Cerebrovascular pulsatility indicates preoperative subcortical cognitive impairment and an increased risk for postoperative delirium in elderly patients undergoing elective spine surgery.

Introduction: Advances in spine surgery enable safe interventions in elderly patients, but perioperative neurocognitive disorders (pNCD), such as post-operative delirium (POD) and cognitive dysfunction (POCD), remain a serious concern. Pre-operative cognitive impairment is a major risk factor for pNCD. Comprehensive pre-operative cognitive assessments are not feasible in clinical practice, making effective screening methods desirable. This study investigates whether pre-operative cerebrovascular duplex sonography can assess subcortical (vascular) cognitive impairment and the risk for POD. Methods: This prospective single-center study recruited patients aged ≥60 years scheduled for elective spine surgery at a German university hospital. Patients underwent pre-operative assessments including cognitive abilities (CERAD test battery), structural MRI, and cerebrovascular duplex sonography. POD screening was conducted three times daily for at least 3 days. The primary hypothesis, that the mean pulsatility index (PI) of both internal carotid arteries (ICA) predicts POD risk, was tested using logistic regression. Secondary analyses examined the association between POD risk and ICA flow (time-averaged peak velocities, TAPV) and correlations with cognitive profiles and MRI characteristics. Results: POD occurred in 22% of patients (n = 22/99) within three postoperative days. Patients with POD were significantly older (75.9 ± 5.4 vs. 70.0 ± 6.9 years, p < 0.01) but did not differ by gender (p = 0.51). ICA PI significantly predicted POD risk (OR = 5.46 [95%CI: 1.81-16.49], p = 0.003), which remained significant after adjustment for age and duration of surgery (ORadj = 6.38 [95% CI: 1.77-23.03], p = 0.005). TAPV did not inform the POD risk (p = 0.68). ICA PI Pre-operative cognitive scores were significantly associated with ICA PI (mean CERAD score: r = -0.32, p < 0.001). ICA PI was also significantly associated with total white matter lesion volume (τ = 0.19, p = 0.012) and periventricular white matter lesion volume (τ = 0.21, p = 0.007). Discussion: This is the first study to demonstrate that cerebrovascular duplex sonography can assess the risk for POD in elderly spine surgery patients. Increased ICA PI may indicate subcortical impairment, larger white matter lesion load, and lower white matter volume, predisposing factors for POD. Pre-operative cerebrovascular duplex sonography of the ICA is widely available, easy-to-use, and efficient, offering a promising screening method for POD risk. Increased ICA PI could supplement established predictors like age to adjust surgical and peri-operative procedures to individual risk profiles.

Novel fungicide and neonicotinoid insecticide impair flight behavior in pollen foraging honey bees, Apis mellifera.

Bees are often exposed to pesticides affecting physiological functions and molecular mechanisms. Studies showed a potential link between altered expression of energy metabolism related transcripts and increased homing flight time of foragers exposed to pesticides. In this study, we investigated the effects of thiamethoxam and pyraclostrobin on longevity, flight behavior, and expression of transcripts involved in endocrine regulation (hbg-3, buffy, vitellogenin) and energy metabolism (cox5a, cox5b, cox17) using radio frequency identification (RFID) technology and quantitative polymerase chain reaction. Parallel, a laboratory study was conducted investigating whether pesticide exposure alone without the influence of flight activity caused similar expression patterns as in the RFID experiment. No significant effect on survival, homing flight duration, or return rate of exposed bees was detected. The overall time foragers spent outside the hive was significantly reduced post-exposure. Irrespective of the treatment group, a correlation was observed between cox5a, cox5b, cox17 and hbg-3 expression and prolonged homing flight duration. Our results suggest that flight behavior can impact gene expression and exposure to pesticides adversely affects the expression of genes that are important for maintaining optimal flight capacity. Our laboratory-based experiment showed significantly altered expression levels of cox5a, cox6c, and cox17. However, further work is needed to identify transcriptional profiles responsible for prolonged homing flight duration.

