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Abstract The increase of antimicrobial resistance constitutes a significant threat to human health. One of the mechanisms responsible for the spread of resistance to antimicrobials is the transfer of plasmids between bacteria by conjugation. This process is mediated by type IV secretion systems (T4SS) and previous studies have provided in vivo evidence for interactions between DNA and components of the T4SS. Here, we purified TraD and TraE, two inner membrane proteins from the Escherichia coli pKM101 T4SS. Using electrophoretic mobility shift assays and fluorescence polarization we showed that the purified proteins both bind single-stranded and double-stranded DNA in the nanomolar affinity range. The previously identified conjugation inhibitor BAR-072 inhibits TraE DNA binding in vitro, providing evidence for its mechanism of action. Site-directed mutagenesis identified conserved amino acids that are required for conjugation that may be targets for the development of more potent conjugation inhibitors. more...

Abstract Background Diversity competence, diversity itself, and a corresponding awareness of possible (intersectional) discrimination mechanisms have not been anchored in the German National Competence based Learning Objectives Catalogue for Medicine 2.0 (Nationaler Kompetenzbasierter Lernzielkatalog 2.0., NKLM) yet, highlighting a systemic gap in national competency frameworks. We present our first experience with a prospective diversity-specific intervention in medical students to assess its short-term impact on students' diversity acceptance (DA) and to develop actionable recommendations for integrating diversity into medical education. Methods We designed a prospective cohort study using a control group (CG) and intervention group (IG) design. The IG absolved a five-day diversity-specific intervention (50 h; field trip; seminar). Quantitative data were collected using the validated DWD-O5 scale at baseline (T0), three months (T3), and six months (T6), complemented by qualitative responses (diversity issues in the medical curriculum; perceptions and criticisms) categorized using Mayring’s content analysis. Descriptive and non-parametric statistics were performed. Results Thirty-one medical students (n = 10, IG vs n = 21, CG) were enrolled. The IG demonstrated a short-term improvement in diversity competence (+ 9.72%) across all DWD-O5 factors during the intervention. While scores slightly declined at T6, they remained above baseline levels. 35% (CG) vs. 56% (IG) have experienced discrimination in context of medical studies on their own. Participants in both groups stressed the importance of integrating diversity criteria into curricula at an early stage (100% agreement). Findings revealed three key themes: perceived inadequacies in current curricula, self-reported discrimination experiences, and a strong desire for practical diversity training, such as simulation-based learning. Conclusion The intervention shows promise as an initial step toward addressing diversity gaps in medical education. By combining historical, cultural, and experiential learning approaches, the program fosters essential competencies such as empathy, self-reflection, and bias recognition. More broadly, sustained improvements in diversity competence require longitudinal integration of diversity training across curricula and systemic reforms to national frameworks like the NKLM. Future research should explore the long-term impact of such interventions and strategies for institutionalizing equity-focused medical education. more...

Abstract Individual enhancers are defined as short genomic regulatory elements, bound by transcription factors, and able to activate cell-specific gene expression at a distance, in an orientation-independent manner. Within mammalian genomes, enhancer-like elements may be found individually or within clusters referred to as locus control regions or super-enhancers (SEs). While these behave similarly to individual enhancers with respect to cell specificity, distribution and distance, their orientation-dependence has not been formally tested. Here, using the α-globin locus as a model, we show that while an individual enhancer works in an orientation-independent manner, the direction of activity of a SE changes with its orientation. When the SE is inverted within its normal chromosomal context, expression of its normal targets, the α-globin genes, is severely reduced and the normally silent genes lying upstream of the α-globin locus are upregulated. These findings add to our understanding of enhancer-promoter specificity that precisely activate transcription. more...

Abstract Background Dialectical behavioral therapy (DBT) and repetitive transcranial magnetic stimulation (rTMS) are both effective in treating borderline personality disorder (BPD). Impulsivity and impaired decision-making are prominent features of BPD, and therapeutic interventions targeting these symptoms could lead to significant improvements. Objective/Hypothesis We hypothesized that intermittent theta burst stimulation (iTBS), a modified rTMS protocol that targets the left dorsolateral prefrontal cortex, would enhance the therapeutic effects of DBT, leading to greater improvements in impulsivity and decision-making compared with sham stimulation. Methods We performed a single-blind, randomized, sham-controlled pilot study to evaluate the efficacy of iTBS as an add-on to an 8-week DBT program for BPD in a routine inpatient setting. A total of 53 BPD patients were randomly assigned to receive either iTBS (n = 25) or sham stimulation (n = 28) during weeks 4 to 8 of DBT, and 36 patients met the inclusion criteria for the present analysis (≥ 16 of 20 iTBS/sham sessions and assessment of delay discounting). The study endpoints were the Barratt Impulsiveness Scale-15 for impulsivity and the Monetary Choice Questionnaire for decision-making/delay discounting. Results A mixed model repeated measures analysis with a 2 × 2 factorial between-subjects design showed a significant overall improvement over time in impulsivity but not in decision-making/delay discounting. No significant differences were found between iTBS and sham, although post hoc tests revealed significant changes in impulsivity in the iTBS group (meandiff = -4.7, p = .001, Cohen’s d = 0.68) but not in the sham group (meandiff = -2.1, p = .077, d = 0.31). Conclusions iTBS may offer long-term benefits as an add-on treatment to DBT for impulsivity in BPD, suggesting the need for further investigation in larger-scale studies. Trial registration Registered at drks.de (no. DRKS00020413) on January 13, 2020. more...

Abstract Background Workplace health promotion is essential for individual and organisational well-being and disease prevention, also in industrial workers. As the transfer of the evidence on the effectiveness of such programs into practice is limited due to scattered effects, the need for a consolidation of the available studies is given. The purpose of this systematic review was to synthesise the evidence on the effectiveness of workplace health promotion programs for industrial workers. Methods An electronic literature search was conducted in PubMed, Cochrane Library, Web of Science™, Scopus, and EBSCOHost until July 26th 2023. Studies investigated industrial workers who performed manual labour for at least 20 h per week were included. They had to receive a workplace health promotion intervention under any control condition. Outcomes were workplace health interventions’ safety and corresponding health-related outcomes. The revised Cochrane risk-of-bias assessed the risk of bias (Rob 2) tool for randomised control trials (RCT) and cluster RCT. Quality assessment was performed using a modified Downs and Black Checklist. Results Of the 25,555 studies initially identified, 39 were included. Generally, the mean quality of the studies was moderate, with most studies judged with a high overall risk of bias. Twenty-seven studies employed a behavioural approach, while one study adopted an organisational one. Ten studies utilised a multicomponent approach, and one intervention improved safety outcomes. The analysis of the results indicated an overall positive but heterogeneous effect across the different approaches. Conclusions The studies included in this review provide evidence that workplace health promotion can be effective. However, the overall findings are inconclusive due to the high risk of bias. Therefore, the results should be interpreted cautiously. Despite the considerable amount of research conducted in this field, additional well-designed studies are needed to fully confirm the effectiveness and determine the most promising types of interventions for improving and maintaining industrial health. more...

Background and Aim: Anaplasmosis in small ruminants is a tick-borne infection caused mainly by the obligate intraerythrocytic bacterium Anaplasma ovis. It is usually subclinical, with persistent infection in affected animals, but acute disease can occur, particularly in young animals. The pathogen is widespread in Central Asia and neighboring regions. In Kazakhstan, the infection was first detected in 1929. However, until now, diagnosis in the country has been based on traditional microscopic examination of blood smears. There were no reliable data on the prevalence and genetic diversity of Anaplasma spp. in sheep in Kazakhstan. This study aimed to determine the occurrence of Anaplasma spp. infection in sheep in southern Kazakhstan, a high-risk region for tick-borne diseases, using PCR and to identify the species by sequencing. Materials and Methods: A cross-sectional study was conducted on apparently healthy adult ewes from 77 settlements in 34 districts of Kyzylorda, Turkistan, Zhambyl, Almaty, and Jetisu, southern Kazakhstan. A total of 2553 whole blood samples collected in midsummer 2022 and 2023 were analyzed for Anaplasma spp. using polymerase chain reaction targeting the 404 bp groEL gene fragment. The amplification products from the 441 positive samples were sequenced using the Sanger sequencing method. Phylogenetic analysis of the obtained sequences was performed using the maximum likelihood model. Results: Overall, 1017/2553 (39.8%; 95% confidence interval: 37.9%-41.7%) ewes tested were positive for Anaplasma spp. Positive animals were found in 68/77 (88%) of the settlements from which samples were taken. The percentage of Anaplasma spp.-positive ewes varied significantly from 21.3% to 50.1% in the provinces. Altitude 99.5% identical to isolates from Africa, Cyprus, and China. Conclusion: This first molecular study revealed a widespread of A. ovis infection in adult ewes in southern Kazakhstan. Altitude more...

