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Spencer E Thomas,1,2,* Jeffrey Comer,1,* Min Jung Kim,1 Shanna Marroquin,1 Vaibhav Murthy,1 Meghana Ramani,1 Tabetha Gaile Hopke,2 Jayden McCall,1 Seong-O Choi,1 Robert K DeLong1 1Nanotechnology Innovation Center of Kansas State, Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS, USA; 2Department of Biomedical Science, Missouri State University, Springfield, MO, USA *These authors contributed equally to this work Introduction: Biomedical applications of nanoparticles (NPs) as enzyme inhibitors have recently come to light. Oxides of metals native to the physiological environment (eg, Fe, Zn, Mg, etc.) are of particular interest—especially the functional consequences of their enzyme interaction. Materials and methods: Here, Fe2O3, zinc oxide (ZnO), magnesium oxide (MgO) and nickel oxide (NiO) NPs are compared to copper (Cu) and boron carbide (B4C) NPs. The functional impact of NP interaction to the model enzyme luciferase is determined by 2-dimensional fluorescence difference spectroscopy (2-D FDS) and 2-dimensional photoluminescence difference spectroscopy (2-D PLDS). By 2-D FDS analysis, the change in maximal intensity and in 2-D FDS area under the curve (AUC) is in the order Cu~B4C>ZnO>NiO>>Fe2O3>MgO. The induced changes in protein conformation are confirmed by tryptic digests and gel electrophoresis. Results: Analysis of possible trypsin cleavage sites suggest that cleavage mostly occurs in the range of residues 112–155 and 372–439, giving a major 45 kDa band. By 2-D PLDS, it is found that B4C NPs completely ablate bioluminescence, while Cu and Fe2O3 NPs yield a unique bimodal negative decay rate, -7.67×103 and -3.50×101 relative light units respectively. Cu NPs, in particular, give a remarkable 271% change in enzyme activity. Molecular dynamics simulations in water predicted that the surfaces of metal oxide NPs become capped with metal hydroxide groups under physiological conditions, while the surface of B4C becomes populated with boronic acid or borinic acid groups. These predictions are supported by the experimentally determined zeta potential. Thin layer chromatography patterns further support this conception of the NP surfaces, where stabilizing interactions were in the order ionic>polar>non-polar for the series tested. Conclusion: Overall the results suggest that B4C and Cu NP functional dynamics on enzyme biochemistry are unique and should be examined further for potential ramifications on other model, physiological or disease-relevant enzymes. Keywords: 2-dimensional fluorescence difference, 2-D FDS, AUC, corrected light intensity emitted, emission wavelength, excitation wavelength, wavelength of max intensity, RLU

Susan R Childs,1,* Emma M Casely,2,* Bianca M Kuehler,1 Stephen Ward,1 Charlotte L Halmshaw,1 Sarah E Thomas,1 Ian D Goodall,1 Carsten Bantel1,3 1Pain Medicine, Chelsea and Westminster Hospital NHS Foundation Trust, London, 2Anaesthetic Department, Hillingdon Hospital, Uxbridge, 3Section of Anaesthetics, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital Campus, London, UK *These authors contributed equally to this manuscript Abstract: Recent research has confirmed that between 25% and 33% of all hospitalized patients experience unacceptable levels of pain. Studies further indicate that this reduces patient satisfaction levels, lengthens hospital stays, and increases cost. Hospitals are aiming to discharge patients earlier, and this can interfere with adequate pain management. Therefore, the pain service at Chelsea and Westminster Hospital has adapted to this changing model of care. An increasing body of evidence demonstrates that psychological factors are key components of patients’ pain experiences in both acute and chronic pain. Therefore, it is reasonable to suggest a clinical psychologist should be involved in inpatient pain management. This small study discusses three cases that highlight how patient care could be improved by including a clinical psychologist as part of the inpatient pain team. Two cases particularly highlight the active role of the psychologist in the diagnosis and management of common conditions such as fear and anxiety, along with other psychiatric comorbidities. The management therefore employed an eclectic approach adapted from chronic pain and comprising of behavioral, cognitive behavioral, and dialectical behavioral therapeutic techniques blended with brief counseling. The third case exemplifies the importance of nurse-patient interactions and the quality of nurse-patient relationships on patient outcomes. Here, the psychologist helped to optimize communication and to resolve a difficult and potentially risk-laden situation. This small case series discusses the benefits derived from the involvement of a clinical psychologist in the management of inpatient pain, and therefore illustrates the need for novel initiatives for inpatient pain services. However, future research is warranted to validate this approach. Keywords: acute pain, aggression, anxiety, borderline personality disorder, psychology

Abstract Background In 2018 Massachusetts mandated that county jails offer all FDA-approved medications for opioid use disorder (MOUD) to incarcerated individuals with OUD. Estimating costs needed to implement and sustain an MOUD program are not clearly known in jail facilities. The objective of this study was to identify the type of MOUD model deployed by the jails serving as research sites for the Massachusetts JCOIN hub, determine which resources were utilized at each stage of development, and estimate the associated costs. Methods Resources required to implement and sustain the MOUD programs were identified through detailed, site-specific microcosting analyses at six participating jails in Massachusetts. Quantitative resource utilization data were captured primarily through in-person site-visits and semi-structured interviews with key personnel. Unit costs were derived from the Federal Supply Schedule and Bureau Labor of Statistics from a site-specific level perspective. Our customizable budget impact tool, designed to assist jails/prisons with assessing the viability of alternative MOUD models, was used to organize each site’s resources and estimate their associated costs. Resources/costs were summarized by site, according to type and phase, and cross-site comparisons were made to identify common program elements and unique models. Results Three MOUD models were identified. Model 1 consisted of a vendor hired to deliver and administer methadone daily, while clinical jail staff administered buprenorphine and extended-release naltrexone. Model 2 included facilities that hired a certified vendor to operate an in-house opioid treatment program (OTP) to oversee the administration of all MOUD. Jails in Model 3 became certified OTPs, thereby allowing jail staff to manage all aspects of the MOUD program. There was considerable variability in implementation costs, both within and across models, driven by model-specific factors, but also with switching models, expanding infrastructure, etc. Entering the sustainment phase, the per-person costs of care were quite similar across models but differed according to the proportion of costs considered time-dependent vs. variable. Conclusion Our findings represent the most detailed and comprehensive estimates of resource/cost requirements for jail-based MOUD programs. Given the budget constraints faced by jails, the investment required to implement/sustain an MOUD program will likely result in the need to obtain additional funding or reallocate existing resources away from other initiatives.

Abstract Background Li-Fraumeni syndrome (LFS) is an autosomal dominant tumor predisposition syndrome characterized by a high familial incidence of various malignancies. It results from pathogenic/likely pathogenic heterozygous constitutional variants of the TP53 gene. Due to impaired DNA damage repair, conventional cytotoxic therapies or radiotherapy should be avoided whenever feasible to mitigate the high incidence of treatment-related secondary malignancies in these patients. However, there is limited evidence supporting the effectiveness of targeted therapy approaches in LFS patients. Case presentation We present the case of a woman with breast cancer and subsequent osteosarcoma, both treated with surgery and chemotherapy. Constitutional genetic germline testing identified a pathogenic TP53 variant in line with the clinical features of Li-Fraumeni syndrome. Subsequent molecular analysis of the osteosarcoma tissue revealed homozygous loss of the CDKN2A gene locus, warranting treatment with CDK4/6 inhibitor palbociclib. Palbociclib therapy was discontinued after one year with no evidence of disease. One year later, ovarian cancer was diagnosed, with molecular analysis indicating interstitial heterozygous loss of the BRCA2 gene locus, providing a rationale for targeted therapy with the PARP inhibitor olaparib. Conclusions In the era of accessible and comprehensive genetic and phenotypic tumor profiling, this case study of a patient with Li-Fraumeni syndrome underscores the success of precision oncology in harnessing additional somatic oncogenic driver alterations. Furthermore, it emphasizes the indispensable role of an interdisciplinary molecular tumor board, enhancing the awareness of molecular profiling and targeted therapies in patients with rare cancer susceptibility disorders.

