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An appropriately designed pharmacokinetic (PK) assay that is sensitive for anti-drug antibody (ADA) impact on relevant exposure is an alternative strategy to understand the neutralizing potential of ADAs. However, guidance on how to develop such PK assays and how to confirm the functional ADA impact on exposure is missing. Here, the PK assay of a T-cell-engaging bispecific antibody, cibisatamab, was developed based on its mechanism of action (MoA). Using critical monoclonal anti-idiotypic (anti-ID) antibody positive controls as ADA surrogates, the impact on exposure was evaluated pre-clinically. In a phase I clinical trial (NCT02324257), initial data suggest that the combination of ADA and PK assays for correlation of the ADA response with cibisatamab exposure. To understand the neutralizing potential of patient-derived ADAs on drug activity, advanced ADA characterization has been performed. Structural binding analysis of ADAs to antibody domains of the drug and its impact on targeting were assessed. For this purpose, relevant patient ADA binding features were identified and compared with the specific monoclonal anti-ID antibody-positive controls. Comparable results of target binding inhibition and similar impacts on exposure suggest that the observed reduction of Cmax and Ctrough levels in patients is caused by the neutralizing potential of ADAs and allows a correlation between ADA response and loss of exposure. Therefore, the described study provides important functional aspects for the development of an appropriately designed PK assay for bispecific antibodies as an alternative option towards understanding the neutralizing ADA impact on exposure.

Scientific and philosophical accounts of cognition and perception have traditionally focused on the brain and external sense organs. The extended view of embodied cognition suggests including other parts of the body in these processes. However, one organ has often been overlooked: the gut. Frequently conceptualized as merely a tube for digesting food, there is much more to the gut than meets the eye. Having its own enteric nervous system, sometimes referred to as the “second brain,” the gut is also an immune organ and has a large surface area interacting with gut microbiota. The gut has been shown to play an important role in many physiological processes, and may arguably do so as well in perception and cognition. We argue that proposals of embodied perception and cognition should take into account the role of the “gut complex,” which considers the enteric nervous, endocrine, immune, and microbiota systems as well as gut tissue and mucosal structures. The gut complex is an interface between bodily tissues and the “internalized external environment” of the gut lumen, involved in many aspects of organismic activity beyond food intake. We thus extend current embodiment theories and suggest a more inclusive account of how to “mind the gut” in studying cognitive processes.

Introduction: Rising industrial emissions of carbon dioxide and methane highlight the important role of carbon sinks and sources in fast-changing northern landscapes. Northern lake systems play a key role in regulating organic carbon input by accumulating carbon in their sediment. Here we look at the lake history of 28 lakes (between 50°N and 80°N) over the past 21,000 years to explore the relationship between carbon accumulation in lakes and temperature changes.Method: For this study, we calculated organic carbon accumulation rates (OCAR) using measured and newly generated organic carbon and dry bulk density data. To estimate new data, we used and evaluated seven different regression techniques in addition to a log-linear model as our base model. We also used combined age-depth modeling to derive sedimentation rates and the TraCE-21ka climate reanalysis dataset to understand temperature development since the Last Glacial Maximum. We determined correlation between temperature and OCAR by using four different correlation coefficients.Results: In our data collection, we found a slightly positive association between OCAR and temperature. OCAR values peaked during warm periods Bølling Allerød (38.07 g·m−2·yr−1) and the Early Holocene (40.68 g·m−2·yr−1), while lowest values occurred during the cold phases of Last Glacial Maximum (9.47 g·m−2·yr−1) and Last Deglaciation (10.53 g·m−2·yr−1). However, high temperatures did not directly lead to high OCAR values.Discussion: We assume that rapid warming events lead to high carbon accumulation in lakes, but as warming progresses, this effect appears to change as increased microbial activity triggers greater outgassing. Despite the complexity of environmental forcing mechanisms affecting individual lake systems, our study showed statistical significance between measured OCAR and modelled paleotemperature for 11 out of 28 lakes. We concluded that air temperature alone appears to drive the carbon accumulation in lakes. We expected that other factors (catchment vegetation, permafrost, and lake characteristics) would influence accumulation rates, but could not discover a conclusive factor that had a statistical significant impact. More data available on long-term records from northern lake systems could lead to more confidence and accuracy on the matter.

Decompensation episodes in chronic heart failure patients frequently result in unplanned outpatient or emergency room visits or even hospitalizations. Early detection of these episodes in their pre-symptomatic phase would likely enable the clinicians to manage this patient cohort with the appropriate modification of medical therapy which would in turn prevent the development of more severe heart failure decompensation thus avoiding the need for heart failure-related hospitalizations. Currently, heart failure worsening is recognized by the clinicians through characteristic changes of heart failure-related symptoms and signs, including the changes in heart sounds. The latter has proven to be largely unreliable as its interpretation is highly subjective and dependent on the clinicians’ skills and preferences. Previous studies have indicated that the algorithms of artificial intelligence are promising in distinguishing the heart sounds of heart failure patients from those of healthy individuals. In this manuscript, we focus on the analysis of heart sounds of chronic heart failure patients in their decompensated and recompensated phase. The data was recorded on 37 patients using two types of electronic stethoscopes. Using a combination of machine learning approaches, we obtained up to 72% classification accuracy between the two phases, which is better than the accuracy of the interpretation by cardiologists, which reached 50%. Our results demonstrate that machine learning algorithms are promising in improving early detection of heart failure decompensation episodes.

Cold-water corals mounds develop over millennial timescales as a result of sustained coral growth and concurrent with sediment deposition within their coral frameworks. So far, coral mounds have been primarily investigated as deep-sea biodiversity hotspots and geo-biological paleo-archives, whereas their morphological appearance and spatial arrangement have received much less attention. Here, we analysed the spatial distribution and the morphometry of coral mounds that developed on the Namibian shelf during a single short period dating back to the Early. The spatial distribution of these “early-stage” mounds and their morphological characteristics revealed a hierarchy of three different patterns. These comprise an alongslope mound distribution at a regional scale (first-order pattern), a topography-steered downslope alignment of mounds at a local scale (second-order pattern), and a hydrodynamic-controlled downslope orientation of the individual mounds at a mound scale (third-order pattern). In addition, because the Namibian mounds rarely exceed 20 m in height, key steps in the development of early-stage coral mounds (e.g. elongation, merging, limited gain in height compared to lateral extension) have been identified. With increasing size, coral mounds are more elongated, parallel to the prevailing tidal system, which is interpreted to reflect the transition from an “inherited” to a “developed” mound morphology. Besides supporting this earlier hypothesis on mound development, we could show that this transition takes place when the Namibian coral mounds reach ~150 m in length and ~8 m in height. This study reveals that the spatial-morphological appearance of coral mounds, often treated as a descriptive information, can provide valid information to understand their formation.

The stress response to the COVID-19 pandemic might differ between early and later stages. Longitudinal data on the development of population mental health during COVID-19 pandemic is scarce. We have investigated mental health trajectories and predictors for change in a probability sample of the general population in Germany at the beginning and after 6 months of the pandemic. We conducted a longitudinal survey in a population-based probability sample of German adults. The current study analyzed data from a first assessment in May 2020 (T1; N = 1,412) and a second in November 2020 (T2; N = 743). Mental health was assessed in terms of anxiety and depression using the Patient Health Questionnaire-4 (PHQ-4). Mental health outcomes at T1 were compared with PHQ-4 norm data. Trajectories over time were investigated based on outcome classifications of PHQ-4 scores. Predictors of mental health outcomes and change were identified using multiple regression analysis. In spring 2020, participants showed significantly higher PHQ-4 scores as compared to the norm data, however, overall anxiety and depression remained low also 6 months later. 6.6% of respondents showed a mental health deterioration in autumn 2020, entering subclinical and clinical ranges, outweighing the proportion of people with improved outcomes. Sociodemographic variables associated with mental distress at T1 were mainly not predictive for change at T2. Even under prolonged pandemic-related stress, mental health remained mainly stable in the general population. Further development of the considerable subgroup experiencing deterioration of depression and anxiety should be monitored, in order to tailor prevention and intervention efforts.

