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Abstract Stroke, the second leading cause of mortality globally, predominantly results from ischemic conditions. Immediate attention and diagnosis, related to the characterization of brain lesions, play a crucial role in patient prognosis. Standard stroke protocols include an initial evaluation from a non-contrast CT to discriminate between hemorrhage and ischemia. However, non-contrast CTs lack sensitivity in detecting subtle ischemic changes in this phase. Alternatively, diffusion-weighted MRI studies provide enhanced capabilities, yet are constrained by limited availability and higher costs. Hence, we idealize new approaches that integrate ADC stroke lesion findings into CT, to enhance the analysis and accelerate stroke patient management. This study details a public challenge where scientists applied top computational strategies to delineate stroke lesions on CT scans, utilizing paired ADC information. Also, it constitutes the first effort to build a paired dataset with NCCT and ADC studies of acute ischemic stroke patients. Submitted algorithms were validated with respect to the references of two expert radiologists. The best achieved Dice score was 0.2 over a test study with 36 patient studies. Despite all the teams employing specialized deep learning tools, results reveal limitations of computational approaches to support the segmentation of small lesions with heterogeneous density.

Abstract Background Mirror movements (MM) are commonly caused by a defect of interhemispheric pathways also affected in multiple sclerosis (MS), particularly the corpus callosum. We investigated the prevalence of MM in MS in relation to functional and morphological callosal fiber integrity by transcranial magnetic stimulation (TMS), magnetic resonance imaging (MRI), as well as fatigue. Methods In 21 patients with relapsing–remitting MS and 19 healthy controls, MM were assessed and graded (Woods and Teuber scale: MM 1—4) using a bedside test. Fatigue was evaluated using the Fatigue Scale for Motor and Cognitive Functions (FSMC) questionnaire. TMS measured ipsilateral silent period latency and duration. MRI assessed callosal atrophy by measuring the normalized corpus callosum area (nCCA), corpus callosum index (CCI), and lesion volume. Results MS patients had significantly more often and pronounced MM compared to healthy controls (p = 0.0002) and nCCA was significantly lower (p = 0.045) in MRI studies. Patients with higher MM scores (MM > 1 vs. MM 0/1) showed significantly more fatigue (higher FSMC sum score, p = 0.04, motor score, p = 0.01). In TMS and MRI studies, no significant differences were found between patients with MM 0/1 and those with MM > 1 (ipsilateral silent period measurements, CCA, CCI and lesion volume). Conclusions MM are common in MS and can easily be detected through bedside testing. As MM are associated with fatigue, they might indicate fatigue in MS. It is possible that other cerebral structures, in addition to the corpus callosum, may contribute to the origin of MM in MS.

Abstract 2023 was the warmest year on record, influenced by multiple warm ocean basins. This has prompted speculation of an acceleration in surface warming, or a stronger than expected influence from loss of aerosol induced cooling. Here we use a recent Green’s function-based method to quantify the influence of sea surface temperature patterns on the 2023 global temperature anomaly, and compare them to previous record warm years. We show that the strong deviation from recent warming trends is consistent with previously observed sea surface temperature influences, and regional forcing. This indicates that internal variability was a strong contributor to the exceptional 2023 temperature evolution, in combination with steady anthropogenic global warming.

Abstract Background To investigate the reproducibility of automated volumetric bone mineral density (vBMD) measurements from routine thoracoabdominal computed tomography (CT) assessed with segmentations by a convolutional neural network and automated correction of contrast phases, on diverse scanners, with scanner-specific asynchronous or scanner-agnostic calibrations. Methods We obtained 679 observations from 278 CT scans in 121 patients (77 males, 63.6%) studied from 04/2019 to 06/2020. Observations consisted of two vBMD measurements from Δdifferent reconstruction kernels (n = 169), Δcontrast phases (n = 133), scan Δsessions (n = 123), Δscanners (n = 63), or Δall of the aforementioned (n = 20), and observations lacking scanner-specific calibration (n = 171). Precision was assessed using root-mean-square error (RMSE) and root-mean-square coefficient of variation (RMSCV). Cross-measurement agreement was assessed using Bland-Altman plots; outliers within 95% confidence interval of the limits of agreement were reviewed. Results Repeated measurements from Δdifferent reconstruction kernels were highly precise (RMSE 3.0 mg/cm3; RMSCV 1.3%), even for consecutive scans with different Δcontrast phases (RMSCV 2.9%). Measurements from different Δscan sessions or Δscanners showed decreased precision (RMSCV 4.7% and 4.9%, respectively). Plot-review identified 12 outliers from different scan Δsessions, with signs of hydropic decompensation. Observations with Δall differences showed decreased precision compared to those lacking scanner-specific calibration (RMSCV 5.9 and 3.7, respectively). Conclusion Automatic vBMD assessment from routine CT is precise across varying setups, when calibrated appropriately. Low precision was found in patients with signs of new or worsening hydropic decompensation, what should be considered an exclusion criterion for both opportunistic and dedicated quantitative CT. Relevance statement Automated CT-based vBMD measurements are precise in various scenarios, including cross-session and cross-scanner settings, and may therefore facilitate opportunistic screening for osteoporosis and surveillance of BMD in patients undergoing routine clinical CT scans. Key Points Artificial intelligence-based tools facilitate BMD measurements in routine clinical CT datasets. Automated BMD measurements are highly reproducible in various settings. Reliable, automated opportunistic osteoporosis diagnostics allow for large-scale application. Graphical Abstract

Abstract α-Synuclein (α-syn) accumulates as insoluble amyloid but also forms soluble α-syn oligomers (αSOs), thought to be even more cytotoxic than fibrils. To detect and block the unwanted activities of these αSOs, we have raised 30 monoclonal antibodies (mAbs) against different forms of αSOs, ranging from unmodified αSOs to species stabilized by lipid peroxidation products and polyphenols, αSOs formed by C-terminally truncated α-syn, and multivalent display of α-syn on capsid virus-like particles (cVLPs). While the mAbs generally show a preference for αSOs, they also bind fibrils, but to variable extents. Overall, we observe great diversity in the mAbs’ relative affinities for monomers and αSOs, varied requirements for the C-terminal extension of α-syn, and only a modest effect on α-syn fibrillation. Several mAbs show several orders of magnitude preference for αSOs over monomers in in-solution studies, while the commercial antibody MJF14 only bound 10-fold more strongly to αSOs than monomeric α-syn. Gratifyingly, seven mAbs almost completely block αSO permeabilization of membrane vesicles. Five selected mAbs identified α-syn-related pathologies like Lewy bodies (LBs) and Lewy Neurites, as well as Glial Cytoplasmic Inclusions in postmortem brains from people diagnosed for PD, dementia with LBs or multiple system atrophy, although to different extents. Three mAbs were particularly useful for pathological evaluation of postmortem brain human tissue, including early stages of PD. Although there was no straightforward connection between the mAbs’ biophysical and immunohistochemical properties, it is encouraging that this comprehensive collection of mAbs able to recognize different aggregated α-syn species in vitro also holds diagnostic potential.

Abstract Background A significant proportion of the global population has been infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at some point since the onset of the pandemic. Although most individuals who develop coronavirus disease 2019 (COVID-19) recover without complications, about 6% have persistent symptoms, referred to as post-COVID-19 condition (PCC). Intervention studies investigating treatments that potentially alleviate PCC-related symptoms and thus aim to mitigate the global public health burden and healthcare costs linked to PCC are desperately needed. The PYCNOVID trial investigates the effects of Pycnogenol®, a French maritime pine bark extract with anti-inflammatory and antioxidative properties, versus placebo on patient-reported health status in people with PCC. Methods This is a single-center, placebo-controlled, quadruple blind, randomized trial. We aim to randomly assign 150 individuals with PCC (1:1 ratio) to receive either 200 mg Pycnogenol® or placebo daily for 12 weeks. Randomization is stratified for duration of PCC symptoms (≤ 6 months versus > 6 months) and presence of symptomatic chronic disease(s). The primary endpoint is perceived health status at 12 weeks (EuroQol—Visual Analogue Scale) adjusted for baseline values and stratification factors. Secondary endpoints include change in self-reported PCC symptoms, health-related quality of life, symptoms of depression and anxiety, cognitive function, functional exercise capacity, physical activity measured with accelerometry, and blood biomarkers for endothelial health, inflammation, coagulation, platelet function, and oxidative stress. Investigators, study participants, outcome assessors, and data analysts are blinded regarding the intervention assignment. Individuals with PCC were involved in the design of this study. Discussion This is the first trial to investigate the effects of Pycnogenol® versus placebo on patient-reported health status in people with PCC. Should the trial proof clinical effectiveness, Pycnogenol® may serve as a therapeutic approach to mitigate symptoms associated with PCC. Trial registration The study is registered at ClinicalTrials.gov. :NCT05890534, June 6, 2023.

