Search

Abstract Cancer-associated fibroblasts (CAFs) play a key role in cancer progression and treatment outcome. This study dissects the intra-tumoral diversity of CAFs in basal cell carcinoma, squamous cell carcinoma, and melanoma using molecular and spatial single-cell analysis. We identify three distinct CAF subtypes: myofibroblast-like RGS5+ CAFs, matrix CAFs (mCAFs), and immunomodulatory CAFs (iCAFs). Large-cohort tissue analysis reveals significant shifts in CAF subtype patterns with increasing malignancy. Two CAF subtypes exhibit immunomodulatory properties via different mechanisms. mCAFs sythesize extracellular matrix and may restrict T cell invasion in low-grade tumors via ensheathing tumor nests, while iCAFs are enriched in late-stage tumors, and express high levels of cytokines and chemokines to aid immune cell recruitment and activation. This is supported by the induction of an iCAF-like phenotype with immunomodulatory functions in primary healthy fibroblasts exposed to skin cancer cell secretomes. Thus, targeting CAF variants holds promise to enhance immunotherapy efficacy in skin cancers.

Abstract Background Early in the host-response to infection, neutrophils release calprotectin, triggering several immune signalling cascades. In acute infection management, identifying infected patients and stratifying these by risk of deterioration into sepsis, are crucial tasks. Recruiting a heterogenous population of patients with suspected infections from the emergency department, early in the care-path, the CASCADE trial aimed to evaluate the accuracy of blood calprotectin for detecting bacterial infections, estimating disease severity, and predicting clinical deterioration. Methods In a prospective, observational trial from February 2021 to August 2022, 395 patients (n = 194 clinically suspected infection; n = 201 controls) were enrolled. Blood samples were collected at enrolment. The accuracy of calprotectin to identify bacterial infections, and to predict and identify sepsis and mortality was analysed. These endpoints were determined by a panel of experts. Results The Area Under the Receiver Operating Characteristic (AUROC) of calprotectin for detecting bacterial infections was 0.90. For sepsis within 72 h, calprotectin’s AUROC was 0.83. For 30-day mortality it was 0.78. In patients with diabetes, calprotectin had an AUROC of 0.94 for identifying bacterial infection. Conclusions Calprotectin showed notable accuracy for all endpoints. Using calprotectin in the emergency department could improve diagnosis and management of severe infections, in combination with current biomarkers. Clinical trial registration number DRKS00020521

Abstract Background Providing individualised healthcare in line with patient wishes is a particular challenge for emergency healthcare professionals. Documentation of patient wishes (DPW), e.g. as advance directives, can guide clinicians in making end-of-life decisions that respect the patient’s wishes and autonomy. However, patient centered decisions are hindered by limited availability of DPWs in emergency settings. Objective This systematic review aims to congregate present data on recorded rates for DPW existence and availability in the emergency department (ED) as well as contributing factors for these rates. Methods We searched MEDLINE, Google Scholar, Embase and Web of Science databases in September 2023. Publications providing primary quantitative data on DPW in the ED were assessed. Publications referring only to a subset of ED patients (other than geriatric) and investigating DPW issued after admission were excluded. Results A total of 22 studies from 1996 to 2021 were included in the analysis. Most were from the US (n = 12), followed by Australia (n = 4), Canada (n = 2), South Korea, Germany, the United Kingdom and Switzerland (n = 1 each). In the general adult population presenting to the ED, 19.9–27.8% of patients reported having some form of DPW, but only in 6.8% or less it was available on presentation. In the geriatric population, DPW rates (2.6–79%) as well as their availability (1.1–48.8%) varied widely. The following variables were identified as positive predictors of having DPW, among others: higher age, poorer overall health, as well as sociodemographic factors, such as female gender, having children, being in a relationship, higher level of education or a recent previous presentation to hospital. Conclusions Existence and availability of a recorded DPW among ED patients was low in general and even in geriatric populations mostly well below 50%. While we were able to gather data on prevalence and predictors, this was limited by heterogeneous data. We believe further research is needed to explore the quality of DPW and measures to increase both rates of existence and availability of DPW in the ED.