ObjectivesTo determine the profile of cytokines in patients with severe COVID-19 who were enrolled in a trial of COVID-19 convalescent plasma (CCP).MethodsPatients were randomized to receive standard treatment and 3 CCP units or standard treatment alone (CAPSID trial, ClinicalTrials.gov NCT04433910). The primary outcome was a dichotomous composite outcome (survival and no longer severe COVID-19 on day 21). Time to clinical improvement was a key secondary endpoint. The concentrations of 27 cytokines were measured (baseline, day 7). We analyzed the change and the correlation between serum cytokine levels over time in different subgroups and the prediction of outcome in receiver operating characteristics (ROC) analyses and in multivariate models.ResultsThe majority of cytokines showed significant changes from baseline to day 7. Some were strongly correlated amongst each other (at baseline the cluster IL-1ß, IL-2, IL-6, IL-8, G-CSF, MIP-1α, the cluster PDGF-BB, RANTES or the cluster IL-4, IL-17, Eotaxin, bFGF, TNF-α). The correlation matrix substantially changed from baseline to day 7. The heatmaps of the absolute values of the correlation matrix indicated an association of CCP treatment and clinical outcome with the cytokine pattern. Low levels of IP-10, IFN-γ, MCP-1 and IL-1ß on day 0 were predictive of treatment success in a ROC analysis. In multivariate models, low levels of IL-1ß, IFN-γ and MCP-1 on day 0 were significantly associated with both treatment success and shorter time to clinical improvement. Low levels of IP-10, IL-1RA, IL-6, MCP-1 and IFN-γ on day 7 and high levels of IL-9, PDGF and RANTES on day 7 were predictive of treatment success in ROC analyses. Low levels of IP-10, MCP-1 and high levels of RANTES, on day 7 were associated with both treatment success and shorter time to clinical improvement in multivariate models.ConclusionThis analysis demonstrates a considerable dynamic of cytokines over time, which is influenced by both treatment and clinical course of COVID-19. Levels of IL-1ß and MCP-1 at baseline and MCP-1, IP-10 and RANTES on day 7 were associated with a favorable outcome across several endpoints. These cytokines should be included in future trials for further evaluation as predictive factors.

The surface finish of organic and inorganic materials treated by gaseous plasma usually depends on the fluxes and fluencies of chemically reactive species such as molecular radicals. In low-pressure plasmas, the dissociation of molecules to parent atoms depends on the production rate in the gas phase and on the loss rate on surfaces. The processing will be efficient if the loss rate is minimized. The methods for minimizing the loss rate and thus increasing the processing efficiency are presented and discussed. The dissociation fraction of simple molecules exceeds 10% providing the plasma-facing materials are smooth with a low coefficient for heterogeneous surface recombination. The density of atoms in a plasma reactor increases with increasing pressure reaching a maximum and decreases with further pressure increase, which is explained by two competing processes. The energy efficiency also exhibits a maximum, which may be as high as 30% if plasma is sustained by electrodeless high-frequency discharges. Optimization of energy efficiency is not only beneficial for the costs of material processing but also for the prevention of excessive heating of treated materials. The latter is particularly important for organic materials because the surface functional groups are not stable but decay with increasing surface temperature.

Millennial-scale climate change history in eastern Siberia and relationships between diatom diversity, paleoclimate, and sediment-geochemical lake system trajectories are still poorly understood. This study investigates multi-proxy time series reaching back to the Late Pleistocene derived from radiocarbon dated Lake Bolshoe Toko sediment cores, southeastern Yakutia, Russia. We analyzed diatoms, elements (XRF), minerals (XRD), grain-size, organic carbon, and included chironomid analyses and published pollen-data for quantitative paleoclimate reconstruction. Changes in diatom species abundances reveal repeated episodes of thermal stratification indicated by shifts from euplanktonic Aulacoseira to Cyclotella species. Chironomid and pollen-inferred temperature reconstruction reveal that the main shift between these diatom species is related to the onset of Holocene Thermal Maximum (HTM) at 7.1 cal ka BP. Comparison to other paleoclimate records along a north-south transect through Yakutia shows that the HTM was delayed as far south as the Stanovoy mountains. Relationships between sediment-geochemistry, paleoclimate variability and diatom species richness (alpha diversity) was tested in a moving temporal offset approach to detect lead-lag relationships. Sediment-geochemical data, mainly uniform during the Holocene, revealed strongest positive or negative correlations ahead of species richness changes. Mean July air temperature (TJuly) reconstructions correlate with both Hill numbers and relative assemblage changes indicated by sample scores of multidimensional scaling analysis (MDS) over the entire time series. We found that sediment organic carbon revealed distinct positive correlations, i.e., centennial-scale delay to increases in diatom effective richness (Hill numbers N0 and N2). We conclude that a lag of deposited organic carbon concentrations behind changes in diatom alpha diversity reveals that species richness can augment the production and thus sequestration of organic matter in comparable lake systems.

Water scarcity is one of the greatest threats for human survival and quality of life, and this is increasingly contributing to the risk of human, animal and plant infections due to waterborne viruses. Viruses are transmitted through polluted water, where they can survive and cause infections even at low concentrations. Plant viruses from the genus Tobamovirus are highly mechanically transmissible, and cause considerable damage to important crops, such as tomato. The release of infective tobamoviruses into environmental waters has been reported, with the consequent risk for arid regions, where these waters are used for irrigation. Virus inactivation in water is thus very important and cold atmospheric plasma (CAP) is emerging in this field as an efficient, safe, and sustainable alternative to classic waterborne virus inactivation methods. In the present study we evaluated CAP-mediated inactivation of pepper mild mottle virus (PMMoV) in water samples. PMMoV is a very resilient water-transmissible tobamovirus that can survive transit through the human digestive tract. The efficiency of PMMoV inactivation was characterized for infectivity and virion integrity, and at the genome level, using test plant infectivity assays, transmission electron microscopy, and molecular methods, respectively. Additionally, the safety of CAP treatment was determined by testing the cytotoxic and genotoxic properties of CAP-treated water on the HepG2 cell line. 5-min treatment with CAP was sufficient to inactivate PMMoV without introducing any cytotoxic or genotoxic effects in the in-vitro cell model system. These data on inactivation of such stable waterborne virus, PMMoV, will encourage further examination of CAP as an alternative for treatment of potable and irrigation waters, and even for other water sources, with emphasis on inactivation of various viruses including enteric viruses.

High-definition video surveys of remotely-operated vehicle (ROV) dives from the NOAA’s Mountains in the Deep 2017 expedition (EX1705) along volcanic ridges and seamounts of the Manihiki Plateau coupled with multibeam bathymetry data and water column profiles, reveal no or minimal sediment cover on the basaltic edifice, but variable amounts of cold-water corals on ferromanganese-encrusted basaltic rocks. Coarse sediment, however, accumulates in crevasses and sedimentary ripples testify the existence of currents in the area. Collectively, these observations illustrate the strong influence of deep currents on the surficial geology and cold-water coral distribution at ∼2,000 m water depths. Dive transects along two basaltic seamounts show stark differences of sedimentary features and cold-water coral distribution. On the ridges of “Te Kawhiti” (water depth: 2,089–2,220 m), basaltic slabs, and cold-water corals are far more abundant in comparison to the slope of a mesa in “Te Tuku” (water depth: 2,440–2,495 m). The increased abundance on “Te Kawhiti” is due to the exposure of “Te Kawhiti” to Lower Circumpolar Deep Water that sweeps the summit of the ridges as indicated by frequent ripples observed in between the basaltic rocks. The currents are strong enough to sweep fine-grained sediments away, leaving coarse-grained sediments behind, inducing the formation of ferromanganese crust on the basaltic rocks. Both dive sites are below the high-Mg calcite saturation horizon, and as a result, the cold-water coral community is dominated by Isididae, which can build a high-Mg calcite skeleton in water undersaturated in regards to high-Mg calcite.