Abstract Background Fecal microbiota transplantation (FMT) is increasingly used for gastrointestinal and extra‐gastrointestinal diseases in veterinary medicine. However, its effects on immune responses and possible adverse events have not been systematically investigated. Hypothesis/Objectives Determine the short‐term safety profile and changes in the peripheral immune system after a single FMT administration in healthy dogs. Animals Ten client‐owned, clinically healthy dogs as FMT recipients, and 2 client‐owned clinically healthy dogs as FMT donors. Methods Prospective non‐randomized clinical trial. A single rectal enema of 5 g/kg was given to clinically healthy canine recipients. During the 28 days after FMT administration, owners self‐reported adverse events and fecal scores. On Days 0 (baseline), 1, 4, 10, and 28 after FMT, fecal and blood samples were collected. The canine fecal dysbiosis index (DI) was calculated using qPCR. Results No significant changes were found in the following variables: CBC, serum biochemistry, C‐reactive protein, serum cytokines (interleukins [IL]‐2, ‐6, ‐8, tumor necrosis factor [TNF]‐α), peripheral leukocytes (B cells, T cells, cluster of differentiation [CD]4+ T cells, CD8+ T cells, T regulatory cells), and the canine DI. Mild vomiting (n = 3), diarrhea (n = 4), decreased activity (n = 2), and inappetence (n = 1) were reported, and resolved without intervention. Conclusions and Clinical Importance Fecal microbiota transplantation did not significantly alter the evaluated variables and recipients experienced minimal adverse events associated with FMT administration. Fecal microbiota transplantation was not associated with serious adverse events, changes in peripheral immunologic variables, or the canine DI in the short‐term.

Abstract (301 words): Introduction: The effects of low energy availability (LEA) on the immune system are poorly understood. This study examined the effects of 14 days of LEA on immune cell redox balance and inflammation at rest and in response to acute exercise, and exercise performance in female athletes. Methods: Twelve female endurance athletes (age: 26.8 ± 3.4 yrs, maximum oxygen uptake (V˙O2max): 55.2 ± 5.1 mL × min−1 × kg−1) were included in a randomized, single-blinded crossover study. They were allocated to begin with either 14 days of optimal energy availability diet (OEA, 52 ± 2 kcal × kg fat free mass (FFM)−1 × day−1) or LEA diet (22 ± 2 kcal × kg FFM−1 × day−1), followed by 3 days of refueling (OEA) with maintained training volume. Peripheral blood mononuclear cells (PBMCs) were isolated, and plasma obtained at rest before and after each dietary period. The PBMCs were used for analysis of mitochondrial respiration and H2O2 emission and specific proteins. Exercise performance was assessed on cycle by a 20-min time trial and time to exhaustion at an intensity corresponding to ∼110 % V˙O2max). Results: LEA was associated with a 94 % (P = 0.003) increase in PBMC NADPH oxidase 2 protein content, and a 22 % (P = 0.013) increase in systemic cortisol. LEA also caused an alteration of several inflammatory related proteins (P

Abstract Chronic enteropathies (CE) are common disorders in cats and the differentiation between the two main underlying diseases, inflammatory bowel disease (IBD) and low-grade intestinal T-cell lymphoma (LGITL), can be challenging. Characterization of the serum metabolome could provide further information on alterations of disease-associated metabolic pathways and may identify diagnostic or therapeutic targets. Unbiased metabolomics analysis of serum from 28 cats with CE (14 cats with IBD, 14 cats with LGITL) and 14 healthy controls identified 1,007 named metabolites, of which 129 were significantly different in cats with CE compared to healthy controls at baseline. Random Forest analysis revealed a predictive accuracy of 90% for differentiating controls from cats with chronic enteropathy. Metabolic pathways found to be significantly altered included phospholipids, amino acids, thiamine, and tryptophan metabolism. Several metabolites were found to be significantly different between cats with IBD versus LGITL, including several sphingolipids, phosphatidylcholine 40:7, uridine, pinitol, 3,4-dihydroxybenzoic acid, and glucuronic acid. However, random forest analysis revealed a poor group predictive accuracy of 60% for the differentiation of IBD from LGITL. Of 129 compounds found to be significantly different between healthy cats and cats with CE at baseline, 58 remained different following treatment.

Abstract Introduction In Multiple Sclerosis (MS), patients´ characteristics and (bio)markers that reliably predict the individual disease prognosis at disease onset are lacking. Cohort studies allow a close follow-up of MS histories and a thorough phenotyping of patients. Therefore, a multicenter cohort study was initiated to implement a wide spectrum of data and (bio)markers in newly diagnosed patients. Methods ProVal-MS (Prospective study to validate a multidimensional decision score that predicts treatment outcome at 24 months in untreated patients with clinically isolated syndrome or early Relapsing–Remitting-MS) is a prospective cohort study in patients with clinically isolated syndrome (CIS) or Relapsing–Remitting (RR)-MS (McDonald 2017 criteria), diagnosed within the last two years, conducted at five academic centers in Southern Germany. The collection of clinical, laboratory, imaging, and paraclinical data as well as biosamples is harmonized across centers. The primary goal is to validate (discrimination and calibration) the previously published DIFUTURE MS-Treatment Decision score (MS-TDS). The score supports clinical decision-making regarding the options of early (within 6 months after study baseline) platform medication (Interferon beta, glatiramer acetate, dimethyl/diroximel fumarate, teriflunomide), or no immediate treatment (> 6 months after baseline) of patients with early RR-MS and CIS by predicting the probability of new or enlarging lesions in cerebral magnetic resonance images (MRIs) between 6 and 24 months. Further objectives are refining the MS-TDS score and providing data to identify new markers reflecting disease course and severity. The project also provides a technical evaluation of the ProVal-MS cohort within the IT-infrastructure of the DIFUTURE consortium (Data Integration for Future Medicine) and assesses the efficacy of the data sharing techniques developed. Perspective Clinical cohorts provide the infrastructure to discover and to validate relevant disease-specific findings. A successful validation of the MS-TDS will add a new clinical decision tool to the armamentarium of practicing MS neurologists from which newly diagnosed MS patients may take advantage. Trial registration ProVal-MS has been registered in the German Clinical Trials Register, `Deutsches Register Klinischer Studien` (DRKS)—ID: DRKS00014034, date of registration: 21 December 2018; https://drks.de/search/en/trial/DRKS00014034

Abstract Despite the extensive knowledge about the effects of chronic stress on cognition, the underlying mechanisms remain unclear. We conducted a cross-sectional moderation analysis on a population-based sample of 596 adults to examine the age- and sex-specific role of emotion regulation (ER) in the relationship between chronic stress and cognitive performance using validated self-report questionnaires. While women showed no direct or moderated relationship between stress and cognition, men displayed a distinct age-related pattern where stress was negatively associated with poorer cognitive performance at older ages, and the onset of this relationship was detected earlier in men with ER problems. These results showed that suppression of emotions and lack of executive control of ER amplify the negative consequences of chronic stress and suggest that there are sex-specific differences in the decline of ability to cope with long-term exposure to stressors.

Abstract Background A deep learning (DL) model that automatically detects cardiac pathologies on cardiac MRI may help streamline the diagnostic workflow. To develop a DL model to detect cardiac pathologies on cardiac MRI T1-mapping and late gadolinium phase sensitive inversion recovery (PSIR) sequences were used. Methods Subjects in this study were either diagnosed with cardiac pathology (n = 137) including acute and chronic myocardial infarction, myocarditis, dilated cardiomyopathy, and hypertrophic cardiomyopathy or classified as normal (n = 63). Cardiac MR imaging included T1-mapping and PSIR sequences. Subjects were split 65/15/20% for training, validation, and hold-out testing. The DL models were based on an ImageNet pretrained DenseNet-161 and implemented using PyTorch and fastai. Data augmentation with random rotation and mixup was applied. Categorical cross entropy was used as the loss function with a cyclic learning rate (1e-3). DL models for both sequences were developed separately using similar training parameters. The final model was chosen based on its performance on the validation set. Gradient-weighted class activation maps (Grad-CAMs) visualized the decision-making process of the DL model. Results The DL model achieved a sensitivity, specificity, and accuracy of 100%, 38%, and 88% on PSIR images and 78%, 54%, and 70% on T1-mapping images. Grad-CAMs demonstrated that the DL model focused its attention on myocardium and cardiac pathology when evaluating MR images. Conclusions The developed DL models were able to reliably detect cardiac pathologies on cardiac MR images. The diagnostic performance of T1 mapping alone is particularly of note since it does not require a contrast agent and can be acquired quickly.

