (Cho) concentrations), and neurocognitive function (NCF) tests (HVLT and BVMT) performed by certified psychologists were evaluated. Clinical variables and NAA concentrations were correlated with pre-RT NCFs. Results. HVLT and BVMT subtests showed pre-RT deterioration except for BVMT recognition. Significantly better NCFs were observed in women in HVLT subsets. Significantly higher NAA/Cr + Cho was measured in women (median 0.63 vs. 0.55; P=0.048) in the left hippocampus (no difference in the right hippocampus). In men, a positive correlation (0.51, P=0.018) between total brain volume and HVLT-TR, between left hippocampal NAA/Cr + Cho and HVLT-R (0.45, P=0.063), and between right hippocampal NAA/Cr + Cho and BVMT-recognition (0.49, P=0.054) was observed. In women, a borderline significant negative correlation was observed between left hippocampal NAA/Cr + Cho and BVMT-TR (-0.43, P=0.076) and between right NAA/Cr + Cho and HVLT-DR (-0.42, P=0.051). Conclusion. Borderline statistically significant correlations were observed with speculative interpretation underlying the challenges of hippocampal MRS as a surrogate for neurocognitive impairment. Further studies need to be done to ascertain the opportunities for imaging predictors of benefit from memory sparing radiotherapy.

Abstract Background Predictive modeling based on multi-omics data, which incorporates several types of omics data for the same patients, has shown potential to outperform single-omics predictive modeling. Most research in this domain focuses on incorporating numerous data types, despite the complexity and cost of acquiring them. The prevailing assumption is that increasing the number of data types necessarily improves predictive performance. However, the integration of less informative or redundant data types could potentially hinder this performance. Therefore, identifying the most effective combinations of omics data types that enhance predictive performance is critical for cost-effective and accurate predictions. Methods In this study, we systematically evaluated the predictive performance of all 31 possible combinations including at least one of five genomic data types (mRNA, miRNA, methylation, DNAseq, and copy number variation) using 14 cancer datasets with right-censored survival outcomes, publicly available from the TCGA database. We employed various prediction methods and up-weighted clinical data in every model to leverage their predictive importance. Harrell’s C-index and the integrated Brier Score were used as performance measures. To assess the robustness of our findings, we performed a bootstrap analysis at the level of the included datasets. Statistical testing was conducted for key results, limiting the number of tests to ensure a low risk of false positives. Results Contrary to expectations, we found that using only mRNA data or a combination of mRNA and miRNA data was sufficient for most cancer types. For some cancer types, the additional inclusion of methylation data led to improved prediction results. Far from enhancing performance, the introduction of more data types most often resulted in a decline in performance, which varied between the two performance measures. Conclusions Our findings challenge the prevailing notion that combining multiple omics data types in multi-omics survival prediction improves predictive performance. Thus, the widespread approach in multi-omics prediction of incorporating as many data types as possible should be reconsidered to avoid suboptimal prediction results and unnecessary expenditure.

Abstract Genome-wide association studies (GWASs) based on common single nucleotide polymorphisms (SNPs) have identified several loci associated with the risk of monoclonal gammopathy of unknown significance (MGUS), a precursor condition for multiple myeloma (MM). We hypothesized that analyzing haplotypes might be more useful than analyzing individual SNPs, as it could identify functional chromosomal units that collectively contribute to MGUS risk. To test this hypothesis, we used data from our previous GWAS on 992 MGUS cases and 2910 controls from three European populations. We identified 23 haplotypes that were associated with the risk of MGUS at the genome-wide significance level (p

