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Abstract Correlation is not causation: this simple and uncontroversial statement has far-reaching implications. Defining and applying causality in biomedical research has posed significant challenges to the scientific community. In this perspective, we attempt to connect the partly disparate fields of systems biology, causal reasoning, and machine learning to inform future approaches in the field of systems biology and molecular medicine.

Abstract Jaundice, the clinical hallmark of infection‐associated liver dysfunction, reflects altered membrane organization of the canalicular pole of hepatocytes and portends poor outcomes. Mice lacking phosphoinositide 3‐kinase‐γ (PI3Kγ) are protected against membrane disintegration and hepatic excretory dysfunction. However, they exhibit a severe immune defect that hinders neutrophil recruitment to sites of infection. To exploit the therapeutic potential of PI3Kγ inhibition in sepsis, a targeted approach to deliver drugs to hepatic parenchymal cells without compromising other cells, in particular immune cells, seems warranted. Here, we demonstrate that nanocarriers functionalized through DY‐635, a fluorescent polymethine dye, and a ligand of organic anion transporters can selectively deliver therapeutics to hepatic parenchymal cells. Applying this strategy to a murine model of sepsis, we observed the PI3Kγ‐dependent restoration of biliary canalicular architecture, maintained excretory liver function, and improved survival without impairing host defense mechanisms. This strategy carries the potential to expand targeted nanomedicines to disease entities with systemic inflammation and concomitantly impaired barrier functionality.

Background: The "PromeTheus" trial is evaluating a home-based, multifactorial, interdisciplinary prevention program for community-dwelling (pre-)frail older adults. These individuals often suffer from reduced participation, which can complicate the recruitment and enrollment in a clinical trial. Aims: The aim of this study was to evaluate different recruitment strategies and differences in participant characteristics in relation to these strategies. Methods: This cross-sectional study used baseline data from the randomized-controlled PromeTheus trial, in which community-dwelling (pre-)frail older persons (Clinical Frailty Scale [CFS] 4–6 pt., ≥ 70 years) were recruited via general practitioners ("GP recruitment") or flyers, newspaper articles, and personalized letters ("direct recruitment"). Differences in the sociodemographic, clinical, physical, functional, mobility-related, psychological and social characteristics were analyzed in relation to the recruitment strategy. Results: A total of 385 participants (mean age = 81.2, SD 5.9 years; women: n = 283, 73.5%) were enrolled, of which 60 (16%) were recruited by GPs and 325 (84%) through direct recruitment. Participants recruited via GPs had significantly higher subjective frailty levels (CFS), were more often physically frail (Fried Frailty Phenotype), and showed lower physical capacity (Short Physical Performance Battery), participation (disability component of the short version of the Late-Life Function and Disability Instrument), and life-space mobility (Life-Space Assessment) compared to those recruited via the direct approach (p = 0.002–0.026). Costs per randomized participant were 94€ for the GP recruitment strategy and €213 for the direct recruitment strategy. Conclusion: Different strategies may be required to successfully recruit (pre-)frail home-living older adults into preventive programs. Direct recruitment strategies, in which potential participants are directly informed about the prevention program, seem to be more promising than GP recruitment but may result in enrolment of persons with less functional impairment and higher recruitment costs. Trial registration: German Clinical Trials Register, DRKS00024638. Registered on March 11, 2021. [ABSTRACT FROM AUTHOR]

Tumor immune microenvironmental alterations occur early in multiple myeloma (MM) development. In this study, we aim to systematically characterize the tumor immune microenvironment (TME) and the tumor-immune interactions from precursor stages, i.e., monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM), to newly diagnosed MM, comparing these to healthy donors. Using CIBERSORT, mass cytometry (CyTOF), and single-cell RNA sequencing (scRNA-Seq), we examined innate and adaptive immune changes across these stages. We found a decrease in granulocytes in the TME predicts MM outcomes. HLA-DR is reduced in CD16+ monocytes and plasmacytoid dendritic cells, while myeloid dendritic cells show decreased expression of stress and immune-response genes. NK cells and CD8+ T cells shift from a GZMK+ to a GZMB+ cytotoxic phenotype in the TME, with increased inhibitory markers TIM3 and TIGIT. In paired samples, the proportion and gene expression pattern in patient-specific GZMB+CD8+ T cells remain largely unchanged despite MM progression. Our findings provide a comprehensive immune landscape of MM and its precursors, offering insights into therapeutic strategies. Enhancing neutrophil and NK cell cytotoxicity, tumor antigen presentation, and CD8+ T cell versatility in precursor stages may prevent MM progression. [ABSTRACT FROM AUTHOR]

Background: Accurate pharmacokinetic modelling in PET necessitates measurements of an input function, which ideally is acquired non-invasively from image data. For hepatic pharmacokinetic modelling two input functions need to be considered, to account for the blood supply from the hepatic artery and portal vein. Image-derived measurements at the portal vein are challenging due to its small size and image artifacts caused by respiratory motion. In this work we seek to demonstrate, using phantom experiments, how a dedicated PET/MR protocol can tackle these challenges and potentially provide input function measurements of the portal vein in a clinical setup. Methods: A custom 3D printed PET/MR phantom was constructed to mimic the liver and portal vein. PET/MR acquisitions were made with emulated respiratory motion. The PET/MR imaging protocol consisted of high-resolution anatomical MR imaging of the portal vein, followed by a PET acquisition in parallel to a dedicated motion-tracking MR sequence. Motion tracking and deformation information were extracted from PET data and subsequently used in PET reconstruction to produce dynamic series of motion-free PET images. Anatomical MR images were used post PET reconstruction for partial volume correction of the input function measurements. Results: Reconstruction of dynamic PET data with motion-compensation provided nearly motion-free series of PET frame data, suitable for image derived input function measurements of the portal vein. After partial volume correction, the individual input function measurements were within a 16.1% error range from the true activity in the portal vein compartment at the time of PET acquisition. Conclusion: The proposed protocol demonstrates clinically feasible PET/MR imaging of the liver for pharmacokinetic studies with accurate quantification of the portal vein input function, including correction for respiratory motion and partial volume effects. [ABSTRACT FROM AUTHOR]

