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Abstract Background Metastatic urothelial carcinoma (mUC) has a poor prognosis, despite recent therapeutic advancements. Prostaglandin Reductase 1 (PTGR1) is essential for activating acylfulvens, a promising class of drugs for treating a subset of urothelial carcinoma (UC) patients. The efficacy of acylfulvens depends on PTGR1 activity and defects in the nucleotide excision repair (NER) pathway, notably ERCC2 mutations present in 10–15% of bladder tumors. This study identifies patients eligible to be included in acylfulven clinical trials based on the presence of PTGR-1 by immunohistochemistry (IHC) staining, RNA expression level and mutations in the NER pathway. Additionally, it evaluates PTGR-1 expression as a prognostic biomarker. Methods Three PTGR-1 antibodies were tested in a kidney cancer cell line A498 and in tissues with known PTGR1 expression (liver, tonsils, pancreas, small intestine, etc.). Patients with untreated mUC receiving 1st line platinum from Dec. 2019 to Dec. 2021 in the Capital Region, Denmark, were included retrospectively. FFPE tumor samples were collected, and tissue microarrays (TMAs) were constructed. TMAs were stained with the best-performing PTGR1 antibody, RNA expression was analyzed using Nanostring nCounter PanCancer panel and gene mutations were assessed using a targeted genomic panel (TSO-500). Kaplan-Meier and multivariate Cox regression assessed overall survival and covariate impacts. Results The AB181131 PTGR1 antibody was the most reliable in validation tissues. Tumors from 71 mUC patients were used to construct the TMA, and 40% of tumors scored positive for PTGR1 by IHC staining. A normalized PTGR1 RNA cutoff at 2,550 normalized counts achieved an AUC of 0.9, defining 35 samples as positive with a sensitivity of 96% and specificity of 85% in relation to IHC-positivity. Differential expression showed a significant upregulation of PTGR1 RNA in PTGR1 IHC-positive cases. NER-deficiency and PTGR1 positivity (mutations in ERCC1, ERCC2, ERCC3, ERCC4) was seen in 9 patients (13%). Median overall survival was 16 months in the cohort. Overall survival (OS) analysis indicates that overexpression of PTGR1 RNA was associated with a reduced median OS (12 months vs. 25 months, p = 0.039, log-rank). Conclusion PTGR1 IHC staining pattern using the Abcam AB181131 antibody is highly correlated with PTGR1 RNA expression. 13% in our cohort were identified as NER deficient and PTGR1 positive. Lower levels of PTGR1 indicates better outcome in this cohort.

This paper describes the experiences of two teachers, Ms. Santiago and Mr. Jelenik, who participated in a comprehensive National Science Foundation-supported science, technology, engineering, and mathematics (STEM) professional learning experience. This comparative case study describes how Ms. Santiago and Mr. Jelenik leveraged the justice-oriented curriculum of a STEM professional learning opportunity to transform their identities as educators while influencing their instructional practices. The professional learning experience included access to a justice-oriented curriculum introduced through monthly content-focused experiences, regular faculty learning communities, and support from an expert onsite coach. Evidence of transformed identities and instructional practices is derived from semi-structured in-depth interviews and video recordings of classroom teaching and learning. Analysis of the interview data suggests that Ms. Santiago and Mr. Jelenik found the professional learning experience transformative and that the experience served as a pedagogical identity project. Evidence from the classroom videos suggests that Ms. Santiago and Mr. Jelenik's instructional practices shifted, becoming more justice-oriented and student-centered. Moreover, Ms. Santiago's practices shifted in a manner more aligned with an engaged teaching approach. We conclude that the comprehensive STEM professional learning experience served as a pedagogical identity project while positively influencing the instructional practices of Ms. Santiago and Mr. Jelenik. Implications for preservice and in-service teacher education are discussed.

This interdisciplinary investigation of the human remains of Balduin Helm, one of the most important abbots of the Fürstenfeld monastery, provides novel information on this historic individual. This is particularly interesting since Balduin, during the early 18th century, was involved in the renovation of this large Bavarian monastery. Metastatic prostate cancer was found as evidenced by multiple mixed osteolytic–osteoblastic bone lesions in all available vertebral bodies, fragments of both os coxae, and isolated metastases in skull bones. Distribution, radio- and histomorphology, and especially the immunohistochemical detection of prostate-specific antigens in those metastases definitively confirm this diagnosis. Further investigation, especially by stable isotope analysis, showed a balanced high-level diet with considerable contribution from animal protein and significant freshwater fish. These additional findings suggest a significant radiocarbon reservoir effect as an explanation for a “too old” radiocarbon date. Finally, the obviously high-level protein diet may have contributed to the tumorigenesis which caused the death of the abbot at an advanced age.

Extracellular biophysical cues such as matrix stiffness are key stimuli tuning cell fate and affecting tumor progression in vivo. However, it remains unclear how cancer spheroids in a 3D microenvironment perceive matrix mechanical stiffness stimuli and translate them into intracellular signals driving progression. Mechanosensitive Piezo1 and TRPV4 ion channels, upregulated in many malignancies, are major transducers of such physical stimuli into biochemical responses. Most mechanotransduction studies probing the reception of changing stiffness cues by cells are, however, still limited to 2D culture systems or cell-extracellular matrix models, which lack the major cell–cell interactions prevalent in 3D cancer tumors. Here, we engineered a 3D spheroid culture environment with varying mechanobiological properties to study the effect of static matrix stiffness stimuli on mechanosensitive and malignant phenotypes in oral squamous cell carcinoma spheroids. We find that spheroid growth is enhanced when cultured in stiff extracellular matrix. We show that the protein expression of mechanoreceptor Piezo1 and stemness marker CD44 is upregulated in stiff matrix. We also report the upregulation of a selection of genes with associations to mechanoreception, ion channel transport, extracellular matrix organization, and tumorigenic phenotypes in stiff matrix spheroids. Together, our results indicate that cancer cells in 3D spheroids utilize mechanosensitive ion channels Piezo1 and TRPV4 as means to sense changes in static extracellular matrix stiffness, and that stiffness drives pro-tumorigenic phenotypes in oral squamous cell carcinoma.