Abstract Scenarios have been an important integrating element in the Sixth Assessment Report (AR6) of the Intergovernmental Panel on Climate Change (IPCC) in the understanding of possible climate outcomes, impacts and risks, and mitigation futures. Integration supports a consistent, coherent assessment, new insights and the opportunity to address policy-relevant questions that would not be possible otherwise, for example, which impacts are unavoidable, which are reversible, what is a consistent remaining carbon budget to keep temperatures below a level and what would be a consistent route of action to achieve that goal. The AR6 builds on community frameworks that are developed to support a coherent use of scenarios across the assessment, yet their use in the assessment and the related timelines presented coordination challenges. From lessons within each Working Group (WG) assessment and the cross-WG experience, we present insights into the role of scenarios in future assessments, including the enhanced integration of impacts into scenarios, near-term information and community coordination efforts. Recommendations and opportunities are discussed for how scenarios can support strengthened consistency and policy relevance in the next IPCC assessment cycle.

Abstract Maintenance metabolism as the minimum energy expenditure needed to maintain homeothermy (a high and stable body temperature, Tb), reflects the magnitude of metabolic machinery and the associated costs of self‐maintenance in endotherms (organisms able to produce heat endogenously). Therefore, it can interact with most, if not all, organismal functions, including the behavior–fitness linkage. Many endothermic animals can avoid the costs of maintaining homeothermy and temporally reduce Tb and metabolism by entering heterothermic states like torpor, the most effective energy‐saving strategy. Variations in BMR, behavior, and torpor use are considered to be shaped by food resources, but those conclusions are based on research studying these traits in isolation. We tested the effect of ecological contexts (food availability and predation risk) on the interplay between the maintenance costs of homeothermy, heterothermy, and exploration in a wild mammal—the yellow‐necked mouse. We measured maintenance metabolism as basal metabolic rate (BMR) using respirometry, distance moved (exploration) in the open‐field test, and variation in Tb (heterothermy) during short‐term fasting in animals captured at different locations of known natural food availability and predator presence, and with or without supplementary food resources. We found that in winter, heterothermy and exploration (but not BMR) negatively correlated with natural food availability (determined in autumn). Supplementary feeding increased mouse density, predation risk and finally had a positive effect on heterothermy (but not on BMR or exploration). The path analysis testing plausible causal relationships between the studied traits indicated that elevated predation risk increased heterothermy, which in turn negatively affected exploration, which positively correlated with BMR. Our study indicates that adaptive heterothermy is a compensation strategy for balancing the energy budget in endothermic animals experiencing low natural food availability. This study also suggests that under environmental challenges like increased predation risk, the use of an effective energy‐saving strategy predicts behavioral expression better than self‐maintenance costs under homeothermy.

IntroductionAnxiety and cognitive dysfunction are frequent, difficult to treat and burdensome comorbidities in human and canine epilepsy. Fecal microbiota transplantation (FMT) has been shown to modulate behavior in rodent models by altering the gastrointestinal microbiota (GIM). This study aims to investigate the beneficial effects of FMT on behavioral comorbidities in a canine translational model of epilepsy.MethodsNine dogs with drug-resistant epilepsy (DRE) and behavioral comorbidities were recruited. The fecal donor had epilepsy with unremarkable behavior, which exhibited a complete response to phenobarbital, resulting in it being seizure-free long term. FMTs were performed three times, two weeks apart, and the dogs had follow-up visits at three and six months after FMTs. Comprehensive behavioral analysis, including formerly validated questionnaires and behavioral tests for attention deficit hyperactivity disorder (ADHD)- and fear- and anxiety-like behavior, as well as cognitive dysfunction, were conducted, followed by objective computational analysis. Blood samples were taken for the analysis of antiseizure drug (ASD) concentrations, hematology, and biochemistry. Urine neurotransmitter concentrations were measured. Fecal samples were subjected to analysis using shallow DNA shotgun sequencing, real-time polymerase chain reaction (qPCR)-based Dysbiosis Index (DI) assessment, and short-chain fatty acid (SCFA) quantification.ResultsFollowing FMT, the patients showed improvement in ADHD-like behavior, fear- and anxiety-like behavior, and quality of life. The excitatory neurotransmitters aspartate and glutamate were decreased, while the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and GABA/glutamate ratio were increased compared to baseline. Only minor taxonomic changes were observed, with a decrease in Firmicutes and a Blautia_A species, while a Ruminococcus species increased. Functional gene analysis, SCFA concentration, blood parameters, and ASD concentrations remained unchanged.DiscussionBehavioral comorbidities in canine IE could be alleviated by FMT. This study highlights FMT’s potential as a novel approach to improving behavioral comorbidities and enhancing the quality of life in canine patients with epilepsy.

Feline chronic enteropathies (FCE) are common causes of chronic gastrointestinal signs in cats and include different diseases such as food-responsive enteropathy (FRE), inflammatory bowel diseases (IBD), and low-grade intestinal T-cell lymphoma (LGITL). Although changes in intestinal microbiota and fecal metabolites have been reported in dogs and humans with chronic enteropathy, research in cats has been limited. Therefore, this study aimed to evaluate the fecal microbiota and lipid-related fecal metabolites in cats with FCE to a clinically healthy comparison group (CG). A total of 34 cats with FCE (13 FRE, 15 IBD, and 6 LGITL) and 27 cats in the CG were enrolled in this study. The fecal microbiota was evaluated by the qPCR-based feline Dysbiosis Index (DI). The feline DI in cats with CE (median: 1.3, range: −2.4 to 3.8) was significantly higher (p

Introduction: Achieving an adequate level of detail is a crucial part of any modeling process. Thus, oversimplification of complex systems can lead to overestimation, underestimation, and general bias of effects, while elaborate models run the risk of losing validity due to the uncontrolled interaction of multiple influencing factors and error propagation.Methods: We used a validated pipeline for the automated generation of multi-body models of the trunk to create 279 models based on CT data from 93 patients to investigate how different degrees of individualization affect the observed effects of different morphological characteristics on lumbar loads. Specifically, individual parameters related to spinal morphology (thoracic kyphosis (TK), lumbar lordosis (LL), and torso height (TH)), as well as torso weight (TW) and distribution, were fully or partly considered in the respective models according to their degree of individualization, and the effect strengths of these parameters on spinal loading were compared between semi- and highly individualized models. T-distributed stochastic neighbor embedding (T-SNE) analysis was performed for overarching pattern recognition and multiple regression analyses to evaluate changes in occurring effects and significance.Results: We were able to identify significant effects (p < 0.05) of various morphological parameters on lumbar loads in models with different degrees of individualization. Torso weight and lumbar lordosis showed the strongest effects on compression (β ≈ 0.9) and anterior–posterior shear forces (β ≈ 0.7), respectively. We could further show that the effect strength of individual parameters tended to decrease if more individual characteristics were included in the models.Discussion: The induced variability due to model individualization could only partly be explained by simple morphological parameters. Our study shows that model simplification can lead to an emphasis on individual effects, which needs to be critically assessed with regard to in vivo complexity. At the same time, we demonstrated that individualized models representing a population-based cohort are still able to identify relevant influences on spinal loading while considering a variety of influencing factors and their interactions.

