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- Theodor-Boveri-Institut für Biowissenschaften (39)
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Current crises have highlighted the importance of integrating research, politics and practice to work on solutions for complex social problems. In recent years, policy deliberation fora, policy pilots and policy labs have increasingly been deployed to mobilise science to produce solutions, help create popular support and guide implementation of policies addressing major public policy problems. Yet, we know little about how these approaches manage to transcend the boundaries between research, politics and practice. By systematically comparing policy deliberation fora, policy pilots and policy labs, this paper explores their mechanisms of boundary spanning including relationship and trust building, knowledge translation and developing solutions. We situate our analysis in healthcare policy and climate change policy in Germany, two contrasting policy fields that share a perpetual and escalating sense of crisis. Our findings suggest that deliberation fora, policy pilots and policy labs address different dilemmas of policymaking, namely the idea dilemma, the implementation dilemma and the legitimacy dilemma. All three approaches reduce wicked problems to a manageable scale, by grounding them in local decision-making, reducing their scope or reducing the problem analytically. We argue that despite their ambition to modernise democratic practices, unless they are institutionally well embedded, their effects are likely to be small scale, local and temporary.
Purpose
Growing evidence implies that transition to parenthood triggers symptoms of mental burden not only in women but likewise in men, especially in high-risk pregnancies. This is the first study that examined and compared the prevalence rates of depression, anxiety, and somatic symptom burden of expectant fathers who face different risk situations during pregnancy.
Methods
Prevalence rates of paternal depression (Edinburgh postnatal depression scale), anxiety (generalized anxiety disorder seven), and somatic symptom burden (somatic symptom scale eight) were examined in two risk samples and one control group in the third trimester of their partners’ pregnancy: risk sample I (n = 41) consist of expectant fathers whose partners were prenatally hospitalized due to medical complications; risk sample II (n = 52) are fathers whose partners were prenatally mentally distressed; and control group (n = 70) are those non-risk pregnancies.
Results
On a purely descriptive level, the data display a trend of higher symptom burden of depression, anxiety, and somatic symptoms in the two risk samples, indicating that expectant fathers, whose pregnant partners were hospitalized or suffered prenatal depression, were more prenatally distressed. Exploratory testing of group differences revealed an almost three times higher prevalence rate of anxiety in fathers whose partner was hospitalized (12.2%) compared to those non-risks (4.3%).
Conclusion
Results underline the need for screening implementations for paternal prenatal psychological distress, as well as specific prevention and treatment programs, especially for fathers in risk situations, such as their pregnant partners’ prenatal hospitalization.
The study was registered with the German clinical trials register (DRKS00020131) on 2019/12/09.
Despite promising clinical results in osteochondral defect repair, a recently developed bi-layered collagen/collagen-magnesium-hydroxyapatite scaffold has demonstrated less optimal subchondral bone repair. This study aimed to improve the bone repair potential of this scaffold by adsorbing bone morphogenetic protein 2 (BMP-2) and/or platelet-derived growth factor-BB (PDGF-BB) onto said scaffold. The in vitro release kinetics of BMP-2/PDGF-BB demonstrated that PDGF-BB was burst released from the collagen-only layer, whereas BMP-2 was largely retained in both layers. Cell ingrowth was enhanced by BMP-2/PDFG-BB in a bovine osteochondral defect ex vivo model. In an in vivo semi-orthotopic athymic mouse model, adding BMP-2 or PDGF-BB increased tissue repair after four weeks. After eight weeks, most defects were filled with bone tissue. To further investigate the promising effect of BMP-2, a caprine bilateral stifle osteochondral defect model was used where defects were created in weight-bearing femoral condyle and non-weight-bearing trochlear groove locations. After six months, the adsorption of BMP-2 resulted in significantly less bone repair compared with scaffold-only in the femoral condyle defects and a trend to more bone repair in the trochlear groove. Overall, the adsorption of BMP-2 onto a Col/Col-Mg-HAp scaffold reduced bone formation in weight-bearing osteochondral defects, but not in non-weight-bearing osteochondral defects.
In recent years, various forms of caloric restriction (CR) and amino acid or protein restriction (AAR or PR) have shown not only success in preventing age-associated diseases, such as type II diabetes and cardiovascular diseases, but also potential for cancer therapy. These strategies not only reprogram metabolism to low-energy metabolism (LEM), which is disadvantageous for neoplastic cells, but also significantly inhibit proliferation. Head and neck squamous cell carcinoma (HNSCC) is one of the most common tumour types, with over 600,000 new cases diagnosed annually worldwide. With a 5-year survival rate of approximately 55%, the poor prognosis has not improved despite extensive research and new adjuvant therapies. Therefore, for the first time, we analysed the potential of methionine restriction (MetR) in selected HNSCC cell lines. We investigated the influence of MetR on cell proliferation and vitality, the compensation for MetR by homocysteine, the gene regulation of different amino acid transporters, and the influence of cisplatin on cell proliferation in different HNSCC cell lines.
Spinal muscular atrophy (SMA) is a disabling disease that affects not only the patient’s health-related quality of life (HRQoL), but also causes a high caregiver burden (CGB). The aim of this study was to evaluate HRQoL, CGB, and their predictors in SMA. In two prospective, cross-sectional, and multi-center studies, SMA patients (n = 39) and SMA patient/caregiver couples (n = 49) filled in the EuroQoL Five Dimension Five Level Scale (EQ-5D-5L) and the Short Form Health Survey 36 (SF-36). Caregivers (CGs) additionally answered the Zarit Burden Interview (ZBI) and the Hospital Anxiety and Depression Scale (HADS). Patients were clustered into two groups with either low or high HRQoL (EQ-5D-5L index value <0.259 or >0.679). The latter group was mostly composed of ambulatory type III patients with higher motor/functional scores. More severely affected patients reported low physical functioning but good mental health and vitality. The CGB (mean ZBI = 22/88) correlated negatively with patients’ motor/functional scores and age. Higher CGB was associated with a lower HRQoL, higher depression and anxiety, and more health impairments of the CGs. We conclude that patient and CG well-being levels interact closely, which highlights the need to consider the health of both parties while evaluating novel treatments.
A cyclic alkyl(amino)carbene (CAAC)‐stabilized dicoordinate aminoborylene is synthesized by the twofold reduction of a [(CAAC)BCl\(_{2}\)(TMP)] (TMP=2,6‐tetramethylpiperidyl) precursor. NMR‐spectroscopic, X‐ray crystallographic and computational analyses confirm the cumulenic nature of the central C=B=N moiety. Irradiation of [(CAAC)B(TMP)] (2) resulted in an intramolecular C−C bond activation, leading to a doubly‐fused C\(_{10}\)BN heterocycle, while the reaction with acetonitrile resulted in an aryl migration from the CAAC to the acetonitrile nitrogen atom, concomitant with tautomerization of the latter to a boron‐bound allylamino ligand. One‐electron oxidation of 2 with CuX (X=Cl, Br) afforded the corresponding amino(halo)boryl radicals, which were characterized by EPR spectroscopy and DFT calculations. Placing 2 under an atmosphere of CO afforded the tricoordinate (CAAC,CO)‐stabilized aminoborylene. Finally, the twofold oxidation of 2 with chalcogens led, in the case of N\(_{2}\)O and sulfur, to the splitting of the B−C\(_{CAAC}\) bond and formation of the 2,4‐diamino‐1,3,2,4‐dichalcogenadiboretanes and CAAC‐chalcogen adducts, whereas with selenium a monomeric boraselenone was isolated, which showed some degree of B−Se multiple bonding.