Abstract Introduction Locoregional recurrence (LR) is common in locally advanced head and neck cancer (HNSCC), posing challenges for treatment. We analysed outcome parameters and toxicities for patients being treated with radiotherapy (RT) for LR-HNSCC and investigated patient and disease related prognostic factors in this prognostically unfavourable group. Methods This analysis includes 101 LR-HNSCC patients treated with RT, radio-chemotherapy (RCT) or radio-immunotherapy (RIT) between 2010 and 2018 at a high-volume tertiary centre. Patient characteristics, tumour and treatment details were retrospectively collected. Overall survival (OS), progression-free survival (PFS) and toxicities according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0 were assessed. Results 62% of patients were radiotherapy-naïve (initial RT group) while 38% were re-irradiated at site of LR (re-RT group). Median OS for initial RT was 24 months, for re-RT 12 months (p more...

Abstract The ICH E9 (R1) guidance and the related estimand framework propose to clearly define and separate the clinical question of interest formulated as estimand from the estimation method. With that it becomes important to assess the validity of the estimation method and the assumptions that must be made. When going beyond the intention to treat analyses that can rely on randomization, causal inference is usually used to discuss the validity of estimation methods for the estimand of interest. In pharmacometrics, mixed‐effects models are routinely used to analyze longitudinal clinical trial data; however, they are rarely discussed as a method for causal inference. Here, we evaluate nonlinear mixed‐effects modeling and simulation (NLME M&S) in the context of causal inference as a standardization method for longitudinal data in the presence of confounders. Standardization is a well‐known method in causal inference to correct for confounding by analyzing and combining results from subgroups of patients. We show that nonlinear mixed‐effects modeling is a particular implementation of standardization that conditions on individual parameters described by the random effects of the mixed‐effects model. As an example, we use a simulated clinical trial with within‐subject dose titration. Being interested in the outcome of the hypothetical situation that patients adhere to the planned treatment schedule, we put assumptions in a causal diagram. From the causal diagram, conditional independence assumptions are derived either by conditioning on the individual parameters or on earlier outcomes. With both conditional independencies unbiased estimates can be obtained. more...

Abstract Although Emergency Medicine is now globally an established specialty, the Nordic countries have been relatively slow to implement it into their health care systems. To facilitate the development of EM in the Nordic area, a working group was formed with representation from all national EM societies; DASEM (Danish Society for Emergency Medicine), FiSEM (Finnish Society of Emergency Medicine), ISEM (Icelandic Society for Emergency Medicine), NCEM (Norwegian College of Emergency Medicine), and SWESEM (Swedish Society for Emergency Medicine). This group was tasked with creating a Nordic EM manifesto—to create a definition and developmental goals for Nordic Emergency Medicine. The commentary provides an overview of the current status and challenges facing EM in the Nordic countries. more...

Abstract Background The prehospital use of blood lactate measurements is increasing. However, the test’s benefits have not been methodically evaluated in non-trauma patients. This study had three aims: (1) To assess the evidence of prehospital blood lactate measurements’ prognostic value in non-trauma patients, (2) to investigate to what extent the test changed early patient treatment, and (3) to evaluate the healthcare personnel’s attitude towards the test. Methods MEDLINE, Embase, and Cochrane Central Register of Controlled Trials were systematically searched until Aug 26, 2023. Cohort and randomized controlled trials assessing ≥ 20 acute non-trauma patients with prehospital lactate measurements were included if they reported (1) prognostic outcomes such as short-term mortality or (2) changes in early patient treatments. All study designs were included to assess (3) the healthcare personnel’s opinion on prehospital lactate measurements. The risks of bias were assessed using the QUIPS tool, the Newcastle–Ottawa Scale, and the RoB-2. Study registration number CRD42020167169 (PROSPERO). Results We screened 6028 study reports. We included 15 studies on (1) the prognostic value of prehospital lactate measurements. Elevated blood lactate levels were correlated to a higher short-term mortality risk in most of the studies but not in studies with out-of-hospital cardiac arrest (OHCA) patients. The 15 prognostic studies were all cohort studies with moderate or high risks of bias. Four studies investigated (2) early treatment changes. They found that the prehospital lactate measurement may have changed early treatment in sepsis patients. However, all four studies on treatment changes were at high risk of bias. Four studies were included on (3) the healthcare personnel’s attitude towards the lactate measurement. Evidence of the healthcare personnel’s opinion on prehospital lactate measurements was scarce. Conclusion Most acute non-trauma patients with elevated prehospital lactate levels had increased risks of short-term mortality, except OHCA patients. Few studies suggested that measuring prehospital lactate levels could change early patient care, particularly in patients with suspected sepsis. The certainty of the evidence is low in this systematic review. The included studies were heterogeneous, and many had high risks of bias. Further studies are needed to investigate the impact of prehospital lactate measurements on patient care. more...

The Kindergarten Curriculum in the Philippines (2016) recommends introducing alphabet names, sounds, and symbols during the 11th week, coinciding with the second quarter of the academic year. The curriculum initially presents two letters each week and another two in the subsequent weeks, which may challenge five-year-old pupils in comprehending the abstract nature of the alphabet. This study aimed to determine the effects of introducing one letter per week and another in the subsequent weeks, thereby creating a more engaging learning environment without overwhelming the pupils with two letters at once. The implementation began in the third week of the first quarter. A Sound-Recognize-Write assessment checklist was used in this study, involving thirty-five kindergarten pupils from a single section. The results revealed that 30 out of 35 mastered the sound, name, and symbol of all twenty–eight (28) letters in the Filipino alphabet. In this study, researchers also found out the most difficult letters to master and the easiest letters to recognize. It was then recommended that additional time be provided to explore the letters, especially those letters that are difficult to master. A 5-day activity plan was proposed to help the struggling learners to improve their literacy skills. more...

Abstract Low back pain (LBP) is a global issue involving biological, psychological, and social factors. Pain-related fear has been shown to influence movement behavior, however, its association with some measures of movement behavior, such as spinal movement variability, remains inconclusive. To further investigate this, spinal kinematics during various activities of daily living (i.e., walking, running, lifting, and stair climbing) of 49 patients with chronic LBP and a group of 51 sex-, age-, and BMI-matched healthy controls were used to calculate lumbar spine movement variability which was quantified using different indices (i.e., coefficient of variation, coupling angle variability in vector coding, deviation phase of the continuous relative phase and an angle-angular velocity variability). General and task-specific pain-related fear was assessed using the Tampa Scale of Kinesiophobia and the Photograph Series of Daily Activities—Short Electronic Version, respectively. Linear regression analyses showed no significant association between movement variability and pain-related fear, however, the sample consisted of younger individuals with moderate disability and with low levels of pain and pain-related fear. In addition, the different variability indices were weakly correlated and varied greatly depending on the method used and the task performed. Therefore, comparisons between studies with different movement variability calculation methods or different activities should be treated with caution. more...