Introduction: Numerical modeling of the intervertebral disc (IVD) is challenging due to its complex and heterogeneous structure, requiring careful selection of constitutive models and material properties. A critical aspect of such modeling is the representation of annulus fibers, which significantly impact IVD biomechanics. This study presents a comparative analysis of different methods for fiber reinforcement in the annulus fibrosus of a finite element (FE) model of the human IVD.Methods: We utilized a reconstructed L4-L5 IVD geometry to compare three fiber modeling approaches: the anisotropic Holzapfel-Gasser-Ogden (HGO) model (HGO fiber model) and two sets of structural rebar elements with linear-elastic (linear rebar model) and hyperelastic (nonlinear rebar model) material definitions, respectively. Prior to calibration, we conducted a sensitivity analysis to identify the most important model parameters to be calibrated and improve the efficiency of the calibration. Calibration was performed using a genetic algorithm and in vitro range of motion (RoM) data from a published study with eight specimens tested under four loading scenarios. For validation, intradiscal pressure (IDP) measurements from the same study were used, along with additional RoM data from a separate publication involving five specimens subjected to four different loading conditions.Results: The sensitivity analysis revealed that most parameters, except for the Poisson ratio of the annulus fibers and C01 from the nucleus, significantly affected the RoM and IDP outcomes. Upon calibration, the HGO fiber model demonstrated the highest accuracy (R2 = 0.95), followed by the linear (R2 = 0.89) and nonlinear rebar models (R2 = 0.87). During the validation phase, the HGO fiber model maintained its high accuracy (RoM R2 = 0.85; IDP R2 = 0.87), while the linear and nonlinear rebar models had lower validation scores (RoM R2 = 0.71 and 0.69; IDP R2 = 0.86 and 0.8, respectively).Discussion: The results of the study demonstrate a successful calibration process that established good agreement with experimental data. Based on our findings, the HGO fiber model appears to be a more suitable option for accurate IVD FE modeling considering its higher fidelity in simulation results and computational efficiency.

BackgroundProtein phosphatase 2A (PP2A) is a serine/threonine-selective holoenzyme that controls Ca2+ homeostasis and contractility of the heart via dephosphorylation of regulatory proteins. In some genetically modified mouse models with increased arrhythmogenicity, a reduced expression of the regulatory subunit B56α of PP2A was found as a concomitant effect. Whether there is a general correlation between the abundance of B56α and the promotion of cardiac arrhythmogenesis remains unclear.MethodsThe aim of this study was therefore to investigate the role of PP2A-B56α in the propensity for arrhythmic activity in the heart. The experimental analysis of this question has been addressed by using a mouse model with deletion of the PP2A-B56α gene, PPP2R5A (KO), in comparison to wild-type animals (WT). Evidence for arrhythmogenicity was investigated in whole animal, isolated heart and cardiomyocytes by ECG, recording of monophasic action potential (MAP) induced by programmed electrical stimulation (PES), measurement of Ca2+ transients under increased pacing frequencies and determination of total K+ channel currents (IK).ResultsECG measurements showed a prolongation of QT time in KO vs. WT. KO mice exhibited a higher rate of premature ventricular contractions in the ECG. MAP measurements in Langendorff-perfused KO hearts showed increased episodes of ventricular tachyarrhythmia induced by PES. However, the KO hearts showed values for MAP duration that were similar to those in WT hearts. In contrast, KO showed more myocardial cells with spontaneous arrhythmogenic Ca2+ transient events compared to WT. The whole-cell patch-clamp technique applied to ventricular cardiomyocytes revealed comparable peak potassium channel current densities between KO and WT.ConclusionThese findings support the assumption that a decrease or even the loss of PP2A-B56α leads to an increased propensity of triggered arrhythmias. This could be based on the increased spontaneous Ca2+ tansients observed.

ObjectiveEndovascular thrombectomy (EVT) is the standard of care for acute large vessel occlusion stroke. Recently, the ANGEL-ASPECT and SELECT 2 trials showed improved outcomes in patients with acute ischemic Stroke presenting with large infarcts. The cost-effectiveness of EVT for this subpopulation of stroke patients has only been calculated using data from the previously published RESCUE-Japan LIMIT trial. It is, therefore, limited in its generalizability to an international population. With this study we primarily simulated patient-level costs to analyze the economic potential of EVT for patients with large ischemic stroke from a public health payer perspective based on the recently published data and secondarily identified determinants of cost-effectiveness.MethodsCosts and outcome of patients treated with EVT or only with the best medical care based on the recent prospective clinical trials ANGEL-ASPECT, SELECT2 and RESCUE-Japan LIMIT. A A Markov model was developed using treamtment outcomes derived from the most recent available literature. Deterministic and probabilistic sensitivity analyses addressed uncertainty.ResultsEndovascular treatment resulted in an incremental gain of 1.32 QALYs per procedure with cost savings of $17,318 per patient. Lifetime costs resulted to be most sensitive to the costs of the endovascular procedure.ConclusionEVT is a cost-saving (i.e., dominant) strategy for patients presenting with large ischemic cores defined by inclusion criteria of the recently published ANGEL-ASPECT, SELECT2, and RESCUE-Japan LIMIT trials in comparison to best medical care in our simulation. Prospective data of individual patients need to be collected to validate these results.

Abstract Background Evidence from many parts of the world shows that sexual and gender minority (SGM) people have poorer health than their cisgender heterosexual counterparts. Minority stressors, particularly stigma and discrimination, have been identified as major contributors to sexual orientation- and gender identity-related health disparities, particularly negative mental health and behavioral health outcomes. To better understand factors that contribute to these disparities, we conducted a scoping review of SGM mental health and substance use research in the Netherlands—a country with a long-standing reputation as a pioneer in SGM equality. Methods Using Joanna Briggs Institute guidelines and the PRISMA-ScR protocol, we searched seven databases to identify studies published between 2010 and 2022 that focused on substance use and/or mental health of SGM youth and adults in the Netherlands. Results Although there was some evidence that SGM people in the Netherlands report fewer substance use and mental health concerns than those in less progressive countries, with very few exceptions studies found poorer outcomes among SGM participants than cisgender, heterosexual participants. However, this observation must be considered cautiously given major gaps in the literature. For example, only one study focused exclusively on adult sexual minority women, two focused on older SGM adults, and very little attention was given to nonbinary individuals. Most studies used non-probability samples that were quite homogenous. Many studies, especially those with youth, assessed sexual orientation based on sexual attraction; some studies of adults operationalized SGM status as having a same-sex partner. Importantly, we found no studies that directly assessed associations between structural-level stigma and health outcomes. Studies were mostly focused at the individual level and on health problems; very little attention was given to strengths or resilience. Conclusions Findings of persistent health disparities—despite the relatively long history of SGM supportive policies in the Netherlands—highlight the need for more research and greater attention to population groups that have been underrepresented. Such research would not only provide guidance on strategies to improve the health of SGM people in the Netherlands, but also in other countries that are seeking to reduce health inequities. Addressing SGM health disparities in the Netherlands and elsewhere is complex and requires a multifaceted approach that addresses individual, interpersonal and structural factors.

Abstract Background Proton pump inhibitors can cause diarrhea and a transient increase in fecal dysbiosis index in dogs. It is unknown if concurrent probiotic administration mitigates these effects. Objective/Hypothesis To assess the fecal Canine Microbial Dysbiosis Index (CMDI), fecal short chain fatty acid (SCFA), and fecal calprotectin concentrations in dogs administered esomeprazole with and without a probiotic. Animals Eleven healthy dogs. Methods Prospective, within‐subjects before and after study. All dogs received 7‐day courses of esomeprazole (1 mg/kg PO q 24h) alone followed by esomeprazole with a probiotic (15 billion CFU/kg), separated by a 4‐week washout period. Data were compared between phases using mixed effects ANOVA or generalized estimating equations with post‐hoc Holm adjustment for 2‐way comparisons. Results Compared to baseline (mean CMDI −2.66, SD 3.04), fecal CMDI was not different with esomeprazole administration alone (mean CMDI −1.48, SD 3.32, P = .08), but there was a significant increase (Diff 3.05, 95% CI [1.37, 4.74], P

Heterothermy is considered to be the most effective energy-saving strategy improving survival under natural conditions. Interspecific studies suggest that this strategy is also associated with reduced reproductive output. Yet little is known about the reproductive consequences of heterothermy use at the intraspecific level and thus its repercussions for microevolutionary processes. Moreover, as yet no study has aimed to test if litter size and juvenile mass are affected by torpor use in wild captured animals under undemanding laboratory conditions. Here we tested the hypothesis that intraspecific variation in heterothermy use is associated with different reproductive successes, being the result of the evolution of distinct life histories. We predicted that heterothermy use in winter negatively correlates with litter size and juvenile body mass during the subsequent breeding season. To test this prediction, we used yellow-necked mice from a population in which individuals consistently differ in their use of heterothermy in winter. We measured body size (head width) and body mass, basal metabolic rate, as well as metabolism and body temperature during fasting-induced torpor in wild caught mice in winter. Phenotyped mice were bred in the subsequent summer selectively – males and females with similar heterothermy characteristics were paired, the most to the least heterothermic. Dam body size, but not basal metabolism, was positively correlated with litter size (but not juvenile mass). However, when accounting for this relationship, litter size was negatively while juvenile mass was positively correlated with the average heterothermy use of a given couple. Our study indicates that heterothermy use correlates with specific life-history strategies arising from a fundamental evolutionary trade-off between survival and reproduction.