Propofol is a widely used general anesthetic in clinical practice, but its use is limited by its water-insoluble nature and associated pharmacokinetic and pharmacodynamic limitations. Therefore, researchers have been searching for alternative formulations to lipid emulsion to address the remaining side effects. In this study, novel formulations for propofol and its sodium salt Na-propofolat were designed and tested using the amphiphilic cyclodextrin (CD) derivative hydroxypropyl-β-cyclodextrin (HPβCD). The study found that spectroscopic and calorimetric measurements suggested complex formation between propofol/Na-propofolate and HPβCD, which was confirmed by the absence of an evaporation peak and different glass transition temperatures. Moreover, the formulated compounds showed no cytotoxicity and genotoxicity compared to the reference. The molecular modeling simulations based on molecular docking predicted a higher affinity for propofol/HPβCD than for Na-propofolate/HPβCD, as the former complex was more stable. This finding was further confirmed by high-performance liquid chromatography. In conclusion, the CD-based formulations of propofol and its sodium salt may be a promising option and a plausible alternative to conventional lipid emulsions.
Social patterns and roles can develop when users talk to intelligent voice assistants (IVAs) daily. The current study investigates whether users assign different roles to devices and how this affects their usage behavior, user experience, and social perceptions. Since social roles take time to establish, we equipped 106 participants with Alexa or Google assistants and some smart home devices and observed their interactions for nine months. We analyzed diverse subjective (questionnaire) and objective data (interaction data). By combining social science and data science analyses, we identified two distinct clusters—users who assigned a friendship role to IVAs over time and users who did not. Interestingly, these clusters exhibited significant differences in their usage behavior, user experience, and social perceptions of the devices. For example, participants who assigned a role to IVAs attributed more friendship to them used them more frequently, reported more enjoyment during interactions, and perceived more empathy for IVAs. In addition, these users had distinct personal requirements, for example, they reported more loneliness. This study provides valuable insights into the role-specific effects and consequences of voice assistants. Recent developments in conversational language models such as ChatGPT suggest that the findings of this study could make an important contribution to the design of dialogic human–AI interactions.
Orthopteran diversity in steep slope vineyards: the role of vineyard type and vegetation management
(2023)
The abandonment of traditional agricultural practices and subsequent succession are major threats to many open-adapted species and species-rich ecosystems. Viticulture on steep slopes has recently suffered from strong declines due to insufficient profitability, thus increasing the area of fallow land considerably. Changing cultivation systems from vertically oriented to modern vineyard terraces offers an opportunity to maintain management economically viable and thus reduces further abandonment. Hillside parallel terraces favor mechanization, and their embankments offer large undisturbed areas that could provide valuable habitats. We investigated the effects of vineyard abandonment, different vineyard management types (vertically oriented vs. terraced), and local parameters on Orthoptera diversity in 45 study sites along the Upper Middle Rhine Valley in Germany. Our results show that woody structures and vineyard abandonment reduced Orthoptera diversity at the local and landscape scale due to decreased habitat quality, especially for open-adapted species. In contrast, open inter-rows of actively managed vineyard types supported heat-adapted Caelifera species. On terrace embankments, extensive management and taller vegetation benefited Ensifera species, while short and mulched vegetation in vertically oriented vineyards favored the dominance of one single Caelifera species. Our results highlight the significance of maintaining viticultural management on steep slopes for the preservation of both open-adapted Orthoptera species and the cultural landscape.
We generalize a theorem by Titchmarsh about the mean value of Hardy’s \(Z\)-function at the Gram points to the Hecke \(L\)-functions, which in turn implies the weak Gram law for them. Instead of proceeding analogously to Titchmarsh with an approximate functional equation we employ a different method using contour integration.
The development of ligands capable of effectively stabilizing highly reactive main‐group species has led to the experimental realization of a variety of systems with fascinating properties. In this work, we computationally investigate the electronic, structural, energetic, and bonding features of proximity‐enforced group 13–15 homodimers stabilized by a rigid expanded pincer ligand based on the 1,8‐naphthyridine (napy) core. We show that the redox‐active naphthyridine diimine (NDI) ligand enables a wide variety of structural motifs and element‐element interaction modes, the latter ranging from isolated, element‐centered lone pairs (e.g., E = Si, Ge) to cases where through‐space π bonds (E = Pb), element‐element multiple bonds (E = P, As) and biradical ground states (E = N) are observed. Our results hint at the feasibility of NDI‐E2 species as viable synthetic targets, highlighting the versatility and potential applications of napy‐based ligands in main‐group chemistry.
Evidence synthesis findings depend on the assumption that the included studies follow good clinical practice and results are not fabricated or false. Studies which are problematic due to scientific misconduct, poor research practice, or honest error may distort evidence synthesis findings. Authors of evidence synthesis need transparent mechanisms to identify and manage problematic studies to avoid misleading findings. As evidence synthesis authors of the Cochrane COVID-19 review on ivermectin, we identified many problematic studies in terms of research integrity and regulatory compliance. Through iterative discussion, we developed a research integrity assessment (RIA) tool for randomized controlled trials for the update of this Cochrane review. In this paper, we explain the rationale and application of the RIA tool in this case study. RIA assesses six study criteria: study retraction, prospective trial registration, adequate ethics approval, author group, plausibility of methods (e.g., randomization), and plausibility of study results. RIA was used in the Cochrane review as part of the eligibility check during screening of potentially eligible studies. Problematic studies were excluded and studies with open questions were held in awaiting classification until clarified. RIA decisions were made independently by two authors and reported transparently. Using the RIA tool resulted in the exclusion of >40% of studies in the first update of the review. RIA is a complementary tool prior to assessing “Risk of Bias” aiming to establish the integrity and authenticity of studies. RIA provides a platform for urgent development of a standard approach to identifying and managing problematic studies.
Among the parent borirane, benzoborirene and ortho‐dicarbadodecaborane‐fused borirane, the latter possesses the highest ring strain and the highest Lewis acidity according to our density functional theory (DFT) studies. The synthesis of this class of compounds is thus considerably challenging. The existing examples require either a strong π‐donating group or an extra ligand for B‐coordination, which nevertheless suppresses or completely turns off the Lewis acidity. The title compound, which possesses both features, not only allows the 1,2‐insertion of P=O, C=O or C≡N to proceed under milder conditions, but also enables the heretofore unknown dearomative 1,4‐insertion of Ar−(C=O)− into a B−C bond. The fusion of strained molecular systems to an o‐carborane cage shows great promise for boosting both the ring strain and acidity.