Abstract Hepatocellular carcinoma (HCC) remains the most prevalent type of primary liver cancer worldwide. p53 is one of the most frequently mutated tumor-suppressor genes in HCC and its deficiency in hepatocytes triggers tumor formation in mice. To investigate iron metabolism during liver carcinogenesis, we employed a model of chronic carbon tetrachloride injections in liver-specific p53-deficient mice to induce liver fibrosis, cirrhosis and subsequent carcinogenesis. A transcriptome analysis of liver carcinoma was employed to identify p53-dependent gene expression signatures with subsequent in-depth analysis of iron metabolic parameters being conducted locally within liver cancers and at systemic levels. We show that all mutant mice developed liver cancer by 36-weeks of age in contrast to 3.4% tumors identified in control mice. All liver cancers with a p53-deficient background exhibited a local iron-poor phenotype with a “high transferrin receptor 1 (Tfr1) and low hepcidin (Hamp)” signature. At systemic levels, iron deficiency was restricted to female mice. Additionally, liver tumorigenesis correlated with selective deficits of selenium, zinc and manganese. Our data show that iron deficiency is a prevalent phenomenon in p53-deficient liver cancers, which is associated with alterations in Hamp and Tfr1 and a poor prognosis in mice and patients.

Background: In Japan, urticaria is a common skin disorder with chronic spontaneous urticaria (CSU) being the most frequent subtype. This study evaluated the safety of ligelizumab (anti-IgE monoclonal antibody) in Japanese CSU patients. Methods: This was a Phase 3 multicenter, open-label, single-arm 52-week study in adult Japanese patients with CSU inadequately controlled with locally approved doses of H1-antihistamines. The primary objective reported the safety of ligelizumab 120 mg subcutaneously every 4 weeks, by evaluation of treatment emergent adverse events (TEAE). Secondary objectives evaluated efficacy by absolute change from baseline (CFB) in weekly urticaria activity score (UAS7), and the proportion of patients with UAS7 = 0, and dermatology life quality index (DLQI) = 0–1 over time. Results: From a total of 66 CSU patients (80.3% females; mean ± SD age 46.4 ± 13.2 years; mean ± SD baseline UAS7 28.7 ± 6.5) enrolled, 53 patients (80.3%) reported ≥1 TEAE during the study, with no severe or serious adverse events, no anaphylaxis events and low frequency of TEAEs leading to treatment discontinuations (6.1%). Absolute mean CFB of UAS7 showed a rapid onset of response at Week 4 (−14.2) with further improvement until end of treatment at Week 52 (−22.9). The proportion of patients achieving UAS7 = 0 improved over time (14.5% at Week 4; 50.0% at Week 52). A sizable proportion of patients achieved DLQI 0–1 with the first dose of ligelizumab (38.5%), and improvements observed throughout the study until Week 52 (68.8%). Conclusions: Treatment with ligelizumab 120 mg was well-tolerated with mild to moderate adverse events and was efficacious in Japanese patients.

Background: Femoral head fractures with osteochondral defects are rare injuries often resulting from traumatic hip dislocations. These injuries create a significant risk for post-traumatic osteoarthritis. Various surgical methods for repair have been utilized to restore these osteochondral defects, including mosaicplasty, autologous cartilage implantation, osteochondral allograft transplant (OAT), and demineralized bone matrix (DBM). Methods: We present a case of a 21-year-old male who sustained a fracture-dislocation of the left femoral head with impaction of the weight-bearing surface due to a motor vehicle collision. Due to the patient’s relatively young age, OAT plugs from a fresh-frozen proximal humerus with DBM supplementation during fracture fragment fixation were chosen to reduce the likelihood of post-traumatic arthritis. Results: The patient regained subjective function and full strength on exam with no pain at 2 years postoperatively. Conclusions: We propose that a proximal humerus allograft is a suitable alternative in an urgent setting when a femoral head allograft is not available.

Abstract Purpose of Review Embedding machine learning workflows into real-world hospital environments is essential to ensure model alignment with clinical workflows and real-world data. Many non-healthcare industries undergoing digital transformation have already developed data labelling and data quality management services as a vertically integrated business process. Recent Findings In this paper, we describe our experiences developing and implementing a first-of-its-kind clinical NLP (natural language processing) service in the National Health Service, United Kingdom using parallel harmonised platforms. We report on our work developing clinical NLP resources and implementation framework to distil expert clinical knowledge into our NLP models. To date, we have amassed over 26,086 annotations spanning 556 SNOMED CT concepts working with secondary care specialties. Summary Our integrated language modelling service has delivered numerous clinical and operational use-cases using named entity recognition (NER). Such services improve efficiency of healthcare delivery and drive downstream data-driven technologies. We believe it will only be a matter of time before NLP services become an integral part of healthcare providers.

Abstract Background Task-shifting from primary care physicians (PCPs) to nurses is a means of overcoming PCP shortages and meeting the needs of patients receiving primary care. The aim of this overview of systematic reviews is to assess the effects of delegation or substitution of PCPs’ activities by nurses on patient relevant, clinical, professional and health services-related outcomes. Methods We conducted a systematic literature search for secondary literature in Medline, Embase, Pubmed, the Cochrane Library, and the Cumulative Index of Nursing and Allied Health Literature (CINAHL). We included systematic reviews and meta-analyses that analysed randomised controlled trials (RCTs) and controlled, prospective trials in English and German. Abstracts and full-text articles were screened independently by two reviewers. Full-text articles were assessed using the Overview Quality Assessment Questionnaire. After data extraction a narrative synthesis was performed. We defined patient-relevant outcomes as our primary outcomes. Results We included six systematic reviews. The interventions included first contact, history taking and assessment, patient education, review of drug treatment, referrals to GPs and other health professionals, ordering further investigations and ongoing care. Two meta-analyses showed a relative risk reduction of mortality in favour of nurse-led care, whereby the reduction in one analysis was significant. The effect was highest in the group of more highly qualified nurse practitioners (RR 0.19), as opposed to nurse practitioners (RR 0.76) and registered nurses (RR 0.92). Two meta-analyses showed a relative risk reduction in hospital admissions and patient satisfaction. Whereas care conducted by physicians and registered nurses led to the same outcomes, care conducted by nurse practitioners led to better outcomes (RR 0.74). An analysis according to nursing group showed that patients were more satisfied with treatment by registered nurses (SMD 1.37) than with treatment conducted by nurse practitioners and more qualified nurse practitioners (SMD 0.17). In terms of patient-relevant outcomes, no differences were observed between physician-led care and nurse-led care in terms of physical function, quality of life and pain. Conclusion Nurse-led care is probably as safe or safer than physician-led care in terms of mortality and hospital admissions. However, the impact of nursing staff training has not been sufficiently examined.