Purpose: The radionuclide pair cerium-134/lanthanum-134 (134Ce/134La) was recently proposed as a suitable diagnostic counterpart for the therapeutic alpha-emitter actinium-225 (225Ac). The unique properties of 134Ce offer perspectives for developing innovative in vivo investigations that are not possible with 225Ac. In this work, 225Ac- and 134Ce-labelled tracers were directly compared using internalizing and slow-internalizing cancer models to evaluate their in vivo comparability, progeny meandering, and potential as a matched theranostic pair for clinical translation. Despite being an excellent chemical match, 134Ce/134La has limitations to the setting of quantitative positron emission tomography imaging. Methods: The precursor PSMA-617 and a macropa-based tetrazine-conjugate (mcp-PEG8-Tz) were radiolabelled with 225Ac or 134Ce and compared in vitro and in vivo using standard (radio)chemical methods. Employing biodistribution studies and positron emission tomography (PET) imaging in athymic nude mice, the radiolabelled PSMA-617 tracers were evaluated in a PC3/PIP (PC3 engineered to express a high level of prostate-specific membrane antigen) prostate cancer mouse model. The 225Ac and 134Ce-labelled mcp-PEG8-Tz were investigated in a BxPC-3 pancreatic tumour model harnessing the pretargeting strategy based on a trans-cyclooctene-modified 5B1 monoclonal antibody. Results: In vitro and in vivo studies with both 225Ac and 134Ce-labelled tracers led to comparable results, confirming the matching pharmacokinetics of this theranostic pair. However, PET imaging of the 134Ce-labelled precursors indicated that quantification is highly dependent on tracer internalization due to the redistribution of 134Ce's PET-compatible daughter 134La. Consequently, radiotracers based on internalizing vectors like PSMA-617 are suited for this theranostic pair, while slow-internalizing 225Ac-labelled tracers are not quantitatively represented by 134Ce PET imaging. Conclusion: When employing slow-internalizing vectors, 134Ce might not be an ideal match for 225Ac due to the underestimation of tumour uptake caused by the in vivo redistribution of 134La. However, this same characteristic makes it possible to estimate the redistribution of 225Ac's progeny noninvasively. In future studies, this unique PET in vivo generator will further be harnessed to study tracer internalization, trafficking of receptors, and the progression of the tumour microenvironment. [ABSTRACT FROM AUTHOR]

K-12 schools are a major sector for efforts to prevent and treat student mental health problems. In the United States, these efforts have led to the emergence of the MultiTiered System of Supports (MTSS) universal prevention, early intervention, and treatment policy framework. With a major focus on behavioral and mental health, MTSS has been adopted by all fifty state education departments. However, multi-level complexities of addressing student mental health within and across organizational structures complicate MTSS and broader policy development, implementation, and evaluation; disconnects between policy writers and practitioners obstruct progress, limiting positive outcomes. To bridge these policy-to-practice gaps, a multi-component solution is needed. The authors propose integrating the following elements: the Massachusetts School Mental Health Consortium's Five Guiding Principles for Building a Coordinated School Mental Health System, the comprehensive school improvement methodology Evolutionary Systems Improvement (ESI); and the ontological framework of BioPsychoSocioTechnical Systems Theory (BPST). Individual application of these components has already yielded systems-level improvements outperforming compliance-driven procedures. Used together, these components offer a multi-level solution for establishing conceptually-guided, measurement-based loops that transcend the restrictions of uninformed policy, supporting stakeholders as they work to systematically eliminate barriers and improve student mental health. [ABSTRACT FROM AUTHOR]

Purpose: Clear cell sarcoma (CCS) of tendons and aponeuroses and CCS-like malignant gastrointestinal neuroectodermal tumor/sarcoma (GINET) are characterized by frequent local and distant relapses, alongside with low efficacy of all systemic treatments. We aimed to collect a comprehensive dataset to identify prognostic factors and treatment outcomes. Methods: We performed a retrospective single center analysis for diagnosed CCS and GINET on demographic, tumor, treatment and survival data. Results: We identified 43 patients (w:25, m:18) with a median follow-up of 35mo and a 5y-OS-rate of 42%. At diagnosis the median age was 42yrs. Median tumor size was 3.6 cm (0.3–11.1 cm), and 24/26 (94%) tissues analyzed at our institute were EWSR1::ATF1-translocation-positive. Distant extremities (incl. knee or elbow) were affected in 72.5%. Of note, 79.5% received an excisional biopsy (benign histology suspected in 30.2%) leading to frequent incomplete resection. Final R0 status correlated significantly (p = 0.017) with longer survival rates compared to R + status in localized CCS (N0M0, 5-yr OS 0% vs 64%). Radiation and systemic treatment had limited antitumor effects while isolated limb perfusion was active in some patients. 18.6% of patients showed lymphatic spread and 20.9% distant metastases. Presence of initial M + was associated with a dismal survival of 1.4 years (M +) vs 7.1 years (M0; p <.001). Conclusion: We here present one of the largest clinical cohorts of patients with CCS/GINET. Our data underscores the exceptional risk of metastatic disease even in small tumors. As systemic treatment and radiation showed limited efficacy, complete resection was the most important treatment option. [ABSTRACT FROM AUTHOR]

Purpose: The prognosis of patients with metastatic GIST and imatinib-sensitive primary mutations has significantly improved. However, limited data are available to inform patients about outcomes across different lines of treatment. This retrospective analysis aims to evaluate patient outcomes at a large German GIST referral center over the past 15 years. Patients and methods: Overall survival (OS) and progression-free survival (PFS) were analyzed in patients with metastatic GIST, with diagnosis of metastases between 2008 and 2021, when at least three lines of treatment were available in Germany (n = 174). Results: The median overall survival far exceeds historical data for patients with primary exon 11 and exon 9 mutations (median OS in palliative treatment with imatinib: 7.1 years; median OS in second-line palliative treatment with sunitinib: 2.9 years; median OS in third-line palliative treatment with regorafenib: 1.9 years). Among those patients who received palliative imatinib treatment, no significant difference in median OS survival was observed between those who had received perioperative imatinib for localized disease and those who did not. Furthermore, the location of metastases significantly impacted survival, whereas the time between the initial diagnosis and the diagnosis of metastases had no significant effect on survival. Conclusion: In conclusion, this study provides a novel, real-world reference for survival outcomes in patients with metastatic GIST. [ABSTRACT FROM AUTHOR]