Unicompartmental knee arthroplasty (UKA) in isolated medial or lateral osteoarthritis leads to good clinical results. However, revision rates are higher in comparison to total knee arthroplasty (TKA). One reason is suboptimal fitting of conventional off-the-shelf prostheses, and major overhang of the tibial component over the bone has been reported in up to 20% of cases. In this retrospective study, a total of 537 patient-specific UKAs (507 medial prostheses and 30 lateral prostheses) that had been implanted in 3 centers over a period of 10 years were analyzed for survival, with a minimal follow-up of 1 year (range 12 to 129 months). Furthermore, fitting of the UKAs was analyzed on postoperative X-rays, and tibial overhang was quantified. A total of 512 prostheses were available for follow-up (95.3%). Overall survival rate (medial and lateral) of the prostheses after 5 years was 96%. The 30 lateral UKAs showed a survival rate of 100% at 5 years. The tibial overhang of the prosthesis was smaller than 1 mm in 99% of cases. In comparison to the reported results in the literature, our data suggest that the patient-specific implant design used in this study is associated with an excellent midterm survival rate, particularly in the lateral knee compartment, and confirms excellent fitting.
Tissue-engineered anterior segment eye cultures demonstrate hallmarks of conventional organ culture
(2023)
Background
Glaucoma is a blinding disease largely caused by dysregulation of outflow through the trabecular meshwork (TM), resulting in elevated intraocular pressure (IOP). We hypothesized that transplanting TM cells into a decellularized, tissue-engineered anterior segment eye culture could restore the outflow structure and function.
Methods
Porcine eyes were decellularized with freeze–thaw cycles and perfusion of surfactant. We seeded control scaffolds with CrFK cells transduced with lentiviral vectors to stably express eGFP and compared them to scaffolds seeded with primary TM cells as well as to normal, unaltered eyes. We tracked the repopulation behavior, performed IOP maintenance challenges, and analyzed the histology.
Results
Transplanted cells localized to the TM and progressively infiltrated the extracellular matrix, reaching a distribution comparable to normal, unaltered eyes. After a perfusion rate challenge to mimic a glaucomatous pressure elevation, transplanted and normal eyes reestablished a normal intraocular pressure (transplanted = 16.5 ± 0.9 mmHg, normal = 16.9 ± 0.9). However, eyes reseeded with eGFP-expressing CrFK cells could not regulate IOP, remaining high and unstable (27.0 ± 6.2 mmHg) instead.
Conclusion
Tissue-engineered anterior segment scaffolds can serve as readily available, scalable ocular perfusion cultures. This could reduce dependency on scarce donor globes in outflow research and may allow engineering perfusion cultures with specific geno- and phenotypes.
The parotid gland is one of the major salivary glands producing a serous secretion, and it plays an essential role in the digestive and immune systems. Knowledge of peroxisomes in the human parotid gland is minimal; furthermore, the peroxisomal compartment and its enzyme composition in the different cell types of the human parotid gland have never been subjected to a detailed investigation. Therefore, we performed a comprehensive analysis of peroxisomes in the human parotid gland’s striated duct and acinar cells. We combined biochemical techniques with various light and electron microscopy techniques to determine the localization of parotid secretory proteins and different peroxisomal marker proteins in parotid gland tissue. Moreover, we analyzed the mRNA of numerous gene encoding proteins localized in peroxisomes using real-time quantitative PCR. The results confirm the presence of peroxisomes in all striated duct and acinar cells of the human parotid gland. Immunofluorescence analyses for various peroxisomal proteins showed a higher abundance and more intense staining in striated duct cells compared to acinar cells. Moreover, human parotid glands comprise high quantities of catalase and other antioxidative enzymes in discrete subcellular regions, suggesting their role in protection against oxidative stress. This study provides the first thorough description of parotid peroxisomes in different parotid cell types of healthy human tissue.
On-orbit verification of RL-based APC calibrations for micrometre level microwave ranging system
(2023)
Micrometre level ranging accuracy between satellites on-orbit relies on the high-precision calibration of the antenna phase center (APC), which is accomplished through properly designed calibration maneuvers batch estimation algorithms currently. However, the unmodeled perturbations of the space dynamic and sensor-induced uncertainty complicated the situation in reality; ranging accuracy especially deteriorated outside the antenna main-lobe when maneuvers performed. This paper proposes an on-orbit APC calibration method that uses a reinforcement learning (RL) process, aiming to provide the high accuracy ranging datum for onboard instruments with micrometre level. The RL process used here is an improved Temporal Difference advantage actor critic algorithm (TDAAC), which mainly focuses on two neural networks (NN) for critic and actor function. The output of the TDAAC algorithm will autonomously balance the APC calibration maneuvers amplitude and APC-observed sensitivity with an object of maximal APC estimation accuracy. The RL-based APC calibration method proposed here is fully tested in software and on-ground experiments, with an APC calibration accuracy of less than 2 mrad, and the on-orbit maneuver data from 11–12 April 2022, which achieved 1–1.5 mrad calibration accuracy after RL training. The proposed RL-based APC algorithm may extend to prove mass calibration scenes with actions feedback to attitude determination and control system (ADCS), showing flexibility of spacecraft payload applications in the future.
An alternative to the time-consuming and error-prone pharmacopoeial gas chromatography method for the analysis of fatty acids (FAs) is urgently needed. The objective was therefore to propose a robust liquid chromatography method with charged aerosol detection for the analysis of polysorbate 80 (PS80) and magnesium stearate. FAs with different numbers of carbon atoms in the chain necessitated the use of a gradient method with a Hypersil Gold C\(_{18}\) column and acetonitrile as organic modifier. The risk-based Analytical Quality by Design approach was applied to define the Method Operable Design Region (MODR). Formic acid concentration, initial and final percentages of acetonitrile, gradient elution time, column temperature, and mobile phase flow rate were identified as critical method parameters (CMPs). The initial and final percentages of acetonitrile were fixed while the remaining CMPs were fine-tuned using response surface methodology. Critical method attributes included the baseline separation of adjacent peaks (α-linolenic and myristic acid, and oleic and petroselinic acid) and the retention factor of the last compound eluted, stearic acid. The MODR was calculated by Monte Carlo simulations with a probability equal or greater than 90%. Finally, the column temperature was set at 33 °C, the flow rate was 0.575 mL/min, and acetonitrile linearly increased from 70 to 80% (v/v) within 14.2 min.
Physicians play an important role in adapting to and mitigating the adverse health effects of the unfolding climate and ecological crises. To fully harness this potential, future physicians need to acquire knowledge, values, skills, and leadership attributes to care for patients presenting with environmental change-related conditions and to initiate and propel transformative change in healthcare and other sectors of society including, but not limited to, the decarbonization of healthcare systems, the transition to renewable energies and the transformation of transport and food systems. Despite the potential of Planetary Health Education (PHE) to support medical students in becoming agents of change, best-practice examples of mainstreaming PHE in medical curricula remain scarce both in Germany and internationally. The process of revising and updating the Medical Licensing Regulations and the National Competency-based Catalog of Learning Objectives for Medical Education in Germany provided a window of opportunity to address this implementation challenge. In this article, we describe the development and content of national Planetary Health learning objectives for Germany. We anticipate that the learning objectives will stimulate the development and implementation of innovative Planetary Health teaching, learning and exam formats in medical schools and inform similar initiatives in other health professions. The availability of Planetary Health learning objectives in other countries will provide opportunities for cross-country and interdisciplinary exchange of experiences and validation of content, thus supporting the consolidation of Planetary Health learning objectives and the improvement of PHE for all health professionals globally.