Abstract Background Ductal pancreatic adenocarcinoma (PDAC) still has a dismal prognosis even when deemed resectable. A cancer free resection margin (R0) is associated with a more favourable prognosis than the presence of tumour cells at resection margin (R1). However, the precise definition of the R0 status is still a matter of debate in PDAC. For a more accurate determination of R0 in PDAC the concept of circumferential resection margins (CRM) has been established and has been incorporated into the German national S3 guideline on exocrine pancreatic cancer. However, an international standardized nomenclature of CRM is still missing, and the clinical value of the CRM concept is not yet fully established. Here we evaluate whether the CRM status as defined in the national German S3 guideline corresponds with overall and progression free survival in PDAC using data from the regional cancer registry of the State of Baden Württemberg in Germany. Methods Data from the cancer registry of the State of Baden-Württemberg, Germany, were used to assess the relationship between CRM-status and progression free survival (PFS) as well as 3-year overall survival (OS) using documented patients diagnosed with resectable ductal adenocarcinoma of the pancreas between 2015 and 2020. Patients were residents of the State of Baden-Württemberg and underwent surgery for PDAC. The R-status was assessed according to the national German S3 guideline with R0 wide/CRM- when CRM is > 1 mm from the tumour, R0 narrow/CRM + when CRM is ≤ 1 mm from the tumour and R1 when tumour cells are found at the resection margin. Results In total we identified 1098 cases surgically treated for pancreatic cancer and fulfilling the inclusion criteria. 340 patients had an R0 wide/CRM- resection, 410 patients an R0 narrow/CRM + resection, and 348 patients an R1 resection. The R0 wide/CRM- status was associated with a significantly increased median OS rate compared to the other two groups (51,5%, 37,4% and 26,7% for R0 wide/CRM-, R0 narrow/CRM + and R1, respectively). mPFS was also longer in the R0 wide/CRM- group. These findings were robust with regards to grading and tumour location. Conclusions CRM is prognostic for patients with resectable PDAC making the pathological assessment of the R-status according to the CRM concept worthwhile.

Estimating spatiotemporal, kinematic, and kinetic movement variables with little obtrusion to the user is critical for clinical and sports applications. One possible approach is using a sparse inertial sensor setup, where sensors are not placed on all relevant body segments. Here, we investigated if movement variables can be estimated similarly accurate from sparse sensor setups as from a full lower-body sensor setup. We estimated the variables by solving optimal control problems with sagittal plane lower-body musculoskeletal models, in which we minimized an objective that combined tracking of accelerometer and gyroscope data with minimizing muscular effort. We created simulations for 10 participants at three walking and three running speeds, using seven sensor setups with between two and seven sensors located at the feet, shank, thighs, and/or pelvis. We found that differences between variables estimated from inertial sensors and those from optical motion capture were small for all sensor setups. Including all sensors did not necessarily lead to the smallest root mean square deviations (RMSDs) and highest coefficients of determination (R2). Setups without a pelvis sensor led to too much forward trunk lean and inaccurate spatiotemporal variables. Mean RMSDs were highest for the setup with two foot-worn inertial sensors (largest error in knee angle during running: 18 deg vs. 11 deg for the full lower-body setup), and ranged between 4.8–18 deg for the joint angles, between 1.0–5.4 BW BH% for the joint moments, and between 0.03 BW–0.49 BW for the ground reaction forces. We found strong or moderate relationships (R2>0.5) on average for all kinematic and kinetic variables, except for the hip and knee moment for five out of the seven setups. The large range of the coefficient of determination for most kinetic variables indicated individual differences in simulation quality. Therefore, we conclude that we can perform a comprehensive sagittal-plane motion analysis with sparse sensor setups as accurately as with a full sensor setup with sensors on the feet and on either the pelvis or the thighs. Such a sparse sensor setup enables comprehensive movement analysis outside the laboratory, by increasing usability of inertial sensors.

In this paper, we present a new methodology that directly extracts the geometry of woody features (wood and bark) and foliage from 3D data originating from terrestrial laser scans. Our goal was to enhance the precision of radiative transfer models for modelling tree shading by using highly resolved 3D tree models. The approach was tested on a single apple tree (Malus domestica (Suckow) Borkh.) in a peri-urban setting and was validated by utilising an open-source radiative transfer model and comparing the simulation output with in-situ measurements of photosynthetically active radiation (PAR) as well as simulations utilizing turbid voxels of 0.2 m and 1 m edge length. The in-situ measurements of 60 PAR sensors showed a correlation coefficient (r) of 0.92 with the simulated light intensities for the reconstructed polygons which was higher than for the voxel-based approaches (0.2 m: r = 0.85, 1 m: r = 0.73). We were able to demonstrate that our approach effectively simulates light extinction through the canopy. This innovative method has the potential to easily provide detailed insights into high resolution radiation patterns within forests, which are connected to multiple ecosystem functions like species and habitat diversity.

Spike-wave-discharges (SWD) are the electrophysiological hallmark of absence epilepsy. SWD are generated in the thalamo-cortical network and a seizure onset zone was identified in the somatosensory cortex (S1). We have shown before that inhibition of the centromedian thalamic nucleus (CM) in GAERS rats resulted in a selective suppression of the spike component while rhythmic cortical 5–9 Hz oscillations remained present. Such oscillations are often seen to precede SWD activity in this well-validated genetic rat model of absence epilepsy, but are also seen in seizure-free periods. The present study characterizes the profile of 5–9 Hz oscillations in thalamo-cortical circuits during pre- and inter-ictal states.Here we recorded local-field-potentials in S1, CM and the secondary motor cortex of GAERS. Time-frequency analysis was used to assess spectral power and non-linear-association analysis was used to determine coupling strength and directionality between brain areas. Phase-specific electrical stimulation was used to compare cortical excitability and to assess the risk for epileptic afterdischarges.Coupling strength and spectral power were higher for the inter-ictal compared to the pre-ictal 5–9 Hz oscillations. However, coupling strength during pre-ictal oscillations was higher than during passive wakefulness. Double pulse stimulation during 5–9 Hz oscillations was more likely to induce epileptic afterdischarges compared to stimulation during passive wakefulness. While no overall differences in cortical excitability were revealed, phase-specific differences in excitability were noticed during the oscillation.Our findings indicate that intermediate coupling between S1 and CM favors SWD generation, thereby adding to the previous notion that 5–9 Hz oscillations represent high-risk periods for seizure generation. In general, pre-ictal oscillations display a unique electrophysiological profile in GAERS that might pave the way for qualification as biomarker for SWD generation and seizure prediction.

Background Pancreatic ductal adenocarcinoma (PDAC) is mostly refractory to immunotherapy due to immunosuppression in the tumor microenvironment and cancer cell-intrinsic T cell tolerance mechanisms. PDAC is described as a “cold” tumor type with poor infiltration by T cells and factors leading to intratumoral T cell suppression have thus received less attention. Here, we identify a cancer cell-intrinsic mechanism that contributes to a T cell-resistant phenotype and describes potential combinatorial therapy.Methods We used an unbiased screening approach of T cell resistant and sensitive murine KPC (KrasLSL-G12D/+; Trp53fl/fl; Ptf1aCre/+) PDAC cells in a three-dimensional co-culture platform with syngeneic antigen-educated T cells to identify potential cell-intrinsic drivers of T cell suppression in PDAC. Comparative transcriptomic analysis was performed to reveal promising candidates that mediate resistance to T cells. We investigated their contribution by shRNA-mediated knockdown and pharmacological inhibition in murine in vitro and in vivo studies, as well as in patient-derived organoids (PDOs). A combination of transcriptomic analyses, cytometric and immunohistochemistry techniques allowed us to validate the underlying T cell response phenotypes of PDAC cells. The action of TGM2 via interaction with tubulin and the impact of microtubule dynamics and vesicle trafficking were evaluated by protein analyses and live-cell imaging. Correlation analyses via TCGA data complemented the functional studies.Results We identified transglutaminase 2 (TGM2) as a mediator of T cell suppression in PDAC. We report that high levels of TGM2 expression in patients’ tumors correlate with immunosuppressive signatures and poor overall survival. We found that TGM2 regulates vesicle trafficking by modulating microtubule network density and dynamics in pancreatic cancer cells, thus facilitating the secretion of immunosuppressive cytokines, which impair effector T cell functionality. In TGM2-expressing PDOs, pharmacological TGM2 inhibition or treatment with nocodazole increased T cell-mediated apoptosis. Also, pretreatment of TGM2high PDOs with sublethal doses of the spindle poisons paclitaxel or vincristine increased CD8+T cell activation and sensitized PDOs toward T cell-mediated cytotoxicity.Conclusions These findings indicate that targeting microtubular function therapeutically may enhance antitumor T cell responses by impacting activity of immunosuppressive cytokines in the PDAC microenvironment.