Purpose: Disease heterogeneity in coronavirus disease 2019 (COVID-19) may render the current one-size-fits-all treatment approach suboptimal. We aimed to identify and immunologically characterize clinical phenotypes among critically ill COVID-19 patients, and to assess heterogeneity of corticosteroid treatment effect. Methods: We applied consensus k-means clustering on 21 clinical parameters obtained within 24 h after admission to the intensive care unit (ICU) from 13,279 COVID-19 patients admitted to 82 Dutch ICUs from February 2020 to February 2022. Derived phenotypes were reproduced in 6225 COVID-19 ICU patients from Spain (February 2020 to December 2021). Longitudinal immunological characterization was performed in three COVID-19 ICU cohorts from the Netherlands and Germany, and associations between corticosteroid treatment and survival were assessed across phenotypes. Results: We derived three phenotypes: COVIDICU1 (43% of patients) consisted of younger patients with the lowest Acute Physiology And Chronic Health Evaluation (APACHE) scores, highest body mass index (BMI), lowest PaO2/FiO2 ratio, and a 90-day in-hospital mortality rate of 18%. COVIDICU2 patients (37%) had the lowest BMI, were older and had higher APACHE scores and mortality rate (24%) than COVIDICU1. Patients with COVIDICU3 (20%) were the eldest with the most comorbidities, the highest APACHE scores, acute kidney injury and metabolic dysregulations, and the highest mortality rate (47%). These patients also displayed the most pronounced inflammatory response. Corticosteroid therapy started at day 5 [2–9] after ICU admission and administered for 5 [3–7] days was associated with an increased risk for 90-day mortality in patients with the COVIDICU1 and COVIDICU2 phenotypes (hazard ratio [HR] 1.59 [1.09–2.31], p = 0.015 and HR 1.79 [1.42–2.26], p < 0.001, respectively), but not in patients with the COVIDICU3 phenotype (HR 1.08 [0.76–1.54], p = 0.654). Conclusion: Our multinational study identified three distinct clinical COVID-19 phenotypes, each exhibiting marked differences in demographic, clinical, and immunological features, and in the response to late and short-term corticosteroid treatment. [ABSTRACT FROM AUTHOR]

We investigate the geometry of a family of equations in two dimensions which interpolate between the Euler equations of ideal hydrodynamics and the inviscid surface quasi-geostrophic equation. This family can be realised as geodesic equations on groups of diffeomorphisms. We show precisely when the corresponding Riemannian exponential map is non-linear Fredholm of index 0. We further illustrate this by examining the distribution of conjugate points in these settings via a Morse theoretic approach [ABSTRACT FROM AUTHOR]

Understanding how genetically encoded rules drive and guide complex neuronal growth processes is essential to comprehending the brain’s architecture, and agent-based models (ABMs) offer a powerful simulation approach to further develop this understanding. However, accurately calibrating these models remains a challenge. Here, we present a novel application of Approximate Bayesian Computation (ABC) to address this issue. ABMs are based on parametrized stochastic rules that describe the time evolution of small components–the so-called agents–discretizing the system, leading to stochastic simulations that require appropriate treatment. Mathematically, the calibration defines a stochastic inverse problem. We propose to address it in a Bayesian setting using ABC. We facilitate the repeated comparison between data and simulations by quantifying the morphological information of single neurons with so-called morphometrics and resort to statistical distances to measure discrepancies between populations thereof. We conduct experiments on synthetic as well as experimental data. We find that ABC utilizing Sequential Monte Carlo sampling and the Wasserstein distance finds accurate posterior parameter distributions for representative ABMs. We further demonstrate that these ABMs capture specific features of pyramidal cells of the hippocampus (CA1). Overall, this work establishes a robust framework for calibrating agent-based neuronal growth models and opens the door for future investigations using Bayesian techniques for model building, verification, and adequacy assessment. [ABSTRACT FROM AUTHOR]

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Mucosal-associated invariant T (MAIT) cells express semi-invariant T cell receptors (TCR) for recognizing bacterial and yeast antigens derived from riboflavin metabolites presented on the non-polymorphic MHC class I-related protein 1 (MR1). Neuroinflammation in multiple sclerosis (MS) is likely initiated by autoreactive T cells and perpetuated by infiltration of additional immune cells, but the precise role of MAIT cells in MS pathogenesis remains unknown. Here, we use experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, and find an accumulation of MAIT cells in the inflamed central nervous system (CNS) enriched for MAIT17 (RORγt+) and MAIT1/17 (T-bet+RORγt+) subsets with inflammatory and protective features. Results from transcriptome profiling and Nur77GFP reporter mice show that these CNS MAIT cells are activated via cytokines and TCR. Blocking TCR activation with an anti-MR1 antibody exacerbates EAE, whereas enhancing TCR activation with the cognate antigen, 5-(2-oxopropylideneamino)−6-D-ribitylaminouracil, ameliorates EAE severity, potentially via the induction of amphiregulin (AREG). In summary, our findings suggest that TCR-mediated MAIT cell activation is protective in CNS inflammation, likely involving an induction of AREG. Mucosal-associated invariant T (MAIT) cells mediate protection from pathogens, but their role in autoimmunity is unclear. Here the authors show that, in a mouse experimental autoimmune encephalomyelitis model, MAIT cells accumulate in the inflamed central nervous system and serve protective functions when activated via their T cell receptor. [ABSTRACT FROM AUTHOR]

Background: Obesity and type 2 diabetes (T2D) are associated with alterations in testosterone concentrations. While evidence indicates that aerobic training can influence testosterone in healthy populations or females with hyperandrogenism, its impact in individuals with obesity or T2D remains unclear. Thus, the aim of this study was to investigate whether aerobic training can influence circulating testosterone concentrations in individuals with obesity or T2D. Methods: EBSCOhost (CINAHL, MEDLINE, SPORTDiscus), PubMed and Embase were searched for articles published until August 2023. Eligible articles included individuals with obesity or T2D that underwent an aerobic exercise intervention with testosterone concentrations measured at baseline and post intervention. Two reviewers independently screened the seven articles included in this meta-analysis and conducted data extraction and risk of bias assessments. Results: A total of 103 participants (62 men / 41 women) from three randomised controlled trials and four non-randomised controlled trials were included. Effect sizes were computed with random effects models. Aerobic exercise moderately increased testosterone concentrations in men (g = 0.565, 95% CI = 0.307 to 0.822, p < 0.001), but had no significant effect in women (g = -0.523, 95% CI = -1.541, 0.496, p = 0.314). Aerobic exercise had no significant effect on sex hormone-binding globulin or markers of insulin sensitivity (p > 0.05). Conclusions: Aerobic training may be used to increase testosterone concentrations in men with obesity or T2D, but potentially has no influence in women. Given the low number of studies, further studies investigating the effect of exercise on circulating sex hormones in men and women with obesity or T2D are needed. Key Points: • Aerobic exercise training can significantly increase testosterone concentrations in men who are obese or have type 2 diabetes. • Aerobic exercise training does not appear to significantly influence testosterone concentrations in women who are obese or have type 2 diabetes. • Aerobic exercise training could be utilised to improve testosterone concentrations in men who are obese or have type 2 diabetes. [ABSTRACT FROM AUTHOR]