Abstract Background Pulp refining is an energy consuming, but integral part of paper production with the aim to increase tensile strength and smoothness of paper sheets. Commercial enzyme formulations are used to lower the energy requirements by pre-treatment of pulp before refining. However, a high number of different commercial enzyme products are available on the market containing enzymes of varying origin and composition, which complicates the prediction of their behavior, especially using different pulp types. Results Endoglucanase-rich enzyme formulations were characterized regarding enzyme activity at different temperatures, resulting in a significant decrease of activity above 70 °C. Some enzyme preparations additionally contained arabinosidase, xylanase and β-glucosidase activity consequently resulting in a release of xylose and glucose from pulp as determined by high-performance liquid chromatography. Interestingly, one enzyme formulation even showed lytic polysaccharide monooxygenase (LPMO) activity of 3.05 nkat mg−1. A correlation between enzyme activity using the endoglucanase specific derivatized cellopentaose (CellG5) substrate and enzyme performance in laboratory PFI (Papirindustriens forskningsinstitut) refining trials was observed on softwood pulp resulting in a maximum increase in the degree of refining values from 27.7°SR to 32.7°SR. When added to a purified endoglucanase enzyme (31.6°SR), synergistic effects were found for cellobiohydrolase II (34.7°SR) or β-glucosidase enzymes (35.7°SR) in laboratory refining. Comparison with previously obtained laboratory refining results on hardwood pulp allowed differences in enzyme performance based on varying pulp types to be elucidated. Conclusions Interestingly, the individual enzymes indeed showed different refining effects on softwood and hardwood pulp. This difference could be predicted after development of an adapted enzyme activity assay by combination of the derivatized cellopentaose CellG5 substrate with either softwood or hardwood sulfate pulp.

Background: The pulmonary artery wedge pressure (PAWP) is regarded as a reliable indicator of left ventricular end-diastolic pressure (LVEDP), but this association is weaker in patients with left-sided heart disease (LHD). We compared morphological differences in cardiac magnetic resonance imaging (CMR) in patients with heart failure (HF) and a reduced left ventricular ejection fraction (LVEF), with or without elevation of PAWP or LVEDP. Methods: We retrospectively identified 121 patients with LVEF < 50% who had undergone right heart catheterization (RHC) and CMR. LVEDP data were available for 75 patients. Results: The mean age of the study sample was 63 ± 14 years, the mean LVEF was 32 ± 10%, and 72% were men. About 53% of the patients had an elevated PAWP (>15 mmHg). In multivariable logistic regression analysis, NT-proBNP, left atrial ejection fraction (LAEF), and LV end-systolic volume index independently predicted an elevated PAWP. Of the 75 patients with available LVEDP data, 79% had an elevated LVEDP, and 70% had concomitant PAWP elevation. By contrast, all but one patient with elevated PAWP and half of the patients with normal PAWP had concomitant LVEDP elevation. The Bland–Altman plot revealed a systematic bias of +5.0 mmHg between LVEDP and PAWP. Notably, LAEF was the only CMR variable that differed significantly between patients with elevated LVEDP and a PAWP ≤ or >15 mmHg. Conclusions: In patients with LVEF < 50%, a normal PAWP did not reliably exclude LHD, and an elevated LVEDP was more frequent than an elevated PAWP. LAEF was the most relevant determinant of an increased PAWP, suggesting that a preserved LAEF in LHD may protect against backward failure into the lungs and the subsequent increase in pulmonary pressure.

Abstract Tight carbonate rocks are important hydrocarbon and potential geothermal reservoirs, for example, in CO2-Enhanced Geothermal Systems. We report a study of outcrop samples of tectonically undeformed tight carbonates from the upper Jurassic “Malm ß” formation in Southern Germany near the town of Simmelsdorf (38 km NE of Nuremberg) to understand bulk petrophysical properties in relation to microstructure and to compare models for permeability prediction in these samples. We applied Archimedes isopropanol immersion, Helium pycnometry, mercury injection, gamma density core logging, and gas permeability measurements, combined with microstructural investigations and liquid metal injection (LMI-BIB-SEM). In addition, ultrasonic velocity was measured to allow geomechanical comparison of stratigraphically equivalent rocks in the South German Molasse Basin (SGMB). Results show only small variations, showing that the formation is rather homogeneous with bulk porosities below 5% and argon permeabilities around 1.4E−17 m2. The presence of stylolites in some of the samples has neither a significant effect on porosity nor permeability. Pores are of submicron size with pore throats around 10 nm and connected as shown by Mercury injection and Liquid Metal injection. Samples have high dynamic Young’s Modulus of 73 ± 5 GPa as expected for lithified and diagenetically overmature limestones. Moreover, no trends in properties were observable toward the faults at meter scale, suggesting that faulting was post-diagenetic and that the matrix permeabilities were too low for intensive post-diagenetic fluid–rock interaction. Petrophysical properties are very close to those measured in the SGMB, illustrating the widespread homogeneity of these rocks and justifying the quarry as a reasonable reservoir analog. Permeability prediction models, such as the percolation theory-based Katz-Thompson Model, Poiseuille-based models, like the Winland, the Dastidar, the capillary tube, and the Kozeny-Carman Models, as well as several empirical models, namely, the Bohnsack, the Saki, and the GPPT Models, were applied. It is shown that the capillary tube Model and the Saki Model are best suited for permeability predictions from BIB-SEM and mercury injection capillary pressure results, respectively, providing a method to estimate permeability in the subsurface from drill cuttings. Matrix permeability is primarily controlled by the pore (throat) diameters rather than by the effective porosity.