ObjectivesTo quantitatively investigate the age- and sex-related longitudinal changes in trabecular volumetric bone mineral density (vBMD) and vertebral body volume at the thoracolumbar spine in adults.MethodsWe retrospectively included 168 adults (mean age 58.7 ± 9.8 years, 51 women) who received ≥7 MDCT scans over a period of ≥6.5 years (mean follow-up 9.0 ± 2.1 years) for clinical reasons. Level-wise vBMD and vertebral body volume were extracted from 22720 thoracolumbar vertebrae using a convolutional neural network (CNN)-based framework with asynchronous calibration and correction of the contrast media phase. Human readers conducted semiquantitative assessment of fracture status and bony degenerations.ResultsIn the 40-60 years age group, women had a significantly higher trabecular vBMD than men at all thoracolumbar levels (p

BackgroundPatients undergoing spinal surgery report high levels of insecurity, pain, stress, and anxiety before and after surgery. Unfortunately, there is no guarantee that surgery will resolve all issues; postsurgical recovery often entails moderate to severe postoperative pain, and some patients undergoing spinal surgery do not experience (long-term) pain relief after surgery. Therefore, focusing on sustainable coping skills and resilience is crucial for these patients. A digital health intervention based on acceptance and commitment therapy (ACT) and positive psychology (PP) was developed to enhance psychological flexibility and well-being and reduce postsurgical pain. ObjectiveThe objective of this study was 3-fold: to explore the potential benefits for patients undergoing spinal surgery of the digital ACT and PP intervention Strength Back (research question [RQ] 1), explore the feasibility of a future randomized controlled trial in terms of recruitment and dropout (RQ 2), and assess the acceptability of Strength Back by patients undergoing spinal surgery (RQ 3). MethodsWe used a nonrandomized experimental design with an intervention group (n=17) and a control group (n=20). To explore the potential benefits of the intervention, participants in both groups filled out questionnaires before and after surgery. These questionnaires included measurements of pain intensity (Numeric Pain Rating Scale), pain interference (Multidimensional Pain Inventory), anxiety and depression (Hospital Anxiety and Depression Scale), valued living (Engaged Living Scale), psychological flexibility (Psychological Inflexibility in Pain Scale), and mental well-being (Mental Health Continuum–Short Form). Semistructured interviews combined with log data and scores on the Twente Engagement With eHealth Technologies Scale were used to assess the acceptability of the intervention. ResultsA significant improvement over time in emotional (V=99; P=.03) and overall (V=55; P=.004) well-being (Mental Health Continuum–Short Form) was observed only in the intervention group. In addition, the intervention group showed a significantly larger decline in pain intensity (Numeric Pain Rating Scale) than did the control group (U=75; P=.003). Of the available weekly modules on average 80% (12/15) was completed by patients undergoing spinal fusion and 67% (6/9) was completed by patients undergoing decompression surgery. A total of 68% (17/25) of the participants used the intervention until the final interview. Most participants (15/17, 88%) in the intervention group would recommend the intervention to future patients. ConclusionsThis pilot feasibility study showed that combining ACT and PP in a digital health intervention is promising for patients undergoing spinal surgery as the content was accepted by most of the participants and (larger) improvements in pain intensity and well-being were observed in the intervention group. A digital intervention for patients undergoing (spinal) surgery can use teachable moments, when patients are open to learning more about the surgery and rehabilitation afterward. A larger randomized controlled trial is now warranted.

Summary: Background: Inflammatory demyelinating diseases of the central nervous system, such as multiple sclerosis, are significant sources of morbidity in young adults despite therapeutic advances. Current murine models of remyelination have limited applicability due to the low white matter content of their brains, which restricts the spatial resolution of diagnostic imaging. Large animal models might be more suitable but pose significant technological, ethical and logistical challenges. Methods: We induced targeted cerebral demyelinating lesions by serially repeated injections of lysophosphatidylcholine in the minipig brain. Lesions were amenable to follow-up using the same clinical imaging modalities (3T magnetic resonance imaging, 11C-PIB positron emission tomography) and standard histopathology protocols as for human diagnostics (myelin, glia and neuronal cell markers), as well as electron microscopy (EM), to compare against biopsy data from two patients. Findings: We demonstrate controlled, clinically unapparent, reversible and multimodally trackable brain white matter demyelination in a large animal model. De-/remyelination dynamics were slower than reported for rodent models and paralleled by a degree of secondary axonal pathology. Regression modelling of ultrastructural parameters (g-ratio, axon thickness) predicted EM features of cerebral de- and remyelination in human data. Interpretation: We validated our minipig model of demyelinating brain diseases by employing human diagnostic tools and comparing it with biopsy data from patients with cerebral demyelination. Funding: This work was supported by the DFG under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy, ID 390857198) and TRR 274/1 2020, 408885537 (projects B03 and Z01).

IntroductionAlterations in the composition and function of the gut microbiome have been reported in idiopathic epilepsy (IE), however, interactions of gut microbes with the enteric nervous system (ENS) in this context require further study. This pilot study examined how gastrointestinal microbiota (GIM), their metabolites, and nutrients contained in intestinal contents communicate with the ENS.MethodsFecal supernatants (FS) from healthy dogs and dogs with IE, including drug-naïve, phenobarbital (PB) responsive, and PB non-responsive dogs, were applied to cultured myenteric neurons to test their activation using voltage-sensitive dye neuroimaging. Additionally, the concentrations of short-chain fatty acids (SCFAs) in the FS were quantified.ResultsOur findings indicate that FS from all examined groups elicited neuronal activation. Notably, FS from PB non-responsive dogs with IE induced action potential discharge in a higher proportion of enteric neurons compared to healthy controls, which exhibited the lowest burst frequency overall. Furthermore, the highest burst frequency in enteric neurons was observed upon exposure to FS from drug-naïve dogs with IE. This frequency was significantly higher compared to that observed in PB non-responsive dogs with IE and showed a tendency to surpass that of healthy controls.DiscussionAlthough observed disparities in SCFA concentrations across the various FS samples might be associated with the induced neuronal activity, a direct correlation remains elusive at this point. The obtained results hint at an involvement of the ENS in canine IE and set the basis for future studies.

Abstract A genetic system, ProTracer, has been recently developed to record cell proliferation in vivo. However, the ProTracer is initiated by an infrequently used recombinase Dre, which limits its broad application for functional studies employing floxed gene alleles. Here we generated Cre-activated functional ProTracer (fProTracer) mice, which enable simultaneous recording of cell proliferation and tissue-specific gene deletion, facilitating broad functional analysis of cell proliferation by any Cre driver.