Temporal entry of pesticides through pollen into the bee hive and their fate in beeswax.

Honey bees are often exposed to a variety of contaminants, including pesticides from agricultural use. The aim of this study was to investigate the temporal entry of pesticides into the hive by examining the seasonal timing of honey bees bringing pesticide-contaminated pollen into their colonies and the subsequent accumulation of these pesticides in beeswax. Pollen and beeswax samples were collected biweekly from five colonies situated in an agricultural environment in Switzerland. In pollen, 23 pesticides (out of 50) were quantified, including 4 insecticides, 4 herbicides, 12 fungicides, a transformation product, an acaricide, and a synergist. The maximal insecticide concentration levels measured in individual pollen samples were 69.4 µg/kg (thiacloprid), 48.3 µg/kg (acetamiprid), 13.8 µg/kg (spinosad), and 11.1 µg/kg (indoxacarb), while fungicide levels ranged up to 2212.7 µg/kg (cyprodinil), and herbicides were up to 71.9 µg/kg (prosulfocarb). Eighteen of the pesticides found in pollen were also quantifiable in beeswax. Among these were 17 lipophilic pesticides with logarithmic octanol water coefficients (log Kow) equal or above 2.5, which showed similar temporal profiles and order of accumulation magnitude as in pollen. For example, maximal concentrations measured in individual beeswax samples were 12.4 µg/kg for indoxacarb (insecticide), 986.4 µg/kg for cyprodinil (fungicide), and 21.6 µg/kg for prosulfocarb (herbicide). Furthermore, pesticides with log Kow between 2.5 and 7.0 remained in the beeswax during wax purification. Our study shows that a large variety of pesticides brought into the hive through pollen potentially stay in the beeswax during recycling, thus constantly exposing honey bees to pesticides.

A novel approach for in vivo DNA footprinting using short double-stranded cell-free DNA from plasma.

Here, we present a method for enrichment of double-stranded cfDNA with an average length of ∼40 bp from cfDNA for high-throughput DNA sequencing. This class of cfDNA is enriched at gene promoters and binding sites of transcription factors or structural DNA-binding proteins, so that a genome-wide DNA footprint is directly captured from liquid biopsies. In short double-stranded cfDNA from healthy individuals, we find significant enrichment of 203 transcription factor motifs. Additionally, short double-stranded cfDNA signals at specific genomic regions correlate negatively with DNA methylation, positively with H3K4me3 histone modifications and gene transcription. The diagnostic potential of short double-stranded cell-free DNA (cfDNA) in blood plasma has not yet been recognized. When comparing short double-stranded cfDNA from patient samples of pancreatic ductal adenocarcinoma with colorectal carcinoma or septic with postoperative controls, we identify 136 and 241 differentially enriched loci, respectively. Using these differentially enriched loci, the disease types can be clearly distinguished by principal component analysis, demonstrating the diagnostic potential of short double-stranded cfDNA signals as a new class of biomarkers for liquid biopsies.

Efficient combinatorial adaptor-mediated targeting of acute myeloid leukemia with CAR T-cells.

CAR T-cell products targeting lineage-specific cell-of-origin antigens, thereby eliminating both tumor and healthy counterpart cells, are currently clinically approved therapeutics in B- and plasma-cell malignancies. While they represent a major clinical improvement, they are still limited in terms of efficacy by e.g. single, sometimes low-expressed antigen targeting, and in terms of safety by e.g., lack of on-off activity. Successful cell-of-origin non-discriminative targeting of heterogeneous hematopoietic stem and progenitor cell malignancies, such as acute myeloid leukemia (AML), will require antigen-versatile targeting and off-switching of effectors in order to then allow rescue by hematopoietic stem cell transplantation (HSCT), preventing permanent myeloablation. To address this, we developed adaptor-CAR (AdFITC-CAR) T-cells targeting fluoresceinated AML antigen-binding diabody adaptors. This platform enables the use of adaptors matching the AML-antigen-expression profile and conditional activity modulation. Combining adaptors significantly improved lysis of AML cells in vitro. In therapeutic xenogeneic mouse models, AdFITC-CAR T-cells co-administered with single diabody adaptors were as efficient as direct CAR T-cells, and combinatorial use of adaptors further enhanced therapeutic efficacy against both, cell lines and primary AML. Collectively, this study provides proof-of-concept that AdFITC-CAR T-cells and combinations of adaptors can efficiently enhance immune-targeting of AML.