Recycling and second life of lithium-ion batteries are vital for lowering the growing resource demand of sectors like mobility or home energy storage. However, an often-overlooked issue is the sometimes-unknown cell chemistry of batteries entering the end-of-life. In this work, a machine learning based approach for the identification of lithium-ion battery cathode chemistries is presented. First, an initial measurement boundary determination is introduced. Using the Python Battery Mathematical Modelling (PyBaMM) framework, synthetical partial open circuit voltage (OCV) charge and discharge curves are generated with an electrochemical single particle model for three different cathode chemistries and the initial state of charge and state of health values as well as the initial capacities are varied. The dV/dQ characteristics are chosen as features and four machine learning algorithms are trained on different lengths of OCV curves. The trade-off between achievable accuracy and the number of OCV steps showed that an increasing accuracy correlates with a higher step number. While extremely small charge and discharge capacities per step did not yield sufficient testing accuracies, capacities starting from 0.2 Ah per step up to 0.6 Ah per step showed increasingly good results with an accuracy of up to 89.3 % for 0.5 Ah and 15 OCV steps. Additionally, the approach was validated by classifying experimental data. The results especially demonstrate the effectiveness of the approach to distinguish between lithium iron phosphate (LFP) and lithium nickel manganese cobalt (NMC) cells.

Aiming to sustainable manufacturing options, materials that are discarded from the industry and to which a second life may be given are highly desirable. Condensed tannins constitute the starting point to create tannin-furanic foams, a rigid biobased material that could be a sustainable alternative to those derived from fossil fuel-based chemicals. With the objective of developing novel foam production strategies, three different tannin-furanic foams, namely mechanical, sulfuric and nitric, were thoroughly chemically characterized, and their morphological and macroscopic properties were compared with those of commercial plastic foams made of polystyrene and of polyethylene terephthalate. Understanding the influence of the foaming method on the foam properties is of utmost importance when aiming to substitute existing, well-established products. The chemical characterization was performed by using NMR, FTIR and UV Raman, assisted by DFT quantum mechanics simulations. The morphological characterization was done by Scanning Electron Microscopy and X-ray micro-Tomography. Macroscopic characterization was done by strain–stress, thermal conductivity, and thermal gravimetric analysis. Our studies demonstrated nitric tannin-furanic foams as the closest to an insulating material, while mechanical tannin-furanic foam is more appropriate as a tough material. Overall, they prove that bio-based tannin-furanic foams appear to be a feasible green alternative to conventional plastic foams.

Intercalation is a promising approach for tailoring the electronic structure of epitaxial graphene on SiC. It enables the formation of otherwise unstable 2D phases of elements and allows the investigation of the interplay between the 2D materials and the substrate. Detailed studies have been conducted on the Pb intercalation process, as well as the structure and electronic properties of the 2D Pb layer using low‐energy electron microscopy and photoelectron spectroscopy. The low‐energy bands of Pb show good agreement with density‐functional theory calculations. A uniform Pb intercalation layer with (1 × 1) periodicity with respect to the SiC substrate is found. The quasifreestanding graphene is effectively screened from the doping influence of the substrate, leading to charge neutrality. Instead, the 2D Pb layer compensates for the spontaneous polarization of the substrate, allowing for the doping of a metal layer under cover. A phase transformation from the (1 × 1) intercalation phase into a bubble phase with quasi‐tenfold periodicity with respect to graphene occurs if the system is provided with sufficient energy. These results experimentally quantify the interaction between the 2D Pb layer, the substrate, and the graphene layer, demonstrating a first step toward controlling the diversity of 2D Pb phases.

Abstract Aims Right ventricular failure after left ventricular assist device (LVAD) implantation is a major concern that remains challenging to predict. We sought to investigate the relationship between preoperative pulmonary artery pulsatility index (PAPi) and mortality after LVAD implantation. Methods and results A retrospective analysis of the ASSIST‐ICD multicentre registry allowed the assessment of PAPi before LVAD according to the formula [(systolic pulmonary artery pressure − diastolic pulmonary artery pressure)/central venous pressure]. The primary endpoint was survival at 3 months, according to the threshold value of PAPi determined by the receiver operating characteristic (ROC) curve. A multivariate analysis including demographic, echographic, haemodynamic, and biological variables was performed to identify predictive factors for 2 year mortality. One hundred seventeen patients were included from 2007 to 2021. The mean age was 58.45 years (±13.16), with 15.4% of women (sex ratio 5.5). A total of 53.4% were implanted as bridge to transplant and 43.1% as destination therapy. Post‐operative right ventricular failure was observed in 57 patients (48.7%), with no significant difference between survivors and non‐survivors at 1 month (odds ratio 1.59, P = 0.30). The median PAPi for the whole study population was 2.83 [interquartile range 1.63–4.69]. The threshold value of PAPi determined by the ROC curve was 2.84. Patients with PAPi ≥ 2.84 had a higher survival rate at 3 months [PAPi

Abstract Small open reading frames (smORFs) shorter than 100 codons are widespread and perform essential roles in microorganisms, where they encode proteins active in several cell functions, including signal pathways, stress response, and antibacterial activities. However, the ecology, distribution and role of small proteins in the global microbiome remain unknown. Here, we construct a global microbial smORFs catalog (GMSC) derived from 63,410 publicly available metagenomes across 75 distinct habitats and 87,920 high-quality isolate genomes. GMSC contains 965 million non-redundant smORFs with comprehensive annotations. We find that archaea harbor more smORFs proportionally than bacteria. We moreover provide a tool called GMSC-mapper to identify and annotate small proteins from microbial (meta)genomes. Overall, this publicly-available resource demonstrates the immense and underexplored diversity of small proteins.

Abstract Background Social isolation and loneliness are urgent public health concerns associated with negative physical and mental health outcomes. Understanding effective remedies is crucial in addressing these problems. This umbrella review aimed to synthesize and critically appraise scientific evidence on the effectiveness of social isolation and loneliness interventions overall and across subgroups. We focused on systematic reviews (SRs) of randomized controlled trials (RCTs). Methods We searched seven databases (June 2022 and updated June 2023) and supplemented the search with grey literature and reference screening to identify SRs published since 2017. Screening, data extraction, and quality assessment using the AMSTAR2 tool were conducted independently by author pairs, with disagreements resolved through discussion. Results We included 29 SRs, 16 with meta-analysis and 13 with narrative synthesis. All SRs focused on loneliness, with 12 additionally examining social isolation. Four SRs focused on young people, 11 on all ages, and 14 on older adults. The most frequently examined intervention types were social (social contact, social support), psychological (therapy, psychoeducation, social skills training), and digital (e.g., computer use and online support). Meta-analyses indicated small-to-moderate beneficial effects, while narrative synthesis demonstrated mixed or no effect. Social interventions for social isolation and psychological interventions for loneliness were the most promising. However, caution is warranted due to the effects’ small magnitude, significant heterogeneity, and the variable quality of SRs. Digital and other interventions showed mixed or no effect; however, caution is advised in interpreting these results due to the highly diverse nature of the interventions studied. Conclusions This overview of SRs shows small to moderate effectiveness of social interventions in reducing social isolation and psychological ones in tackling loneliness. Further rigorously conducted RCTs and SRs are needed to guide policy decisions regarding the implementation of efficacious and scalable interventions. Evaluation should focus on both preventive structural interventions and tailored mitigating strategies that address specific types and causes of loneliness.

The abstract nature of algorithms and data structures poses challenges for students, and the integration of visualization into comprehensive learning systems remains underexplored. This article presents VisualCodeMOOC, incorporating VisualCodeChat, a conversational agent that enhances algorithm and data structure learning through dynamic visualizations and personalized feedback. The platform effectively addresses these challenges, improving student engagement and comprehension. With instructions structuring, novel response-based algorithm visualization, exercise design, VisualCodeMOOC provides a cohesive and supportive learning environment that promotes active learning. Evaluation results demonstrate its usability, responsiveness, and educational value, confirming its potential as a promising tool for advancing computer science education.