Periodontitis is one of the most prevalent diseases worldwide. The degree of radiographic bone loss can be used to assess the course of therapy or the severity of the disease. Since automated bone loss detection has many benefits, our goal was to develop a multi-object detection algorithm based on artificial intelligence that would be able to detect and quantify radiographic bone loss using standard two-dimensional radiographic images in the maxillary posterior region. This study was conducted by combining three recent online databases and validating the results using an external validation dataset from our organization. There were 1414 images for training and testing and 341 for external validation in the final dataset. We applied a Keypoint RCNN with a ResNet-50-FPN backbone network for both boundary box and keypoint detection. The intersection over union (IoU) and the object keypoint similarity (OKS) were used for model evaluation. The evaluation of the boundary box metrics showed a moderate overlapping with the ground truth, revealing an average precision of up to 0.758. The average precision and recall over all five folds were 0.694 and 0.611, respectively. Mean average precision and recall for the keypoint detection were 0.632 and 0.579, respectively. Despite only using a small and heterogeneous set of images for training, our results indicate that the algorithm is able to learn the objects of interest, although without sufficient accuracy due to the limited number of images and a large amount of information available in panoramic radiographs. Considering the widespread availability of panoramic radiographs as well as the increasing use of online databases, the presented model can be further improved in the future to facilitate its implementation in clinics.
Background
Medical resource management can be improved by assessing the likelihood of prolonged length of stay (LOS) for head and neck cancer surgery patients. The objective of this study was to develop predictive models that could be used to determine whether a patient's LOS after cancer surgery falls within the normal range of the cohort.
Methods
We conducted a retrospective analysis of a dataset consisting of 300 consecutive patients who underwent head and neck cancer surgery between 2017 and 2022 at a single university medical center. Prolonged LOS was defined as LOS exceeding the 75th percentile of the cohort. Feature importance analysis was performed to evaluate the most important predictors for prolonged LOS. We then constructed 7 machine learning and deep learning algorithms for the prediction modeling of prolonged LOS.
Results
The algorithms reached accuracy values of 75.40 (radial basis function neural network) to 97.92 (Random Trees) for the training set and 64.90 (multilayer perceptron neural network) to 84.14 (Random Trees) for the testing set. The leading parameters predicting prolonged LOS were operation time, ischemia time, the graft used, the ASA score, the intensive care stay, and the pathological stages. The results revealed that patients who had a higher number of harvested lymph nodes (LN) had a lower probability of recurrence but also a greater LOS. However, patients with prolonged LOS were also at greater risk of recurrence, particularly when fewer (LN) were extracted. Further, LOS was more strongly correlated with the overall number of extracted lymph nodes than with the number of positive lymph nodes or the ratio of positive to overall extracted lymph nodes, indicating that particularly unnecessary lymph node extraction might be associated with prolonged LOS.
Conclusions
The results emphasize the need for a closer follow-up of patients who experience prolonged LOS. Prospective trials are warranted to validate the present results.
Josephson junctions (JJs) in the presence of a magnetic field exhibit qualitatively different interference patterns depending on the spatial distribution of the supercurrent through the junction. In JJs based on two-dimensional topological insulators (2DTIs), the electrons/holes forming a Cooper pair (CP) can either propagate along the same edge or be split into the two edges. The former leads to a SQUID-like interference pattern, with the superconducting flux quantum ϕ\(_0\) (where ϕ\(_0\)=h/2e) as a fundamental period. If CPs’ splitting is additionally included, the resultant periodicity doubles. Since the edge states are typically considered to be strongly localized, the critical current does not decay as a function of the magnetic field. The present paper goes beyond this approach and inspects a topological JJ in the tunneling regime featuring extended edge states. It is here considered the possibility that the two electrons of a CP propagate and explore the junction independently over length scales comparable to the superconducting coherence length. As a consequence of the spatial extension, a decaying pattern with different possible periods is obtained. In particular, it is shown that, if crossed Andreev reflections (CARs) are dominant and the edge states overlap, the resulting interference pattern features oscillations whose periodicity approaches 2ϕ\(_0\).
Non-small cell lung cancer, ovarian cancer, and pancreatic cancer all present with high morbidity and mortality. Systemic chemotherapies have historically been the cornerstone of standard of care (SOC) regimens for many cancers, but are associated with systemic toxicity. Multimodal treatment combinations can help improve patient outcomes; however, implementation is limited by additive toxicities and potential drug–drug interactions. As such, there is a high unmet need to develop additional therapies to enhance the efficacy of SOC treatments without increasing toxicity. Tumor Treating Fields (TTFields) are electric fields that exert physical forces to disrupt cellular processes critical for cancer cell viability and tumor progression. The therapy is locoregional and is delivered noninvasively to the tumor site via a portable medical device that consists of field generator and arrays that are placed on the patient’s skin. As a noninvasive treatment modality, TTFields therapy-related adverse events mainly consist of localized skin reactions, which are manageable with effective acute and prophylactic treatments. TTFields selectively target cancer cells through a multi-mechanistic approach without affecting healthy cells and tissues. Therefore, the application of TTFields therapy concomitant with other cancer treatments may lead to enhanced efficacy, with low risk of further systemic toxicity. In this review, we explore TTFields therapy concomitant with taxanes in both preclinical and clinical settings. The summarized data suggest that TTFields therapy concomitant with taxanes may be beneficial in the treatment of certain cancers.
Background
Patients with coronary heart disease (CHD) with and without diabetes mellitus have an increased risk of recurrent events requiring multifactorial secondary prevention of cardiovascular risk factors. We compared prevalences of cardiovascular risk factors and its determinants including lifestyle, pharmacotherapy and diabetes mellitus among patients with chronic CHD examined within the fourth and fifth EUROASPIRE surveys (EA-IV, 2012–13; and EA-V, 2016–17) in Germany.
Methods
The EA initiative iteratively conducts European-wide multicenter surveys investigating the quality of secondary prevention in chronic CHD patients aged 18 to 79 years. The data collection in Germany was performed during a comprehensive baseline visit at study centers in Würzburg (EA-IV, EA-V), Halle (EA-V), and Tübingen (EA-V).
Results
384 EA-V participants (median age 69.0 years, 81.3% male) and 536 EA-IV participants (median age 68.7 years, 82.3% male) were examined. Comparing EA-IV and EA-V, no relevant differences in risk factor prevalence and lifestyle changes were observed with the exception of lower LDL cholesterol levels in EA-V. Prevalence of unrecognized diabetes was significantly lower in EA-V as compared to EA-IV (11.8% vs. 19.6%) while the proportion of prediabetes was similarly high in the remaining population (62.1% vs. 61.0%).
Conclusion
Between 2012 and 2017, a modest decrease in LDL cholesterol levels was observed, while no differences in blood pressure control and body weight were apparent in chronic CHD patients in Germany. Although the prevalence of unrecognized diabetes decreased in the later study period, the proportion of normoglycemic patients was low. As pharmacotherapy appeared fairly well implemented, stronger efforts towards lifestyle interventions, mental health programs and cardiac rehabilitation might help to improve risk factor profiles in chronic CHD patients.