No negative effects of intra-abdominal bio-logger implantation under general anaesthesia on spatial cognition learning in a hibernator the edible dormouse.

The effect of hibernation on cognitive capacities of individuals is not fully understood, as studies provide conflicting results. Most studies focus on behavioural observations without taking the physiological state of individuals to account. To mechanistically understand the effect of hibernation on the brain, physiological parameters need to be included. The implantation of bio-loggers can provide insights on i.e. body temperature without further manipulation of the animals. Surgeries and anaesthesia, however, can harm animals' health and cause cognitive dysfunction, potentially biasing data collected through bio-loggers. We investigated the effects of bio-logger implantation surgery on cognitive performance and learning, controlling for animal and study design characteristics. First, juvenile dormice successfully learned to solve a spatial cognition task using a vertical maze. Distance, transitions, velocity, and duration were measured as indicators for performance. After training, bio-loggers were implanted intra-abdominally under general anaesthesia. Animals were re-tested in the maze two weeks after. We found no effect of bio-logger implantation and surgery on performance. This study is the first to show spatial cognition learning in edible dormice and provides a full description of the peri-anaesthetic management and a protocol for bio-logger implantation surgery in dormice. Importantly, measures were taken to mitigate common anaesthetic complications that could lead to post-operative cognitive dysfunction and influence animal behaviour. By pairing physiological measurements through bio-logger implantation with behaviour and cognition measurements, future research will significantly advance the understanding on mechanisms of learning and behaviour.

Evaluation of the gamified application KIJANI to promote physical activity in children and adolescents: A multimethod study.

Objective: Digital approaches have the potential to make activity promotion attractive and age-appropriate for children and adolescents. KIJANI is a mobile application aiming to increase physical activity (PA) in youth via gamification and augmented reality. This study investigates the user experience with KIJANI through a multimethod approach. Approaches: KIJANI is based on the concept that virtual coins can be earned through PA, for example, in the form of collected step counts. With these coins, blocks can be bought, which can be used to create virtual buildings and landscapes and integrate these into the player's real-world environment via augmented reality. To evaluate the user experience, participants played KIJANI in groups of three for 25 min. Afterwards KIJANI was evaluated qualitatively with one-on-one semi-structured interviews as well as quantitatively with standardized questionnaires. Results: Overall, 22 participants (12.6 ± 1.7 years, 6 girls) were included in the study. The overall game concept and realization were well received by the target group. Study participants did have various and creative ideas for the further development of KIJANI. The majority (n = 16) thought that using KIJANI would increase their PA level. User experience based on the UEQ scale was (mean ± SD): attractiveness (1.78 ± 1.82), perspicuity (2.15 ± 0.680), efficiency (0.67 ± 1.25), dependability, (1.21 ± 0.93), stimulation (1.24 ± 1.78), and novelty (1.27 ± 1.34). Conclusion: With these insights, a further step has been taken in the participatory development of KIJANI. Apps like KIJANI appear to be suitable for PA promotion in children and adolescents.

Immediate Increase in the Root Mean Square of Successive Differences after Three Bouts of Remote Ischemic Preconditioning: A Randomized Controlled Trial.