A key step in translational cardiovascular research is the use of large animal models to better understand normal and abnormal physiology, to test drugs or interventions, or to perform studies which would be considered unethical in human subjects. Ultrahigh field magnetic resonance imaging (UHF-MRI) at 7 T field strength is becoming increasingly available for imaging of the heart and, when compared to clinically established field strengths, promises better image quality and image information content, more precise functional analysis, potentially new image contrasts, and as all in-vivo imaging techniques, a reduction of the number of animals per study because of the possibility to scan every animal repeatedly. We present here a solution to the dual use problem of whole-body UHF-MRI systems, which are typically installed in clinical environments, to both UHF-MRI in large animals and humans. Moreover, we provide evidence that in such a research infrastructure UHF-MRI, and ideally combined with a standard small-bore UHF-MRI system, can contribute to a variety of spatial scales in translational cardiovascular research: from cardiac organoids, Zebra fish and rodent hearts to large animal models such as pigs and humans. We present pilot data from serial CINE, late gadolinium enhancement, and susceptibility weighted UHF-MRI in a myocardial infarction model over eight weeks. In 14 pigs which were delivered from a breeding facility in a national SARS-CoV-2 hotspot, we found no infection in the incoming pigs. Human scanning using CINE and phase contrast flow measurements provided good image quality of the left and right ventricle. Agreement of functional analysis between CINE and phase contrast MRI was excellent. MRI in arrested hearts or excised vascular tissue for MRI-based histologic imaging, structural imaging of myofiber and vascular smooth muscle cell architecture using high-resolution diffusion tensor imaging, and UHF-MRI for monitoring free radicals as a surrogate for MRI of reactive oxygen species in studies of oxidative stress are demonstrated. We conclude that UHF-MRI has the potential to become an important precision imaging modality in translational cardiovascular research.

Abstract Autoimmune diseases caused by pathogenic IgG4 subclass autoantibodies (IgG4-AID) include diseases like MuSK myasthenia gravis, pemphigus vulgaris or thrombotic thrombocytopenic purpura. Their etiology is still unknown. Polymorphisms in the human leukocyte antigen (HLA) gene locus, particularly in HLA-DRB1, are known genetic susceptibility factors for autoimmune diseases. We hypothesized a similar role for HLA polymorphisms in IgG4-AID and conducted a systematic review and meta-analysis with case–control studies on IgG4-AID based on MOOSE/ HuGENet guidelines. Genotype (G) and allele (A) frequencies of HLA-DQB1*05 (G: OR 3.8; 95% CI 2.44–5.9; p

At large institutions of higher education, students frequently have a choice whether to attend the introductory physics sequence asynchronously online, on-site in a traditional lecture setting, or in a reformed studio setting. In this study, we investigate how these different settings are correlated with measures of self-efficacy, interest in physics, and success in subsequent physics and engineering courses, which have the introductory physics sequence as prerequisites. As previous research indicates, some of these measures may depend on gender. We found that the course setting had no significant correlation with the grade in subsequent courses, but that studio settings gave students the feeling of being better prepared, particularly for subsequent courses that included laboratory or recitation components. We also found that gender was correlated with measures of interest in physics, where female students expressed significantly less interest in the subject, regardless of course setting.