Purpose: A new PET radiotracer \(^{18}\)F-AF78 showing great potential for clinical application has been reported recently. It belongs to a new generation of phenethylguanidine-based norepinephrine transporter (NET)-targeting radiotracers. Although many efforts have been made to develop NET inhibitors as antidepressants, systemic investigations of the structure–activity relationships (SARs) of NET-targeting radiotracers have rarely been performed. Methods: Without changing the phenethylguanidine pharmacophore and 3-fluoropropyl moiety that is crucial for easy labeling, six new analogs of \(^{18}\)F-AF78 with different meta-substituents on the benzene-ring were synthesized and evaluated in a competitive cellular uptake assay and in in vivo animal experiments in rats. Computational modeling of these tracers was established to quantitatively rationalize the interaction between the radiotracers and NET. Results: Using non-radiolabeled reference compounds, a competitive cellular uptake assay showed a decrease in NET-transporting affinity from meta-fluorine to iodine (0.42 and 6.51 µM, respectively), with meta-OH being the least active (22.67 µM). Furthermore, in vivo animal studies with radioisotopes showed that heart-to-blood ratios agreed with the cellular experiments, with AF78(F) exhibiting the highest cardiac uptake. This result correlates positively with the electronegativity rather than the atomic radius of the meta-substituent. Computational modeling studies revealed a crucial influence of halogen substituents on the radiotracer–NET interaction, whereby a T-shaped π–π stacking interaction between the benzene-ring of the tracer and the amino acid residues surrounding the NET binding site made major contributions to the different affinities, in accordance with the pharmacological data. Conclusion: The SARs were characterized by in vitro and in vivo evaluation, and computational modeling quantitatively rationalized the interaction between radiotracers and the NET binding site. These findings pave the way for further evaluation in different species and underline the potential of AF78(F) for clinical application, e.g., cardiac innervation imaging or molecular imaging of neuroendocrine tumors.
A series of tetracationic bis-triarylborane dyes, differing in the aromatic linker connecting two dicationic triarylborane moieties, showed very high submicromolar affinities toward ds-DNA and ds-RNA. The linker strongly influenced the emissive properties of triarylborane cations and controlled the fluorimetric response of dyes. The fluorene-analog shows the most selective fluorescence response between AT-DNA, GC-DNA, and AU-RNA, the pyrene-analog’s emission is non-selectively enhanced by all DNA/RNA, and the dithienyl-diketopyrrolopyrrole analog’s emission is strongly quenched upon DNA/RNA binding. The emission properties of the biphenyl-analog were not applicable, but the compound showed specific induced circular dichroism (ICD) signals only for AT-sequence-containing ds-DNAs, whereas the pyrene-analog ICD signals were specific for AT-DNA with respect to GC-DNA, and also recognized AU-RNA by giving a different ICD pattern from that observed upon interaction with AT-DNA. The fluorene- and dithienyl-diketopyrrolopyrrole analogs were ICD-signal silent. Thus, fine-tuning of the aromatic linker properties connecting two triarylborane dications can be used for the dual sensing (fluorimetric and CD) of various ds-DNA/RNA secondary structures, depending on the steric properties of the DNA/RNA grooves.
Red fruit oil (RFO) can be extracted from fruits of Pandanus conoideus, Lam., an endogenous plant of Papua, Indonesia. It is a commonly used essential original traditional medicine. By applying a newly developed quantitative \(^1\)H NMR (qNMR) spectroscopy method for quality assessment, a simultaneous determination of the saponification value (SV), acid value (AV), ester value (EV), and iodine value (IV) in RFO was possible. Dimethyl sulfone (DMSO\(_2\)) was used as an internal standard. Optimization of NMR parameters, such as NMR pulse sequence, relaxation delay time, and receiver gain, finally established the \(^1\)H NMR-based quantification approach. Diagnostic signals of the internal standard at δ = 2.98 ppm, SV at δ = 2.37–2.20 ppm, AV at δ = 2.27–2.20 ppm, EV at δ = 2.37–2.27 ppm, and IV at δ = 5.37–5.27 ppm, respectively, were used for quantitative analysis. The method was validated concerning linearity (R\(^2\) = 0.999), precision (less than 0.83%), and repeatability in the range 99.17–101.17%. Furthermore, this method was successfully applied to crude RFO, crude RFO with palmitic and oleic acid addition, and nine commercial products. The qNMR results for the respective fat values are in accordance with the results of standard methods, as can be seen from the F- and t-test (< 1.65 and < 1.66, respectively). The fundamental advantages of qNMR, such as its rapidity and simplicity, make it a feasible and existing alternative to titration for the quality control of RFO.
The pro-inflammatory phase of bone healing, initiated by platelet activation and eventually hematoma formation, impacts bone marrow mesenchymal stromal cells (MSCs) in unknown ways. Here, we created platelet-rich plasma (PRP) hydrogels to study how platelet-derived factors modulate functional properties of encapsulated MSCs in comparison to a non-inflammatory fibrin (FBR) hydrogel environment. MSCs were isolated from human bone marrow, while PRP was collected from pooled apheresis thrombocyte concentrates and used for hydrogel preparation. After their encapsulation in hydrogels for 72 h, retrieved MSCs were analyzed for immunomodulatory activities, apoptosis, stem cell properties, senescence, CD9\(^+\), CD63\(^+\) and CD81\(^+\) extracellular vesicle (EV) release, and metabolism-related changes. PRP-hydrogels stimulated immunosuppressive functions of MSCs, along with their upregulated susceptibility to cell death in communication with PBMCs and augmented caspase 3/7 activity. We found impaired clonal growth and cell cycle progression, and more pronounced β-galactosidase activity as well as accumulation of LC3-II-positive vacuoles in PRP-MSCs. Stimuli derived from PRP-hydrogels upregulated AKT and reduced mTOR phosphorylation in MSCs, which suggests an initiation of survival-related processes. Our results showed that PRP-hydrogels might represent a metabolically stressful environment, inducing acidification of MSCs, reducing polarization of the mitochondrial membrane and increasing lipid accumulation. These features were not detected in FBR-MSCs, which showed reduced CD63\(^+\) and CD81\(^+\) EV production and maintained clonogenicity. Our data revealed that PRP-derived hematoma components cause metabolic adaptation of MSCs followed by increased immune regulatory functions. For the first time, we showed that PRP stimuli represent a survival challenge and “apoptotic priming” that are detrimental for stem cell-like growth of MSCs and important for their therapeutic consideration.
Acute and chronic cardiac disorders predispose to alterations in cognitive performance, ranging from mild cognitive impairment to overt dementia. Although this association is well-established, the factors inducing and accelerating cognitive decline beyond ageing and the intricate causal pathways and multilateral interdependencies involved remain poorly understood. Dysregulated and persistent inflammatory processes have been implicated as potentially causal mediators of the adverse consequences on brain function in patients with cardiac disease. Recent advances in positron emission tomography disclosed an enhanced level of neuroinflammation of cortical and subcortical brain regions as an important correlate of altered cognition in these patients. In preclinical and clinical investigations, the thereby involved domains and cell types of the brain are gradually better characterized. Microglia, resident myeloid cells of the central nervous system, appear to be of particular importance, as they are extremely sensitive to even subtle pathological alterations affecting their complex interplay with neighboring astrocytes, oligodendrocytes, infiltrating myeloid cells, and lymphocytes. Here, we review the current evidence linking cognitive impairment and chronic neuroinflammation in patients with various selected cardiac disorders including the aspect of chronic neuroinflammation as a potentially druggable target.