(1) Background: Remote ischemic preconditioning (RIPC) is an intervention involving the application of brief episodes of ischemia and reperfusion to distant tissues to activate protective pathways in the heart. There is evidence suggesting the involvement of the autonomic nervous system (ANS) in RIPC-induced cardioprotection. This study aimed to investigate the immediate effects of RIPC on the ANS using a randomized controlled trial. (2) Methods: From March 2018 to November 2018, we conducted a single-blinded randomized controlled study involving 51 healthy volunteers (29 female, 24.9 [23.8, 26.4] years). Participants were placed in a supine position and heart rate variability was measured over 260 consecutive beats before they were randomized into either the intervention or the SHAM group. The intervention group underwent an RIPC protocol (3 cycles of 5 min of 200 mmHg ischemia followed by 5 min reperfusion) at the upper thigh. The SHAM group followed the same protocol but on the right upper arm, with just 40 mmHg of pressure inflation, resulting in no ischemic stimulus. Heart rate variability measures were reassessed afterward. (3) Results: The intervention group showed a significant increase in RMSSD, the possible marker of the parasympathetic nervous system (IG: 14.5 [5.4, 27.5] ms vs. CG: 7.0 [-4.3, 23.1 ms], p = 0.027), as well as a significant improvement in Alpha 1 levels compared to the control group (IG: -0.1 [-0.2, 0.1] vs. CG: 0.0 [-0.1, 0.2], p = 0.001). (4) Conclusions: Our results hint that RIPC increases the RMSSD and Alpha 1 parameters showing possible immediate parasympathetic modulations. RIPC could be favorable in promoting cardioprotective or/and cardiovascular effects by ameliorating ANS modulations.

Cardiopulmonary Exercise Test and Daily Physical Activity in Pediatric Congenital Heart Disease: an Exploratory Analysis.

Sedentary lifestyle is reported to be associated with diminished exercise capacity, resulting in increased cardiovascular risk in adults with congenital heart disease (CHD). This cross-sectional study examined the association between objectively measured physical activity (PA) and exercise capacity in children and adolescents with CHD. Therefore, 107 patients (aged 13.0 ± 2.7 years, 41 girls) with various CHD performed a cardiopulmonary exercise test to quantify their peak oxygen uptake (peakV'O2). Moderate to vigorous PA (MVPA) and daily step count were assessed using Garmin vivofit jr. (Garmin, Germany) for 7 consecutive days. For association between PA and submaximal exercise capacity, Spearman correlation was performed. Patients with CHD showed almost normal values compared with the reference (79.5 ± 17.2% [31.6 to 138.1] %peakV'O2 predicted), with roughly normal ventilatory anerobic thresholds (50.6 ± 14.0% [20.3 to 97.9] % oxygen uptake at ventilatory anaerobic threshold [VATV'O2]). Step counts are below the recommendations (9,304 ± 3,792 steps/day [1,701 to 20,976]), whereas MVPA data are above the recommendations for children with ≥60 min/day (83.6 ± 34.6 min/day [10.1 to 190.9]). The Spearman rho showed significant positive correlations to VATV'O2 (r = 0.353, p <0.001) and %VATV'O2 (r = 0.307, p = 0.001), with similar results regarding MVPA (VATV'O2: r = 0.300, p = 0.002 and %VATV'O2: r = 0.270, p = 0.005). In conclusion, submaximal exercise capacity and PA correlate positively, making both assessments relevant in a clinical setting: PA in the context of cardiovascular prevention and peakV'O2 as the strongest predictor for morbidity and mortality.

KIJANI App to Promote Physical Activity in Children and Adolescents: Protocol for a Mixed Method Evaluation.