Abstract Multiple myeloma (MM) is the second most prevalent hematological malignancy, characterized by infiltration of the bone marrow by malignant plasma cells. Extramedullary disease (EMD) represents a more aggressive condition involving the migration of a subclone of plasma cells to paraskeletal or extraskeletal sites. Liquid biopsies could improve and speed diagnosis, as they can better capture the disease heterogeneity while lowering patients’ discomfort due to minimal invasiveness. Recent studies have confirmed alterations in the proteome across various malignancies, suggesting specific changes in protein classes. In this study, we show that MALDI-TOF mass spectrometry fingerprinting of peripheral blood can differentiate between MM and primary EMD patients. We constructed a predictive model using a supervised learning method, partial least squares-discriminant analysis (PLS-DA) and evaluated its generalization performance on a test dataset. The outcome of this analysis is a method that predicts specifically primary EMD with high sensitivity (86.4%), accuracy (78.4%), and specificity (72.4%). Given the simplicity of this approach and its minimally invasive character, this method provides rapid identification of primary EMD and could prove helpful in clinical practice.

Abstract Multiple myeloma (MM) is an incurable malignancy of plasma cells. Epidemiological studies indicate a substantial heritable component, but the underlying mechanisms remain unclear. Here, in a genome-wide association study totaling 10,906 cases and 366,221 controls, we identify 35 MM risk loci, 12 of which are novel. Through functional fine-mapping and Mendelian randomization, we uncover two causal mechanisms for inherited MM risk: longer telomeres; and elevated levels of B-cell maturation antigen (BCMA) and interleukin-5 receptor alpha (IL5RA) in plasma. The largest increase in BCMA and IL5RA levels is mediated by the risk variant rs34562254-A at TNFRSF13B. While individuals with loss-of-function variants in TNFRSF13B develop B-cell immunodeficiency, rs34562254-A exerts a gain-of-function effect, increasing MM risk through amplified B-cell responses. Our results represent an analysis of genetic MM predisposition, highlighting causal mechanisms contributing to MM development.

Abstract Purpose This study was designed to elicit medical students’ opinions on the characteristics of a good ultrasound tutor. The results should help educators to create an optimal teaching environment and inform tutor training. Materials and methods The qualitative study recruited 15 participants from a larger mixed-methods study of 64 medical students who underwent a basic course on abdominal ultrasound taught by faculty and near-peer tutors. During semi-structured interviews, they were asked which characteristics make a good ultrasound tutor. We used inductive thematic analysis to identify the most important categories. Results Medical students identified teaching themes and subthemes relating to teaching skills (e.g., course structure, repetition, vocabulary, feedback, guidance of participants), tutors’ attitudes (e.g., atmosphere creation, empathy) and knowledge as the crucial components of being a good ultrasound tutor. Conclusions While some of the themes that students identified are generic to medical education, others are specific to ultrasound teaching. Tutors can use our results to assess their own teaching. They should aim to address learning needs, optimise understanding, give adequate feedback, and create a non-threatening atmosphere with empathic interactions. Accounting for the ultrasound-specific setting they should possess the necessary knowledge, provide verbal guidance to their students, and distribute examination time wisely.

Abstract Background Diagnostic ultrasound has become a bedside tool widely available to many primary care physicians (PCPs) in Europe. It is often used as point-of-care ultrasonography (POCUS) in this setting. In Switzerland, certain POCUS examinations are listed as learning objectives in existing ultrasound training programs (we defined these examinations as swissPOCUS = sPOCUS). Ultrasound performed by PCPs can lead to faster diagnostic workup and reduce referral to secondary care units. However, adequate training is crucial to guarantee high quality. To guide the development of ultrasound training programs for PCPs, this study explores the use of ultrasound in primary care in Switzerland. Methods This was a cross-sectional study. We invited PCPs from the Swiss practice-based research network “Sentinella” to collect data on the first 5 daily ultrasounds they ordered or performed themselves. Participating PCPs collected data for 3 months – divided into 4 groups to account for seasonal differences. Results Out of 188 PCPs invited, 81.9% provided data through an initial questionnaire. 46.8% provided data on 1616 ultrasounds. 56.5% of PCPs had access to ultrasound machines, while 29.8% had completed formal training. 77% of the reported ultrasounds were self-performed; 27% of the reported scans (35% of all self-performed scans) were performed by PCPs with incomplete or no formal training. The main areas of interest were the abdominal (57.9%) and the musculoskeletal (22%) region. 36.9% of reported examinations were sPOCUS exams. Among PCPs with access to US machines, the percentages of referred examinations were similar for sPOCUS (11.9%) and non-sPOCUS (11.3%) indications. However, some sPOCUS musculoskeletal ultrasounds were often referred (e.g. tendon/ligament/muscle injuries or cutaneous/subcutaneous tumour). Conclusion Most Swiss PCPs had access to ultrasound equipment and performed a majority of both sPOCUS and non-sPOCUS scans themselves, often without or with incomplete training. This reflects the fact that POCUS was only recently introduced in Switzerland. There is a need for easily accessible POCUS training programs aimed at PCPs in Switzerland. Training courses for PCPs should focus on abdominal and musculoskeletal ultrasound, because these were the most common sites for scans, and because some sPOCUS musculoskeletal examinations showed a particularly high percentage of referral.