Canopy temperature (CT) has been related to water-use and yield formation in crops. However, constantly (e.g., sun illumination angle, ambient temperature) as well as rapidly (e.g., clouds) changing environmental conditions make it difficult to compare measurements taken even at short time intervals. This poses a great challenge for high-throughput field phenotyping (HTFP). The aim of this study was to i) set up a workflow for unmanned aerial vehicles (UAV) based HTFP of CT, ii) investigate different data processing procedures to combine information from multiple images into orthomosaics, iii) investigate the repeatability of the resulting CT by means of heritability, and iv) investigate the optimal timing for thermography measurements. Additionally, the approach was v) compared with other methods for HTFP of CT. The study was carried out in a winter wheat field trial with 354 genotypes planted in two replications in a temperate climate, where a UAV captured CT in a time series of 24 flights during 6 weeks of the grain-filling phase. Custom-made thermal ground control points enabled accurate georeferencing of the data. The generated thermal orthomosaics had a high spatial accuracy (mean ground sampling distance of 5.03 cm/pixel) and position accuracy [mean root-mean-square deviation (RMSE) = 4.79 cm] over all time points. An analysis on the impact of the measurement geometry revealed a gradient of apparent CT in parallel to the principle plane of the sun and a hotspot around nadir. Averaging information from all available images (and all measurement geometries) for an area of interest provided the best results by means of heritability. Correcting for spatial in-field heterogeneity as well as slight environmental changes during the measurements were performed with the R package SpATS. CT heritability ranged from 0.36 to 0.74. Highest heritability values were found in the early afternoon. Since senescence was found to influence the results, it is recommended to measure CT in wheat after flowering and before the onset of senescence. Overall, low-altitude and high-resolution remote sensing proved suitable to assess the CT of crop genotypes in a large number of small field plots as is required in crop breeding and variety testing experiments.

An appropriately designed pharmacokinetic (PK) assay that is sensitive for antidrug antibody (ADA) impact on relevant exposure is an alternative strategy to understand the neutralizing potential of ADAs. However, guidance on how to develop such PK assays and how to confirm the functional ADA impact on exposure is missing. Here, the PK assay of a T-cell-engaging bispecific antibody, cibisatamab, was developed based on its mechanism of action (MoA). Using critical monoclonal anti-idiotypic (anti-ID) antibody positive controls as ADA surrogates, the impact on exposure was evaluated pre-clinically. In a phase I clinical trial (NCT02324257), initial data suggest that the combination of ADA and PK assays for correlation of the ADA response with cibisatamab exposure. To understand the neutralizing potential of patient-derived ADAs on drug activity, advanced ADA characterization has been performed. Structural binding analysis of ADAs to antibody domains of the drug and its impact on targeting were assessed. For this purpose, relevant patient ADA binding features were identified and compared with the specific monoclonal anti-ID antibody-positive controls. Comparable results of target binding inhibition and similar impacts on exposure suggest that the observed reduction of Cmax and Ctrough levels in patients is caused by the neutralizing potential of ADAs and allows a correlation between ADA response and loss of exposure. Therefore, the described study provides important functional aspects for the development of an appropriately designed PK assay for bispecific antibodies as an alternative option towards understanding the neutralizing ADA impact on exposure. [ABSTRACT FROM AUTHOR]

Scientific and philosophical accounts of cognition and perception have traditionally focused on the brain and external sense organs. The extended view of embodied cognition suggests including other parts of the body in these processes. However, one organ has often been overlooked: the gut. Frequently conceptualized as merely a tube for digesting food, there is much more to the gut than meets the eye. Having its own enteric nervous system, sometimes referred to as the "second brain," the gut is also an immune organ and has a large surface area interacting with gut microbiota. The gut has been shown to play an important role in many physiological processes, and may arguably do so as well in perception and cognition. We argue that proposals of embodied perception and cognition should take into account the role of the "gut complex," which considers the enteric nervous, endocrine, immune, and microbiota systems as well as gut tissue and mucosal structures. The gut complex is an interface between bodily tissues and the "internalized external environment" of the gut lumen, involved in many aspects of organismic activity beyond food intake. We thus extend current embodiment theories and suggest a more inclusive account of how to "mind the gut" in studying cognitive processes. [ABSTRACT FROM AUTHOR]

BackgroundAnterior column realignment (ACR), using a lateral lumbar or thoracic interbody fusion (LLIF) approach to release the anterior longitudinal ligament (ALL), is a powerful technique to increase segmental lordosis. We here report our experience with the use of expandible LLIF cages for ACR.MethodsRetrospective, single-center observational cohort study including consecutive patients treated by LLIF using an expandible interbody implant. Patients with ACR were compared to patients without ACR. Our outcomes include adverse events (AEs), radiological (segmental sagittal cobb angle, spinopelvic parameters) and clinical outcomes until 12 months postoperative.ResultsWe identified 503 patients, in which we performed LLIF at 732 levels. In 63 patients (12.5%) and 70 levels (9.6%) an expandable cage was used. Of those, in 30 patients (47.6%) and 30 levels, the ALL was released (42.8%). Age (mean 61.4 years), sex (57.1% female), comorbidities and further demographic features were similar, but patients in the ACR group had a higher anesthesiologic risk, were more frequently operated for degenerative deformity and had a more severely dysbalanced spine (all p 7 levels). Intraoperative AEs occurred in 3.3% (ACR) and 3.0% (no ACR; p = 0.945). In ACR cases, mean segmental lordosis changed from −2.8° (preoperative) to 16.4° (discharge; p 0.05)]. Total lumbar lordosis increased from 27.8° to 45.2° (discharge; p 0.05) and no pseudarthrosis at the LLIF level was noted.ConclusionsACR using an expandible LLIF interbody implant was safe, promoted solid fusion and restored significantly more segmental lordosis compared to LLIF without ALL release, which was maintained during follow-up.

BackgroundHidradenitis suppurativa (HS) is a chronic inflammatory skin condition that affects hair follicles in areas with apocrine sweat glands, such as the underarms, groin, and buttocks. The pathogenesis of HS is not fully understood, but considering the key role played by the biological clock in the control of immune/inflammatory processes the derangement of circadian and ultradian pathways could be hypothesized.MethodsWe analyzed genome-wide DNA methylation patterns in peripheral blood from 24 HS cases and 24 controls using the Infinium HumanMethylation450 BeadChip array (Illumina), followed by bioinformatics and statistical analyses.ResultsWe found that several circadian and ultradian genes were differentially methylated in HS patients, predominantly exhibiting hypomethylation. These genes were enriched in pathways such as MAPK and WNT cascades, acute phase response, cytokine release, inflammation, innate immune response, xenobiotic detoxification, and oxidative stress response.ConclusionAltered DNA methylation patterns of genes related to circadian and ultradian pathways could contribute to immune system derangement and inflammatory processes chronicization in addition to other comorbidities hallmarking HS onset and progression, at the same time representing possible druggable targets.

We introduce an open-source Python package for the analysis of large-scale electrophysiological data, named SyNCoPy, which stands for Systems Neuroscience Computing in Python. The package includes signal processing analyses across time (e.g., time-lock analysis), frequency (e.g., power spectrum), and connectivity (e.g., coherence) domains. It enables user-friendly data analysis on both laptop-based and high-performance computing systems. SyNCoPy is designed to facilitate trial-parallel workflows (parallel processing of trials), making it an ideal tool for large-scale analysis of electrophysiological data. Based on parallel processing of trials, the software can support very large-scale datasets via innovative out-of-core computation techniques. It also provides seamless interoperability with other standard software packages through a range of file format importers and exporters and open file formats. The naming of the user functions closely follows the well-established FieldTrip framework, which is an open-source MATLAB toolbox for advanced analysis of electrophysiological data.