Representational drift—the gradual continuous change of neuronal representations—has been observed across many brain areas. It is unclear whether drift is caused by synaptic plasticity elicited by sensory experience, or by the intrinsic volatility of synapses. Here, using chronic two-photon calcium imaging in primary visual cortex of female mice, we find that the preferred stimulus orientation of individual neurons slowly drifts over the course of weeks. By using cylinder lens goggles to limit visual experience to a narrow range of orientations, we show that the direction of drift, but not its magnitude, is biased by the statistics of visual input. A network model suggests that drift of preferred orientation largely results from synaptic volatility, which under normal visual conditions is counteracted by experience-driven Hebbian mechanisms, stabilizing preferred orientation. Under deprivation conditions these Hebbian mechanisms enable adaptation. Thus, Hebbian synaptic plasticity steers drift to match the statistics of the environment. Neural mechanisms underlying representational drift are not fully understood. Here authors report that the preferred orientation of mouse visual cortex neurons drifts over time. Altering visual experience does not change drift magnitude, but rather its direction, such that neurons' tuning matches the statistics of the environment. [ABSTRACT FROM AUTHOR]

Background: Oilseed plants of the Brassicaceae plant family are cultivated for food, feed and industrial purposes on large-scale in Europe. This review gives an overview of current market-oriented applications of new genomic techniques (NGTs) in relevant Brassicaceae oilseed crops based on a literature survey. In this respect, changes in oil quality, yield, growth and resistance to biotic and abiotic stress are under development in oilseed rape (Brassica napus), camelina (Camelina sativa), and pennycress (Thlaspi arvense). Main findings: Environmental risk scenarios starting with hazard identification are developed for specific NGT applications in Brassicaceae oilseed crops with either a changed oil composition or with fitness-related traits. In case of a changed oil composition, an increase or decrease of polyunsaturated fatty acids (PUFA) may lead to risks for health and survival of pollinators. Regarding fitness-related traits, other risks were identified, i.e. an increased spread and persistence of NGT plants. Furthermore, there are indications for potential disturbance of interactions with the environment, involving signalling pathways and reaction to stress conditions. Conclusion: It is shown that for environmental risk scenarios of the technological specificities of NGTs, the plants' biology and the scale of releases have to be considered in combination. Therefore, the release of NGT plants into the environment for agricultural purposes will, also in future, require risk assessment and monitoring of individual traits as well as of combinatorial and long-term cumulative effects. In addition, risk management should develop concepts and measures to control and potentially limit the scale of releases. This is especially relevant for NGT Brassicaceae in Europe, which is a centre of diversity of this plant family. [ABSTRACT FROM AUTHOR]

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Medulloblastomas with extensive nodularity are cerebellar tumors characterized by two distinct compartments and variable disease progression. The mechanisms governing the balance between proliferation and differentiation in MBEN remain poorly understood. Here, we employ a multi-modal single cell transcriptome analysis to dissect this process. In the internodular compartment, we identify proliferating cerebellar granular neuronal precursor-like malignant cells, along with stromal, vascular, and immune cells. In contrast, the nodular compartment comprises postmitotic, neuronally differentiated malignant cells. Both compartments are connected through an intermediate cell stage resembling actively migrating CGNPs. Notably, we also discover astrocytic-like malignant cells, found in proximity to migrating and differentiated cells at the transition zone between the two compartments. Our study sheds light on the spatial tissue organization and its link to the developmental trajectory, resulting in a more benign tumor phenotype. This integrative approach holds promise to explore intercompartmental interactions in other cancers with varying histology. The mechanisms regulating the balance between proliferation and differentiation in medulloblastomas with extensive nodularity (MBEN) remain poorly understood. Here, single cell multi-omics and spatial analysis characterises the spatial tissue organisation of MBEN in the context of the developmental trajectory. [ABSTRACT FROM AUTHOR]

Background: Due to the proximity to bony structures and the complex anatomy of the three-layered lateral abdominal wall, the surgical treatment of lateral ventral hernias is technically demanding. With this study we would like to demonstrate how lateral abdominal wall hernias can be treated using new robotic surgical techniques with extraperitoneal mesh placement. Objectives: The purpose of this study is to demonstrate that the application of the robot in minimally invasive treatment of lateral abdominal wall hernias is safe and efficient. Materials and methods: A retrospective analysis of all patients who underwent robotically-assisted lateral ventral hernia repair surgery from June 2019 to December 2023 was performed. Results: A total of 50 ventral hernias were operated robotically due to a lateral hernia in the study period. 45 patients had an incisional hernia and 5 patients a primary spighelian hernia. 27 patients had only lateral findings, whereas 23 patients had combined hernias with lateral and medial hernial defects. 18 patients were treated with a preperitoneal mesh (r-vTAPP). 31 patients required TAR to achieve complete fascial closure and sufficient mesh overlap (24 extraperitoneal approach r-eTAR/7 transperitonel approach r-TAR). One patient had to be converted intraoperatively from a planned preperitoneal mesh to an intraperitoneal mesh repair (r-IPOM). The median hernia defect area was 71 cm² (3–375 cm²). The median mesh size was 600 cm² (150–1290 cm²). The median mesh defect ratio (MDR) was 10 (2,33–133,33). Five postoperative complications were encountered (10%). Two reoperations (4%) were required. Conclusion: The utilization of new robotic surgical techniques provides a safe minimally invasive treatment option even for complex lateral ventral hernias that previously posed difficulties in surgical management. The early postoperative results show promising outcomes. [ABSTRACT FROM AUTHOR]

Progressive inflammation of one hemisphere characterises Rasmussen's encephalitis (RE), but contralesional epileptiform activity has been repeatedly reported. We aimed to quantify contralesional epileptiform activity in RE and uncover its functional and structural underpinnings. We retrospectively ascertained people with RE treated between 2000 and 2018 at a tertiary centre (Centre 1) and reviewed all available EEG datasets. The temporal occurrence of preoperative contralesional epileptiform activity (interictal/ictal) was evaluated using mixed-effects logistic regression. Cases with/without contralesional epileptiform activity were compared for cognition, inflammation (ipsilesional brain biopsies), and MRI (cortical and fixel-based morphometry). EEG findings were validated in a second cohort treated at another tertiary centre (Centre 2) between 1995 and 2020. We included 127 people with RE and 687 EEG samples. Preoperatively, contralesional epileptiform activity was seen in 30/68 (44%, Centre 1) and 8/59 (14%, Centre 2). In both cohorts, this activity was associated with younger onset age (OR = 0.9; 95% CI 0.83–0.97; P = 0.006). At centre 1, contralesional epileptiform activity was associated with contralesional MRI alterations, lower intelligence (OR = 5.19; 95% CI 1.28–21.08; P = 0.021), and impaired verbal memory (OR = 10.29; 95% CI 1.97–53.85; P = 0.006). After hemispherotomy, 11/17 (65%, Centre 1) and 28/37 (76%, Centre 2) were seizure-free. Contralesional epileptiform activity was persistent postoperatively in 6/12 (50%, Centre 1) and 2/34 (6%, Centre 2). Preoperative contralesional epileptiform activity reduced the chance of postoperative seizure freedom in both cohorts (OR = 0.69; 95% CI 0.50–0.95; P = 0.029). Our findings question the concept of strict unilaterality of RE and provide the evidence of contralesional epileptiform activity as a possible EEG predictor for persisting postoperative seizures. [ABSTRACT FROM AUTHOR]