Introduction Previous studies demonstrated that the implementation of the Kidney Disease Improving Global Outcomes (KDIGO) guideline-based bundle, consisting of different supportive measures in patients at high risk for acute kidney injury (AKI), might reduce rate and severity of AKI after surgery. However, the effects of the care bundle in broader population of patients undergoing surgery require confirmation.Methods and analysis The BigpAK-2 trial is an international, randomised, controlled, multicentre trial. The trial aims to enrol 1302 patients undergoing major surgery who are subsequently admitted to the intensive care or high dependency unit and are at high-risk for postoperative AKI as identified by urinary biomarkers (tissue inhibitor of metalloproteinases 2*insulin like growth factor binding protein 7 (TIMP-2)*IGFBP7)). Eligible patients will be randomised to receive either standard of care (control) or a KDIGO-based AKI care bundle (intervention). The primary endpoint is the incidence of moderate or severe AKI (stage 2 or 3) within 72 hours after surgery, according to the KDIGO 2012 criteria. Secondary endpoints include adherence to the KDIGO care bundle, occurrence and severity of any stage of AKI, change in biomarker values during 12 hours after initial measurement of (TIMP-2)*(IGFBP7), number of free days of mechanical ventilation and vasopressors, need for renal replacement therapy (RRT), duration of RRT, renal recovery, 30-day and 60-day mortality, intensive care unit length-of-stay and hospital length-of-stay and major adverse kidney events. An add-on study will investigate blood and urine samples from recruited patients for immunological functions and kidney damage.Ethics and dissemination The BigpAK-2 trial was approved by the Ethics Committee of the Medical Faculty of the University of Münster and subsequently by the corresponding Ethics Committee of the participating sites. A study amendment was approved subsequently. In the UK, the trial was adopted as an NIHR portfolio study. Results will be disseminated widely and published in peer-reviewed journals, presented at conferences and will guide patient care and further research.Trial registration number NCT04647396.

Refining of cellulose fibers is essential for reaching desired paper properties, yet highly energy demanding. Enzymes like endoglucanases (e.g. EndoC) are increasingly used to reduce energy consumption during pulp refining. However, prediction of the enzyme effect is still a major concern, considering the high variety of commercially available enzyme formulations, containing a range of different enzymes. In this study, synergisms of xylanases and β-glucosidases in combination with endoglucanases purified from enzyme formulations were studied and related to their refining performance. Size exclusion chromatography with multi-angle laser light scattering (SEC-MALLS) of carboxymethylcellulose revealed that a narrow size distribution and a high reduction in molecular weight are beneficial characteristics for refining. SEC-MALLS of hardwood pulp resulted in pronounced formation of low molecular weight fractions (log MW 4.3) for most efficient refining enzymes. Application of enzyme formulations and combinations of endoglucanase EndoC with β-glucosidase or xylanase using Fourier-transform infrared spectroscopy (FTIR) revealed synergistic effects that promoted degradation of amorphous parts of cellulose. Laboratory refining trials on hardwood pulp confirmed the increase in degree of refining and tensile index after addition of xylanase and β-glucosidase. Surface plasmon resonance (SPR) analysis resulted in strong binding of endoglucanases to regenerated cellulose, which correlated to refining performance.

Herein, we report a case of a new-onset Raynaud’s phenomenon (RP), which occurred in an otherwise healthy 31-year-old Caucasian woman, who lacked any known risk factors and associations with possible causes for secondary RP. However, 2 weeks prior to the development of RP, the patient had received her first injection of the COVID-19 vaccine containing ChAdOx1-SARS-COV-2. The patient presented with well-demarcated, white-pale, cold areas involving the middle fingers of both hands and the ring finger of the right hand, which were triggered by exposure to cold environment and accompanied by a sensation of numbness. Infrared thermography revealed notable temperature differences of up to 10.9°C between affected and nonaffected fingers. Coagulation and immunological parameters, including cryoglobulins and pathological autoantibodies, were within the normal range and antibodies to the heparin/platelet factor 4 complex not detectable. It remains unclear if the development of RP in our patient is causally related to antecedent COVID-19 vaccination; however, the temporal connection to the vaccination, the complete absence of RP in her past medical history, and the lack of any risk factors and triggers raise the suspicion of a yet unknown association with the vaccine. Whether a clear association between the development of RP and COVID-19 vaccination exists or whether RP represents a bystander effect needs to be awaited in case observational reports on RP accumulate. Given the steadily rising numbers of people receiving COVID-19 vaccinations, physicians may remain alert to still unrecognized side effects.

The concept of sharable LOs has been around for decades, but implementing repositories, guaranteeing interoperability, managing metadata, and achieving organizational and financial sustainability has proven challenging. The realization that there will likely never be a universal Learning Management System (LMS) made the idea of universally shareable content appear even more illusionary on the one hand, but on the other hand also led to the development of learning system interoperability standards. The paper proposes to use either tool-interoperability or self-sovereignty as key technologies for establishing near-universal content repositories.

We show a shift in the prevalence of respiratory viral pathogens in community-acquired pneumonia patients during the COVID-19 pandemic. Our data support the efficiency of non-pharmaceutical interventions on virus circulation except for rhinoviruses. The consequences of an altered circulation on subsequent winter seasons remain unclear and support the importance of systematic virological surveillance.