Abstract The current study aimed to evaluate short‐ and long‐term complication rates and functional outcomes in a substantial cohort of patients undergoing ileal ureter interposition at two high‐volume medical centres. Materials and methods A retrospective single‐arm analysis was conducted on patients who underwent ureter reconstruction using ileum between 2003 and 2022 at the University Clinic of Cologne and the National Cancer Institute of Ukraine. Data on aetiology, surgical techniques, pre‐ and postoperative kidney function changes, readmission rates and complication management were collected. Postoperative complications were classified according to Clavien–Dindo, and estimated glomerular filtration rate (eGFR) was calculated using the CKD‐EPI formula. Results Results revealed 107 cases with consistent data. Within 90 days post‐surgery, 53% experienced complications, mainly graded as I–II. Grade III complications were seen in 13%, with two cases of grade IV complications leading to extended hospitalisation and patient death. The 90‐day mortality rate was 1.8%. Over a mean follow‐up of 52 months, clinically significant vesico‐renal refluxes occurred in 28%, with only 5.4% leading to persistent urinary tract infection. Antireflux techniques appeared to reduce urine upflow incidence compared with conventional interposition. Anastomosis stricture occurred in 15% of patients, with 63% requiring permanent re‐stenting and 37% needing re‐anastomosis. Metabolic acidosis was clinically significant in 7.5% of cases. A slight improvement in renal function was observed during the first year post‐surgery (average postoperative eGFR = 76 ± 22 ml/min; Mann–Witney U test, p = 0,0198). Affected kidney function improved in 56 (52%), was stable in 41 (38%) and deteriorated in 10 (9.3%). Loss of kidney function on the surgery side was seen in 4 (3.7%) patients and resulted in nephrectomy in 3 (2.8%) cases. Conclusion Ileal ureter interposition demonstrated a favourable safety profile and functional outcomes. This surgical intervention provides an effective tension‐free bypass, irrespective of healthy ureter length. more...

Abstract Background Persons with dementia frequently experience mealtime behavioral problems that can result in reduced or lack of intake of food or fluids. Multiple underlying causes and expressions of mealtime behavioral problems complicate its interpretation and intervention, because problems originating from cognitive and functional decline and behavioral changes may interact. Healthcare professionals and family caregivers may encounter a variety of practical and moral dilemmas in dealing with these problems. We aimed at a better understanding of mealtime behavioral problems and related complex issues in nursing home residents with dementia from a daily practice perspective. Methods We used a mixed-method Group Concept Mapping approach in this study, and collected data online with a panel of 67 healthcare professionals, researchers and relatives from across The Netherlands. The participants contributed to either or all of the following phases: (1) the generation of ideas (brainstorm), (2) sorting, and (3) rating of the ideas. Subsequent phases included data analysis with Groupwisdom® software and interpretation of the results. Multidimensional scaling and hierarchical cluster analysis resulted in a concept map visualizing the coherence and importance of ideas. Bridging values were calculated, with low values indicating a distinct, clear concept. Results Brainstorming resulted in 285 statements representing 85 ideas. The concept map visualized three categories capturing ten clusters which describe the management of mealtime behavioral problems, causes of mealtime behavioral problems, and expressions and interpretations of mealtime behavioral problems. Concepts reflecting direct consequences, ethical components, and considerations to handle challenging situations overlapped on the concept map with the highest bridging values (range 0.58–0.87). Conclusion This study added to unraveling the complex nature of mealtime behavioral problems, as perceived in practice. It is recommended to comprehensively analyze all components in the management of these problems, in particular being aware of ethical factors and align care for residents with dementia accordingly. more...

Abstract Fabry disease is a multi-organ disease, caused by mutations in the GLA gene and leading to a progressive accumulation of glycosphingolipids due to enzymatic absence or malfunction of the encoded alpha-galactosidase A. Since pathomechanisms are not yet fully understood and available treatments are not efficient for all mutation types and tissues, further research is highly needed. This research involves many different model types, with significant effort towards the establishment of an in vivo model. However, these models did not replicate the variety of symptoms observed in patients. As an alternative strategy, patient-derived somatic cells as well as patient-independent cell lines were used to model specific aspects of the disease in vitro. Fabry disease patients present different phenotypes according to the mutation and the level of residual enzyme activity, pointing to the necessity of personalized disease modeling. With the advent of induced pluripotent stem cells, the derivation of a multitude of disease-affected cell types became possible, even in a patient-specific and mutation-specific manner. Only recently, three-dimensional Fabry disease models were established that even more closely resemble the native tissue of investigated organs and will bring research closer to the in vivo situation. This review provides an overview of human in vitro models and their achievements in unravelling the Fabry disease pathomechanism as well as in elucidating current and future treatment strategies. more...

Abstract Background Life-sustaining therapy, including heart and lung resuscitation and transfer to the intensive care department, is demanding for patients and relatives and utilizes large amounts of healthcare resources. For older patients acutely admitted to the hospital, very sparse data exist on decision making about life-sustaining therapy. Methods Retrospective data were extracted from patients ≥ 70 years old who were acutely admitted to the hospital. Age, sex, clinical frailty scale score and Charlson comorbidity index were manually extracted from patients’ files. Furthermore, data about life-sustaining treatment decisions were extracted. This was further divided into decisions documented within 24 h from admission or during the hospital stay. Results Data were extracted for 200 patients with a median age of 80 years. Patients had a Charlson Comorbidity Index of 6 (5–8 IQR) and a Clinical Frailty Scale (CFS) score of 5 (3–6 IQR). During the first 24 h, 61 patients (30.5%) had a written decision about heart and cardiopulmonary resuscitation (CPR), and 52 patients (26%) had written information about intensive care therapy. A total of 93 patients (46.5%) had a written decision about cardiopulmonary resuscitation (CPR), intensive care therapy or both during their hospital stay. With increasing Charlson Comorbidity Index and Clinical Frailty Scale scores, more patients had decisions about limitations in therapy documented in their files. Conclusions Within the first 24 h, 30.5% of the patients had a written decision about cardiopulmonary resuscitation (CPR), and 26% had written information about intensive care therapy. These numbers increased to 46.5% of patients who had a decision made during their hospital stay whether they were candidates for either cardiopulmonary resuscitation (CPR), intensive care therapy or both. These data suggest that further work should be done to determine the limitations of therapy early on the admission for all older frail acutely admitted patients. more...

Introduction Improving medication adherence is essential for the effective management of hypertension. Purpose This study aimed to assess the level of antihypertensive medication adherence among adult hypertensive patients at Monkole Hospital Center, evaluate their knowledge of hypertension complications, and identify predictive factors for good adherence. Methods A cross-sectional study was conducted on a sample of 121 hypertensive patients attending the Internal Medicine Department of Monkole Hospital Center from 1 August 2021 to 31 December 2021. Data were collected through interviews using a structured questionnaire. Medication adherence was assessed using the Girerd scale. Factors associated with adherence were identified using binary logistic regression analysis. Adjusted odds ratios (AOR) and 95% confidence intervals (CI) were calculated with SPSS version 25. A P-value < 0.05 was considered statistically significant. Results Among the 121 hypertensive patients, 32.2% demonstrated good adherence, 44.6% had minimal adherence problems, and 23.1% had poor adherence. Overall, 76.8% were classified as good adherents. More than half of the participants (52.9%) were female, with a mean age of 55.8 ± 10.9 years. Patients younger than 50 years (AOR = 0.136, 95% CI = 0.048–0.897, P = 0.000) and single patients (AOR = 0.086, 95% CI = 0.012–0.629, P = 0.016) were less adherent compared to those aged 50 years or older and married patients. Conclusion Patients at Monkole Hospital Center were generally classified as good adherents based on the Girerd scale. More than half of the patients were informed about their disease by doctors. Older age and being married were associated with better medication adherence. more...