A series of drained and undrained water-saturated constant mean-stress tests were performed to investigate the strength, elasticity, and poroelastic response of a water-saturated high porosity nonwelded tuff. Drained strengths are found to increase with increasing effective confining pressures. Elastic moduli increase with increasing mean stress. Undrained strengths are small due to development of high pore pressures that generate low effective confining pressures. Skempton’s values are pressure dependent and appear to reflect the onset of inelastic deformation. Permeabilities decrease after deformation from ∼ 10–14 to ∼ 10–16 m2 and are a function of the applied confining pressure. Deformation is dominated by pore collapse, compaction, and intense microfracturing, with the undrained tests favoring microfracture-dominant deformation and the drained tests favoring compaction-dominant deformation. These property determinations and observations are used to develop/parameterize physics-based models for underground explosives testing. [ABSTRACT FROM AUTHOR]

Objectives: Worldviews (WVs) are the set of beliefs that underlie the way we conceive of reality and selfhood. Buddhist meditation allegedly leads to long-lasting changes in WVs, and trait-like neurophysiological and behavioral differences between novice and expert meditators support this possibility. However, this claim has not yet been fully tested, and there is still no qualitative evidence. The purpose of the present qualitative study was to compare the WVs of a representative sample of European novices and long-term Buddhist trainees. Method: As part of the European Research Council Brain and Mindfulness project, the present qualitative study involved interviewing 32 participants trained in mindfulness meditation ("novices") and 30 long-term practitioners with more than 20,000 hr of practice in Tibetan Buddhism ("experts"). We used an interpretive-phenomenological approach to explore their core beliefs about the nature of reality, metaphysics, and ethics. For each area of inquiry, we used structural-thematic analysis to identify representative clusters that described the variety of WVs of the two samples. Results: Emergent clusters show a strong dependence on expertise along a progressive distribution (gradient). This gradient shows that groups differ in terms of dereification, i.e., different degrees of identification with experiential contents (such as thoughts and emotions) while bringing insight about them as mental components. This applied to (1) subjectivity and agentivity, the latter being defined as the ability to make choices and determine one's own outcomes; (2) linear temporality and causality; and (3) ontological substantialism, defined as the inherent essence or nature that grounds things. Finally, the gradient also describes a narrative-conversational shift from being content-oriented to process-oriented. Answers from novices tended to be based on knowledge organized on representational beliefs, while in the answers of experts, there was more metacognitive awareness and questioning of the ongoing experience of being interviewed. This result is consistent with the progressive cognitive and experiential dereification hypothesized to underlie this gradient. These results suggest that WVs depend on meditative experience, possibly due to metacognitive functions that shape thinking and knowledge about thinking. Conclusions: These findings are consistent with the common Buddhist advice not to take contemplative beliefs at faith value, but instead to question and deconstruct any belief through close observation and analysis of one's own experience. This exploratory journey is traditionally conceptualized as an interdependent, dynamic process. Future longitudinal studies are needed to explore how meditative practices can induce changes in WVs, and, reciprocally, the role of beliefs in cultivating targeted contemplative states, contributing to cognitive and emotional regulation. Preregistration: This study was not preregistered. [ABSTRACT FROM AUTHOR]

Main conclusion: Seed-application of the natural products protects sugar beet and wheat plants against infection with plasmodiophorid-transmitted viruses and thus may represent an efficient, environmentally friendly, easy and cost effective biocontrol strategy. In times of intensive agriculture, resource shortening and climate change, alternative, more sustainable and eco-friendly plant protection strategies are required. Here, we tested the potential of the natural plant substances Glycyrrhiza glabra leaf extract (GE) and the rhamnolipid Rhapynal (Rha) applied to seeds to protect against infection of sugar beet and wheat with soil-borne plant viruses. The soil-borne Polymyxa betae- and Polymyxa graminis-transmitted viruses cause extensive crop losses in agriculture and efficient control strategies are missing. We show that GE and Rha both efficiently protect plants against infection with soil-borne viruses in sugar beet and wheat when applied to seeds. Moreover, the antiviral protection effect is independent of the cultivar used. No protection against Polymyxa sp. was observed after seed treatment with the bio-substances at our analysis time points. However, when we applied the bio-substances directly to soil a significant anti-Polymyxa graminis effect was obtained in roots of barley plants grown in the soil as well as in the treated soil. Despite germination can be affected by high concentrations of the substances, a range of antiviral protection conditions with no effect on germination were identified. Seed-treatment with the bio-substances did not negatively affect plant growth and development in virus-containing soil, but was rather beneficial for plant growth. We conclude that seed treatment with GE and Rha may represent an efficient, ecologically friendly, non-toxic, easy to apply and cost efficient biocontrol measure against soil-borne virus infection in plants. [ABSTRACT FROM AUTHOR]

Purpose: Our study aimed to provide consensus and expert clinical practice statements related to airway management in critically ill adults with a physiologically difficult airway (PDA). Methods: An international Steering Committee involving seven intensivists and one Delphi methodology expert was convened by the Society of Critical Care Anaesthesiologists (SOCCA) Physiologically Difficult Airway Task Force. The committee selected an international panel of 35 expert clinician–researchers with expertise in airway management in critically ill adults. A Delphi process based on an iterative approach was used to obtain the final consensus statements. Results: The Delphi process included seven survey rounds. A stable consensus was achieved for 53 (87%) out of 61 statements. The experts agreed that in addition to pathophysiological conditions, physiological alterations associated with pregnancy and obesity also constitute a physiologically difficult airway. They suggested having an intubation team consisting of at least three healthcare providers including two airway operators, implementing an appropriately designed checklist, and optimizing hemodynamics prior to tracheal intubation. Similarly, the experts agreed on the head elevated laryngoscopic position, routine use of videolaryngoscopy during the first attempt, preoxygenation with non-invasive ventilation, careful mask ventilation during the apneic phase, and attention to cardiorespiratory status for post-intubation care. Conclusion: Using a Delphi method, agreement among a panel of international experts was reached for 53 statements providing guidance to clinicians worldwide on safe tracheal intubation practices in patients with a physiologically difficult airway to help improve patient outcomes. Well-designed studies are needed to assess the effects of these practice statements and address the remaining uncertainties. [ABSTRACT FROM AUTHOR]