Abstract is missing (Short communication)

In a partially flipped, hybrid introductory physics course where students had a free choice between attending any lecture session in person or via video conferencing, and where recordings of the lecture sessions were made available for asynchronous viewing, a total of 16 learner attributes and their relationships were investigated. Five of these attributes reflect participation choices, while eleven attributes reflect assessment outcomes on different course components. In line with the “no significant difference phenomenon,” correlations between exam scores and participation choices were weaker than correlations with, for example, prior knowledge as evidenced by pretest scores. Overall, in terms of correlations, participation, and assessment attributes clustered together, respectively, with clicker questions being a connecting attribute between the clusters. Performance aside, we found two populations in the course, which, divided along the line of above and below average in-class attendance, exhibited other distinct behavior attributes mostly related to investment of time and effort in the course.

The regulation of tumor inflammation is incompletely understood and the role of B cells is unclear. Here, the authors show that a specific subtype of B cells is induced in melanoma and required to recruit T lymphocytes and elicit inflammation.

Various autoantibodies are detected more frequently in HIV-infected individuals than in HIV-negative controls; however, limited data exist regarding autoimmune blistering skin diseases. Using enzyme-linked immunoassay (ELISA) and indirect immunofluore­scence, no difference in the frequency and magnitude of autoantibodies against BP180, BP230, desmoglein 1 and 3 was found between 594 HIV-infected patients and 248 uninfected controls in this cross-sectional study (16.0% vs. 11.7%, respectively, for at least one positive ELISA, p = 0.11). Interestingly, reactive syphilis serology in both HIV-infected individuals and uninfected controls was associated with positive anti-BP180 ELISA results (adjusted odds ratio (OR) 2.14, 95% confidence interval (CI) 1.07–4.29, p = 0.03 and OR 4.70, CI 1.3–16.86; p = 0.0180). Our study shows a comparably low prevalence of cutaneous autoantibodies in both HIV-infected patients and uninfected controls lacking signs of autoimmune blistering skin disease. Positive BP180 ELISA in the absence of clinical signs of bullous pemphigoid should prompt further evaluation for syphilis antibodies.

Abstract Background European visions such as the European Commission’s Strategic Energy Technology (SET) Plan and the SET Plan Roadmap Education and Training encourages higher education institutions (HEI) and business to establish adequate co-operative education and training approaches in the face of the challenges posed by the energy transition necessary to achieve European Union’s climate goals. The development of integrated co-operative education, training and learning systems is a fundamental strategy to foster co-operation between academic institutions and business. Methods Available sources about the theoretical and practical knowledge of co-operative education and training are limited. To identify available information and create new information where there is no this research was carried out by means of a literature study and a database search on existing co-operative education formats. This was supplemented by an analysis of seven actual case study reports regarding examples drawn from the BioEnergyTrain (BET) project commissioned under the European Union’s Horizon 2020 programme. Results Co-operation for educational purposes between higher education institutions (HEI) and business exists on the curricular, course and internship level.Considering the total number of studies on a curricular level in Europe, only very few co-operative education programmes exist. On the curricular level, most of the appropriate formats are dual studies with Bachelors’ programmes, fewer are dual studies with Master’s programmes. Co-operation formats on the course level do not follow institutionalised rules and are case-specifically applied. The studies presented in this journal dealing with practical examples emphasise the high potential for improving student’s skills and insight into business that such co-operative formats offer to universities and business partners.Co-operation on an internship level has a long tradition of exposing students to the business environment they will later work in. Internships however do not provide high-intensity co-operation between business and HEIs. Therefore, it is outside the focus of this paper’s attention. Results of statistical analysis reveal a total number of 19,822 related dual study programmes in the year 2018 alone in Germany whereas, for co-operative curricula on a master’s level, just 73 can be tracked in whole Europe. Results of the case study reports are further discussed in Additional files 1, 2, 3, 4, 5, 6, 7 and 8. Discussion Existing research and descriptions of co-operative education and training are limited. However, based on the available sources, this study discusses co-operative education regarding its roots, types, role of business, type of rotation, salary, and legal issues as well as efforts on a European level to create and put into practice adequate forms of co-operative education supplemented by case studies. The huge gap between generally available dual study programmes on a bachelor’s and master’s level and available studies throughout Europe is partly related to the fact that most of the dual study programmes are on a bachelor’s level and partly related to a limited sharing of collective university information on comprehensive platforms. Through the main foci of the study on the theoretical background of co-operative studies as well as the practical implementation of co-operative education practice, all European academic institutions could not be contacted and analysed individually. Conclusions There is not much available data on co-operative study programmes. This may be due to the fact that co-operation in education and training between academic institutions and business plays only a minor role in the overall education system. Apart from dual study programmes, co-operative education and training formats usually are not defined unambiguously because the number of co-operative education programmes directed towards meeting the challenges posed by the energy transition is low. Although both the SET Plan Roadmap Education and Training developed within the SET Plan process and the Action Agenda for European Universities developed by the European University Association (EUA) identify co-operation between HEIs and business as crucial to meet these challenges (Borrell-Damian and Narodoslawsky [Additional file 1]), much remains to be done in this respect. There is a need for institutions all over Europe which are able and willing to provide a platform for such co-operation and co-ordinate the development of co-operative learning formats, especially on the course level, across sectoral boundaries. The energy transition definitely requires adequately trained people to deal with and create low emission energy systems and the challenges arising therewith.