IntroductionThe marking of interchangeable cutting inserts according to ISO 6987 does not include the know-how of cutting tool manufacturers in the design of chip-breakers or the application of coatings. These small differences have a key effect on the efficiency and service life of cutting tools and result in qualitative and quantitative differences in production, which is related to the reduction or increase in costs associated with the appropriate choice of cutting tool. The design of the inserts also affects the shape and size of the chips produced, which is important to monitor for a safe machining process and subsequent waste management. This research deals with the effect of selected factors on the tool life and the form of the chips produced.MethodsIndexable cutting inserts of the type CNMG 120408 from three different manufacturers were tested for their lifetime under identical cutting conditions (vc = 80 m s−1, ap = 1.5 mm, f = 0.3 mm·ot−1) on steel 1.6582 hardened to 40–44 HRC. These inserts are made of sintered tungsten carbide in a cobalt binder, coated with Al2O3 and TiCN layers. During machining, the wear of the main flank was continuously measured until the critical wear rate VBmax = 0.3 mm was reached. At the same time, the produced chips were continuously collected and analyzed in terms of their shape and size. The number of chips produced per 100 g of chips was calculated to obtain an analogous value indicating the total chip collection in terms of waste management. The SEM was used to identify both the types of coating layers present on the investigated inserts and the types of wear observed after reaching critical wear.ResultsThe longest lifetime was achieved by the PM 4325 insert coated by 11.5 ± 1.2 µm TiCN layer and 5.3 ± 0.3 µm Al2O3 layer with a time T = 19.5 min. The chips produced were in the forms of arch connected and arch loose and the average chip length was 27.9 ± 7.6 mm. The number of chips per 100 g produced by the PM 4325 was 1,494 ± 401 pieces, which was the lowest count of chips within the experiment (which is not optimal). The MP3 -WPP20S insert coated by 17.8 ± 0.4 µm TiCN layer and 15.1 ± 0.3 µm Al2O3 layer achieved lifetime T = 17.4 min even though it has twice the thickness of the coating compared to PM 4325. Produced chips in the forms of arch connected, arch loose and tubular short shape and the average chip length was 34.1 ± 5.5 mm, which was the worst chip length result within the experiment in terms of chip evaluation. The number of chips per 100 g produced by MP3 -WPP20S was 1,520 ± 401 pieces. The E-M GRADE T9325 insert coated by 7.2 ± 0.5 µm TiCN layer and 5.1 ± 0.2 µm Al2O3 layer achieved the shortest lifetime with a time T = 10.8 min. The chips produced were arch loose in shape, with an average chip length of 8.2 ± 0.7 mm. The number of chips per 100 g produced by the E-M GRADE T9325 was 2,392 ± 259 pieces, achieving the best result in the experiment in terms of chips produced. The achieved results are correlated with different combinations of thicknesses of Al2O3 and TiCN protective coatings revealed by SEM analysis.Discussion/ConclusionTogether with the geometrical nuances of the design of the different manufacturers, factor of combinations of coatings thicknesses has an influence on the variation of the wear progress and the achievement of a specific lifetime value of the cutting inserts. The experiment concludes that the thickness of the coating layers alone does not have a direct effect on the overall lifetime of the tool, and the approximate lifetime of the cutting edge cannot be predicted based on the parameters of the coating layers. When choosing a cutting tool, the manufacturer should carry out a test series for the specific material to be machined, despite the declaration of the composition and thickness of the coating layers. The analysis of the produced chips led to the conclusion that the wafers with a thinner coating layer, especially the Al2O3 layer, formed better chips in terms of their shape and size due to the different heat distribution during machining.