IntroductionThe COVID-19 pandemic has faced students with many challenges, contributing to their mental distress. This article explores the role of demographic characteristics, psychological status, year of study, and social support during the COVID-19 pandemic in explaining Slovenian university students’ mental health problems and help-seeking behavior.MethodsIn February and March 2021, data were collected on 5,234 full-time Slovenian postsecondary students who were enrolled in public and concessionary independent higher education institutions. Participants completed a questionnaire, which included The Patient Health Questionnaire (PHQ-9), General Anxiety Disorder questionnaire (GAD-7), Oslo Social Support Scale (OSSS-3), and items measuring psychological status, help-seeking behavior and demographics. Data were analyzed using multiple linear regression and hypothesis testing for differences.ResultsFactors, such as gender, age, psychological status and social support, contributed to experiencing anxiety and depression among Slovenian students during the COVID-19 pandemic, with year of study additionally contributing to experiencing depression. Similarly, gender, age, psychological status and social support contributed to help-seeking behavior. Higher levels of depression and anxiety were reported by female students, students with prior mental disorders, and students with lower social support levels. Female students and students with lower social support levels reported more frequent help-seeking behaviors.ConclusionThe results provide insight into the mental state of the Slovenian student population in the context of imposed public health measures at the end of the second COVID-19 wave in Slovenia. The findings can help identify vulnerable groups within the student population to whom we must be particularly attentive in times of crisis.

Glioblastoma is the commonest primary malignant brain tumor, with a very poor prognosis and short overall survival. It is characterized by its high intra- and intertumoral heterogeneity, in terms of both the level of single-nucleotide variants, copy number alterations, and aneuploidy. Therefore, routine diagnosis can be challenging in some cases. We present a complicated case of glioblastoma, which was characterized with five cytogenomic methods: interphase fluorescence in situ hybridization, multiplex ligation-dependent probe amplification, comparative genomic hybridization array and single-nucleotide polymorphism, targeted gene panel, and whole-genome sequencing. These cytogenomic methods revealed classical findings associated with glioblastoma, such as a lack of IDH and TERT mutations, gain of chromosome 7, and loss of chromosome 10. At least three pathological clones were identified, including one with whole-genome duplication, and one with loss of 1p and suspected loss of 19q. Deletion and mutation of the TP53 gene were detected with numerous breakends on 17p and 20q. Based on these findings, we recommend a combined approach to the diagnosis of glioblastoma involving the detection of copy number alterations, mutations, and aneuploidy. The choice of the best combination of methods is based on cost, time required, staff expertise, and laboratory equipment. This integrated strategy could contribute directly to tangible improvements in the diagnosis, prognosis, and prediction of the therapeutic responses of patients with brain tumors.

Attention in social interactions is directed by social cues such as the face or eye region of an interaction partner. Several factors that influence these attentional biases have been identified in the past. However, most findings are based on paradigms with static stimuli and no interaction potential. Therefore, the current study investigated the influence of one of these factors, namely facial affect in natural social interactions using an evaluated eye-tracking setup. In a sample of 35 female participants, we examined how individuals' gaze behavior responds to changes in the facial affect of an interaction partner trained in affect modulation. Our goal was to analyze the effects on attention to facial features and to investigate their temporal dynamics in a natural social interaction. The study results, obtained from both aggregated and dynamic analyses, indicate that facial affect has only subtle influences on gaze behavior during social interactions. In a sample with high measurement precision, these findings highlight the difficulties of capturing the subtleties of social attention in more naturalistic settings. The methodology used in this study serves as a foundation for future research on social attention differences in more ecologically valid scenarios.

Social cognitive deficits and social behavior impairments are common in major depressive disorder (MDD) and affect the quality of life and recovery of patients. This review summarizes the impact of standard and novel treatments on social functioning in MDD and highlights the potential of combining different approaches to enhance their effectiveness. Standard treatments, such as antidepressants, psychotherapies, and brain stimulation, have shown mixed results in improving social functioning, with some limitations and side effects. Newer treatments, such as intranasal oxytocin, mindfulness-based cognitive therapy, and psychedelic-assisted psychotherapy, have demonstrated positive effects on social cognition and behavior by modulating self-referential processing, empathy, and emotion regulation and through enhancement of neuroplasticity. Animal models have provided insights into the neurobiological mechanisms underlying these treatments, such as the role of neuroplasticity. Future research should explore the synergistic effects of combining different treatments and investigate the long-term outcomes and individual differences in response to these promising interventions.

Biodielectrics is a subset of biological and/or bioinspired materials that has brought a huge transformation in the advancement of medical science, such as localized drug delivery in cancer therapeutics, health monitoring, bone and nerve repair, tissue engineering and use in other nanoelectromechanical systems (NEMS). While biodielectrics has long been used in the field of electrical insulation for over a century, polar dielectric properties of biological building blocks have not been well understood at the fundamental building block level. In this review article, we provide a brief overview of dielectric properties of biological building blocks and its hierarchical organisations to include polar dielectric properties such as piezo, pyro, and ferroelectricity. This review article also discusses recent trends, scope, and potential applications of these dielectrics in science and technology. We highlight electromechanical properties embedded in rationally designed organic assemblies, and the challenges and opportunities inherent in mapping from molecular amino acid building blocks to macroscopic analogs of biological fibers and tissues, in pursuit of sustainable materials for next-generation technologies.

BackgroundThe benefit of chronic total occlusion (CTO)-percutaneous coronary intervention (PCI) is controversial because of a lack of high-quality evidence. We aim to evaluate the impact of CTO-PCI on symptoms, quality of life and mortality.MethodsWe conducted a retrospective single center study of patients with CTO-PCI in a tertiary center in Austria. The study outcomes were Canadian Cardiovascular Society (CCS) angina score, quality of life measured by Seattle Angina Questionnaire (SAQ), and death at median follow up for patients with successful vs. failed CTO-PCI.ResultsA total of 300 patients underwent CTO-PCI for coronary artery disease, of which 252 (84%) were technically successful with median follow up of 3.4 years. There were no significant differences in in-hospital or all-cause mortality, major adverse cardiovascular event, or stent-related complications between the groups of failed and successful CTO-PCI. Among patients with successful CTO-PCI there was a significant improvement in CCS score, which was not found for the group with failed CTO-PCI. Successful reopening was associated with significant benefits of the SAQ domains of angina with stressful activity [3.7 ± 0.9 vs. 3.1 ± 0.5, p = 0.004, use of nitrates (4.7 ± 0.5 vs. 3.0 ± 1.0) p = 0.005] and satisfaction from angina relief (4.4 ± 1.1 vs. 3.6 ± 1.4 p

IntroductionDichotic listening (DL) has been extensively used as a task to investigate auditory processing and hemispheric lateralisation in humans. According to the “callosal relay model,” the typical finding of a right ear advantage (REA) occurs because the information coming from the right ear has direct access to the left dominant hemisphere while the information coming from the left ear has to cross via the corpus callosum. The underlying neuroanatomical correlates and neurophysiological mechanisms have been described using diffusion tensor imaging (DTI) and lagged phase synchronization (LPS) of the interhemispheric auditory pathway. During the non-forced condition of DL, functional connectivity (LPS) of interhemispheric gamma-band coupling has been described as a relevant mechanism related to auditory perception in DL. In this study, we aimed to extend the previous results by exploring the effects of top-down modulation of DL (forced-attention condition) on interhemispheric gamma-band LPS.MethodsRight-handed healthy participants (n = 31; 17 females) performed three blocks of DL with different attention instructions (no-attention, left-ear attention, right-ear attention) during simultaneous EEG recording with 64 channels. Source analysis was done with exact low-resolution brain electromagnetic tomography (eLORETA) and functional connectivity between bilateral auditory areas was assessed as LPS in the gamma-band frequency range.ResultsTwenty-four participants (77%) exhibited a right-ear advantage in the no-attention block. The left- and right-attention conditions significantly decreased and increased right-ear reports, respectively. Similar to the previous studies, functional connectivity analysis (gamma-band LPS) showed significantly increased connectivity between left and right Brodmann areas (BAs) 41 and 42 during left ear reports in contrast with right ear reports. Our new findings notably indicated that the right-attention condition exhibited significantly higher connectivity between BAs 42 compared with the no-attention condition. This enhancement of connectivity was more pronounced during the perception of right ear reports.DiscussionOur results are in line with previous reports describing gamma-band synchronization as a relevant neurophysiological mechanism involved in the interhemispheric connectivity according to the callosal relay model. Moreover, we newly added some evidence of attentional effects on this interhemispheric connectivity, consistent with the attention-executive model. Our results suggest that reciprocal inhibition could be involved in hemispheric lateralization processes.