BACKGROUND: The prevalence of physical inactivity among children and adolescents is alarmingly high despite the well-documented and comprehensive benefits of regular physical activity (PA). Therefore, PA promotion should start early in childhood and adolescence. Although reducing recreational screen time in children and adolescents is an urgent concern, digital approaches have the potential to make activity promotion attractive and age appropriate for the target group. KIJANI is a mobile app approach to promote PA in children and adolescents via gamification and augmented reality. OBJECTIVE: This study protocol aims to describe the KIJANI intervention in detail, as well as the evaluation approach. METHODS: KIJANI is based on the concept that virtual coins can be earned through PA, for example, in the form of a collected step count. With these coins, in turn, blocks can be bought, which can be used to create virtual buildings and integrate them into the player's real-world environment via augmented reality. PA of users is detected via accelerometers integrated into the smartphones. KIJANI can be played at predefined play locations that were comprehensively identified as safe, child-friendly, and attractive for PA by the target group in a partner project. The evaluation process will be divided into 2 different stages. The phase-I evaluation will be a mixed methods approach with one-on-one semistructured interviews and questionnaires to evaluate the user experience and receive feedback from the target group. After the implementation of results and feedback from the target group, the phase-II evaluation will proceed in the form of a 2-arm randomized controlled trial, in which the effectiveness of KIJANI will be assessed via objectively measured PA as well as questionnaires. RESULTS: The study received ethical approval from the ethical board of the Technical University of Munich. Participants for the phase-I evaluation are currently being recruited. CONCLUSIONS: The study will help to determine the efficacy, applicability, and user experience of a gamified activity promotion application in children and adolescents. Overall, digital health approaches provide easy and wide reachability at low cost and are age appropriate and attractive for the target group of adolescents. Strategies have to be developed to apply digital health approaches in the best possible way for activity promotion. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/55156.

Homeostatic T helper 17 cell responses triggered by complex microbiota are maintained in ex vivo intestinal tissue slices.

Segmented filamentous bacteria (SFB) are members of the commensal intestinal microbiome. They are known to contribute to the postnatal maturation of the gut immune system, but also to augment inflammatory conditions in chronic diseases such as Crohn's disease. Living primary tissue slices are ultrathin multicellular sections of the intestine and provide a unique opportunity to analyze tissue-specific immune responses ex vivo. This study aimed to investigate whether supplementation of the gut flora with SFB promotes T helper 17 (Th17) cell responses in primary intestinal tissue slices ex vivo. Primary tissue slices were prepared from the small intestine of healthy Taconic mice with SFB-positive and SFB-negative microbiomes and stimulated with anti-CD3/CD28 or Concanavalin A. SFB-positive and -negative mice exhibited distinct microbiome compositions and Th17 cell frequencies in the intestine and complex microbiota including SFB induced up to 15-fold increase in Th17 cell-associated mediators, serum amyloid A (SAA), and immunoglobulin A (IgA) responses ex vivo. This phenotype could be transmitted by co-housing of mice. Our findings highlight that changes in the gut microbiome can be observed in primary intestinal tissue slices ex vivo. This makes the system very attractive for disease modeling and assessment of new therapies.

Implanted Carbon Nanotubes Harvest Electrical Energy from Heartbeat for Medical Implants.

Reliability of power supply for current implantable electronic devices is a critical issue for longevity and for reducing the risk of device failure. Energy harvesting is an emerging technology, representing a strategy for establishing autonomous power supply by utilizing biomechanical movements in human body. Here, a novel "Twistron energy cell harvester" (TECH), consisting of coiled carbon nanotube yarn that converts mechanical energy of the beating heart into electrical energy, is presented. The performance of TECH is evaluated in an in vitro artificial heartbeat system which simulates the deformation pattern of the cardiac surface, reaching a maximum peak power of 1.42 W kg-1 and average power of 0.39 W kg-1 at 60 beats per minute. In vivo implantation of TECH onto the left ventricular surface in a porcine model continuously generates electrical energy from cardiac contraction. The generated electrical energy is used for direct pacing of the heart as documented by extensive electrophysiology mapping. Implanted modified carbon nanotubes are applicable as a source for harvesting biomechanical energy from cardiac motion for power supply or cardiac pacing.

KIJANI: Designing a Physical Activity Promoting Collaborative Augmented Reality Game.