Abstract Background Contrast-enhancing (CE) lesions are an important finding on brain magnetic resonance imaging (MRI) in patients with multiple sclerosis (MS) but can be missed easily. Automated solutions for reliable CE lesion detection are emerging; however, independent validation of artificial intelligence (AI) tools in the clinical routine is still rare. Methods A three-dimensional convolutional neural network for CE lesion segmentation was trained externally on 1488 datasets of 934 MS patients from 81 scanners using concatenated information from FLAIR and T1-weighted post-contrast imaging. This externally trained model was tested on an independent dataset comprising 504 T1-weighted post-contrast and FLAIR image datasets of MS patients from clinical routine. Two neuroradiologists (R1, R2) labeled CE lesions for gold standard definition in the clinical test dataset. The algorithmic output was evaluated on both patient- and lesion-level. Results On a patient-level, recall, specificity, precision, and accuracy of the AI tool to predict patients with CE lesions were 0.75, 0.99, 0.91, and 0.96. The agreement between the AI tool and both readers was within the range of inter-rater agreement (Cohen’s kappa; AI vs. R1: 0.69; AI vs. R2: 0.76; R1 vs. R2: 0.76). On a lesion-level, false negative lesions were predominately found in infratentorial location, significantly smaller, and at lower contrast than true positive lesions (p

The usefulness of antibiotics in dogs with acute diarrhea (AD) is controversial. It is also unclear what effect metronidazole has on potential enteropathogens such as Clostridium perfringens and Escherichia coli. Thus, the aim of this study was to evaluate the effect of metronidazole vs. a synbiotic on the clinical course and core intestinal bacteria of dogs with AD. Twenty-seven dogs with AD were enrolled in this prospective, randomized, blinded clinical trial and treated with either metronidazole (METg) or a synbiotic (SYNg; E. faecium DSM 10663; NCIMB 10415/4b170). The Canine Acute Diarrhea Severity (CADS) index was recorded daily for eleven days. Bacteria were quantified using qPCR. Data were analyzed using mixed models with repeated measures. A higher concentration of E. coli was observed in the METg group vs. the SYNg group on Day 6 (p < 0.0001) and Day 30 (p = 0.01). Metronidazole had no effect on C. perfringens. C. hiranonis was significantly lower in the METg group than in the SYNg group on Days 6 and 30 (p < 0.0001; p = 0.0015). No significant differences were observed in CADS index, fecal consistency, or defecation frequency between treatment groups (except for the CADS index on one single day). In conclusion, metronidazole negatively impacts the microbiome without affecting clinical outcomes. Thus, synbiotics might be a preferred treatment option for dogs with AD.

Abstract Background In cancer care, the promotion and implementation of shared decision‐making in clinical practice guidelines (CPG) and consensus statements may have potential differences by gender. Objective To systematically analyse recommendations concerning shared decision‐making in CPGs and consensus statements for the most frequent cancers exclusively among males (prostate) and females (endometrial). Search Strategy We prospectively registered the protocol at PROSPERO (ID: RD42021241127). MEDLINE, EMBASE, Web of Science, Scopus and online sources (8 guideline databases and 65 professional society websites) were searched independently by two reviewers, without language restrictions. Inclusion Criteria CPGs and consensus statements about the diagnosis or treatment of prostate and endometrial cancers were included from January 2015 to August 2021. Data Extraction and Synthesis Quality assessment deployed a previously developed 31‐item tool and differences between the two cancers analysed. Main Results A total of 176 documents met inclusion criteria, 97 for prostate cancer (84 CPGs and 13 consensus statements) and 79 for endometrial cancer (67 CPGs and 12 consensus statements). Shared decision‐making was recommended more often in prostate cancer guidelines compared to endometrial cancer (46/97 vs. 13/79, 47.4% vs. 16.5%; p

Abstract Prenatal experiences can influence offspring physiology and behaviour through the lifespan. Various forms of prenatal stress impair adult learning and memory function and can lead to increased occurrence of anxiety and depression. Clinical work suggests that prenatal stress and maternal depression lead to similar outcomes in children and adolescents, however the long-term effects of maternal depression are less established, particularly in well controlled animal models. Social isolation is common in depressed individuals and during the recent COVID-19 pandemic. Accordingly, for this study we were interested in the effects of maternal stress induced via social isolation on adult offspring cognitive functions including spatial, stimulus–response, and emotional learning and memory that are mediated by different networks centered on the hippocampus, dorsal striatum, and amygdala, respectively. Tasks included a discriminative contextual fear conditioning task and cue-place water task. Pregnant dams in the social isolation group were single housed prior to and throughout gestation. Once offspring reached adulthood the male offspring were trained on a contextual fear conditioning task in which rats were trained to associate one of two contexts with an aversive stimulus and the opposing context remained neutral. Afterwards a cue-place water task was performed during which they were required to navigate to both a visible and invisible platform. Fear conditioning results revealed that the adult offspring of socially isolated mothers, but not controls, were impaired in associating a specific context with a fear-inducing stimulus as assessed by conditioned freezing and avoidance. Results from the water task indicate that adult offspring of mothers that were socially isolated showed place learning deficits but not stimulus-response habit learning on the same task. These cognitive impairments, in the offspring of socially isolated dams, occurred in the absence of maternal elevated stress hormone levels, anxiety, or altered mothering. Some evidence suggested that maternal blood-glucose levels were altered particularly during gestation. Our results provide further support for the idea that learning and memory networks, centered on the amygdala and hippocampus are particularly susceptible to the negative impacts of maternal social isolation and these effects can occur without elevated glucocorticoid levels associated with other forms of prenatal stress.

Abstract Objective Cortical gray matter (GM) atrophy plays a central role in multiple sclerosis (MS) pathology. However, it is not commonly assessed in clinical routine partly because a number of methodological problems hamper the development of a robust biomarker to quantify GM atrophy. In previous work, we have demonstrated the clinical utility of the “mosaic approach” (MAP) to assess individual GM atrophy in the motor neuron disease spectrum and frontotemporal dementia. In this study, we investigated the clinical utility of MAP in MS, comparing this novel biomarker to existing methods for computing GM atrophy in single patients. We contrasted the strategies based on correlations with established biomarkers reflecting MS disease burden. Methods We analyzed T1‐weighted MPRAGE magnetic resonance imaging data from 465 relapsing‐remitting MS patients and 89 healthy controls. We inspected how variations of existing strategies to estimate individual GM atrophy (“standard approaches”) as well as variations of MAP (i.e., different parcellation schemes) impact downstream analysis results, both on a group and an individual level. We interpreted individual cortical disease burden as single metric reflecting the fraction of significantly atrophic data points with respect to the control group. In addition, we evaluated the correlations to lesion volume (LV) and Expanded Disability Status Scale (EDSS). Results We found that the MAP method yielded highest correlations with both LV and EDSS as compared to all other strategies. Although the parcellation resolution played a minor role in terms of absolute correlations with clinical variables, higher resolutions provided more clearly defined statistical brain maps which may facilitate clinical interpretability. Conclusion This study provides evidence that MAP yields high potential for a clinically relevant biomarker in MS, outperforming existing methods to compute cortical disease burden in single patients. Of note, MAP outputs brain maps illustrating individual cortical disease burden which can be directly interpreted in daily clinical routine.

BackgroundOptical coherence tomography angiography (OCTA) allows non-invasive assessment of retinal vessel structures. Thinning and loss of retinal vessels is evident in eyes of patients with multiple sclerosis (MS) and might be associated with a proinflammatory disease phenotype and worse prognosis. We investigated whether changes of the retinal vasculature are linked to brain atrophy and disability in MS.Material and methodsThis study includes one longitudinal observational cohort (n=79) of patients with relapsing-remitting MS. Patients underwent annual assessment of the expanded disability status scale (EDSS), timed 25-foot walk, symbol digit modalities test (SDMT), retinal optical coherence tomography (OCT), OCTA, and brain MRI during a follow-up duration of at least 20 months. We investigated intra-individual associations between changes in the retinal architecture, vasculature, brain atrophy and disability. Eyes with a history of optic neuritis (ON) were excluded.ResultsWe included 79 patients with a median disease duration of 12 (interquartile range 2 - 49) months and a median EDSS of 1.0 (0 - 2.0). Longitudinal retinal axonal and ganglion cell loss were linked to grey matter atrophy, cortical atrophy, and volume loss of the putamen. We observed an association between vessel loss of the superficial vascular complex (SVC) and both grey and white matter atrophy. Both observations were independent of retinal ganglion cell loss. Moreover, patients with worsening of the EDSS and SDMT revealed a pronounced longitudinal rarefication of the SVC and the deep vascular complex.DiscussionON-independent narrowing of the retinal vasculature might be linked to brain atrophy and disability in MS. Our findings suggest that retinal OCTA might be a new tool for monitoring neurodegeneration during MS.

Child Sexual Abuse (CSA) and the production, use, and distribution of Child Sexual Abuse Material (CSAM) are key threats to children’s mental health. From the perspective of indicated prevention, it can be assumed that some persons with a sexual interest in children commit such unreported crimes. Accordingly, the German Network kein Täter werden (meaning do not offend) has implemented a confidential treatment service for persons with a sexual interest in minors who voluntarily seek therapy, might or might not have offended but have not yet been detected or have fulfilled all legal requirements (here referred to as non-forensic individuals). However, this offer has been questioned for investing resources in a group which critics consider as low risk. The following study addresses the question of recidivism risks for CSA or viewing CSAM among non-forensic individuals. We found significantly higher rates of CSA/CSAM in our participants’ history compared to a German study on a representative sample of males. Regarding CSAM, the recidivism rate of 39% was found to be 11 times higher than the expected recidivism rate based on previous publications. Regarding CSA, the recidivism rate of 14% was not significantly different from the expected rate reported for subjects with a conviction for a sexual contact offense. Among various risk instruments, only the CPORT with CASIC rating was able to predict CSA (AUC = 0.69, 95% CI = 0.55, 0.82) and CSAM (AUC = 0.63, 95% CI = 0.53, 0.73) among individuals with a history of CSAM, but with poor discrimination. We conclude that a large proportion of our sample poses a substantial risk and therefore treatment resources are well invested. However, further studies are needed to improve risk assessment among non-forensic clients.