Background: Proaporphine alkaloids are present in many plant families. They are often considered as metabolic precursors to aporphines. They generally contain a cyclohexadienone system and can rearrange to aporphines on treatment with acid. Typical proaporphines include the alkaloids pronuciferine, stepharine, crotsparine, glaziovine and many analogues with different substitution patterns. The proaporphine glaziovine has been used in human as a tranquilizer to treat anxiety and depression but otherwise proaporphines have received little attention as medicinal products. Proaporphines have been neglected compared to aporphines. Purpose: The present review provides a survey of a hundred of proaporphine alkaloids isolated from plants, divided into three groups: conventional proaporphines (including mecambrine, roemeronine and orientalinone among others), homoproaporphines with a tetracyclic or pentacyclic core (such as kreysiginone and robustamine), and various proaporphine hybrid molecules (roemeridine, magnostepharine and diverse analogues). Results: The structural diversity of proaporphines is presented. The properties of prototypic proaporphine alkaloids are discussed, and their mechanisms of action are underlined. The case of atypical but promising proaporphine dimers, such as distepharinamide targeting tumor infiltrating T regulatory cells, is also addressed. Conclusion: The analysis offers a survey of the proaporphine landscape with the goal to highlight the molecular diversity in the family and to encourage further researches into their mechanism of action and medicinal properties. more...

Background Atrial fibrillation (AF) is the most common cardiac arrhythmia with a massive burden on global health. The prevalence of AF increases dramatically with age and can be up to 18% in patients older than 80 years. Telomeres, which are short, repeated DNA sequences at the end of chromosomes, are known to act as a biological aging marker. In this study, we investigated the relation of telomere shortening and AF in the context of atrial remodeling. Furthermore, we assessed changes in the gene expression profiles of patients with AF according to telomere length (TL) and left atrial fibrosis. Methods We included 72 patients undergoing catheter ablation for AF. Bipolar voltage maps were obtained to determine left atrial low voltage areas as a surrogate for atrial fibrosis. TL was quantified and correlated to low voltage areas. 3′ mRNA sequencing was performed for gene expression profiling. Clonal hematopoiesis of indeterminate potential was assessed by next generation sequencing. Telomerase reverse transcriptase knockout (Tert−/−) and telomerase RNA component knockout (Terc−/−) mice were used to investigate the mechanistic impact of telomere shortening on atrial remodeling. Results Patients with advanced left atrial fibrosis had shorter telomeres compared with patients with healthy left atria. Furthermore, there was a strong correlation between the extent of left atrial low voltage areas, TL, and outcome after catheter ablation of AF. 24 months after ablation, only 26.5% of patients with advanced fibrosis and short TL were in sinus rhythm compared with 62.5% of patients with no/low fibrosis and long TL. Gene expression profiles and clonal hematopoiesis of indeterminate potential frequency differed in patients with AF with short and long telomeres. Finally, atrial tissue of mouse models with shortened telomeres showed marked left atrial fibrosis and over‐expression of fibrosis‐related genes. Conclusions Telomere shortening is correlated with left atrial remodeling. Shorter telomeres are associated with a series of molecular events which could eventually lead to cardiac fibrosis and perpetuate AF. more...

This study delves into spin current-induced phenomena, such as spin-Hall magnetoresistance and the spin Seebeck effect within Pt films deposited on a noncollinear magnet, CoCr[Formula: see text]O[Formula: see text] (CCO), particularly at low temperatures. Detailed investigation of the angular dependencies of spin Hall magnetoresistance (SMR) and spin Seebeck effect (SSE) was carried out. The temperature-dependent behavior of both SMR and SSE signals exhibits a discernible variation correlated with different magnetic phases of CCO. To distinguish the contributions arising from magnetic proximity effects, we conducted X-ray magnetic dichroism (XMCD) at the Pt-M[Formula: see text] edge. XMCD data from Pt/CCO heterostructures suggest that any magnetic moment associated with Pt, if present, is below the detection limit. This supports the notion that the observed signals primarily stem from SMR and SSE. This study offers insights into spin-current-driven phenomena, paving the way for potential spintronic applications. more...

Abstract The editorial, “Clinical and translational mode of single‐cell measurements: An artificial intelligent single‐cell,” introduces the innovative clinical artificial intelligence single‐cell (caiSC) system, which merges AI with single‐cell informatics to advance real‐time diagnostics, disease monitoring, and treatment prediction. By combining clinical data and multimodal molecular inputs, caiSC facilitates personalized medicine, promising enhanced diagnostic precision and tailored therapeutic approaches. Despite its potential, caiSC lacks comprehensive data coverage across cell types and diseases, presenting challenges in data quality and model robustness. The article explores development strategies such as data expansion, machine learning advancements, and interpretability improvements. Future applications of caiSC could include digital cell twins, offering in‐depth simulations of cellular behavior to support drug discovery and personalized treatments. Regulatory considerations are discussed, underscoring the need for SaMD/AIaMD certifications for clinical use. Ultimately, with further refinement, caiSC could transform clinical decision‐making, driving personalized, precision medicine, and improved patient outcomes. Key points Integration of AI with Single‐Cell Informatics for Precision Medicine: The caiSC system combines artificial intelligence and single‐cell data to improve diagnostics, treatment predictions, and personalized medical decision‐making. Challenges in Data Coverage and Model Robustness: caiSC currently faces limitations due to incomplete data across cell types, diseases, and organs, as well as challenges in data quality and high computational demands, which affect model accuracy and clinical applicability. Future Potential and Regulatory Needs: The caiSC framework's development could lead to innovations such as digital cell twins, enabling personalized simulations of cellular responses for better treatment planning, though regulatory certification is essential for safe clinical use. more...

The European Clozapine Task Force is a group of psychiatrists and pharmacologists practicing in 18 countries under European Medicines Agency (EMA) regulation, who are deeply concerned about the underuse of clozapine in European countries. Although clozapine is the most effective antipsychotic for people with treatment-resistant schizophrenia, a large proportion of them do not have access to this treatment. Concerns about clozapine-induced agranulocytosis and stringent blood monitoring rules are major barriers to clozapine prescribing and use. There is a growing body of evidence that the incidence of clozapine-induced agranulocytosis is very low after the first year of treatment. Maintaining lifelong monthly blood monitoring after this period contributes to unjustified discontinuation of clozapine. We leverage recent and replicated evidence on the long-term safety of clozapine to call for the revision and updating of the EMA’s blood monitoring rules, thus aiming to overcome this major barrier to clozapine prescribing and use. We believe the time has come for relaxing the rules without increasing the risks for people using clozapine in Europe. more...

IntroductionThis study investigated potential health status differences among forging, manufacturing, and logistics workers.MethodsWe included 403 participants (age: 41 ± 12 years) from a medium-sized steel company (forge: 64, manufacturing: 299, logistics: 99). Health status was multifactorial assessed: (1) Frequency of musculoskeletal complaints (German Pain Questionnaire). (2) Pain intensity, physical and psychological load [visual analog scales (VAS) 0–100 points]. (3) Occupational moderate-to-vigorous physical activity (MVPA), total MVPA, and sedentary behavior [Global Physical Activity Questionnaire (GPAQ)]. (4) Quality of life [Short Form Health Survey (SF-36)]. Between-group effects were analyzed via one-way ANOVAs with post-hoc Tukey correction.Results308 workers (76.4%) reported at least one musculoskeletal issue. A significant between-group difference was revealed for left shoulder [F(2,40) = 5.40; p = 0.008; ω2 = 0.17], occupational MVPA [F(2,368) = 9.49; p more...

Abstract Unlike adult mammals, the hearts of neonatal mice possess the ability to completely regenerate from myocardial infarction (MI). This observation has sparked vast interest in deciphering the potentially lifesaving and morbidity-reducing mechanisms involved in neonatal cardiac regeneration. In mice, the regenerative potential is lost within the first week of life and coincides with a reduction of Insulin-like growth factor 1 receptor (Igf1r) expression in the heart. Igf1r is a well-known regulator of cardiomyocyte maturation and proliferation in neonatal mice. To test the role of Igf1r as a pivotal factor in cardiac regeneration, we knocked down (KD) Igf1r specifically in cardiomyocytes using recombinant adeno-associated virus (rAAV) delivery and troponin T promotor driven shRNAmirs. Cardiomyocyte specific Igf1r KD versus control mice were subjected to experimental MI by permanent ligation of the left anterior descending artery (LAD). Cardiac functional and morphological data were analyzed over a 21-day period. Neonatal Igf1r KD mice showed reduced systolic cardiac function and increased fibrotic cardiac remodeling 21 days post injury. This cardiac phenotype was associated with reduced cardiomyocyte nuclei mitosis and decreased AKT and ERK phosphorylation in Igf1r KD, compared to control neonatal mouse hearts. Our in vivo murine data show that Igf1r KD shifts neonatal cardiac regeneration to a more adult-like scarring phenotype, identifying cardiomyocyte-specific Igf1r signaling as a crucial component of neonatal cardiac regeneration. more...