Systemic monotherapy with rituximab is a well-known treatment approach for primary cutaneous follicle centre lymphoma and primary cutaneous marginal zone lymphoma. Both have excellent prognosis despite high relapse rates. To investigate the long-term effectiveness and clinical outcome of intravenous rituximab at a dose of 375 mg/m2 once weekly, data for 26 patients (17 primary cutaneous follicle centre lymphoma and 9 primary cutaneous marginal zone lymphoma) were analysed retrospectively. Complete remissions occurred in 20 (77%) and partial remissions in 6 patients (23%), demonstrating an overall response rate of 100%. The relapse rate was 52.9% in primary cutaneous follicle centre lymphoma and 88.9% in primary cutaneous marginal zone lymphoma. Ongoing complete remissions after therapy with rituximab were observed in 9 patients (34.6%) with a median progression-free survival of 161 months (13.4 years). These results confirm that intravenous rituximab is an effective and well-tolerated treatment with durable responses in a relevant percentage of patients at a median follow-up of 148 months (12.3 years).

COVID-19 (coronavirus disease 2019) patients often show excessive activation of coagulation, associated with increased risk of thrombosis. However, the diagnostic value of coagulation at initial clinical evaluation is not clear. We present an in-depth analysis of coagulation in patients presenting to the emergency department (ED) with suspected COVID-19. N = 58 patients with clinically suspected COVID-19 in the ED were enrolled. N = 17 subsequently tested positive using SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) polymerase chain reaction (PCR) swabs, while in n = 41 COVID-19 was ruled-out. We analyzed both standard and extended coagulation parameters, including thromboplastin time (INR), activated partial thromboplastin time (aPTT), antithrombin, plasminogen, plasminogen activator inhibitor-1 (PAI-1), D-dimers, and fibrinogen at admission, as well as α2-antiplasmin, activated protein C -resistance, factor V, lupus anticoagulant, protein C, protein S, and von Willebrand diagnostics. These data, as well as mortality and further laboratory parameters, were compared across groups based on COVID-19 diagnosis and severity of disease. In patients with COVID-19, we detected frequent clotting abnormalities, including D-dimers. The comparison cohort in the ED, however, showed similarly altered coagulation. Furthermore, parameters previously shown to distinguish between severe and moderate COVID-19 courses, such as platelets, plasminogen, fibrinogen, aPTT, INR, and antithrombin, as well as multiple nonroutine coagulation analytes showed no significant differences between patients with and without COVID-19 when presenting to the ED. At admission to the ED the prevalence of coagulopathy in patients with COVID-19 is high, yet comparable to the non-COVID-19 cohort presenting with respiratory symptoms. Nevertheless, coagulopathy might worsen during disease progression with the need of subsequent risk stratification.

Cathelicidins have been reported to inhibit human papillomavirus infection in vitro; however, nothing is known about their activity in vivo. In this study, experimental skin infection with Mus musculus papillomavirus 1 resulted in robust development of cutaneous papillomas in cyclosporine A-treated C57BL/6J mice deficient for the murine cathelicidin-related antimicrobial peptide (CRAMP), in contrast to wild-type controls. Analysis of the underlying mechanisms revealed moderate disruption of virion integrity and lack of interference with viral entry and intracellular trafficking by a synthetic CRAMP peptide. Differences in the immune response to Mus musculus papillomavirus 1 infection were observed between CRAMP-deficient and wild-type mice. These included a stronger reduction in CD4+ and CD8+ T-cell numbers in infected skin, and lack of Mus musculus papillomavirus 1-specific neutralizing antibodies in response to cyclosporine A in the absence of endogenous CRAMP. CRAMP has modest direct anti-papillomaviral effects in vitro, but exerts protective functions against Mus musculus papillomavirus 1 skin infection and disease development in vivo, primarily by modulation of cellular and humoral immunity.