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Background: Surgical decision-making for preference-sensitive operations among older adults is understudied. Ventral hernia repair (VHR) is one operation where granular data are limited to guide preoperative decision-making. We aimed to determine risk for VHR in older adults given clinically nuanced data including surgical and hernia characteristics. Methods: We performed a retrospective analysis of the Michigan Surgical Quality Collaborative Core Optimization Hernia Registry from January 2020 to March 2023. The primary outcome was postoperative complication across age groups: 18–64, 65–74, and ≥ 75 years, with secondary outcome of surgical approach. Mixed-effects logistic regression evaluated association between minimally invasive surgery (MIS) and 30-day complications, controlling for patient and hernia characteristics. Results: Among 8,659 patients, only 7% were 75 or older. MIS rates varied across hospitals [Median = 31.4%, IQR: (14.8–51.6%)]. The overall complication rate was 2.2%. Complication risk for undergoing open versus MIS approach did not vary between age groups; however, patients over age 75 undergoing laparoscopic repair had increased risk (aOR = 4.58, 95% CI 1.13–18.67). Other factors associated with risk included female sex (aOR = 2.10, 95% CI 1.51–2.93), higher BMI (aOR = 1.18, 95% CI 1.03–1.34), hernia width ≥ 6 cm (aOR = 3.15, 95% CI 1.96–5.04), previous repair (aOR = 1.44, 95% CI 1.02–2.05), and component separation (aOR = 1.98, 95% CI 1.28–3.05). Patients most likely to undergo MIS were female (aOR = 1.21, 95% CI 1.09–1.34), black (aOR = 1.30, 95% CI 1.12–1.52), with larger hernias: 2–5.9 cm (aOR = 1.76, 95% CI 1.57–1.97), or intraoperative mesh placement (aOR = 14.4, 95% CI 11.68–17.79). There was no difference in likelihood to receive MIS across ages when accounting for hospital (SD of baseline likelihood = 1.53, 95% CI 1.14–2.05) and surgeon (SD of baseline likelihood = 2.77, 95% CI 2.46–3.11) variation. Conclusions: Our findings demonstrate that hernia, intraoperative, and patient characteristics other than age increase probability for complication following VHR. These findings can empower surgeons and older patients considering preoperative risk for VHR. [ABSTRACT FROM AUTHOR]

Background: Mycoplasma genitalium (MG) is an emerging sexually transmitted infection, often harboring resistance-associated mutations to azithromycin (AZM). Global surveillance has been mandated to tackle the burden caused by MG, yet no data are available for Austria. Thus, we aimed to investigate the prevalence of MG, disease characteristics, and treatment outcomes at the largest Austrian HIV—and STI clinic. Methods: All MG test results at the Medical University of Vienna from 02/2019 to 03/2022 were evaluated. Azithromycin resistance testing was implemented in 03/2021. Results: Among 2671 MG tests, 199 distinct and mostly asymptomatic (68%; 135/199) MG infections were identified, affecting 10% (178/1775) of all individuals. This study included 83% (1479/1775) men, 53% (940/1775) men who have sex with men (MSM), 31% (540/1754) HIV+, and 15% (267/1775) who were using HIV pre-exposure prophylaxis (PrEP). In logistic regression analysis, 'MSM' (aOR 2.55 (95% CI 1.65–3.92)), 'use of PrEP' (aOR 2.29 (95% CI 1.58–3.32)), and 'history of syphilis' (aOR 1.57 (95% CI 1.01–2.24) were independent predictors for MG infections. Eighty-nine percent (178/199) received treatment: 11% (21/178) doxycycline (2 weeks), 52% (92/178) AZM (5 days), and 37% (65/178) moxifloxacin (7–10 days) and 60% (106/178) had follow-up data available showing negative tests in 63% (5/8), 76% (44/58) and 85% (34/40), respectively. AZM resistance analysis was available for 57% (114/199)) and detected in 68% (78/114). Resistance-guided therapy achieved a cure in 87% (53/61), yet, empiric AZM-treatment (prior to 03/2021) cleared 68% (26/38). Conclusions: Mycoplasma genitalium was readily detected in this Austrian observational study, affected predominantly MSM and often presented as asymptomatic disease. We observed a worryingly high prevalence of AZM resistance mutations; however, empiric AZM treatment cleared twice as many MG infections as expected. [ABSTRACT FROM AUTHOR]

This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of BI 685509 after oral single rising doses (SRDs) or multiple rising doses (MRDs) in healthy volunteers. In the SRD trial (NCT02694354; February 29, 2016), within each of the three dose groups (DGs), six subjects received BI 685509 (1.0, 2.5, or 5.0 mg) and two received placebo (N = 24). In the MRD trial (NCT03116906; April 17, 2017), within each of the five DGs, nine subjects received BI 685509 (uptitrated to 1 mg once daily [qd; DG1], 2.5 mg twice daily [DG2], 5.0 mg qd [DG3]; 3.0 mg three times daily [tid; DG4] or 4.0 mg tid [DG5]) and three received placebo, for 14–17 days (N = 60). In the SRD trial, 7/24 subjects (29.2%) had ≥ 1 adverse event (AE), most frequently orthostatic dysregulation (n = 4). In the MRD trial, 26/45 subjects (57.8%) receiving BI 685509 had ≥ 1 AE, most frequently orthostatic dysregulation and fatigue (each n = 12). Tolerance development led to a marked decrease in orthostatic dysregulation events (DG3). BI 685509 was rapidly absorbed after oral administration, and exposure increased in a dose-proportional manner after single doses. Multiple dosing resulted in near–dose-proportional increase in exposure and limited accumulation. BI 685509 pharmacokinetics appeared linear with time; steady state occurred 3–5 days after each multiple-dosing period. Increased plasma cyclic guanosine monophosphate and decreased blood pressure followed by a compensatory increase in heart rate indicated target engagement. BI 685509 was generally well tolerated; orthostatic dysregulation may be appropriately countered by careful uptitration. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to explore the role of CT in septic patients presenting to the emergency department (ED). Materials and methods: We performed a retrospective secondary analysis of 192 septic patients from a prospective observational study, i.e., the "LIFE POC" study. Sepsis was diagnosed in accordance with the Sepsis-3 definition. Clinical and radiological data were collected from the hospital administration and radiological systems. Information on mortality and morbidity was collected. Time-to-CT between CT scan and sepsis diagnosis (ttCTsd) was calculated. Diagnostic accuracy was assessed with the final sepsis source as reference standard. The reference standard was established through the treating team of the patient based on all available clinical, imaging, and microbiological data. Results: Sixty-two of 192 patients underwent a CT examination for sepsis focus detection. The final septic source was identified by CT in 69.4% (n = 43). CT detected septic foci with 81.1% sensitivity (95% CI, 68.0–90.6%) and 55.6% specificity (95% CI, 21.2–86.3%). Patients with short versus long ttCTsd did not differ in terms of mortality (16.1%, n = 5 vs 9.7, n = 3; p = 0.449), length of hospital stay (median 16 d, IQR 9 d 12 h–23 d 18 h vs median 13 d, IQR 10 d 00 h–24 d 00 h; p = 0.863), or duration of intensive care (median 3d 12 h, IQR 2 d 6 h–7 d 18 h vs median 5d, IQR 2 d–11 d; p = 0.800). Conclusions: Our findings show a high sensitivity of CT in ED patients with sepsis, confirming its relevance in guiding treatment decisions. The low specificity suggests that a negative CT requires further ancillary diagnostic tests for focus detection. The timing of CT did not affect morbidity or mortality outcomes. Clinical relevance statement: In patients with sepsis who present to the ED, CT can be used to identify infectious foci on the basis of clinical suspicion, but should not be used as a rule-out test. Scientific evidence for the optimal timing of CT beyond clinical decision-making is currently missing, as potential mortality benefits are clouded by differences in clinical severity at the time of ED presentation. Key Points: • In patients with sepsis who present to the ED, CT for focus identification has a high sensitivity and can thereby be valuable for patient management. • As the specificity is considerably lower, a thorough microbiological assessment is important in these cases. • The timing of CT did not affect morbidity and mortality outcomes in this study, which might be due to variability in clinical severity at the time of ED presentation. [ABSTRACT FROM AUTHOR]