Abstract. Objectives:. To develop and validate a prediction model for a deep surgical site infection (SSI) after fixation of a tibial plateau or pilon fracture. Design:. Pooled data from 2 randomized trials (VANCO and OXYGEN). Setting:. Fifty-two US trauma centers. Patients:. In total, 1847 adult patients with operatively treated tibial plateau or pilon fractures who met criteria for a high risk of infection. Intervention:. We considered 13 baseline patient characteristics and developed and externally validated prediction models using 3 approaches (logistic regression, stepwise elimination, and machine learning). Main Outcomes and Measures:. The primary prediction model outcome was a deep SSI requiring operative debridement within 182 days of definitive fixation. Our primary prognostic performance metric for evaluating the models was area under the receiver operating characteristic curve (AUC) with clinical utility set at 0.7. Results:. Deep SSI occurred in 75 VANCO patients (8%) and in 56 OXYGEN patients (6%). The machine learning model for VANCO (AUC = 0.65) and stepwise elimination model for OXYGEN (AUC = 0.62) had the highest internal validation AUCs. However, none of the external validation AUCs exceeded 0.64 (range, 0.58 to 0.64). Conclusions:. The predictive models did not reach the prespecified clinical utility threshold. Our models' inability to distinguish high-risk from low-risk patients is likely due to strict eligibility criteria and, therefore, homogeneous patient populations.

AbstractBackground The beneficial effects of a plant-based diet on gut microbiota diversity are well documented, however, its impact on clinical bowel health and defecation patterns are less well understood. Vegetarian diets have been associated with a higher bowel movement (BM) frequency as well as softer stools in cross-sectional studies. The effects of the de-novo adoption of a vegan diet on bowel health, however, have never been investigated in a randomized-controlled trial.Materials and Methods The present study examined bowel health and defecation patterns in relation to diet and nutrient intake in a young and healthy sample of n = 65 physically-active German university students who were randomly assigned to either a vegan or a meat-rich diet for eight weeks. Bowel health assessment included the Bristol Stool Form Scale (BSFS), the Gastrointestinal Quality of Life Index (GIQLI) and the Cleveland Clinic Fecal Incontinence Score (CCFIS). Nutrient intake was assessed using weighed food diaries. The study was prospectively registered at the German Clinical Trial Register (DRKS00031541).Results Weekly BM frequency slightly increased in vegans, whereas it remained unaltered in participants assigned to a meat-rich diet. Fiber intake increased significantly in vegans (34.89 (18.46) g/d) whereas it decreased in those assigned to the meat-rich group (22.79 (12.5) g/d). No significant intergroup differences in BSFS and CCFIS patterns were observed. Adoption of a vegan diet neither resulted in a transient increase in abdominal discomfort nor in a decreased gastrointestinal quality of life, which was comparable across the diet groups.Conclusions The short-term de-novo adoption of a vegan diet did not negatively affect markers of bowel health in this study.