BackgroundSupporting individuals in managing their suicidality can prevent suicidal behavior. This study evaluated the suicide prevention project SERO, which was launched in Central Switzerland in 2021. SERO comprises four components: the suicide risk assessment technique PRISM-S, a personal safety plan, mental health first aid courses for relatives, and a self-management app. We assessed the mental health of individuals at increased suicide risk after hospital discharge and evaluated the usage and usefulness of SERO components.MethodsA cross-sectional study targeted former patients of Lucerne Psychiatry with an increased suicide risk. Between March 2023 and March 2024, we collected data from 24 individuals through a questionnaire administered six months post-discharge. Descriptive statistics characterized sociodemographics, assessed self-efficacy, self-management, and health literacy, and analyzed the usage and usefulness of SERO components. Associations between the usage of SERO components and mental health outcomes were investigated using Wilcoxon rank sum tests.ResultsMental health assessments indicated, on average, low to moderate levels of self-efficacy, self-management, and health literacy, with substantial variations across individuals. Participants’ exposure to SERO components varied: 83% used PRISM-S for suicide risk assessment, 67% developed a personal safety plan, 38% used the SERO app, and 8% reported that their relatives participated in a mental health first aid course. 50% of safety plan users and 44% of SERO app users found the tools helpful before or during a suicidal crisis. 78% of SERO app users would recommend the app to others.ConclusionLow to moderate levels of self-efficacy, self-management, and health literacy underscore the need for targeted interventions to support individuals at suicide risk. Positive feedback on the personal safety plan and the SERO app suggests their potential effectiveness in helping individuals manage their suicidality. Therefore, integrating structured measures for promoting self-management into standard care protocols in psychiatric hospitals and into patients’ lives may contribute to preventing suicides. The main limitation of our study is its small sample size. Future larger-scale studies should investigate user experiences in detail, assess the causal effects of SERO components on specific mental health and suicide outcomes, and evaluate the cost-effectiveness of each component separately and in combination.

Demonstratives (“this”/“that”) express a speaker-relative distance contrast and need to be substituted for each other systematically: depending on their relative position, what one speaker refers to by saying “this” another speaker has to refer to by saying “that.” This substitution aspect of demonstratives poses additional difficulties for learning demonstratives, because it requires recognizing that two speakers have to refer to the same thing with different words, and might be one reason for the reportedly protracted acquisition of demonstratives. In an online study conducted in German, it was investigated whether children in the estimated upper age range of demonstrative acquisition (5 to 7 years) understand demonstratives' substitution aspect with familiar (“dies”/“das”) and novel (“schmi”/“schmu”) demonstratives, and whether they understand novel words (“schmi”/“schmu”) when used non-demonstratively as labels (N = 73; between-subject). Children's accuracy was compared with adult performance (N = 74). The study shows that children between 5 and 7 years of age perform less accurately than adults in all conditions. While adults' performance was highly accurate in all conditions (between 75% and 92% correct), children performed below chance in both demonstrative conditions and above chance in the labeling condition. This suggests that children do not understand demonstratives in the presented setup. More detailed analyses of children's response patterns indicate that they instead treat words as mutually exclusive labels in any condition.

Alterations in mRNA 3’ end processing and polyadenylation are widely implicated in the biology of many cancer types, including glioblastoma (GBM), one the most aggressive tumor types. Although several RNA-binding proteins (RBPs) responsible for alternative polyadenylation (APA) were identified from functional studies in cell lines, their contribution to the APA landscape in tumors in vivo was not thoroughly addressed. In this study we analyzed a large RNA-seq data set of glioblastoma (GBM) samples from The Cancer Genome Atlas (TCGA) to identify APA patterns differentiating the main molecular subtypes of GBM. We superimposed these to RBP footprinting data and to APA events occurring upon depletion of individual RBPs from a large panel tested by the ENCODE Consortium. Our analysis revealed 22 highly concordant and statistically significant RBP-APA associations, whereby changes in RBP expression were accompanied by APA in both TCGA and ENCODE datasets. Among these, we found a previously unknown PTBP1-regulated APA event in the PRRC2B gene and an HNRNPU-regulated event in the SC5D gene. Both of these were further supported by RNA-sequencing data of paired tumor center-periphery GBM samples obtained at the University Hospital of Basel. In addition, we validated the regulation of APA in PRRC2B by PTBP1 in siRNA-knockdown and overexpression experiments followed by RNA-sequencing in two glioblastoma cell lines. The transcriptome analysis workflow that we present here enables the identification of concordant RBP-APA associations in cancers.

In the past decade, significant European calls for research proposals have supported translational collaborative research on non-communicable and infectious diseases within the biomedical life sciences by bringing together interdisciplinary and multinational consortia. This research has advanced our understanding of disease pathophysiology, marking considerable scientific progress. Yet, it is crucial to retrospectively evaluate these efforts’ societal impact. Research proposals should be thoughtfully designed to ensure that the research findings can be effectively translated into actionable policies. In addition, the choice of scientific methods plays a pivotal role in shaping the societal impact of research discoveries. Understanding the factors responsible for current unmet public health issues and medical needs is crucial for crafting innovative strategies for research policy interventions. A multistakeholder survey and a roundtable helped identify potential needs for consideration in the EU research and policy agenda. Based on survey findings, mental health disorders, metabolic syndrome, cancer, antimicrobial resistance, environmental pollution, and cardiovascular diseases were considered the public health challenges deserving prioritisation. In addition, early diagnosis, primary prevention, the impact of environmental pollution on disease onset and personalised medicine approaches were the most selected unmet medical needs. Survey findings enabled the formulation of some research-policies interventions (RPIs), which were further discussed during a multistakeholder online roundtable. The discussion underscored recent EU-level activities aligned with the survey-derived RPIs and facilitated an exchange of perspectives on public health and biomedical research topics ripe for interdisciplinary collaboration and warranting attention within the EU’s research and policy agenda. Actionable recommendations aimed at facilitating the translation of knowledge into transformative, science-based policies are also provided.

IntroductionGenetic predisposition to autoimmune encephalitis with antibodies against N-methyl-D-aspartate receptor (NMDAR) is poorly understood. Given the diversity of associated environmental factors (tumors, infections), we hypothesized that human leukocyte antigen (HLA) and killer-cell immunoglobulin-like receptors (KIR), two extremely polymorphic gene complexes key to the immune system, might be relevant for the genetic predisposition to anti-NMDAR encephalitis. Notably, KIR are chiefly expressed by Natural Killer (NK) cells, recognize distinct HLA class I allotypes and play a major role in anti-tumor and anti-infection responses.MethodsWe conducted a Genome Wide Association Study (GWAS) with subsequent control-matching using Principal Component Analysis (PCA) and HLA imputation, in a multi-ethnic cohort of anti-NMDAR encephalitis (n=479); KIR and HLA were further sequenced in a large subsample (n=323). PCA-controlled logistic regression was then conducted for carrier frequencies (HLA and KIR) and copy number variation (KIR). HLA-KIR interaction associations were also modeled. Additionally, single cell sequencing was conducted in peripheral blood mononuclear cells from 16 cases and 16 controls, NK cells were sorted and phenotyped.ResultsAnti-NMDAR encephalitis showed a weak HLA association with DRB1*01:01~DQA1*01:01~DQB1*05:01 (OR=1.57, 1.51, 1.45; respectively), and DRB1*11:01 (OR=1.60); these effects were stronger in European descendants and in patients without an underlying ovarian teratoma. More interestingly, we found increased copy number variation of KIR2DL5B (OR=1.72), principally due to an overrepresentation of KIR2DL5B*00201. Further, we identified two allele associations in framework genes, KIR2DL4*00103 (25.4% vs. 12.5% in controls, OR=1.98) and KIR3DL3*00302 (5.3% vs. 1.3%, OR=4.44). Notably, the ligands of these KIR2DL4 and KIR3DL3, respectively, HLA-G and HHLA2, are known to act as immune checkpoint with immunosuppressive functions. However, we did not find differences in specific KIR-HLA ligand interactions or HLA-G polymorphisms between cases and controls. Similarly, gene expression of CD56dim or CD56bright NK cells did not differ between cases and controls.DiscussionOur observations for the first time suggest that the HLA-KIR axis might be involved in anti-NMDAR encephalitis. While the genetic risk conferred by the identified polymorphisms appears small, a role of this axis in the pathophysiology of this disease appears highly plausible and should be analyzed in future studies.