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Copyright of Zeitschrift für Gerontologie und Geriatrie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Zeitschrift für Gerontologie und Geriatrie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Zeitschrift für Gerontologie und Geriatrie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Objectives: This cross-sectional study aimed to determine the prevalence, manifestation, and risk factors of pulmonary involvement in newly diagnosed, untreated rheumatoid arthritis (RA) and psoriatic arthritis (PsA) patients, and to evaluate the efficacy of various diagnostic tools in screening for pulmonary involvement. Methods: Untreated, newly diagnosed patients with RA and PsA underwent an extensive multimodal diagnostic approach including clinical and laboratory assessment, pulmonary function tests, and chest radiography. Results: We recruited 50 arthritis patients (26 RA, 24 PsA) and 26 control subjects. Respiratory symptoms were found in 36.0 % of arthritis patients and 11.5 % of controls (p = 0.031). Pathologically reduced breathing width (< 3.0 cm) was significantly more common in arthritis patients (64.0 %) than in controls (23.1 %) (p < 0.001). Pulmonary function test results did not differ significantly between groups. Chest radiography revealed pulmonary involvement in 37.0 % of arthritis patients, higher in RA (50.0 %) than in PsA (22.7 %). Notably, only 35.3 % of arthritis patients with radiographic pulmonary involvement were symptomatic, with 64.7 % being asymptomatic. Radiographic pulmonary involvement was associated with advanced age (p = 0.002) and increased rheumatoid factor levels (p = 0.024). Conclusion: Our research underscores the significant prevalence of largely asymptomatic pulmonary involvement in newly diagnosed RA and PsA patients. These findings highlight the importance of an early, multidisciplinary screening approach, particularly for high-risk individuals. Further large-scale studies are needed to develop comprehensive screening protocols to improve early detection and treatment of pulmonary involvement in arthritis. [ABSTRACT FROM AUTHOR]

This study assesses the use of fructosamine as a diagnostic tool for hyperglycemia in alpacas in view of their sensitivity to stress and susceptibility to conditions like lipid mobilization syndrome. Plasma fructosamine, like in diagnosing diabetes in cats and dogs, can reveal long-term blood glucose trends, differentiating stress-induced spikes from persistent diabetic hyperglycemia. In 125 alpacas presented as patients of a veterinary clinic, plasma glucose and fructosamine concentrations were compared for correlations with findings of the general clinical examination, laboratory parameters, demographic data, and a behavioral stress assessment processed by using principal component analysis. Hyperglycemia was observed on admission of 71% (89/125) of the animals. This was significantly associated with a higher concentration of serum cortisol and a higher behavioral stress scoring. Fructosamine above the reference limit was detected in only 15% (13/89) of the hyperglycemic individuals. In addition to a positive correlation of fructosamine to glucose concentration, positive relationships with different plasma proteins were detected. A relationship to stress parameters was not observed. These findings underscore stress as a significant trigger for hyperglycemia in alpacas and suggest fructosamine as a valuable parameter for distinguishing between stress-induced and diabetic hyperglycemia. However, the dependence of fructosamine formation on total plasma protein concentration should be considered to avoid misinterpretation. [ABSTRACT FROM AUTHOR]

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

Background: The German multicenter research consortium BipoLife aims to investigate the mechanisms underlying bipolar disorders. It focuses in particular on people at high risk of developing the disorder and young patients in the early stages of the disease. Functional and structural magnetic resonance imaging (MRI) data was collected in all participating centers. The collection of neuroimaging data in a longitudinal, multicenter study requires the implementation of a comprehensive quality assurance (QA) protocol. Here, we outline this protocol and illustrate its application within the BipoLife consortium. Methods: The QA protocol consisted of (1) a training of participating research staff, (2) regular phantom measurements to evaluate the MR scanner performance and its temporal stability across the course of the study, and (3) the assessment of the quality of human MRI data by evaluating a variety of image metrics (e.g., signal-to-noise ratio, ghosting level). In this article, we will provide an overview on these QA procedures and show exemplarily the influence of its application on the results of standard neuroimaging analysis pipelines. Discussion: The QA protocol helped to characterize the various MR scanners, to record their performance over the course of the study and to detect possible malfunctions at an early stage. It also assessed the quality of the human MRI data systematically to characterize its influence on various analyses. Furthermore, by setting up and publishing this protocol, we define standards that must be considered when analyzing data from the BipoLife consortium. It further promotes a systematic evaluation of data quality and a definition of subject inclusion criteria. In the long term, it will help to increase the chance of achieving clinically relevant results. [ABSTRACT FROM AUTHOR]

Oceanic anoxic events (OAEs) are historical intervals of global-scale ocean deoxygenation associated with hyperthermal climate states and biological crises1,2. Massive volcanic carbon dioxide (CO2) emissions frequently associated with these events are thought to be a common driver of ocean deoxygenation through several climate-warming-related mechanisms1,3,4. The Early Cretaceous OAE1a is one of the most intense ocean deoxygenation events, persisting for more than 1 Myr (refs. 5,6). However, existing records of marine chemistry and climate across OAE1a are insufficient to fully resolve the timing and dynamics of the underlying processes, thus obscuring cause-and-effect relationships between climate forcing and ocean oxygenation states. Here we show that rapid ocean deoxygenation during OAE1a is linked to volcanic CO2 emissions and the crossing of an associated climate threshold, after which the sluggish pace of the silicate-weathering feedback and climate recovery delayed reoxygenation for >1 Myr. At the end of OAE1a, recrossing this threshold allowed for ocean reoxygenation. Following OAE1a, however, the Earth system remained sufficiently warm such that orbitally forced climate dynamics led to continued cyclic ocean deoxygenation on approximately 100-kyr timescales for another 1 Myr. Our results thus imply a tight coupling between volcanism, weathering and ocean oxygen content that is characterized by a climate threshold.Rapid ocean deoxygenation during the Early Cretaceous OAE1a is shown to provide evidence for a strong link between volcanic CO2 emissions, weathering and ocean oxygen content that is characterized by a climate threshold. [ABSTRACT FROM AUTHOR]