BACKGROUND: There is an increased need for physical activity among children and adolescents. KIJANI, a mobile augmented reality game, is designed to increase physical activity through gamified exercises. OBJECTIVES: The primary aim of this study is to get feedback on the design and implementation of potentially physical activity-increasing features in KIJANI. METHODS: A mixed-method study (n=13) evaluates newly implemented game design features quantitatively through measuring physical activity and qualitatively through participant feedback. RESULTS: Preliminary results are limited and need further studies. Participants' feedback shows a positive trend and highlights the game's potential effectiveness. CONCLUSION: KIJANI shows potential for increasing physical activity among children and adolescents through gamified exercise. Future work will refine the game based on user feedback and findings presented in related work. The game's long-term impact is to be explored.

Acremonium sp. diglycosidase-aid chemical diversification: valorization of industry by-products.

The fungal diglycosidase α-rhamnosyl-ß-glucosidase I (αRßG I) from Acremonium sp. DSM 24697 catalyzes the glycosylation of various OH-acceptors using the citrus flavanone hesperidin. We successfully applied a one-pot biocatalysis process to synthesize 4-methylumbellipheryl rutinoside (4-MUR) and glyceryl rutinoside using a citrus peel residue as sugar donor. This residue, which contained 3.5 % [w/w] hesperidin, is the remaining of citrus processing after producing orange juice, essential oil, and peel-juice. The low-cost compound glycerol was utilized in the synthesis of glyceryl rutinoside. We implemented a simple method for the obtention of glyceryl rutinoside with 99 % yield, and its purification involving activated charcoal, which also facilitated the recovery of the by-product hesperetin through liquid-liquid extraction. This process presents a promising alternative for biorefinery operations, highlighting the valuable role of αRßG I in valorizing glycerol and agricultural by-products. KEYPOINTS: • αRßG I catalyzed the synthesis of rutinosides using a suspension of OPW as sugar donor. • The glycosylation of aliphatic polyalcohols by the αRßG I resulted in products bearing a single rutinose moiety. • αRßG I catalyzed the synthesis of glyceryl rutinoside with high glycosylation/hydrolysis selectivity (99 % yield).

Prognostic Impact and Spatial Interplay of Immune Cells in Urothelial Cancer.

BACKGROUND AND OBJECTIVE: Quantity and the spatial relationship of specific immune cell types can provide prognostic information in bladder cancer. The objective of the study was to characterize the spatial interplay and prognostic role of different immune cell subpopulations in bladder cancer. METHODS: A total of 2463 urothelial bladder carcinomas were immunostained with 21 antibodies using BLEACH&STAIN multiplex fluorescence immunohistochemistry in a tissue microarray format and analyzed using a framework of neuronal networks for an image analysis. Spatial immune parameters were compared with histopathological parameters and overall survival data. KEY FINDINGS AND LIMITATIONS: The identification of > 300 different immune cell subpopulations and the characterization of their spatial relationship resulted in numerous spatial interaction patterns. Thirty-nine immune parameters showed prognostic significance in univariate analyses, of which 16 were independent from pT, pN, and histological grade in muscle-invasive bladder cancer. Among all these parameters, the strongest association with prolonged overall survival was identified for intraepithelial CD8+ cytotoxic T cells (time-dependent area under receiver operating characteristic curve [AUC]: 0.70), while stromal CD8+ T cells were less relevant (AUC: 0.65). A favorable prognosis of inflamed cancers with high levels of "exhaustion markers" suggests that TIM3, PD-L1, PD-1, and CTLA-4 on immune cells do not hinder antitumoral immune response in tumors rich of tumor infiltrating immune cells. CONCLUSIONS AND CLINICAL IMPLICATIONS: The density of intraepithelial CD8+ T cells was the strongest prognostic feature in muscle-invasive bladder cancer. Given that tumor cell killing by CD8+ cytotoxic T lymphocytes through direct cell-to-cell-contacts represents the "terminal end route" of antitumor immunity, the quantity of "tumor cell adjacent CD8+ T cells" may constitute a surrogate for the efficiency of cancer recognition by the immune system that can be measured straightaway in routine pathology as the CD8 labeling index. PATIENT SUMMARY: Quantification of intraepithelial CD8+ T cells, the strongest prognosticfeature identified in muscle-invasive bladder cancer, can easily be assessed by brightfield immunohistochemistry and is therefore "ready to use" for routine pathology.