(1) Background: The health-related quality of life (HRQOL) of colorectal cancer (CRC) survivors >10 years post-diagnosis is understudied. We aimed to compare the HRQOL of CRC survivors 14–24 years post-diagnosis to that of age- and sex-matched non-cancer controls, stratified by demographic and clinical factors. (2) Methods: We used data from 506 long-term CRC survivors and 1489 controls recruited from German population-based multi-regional studies. HRQOL was assessed with the European Organization for Research and Treatment of Cancer Quality of Life Core-30 (EORTC QLQ-C30) questionnaire. We estimated differences in the HRQOL of CRC survivors and controls with multiple regression, adjusted for age at survey, sex, and education, where appropriate. (3) Results: CRC survivors reported poorer social functioning but better health status/QOL than controls. CRC survivors, in general, had higher levels of symptom burden, and in particular diarrhea and constipation, regardless of demographic or clinical factors. In stratified analyses, HRQOL differed by age, sex, cancer type, and having a permanent stoma. (4) Conclusions: Although CRC survivors may have a comparable health status/QOL to controls 14–24 years after diagnosis, they still live with persistent bowel dysfunction that can negatively impact aspects of functioning. Healthcare providers should provide timely and adapted follow-up care to ameliorate potential long-term suffering.
Interleukin-4 (IL-4) plays a key role in atopic diseases. It coordinates T-helper cell differentiation to subtype 2, thereby directing defense toward humoral immunity. Together with Interleukin-13, IL-4 further induces immunoglobulin class switch to IgE. Antibodies of this type activate mast cells and basophilic and eosinophilic granulocytes, which release pro-inflammatory mediators accounting for the typical symptoms of atopic diseases. IL-4 and IL-13 are thus major targets for pharmaceutical intervention strategies to treat atopic diseases. Besides neutralizing antibodies against IL-4, IL-13, or its receptors, IL-4 antagonists can present valuable alternatives. Pitrakinra, an Escherichia coli-derived IL-4 antagonist, has been evaluated in clinical trials for asthma treatment in the past; however, deficits such as short serum lifetime and potential immunogenicity among others stopped further development. To overcome such deficits, PEGylation of therapeutically important proteins has been used to increase the lifetime and proteolytic stability. As an alternative, glycoengineering is an emerging strategy used to improve pharmacokinetics of protein therapeutics. In this study, we have established different strategies to attach glycan moieties to defined positions in IL-4. Different chemical attachment strategies employing thiol chemistry were used to attach a glucose molecule at amino acid position 121, thereby converting IL-4 into a highly effective antagonist. To enhance the proteolytic stability of this IL-4 antagonist, additional glycan structures were introduced by glycoengineering utilizing eucaryotic expression. IL-4 antagonists with a combination of chemical and biosynthetic glycoengineering could be useful as therapeutic alternatives to IL-4 neutralizing antibodies already used to treat atopic diseases.
Spontaneous brain activity builds the foundation for human cognitive processing during external demands. Neuroimaging studies based on functional magnetic resonance imaging (fMRI) identified specific characteristics of spontaneous (intrinsic) brain dynamics to be associated with individual differences in general cognitive ability, i.e., intelligence. However, fMRI research is inherently limited by low temporal resolution, thus, preventing conclusions about neural fluctuations within the range of milliseconds. Here, we used resting-state electroencephalographical (EEG) recordings from 144 healthy adults to test whether individual differences in intelligence (Raven’s Advanced Progressive Matrices scores) can be predicted from the complexity of temporally highly resolved intrinsic brain signals. We compared different operationalizations of brain signal complexity (multiscale entropy, Shannon entropy, Fuzzy entropy, and specific characteristics of microstates) regarding their relation to intelligence. The results indicate that associations between brain signal complexity measures and intelligence are of small effect sizes (r ∼ 0.20) and vary across different spatial and temporal scales. Specifically, higher intelligence scores were associated with lower complexity in local aspects of neural processing, and less activity in task-negative brain regions belonging to the default-mode network. Finally, we combined multiple measures of brain signal complexity to show that individual intelligence scores can be significantly predicted with a multimodal model within the sample (10-fold cross-validation) as well as in an independent sample (external replication, N = 57). In sum, our results highlight the temporal and spatial dependency of associations between intelligence and intrinsic brain dynamics, proposing multimodal approaches as promising means for future neuroscientific research on complex human traits.
In spinal muscular atrophy (SMA), mutations in or loss of the Survival Motor Neuron 1 (SMN1) gene reduce full-length SMN protein levels, which leads to the degeneration of a percentage of motor neurons. In mouse models of SMA, the development and maintenance of spinal motor neurons and the neuromuscular junction (NMJ) function are altered. Since nifedipine is known to be neuroprotective and increases neurotransmission in nerve terminals, we investigated its effects on cultured spinal cord motor neurons and motor nerve terminals of control and SMA mice. We found that application of nifedipine increased the frequency of spontaneous Ca\(^{2+}\) transients, growth cone size, cluster-like formations of Cav2.2 channels, and it normalized axon extension in SMA neurons in culture. At the NMJ, nifedipine significantly increased evoked and spontaneous release at low-frequency stimulation in both genotypes. High-strength stimulation revealed that nifedipine increased the size of the readily releasable pool (RRP) of vesicles in control but not SMA mice. These findings provide experimental evidence about the ability of nifedipine to prevent the appearance of developmental defects in SMA embryonic motor neurons in culture and reveal to which extent nifedipine could still increase neurotransmission at the NMJ in SMA mice under different functional demands.
Surgical management of lateral neck abscesses in children: a retrospective analysis of 100 cases
(2023)
Cervical abscesses are relatively common infections in pediatric patients. There is an ongoing debate about the necessity and time point of surgical drainage. The identification of a focus of infection might play an important role in facilitating a therapeutic decision. In a retrospective study, 100 pediatric patients aged 1–18 years who underwent incision and drainage of a lateral cervical abscess at our institution were analyzed. Patients were divided into two groups based on whether a focus of infection could be identified or not. Data collection included patient characteristics, microbiological results, antibiotic regimen, and clinical course. A focus of infection was found in 29% (29/100) of the patients, most frequently in the tonsils. A causative microorganism was found in 75% (75/100) of all patients, with Staphylococcus aureus and Streptococcus pyogenes being the most common pathogens. All patients received an empiric antibiotic therapy in addition to surgery. Antibiotic medication was changed in 31% in both groups (9/29 with a focus of infection and 22/71 without a focus of infection) during therapy. Children without an identified focus of infection generally were younger and had more comorbidities reducing immune response while also showing differences in the pathogens involved. There were no complications associated to surgery or antibiotic therapy in any of the patients involved.
Conclusion: Children with an identified focus of infection show several differences compared to those with isolated lateral abscesses, especially regarding the microorganisms involved. But the focus of infection seems not to have an impact on patient’s outcome.
What is Known:
• Neck abscesses are a relatively common disease in the pediatric population and may cause serious complications.
• Therapy in general consists of intravenous antibiotics with or without surgery.
What is New:
• The focus identification has no impact on patient’s outcome.
• Children with an identified focus of infection show several differences compared to those with isolated lateral abscesses, especially regarding their medical history, age, and the microorganisms involved.
Whether, and in what sense, research in phenomenology and phenomenological psychopathology has—in addition to its descriptive and hermeneutic value—explanatory power is somewhat controversial. This paper shows why it is legitimate to recognize such explanatory power. To this end, the paper analyzes two central concerns underlying the debate about explanation in phenomenology: (a) the warning against reductionism, which is implicit in a conception of causal explanation exclusively based on models of natural/physical causation; and (b) the warning against top-down generalizations, which neglect the specificity of the individual. While acknowledging that these two caveats express serious concerns regarding the debate on explanatory models, I show that phenomenology has the resources to respond to them. These can be found in analyses of different types of causation relating to different regions of reality and in the structure of explanatory models based on exemplarity. On the basis of these analyses, I defend a pluralist account vis-à-vis explanatory models.