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A new approach for the growth of vertical 2D van‐der‐Waals heterostructures is reported: Using metal‐organic molecular beam epitaxy (MOMBE), aspects of chemical and physical vapor deposition are combined to grow ultrathin films of WX2 (X = Se, S) on epitaxial graphene on SiC(0001). Thorough investigation of the films using a variety of spectroscopy, diffraction, and microscopy techniques reveals an island‐like growth of predominantly mono‐ and bilayer regions with crystallite size up to 300 nm, which show a preferred epitaxial alignment with the graphene substrate. Angle‐resolved photoemission reveals a well‐developed band structure of the heterostructure, with the growth process showing minimal effect on the electronic structure of the graphene sheet.

Therapeutic antibodies (Ab) have revolutionized the management of multiple illnesses including respiratory tract infections (RTIs). However, anti-infectious Ab displayed several limitations including antigen restrictiveness, narrowed therapeutic windows, and limited dose in the vicinity of the target when delivered by parenteral routes. Strategies enhancing further Ab-dependent containment of infection are currently needed. Here we showed that a combination of inhaled anti-infectious Ab and probiotics is an efficient formulation to protect against lung infection. Using a mouse model of Pseudomonas aeruginosa-induced pneumonia, we demonstrated a synergistic effect reducing both bacterial burden and pro-inflammatory response affording protection against primary and secondary infections. This is the first study showing that the local combination in the airways of anti-infective Ab and probiotics subverts suboptimal potency of Ab monotherapy and provides protection against respiratory pathogen.

Exploring the capabilities of remote sensing technologies for identifying stress responses in trees due to environmental pressures is crucial for comprehension, management, and maintenance of forests that are productive, healthy, and resilient. In recent decades, research on forest health monitoring has been predominantly focused on data obtained remotely, either from satellites or crewed aircraft. During the last few years, Uncrewed Aerial Vehicles (UAVs) have gained prominence as invaluable remote sensing platforms, increasingly being employed for forest surveying. As intermediary between traditional remote sensing methods and ground-level observations, UAVs can capture high-resolution imagery from low altitudes, even below cloud cover, in unprecedented detail. This ability allows for the precise detection of stress responses at the individual tree scale. In our study, we have acquired a highly heterogenous, multispectral time-series dataset from the International Co-operative Programme on Assessment and Monitoring of Air Pollution Effects on Forests (ICP Forests) inventory plots across Bavaria, Germany, focusing on the main tree species. The data was recorded over three consecutive years from a UAV with the objective of monitoring tree physiological stress responses. Concurrently, with the drone flights, the ground-based forest condition surveying (Level-1 monitoring) was conducted, serving as ground-truth validation, and providing detailed information on tree health indicators, such as defoliation and discoloration. Our findings revealed that multispectral imagery obtained from a UAV closely aligns with field data, proving effective detection of physiological stress in trees. Remarkably, in conjunction to the red, red edge, and near-infrared band, the inclusion of the blue band emerged as a critical indicator of tree stress when incorporated into the Blue Normalized Difference Vegetation Index (BNDVI), depending on factors such as tree species, class division, and atmospheric conditions. Furthermore, the averaged values per sample tree over three years, alongside the 5th and 25th percentile of the data distribution, have proven to be of key importance. Based on spectral indices, we achieved good classification accuracies by training species-specific gradient boosting models (macro F1-scores ranging from 0.492 to 0.769). These models can assist in quantifying tree stress responses, thereby supporting the objectives of the ICP Forests program, potentially leading to substantial cost savings or increased coverage in the future.

Abstract Poor treatment responses of pancreatic ductal adenocarcinoma (PDAC) are in large part due to tumor heterogeneity and an immunosuppressive desmoplastic tumor stroma that impacts interactions with cells in the tumor microenvironment (TME). Thus, there is a pressing need for models to probe the contributions of cellular and noncellular crosstalk. Organoids are promising model systems with the potential to generate a plethora of data including phenotypic, transcriptomic and genomic characterization but still require improvements in culture conditions mimicking the TME. Here, we describe an INTERaction with Organoid-in-MatriX ("InterOMaX") model system, that presents a 3D co-culture-based platform for investigating matrix-dependent cellular crosstalk. We describe its potential to uncover new molecular mechanisms of T cell responses to murine KPC (LSL-Kras G12D/+27 /Trp53 tm1Tyj/J /p48 Cre/+) PDAC cells as well as PDAC patient-derived organoids (PDOs). For this, a customizable matrix and homogenously sized organoid-in-matrix positioning of cancer cells were designed based on a standardized agarose microwell chip array system and established for co-culture with T cells and inclusion of stromal cells. We describe the detection and orthogonal analysis of murine and human PDAC cell populations with distinct sensitivity to T cell killing that is corroborated in vivo. By enabling both identification and validation of gene candidates for T cell resistance, this platform sets the stage for better mechanistic understanding of cancer cell-intrinsic resistance phenotypes in PDAC.

Summary: Pancreatic ductal adenocarcinoma (PDAC) presents significant challenges for targeted clinical interventions due to prevalent KRAS mutations, rendering PDAC resistant to RAF and MEK inhibitors (RAFi and MEKi). In addition, responses to targeted therapies vary between patients. Here, we explored the differential sensitivities of PDAC cell lines to RAFi and MEKi and developed an isogenic pair comprising the most sensitive and resistant PDAC cells. To simulate patient- or tumor-specific variations, we constructed cell-line-specific mechanistic models based on protein expression profiling and differential properties of KRAS mutants. These models predicted synergy between two RAFi with different conformation specificity (type I½ and type II RAFi) in inhibiting phospho-ERK (ppERK) and reducing PDAC cell viability. This synergy was experimentally validated across all four studied PDAC cell lines. Our findings underscore the need for combination approaches to inhibit the ERK pathway in PDAC.

In this study, fluid flow predictions using three different methods were compared: DeepCFD, an artificial intelligence code; computational fluid dynamics (CFD) using Ansys Fluent and OpenFOAM; and two-dimensional, two-component particle image velocimetry (PIV) measurements. The airfoils under investigation were the NACA 0012 with a 10° angle of attack and the NACA 6412 with a 0° angle of attack. To train DeepCFD, 763, 2585, and 6283 OpenFOAM simulations based on primitives were utilized. The investigation was conducted at a free stream velocity of 10 m/s and a Reynolds number of 82000. Results show that once the DeepCFD network is trained, prediction times are negligible, enabling real-time optimization of airfoils. The mean absolute error between CFD and DeepCFD, with 6283 trained primitives, for NACA 0012 predictions resulted in velocity components Ux = 1.08 m/s, Uy = 0.43 m/s, and static pressure p = 4.57 Pa. For NACA 6412, the corresponding mean absolute errors are Ux = 0.81 m/s, Uy = 0.59 m/s, and p = 7.5 Pa. Qualitative agreement was observed between PIV measurements, DeepCFD, and CFD. Results are promising that artificial intelligence has the potential for real-time fluid flow optimization of NACA airfoils in the future. The main goal was not just to train a network specifically for airfoils, but also for variant shapes. Airfoils are used since they are highly sophisticated in fluid dynamics and experimental data was available.