Abstract Background Without increasing radiation exposure, ultralow-dose computed tomography (CT) of the chest provides improved diagnostic accuracy of radiological pneumonia diagnosis compared to a chest radiograph. Yet, radiologist resources to rapidly report the chest CTs are limited. This study aimed to assess the diagnostic accuracy of emergency clinicians’ assessments of chest ultralow-dose CTs for community-acquired pneumonia using a radiologist’s assessments as reference standard. Methods This was a cross-sectional diagnostic accuracy study. Ten emergency department clinicians (five junior clinicians, five consultants) assessed chest ultralow-dose CTs from acutely hospitalised patients suspected of having community-acquired pneumonia. Before assessments, the clinicians attended a focused training course on assessing ultralow-dose CTs for pneumonia. The reference standard was the assessment by an experienced emergency department radiologist. Primary outcome was the presence or absence of pulmonary opacities consistent with community-acquired pneumonia. Sensitivity, specificity, and predictive values were calculated using generalised estimating equations. Results All clinicians assessed 128 ultralow-dose CTs. The prevalence of findings consistent with community-acquired pneumonia was 56%. Seventy-eight percent of the clinicians’ CT assessments matched the reference assessment. Diagnostic accuracy estimates were: sensitivity = 83% (95%CI: 77–88), specificity = 70% (95%CI: 59–81), positive predictive value = 80% (95%CI: 74–84), negative predictive value = 78% (95%CI: 73–82). Conclusion This study found that clinicians could assess chest ultralow-dose CTs for community-acquired pneumonia with high diagnostic accuracy. A higher level of clinical experience was not associated with better diagnostic accuracy. more...

Abstract Atrial fibrillation (AF) is more common in patients with malignancies than in general population. The pathophysiological processes include the pro-inflammatory condition and the exaggerated inflammatory reaction to chemotherapy, radiotherapy, and surgery interventions. Thus, it is pivotal to decrease morbidity and mortality in this group by providing appropriate care and prevention. In this subset, the risk of thromboembolic and bleeding events is high and the common risk score such as CHA2DS2-VASc and HAS-BLED employed in non-oncologic patients have limited evidence in cancer patients. A paucity of evidence in the setting in individuals having both malignancies and atrial fibrillation entangle the clinician when it comes to therapeutic management. Tailored management is recommended of anticoagulation treatment could be difficult, and there is. In this review, we try to explain the mechanism of AF in cancer patients as well as its management in this setting. more...

Abstract Hydrogen will play a key role in decarbonizing economies. Here, we quantify the costs and environmental impacts of possible large-scale hydrogen economies, using four prospective hydrogen demand scenarios for 2050 ranging from 111–614 megatonne H2 year−1. Our findings confirm that renewable (solar photovoltaic and wind) electrolytic hydrogen production generates at least 50–90% fewer greenhouse gas emissions than fossil-fuel-based counterparts without carbon capture and storage. However, electrolytic hydrogen production could still result in considerable environmental burdens, which requires reassessing the concept of green hydrogen. Our global analysis highlights a few salient points: (i) a mismatch between economical hydrogen production and hydrogen demand across continents seems likely; (ii) region-specific limitations are inevitable since possibly more than 60% of large hydrogen production potentials are concentrated in water-scarce regions; and (iii) upscaling electrolytic hydrogen production could be limited by renewable power generation and natural resource potentials. more...

Background and Aim: Theileria annulata infection in cattle causes major economic losses in livestock production in many Central Asian countries, including the southern region of Kazakhstan. This study aimed to obtain a recombinant T. annulata surface protein (TaSP) and to investigate its possible use as an antigen in an indirect enzyme-linked immunosorbent assay (ELISA) for the serological diagnosis of bovine theileriosis. Materials and Methods: Recombinant TaSP was obtained by cloning a polymorphic region of the TaSP gene, expressing it in Escherichia coli strain BL21, and purifying it by metal chelating chromatography. An indirect ELISA using recombinant TaSP as an antigen was developed and evaluated for the detection of T. annulata-specific antibodies in plasma samples from 69 cows polymerase chain reaction (PCR)-positive or PCR-negative for T. annulata and/or Theileria orientalis from southern Kazakhstan. Results: The obtained recombinant protein had a molecular weight of 32 kDa, and mass spectrometry analysis of the purified protein identified it as a fragment of the surface protein of T. annulata. Initial testing of 69 field plasma samples from cattle showed that the results of indirect ELISA using TaSP as an antigen agreed substantially with those of T. annulata PCR (κ: 0.78). The relative sensitivity and specificity of indirect ELISA were 88.7% and 100%, respectively, using PCR as a reference. There was no evidence of cross-reaction with T. orientalis. Conclusion: Initial results using recombinant TaSP as an antigen in indirect ELISA are promising and support the widespread use of this assay for routine diagnosis and T. annulata seroprevalence studies in cattle in Kazakhstan and possibly neighboring countries. more...

The generation of ozone by dielectric barrier discharge (DBD) is widely used for water and wastewater treatment, the control of catalytic reactions, and surface treatment. Recently, a need for compact, effective, and economical ozone and reactive oxygen–nitrogen species (RONS) generators for medical, biological, and agricultural applications has been observed. In this study, a novel hybrid DBD (HDBD) reactor fulfilling such requirements is presented. Its structured high-voltage (HV) electrode allows for the ignition of both the surface and volume microdischarges contributing to plasma generation. A Peltier module cooling of the dielectric barrier, made of alumina, allows for the efficient control of plasma chemistry. The typical electrical power consumption of this device is below 30 W. The operation frequency of the DBD driver oscillating in the auto-resonance mode is from 20 to 40 kHz. The specific energy input (SEI) of the reactor was controlled by the DBD driver input voltage in the range from 10.5 to 18.0 V, the Peltier current from 0 to 4.5 A, the duty cycle of the pulse-width modulated (PWM) power varied from 0 to 100%, and the gas flow from 0.5 to 10 SLM. The operation with oxygen, synthetic air, and compressed dry air (CDA) was characterized. The ultraviolet light (UV) absorption technique was implemented for the measurement of the ozone concentration. The higher harmonics of the discharge current observed in the frequency range of 5 to 50 MHz were used for monitoring the discharge net power. more...

Soft scaffold materials for cell cultures grafted onto the chorioallantoic membrane (CAM) provide innovative solutions for creating physiologically relevant environments by mimicking the host tissue. Biocompatible hydrogels represent an ideal medium for such applications, but the relationship between scaffold mechanical properties and reactions at the biological interface remains poorly understood. This study examines the attachment and integration of soft hydrogels on the CAM using an accessible ex ovo system. Composite hydrogels of polyvinyl alcohol and Phytagel were fabricated by sterile freeze-thawing. CAM assays, as an alternative to traditional in vivo models, enabled the evaluation of the compatibility, attachment, and biointegration of hydrogels with three distinct compositions. The mechanomimetic properties of the hydrogels were assessed through cyclic compression–tension tests, with nominal peak stresses ranging from 0.26 to 2.82 kPa in tension and −0.33 to −2.92 kPa in compression. Mechanical attachment to the CAM was measured by pull-off tests after five days of incubation. On the first day, the interface strength was similar for all hydrogel compositions. On day 5, softer hydrogels showed the greatest increase (p=0.008), followed by intermediate hydrogels (p=0.020), while the denser hydrogels showed negligible changes (p=0.073). Histological analyses revealed cell infiltration in 100% of soft, 75% of intermediate, and 13% of dense hydrogels, suggesting that softer hydrogels integrate better into the CAM by facilitating cell migration and enhancing interface strength. Chicken embryo survival rates and cytotoxicity assays confirmed the biocompatibility of the hydrogels and supported their potential for use in soft, hydrated three-dimensional scaffolds that mimic tissue environments in dynamic biological systems.Statement of significance Current research on soft scaffold materials for cell cultures often overlooks the critical relationship between mechanical properties and biological integration of these materials with host tissues. Although hydrogels, as soft porous materials, hold promise for creating physiologically relevant environments, the mechanisms driving their attachment and biointegration, especially on the chorioallantoic membrane (CAM), remain largely unexplored. This study addresses this gap by investigating the interaction between soft hydrogels and the CAM, providing valuable insights into how material properties and microstructure influence cellular responses. Our findings emphasize the importance of understanding these dynamics to develop biocompatible scaffolds that better mimic tissue environments, advancing applications in three-dimensional cell cultures on CAM assays and other biological systems. more...