IntroductionThe classical axis of the renin–angiotensin system (RAS) makes an important contribution to blood pressure regulation under general anesthesia via the vasopressor angiotensin II (Ang II). As part of the alternative RAS, angiotensin-converting enzyme 2 (ACE2) modulates the pro-inflammatory and fibrotic effects of Ang II by processing it into the organ-protective Ang 1–7, which is cleaved to Ang 1–5 by ACE. Although the levels of ACE2 may be associated with postoperative complications, alternative RAS metabolites have never been studied perioperatively. This study was designed to investigate the perioperative kinetics and balance of both RAS axes around major abdominal surgery.MethodsIn this observational cohort study, 35 patients undergoing elective major abdominal surgery were included. Blood sampling was performed before and after induction of anesthesia, at 1 h after skin incision, at the end of surgery, and on postoperative days (POD) 1, 3, and 7. The equilibrium concentrations of Ang I–IV, Ang 1–7, and Ang 1–5 in plasma were quantified using mass spectrometry. The plasma protein levels of ACE and ACE2 were measured with ELISA.ResultsSurgery caused a rapid, transient, and primarily renin-dependent activation of both RAS axes that returned to baseline on POD 1, followed by suppression. After induction, the Ang II/Ang I ratio persistently decreased, while the ACE levels started to increase on POD 1 (all p < 0.01 versus before anesthesia). Conversely, the ACE2 levels increased on POD 3 and 7 (both p < 0.001 versus before anesthesia), when the median Ang 1–7 concentrations were unquantifiably low.DiscussionThe postoperative elevation of ACE2 may prolong the decrease of the Ang II/Ang I ratio through the increased processing of Ang II. Further clarification of the intraoperative factors leading to relative Ang II deficiency and the sources of postoperatively elevated ACE2 is warranted.

IntroductionA concern expressed by the clinical community is that the constraint of motion provided by an ankle foot orthosis (AFO) may lead the user to become dependent on its stiffness, leading to learned non-use. To examine this, we hypothesized that using an experimental AFO-footwear combination (exAFO-FC) that constrains ankle motion during walking would result in reduced soleus and tibialis anterior EMG compared to free (exAFO-FC) and control (no AFO, footwear only) conditions.MethodA total of 14 healthy subjects walked at their preferred speed (1.34 ± 0.09 m·s-1) for 15 min, in three conditions, namely, control, free, and stop.ResultsDuring the stance phase of walking in the stop condition, ipsilateral soleus integrated EMG (iEMG) declined linearly, culminating in a 32.1% reduction compared to the control condition in the final 5 min interval of the protocol. In contrast, ipsilateral tibialis anterior iEMG declined in a variable fashion culminating in an 11.2% reduction compared to control in the final 5 min interval. During the swing phase, the tibialis anterior iEMG increased by 6.6% compared to the control condition during the final 5 min interval. The contralateral soleus and tibialis anterior exhibited increased iEMG in the stop condition.DiscussionAn AFO-FC functions as a biomechanical motion control device that influences the neural control system and alters the output of muscles experiencing constraints of motion.

While inadequate relationships in the workplace pose a significant psychosocial risk, quality interpersonal relationships can contribute to positive effects and prevent negative outcomes. Erskine’s model of relational needs, not yet studied in the work environment, can provide a more detailed understanding of the needs employees experience in their workplace relationships. We adapted the general Relational Needs Satisfaction Scale (RNSS) for coworker relationships and examined the factor structure of relational needs in the workplace and their connections to various work aspects. The sample comprised 273 participants, including both employees and students, in a workplace setting with coworkers. The results show that the Workplace Relational Needs Satisfaction Scale (W-RNSS) is a valid and reliable instrument (α = 0.93 for the total scale and 0.77

During the course of their work, teachers may be subjected to conditions that cause different health problems. This study examines occupational health disorders in a representative sample of 858 teachers (528 female; age 44.0 ± 9.67 years) divided into three groups of teachers with specific occupational requirements: specialist physical education teachers (specialist PETs), classroom teachers, and specialist teachers. The number of health disorders in the last 12 months was recorded using the Chronic Health Disorders Questionnaire. The differences between the different types of teachers, controlled for sex and age, were analyzed using binary logistic regression. The results showed that 89% of teachers experienced colds as the most frequently reported health problem, followed by 58% for lower back problems, 57% for headaches, 51% for hoarseness, and 43% for neck problems. A binary logistic regression showed that specialist PETs were the group with the highest health risk. They were about twice as likely to have musculoskeletal or hearing disorders than the other two groups of teachers. They were also significantly more likely to suffer from hoarseness. Understanding these different health challenges is critical to developing targeted interventions and robust support systems. These interventions should include initiatives aimed at raising awareness of health risk factors, implementing injury interventions and vocal cord hygiene programs, making ergonomic adjustments, and promoting awareness of self-care (both mental and physical). Given that the teaching profession is currently struggling with an aging workforce and a shortage of teachers, addressing these challenges is critical to the continued well-being of the teaching professionals.

IntroductionThe standard treatment for preventing rejection in vascularized composite allotransplantation (VCA) currently relies on systemic immunosuppression, which exposes the host to well-known side effects. Locally administered immunosuppression strategies have shown promising results to bypass this hurdle. Nevertheless, their progress has been slow, partially attributed to a limited understanding of the essential mechanisms underlying graft rejection. Recent discoveries highlight the crucial involvement of innate immune components, such as neutrophil extracellular traps (NETs), in organ transplantation. Here we aimed to prolong graft survival through a tacrolimus-based drug delivery system and to understand the role of NETs in VCA graft rejection.MethodsTo prevent off-target toxicity and promote graft survival, we tested a locally administered tacrolimus-loaded on-demand drug delivery system (TGMS-TAC) in a multiple MHC-mismatched porcine VCA model. Off-target toxicity was assessed in tissue and blood. Graft rejection was evaluated macroscopically while the complement system, T cells, neutrophils and NETs were analyzed in graft tissues by immunofluorescence and/or western blot. Plasmatic levels of inflammatory cytokines were measured using a Luminex magnetic-bead porcine panel, and NETs were measured in plasma and tissue using DNA-MPO ELISA. Lastly, to evaluate the effect of tacrolimus on NET formation, NETs were induced in-vitro in porcine and human peripheral neutrophils following incubation with tacrolimus.ResultsRepeated intra-graft administrations of TGMS-TAC minimized systemic toxicity and prolonged graft survival. Nevertheless, signs of rejection were observed at endpoint. Systemically, there were no increases in cytokine levels, complement anaphylatoxins, T-cell subpopulations, or neutrophils during rejection. Yet, tissue analysis showed local infiltration of T cells and neutrophils, together with neutrophil extracellular traps (NETs) in rejected grafts. Interestingly, intra-graft administration of tacrolimus contributed to a reduction in both T-cellular infiltration and NETs. In fact, in-vitro NETosis assessment showed a 62–84% reduction in NETs after stimulated neutrophils were treated with tacrolimus.ConclusionOur data indicate that the proposed local delivery of immunosuppression avoids off-target toxicity while prolonging graft survival in a multiple MHC-mismatch VCA model. Furthermore, NETs are found to play a role in graft rejection and could therefore be a potential innovative therapeutic target.

Traumatic spinal cord injuries (SCIs) continue to be a major healthcare concern, with a rising prevalence worldwide. In response to this growing medical challenge, considerable scientific attention has been devoted to developing neuroprotective and neuroregenerative strategies aimed at improving the prognosis and quality of life for individuals with SCIs. This comprehensive review aims to provide an up-to-date and thorough overview of the latest neuroregenerative and neuroprotective therapies currently under investigation. These strategies encompass a multifaceted approach that include neuropharmacological interventions, cell-based therapies, and other promising strategies such as biomaterial scaffolds and neuro-modulation therapies. In addition, the review discusses the importance of acute clinical management, including the role of hemodynamic management as well as timing and technical aspects of surgery as key factors mitigating the secondary injury following SCI. In conclusion, this review underscores the ongoing scientific efforts to enhance patient outcomes and quality of life, focusing on upcoming strategies for the management of traumatic SCI. Each section provides a working knowledge of the fundamental preclinical and patient trials relevant to clinicians while underscoring the pathophysiologic rationale for the therapies.