Abstract This study aimed to systematically evaluate the impact of dose reduction on image quality and confidence for intervention planning and guidance regarding computed tomography (CT)-based intervertebral disc and vertebral body biopsies. We retrospectively analyzed 96 patients who underwent multi-detector CT (MDCT) acquired for the purpose of biopsies, which were either derived from scanning with standard dose (SD) or low dose (LD; using tube current reduction). The SD cases were matched to LD cases considering sex, age, level of biopsy, presence of spinal instrumentation, and body diameter. All images for planning (reconstruction: “IMR1”) and periprocedural guidance (reconstruction: “iDose4”) were evaluated by two readers (R1 and R2) using Likert scales. Image noise was measured using attenuation values of paraspinal muscle tissue. The dose length product (DLP) was statistically significantly lower for LD scans regarding the planning scans (SD: 13.8 ± 8.2 mGy*cm, LD: 8.1 ± 4.4 mGy*cm, p 0.05). Image noise was similar between SD and LD scans performed for planning of the interventional procedures (SD: 14.62 ± 2.83 HU vs. LD: 15.45 ± 3.22 HU, p = 0.24). Use of a LD protocol for MDCT-guided biopsies along the spine is a practical alternative, maintaining overall image quality and confidence. Increasing availability of model-based iterative reconstruction in clinical routine may facilitate further radiation dose reductions.

Abstract Background Microvascular dysfunction (MVD) is an important contributor to major clinical disease such as stroke, dementia, depression, retinopathy, and chronic kidney disease. Alcohol consumption may be a determinant of MVD. Objective Main objectives were (1) to study whether alcohol consumption was associated with MVD as assessed in the brain, retina, skin, kidney and in the blood; and (2) to investigate whether associations differed by history of cardiovascular disease or sex. Design We used cross-sectional data from The Maastricht Study (N = 3,120 participants, 50.9% men, mean age 60 years, and 27.5% with type 2 diabetes [the latter oversampled by design]). We used regression analyses to study the association between total alcohol (per unit and in the categories, i.e. none, light, moderate, high) and MVD, where all measures of MVD were combined into a total MVD composite score (expressed in SD). We adjusted all associations for potential confounders; and tested for interaction by sex, and history of cardiovascular disease. Additionally we tested for interaction with glucose metabolism status. Results The association between total alcohol consumption and MVD was non-linear, i.e. J-shaped. Moderate versus light total alcohol consumption was significantly associated with less MVD, after full adjustment (beta [95% confidence interval], -0.10 [-0.19; -0.01]). The shape of the curve differed with sex (Pinteraction = 0.03), history of cardiovascular disease (Pinteraction

Abstract Introduction Posttraumatic swelling causes a delay in surgery, a prolonged hospital stay and a higher risk of complications. Thus, soft tissue conditioning following complex ankle fractures is of central importance in their perioperative management. Since the clinical benefit of VIT usage on the clinical course has been shown, it should now be investigated whether it is also cost-efficient in doing so. Materials and methods Included are published clinical results of the prospective, randomised, controlled, monocentric VIT study that have proven the therapeutic benefit in complex ankle fractures. Participants were allocated in a 1:1 ratio into the intervention group (VIT) and the control group (elevation). In this study, the required economic parameters of these clinical cases were collected on the data of the financial accounting and an estimation of annual cases had been performed to extrapolate the cost-efficiency of this therapy. The primary endpoint was the mean savings (in €). Results Thirty-nine cases were studied in the period from 2016 to 2018. There was no difference in the generated revenue. However, due to lower incurred costs in the intervention group, there were potential savings of about €2000 (p ITT = 0.073) to 3000 (p AT = 0.008) per patient compared to the control group with therapy costs decreasing as the number of patients treated increases from €1400 in one case to below €200 per patient in 10 cases. There were 20% more revision surgeries in the control group or 50 min more OR time, respectively, and an increased attendance by staff and medical personnel of more than 7 h. Conclusions VIT therapy has been shown to be a beneficial therapeutic modality, but it is so not only in regard to soft-tissue conditioning but also cost efficiency.

Natural revegetation of abandoned cropland in biodiversity priority areas and afforestation and growth of bioenergy crop in other areas could achieve a climate change mitigation potential of 0.8–4.0 GtCO2-eq. per year, according to bottom-up estimates based on biomass yields and life-cycle emissions.

Abstract Brain atrophy in multiple sclerosis (MS), as measured by percentage brain volume change (PBVC) from brain magnetic resonance imaging (MRI), has been established as an outcome parameter in clinical trials. It is unknown to what extent volume changes within different brain tissue compartments contribute to PBVC. We analyzed pairs of MRI scans (at least 6 months apart) in 600 patients with relapsing–remitting MS. Multiple regression revealed that PBVC mainly reflects volume loss of white and cortical gray matter, while deep gray matter and white matter lesions were less represented. Our findings aid the interpretation of PBVC changes in MS.

Abstract Soft-tissue conditioning due to posttraumatic oedema after complicated joint fractures is a central therapeutic aspect both pre- and postoperatively. On average, 6–10 days pass until the patient is suitable for surgery. This study compares the decongestant effect of vascular impulse technology (VIT) with that of conventional elevation. In this monocentric RCT, 68 patients with joint fractures of the upper (n = 36) and lower (n = 32) extremity were included and randomized after consent in a 1:1 ratio. Variables were evaluated for all fractures together and additionally subdivided into upper or lower extremity for better clinical comparability. Primary endpoint was the time in days from hospital admission to operability. Secondary endpoints were total length of stay, oedema reduction, pain intensity, complications, and revisions. The time from admission until operability was reduced by 1.4 (95% CI − 0.4; 3.1) days in the mITT analysis (p = 0.120) and was statistically significant with 1.7 (95% CI 0.1; 3.3) days in the as-treated sensitivity analysis (pAT = 0.038). Significantly less pain and a faster oedema reduction were found in the intervention group. Due to rare occurrences, nothing can be concluded regarding complications and revisions. Administration of VIT therapy did not lead to a significant reduction in time until operability in the whole population but was superior to elevation for soft-tissue conditioning and pain reduction. However, there was a significant reduction by 2.5 days (95% CI 0.7; 4.3) in the subgroup of lower extremity fractures. VIT therapy therefore seems to be a helpful tool in the treatment of posttraumatic oedema after complex joint fractures of the lower and upper extremity, especially in tibial head and lower leg fractures.

Histopathologic examination of intestinal biopsies from dogs with acute hemorrhagic diarrhea syndrome (AHDS) reveals necrotizing enteritis and epithelial integrity loss. Serum iohexol measurement has been utilized to assess intestinal permeability. Our hypothesis is that dogs with AHDS have increased intestinal permeability, which is associated with the severity of clinical signs. In this prospective case–control study, 53 client-owned dogs (28 AHDS, 25 healthy controls) were evaluated. Clinical severity was assessed using the AHDS index and systemic inflammatory response syndrome (SIRS) criteria. Simultaneously, dogs received oral iohexol, and serum iohexol concentrations (SICs) were measured two hours later. Results indicated significantly higher (p = 0.002) SIC in AHDS dogs (median: 51 µg/mL; min–max: 9–246) than in healthy controls (30 µg/mL; 11–57). There was a significant positive correlation between AHDS index and SIC (rS = 0.4; p = 0.03) and a significant negative between SIC and serum albumin concentrations (Pearson r = −0.55; p = 0.01). Dogs with severe AHDS (mean 106 µg/mL; range: 17–246) demonstrated significantly higher (p = 0.002) SIC than those with mild to moderate disease (29 µg/mL; 9–54). These findings underscore the association between intestinal permeability and clinical severity in dogs with AHDS assessed by iohexol.