Objective Lipomatous hypertrophy of the interatrial septum (LHIS) is a distinct section of epicardial adipose tissue. However, its association with COPD is poorly documented. Methods Patients undergoing coronary computed tomography angiography (CTA) for clinical indications were recruited retrospectively and screened for LHIS and COPD. LHIS density and the coronary artery disease profile were quantified by CTA: stenosis severity (coronary artery disease radiological reporting system (CADRADS)), coronary artery calcium (CAC) and high-risk plaque (HRP). COPD patients with LHIS were matched for age and sex, the major cardiovascular risk factors (CVRFs), and compared to controls. Results The prevalence of LHIS in all 5466 patients was 5.9%. 151 (72.6%) of 208 patients with COPD had LHIS. LHIS density in COPD patients was higher (−10.93 HU versus −21.1 HU; p30 kg·m−2) patients (20.4 versus 13.6 HU; p=0.02). BMI was inversely correlated with LHIS density (BetaR −0.031; 95% CI: −0.054– −0.008; p=0.007). LHIS density was associated with COPD, but not with BMI on multivariate models. CAC and coronary stenosis severity (CADRADS and >50% stenosis) were not different (p=0.106, p=0.156 and p=0.350, respectively). HRPs were observed more frequently in COPD patients with severe Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages ≥2 (32.3% versus 20.1%; p=0.044), but not when adding mild GOLD stages. Conclusions The prevalence of LHIS in COPD patients is high (72.6%), and the adipose tissue density is higher, indicating a higher brown fat component. In obese, patients LHIS density is lower and declines along with BMI. Coronary stenosis severity and calcium were not different; however HRPs were more frequent in severe COPD.

Lab Automation facilitates high-throughput processes and improves reproducibility and efficiency while removing human action, primary source of contaminating particles. Handling poses a risk of contamination due to close contact with the objects. We propose a novel gripper (CrocoGrip) relying on compliant mechanisms to reduce the amount of contaminating particles generated by the gripper rather than preventing their emission, the latter being the common approach in current grippers. Our novel gripper is actuated by linear solenoids and purely relies on deformation for its motion. As a result, abrasive behavior and, therefore, the generation of particles is reduced without the need for additional sealing. We experimentally proved that only particles smaller than 3.0µm are emitted by the gripper, with a large proportion of the particles being generated by the actuation. The CrocoGrip fulfills the demands of ISO14644 class 5. The gripping relies on the deformation energy of the compliant mechanism, making the gripping energy-efficient and safe. The maximum gripping force achieved by the CrocoGrip was 5.5N. Because the force transmitted to the handling object depends on the design of the gripping jaws, which are interchangeable, the force can be reduced for more sensible handling objects. Using three different sets of jaws, CrocoGrip was able to handle a microplate in SBS-standard, a 50mL Falcon tube, and a Ø60mm Petri dish using a robotic arm. Due to the monolithic design of the CrocoGrip and, as a result, the need for few components, we achieve a simplicity of design, making cleaning, sterilization and maintenance easy, even for nonexperts. The CrocoGrip exploits the advantages of compliant mechanisms, especially for applications requiring clean-room environments. This approach of compliant-mechanism-based grippers enables an increase in the cleanliness of handling processes without an increase in system complexity of the gripper to facilitate the lab automation of highly sensible processes, such as in tissue engineering.

The author introduced models of linear logic known as ''Interaction Graphs'' which generalise Girard's various geometry of interaction constructions. In this work, we establish how these models essentially rely on a deep connection between zeta functions and the execution of programs, expressed as a cocycle. This is first shown in the simple case of graphs, before begin lifted to dynamical systems. Focussing on probabilistic models, we then explain how the notion of graphings used in Interaction Graphs captures a natural class of sub-Markov processes. We then extend the realisability constructions and the notion of zeta function to provide a realisability model of second-order linear logic over the set of all (discrete-time) sub-Markov processes.

This study aims to evaluate the clinical outcome of stereotactic radiosurgery as the sole treatment for brain metastases and to assess prognostic factors influencing survival. A total of 108 consecutive patients with 213 metastases were retrospectively analyzed. Treatment was determined with close-meshed MRI follow-up. Various prognostic factors were assessed, and several prognostic indices were compared regarding their reliability to estimate overall survival. Median overall survival was 15 months; one-year overall survival was 50.5%. Both one- and two-year local controls were 90.9%. The rate of new metastases after SRS was 49.1%. Multivariate analysis of prognostic factors revealed that the presence of extracranial metastases, male sex, lower KPI, and progressive extracranial disease were significant risk factors for decreased survival. Of all evaluated prognostic indices, the Basic Score for Brain Metastases (BSBMs) showed the best correlation with overall survival. A substantial survival advantage was found for female patients after SRS when compared to male patients (18 versus 9 months, p = 0.003). SRS of brain metastasis is a safe and effective treatment option when frequent monitoring for new metastases with MRI is performed. Common prognostic scores lack reliable estimation of survival times. Female sex should be considered as an additional independent positive prognostic factor influencing survival.

Abstract Background This paper details the results of an evaluation of the level of consensus amongst clinicians on the use of ataluren in both ambulatory and non-ambulatory patients with nonsense mutation Duchenne muscular dystrophy (nmDMD). The consensus was derived using a modified Delphi methodology that involved an exploration phase and then an evaluation phase. Methods The exploration phase involved 90-minute virtual 1:1 interviews of 12 paediatric neurologists who cared for 30–120 DMD patients each and had patient contact every one or two weeks. The respondents managed one to ten nmDMD patients taking ataluren. The Discussion Guide for the interviews can be viewed as Appendix A. Following the exploration phase interviews, the interview transcripts were analysed by an independent party to identify common themes, views and opinions and developed 43 draft statements that the Steering Group (authors) reviewed, refined and endorsed a final list of 42 statements. Details of the recruitment of participants for the exploration and evaluation phases can be found under the Methods section. Results A consensus was agreed (> 66% of respondents agreeing) for 41 of the 42 statements using results from a consensus survey of healthcare professionals (n = 20) experienced in the treatment of nmDMD. Conclusions The statements with a high consensus suggest that treatment with ataluren should be initiated as soon as possible to delay disease progression and allow patients to remain ambulatory for as long as possible. Ataluren is indicated for the treatment of Duchenne muscular dystrophy that results from a nonsense mutation in the dystrophin gene, in ambulatory patients aged 2 years and older (see Summary of Product Characteristics for each country)

Abstract Dysfunctional Ca2+ signaling affects the myocardial systole and diastole, may trigger arrhythmia and cause transcriptomic and proteomic modifications in heart failure. Thus, synchronous real-time measurement of Ca2+ and force is essential to investigate the relationship between contractility and Ca2+ signaling and the alteration of excitation-contraction coupling (ECC) in human failing myocardium. Here, we present a method for synchronized acquisition of intracellular Ca2+ and contraction force in long-term cultivated slices of human failing myocardium. Synchronous time series of contraction force and intracellular Ca2+ were used to calculate force-calcium loops and to analyze the dynamic alterations of ECC in response to various pacing frequencies, post-pause potentiation, high mechanical preload and pharmacological interventions in human failing myocardium. We provide an approach to simultaneously and repeatedly investigate alterations of contractility and Ca2+ signals in long-term cultured myocardium, which will allow detecting the effects of electrophysiological or pharmacological interventions on human myocardial ECC.

We propose a method to estimate information loss when conducting histogram binning and principal component analysis (PCA) sequentially, as usually done in practice for fleet analytics. Coarser-grained histogram binning results in less data volume, fewer dimensions, but more information loss. Considering fewer principal components (PCs) results in fewer data dimensions but increased information loss. Although information loss with each step is well understood, little guidance exists on the overall information loss when conducting both steps sequentially. We use Monte Carlo simulations to regress information loss on the number of bins and PCs, given few parameters of a dataset related to its scale and correlation structure. A sensitivity study shows that information loss can be approximated well given sufficiently large datasets. Using the number of bins, PCs, and two correlation measures, we derive an empirical loss model with high accuracy. Furthermore, we demonstrate the benefits of estimating information losses and the representativeness of total loss in evaluating the accuracy of k-means clustering for a real-world customer fleet dataset. For preprocessing sensor data which are aggregated from sufficient number of samples, continuously distributed, and can be represented by Beta-distributions, we recommend not to coarsen the histogram binning before PCA.