(1) Background: Interventional endoscopic procedures are growing more popular, requiring innovative instruments and novel techniques. Three-dimensional printing has demonstrated great potential for the rapid development of prototypes that can be used for the early assessment of various concepts. In this work, we present the development of a flexible endoscopic instrument and explore its potential benefits. (2) Methods: The properties of the instrument, such as its maneuverability, flexibility, and bending force, were evaluated in a series of bench tests. Additionally, the effectiveness of the instrument was evaluated in an ex vivo porcine model by medical experts, who graded its properties and performance. Furthermore, the time necessary to complete various interventional endoscopic tasks was recorded. (3) Results: The instrument achieved bending angles of ±216° while achieving a bending force of 7.85 (±0.53) Newtons. The time needed to reach the operating region was 120 s median, while it took 70 s median to insert an object in a cavity. Furthermore, it took 220 s median to insert the instrument and remove an object from the cavity. (4) Conclusions: This study presents the development of a flexible endoscopic instrument using three-dimensional printing technology and its evaluation. The instrument demonstrated high bending angles and forces, and superior properties compared to the current state of the art. Furthermore, it was able to complete various interventional endoscopic tasks in minimal time, thus potentially leading to the improved safety and effectiveness of interventional endoscopic procedures in the future.
Testosterone deficiency in males is linked to various pathological conditions, including muscle and bone loss. This study evaluated the potential of different training modalities to counteract these losses in hypogonadal male rats. A total of 54 male Wistar rats underwent either castration (ORX, n = 18) or sham castration (n = 18), with 18 castrated rats engaging in uphill, level, or downhill interval treadmill training. Analyses were conducted at 4, 8, and 12 weeks postsurgery. Muscle force of the soleus muscle, muscle tissue samples, and bone characteristics were analyzed. No significant differences were observed in cortical bone characteristics. Castrated rats experienced decreased trabecular bone mineral density compared to sham-operated rats. However, 12 weeks of training increased trabecular bone mineral density, with no significant differences among groups. Muscle force measurements revealed decreased tetanic force in castrated rats at week 12, while uphill and downhill interval training restored force to sham group levels and led to muscle hypertrophy compared to ORX animals. Linear regression analyses showed a positive correlation between bone biomechanical characteristics and muscle force. The findings suggest that running exercise can prevent bone loss in osteoporosis, with similar bone restoration effects observed across different training modalities.
We extend Bourgain’s bound for the order of growth of the Riemann zeta function on the critical line to Lerch zeta functions. More precisely, we prove L(λ, α, 1/2 + it) ≪ t\(^{13/84+ϵ}\) as t → ∞. For both, the Riemann zeta function as well as for the more general Lerch zeta function, it is conjectured that the right-hand side can be replaced by t\(^ϵ\) (which is the so-called Lindelöf hypothesis). The growth of an analytic function is closely related to the distribution of its zeros.
Several studies have shown that tapering or stopping disease-modifying anti-rheumatic drugs (DMARDs) in rheumatoid arthritis (RA) patients in sustained remission is feasible. However, tapering/stopping bears the risk of decline in physical function as some patients may relapse and face increased disease activity. Here, we analyzed the impact of tapering or stopping DMARD treatment on the physical function of RA patients. The study was a post hoc analysis of physical functional worsening for 282 patients with RA in sustained remission tapering and stopping DMARD treatment in the prospective randomized RETRO study. HAQ and DAS-28 scores were determined in baseline samples of patients continuing DMARD (arm 1), tapering their dose by 50% (arm 2), or stopping after tapering (arm 3). Patients were followed over 1 year, and HAQ and DAS-28 scores were evaluated every 3 months. The effect of treatment reduction strategy on functional worsening was assessed in a recurrent-event Cox regression model with a study-group (control, taper, and taper/stop) as the predictor. Two-hundred and eighty-two patients were analyzed. In 58 patients, functional worsening was observed. The incidences suggest a higher probability of functional worsening in patients tapering and/or stopping DMARDs, which is likely due to higher relapse rates in these individuals. At the end of the study, however, functional worsening was similar among the groups. Point estimates and survival curves show that the decline in functionality according to HAQ after tapering or discontinuation of DMARDs in RA patients with stable remission is associated with recurrence, but not with an overall functional decline.
Climate models are the tool of choice for scientists researching climate change. Like all models they suffer from errors, particularly systematic and location-specific representation errors. One way to reduce these errors is model output statistics (MOS) where the model output is fitted to observational data with machine learning. In this work, we assess the use of convolutional Deep Learning climate MOS approaches and present the ConvMOS architecture which is specifically designed based on the observation that there are systematic and location-specific errors in the precipitation estimates of climate models. We apply ConvMOS models to the simulated precipitation of the regional climate model REMO, showing that a combination of per-location model parameters for reducing location-specific errors and global model parameters for reducing systematic errors is indeed beneficial for MOS performance. We find that ConvMOS models can reduce errors considerably and perform significantly better than three commonly used MOS approaches and plain ResNet and U-Net models in most cases. Our results show that non-linear MOS models underestimate the number of extreme precipitation events, which we alleviate by training models specialized towards extreme precipitation events with the imbalanced regression method DenseLoss. While we consider climate MOS, we argue that aspects of ConvMOS may also be beneficial in other domains with geospatial data, such as air pollution modeling or weather forecasts.
Small bacterial regulatory RNAs (sRNAs) have been implicated in the regulation of numerous metabolic pathways. In most of these studies, sRNA-dependent regulation of mRNAs or proteins of enzymes in metabolic pathways has been predicted to affect the metabolism of these bacteria. However, only in a very few cases has the role in metabolism been demonstrated. Here, we performed a combined transcriptome and metabolome analysis to define the regulon of the sibling sRNAs NgncR_162 and NgncR_163 (NgncR_162/163) and their impact on the metabolism of Neisseria gonorrhoeae. These sRNAs have been reported to control genes of the citric acid and methylcitric acid cycles by posttranscriptional negative regulation. By transcriptome analysis, we now expand the NgncR_162/163 regulon by several new members and provide evidence that the sibling sRNAs act as both negative and positive regulators of target gene expression. Newly identified NgncR_162/163 targets are mostly involved in transport processes, especially in the uptake of glycine, phenylalanine, and branched-chain amino acids. NgncR_162/163 also play key roles in the control of serine-glycine metabolism and, hence, probably affect biosyntheses of nucleotides, vitamins, and other amino acids via the supply of one-carbon (C\(_1\)) units. Indeed, these roles were confirmed by metabolomics and metabolic flux analysis, which revealed a bipartite metabolic network with glucose degradation for the supply of anabolic pathways and the usage of amino acids via the citric acid cycle for energy metabolism. Thus, by combined deep RNA sequencing (RNA-seq) and metabolomics, we significantly extended the regulon of NgncR_162/163 and demonstrated the role of NgncR_162/163 in the regulation of central metabolic pathways of the gonococcus.