Introduction Early lung cancer screening (LCS) through low-dose CT (LDCT) is crucial but underused due to various barriers, including incomplete or inaccurate patient smoking data in the electronic health record and limited time for shared decision-making. The objective of this trial is to investigate a patient-centred intervention, MyLungHealth, delivered through the patient portal. The intervention is designed to improve LCS rates through increased identification of eligible patients and informed decision-making.Methods and analysis MyLungHealth is a multisite pragmatic trial, involving University of Utah Health and New York University Langone Health primary care clinics. The MyLungHealth intervention was developed using a user-centred design process, informed by patient and provider focus groups and interviews. The intervention’s effectiveness will be evaluated through a patient-randomised trial, comparing the combined use of MyLungHealth and DecisionPrecision+ (a provider-focused shared decision-making intervention) against DecisionPrecision+ alone. The first study hypothesis is that among patients aged 50–79 with uncertain LCS eligibility (eg, 10–19 pack-years or unknown pack-years or unknown quit date for individuals who used to smoke), MyLungHealth eligibility questionnaires will result in increased identification of LCS-eligible patients (n~26 729 patients). The second study hypothesis is that among patients aged 50–79 with documented LCS eligibility (20+ pack-years, quit within the last 15 years if individuals who used to smoke, and no recent screening or screening discussion), MyLungHealth education will result in increased LDCT ordering (n~4574 patients). Primary outcomes will be identification of LCS-eligible patients among individuals with uncertain LCS eligibility and LDCT ordering rates among individuals with documented LCS eligibility.Ethics and dissemination The protocol was approved by the University of Utah Institutional Review Board (# 00153806). The patient data collected for this study will not be shared publicly due to the sensitive nature of the patient health information and the fact that we will not be obtaining written informed consent to allow public sharing of their data. Results will be disseminated through peer-reviewed publications.Trial registration number Clinicaltrials.gov, NCT06338592. more...

BackgroundTrypanosoma cruzi is mainly transmitted to mammals by vectors, but other transmission routes exist. For example, opossums can harbor the infectious form of the parasite in their anal glands, underscoring their potential role in non-vectorial transmission. T. cruzi has been detected in the anal gland secretions of various opossum species, and their infectivity has been confirmed in Didelphis marsupialis and D. albiventris. Vertical transmission has also been proposed in D. virginiana. However, if this occurs in opossums, it remains unclear whether it happens during pregnancy or lactation. In Mexico, Didelphis virginiana and D. marsupialis are the main opossum species. Our objective was to investigate the possible contribution of urban opossums to non-vectorial transmission of T. cruzi in the metropolitan area of Merida, Yucatan, in southeastern Mexico.Methodology/principal findingsBlood, anal gland secretions, and milk were collected from opossums captured in Merida, Mexico, all identified as D. virginiana using taxonomic keys and Cytb sequencing. By PCR, T. cruzi was detected in 16/102 opossums (15.69%) in at least one type of sample. The prevalence was 14.71% (15/102) in blood and 0.98% (1/102) in anal gland secretions. 1/22 milk samples (4.55%) tested positive. Blood of 37 offspring from T. cruzi-positive mothers was collected and tested negative. qPCR revealed that females with offspring tended to have lower parasite load in blood compared to females without offspring and males. Genotyping of the parasite through multiplex PCR revealed only the DTU TcI.Conclusions/significanceThis study agrees with previous works where D. virginiana was the most abundant opossum species in urban areas in southeastern Mexico and confirms that it is associated with TcI. Detection of T. cruzi in a sample of anal gland secretions underscores the potential risk represented by D. virginiana in non-vectorial transmission in urban areas of southeastern Mexico. Detection in the milk of a lactating female, along with the observed tendency towards a lower parasite load in females with offspring, highlight the importance of further investigating vertical transmission in D. virginiana. more...

Identifying new substances that could potentially be used for tumor therapy and the precise analysis of their spectrum of action requires models that are as similar as possible to the tumor present in the patient. Traditionally, two-dimensional (2D) cell cultures are used. However, these only resemble solid tumors to a limited extent. More realistic in vivo models, such as tissue cultures, which are invaluable for the final analysis of the effect of new substances, are unsuitable for high-throughput screening (HTS), such as substance library screening. Therefore, we addressed which parameters need to be optimized to produce 3D cultures suitable for HTS using established tumor cell lines and ultra-low attachment plates, and we tested which experimental parameters need to be considered. In our studies, we have focused on cell lines from gliomas. Gliomas are incurable tumors of the central nervous system and are the subject of intensive research. Our studies used ten glioma cell lines from which we generated spheroids using ultra-low attachment plates. We then determined the spheroid size as a function of the initial cell number and the culture time. We analyzed cell viability using propidium iodide staining, evaluated the effects of temozolomide and radiation on spheroids, and compared the effect to that on 2D cultures. We found that spheroid size correlated linearly with the initial cell number. Fewer cells (250–500) generally resulted in better growth than a higher number. However, not all cell lines produced growing spheroids at all. The spheroids had an outer layer of living cells and an inner core of dead cells. The size of the inner core of dead cells was different in the various cell lines and developed differently during the incubation period. Radiation affected spheroids more than 2D cultures, especially at higher cell densities. Our results provide insight into using glioma cell lines to form spheroids as model systems. We have identified initial cell numbers as a critical parameter for their effective use in research, offering a hopeful outlook for tumor therapy research and drug development. more...

Objective Rapid and accurate infection diagnosis is a prerequisite for appropriate antibiotic prescriptions in an ED. Accurately diagnosing acute infections can be difficult due to nonspecific symptoms and limitations of diagnostic testing. The accuracy of preliminary diagnoses, established on the initial clinical assessment, depends on a physician’s skills and knowledge. It has been scarcely studied, and knowledge of how infected patients present at EDs today is needed to improve it. Based on expert reference diagnoses and a current ED population, this study aimed to characterise adults presenting at EDs with suspected infection to distinguish between infections and non-infections and to investigate the accuracy of the preliminary infection diagnoses.Design This study was multicentre with a design that combined a cross-sectional study and a diagnostic study with a prospective enrolment.Setting Multicenter study including EDs at three Danish hospitals.Participants Adults admitted with a preliminary diagnosis of an infectious disease.Outcome measures Data were collected from medical records and participant interviews. The primary outcome was the reference diagnosis made by two medical experts on chart review. Univariate logistic regression analysis was performed to identify factors associated with infectious diseases.Results We included 954 patients initially suspected of having an infection, with 81% later having an infectious disease confirmed by experts. Parameters correlating to infection were fever, feeling unwell, male sex, high C-reactive protein, symptoms onset within 3 days, high heart rate, low oxygen saturation and abnormal values of neutrophilocytes and leucocytes. The three main conditions were community-acquired pneumonia (CAP) (34%), urinary tract infection (UTI) with systemic symptoms (21%) and cellulitis (10%). The sensitivity of the physician’s preliminary infection diagnoses was 87% for CAP, 74% for UTI and 77% for other infections.Conclusions Four out of five patients with a preliminary infection diagnosis, established on initial clinical assessment, were ultimately confirmed to have an infectious disease. The main infections included CAP, UTI with systemic symptoms and cellulitis. Physicians’ preliminary infection diagnoses were moderately in accordance with the reference diagnoses.Trial registration number NCT04661085, NCT04681963, NCT04667195. more...