Participation in Competitive Sports by Patients With Congenital Heart Disease: AHA/ACC and EAPC/ESC/AEPC Guidelines Comparison.

Sports participation in patients with congenital heart disease is an evolving subject. The American Heart Association/American College of Cardiology released a set of guidelines that advise the type and level of sports participation based primarily on anatomical defects with secondary consideration given to hemodynamic effects. Recently, the European Association of Preventive Cardiology/European Society of Cardiology/Association for European Paediatric and Congenital Cardiology offered a contrasting approach to sports participation that is based on hemodynamic and electrophysiological profiles of each patient, regardless of anatomical consideration. These guidelines are drastically different in their approaches but do have some similarities. In this review, we compare both documents, focusing on the aim, population, classification of sports, and the methodology of making recommendations. This review aims to assist practicing cardiologists in integrating the available published data and recommendations when counseling patients for sports participation.

Discrimination of pancreato-biliary cancer and pancreatitis patients by non-invasive liquid biopsy.

BACKGROUND: Current diagnostics for the detection of pancreato-biliary cancers (PBCs) need to be optimized. We therefore propose that methylated cell-free DNA (cfDNA) derived from non-invasive liquid biopsies serves as a novel biomarker with the ability to discriminate pancreato-biliary cancers from non-cancer pancreatitis patients. METHODS: Differentially methylated regions (DMRs) from plasma cfDNA between PBCs, pancreatitis and clinical control samples conditions were identified by next-generation sequencing after enrichment using methyl-binding domains and database searches to generate a discriminatory panel for a hybridization and capture assay with subsequent targeted high throughput sequencing. RESULTS: The hybridization and capture panel, covering around 74 kb in total, was applied to sequence a cohort of 25 PBCs, 25 pancreatitis patients, 25 clinical controls, and seven cases of Intraductal Papillary Mucinous Neoplasia (IPMN). An unbiased machine learning approach identified the 50 most discriminatory methylation markers for the discrimination of PBC from pancreatitis and controls resulting in an AUROC of 0.85 and 0.88 for a training (n = 45) and a validation (n = 37) data set, respectively. The panel was also able to distinguish high grade from low grade IPMN samples. CONCLUSIONS: We present a proof of concept for a methylation biomarker panel with better performance and improved discriminatory power than the current clinical marker CA19-9 for the discrimination of pancreato-biliary cancers from non-cancerous pancreatitis patients and clinical controls. This workflow might be used in future diagnostics for the detection of precancerous lesions, e.g. the identification of high grade IPMNs vs. low grade IPMNs.

High-sensitive troponin T and N-terminal pro-B-type natriuretic peptide independently predict survival and cardiac-related events in adults with congenital heart disease.

AIMS: High-sensitive troponin T (hs-TnT), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and C-reactive protein (CRP) are established prognostic biomarkers for cardiovascular (CV) morbidity and mortality and frequently used in symptomatic and/or hospitalized adults with congenital heart disease (ACHD). Their prognostic value in clinically stable ACHD has not yet been well established. This study investigates the predictive value of hs-TnT, NT-proBNP, and CRP for survival and CV events in stable ACHD. METHODS AND RESULTS: In this prospective cohort study, 495 outpatient ACHD (43.9 ± 10.0 years, 49.1% female) underwent venous blood sampling including hs-TnT, NT-proBNP, and CRP. Patients were followed up for survival status and the occurrence of CV events. Survival analyses were performed with Cox proportional hazards regression analysis and Kaplan-Meier curves. During a mean follow-up of 2.8 ± 1.0 years, 53 patients (10.7%) died or reached a cardiac-related endpoint including sustained ventricular tachycardia, hospitalization with cardiac decompensation, ablation, interventional catheterization, pacer implantation, or cardiac surgery. Multivariable Cox regression revealed hs-TnT (P = 0.005) and NT-proBNP (P = 0.018) as independent predictors of death or cardiac-related events in stable ACHD, whilst the prognostic value of CRP vanished after multivariable adjustment (P = 0.057). Receiver-operator characteristic curve analysis identified cut-off values for event-free survival of hs-TnT ≤9 ng/L and NT-proBNP ≤200 ng/L. Patients with both increased biomarkers had a 7.7-fold (confidence interval 3.57-16.40, P < 0.001) higher risk for death and cardiac-related events compared with patients without elevated blood values. CONCLUSION: Subclinical values of hs-TnT and NT-proBNP are a useful, simple, and independent prognostic tool for adverse cardiac events and survival in stable outpatient ACHD. REGISTRATION: German Clinical Trial Registry DRKS00015248.