The effect of inherently threatening contexts on visuocortical engagement to conditioned threat
(2023)
Fear and anxiety are crucial for adaptive responding in life‐threatening situations. Whereas fear is a phasic response to an acute threat accompanied by selective attention, anxiety is characterized by a sustained feeling of apprehension and hypervigilance during situations of potential threat. In the current literature, fear and anxiety are usually considered mutually exclusive, with partially separated neural underpinnings. However, there is accumulating evidence that challenges this distinction between fear and anxiety, and simultaneous activation of fear and anxiety networks has been reported. Therefore, the current study experimentally tested potential interactions between fear and anxiety. Fifty‐two healthy participants completed a differential fear conditioning paradigm followed by a test phase in which the conditioned stimuli were presented in front of threatening or neutral contextual images. To capture defense system activation, we recorded subjective (threat, US‐expectancy), physiological (skin conductance, heart rate) and visuocortical (steady‐state visual evoked potentials) responses to the conditioned stimuli as a function of contextual threat. Results demonstrated successful fear conditioning in all measures. In addition, threat and US‐expectancy ratings, cardiac deceleration, and visuocortical activity were enhanced for fear cues presented in threatening compared with neutral contexts. These results are in line with an additive or interactive rather than an exclusive model of fear and anxiety, indicating facilitated defensive behavior to imminent danger in situations of potential threat.
Anxiety is characterized by anxious anticipation and heightened vigilance to uncertain threat. However, if threat is not reliably indicated by a specific cue, the context in which threat was previously experienced becomes its best predictor, leading to anxiety. A suitable means to induce anxiety experimentally is context conditioning: In one context (CTX+), an unpredictable aversive stimulus (US) is repeatedly presented, in contrast to a second context (CTX−), in which no US is ever presented. In this EEG study, we investigated attentional mechanisms during acquisition and extinction learning in 38 participants, who underwent a context conditioning protocol. Flickering video stimuli (32 s clips depicting virtual offices representing CTX+/−) were used to evoke steady‐state visual evoked potentials (ssVEPs) as an index of visuocortical engagement with the contexts. Analyses of the electrocortical responses suggest a successful induction of the ssVEP signal by video presentation in flicker mode. Furthermore, we found clear indices of context conditioning and extinction learning on a subjective level, while cortical processing of the CTX+ was unexpectedly reduced during video presentation. The differences between CTX+ and CTX− diminished during extinction learning. Together, these results indicate that the dynamic sensory input of the video presentation leads to disruptions in the ssVEP signal, which is greater for motivationally significant, threatening contexts.
Due to the wide variety of benign and malignant salivary gland tumors, classification and malignant behavior determination based on histomorphological criteria can be difficult and sometimes impossible. Spectroscopical procedures can acquire molecular biological information without destroying the tissue within the measurement processes. Since several tissue preparation procedures exist, our study investigated the impact of these preparations on the chemical composition of healthy and tumorous salivary gland tissue by Fourier-transform infrared (FTIR) microspectroscopy. Sequential tissue cross-sections were prepared from native, formalin-fixed and formalin-fixed paraffin-embedded (FFPE) tissue and analyzed. The FFPE cross-sections were dewaxed and remeasured. By using principal component analysis (PCA) combined with a discriminant analysis (DA), robust models for the distinction of sample preparations were built individually for each parotid tissue type. As a result, the PCA-DA model evaluation showed a high similarity between native and formalin-fixed tissues based on their chemical composition. Thus, formalin-fixed tissues are highly representative of the native samples and facilitate a transfer from scientific laboratory analysis into the clinical routine due to their robust nature. Furthermore, the dewaxing of the cross-sections entails the loss of molecular information. Our study successfully demonstrated how FTIR microspectroscopy can be used as a powerful tool within existing clinical workflows.
Background: The benefit of hearing rehabilitation is often measured using audiological tests or subjective questionnaires/interviews. It is important to consider both aspects in order to evaluate the overall benefits. Currently, there is no standardized method for reporting combined audiological and patient reported subjective outcome measures in clinical practice. Therefore, this study focuses on showing the patient’s audiological, as well as subjective outcomes in one graph using data from an existing study. Method: The present paper illustrated a graph presenting data on four quadrants with audiological and subjective findings. These quadrants represented speech comprehension in quiet (unaided vs. aided) as WRS% at 65 dB SPL, speech recognition in noise (unaided vs. aided) as SRT dB SNR, sound field threshold (unaided vs. aided) as PTA\(_4\) in dB HL, wearing time and patient satisfaction questionnaire results. Results: As an example, the HEARRING graph in this paper represented audiological and subjective datasets on a single patient level or a cohort of patients for an active bone conduction hearing implant solution. The graph offered the option to follow the user’s performance in time. Conclusion: The HEARRING graph allowed representation of a combination of audiological measures with patient reported outcomes in one single graph, indicating the overall benefit of the intervention. In addition, the correlation and consistency between some results (e.g., aided threshold and aided WRS) can be better visualized. Those users who lacked performance benefits on one or more parameters and called for further insight could be visually identified.
Non-aureus staphylococci (NAS) are ubiquitous bacteria in livestock-associated environments where they may act as reservoirs of antimicrobial resistance (AMR) genes for pathogens such as Staphylococcus aureus. Here, we tested whether housing conditions in pig farms could influence the overall AMR-NAS burden. Two hundred and forty porcine commensal and environmental NAS isolates from three different farm types (conventional, alternative, and organic) were tested for phenotypic antimicrobial susceptibility and subjected to whole genome sequencing. Genomic data were analysed regarding species identity and AMR gene carriage. Seventeen different NAS species were identified across all farm types. In contrast to conventional farms, no AMR genes were detectable towards methicillin, aminoglycosides, and phenicols in organic farms. Additionally, AMR genes to macrolides and tetracycline were rare among NAS in organic farms, while such genes were common in conventional husbandries. No differences in AMR detection existed between farm types regarding fosfomycin, lincosamides, fusidic acid, and heavy metal resistance gene presence. The combined data show that husbandry conditions influence the occurrence of resistant and multidrug-resistant bacteria in livestock, suggesting that changing husbandry practices may be an appropriate means of limiting the spread of AMR bacteria on farms.
At the beginning of the COVID-19 pandemic, patients with primary and secondary immune disorders — including patients suffering from cancer — were generally regarded as a high-risk population in terms of COVID-19 disease severity and mortality. By now, scientific evidence indicates that there is substantial heterogeneity regarding the vulnerability towards COVID-19 in patients with immune disorders. In this review, we aimed to summarize the current knowledge about the effect of coexistent immune disorders on COVID-19 disease severity and vaccination response. In this context, we also regarded cancer as a secondary immune disorder. While patients with hematological malignancies displayed lower seroconversion rates after vaccination in some studies, a majority of cancer patients’ risk factors for severe COVID-19 disease were either inherent (such as metastatic or progressive disease) or comparable to the general population (age, male gender and comorbidities such as kidney or liver disease). A deeper understanding is needed to better define patient subgroups at a higher risk for severe COVID-19 disease courses. At the same time, immune disorders as functional disease models offer further insights into the role of specific immune cells and cytokines when orchestrating the immune response towards SARS-CoV-2 infection. Longitudinal serological studies are urgently needed to determine the extent and the duration of SARS-CoV-2 immunity in the general population, as well as immune-compromised and oncological patients.