Background: We evaluated how plasma proteomic signatures in patients with suspected COVID-19 can unravel the pathophysiology, and determine kinetics and clinical outcome of the infection. Methods: Plasma samples from patients presenting to the emergency department (ED) with symptoms of COVID-19 were stratified into: (1) patients with suspected COVID-19 that was not confirmed (n = 44); (2) non-hospitalized patients with confirmed COVID-19 (n = 44); (3) hospitalized patients with confirmed COVID-19 (n = 53) with variable outcome; and (4) patients presenting to the ED with minor diseases unrelated to SARS-CoV-2 infection (n = 20). Besides standard of care diagnostics, 177 circulating proteins related to inflammation and cardiovascular disease were analyzed using proximity extension assay (PEA, Olink) technology. Results: Comparative proteome analysis revealed 14 distinct proteins as highly associated with SARS-CoV-2 infection and 12 proteins with subsequent hospitalization (p < 0.001). ADM, IL-6, MCP-3, TRAIL-R2, and PD-L1 were each predictive for death (AUROC curve 0.80–0.87). The consistent increase of these markers, from hospital admission to intensive care and fatality, supported the concept that these proteins are of major clinical relevance. Conclusions: We identified distinct plasma proteins linked to the presence and course of COVID-19. These plasma proteomic findings may translate to a protein fingerprint, helping to assist clinical management decisions.

This work describes the preparation of spin-coated thin polymer films composed of cellulose (CE), ethyl cellulose (EC), and cellulose acetate (CA) in the form of bi- or mono-component coatings on sensors of a quartz crystal microbalance with dissipation monitoring (QCM-D). Depending on the composition and derivative, hydrophilicity can be varied resulting in materials with different surface properties. The surfaces of mono- and bi-component films were also analyzed by atomic force microscopy (AFM) and large differences in the morphologies were found comprising nano- to micrometer sized pores. Extended protein adsorption studies were performed by a QCM-D with 0.1 and 10 mg mL−1 bovine serum albumin (BSA) and 0.1 and 1 mg mL−1 fibrinogen from bovine plasma in phosphate buffered saline. Analysis of the mass of bound proteins was conducted by applying the Voigt model and a comparison was made with the Sauerbrey wet mass of the proteins for all films. The amount of deposited proteins could be influenced by the composition of the films. It is proposed that the observed effects can be exploited in biomaterial science and that they can be used to extent the applicability of bio-based polymer thin films composed of commercial cellulose derivatives.

The paper describes different feedback mechanisms available to instructors during the deployment of online formative assessment exercises.

As a result of the pandemic, many physics courses moved online. Alongside, the popularity of Internet-based problem-solving sites and forums rose. With the emergence of large language models, another shift occurred. One year into the public availability of these models, how has online help-seeking behavior among introductory physics students changed, and what is the effect of different patterns of online resource usage? In a mixed-method approach, we investigate student choices and their impact on assessment components of an online introductory physics course for scientists and engineers. We find that students still mostly rely on traditional Internet resources and that their usage strongly influences the outcome of low-stake unsupervised quizzes. We empirically found distinct clusters of help-seeking and resource-usage patterns among the students; the impact of students' cluster membership on the supervised assessment components of the course, however, is nonsignificant.

The current demand to cut back on the use of plastic materials has brought a major boost to the search for bio-based alternatives. Not only are plastic bags and primary food packaging under scrutiny here, but also those materials used as functional barriers to reduce, for example, the migration of mineral oil hydrocarbons (MOH) from recycled paper and board packaging. Most of the barriers now in use are synthetic, often have only moderate barrier functionalities and in addition reduce the environmentally-friendly character of cellulose-based materials. Against this background, bio-based polymers have been evaluated in terms of their functional barrier properties. Chitosan was found to be among the best performers in these materials. In this study, the behavior of a lab-made chitosan acetate film was compared with conventionally produced polymer films. The two-sided migration experiment described recently was used to determine the barrier properties of the tested materials. This not only allowed to test the intrinsic migration of the films and the permeation through them, but also to simulate real packaging situations by using a recycled paper as donor for MOH. The migrated fractions were determined using gas-chromatography-based techniques. While the conventionally produced polymer films showed only moderate barrier function, excellent results were seen for the biopolymer. It reduced the migration from the recycled paper to not detectable, singling it out as a good alternative to conventional materials.