Objective To evaluate the effects of alpha lipoic acid (ALA) on hormonal and metabolic parameters in a group of overweight/obese Polycystic Ovary Syndrome (PCOS) patients.Methods This was a retrospective study in which thirty-two overweight/obese patients with PCOS (n = 32) not requiring hormonal treatment were selected from the database of the ambulatory clinic of the Gynecological Endocrinology Center at the University of Modena and Reggio Emilia, Italy. The hormonal profile, routine exams and insulin and C-peptide response to oral glucose tolerance test (OGTT) were evaluated before and after 12 weeks of complementary treatment with ALA (400 mg/day). Hepatic Insulin Extraction (HIE) index was also calculated.Results ALA administration significantly improved insulin sensitivity and decreased ALT and AST plasma levels in all subjects, though no changes were observed on reproductive hormones. When PCOS patients were subdivided according to the presence or absence of familial diabetes background, the higher effects of ALA were observed in the former group that showed AST and ALT reduction and greater HIE index decrease.Conclusion ALA administration improved insulin sensitivity in overweight/obese PCOS patients, especially in those with familial predisposition to diabetes. ALA administration improved both peripheral sensitivity to insulin and liver clearance of insulin. Such effects potentially decrease the risk of nonalcoholic fat liver disease and diabetes in PCOS patients. more...

Background Simulation-based education in healthcare encompasses a wide array of modalities aimed at providing realistic clinical experiences supported by meticulously designed scenarios. The French-speaking Society for Simulation in Healthcare (SoFraSimS) has developed guidelines to assist educators in the design of scenarios for manikin- or simulated participant- based immersive simulation and procedural simulation, the three mainly used modalities.Methods After establishing a French-speaking group of experts within the SoFraSimS network, we performed an extensive literature review with theory-informed practices and personal experiences. We used this approach identify the essential criteria for practice-based scenario design within the three simulation modalities.Results We present three comprehensive templates for creating innovative scenarios and simulation sessions, each tailored to the specific characteristics of a simulation modality. The SoFraSimS templates include five sections distributed between the three modalities. The first section contextualizes the scenario by describing the practicalities of the setting, the instructors and learners, and its connection to the educational program. The second section outlines the learning objectives. The third lists all the elements necessary during the preparation phase, describing the educational method used for procedural simulation (such as demonstration, discovery, mastery learning, and deliberate practice). The fourth section addresses the simulation phase, detailing the behaviors the instructor aims to analyze, the embedded triggers, and the anticipated impact on simulation proceedings (natural feedback). This ensures maximum control over the learning experience. Finally, the fifth section compiles elements for post-simulation modifications to enhance future iterations.Conclusion We trust that these guidelines will prove valuable to educators seeking to implement simulation-based education and contribute to the standardization of scenarios for healthcare students and professionals. This standardization aims to facilitate communication, comparison of practices and collaboration across different learning and healthcare institutions. more...

The aim of this work was to gain an initial impression of the surface quality that can be achieved with additively manufactured ceramic components. For this purpose, an assessment body was generated, which has partially double-curved surfaces that can be scanned using a confocal microscope. After manufacturing using Vat Photopolymerization for ceramic components (CerAM VPP) with a commercial alumina suspension (Lithalox 350, Lithoz, Vienna, AUT) and thermal processing, the respective surface was measured at four different geometric areas. For evaluation, line sections were extracted to calculate Ra values as well as to determine Sa values for surfaces. Ra and Sa values were determined in all areas, reaching always values below 2.5 μm. The surface quality is therefore an order of magnitude lower than that of typical metallic AM components. more...

The increasing interest in digital games and the reasons behind their popularity worldwide warrants further psychometric investigation of motivation factors for engagement in digital games. The present study aimed to validate the Motives for Online Gaming Questionnaire (MOGQ) in a Swedish sample and compare the associations between the seven motivational factors and gaming disorder symptoms across the American Psychiatric Association and World Health Organization diagnostic frameworks. Furthermore, considering the utility of more concise psychological measures, a 14-item version of the MOGQ was developed (MOGQ-14). A sample of 678 Swedish video game players (68.4% men, 29.7% women, and 1.9% other, Mage = 29.5 years, range 15–66) were included in the analyses after participating in an online survey. The analyses revealed that the Swedish version of the MOGQ had good psychometric properties. All MOGQ factors showed good reliability (McDonald's omega), and all intercorrelations among the MOGQ dimensions were consistent with previous findings. The results showed that, on average, men reported higher gaming motivations concerning competition than women. The relationships between six gaming motivation factors (social, escape, competition, coping, skill development, fantasy) and gaming disorder symptoms were consistent with previous research. Findings indicated that the relationship between motivations (escape and recreation) and gaming disorder symptoms varied across APA and WHO diagnostic frameworks, depending on the motivation scale used (MOGQ or MOGQ-14). Recreation significantly differed in its relationship with symptoms when using MOGQ, and the MOGQ-14 showed larger effect sizes in the WHO framework for escape and recreation motivations. more...

Viral infections can lead to platelet activation and hemostatic complications. However, the extent to which platelet reactivity remains altered after convalescence, contributing to long-term health impairments as observed after COVID-19 is not yet fully understood. Therefore, we conducted a cohort study (DRKS00025217) to determine platelet function in individuals convalesced from mild COVID-19. Assays were performed ex vivo with blood from convalescents at 2–15 weeks and 6–10 months after convalescence, focusing on platelet aggregation, activation markers, and thrombin formation. In addition, two other potentially relevant factors for platelet function were examined: the immunomodulatory mediator sphingosine-1-phosphate (S1P) and the platelet expression of the transporter MRP4 (ABCC4). Our findings indicate that robust platelet functions, including platelet aggregation determined by light transmission aggregometry, and thrombin formation, were not altered in convalescents compared to matched control individuals. However, an elevation in subtle platelet activation markers, such as P-selectin surface expression and activation of glycoprotein IIb/IIIa, was observed 2–15 weeks after convalescence. This was accompanied by an increased expression of MRP4 in platelets and significantly elevated levels of S1P in platelet-poor plasma. Our findings suggest increased platelet sensitization and a pro-inflammatory state even after convalescence from mild COVID-19, pointing toward MRP4 and S1P as associated factors. more...

IntroductionTovertafel® is a VR-based serious game for dementia care (SGDC) that aims to stimulate residents affected by dementia in nursing homes, promote social and cognitive skills and reduce apathy. The aim of this study is to investigate the effects of using Tovertafel® on apathy, social interaction and social activity of people with dementia (PWD) in long-term inpatient care in Germany.MethodsIn this monocentric intervention study, 25 residents of an inpatient long-term care facility with moderate or severe dementia had two weekly applications of Tovertafel® over a period of 8 weeks. Effects on the residents’ social interaction and activity were recorded before (T1), during (T2) and 1 h after (T3) each intervention using the Engagement of a Person with Dementia Scale (EPWDS). The degree of apathy was assessed using the Apathy Evaluation Scale (AES). Effects of Tovertafel® were examined using a simple repeated measures analysis of variance (ANOVA).ResultsThirteen residents with moderate (52%) and 12 residents with severe dementia (48%) were included. Results showed that residents’ apathy changed over the course of the trial and was partially reduced. ANOVA revealed significant changes in the positive expression of social participation in the overall group between individual observation times (p more...