While shifts in gut microbiota have been studied in diseased states, the temporal variability of the microbiome in cats has not been widely studied. This study investigated the temporal variability of the feline dysbiosis index (DI) and the abundance of core bacterial groups in healthy adult cats. The secondary aim was to evaluate the relationship between the fecal abundance of Clostridium hiranonis and the fecal concentrations of unconjugated bile acids. A total of 142 fecal samples collected from 17 healthy cats were prospectively included: nine cats with weekly collection over 3 weeks (at least four time points), five cats with monthly collection over 2 months (three time points), and three cats with additional collections for up to 10 months. The DI remained stable within the reference intervals over two months for all cats (Friedman test, p > 0.2), and 100% of the DI values (n = 142) collected throughout the study period remained within the RI. While some temporal individual variation was observed for individual taxa, the magnitude was minimal compared to cats with chronic enteropathy and antibiotic exposure. Additionally, the abundance of Clostridium hiranonis was significantly correlated with the percentage of fecal primary bile acids, supporting its role as a bile acid converter in cats.

Bile acid metabolism is a key pathway modulated by intestinal microbiota. Peptacetobacter (Clostridium) hiranonis has been described as the main species responsible for the conversion of primary into secondary fecal unconjugated bile acids (fUBA) in dogs. This multi-step biochemical pathway is encoded by the bile acid-inducible (bai) operon. We aimed to assess the correlation between P. hiranonis abundance, the abundance of one specific gene of the bai operon (baiCD), and secondary fUBA concentrations. In this retrospective study, 133 fecal samples were analyzed from 24 dogs. The abundances of P. hiranonis and baiCD were determined using qPCR. The concentration of fUBA was measured by gas chromatography–mass spectrometry. The baiCD abundance exhibited a strong positive correlation with secondary fUBA (ρ = 0.7377, 95% CI (0.6461, 0.8084), p < 0.0001). Similarly, there was a strong correlation between P. hiranonis and secondary fUBA (ρ = 0.6658, 95% CI (0.5555, 0.7532), p < 0.0001). Animals displaying conversion of fUBA and lacking P. hiranonis were not observed. These results suggest P. hiranonis is the main converter of primary to secondary bile acids in dogs.

Fungal infections are rising, with over 1.5 billion cases and more than 1 million deaths recorded each year. Among these, Candida infections are frequent in at-risk populations and the rapid development of drug resistance and tolerance contributes to their clinical persistence. Few antifungal drugs are available, and their efficacy is declining due to the environmental overuse and the expansion of multidrug-resistant species. One way to prolong their utility is by applying them in combination therapy. Here, we highlight recently described azole potentiators belonging to different categories: natural, repurposed, or novel compounds. We showcase examples of molecules and discuss their identified or proposed mode of action. We also emphasise the challenges in azole potentiator development, compounded by the lack of animal testing, the overreliance on Candida albicans and Candida auris, as well as the limited understanding of compound efficacy.

Summary: The process of metabolic liver zonation is spontaneously established by assigning distributed tasks to hepatocytes along the porto-central blood flow. Hepatocytes fulfil critical metabolic functions, while also maintaining hepatocyte mass by replication when needed. Recent technological advances have enabled us to fine-tune our understanding of hepatocyte identity during homeostasis and regeneration. Subsets of hepatocytes have been identified to be more regenerative and some have even been proposed to function like stem cells, challenging the long-standing view that all hepatocytes are similarly capable of regeneration. The latest data show that hepatocyte renewal during homeostasis and regeneration after liver injury is not limited to rare hepatocytes; however, hepatocytes are not exactly the same. Herein, we review the known differences that give individual hepatocytes distinct identities, recent findings demonstrating how these distinct identities correspond to differences in hepatocyte regenerative capacity, and how the plasticity of hepatocyte identity allows for division of labour among hepatocytes. We further discuss how these distinct hepatocyte identities may play a role during liver disease.

Abstract For the last two decades, behavioral physiologists aimed to explain a plausible covariation between energetics and personality, predicted by the “pace‐of‐life syndrome” (POLS) hypothesis. However, the results of these attempts are mixed with no definitive answer as to which of the two most acknowledged models “performance” or “allocation” predicts covariation between consistent among‐individual variation in metabolism and repeatable behavior (animal personality). The general conclusion is that the association between personality and energetics is rather context‐dependent. Life‐history, behavior, and physiology as well as its plausible covariation can be considered a part of sexual dimorphism. However, up to now, only a few studies demonstrated a sex‐specific correlation between metabolism and personality. Therefore, we tested the relationships between physiological and personality traits in a single population of yellow‐necked mice Apodemus flavicollis in the context of a plausible between‐sexes difference in this covariation. We hypothesized that the performance model will explain proactive behavior in males and the allocation model will apply to females. Behavioral traits were determined using the latency of risk‐taking and the open field tests, whereas the basal metabolic rates (BMR) was measured using indirect calorimetry. We have found a positive correlation between body mass‐adjusted BMR and repeatable proactive behavior in male mice, which can support the performance model. However, the females were rather consistent mainly in avoidance of risk‐taking that did not correlate with BMR, suggesting essential differences in personality between sexes. Most likely, the lack of convincing association between energetics and personality traits at the population level is caused by a different selection acting on the life histories of males and females. This may only result in weak support for the predictions of the POLS hypothesis when assuming that only a single model explaining the link between physiology and behavior operates in males and females. Thus, there is a need to consider the differences between sexes in behavioral studies to evaluate this hypothesis.

ObjectivesOpportunistic quantitative computed tomography (oQCT) derived from non-dedicated routine CT has demonstrated high accuracy in diagnosing osteoporosis and predicting incident vertebral fractures (VFs). We aimed to investigate the cost-effectiveness of oQCT screening compared to dual-energy X-ray absorptiometry (DXA) as the standard of care for osteoporosis screening.MethodsThree screening strategies (“no osteoporosis screening”, “oQCT screening”, and “DXA screening”) after routine CT were simulated in a state-transition model for hypothetical cohorts of 1,000 patients (women and men aged 65 years) over a follow-up period of 5 years (base case). The primary outcomes were the cumulative costs and the quality-adjusted life years (QALYs) estimated from a U.S. health care perspective for the year 2022. Cost-effectiveness was assessed based on a willingness-to-pay (WTP) threshold of $70,249 per QALY. The secondary outcome was the number of prevented VFs. Deterministic and probabilistic sensitivity analyses were conducted to test the models’ robustness.ResultsCompared to DXA screening, oQCT screening increased QALYs in both sexes (additional 2.40 per 1,000 women and 1.44 per 1,000 men) and resulted in total costs of $3,199,016 and $950,359 vs. $3,262,934 and $933,077 for women and men, respectively. As a secondary outcome, oQCT screening prevented 2.6 and 2.0 additional VFs per 1,000 women and men, respectively. In the probabilistic sensitivity analysis, oQCT screening remained cost-effective in 88.3% (women) and 90.0% (men) of iterations.ConclusionoQCT screening is a cost-effective ancillary approach for osteoporosis screening and has the potential to prevent a substantial number of VFs if considered in daily clinical practice.

ObjectivesTo investigate vertebral osteoporotic fracture (VF) prediction by automatically extracted trabecular volumetric bone mineral density (vBMD) from routine CT, and to compare the model with fracture prevalence-based prediction models.MethodsThis single-center retrospective study included patients who underwent two thoraco-abdominal CT scans during clinical routine with an average inter-scan interval of 21.7 ± 13.1 months (range 5–52 months). Automatic spine segmentation and vBMD extraction was performed by a convolutional neural network framework (anduin.bonescreen.de). Mean vBMD was calculated for levels T5-8, T9-12, and L1-5. VFs were identified by an expert in spine imaging. Odds ratios (ORs) for prevalent and incident VFs were calculated for vBMD (per standard deviation decrease) at each level, for baseline VF prevalence (yes/no), and for baseline VF count (n) using logistic regression models, adjusted for age and sex. Models were compared using Akaike’s and Bayesian information criteria (AIC & BIC).Results420 patients (mean age, 63 years ± 9, 276 males) were included in this study. 40 (25 female) had prevalent and 24 (13 female) had incident VFs. Individuals with lower vBMD at any spine level had higher odds for VFs (L1-5, prevalent VF: OR,95%-CI,p: 2.2, 1.4–3.5,p=0.001; incident VF: 3.5, 1.8–6.9,p