Spiking neural networks and neuromorphic hardware platforms that simulate neuronal dynamics are getting wide attention and are being applied to many relevant problems using Machine Learning. Despite a well-established mathematical foundation for neural dynamics, there exists numerous software and hardware solutions and stacks whose variability makes it difficult to reproduce findings. Here, we establish a common reference frame for computations in digital neuromorphic systems, titled Neuromorphic Intermediate Representation (NIR). NIR defines a set of computational and composable model primitives as hybrid systems combining continuous-time dynamics and discrete events. By abstracting away assumptions around discretization and hardware constraints, NIR faithfully captures the computational model, while bridging differences between the evaluated implementation and the underlying mathematical formalism. NIR supports an unprecedented number of neuromorphic systems, which we demonstrate by reproducing three spiking neural network models of different complexity across 7 neuromorphic simulators and 4 digital hardware platforms. NIR decouples the development of neuromorphic hardware and software, enabling interoperability between platforms and improving accessibility to multiple neuromorphic technologies. We believe that NIR is a key next step in brain-inspired hardware-software co-evolution, enabling research towards the implementation of energy efficient computational principles of nervous systems. NIR is available at neuroir.org Neuromorphic software and hardware solutions vary widely, challenging interoperability and reproducibility. Here, authors establish a representation for neuromorphic computations in continuous time and demonstrate support across 11 platforms. [ABSTRACT FROM AUTHOR]

Secure and scalable group communication environments are essential for many IoT applications as they are the cornerstone for different IoT devices to work together securely to realize smart applications such as smart cities or smart health. Such applications are often implemented in Wireless Sensor Networks, posing additional challenges. Sensors usually have low capacity and limited network connectivity bandwidth. Over time, a variety of Secure Group Communication (SGC) schemes have emerged, all with their advantages and disadvantages. This variety makes it difficult for users to determine the best protocol for their specific application purpose. When selecting a Secure Group Communication scheme, it is crucial to know the model's performance under varying network conditions. Research focused so far only on performance in terms of server and client runtimes. To the best of our knowledge, we are the first to perform a network-based performance analysis of SGC schemes. Specifically, we analyze the network impact on the two centralized SGC schemes SKDC and LKH and one decentralized/contributory SGC scheme G-DH. To this end, we used the ComBench tool to simulate different network situations and then measured the times required for the following group operations: group creation, adding and removing members. The evaluation of our simulation results indicates that packet loss and delay influence the respective SGC schemes differently and that the execution time of the group operations depends more on the network situations than on the group sizes. [ABSTRACT FROM AUTHOR]

We report on the implementation of quantum entanglement distribution and quantum state teleportation over a 14.4 km urban dark-fiber link, which is partially underground, partially overhead, and patched in several stations. We characterize the link for its use as a quantum channel and realize its active polarization stabilization. Using a type-II cavity-enhanced SPDC photon pair source, a 40Ca+ single-ion quantum memory, and quantum frequency conversion to the telecom C-band, we demonstrate photon-photon entanglement, ion-photon entanglement, and teleportation of a qubit state from the ion onto a remote telecom photon, all realized over the urban fiber link. [ABSTRACT FROM AUTHOR]

Background: Hypophosphatasia (HPP) is a rare disease caused by deficient activity of tissue-nonspecific alkaline phosphatase (ALP), encoded by the ALPL gene. The primary objective was to explore novel ALPL variants by whole genome sequencing (WGS) in patients with HPP who previously tested negative by standard methods for ALPL variants. The secondary objective was to search for genes beyond ALPL that may reduce ALP activity or contribute to HPP symptoms. Methods and results: WGS was performed in 16 patients clinically diagnosed with HPP who had ALP activity below the normal range and tested negative for ALPL variants. Genetic variants in ALPL and genes possibly associated with low ALP activity or phenotypic overlap with HPP were assessed. All 16 patients had ALP activity below the normal range. WGS did not identify any novel disease-causing ALPL variants. Positive findings for other gene variants were identified in 4 patients: 1 patient presented with variants in COL1A1, NLRP12, and SCN9A, coding for collagen, type, I alpha-1 chain, nod-like receptor pyrin domain containing 12, and sodium voltage-gated channel alpha subunit 9, respectively; 1 presented with a heterozygous, likely pathogenic variant in P3H1 coding for prolyl 3 hydroxylase 1; 1 presented with a heterozygous pathogenic variant in SGCE, coding for sarcoglycan epsilon; and 1 presented with a heterozygous variant of uncertain significance in VDR, encoding vitamin D receptor. Conclusion: Genomic analysis did not identify novel ALPL variants or a pattern of disease-causing variants in genes other than ALPL to explain the HPP phenotype in these patients. Registration: Clinicaltrials.gov identifier: NCT04925804. [ABSTRACT FROM AUTHOR]

In soft soil layers, piles are frequently loaded laterally by horizontal soil movements. In many cases, the lateral pressure acting on piles due to horizontal soil movements is calculated with empirically or analytically based approaches, respectively. However, most of these design approaches do not consider possible influences on the resulting pile loads. This paper presents the results of model tests and numerical simulations on single piles and pile groups in cohesive soil subjected to lateral loads which were carried out to overcome limitations of available design approaches. Based on extensive small-scale 1 × g-model tests and numerical investigations with the finite element method, influencing factors on the lateral pressure, such as the roughness of the pile–soil interface, the pile size, the pile shape and the pile spacing were identified. A parametric study with the numerical model quantified the most relevant factors influencing the development of lateral pressure on piles due to adjacent surface loads and lead to the development of a simplified analysis approach. [ABSTRACT FROM AUTHOR]

Recent stabilization work at the Ludlow Massacre Site National Historic Landmark revealed new insights into memorialization activities over time. The site commemorates a battle between striking miners and the Colorado National Guard which culminated in the destruction of a striking miners 'tent colony by fire causing the deaths of two women and eleven children in a cellar. The United Mine Workers of America erected a monument and preserved that cellar in cement sometime after 1918. Unexpected finds encountered during preservation work on the cellar raise issues related to collective memory, memorialization, and scale. These finds offer new understandings of changes made at the site by the strikers and the UMWA since the massacre in 1914. [ABSTRACT FROM AUTHOR]