Biomechanical comparison of two different compression screws for the treatment of odontoid fractures in human dens axis specimen.

BACKGROUND: Lag screw osteosynthesis for odontoid fractures has a high rate of pseudoarthrosis, especially in elderly patients. Besides biomechanical properties of the different screw types, insufficient fragment compression or unnoticed screw stripping may be the main causing factors for this adverse event. The aim of the study was to compare two screws in clinical use with different design principles in terms of compression force and stability against screw stripping. METHODS: Twelve human cadaveric C2 vertebral bodies were considered. Bone density was determined. The specimens were matched according to bone density and randomly assigned to two experimental groups. An odontoid fracture was induced, which were fixed either with a 3.5 mm standard compression screw or with a 5 mm sleeve nut screw. Both screws are certified for the treatment of odontoid fractures. The bone samples were fixed in a measuring device. The screwdriver was driven mechanically. The tests were analyzed for peak interfragmentary compression and screw-in torque with a frequency of 20 Hz. FINDINGS: The maximum fragment compression was significantly higher with screw with sleeve nut at 346.13(SD ±72.35) N compared with classic compression screw at 162.68(SD ±114.13) N (p = 0.025). Screw stripping occurred significantly earlier in classic compression screw at 255.5(SD ±192.0)° rotation after reaching maximum compression than in screw with sleeve nut at 1005.2(SD ±341.1)° (p = 0.0039). INTERPRETATION: Screw with sleeve nut achieves greater fragment compression and is more robust to screw stripping compared to classic compression screw. Whether the better biomechanical properties lead to a reduction of pseudoarthrosis has to be proven in clinical studies.

Longitudinal development of central SBP in children with congenital heart disease.

AIMS: Central SBP (cSBP) was shown to be increased already in children with congenital heart disease (CHD). However, its development over time has not yet been investigated. The aim of this study was to evaluate the natural course of cSBP over time from longitudinal assessment in children with CHD. METHODS: In this longitudinal study, 306 children and adolescents (11.3 ±â€Š2.9 years, 34% girls) with various CHD were prospectively examined from July 2014 to May 2022. Over a mean follow-up length of 30.1 ±â€Š18.9 months, 467 follow-up assessments have been conducted. cSBP was noninvasively assessed by oscillometric measurement via Mobil-O-Graph. A linear mixed effect model was performed to examine the course of cSBP. RESULTS: cSBP increased significantly over time by 1.22 mmHg per year of age (P < 0.001). The longitudinal increase in cSBP over time remained significant when including sex (b = 0.68, P < 0.001), BMI (b = 1.12, P < 0.001), hypertensive medication (b = 1.13, P < 0.001), disease severity (b = 1.04, P < 0.001), and CHD type (b = 3.74, P = 0.03) in the model. Patients with transposition of the great arteries (TGA) after arterial switch had a significantly higher cSBP increase over time (b = 1.78, P < 0.001). The longitudinal cSBP increase was significantly higher in obese CHD children (b = 2.52, P = 0.005) and in boys (b = 0.85, P < 0.001). CONCLUSION: This study shows a longitudinal increase in cSBP in children with CHD. Whether observed trajectories of cSBP are normal or abnormal needs to be investigated in further studies. Monitoring of the vascular function with a special focus on patients with TGA and obese CHD children seems indicated.