Proton therapy is used to eradicate tumors in sensitive areas by targeted delivery of energy. Its effectiveness can be amplified using nanoparticles (NPs) as sensitizers, due to the production of reactive oxygen species at the NP's catalytically active surface, causing the cleavage of DNA. However, the impact of stabilizing macromolecular ligands capping the particles, needed for nanosensitizer dispersion in physiological fluids, is underexplored. Herein, ligand‐free colloidal platinum NPs (PtNPs) fabricated by scalable laser synthesis in liquids are used, which allows studying particle and ligand effects separately. PtNPs are incubated with stabilizing concentrations of the clinically approved ligands albumin, Tween, and polyethylene glycol, and irradiated with proton beams at clinically relevant doses (2 and 5 Gy). At these doses, plasmid DNA cleavage larger than 55% of clustered DNA damage is achieved. Bovine serum albumin, Tween, and polyethylene glycol on the NP surface work as double‐strand breaks (DSB) enhancers and synergetic effects occur even at low and clinically relevant particle concentrations and irradiation doses. Here, DSB enhancement by ligand‐capped PtNP even exceeds the sum of the individual ligand and particle effects. The presented fundamental correlations provide selection rules for nanosensitizer design in proton therapy. more...

ABSTRACT Objective This study aims to analyse high‐grade intraepithelial lesions (LIEHG) observed in a screening programme from 2010 to 2018 to more accurately describe them and formulate recommendations for best practices in the context of screening evolution following the introduction of an HPV test in primary cervical cancer screening in 2020. Methods This study included 305,940 asymptomatic women aged 25–65 years. The eligible population was invited to undergo a screening cervico‐uterine‐smear every 3 years. If this smear was normal, the woman received a new invitation. In the case of a positive screen, the patient underwent further diagnostic procedures, such as colposcopy and biopsy to confirm the diagnosis. Only those diagnosed with LIEHG and above proceeded to treatment. The diagnoses associated with LIEHG were those related to the WHO Classification of tumours of the uterine cervix. Results Positive smears led to the diagnosis of 3230 LIEHG. The prevalence of LIEHG in the screened population was 0.4%. The LIEHG distribution varied significantly according to the age of the women. The probability of diagnosing LIEHG in young women was 12.2% at 25–29 years. This probability decreased by half after 50 years. We observed that the type of smear was significantly associated with LIEHG detection. The positive predictive value for diagnosing LIEHG was 70.3% for high‐grade squamous intraepithelial lesion (HSIL) smears and 35.1% for atypical squamous cells cannot exclude HSIL (ASC‐H) smears. Conclusion In the study population, the prevalence of LIEHG was high in women under 35 years. Low‐grade smears were correlated with the risk of LIEHG and should prompt screening facilities to allocate resources to ensure active follow‐up of LSIL and ASC‐US smears. Adherence to cytological screening recommendations was associated with a reduced risk of LIEHG in multivariate analysis. more...

Background: Anatomical reduction of posterior malleolar fracture is a key goal in achieving good functional outcomes in patients with ankle fractures. Although there are many approaches for managing this type of fracture, no studies have shown reduction quality of posterior malleolar fracture in postoperative CT scan using the modified posteromedial ankle approach. Methods: A retrospective case series of 66 patients of 2 health centers with type 2, 3, and 4 posterior malleolar fractures according to Bartonicek classification treated using the modified posteromedial ankle approach was performed. The postoperative CT scan was used to assess syndesmotic reduction and articular step-off and residual gap in posterior malleolus reduction. Results: Reduction of posterior malleolus fracture was determined to be 2 mm in 4 cases. Syndesmotic reduction quality was considered to be anatomical in 61 patients. Four patients showed mild anterior fibular translation in the axial plane and were not reoperated. One syndesmotic malreduction was considered poor. Conclusion: In this study, we found that 92% (61 of 66) of patients with posterior malleolar fracture were reduced with more...

Hemostasis disorders require particular attention in dental treatment. Dental implants are a very widespread and valid method for total rehabilitation. Flapless dental implant surgery is a minimally invasive treatment that allows the implants to be placed in the jaw bones with minimal surgical trauma. The aim of this study is to report the bleeding incidence in a group of patients with bleeding disorders treated with flapless implants. A total of 52 patients with bleeding disorders (46 in anticoagulant therapy; 4 with hemophilia; 2 with von Willebrandt disease) were treated with 188 flapless implant surgeries Anticoagulants were not discontinued. Patients with hemophilia and VWD were treated following specific protocols. Four late, easy to treat bleeding complications were reported (three mild bleeding, one ecchymosis). No additional sutures or other hemostatic measures were taken, no further infusions or transfusions were reported, and no severe bleeding complications requiring more than easy on-chair treatment, were reported. In conclusion, with adequate knowledge of the procedure and the pathology, dental implantology can be safely performed in patients with bleeding disorders. more...

Aim: New microtubule-targeting agents are needed to improve cancer treatment. The recent characterization of the anticancer alkaloid securinine as a tubulin-binding agent prompted us to explore the interaction of related monomeric and dimeric analogues with tubulin. The interaction between the α/β-tubulin dimer and alkaloids fluevirines A–F and flueggenines A–I, isolated from the bush Flueggea virosa (Roxb. ex Willd.) Royle, was investigated using molecular docking. Methods: Two molecular models were initially compared for the binding of securinine to α/β-tubulin. The pironetin-binding site model (5FNV) was selected for the subsequent docking analysis with all compounds. Empirical energies of interaction (ΔE) were measured and compared. Results: Fluevirine A has been identified as a potent tubulin binder. This dimeric alkaloid formed more stable complexes with tubulin than the monomeric counterparts, such as fluevirines B–D. The bis-indole derivative fluevirine E also provided more stable complexes than (nor)securinine. The study was extended to the dimeric alkaloids flueggenines A–I and three compounds were identified as potential tubulin binders: the polycyclic product flueggenine B, the norsecurinine-indole hybrid flueggenine E, and the norsecurinine dimer flueggenine I. This later compound proved to be well adapted to fit into the pironetin site of tubulin, extending its two norsecurinine units between the colchicine-binding area and the pironetin site, in close proximity to the pironetin-reactive cysteine-316 residue. Structure-binding relationships were delineated. Conclusions: The study identifies the dimeric alkaloids fluevirine A and flueggenine I as potential α-tubulin binding agents. For the first time, dimeric alkaloids including two C-C connected norsecurinine units are characterized as tubulin ligands. The study contributes to a better understanding of the mechanism of action of Flueggea alkaloids and should help the design of anticancer analogues targeting the pironetin site of α-tubulin. more...

Abstract Dialectical behavior therapy (DBT) is widely acknowledged as an effective treatment for individuals with borderline personality disorder (BPD). However, the optimal treatment duration within DBT remains a topic of investigation. This retrospective, naturalistic non-randomized study aimed to compare the efficacy of 8 week and 12 week DBT interventions with equivalent content, focusing on the change of BPD-specific symptomatology as the primary outcome and depressive symptoms as the secondary outcome. Overall, 175 patients who participated in DBT and received either 8 week or 12 week intervention were included in the analysis. Routine inpatient treatment was adapted from standard DBT with the modules: skill training, interpersonal skills, dealing with feelings, and mindfulness. Measurements were taken at baseline, mid-point, and endpoint. The borderline symptom list-23 (BSL-23) was used for the assessment of borderline-specific symptoms, while the Beck depression inventory-II (BDI-II) was used for the assessment of depressive symptoms. Statistical analysis was conducted using linear mixed models. Effect sizes were calculated for both measures. The results of the analysis indicated an improvement in both groups over time. Effect sizes were d = 1.29 for BSL-23 and d = 1.79 for BDI-II in the 8 week group, and d = 1.16 for BSL-23 and d = 1.58 for BDI-II in the 12 week group. However, there were no differences in the change of BPD-specific symptoms or the severity of depressive symptoms between the 8 week and 12 week treatment duration groups. Based on these findings, shorter treatment durations, like 8 weeks, could be a viable alternative, offering comparable therapeutic benefits, potential cost reduction, and improved accessibility. However, further research is needed to explore factors influencing treatment outcomes and evaluate the long-term effects of different treatment durations in DBT for BPD. Trial registration: drks.de (DRKS00030939) registered 19/12/2022. more...