Harmonization in the analytical framework is needed to detect, define and further categorize plastics released into the environment. In the range of particles smaller than 200 μm, hydrocyclones (HCs) have proven their capacity in removing microplastics efficiently by offering technical advantages at low operational costs. This publication aims to expand scientific knowledge by introducing four commercially available, low-priced microplastics to a pilot-scale HC setting. The physicochemical characteristics of particles as well as the separation efficiency of the test rig were investigated in depth. Particles with a density of >1000 kg/m3 passed the primary vortex and were discharged into the underflow, allowing us to employ standard mode operation. Particles with a density of 3 entered the secondary vortex and were removed through the overflow. As expected, separation efficiencies were found to be higher for particles revealing a greater density difference when compared with the mobile phase water. Furthermore, an increase in the inlet volume flow revealed significant positive impacts on the separation efficiency for three plastics to a certain threshold. Data on standard and reverse mode operations presented in this publication can lay out an important source for the harmonization and standardization of future HC research, with the goal of overcoming plastic pollution by developing economically competitive separation processes.

Neural network-based nonlinear system identification is crucial for various multi-step ahead prediction tasks, including model predictive control and digital twins. These applications demand models that are not only accurate but also efficient in training and deployment. While current state-of-the-art neural network-based methods can identify accurate models, they often become prohibitively slow when scaled to achieve high accuracy, limiting their use in resource-constrained or time-critical applications. We propose FranSys, a Fast recurrent neural network-based method for multi-step ahead prediction in non-autoregressive System Identification. FranSys comprises three key innovations: 1) the first non-autoregressive RNN model structure for multi-step ahead prediction that enables much faster training and inference compared to autoregressive RNNs by separating state estimation and prediction into two specialized sub-models, 2) a state distribution alignment training technique that enhances generalizability and 3) a prediction horizon scheduling method that accelerates training by progressively increasing the prediction horizon. We evaluate FranSys on three publicly available benchmark datasets representing diverse systems, comparing its speed and accuracy against state-of-the-art RNN-based multi-step ahead prediction methods. The evaluation includes various prediction horizons, model sizes, and hyperparameter optimization settings, using both our own implementations and those from related work. Results demonstrate that FranSys is 10 to 100 times faster in training and inference with the same and often higher accuracy on test data than state-of-the-art RNN-based multi-step ahead prediction methods, particularly with long prediction horizons. This substantial speed improvement enables the application of larger neural network-based models with longer prediction horizons on resource-constrained systems in time-critical tasks, such as model predictive control and online learning of digital twins. The code of FranSys is publicly available.

Millions of people around the globe are impacted by falls annually, making it a significant public health concern. Falls are particularly challenging to detect in real time, as they often occur suddenly and with little warning, highlighting the need for innovative detection methods. This study aimed to assist in the advancement of an accurate and efficient fall detection system using electroencephalogram (EEG) data to recognize the reaction to a postural disturbance. We employed a state-space-based system identification approach to extract features from EEG signals indicative of reactions to postural perturbations and compared its performance with those of traditional autoregressive (AR) and Shannon entropy (SE) methods. Using EEG epochs starting from 80 ms after the onset of the event yielded improved performance compared with epochs that started from the onset. The classifier trained on the EEG data achieved promising results, with a sensitivity of up to 90.9%, a specificity of up to 97.3%, and an accuracy of up to 95.2%. Additionally, a real-time algorithm was developed to integrate the EEG and accelerometer data, which enabled accurate fall detection in under 400 ms and achieved an over 99% accuracy in detecting unexpected falls. This research highlights the potential of using EEG data in conjunction with other sensors for developing more accurate and efficient fall detection systems, which can improve the safety and quality of life for elderly adults and other vulnerable individuals.

Abstract Expression of CYP3A5 protein is a basal and acquired resistance mechanism of pancreatic ductal adenocarcinoma cells conferring protection against the CYP3A and CYP2C8 substrate paclitaxel through metabolic degradation. Inhibition of CYP3A isozymes restores the cells sensitivity to paclitaxel. The combination of gemcitabine and nab‐paclitaxel is an established regimen for the treatment of metastasized or locally advanced inoperable pancreatic cancer. Cobicistat is a CYP3A inhibitor developed for the pharmacoenhancement of protease inhibitors. The addition of cobicistat to gemcitabine and nab‐paclitaxel may increase the antitumor effect. We will conduct a phase I dose escalation trial with a classical 3 + 3 design to investigate the safety, tolerability, and pharmacokinetics (PKs) of gemcitabine, nab‐paclitaxel, and cobicistat. Although the doses of gemcitabine (1000 mg/m2) and cobicistat (150 mg) are fixed, three dose levels of nab‐paclitaxel (75, 100, and 125 mg/m2) will be explored to account for a potential PK drug interaction. After the dose escalation phase, we will set the recommended dose for expansion (RDE) and treat up to nine patients in an expansion part of the trial. The trial is registered under the following identifiers EudraCT‐Nr. 2019‐001439‐29, drks.de: DRKS00029409, and ct.gov: NCT05494866. Overcoming resistance to paclitaxel by CYP3A5 inhibition may lead to an increased efficacy of the gemcitabine and nab‐paclitaxel regimen. Safety, efficacy, PK, and RDE data need to be acquired before investigating this combination in a large‐scale clinical study.

Simultaneous gas phase temperature and water vapor concentration measurement are important to understand reacting flows such as combustion or gas reforming processes. Here, coherent anti-Stokes Raman scattering (CARS) offers the possibility for non-intrusive measurements with a high temporal and spatial resolution. Therefore, this work demonstrates the simultaneous measurement of temperature and relative water vapor–nitrogen concentrations by using dual-pump vibrational coherent anti-Stokes Raman scattering (DPVCARS). A calibration procedure is developed for a temperature range of 473 K to 673 K and a water vapor concentration of 24% to 46% at ambient pressure. This setup is tested with 500 CARS single pulse spectra taken in a gas cell at a known temperature and concentration. Based on these results, information about precision and accuracy can be delivered.

Abstract Background Transjugular intrahepatic portosystemic shunt (TIPS) is a well-validated treatment option for clinically significant portal hypertension (CSPH) in the context of liver cirrhosis. Its high efficacy and safety in the management of treatment-refractory ascites and variceal bleeding have been extensively proven. Contraindications for TIPS include severe right heart failure, hepatic encephalopathy, and sepsis. However, the role of liver malignancy in TIPS is debatable. Mostly, primary liver malignancies such as hepatocellular carcinoma (HCC) emerge from advanced liver diseases. Coexisting portal hypertension in HCC often results in limited treatment options and a poor prognosis. Summary Previous studies have shown that TIPS implantation in patients with HCC is technically feasible and is usually not associated with major adverse events. Furthermore, TIPS may help in bridging the time to liver transplantation in early HCC and allow for locoregional treatment in advanced HCC. However, several studies suggest that seeding tumour cells to the lungs by TIPS placement might worsen the prognosis. Conclusions TIPS placement in patients with coexisting liver malignancy remains a case-by-case decision, and there is no profound evidence allowing general recommendations. This review aims to provide a state-of-the-art overview of the potential risks and benefits of TIPS placement in patients with liver malignancies.

Abstract The extracellular matrix of bacterial biofilms consists of diverse components including polysaccharides, proteins and DNA. Extracellular RNA (eRNA) can also be present, contributing to the structural integrity of biofilms. However, technical difficulties related to the low stability of RNA make it difficult to understand the precise roles of eRNA in biofilms. Here, we show that eRNA associates with extracellular DNA (eDNA) to form matrix fibres in Pseudomonas aeruginosa biofilms, and the eRNA is enriched in certain bacterial RNA transcripts. Degradation of eRNA associated with eDNA led to a loss of eDNA fibres and biofilm viscoelasticity. Compared with planktonic and biofilm cells, the biofilm matrix was enriched in specific mRNA transcripts, including lasB (encoding elastase). The mRNA transcripts colocalised with eDNA fibres in the biofilm matrix, as shown by single molecule inexpensive FISH microscopy (smiFISH). The lasB mRNA was also observed in eDNA fibres in a clinical sputum sample positive for P. aeruginosa. Thus, our results indicate that the interaction of specific mRNAs with eDNA facilitates the formation of viscoelastic networks in the matrix of Pseudomonas aeruginosa biofilms.