Fines are an important factor in the papermaking industry with respect to their influence on the mechanical properties of paper. A procedure offering the possibility to produce handsheets with a constant amount of fines, as well as the determination of the fines content, is of great importance in evaluating the influences of different types of fines. In this work, a method based on a white water circulation system and fiber morphology characterization using a flow cell was evaluated. Three different wires for handsheet forming were studied (120-mesh, 325-mesh, and 500-mesh), and the 325-mesh wire was chosen for further trials. Using the 325-mesh wire, a constant amount of fines was achieved after discarding seven handsheets. This method allows reliable evaluation of the effects of primary as well as secondary fines and a cellulosic additive on handsheet properties.

The bending stiffness of pulp fibers in both dry and wet states is of great importance with respect to many optical and physical paper properties. We introduce a method that evaluates fiber bending stiffness from the fibers’ Young’s modulus (E) and the area moment of inertia (I) from the fiber cross section. The values for E and I in the dry state are obtained from single fiber tensile testing and image analysis of the fiber cross section. The values for the wet state are estimated from literature results for decreasing elastic modulus due to wetting and by the measurement of swollen, freeze-dried fiber cross sections by serial sectioning. We show a comparison between the results from our method and the bending stiffness of individual fibers measured with other methods.

Among bio-based reinforcement additives for paper existing on the market, microfibrillated cellulose (MFC) turned out to be a promising material, showing outstanding potential in composites science. Its relevance in papermaking as a new family of paper components was suggested more recently. There remains a number of constraints limiting the promotion of their use in papermaking, mostly related to their high cost and effect on dewatering resistance. Also, contrasting results reported in the literature suggest that the effect of fibrillation rate and quantity of such cellulosic additives in a furnish on the technological paper properties needs further research. The purpose of this study is to produce and characterize different MFC-like fine fibrous materials of varying particle size and degree of fibrillation from the same batch of pulp through mechanical treatment or fractionation. The effect of the thus obtained fine fibrous materials on paper properties is evaluated with respect to their concentration within a fiber furnish. We compared: (i) a mixture of primary and secondary fines isolated from the pulp by means of a purpose-built laboratory pressure screen; (ii) MFC-like fine fibrous materials of increasingly fibrillar character obtained by refining and subsequent steps of high-pressure homogenization. The morphology of the different materials was first characterized using flow cell based and microscopic techniques. The thus obtained materials were then applied in handsheet forming in blends of different proportions to evaluate their influence on paper properties. The results of these experiments indicate that all these products lead to a substantial decrease in air permeability and to improved mechanical properties already at low concentration, independent of the type and morphological character of the added fine cellulosic material. At higher addition rates, only highly fibrillated materials allowed a further considerable increase in tensile and z-strength. These observations should help to allow a more targeted application of this new generation of materials in papermaking, depending on the desired application.

Background Nuclear factors of activated T cells (NFAT) are transcription factors that are central to cytokine production in activated T cells and regulate the development and differentiation of various tissues. NFATc2 is expressed in hematopoietic stem cells and regulated during myeloid commitment in a lineage-specific manner. The biological role of NFATc2 in hematopoiesis is, however, unclear.Design and Methods In the present study, we analyzed steady-state hematopoiesis in young (12 months) mice lacking NFATc2. Complete blood counts were performed in the peripheral blood, bone marrow and spleen. Using cytological and histological analyses, the blood cell differential was determined. Colony-formation assays were used to determine the differentiation potential of hematopoietic cells. Bone cell cultures were derived from the bone marrow, and bone remodeling markers were determined in the serum.Results NFATc2−/− mice older than 12 months were anemic and thrombocytopenic. The bone marrows of these mice showed a markedly reduced number of hematopoietic cells, of which megakaryocytic and erythroid lineages were most affected. While the number of hematopoietic progenitor cells in NFATc2-deficent bone marrow was reduced, the myeloid differentiation potential of these cells remained intact. Aged NFATc2−/− mice showed ossification of their bone marrow space and developed extramedullary hematopoiesis in the spleen. Ex vivo differentiation assays revealed an intrinsic defect of NFATc2-deficient stromal cells, in which NFATc2−/− osteoblasts differentiated more efficiently than wild-type cells, whereas osteoclast differentiation was impaired.Conclusions Our data suggest that NFATc2 may play a role in the maintenance of steady-state hematopoiesis and bone remodeling in adult organisms.