We report an unusual constellation of diseases in a 32-year-old woman with neurofibromatosis type 1 (NF1) diagnosed with the recently described precursor entity of malignant peripheral nerve sheath tumor (MPNST), the so-called atypical neurofibromatous neoplasm with unknown biological potential (ANNUBP) and a large symptomatic cervical arteriovenous fistula. An [18F] 2-Fluoro-2-deoxy-D-glucose PET/CT (FDG-PET/CT) was performed to detect and stage a conspicuous symptomatic cervical tumor. The FDG-PET/CT showed high FDG uptake in one of the multiple known tumorous lesions associated with peripheral nerves. However, no relevant FDP uptake was observed in this affected cervical area. After digital subtraction angiography, the cervical mass turned out to be a widespread arteriovenous fistula of the vertebral artery. This was successfully treated using endovascular embolization. Subsequently, magnet resonance imaging (MRI) of the FDG-positive tumor revealed a well-enhanced homogeneous mass of the sciatic nerve measuring 5.2×2.4×2.8 cm. Microsurgical gross total tumor resection was performed using ultrasound. The final histopathological diagnosis was ANNUBP transformed from neurofibroma. The patient benefited excellently from the surgery; no recurrence or metastasis has been observed since resection. According to imaging, ANNUBP can be characterized as a well-enhanced homogeneous mass on MRI, displaying high uptake on FDG-PET/CT and hypoechogenic in ultrasound.

ObjectivePeripheral nerve tumors (PNTs) are rare diseases. So far, no multicenter data on diagnostics, the efficacy of treatment, long-term outcomes, and health-related quality of life (HRQoL) exist. The establishment of the Peripheral Nerve Tumor Registry (PNTR) in 2015 allows for the systematic analysis of patients with tumors associated with peripheral nerves. The present study aims to investigate the impact of PNT on an individual’s HRQoL and the effect of surgery.MethodsHRQoL was pre- and postoperatively assessed by the Euro-Qol-5D-5L (EQ-5D-5L) and Euro-Qol visual analog scale (EQ-VAS) survey in the retrospective and prospective study arm in three active participating study centers. An index was calculated based on the EQ-5D-5L for the quantification of health state (0: worst possible state of health, 1: best possible state of health). The EQ-VAS ranges from 0% (worst imaginable health status) to 100% (best possible health status). Patient characteristics (age, sex), as well as disease (histopathological entity) and treatment (pre- and postoperative symptoms, type of treatment)-specific data, were analyzed.ResultsData from 171 patients from three high-volume centers were included, with schwannoma (70.8%, n = 121) and neurofibroma (15.8%, n = 27) being the most prevalent histopathological diagnoses. Both the median health index value (preoperative: 0.887, n = 167; postoperative: 0.910, n = 166) and the median EQ-VAS (preoperative: 75%, n = 167; postoperative: 85%, n = 166) of the entire cohort regarding all histopathological diagnosis improved significantly after surgical therapy (p < 0.001). Preoperatively, 12.3% (n = 21) reached the highest index score of 1.0 in EQ-5D-5L and 100% in the EQ-VAS score in 5.3% (n = 9) of all patients. Postoperatively, the highest index score of 1.0 and 100% in the EQ-VAS score increased significantly and were achieved in 33.3% (n = 57) and 11.1% (n = 19) of the patients, respectively (p < 0.001).ConclusionFor the first time, our study presents multicenter data on life quality and the effect of surgery in primarily benign peripheral nerve tumors. Early surgery at a specialized center could improve neurological outcomes and, in conclusion, better QoL. In summary, surgical therapy significantly improved the entire cohort’s QoL, VAS, and analgesia.

Adolescent major depressive disorder (MDD) is associated with altered resting-state connectivity between the default mode network (DMN) and the salience network (SN), which are involved in self-referential processing and detecting and filtering salient stimuli, respectively. Using spectral dynamical causal modelling, we investigated the effective connectivity and input sensitivity between key nodes of these networks in 30 adolescents with MDD and 32 healthy controls while undergoing resting-state fMRI. We found that the DMN received weaker inhibition from the SN and that the medial prefrontal cortex and the anterior cingulate cortex showed reduced self-inhibition in MDD, making them more prone to external influences. Moreover, we found that selective serotonin reuptake inhibitor (SSRI) intake was associated with decreased and increased self-inhibition of the SN and DMN, respectively, in patients. Our findings suggest that adolescent MDD is characterized by a hierarchical imbalance between the DMN and the SN, which could affect the integration of emotional and self-related information. We propose that SSRIs may help restore network function by modulating excitatory/inhibitory balance in the DMN and the SN. Our study highlights the potential of prefrontal-amygdala interactions as a biomarker and a therapeutic target for adolescent depression.

Microbial management is central to aquaculture’s efficiency. Pediococcus acidilactici MA18/5M has shown promising results promoting growth, modulation of the immune response, and disease resistance in many fishes. However, the mechanisms through which this strain confers health benefits in fish are poorly understood, particularly in Pacific salmonid models. Briefly, the aims of this study were to i) assess the protective effects of P. acidilactici MA18/5M by examining gut barrier function and the expression of tight junction (TJ) and immune genes in vitro and in vivo, and ii) to determine the protective effects of this strain against a common saltwater pathogen, Vibrio anguillarum J382. An in vitro model of the salmonid gut was employed utilizing the cell line RTgutGC. Barrier formation and integrity assessed by TEER measurements in RTgutGC, showed a significant decrease in resistance in cells exposed only to V. anguillarum J382 for 24 h, but pre-treatment with P. acidilactici MA18/5M for 48 h mitigated these effects. While P. acidilactici MA18/5M did not significantly upregulate tight junction and immune molecules, pre-treatment with this strain protected against pathogen-induced insults to the gut barrier. In particular, the expression of ocldn was significantly induced by V. anguillarum J382, suggesting that this molecule might play a role in the host response against this pathogen. To corroborate these observations in live fish, the effects of P. acidilactici MA18/5M was evaluated in Chinook salmon reared in real aquaculture conditions. Supplementation with P. acidilactici MA18/5M had no effect on Chinook salmon growth parameters after 10 weeks. Interestingly, histopathological results did not show alterations associated with P. acidilactici MA18/5M supplementation, indicating that this strain is safe to be used in the industry. Finally, the expression pattern of transcripts encoding TJ and immune genes in all the treatments suggest that variation in expression is more likely to be due to developmental processes rather than P. acidilactici MA18/5M supplementation. Overall, our results showed that P. acidilactici MA18/5M is a safe strain for use in fish production, however, to assess the effects on growth and immune response previously observed in other salmonid species, an assessment in adult fish is needed.

BackgroundCoronary artery disease (CAD) is a common finding in patients with severe aortic stenosis undergoing transcatheter aortic valve replacement (TAVR). However, the impact on prognosis of chronic total occlusions (CTOs), a drastic expression of CAD, remains unclear.Methods and resultsWe retrospectively reviewed 1,487 consecutive TAVR cases performed at a single tertiary care medical center. Pre-TAVR angiograms were analyzed for the presence of a CTO. At the time of TAVR, 11.2% (n = 167) patients had a CTO. There was no significant association between the presence of a CTO and in-hospital or 30-day mortality. There was also no difference in long-term survival. LV ejection fraction and mean aortic gradients were lower in the CTO group.ConclusionsOur analysis suggests that concomitant CTO lesions in patients undergoing TAVR differ in their risk profile and clinical findings to patients without CTO. CTO lesion per se were not associated with increased mortality, nevertheless CTOs which supply non-viable myocardium in TAVR population were associated with increased risk of death. Additional research is needed to evaluate the prognostic significance of CTO lesions in TAVR patients.