Abstract Objectives It is uncertain, if omitting post-dilatation and stent oversizing (stent optimization) is safe and may decrease the risk for distal thrombus embolization (DTE) in STEMI patients with large thrombus burden (LTB). Background In patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (pPCI) with stenting, (DTE) and flow deterioration are common and increase infarct size leading to worse outcomes. Methods From a prospective registry, 74 consecutive STEMI patients with LTB undergoing pPCI with stenting and intentionally deferred stent optimization were analyzed. Imaging data and outcomes up to 2 years follow-up were analyzed. Results Overall, 74 patients (18% females) underwent deferred stent optimization. Direct stenting was performed in 13 (18%) patients. No major complications occurred during pPCI. Staged stent optimization was performed after a median of 4 (interquartile range (IQR) 3; 7) days. On optical coherence tomography, under-expansion and residual thrombus were present in 59 (80%) and 27 (36%) cases, respectively. During deferred stent optimization, we encountered no case of flow deterioration (slow or no-reflow) or side branch occlusion. Minimal lumen area (mm2) and stent expansion (%) were corrected from 4.87±1.86mm to 6.82±2.36mm (p

Abstract Global cooling has been proposed as a driver of the Great Ordovician Biodiversification Event, the largest radiation of Phanerozoic marine animal Life. Yet, mechanistic understanding of the underlying pathways is lacking and other possible causes are debated. Here we couple a global climate model with a macroecological model to reconstruct global biodiversity patterns during the Ordovician. In our simulations, an inverted latitudinal biodiversity gradient characterizes the late Cambrian and Early Ordovician when climate was much warmer than today. During the Mid-Late Ordovician, climate cooling simultaneously permits the development of a modern latitudinal biodiversity gradient and an increase in global biodiversity. This increase is a consequence of the ecophysiological limitations to marine Life and is robust to uncertainties in both proxy-derived temperature reconstructions and organism physiology. First-order model-data agreement suggests that the most conspicuous rise in biodiversity over Earth’s history – the Great Ordovician Biodiversification Event – was primarily driven by global cooling.

Abstract Background Alcohol is a good and environment-friendly fuel that can be microbially produced, capable of eliminating many of the limitations of the present-day fossil fuels. However, the inherent toxic nature of alcohols to the microbial cells leads to end-product inhibition that limits large-scale alcohol production by fermentation. Fundamental knowledge about the stress responses of microorganisms to alcohols would greatly facilitate to improve the microbial alcohol tolerance. The current study elucidates and compares the changes in the membrane proteome of Escherichia coli in response to a range of alcohols. Results Although alcohol toxicity increased exponentially with alcohol chain length (2–6 carbon), similar stress responses were observed in the inner and outer membrane proteome of E. coli in the presence of 2-, 4- and 6-carbon alcohols at the MIC50. This pertains to: (1) increased levels of inner membrane transporters for uptake of energy-producing metabolites, (2) reduced levels of non-essential proteins, associated with anaerobic, carbon starvation and osmotic stress, for energy conservation, (3) increased levels of murein degrading enzymes (MltA, EmtA, MliC and DigH) promoting cell elongation and 4) reduced levels of most outer membrane β-barrel proteins (LptD, FadL, LamB, TolC and BamA). Major outer membrane β-barrel protein OmpC, which is known to contribute to ethanol tolerance and membrane integrity, was notably reduced by alcohol stress. While LPS is important for OmpC trimerisation, LPS release by EDTA did not lower OmpC levels. This suggests that LPS release, which is reported under alcohol stress, does not contribute to the reduced levels of OmpC in the presence of alcohol. Conclusions Since alcohol primarily targets the integrity of the membrane, maintenance of outer membrane OmpC levels in the presence of alcohol might help in the survival of E. coli to higher alcohol concentrations. The study provides important information about the membrane protein responses of E. coli to a range of alcohols, which can be used to develop targeted strategies for increased microbial alcohol tolerance and hence bioalcohol production.

A polymicrobial biofilm model of Komagataeibacter hansenii and Pseudomonas aeruginosa was developed to understand whether a pre-existing matrix affects the ability of another species to build a biofilm. P. aeruginosa was inoculated onto the preformed K. hansenii biofilm consisting of a cellulose matrix. P. aeruginosa PAO1 colonized and infiltrated the K. hansenii bacterial cellulose biofilm (BC), as indicated by the presence of cells at 19 μm depth in the translucent hydrogel matrix. Bacterial cell density increased along the imaged depth of the biofilm (17-19 μm). On day 5, the average bacterial count across sections was 67 ± 4 % P. aeruginosa PAO1 and 33 ± 6 % K. hansenii. Biophysical characterization of the biofilm indicated that colonization by P. aeruginosa modified the biophysical properties of the BC matrix, which inlcuded increased density, heterogeneity, degradation temperature and thermal stability, and reduced crystallinity, swelling ability and moisture content. This further indicates colonization of the biofilm by P. aeruginosa. While eDNA fibres - a key viscoelastic component of P. aeruginosa biofilm - were present on the surface of the co-cultured biofilm on day 1, their abundance decreased over time, and by day 5, no eDNA was observed, either on the surface or within the matrix. P. aeruginosa-colonized biofilm devoid of eDNA retained its mechanical properties. The observations demonstrate that a pre-existing biofilm scaffold of K. hansenii inhibits P. aeruginosa PAO1 eDNA production and suggest that eDNA production is a response by P. aeruginosa to the viscoelastic properties of its environment.

BackgroundAnti-IgLON5 disease is a rare chronic autoimmune disorder characterized by IgLON5 autoantibodies predominantly of the IgG4 subclass. Distinct pathogenic effects were described for anti-IgLON5 IgG1 and IgG4, however, with uncertain clinical relevance.MethodsIgLON5-specific IgG1-4 levels were measured in 46 sera and 20 cerebrospinal fluid (CSF) samples from 13 HLA-subtyped anti-IgLON5 disease patients (six females, seven males) using flow cytometry. Intervals between two consecutive serum or CSF samplings (31 and 10 intervals, respectively) were categorized with regard to the immunomodulatory treatment active at the end of the interval, changes of anti-IgLON5 IgG1 and IgG4 levels, and disease severity. Intrathecal anti-IgLON5 IgG4 synthesis (IS) was assessed using a quantitative method.ResultsThe median age at onset was 66 years (range: 54–75), disease duration 10 years (range: 15–156 months), and follow-up 25 months (range: 0–83). IgLON5-specific IgG4 predominance was observed in 38 of 46 (83%) serum and 11 of 20 (55%) CSF samples. Anti-IgLON5 IgG4 levels prior clinical improvement in CSF but not serum were significantly lower than in those prior stable/progressive disease. Compared to IgLON5 IgG4 levels in serum, CSF levels in HLA-DRB1*10:01 carriers were significantly higher than in non-carriers. Indeed, IgLON5-specific IgG4 IS was demonstrated not only in four of five HLA-DRB1*10:01 carriers but also in one non-carrier. Immunotherapy was associated with decreased anti-IgGLON5 IgG serum levels. In CSF, lower anti-IgLON5 IgG was associated with immunosuppressive treatments used in combination, that is, corticosteroids and/or azathioprine plus intravenous immunoglobulins or rituximab.ConclusionOur findings might indicate that CSF IgLON5-specific IgG4 is frequently produced intrathecally, especially in HLA-DRB1*10:01 carriers. Intrathecally produced IgG4 may be clinically relevant. While many immunotherapies reduce serum IgLON5 IgG levels, more intense immunotherapies induce clinical improvement and may be able to target intrathecally produced anti-IgLON5 IgG. Further studies need to confirm whether anti-IgLON5 IgG4 IS is a suitable prognostic and predictive biomarker in anti-IgLON5 disease.