Стаття представляє результати дослідження змісту поняття «фінансова грамотність» і стану проблеми формування фінансової грамотності як ключової компетентності у змісті професійної підготовки майбутніх вчителів початкових класів. З метою виокремлення змістового складника готовності майбутніх учителів до формування фінансової грамотності в учнів початкової школи використано методи педагогічного спостереження під час педагогічної практики студентів бакалаврату та магістратури, контент-аналіз наявних методичних матеріалів для початкової школи на предмет виявлення економічної (фінансової) тематики в межах технологічної освітньої галузі. В результаті аналізу теоретико-методичної літератури з’ясовано, що поняття «фінансова грамотність» як ключова компетентність громадянина має однаковий зміст як для здобувачів початкової освіти, так і для майбутніх учителів, що пояснюється самою ідеєю «грамотності» як початкового рівня знань та компетенцій. Методом спостереження виявлено низький рівень фінансової компетентності та зацікавленості у розкритті фінансово-економічних аспектів у майбутніх вчителів під час проведення уроків на практиці. Передбачено, що у професійній підготовці вчителя початкової освіти фінансова грамотність як особисто значуща компетенція має поєднуватися готовністю до формування фінансової грамотності в учнів. Умовами такої підготовки названо використання особистісно-орієнтованого, компетентнісного, коучингового підходів. На основі змісту поняття «фінансова грамотність» сформульовано основні принципи формування фінансової грамотності здобувачів освіти: прозорість інформації, волонтерство в труді та доброчинність, автономність дитячого бюджету; поступовість накопичення фінансового досвіду; поєднання фінансової обізнаності і критичного мислення; формування досвіду через гру; екологічність фінансових звичок та відповідальне споживання.

This article compares the treatment of rectal endometriosis using high-intensity focused ultrasound (HIFU) versus surgery. The study involved 120 patients, with 60 in each group. The results showed that HIFU treatment had a lower rate of complications and shorter hospitalization duration compared to surgery. Both treatments showed significant improvement in symptoms and quality of life outcomes at 6 months. The study suggests that HIFU could be an alternative to surgical treatment for suitable patients, but further research is needed to assess long-term complications and relapse risks. [Extracted from the article]

Abstract Background Trigonocephaly occurs due to the premature fusion of the metopic suture, leading to a triangular forehead and hypotelorism. This condition often requires surgical correction for morphological and functional indications. Metopic ridges also originate from premature metopic closure but are only associated with mid-frontal bulging; their surgical correction is rarely required. Differential diagnosis between these two conditions can be challenging, especially in minor trigonocephaly. Methods Two hundred seven scans of patients with trigonocephaly (90), metopic rigdes (27), and controls (90) were collected. Geometric morphometrics were used to quantify skull and orbital morphology as well as the interfrontal angle and the cephalic index. An innovative method was developed to automatically compute the frontal curvature along the metopic suture. Different machine-learning algorithms were tested to assess the predictive power of morphological data in terms of classification. Results We showed that control patients, trigonocephaly and metopic rigdes have distinctive skull and orbital shapes. The 3D frontal curvature enabled a clear discrimination between groups (sensitivity and specificity > 92%). Furthermore, we reached an accuracy of 100% in group discrimination when combining 6 univariate measures. Conclusion Two diagnostic tools were proposed and demonstrated to be successful in assisting differential diagnosis for patients with trigonocephaly or metopic ridges. Further clinical assessments are required to validate the practical clinical relevance of these tools.

We present a novel method combining anodic aluminum oxide template synthesis and nanolithography to selectively deposit vertically patterned magnetic nanowires on a Si substrate. With this approach we fabricated three-dimensional nanowire-based spin valve devices without the need of complex etching processes or additional spacer coating. Through this method, we successfully obtained NiCu/Cu multilayered nanowire arrays with a controlled sequence along the long axis of the nanowires. Both magnetic switching and excitation phenomena driven by spin-polarized currents were clearly demonstrated in our NiCu/Cu multilayered nanowires. Moreover, the critical currents for switching and excitation were observed to be modulated in an oscillatory manner by the magnetic field in the nanowire-based devices. We present a toy model to qualitatively explain these observations.