IntroductionHead and neck squamous cell carcinoma (HNSCC) patients suffer from frequent local recurrences that negatively impact on prognosis. Hence, distinguishing tumor and normal tissue is of clinical importance as it may improve the detection of residual tumor tissue in surgical resection margins and during imaging-based surgery planning. Differences in O2 consumption (OC) can be used to this aim, as they provide options for improved surgical, image-guided approaches.MethodsIn the present study, the potential of a fluorescent sensor foil-based technology to quantify OC in HNSCC was evaluated in an in vitro 3D model and in situ in patients. ResultsIn vitro measurements of OC using hypopharyngeal and esophageal cell lines allowed a specific detection of tumor cell spheroids embedded together with cancer-associated fibroblasts in type I collagen extracellular matrix down to a diameter of 440 µm. Pre-surgery in situ measurements were conducted with a handheld recording device and sensor foils with an oxygen permeable membrane and immobilized O2-reactive fluorescent dyes. Lateral tongue carcinoma and carcinoma of the floor of the mouth were chosen for analysis owing to their facilitated accessibility. OC was evaluated over a time span of 60 seconds and was significantly higher in tumor tissue compared to healthy mucosa in the vicinity of the tumor.DiscussionHence, OC quantification using fluorescent sensor foil-based technology is a relevant parameter for the differentiation of tumor tissue of the head and neck region and may support surgery planning.

IntroductionThe genotype of symptomatic left ventricular noncompaction phenotype (LVNC) subjects with preserved left ventricular ejection fraction (LVEF) and its effect on clinical presentation are less well studied. We aimed to characterize the genetic, cardiac magnetic resonance (CMR) and clinical background, and genotype-phenotype relationship in LVNC with preserved LVEF.MethodsWe included 54 symptomatic LVNC individuals (LVEF: 65 ± 5%) whose samples were analyzed with a 174-gene next-generation sequencing panel and 54 control (C) subjects. The results were evaluated using the criteria of the American College of Medical Genetics and Genomics. Medical data suggesting a higher risk of cardiovascular complications were considered “red flags”.ResultsOf the LVNC population, 24% carried pathogenic or likely pathogenic (P) mutations; 56% carried variants of uncertain significance (VUS); and 20% were free from cardiomyopathy-related mutations. Regarding the CMR parameters, the LVNC and C groups differed significantly, while the three genetic subgroups were comparable. We found a significant relationship between red flags and genotype; furthermore, the number of red flags in a single subject differed significantly among the genetic subgroups (p = 0.002) and correlated with the genotype (r = 0.457, p = 0.01). In 6 out of 7 LVNC subjects diagnosed in childhood, P or VUS mutations were found.DiscussionThe large number of P mutations and the association between red flags and genotype underline the importance of genetic-assisted risk stratification in symptomatic LVNC with preserved LVEF.

BackgroundHelicobacter pylori (H. pylori) uses various strategies that attenuate mucosal immunity to ensure its persistence in the stomach. We recently found evidence that H. pylori might modulate the natural killer group 2, member 2 (NKG2D) system. The NKG2D receptor and its ligands are a major activation system of natural killer and cytotoxic T cells, which are important for mucosal immunity and tumor immunosurveillance. The NKG2D system allows recognition and elimination of infected and transformed cells, however viruses and cancers often subvert its activation. Here we aimed to identify a potential evasion of the NKG2D system in H. pylori infection.MethodsWe analyzed expression of NKG2D system genes in gastric tissues of H. pylori gastritis and gastric cancer patients, and performed cell-culture based infection experiments using H. pylori isogenic mutants and epithelial and NK cell lines.ResultsIn biopsies of H. pylori gastritis patients, NKG2D receptor expression was reduced while NKG2D ligands accumulated in the lamina propria, suggesting NKG2D evasion. In vitro, H. pylori induced the transcription and proteolytic shedding of NKG2D ligands in stomach epithelial cells, and these effects were associated with specific H. pylori virulence factors. The H. pylori-driven release of soluble NKG2D ligands reduced the immunogenic visibility of infected cells and attenuated the cytotoxic activity of effector immune cells, specifically the anti-tumor activity of NK cells.ConclusionH. pylori manipulates the NKG2D system. This so far unrecognized strategy of immune evasion by H. pylori could potentially facilitate chronic bacterial persistence and might also promote stomach cancer development by allowing transformed cells to escape immune recognition and grow unimpeded to overt malignancy.

Network visualization is one of the most widely used tools in digital humanities research. The idea of uncertain or “fuzzy” data is also a core notion in digital humanities research. Yet network visualizations in digital humanities do not always prominently represent uncertainty. In this article, we present a mathematical and logical model of uncertainty as a range of values which can be used in network visualizations. We review some of the principles for visualizing uncertainty of different kinds, visual variables that can be used for representing uncertainty, and how these variables have been used to represent different data types in visualizations drawn from a range of non-humanities fields like climate science and bioinformatics. We then provide examples of two diagrams: one in which the variables displaying degrees of uncertainty are integrated/pinto the graph and one in which glyphs are added to represent data certainty and uncertainty. Finally, we discuss how probabilistic data and what-if scenarios could be used to expand the representation of uncertainty in humanities network visualizations.

Electrochemotherapy is a novel, locoregional therapy that is used to treat cutaneous and deep-seated tumors. The electric pulses used in electrochemotherapy increase the permeability of the cell membranes of the target lesion and thus enhance the delivery of low-permeant cytotoxic drugs to the cells, leading to their death. It has also been postulated that electrochemotherapy acts as an in situ vaccination by inducing immunogenic cell death. This in turn leads to an enhanced systemic antitumor response, which could be further exploited by immunotherapy. However, only a few clinical studies have investigated the role of combined treatment in patients with melanoma, breast cancer, hepatocellular carcinoma, and cutaneous squamous cell carcinoma. In this review, we therefore aim to review the published preclinical evidence on combined treatment and to review clinical studies that have investigated the combined role of electrochemotherapy and immunotherapy.

BackgroundData are lacking on the effects of the alternation of P2Y12 receptor antagonists (P2Y12) on bleeding and outcome in patients with myocardial infarction (MI) with cardiogenic shock (CS). We compared the effects of different P2Y12 and alternation of P2Y12 (combination) on bleeding and outcome in patients with MI and CS.MethodsData from 247 patients divided into four groups: clopidogrel, ticagrelor, prasugrel, and the combination group, were analyzed. The association between P2Y12 and bleeding as well as 30-day and one-year mortality was examined.ResultsThe highest bleeding rate was observed in patients in the combination group, followed by the clopidogrel, ticagrelor, and prasugrel groups [12(50%) patients, 22(28.2%), 21(18.3%) and 4(13.3%), respectively; p = 0.003]. Bleeding occurred with a similar frequency in the combination and clopidogrel groups (p = 0.081), but more frequently than in the ticagrelor and prasugrel groups (p = 0.002 and p = 0.006, respectively). Bleeding rates were similar in patients receiving P2Y12 alone (p = 0.13). Compared to clopidogrel, both ticagrelor and prasugrel had a lower bleeding risk (aOR: 0.40; 95% CI: 0.18–0.92; p = 0.032 and aOR: 0.20; 95% CI: 0.05–0.85; p = 0.029, respectively) and the combination had a similar bleeding risk (aOR: 2.31; 95% CI: 0.71–7.48; p = 0.16). The ticagrelor and prasugrel groups had more than an 80% and 90% lower bleeding risk than the combination group (aOR: 0.17; 95% CI: 0.06–0.55; p = 0.003 and aOR: 0.09; 95% CI: 0.02–0.44; p = 0.003, respectively). The unadjusted 30-day and one-year mortality were highest in the clopidogrel group, followed by the ticagrelor, prasugrel, and combination groups (44(56.4%) and 55(70.5%) patients died in the clopidogrel group, 53(46.1%) and 56(48.7%) in the ticagrelor group, 12(40%) and 14(46.7%) patients died in the prasugrel, and 6(25%) and 9(37.5%) patients died in the combination group; p = 0.045 and p