Abstract Background Functional neurological disorder (FND) is a common neurological diagnosis that encapsulates a range of incapacitating clinical presentations. These include functional seizures, movement disorders, and sensory disturbances. Safe driving requires both cognitive skills and physical abilities, which may be impacted by FND symptoms. The primary objective of this study was to gain deeper insights into the challenges faced by people with FND when driving. Methods A qualitative study and interpretative phenomenological analysis were conducted. Individuals experiencing functional seizures and/or movement disorders completed both questionnaires and semi‐structured interviews about FND symptoms, driving behavior, and crashes. Results A total of 26 patients with FND participated in this study. Based on the interviews, four key themes were identified: (1) driving difficulties experienced by individuals with FND; (2) strategies utilized by people with FND to overcome difficulties experienced while driving; (3) barriers preventing driving challenges being addressed in this population; and (4) crashes and perceived dangerous driving events experienced by individuals with FND. All participants reported that driving a car provoked FND symptoms and this affected their driving ability. FND sufferers reported using a number of strategies such as limiting how far they drive and relying on advanced driver assistance system features to help manage their associated symptoms, such as fatigue and/or pain. Several participants reported crashes and perceived dangerous driving events since developing FND. Conclusion Individuals experiencing FND often employ self‐regulation techniques, yet the extent to which these methods enhance driving safety remains uncertain. The variable nature of the disorder makes judging an individual's driving risk particularly difficult. The themes emerging from the interviews highlighted the need for further empirical research to inform guidelines and best practice when determining the impact of FND on an individual's driving safety .

Increased focus on the practical components of Danish health care education and greater coherence between theory and practice have been persistently identified as major issues requiring quality improvement. Policy initiatives to standardize education in eight health professional bachelor’s programs, including greater theory-practice coherence, prompted us to explore the types of educational practices highlighted by clinical supervisors to strengthen coherence between theory and practice. Thirty-one qualitative interviews were conducted with clinical supervisors in nursing, physiotherapy, occupational therapy, nutrition and health programs, biomedical laboratory science, midwifery, radiography, and psychomotor therapy. Data were thematically analyzed in a sociology of knowledge framework. We found that theoretical knowledge had a higher status in the programs. The imbalance may have negative consequences, whereby theoria activities in the practical part of the programs may, in unintended and subtle ways, increase in dominance. The intrinsic qualities of clinical practice are, therefore, at risk of being downplayed.

Precambrian sedimentary successions exposed worldwide record microbial deposits within both marine and continental strata. The Camaquã Basin records the transition from the Ediacaran to Cambrian periods in strata that comprise marine to lacustrine environments. The Camaquã Basin fossils comprise microbial mats and organic-walled microfossils in very close association. Carbonaceous laminae are common within the siltstone and mudstone layers and represent remarkably well-preserved Ediacaran microbial mats. These mats occurred along shallow marine through deep and shallow lake settings. The excellent preservation of these structures seems to be the product of calm hydrodynamic conditions and floodings. These hydrodynamic undisturbed environments allowed microbial mat growth. Besides, episodic floodings brought clay particles, which deposits guaranteed isolation from organic decomposition of mats. In general, the siltstones and mudstones record microbially induced sedimentary structures (MISS) that are typical from Ediacaran strata, such as wrinkle marks and elephant skin structures. Our research revealed that the occurrence of these structures is not limited to marine settings, as common in records from this period, but also present in lacustrine environments. Field studies were combined with optical and scanning electron microscopy plus energy-dispersive X-ray spectroscopy (SEM-EDS) analyses to demonstrate the vast occurrence of microbial mats along the deposits that registered the Camaquã Basin development. Geochemical data (whole-rock and total organic carbon (TOC) analyses) contribute to improving sedimentological descriptions, bringing light regarding the depositional environment where these microbial communities have developed. The excellent preservation state of organic matter on these marine and lacustrine siliciclastic sequences represents an impressive record in a Proto-Gondwana basin.

Background The aim of this study was to investigate whether bioactive adrenomedullin (bio-ADM) and interleukin-6 (IL-6) are related to acute kidney injury (AKI) and severe illness in COVID-19 patients. Methods 153 patients with COVID-19 admitted to the emergency department (ED) were included. Blood samples were collected from each patient at admission. Bio-ADM and IL-6, as well as DPP3 and routinely measured markers were evaluated regarding the endpoints AKI (22/128 hospitalized patients) and a composite endpoint of admission to intensive care unit and/or in-hospital death (n = 26/153 patients). Results Bio-ADM and IL-6 were significantly elevated in COVID-19 patients with AKI compared to COVID-19 patients without AKI (each p

Abstract In forensic investigations involving the identification of unknown deceased individuals, isotope analysis can provide valuable provenance information. This is especially pertinent when primary identifiers (i.e., DNA, dactyloscopy, etc.) fail to yield matches. The isotopic composition of human tissues is linked to that of the food consumed, potentially allowing the identification of regions of origin. However, the isotopic composition of deceased newborns and infants fed with milk formula may be influenced by that of the prepared milk. The findings contribute towards the possibility to isotopically identify bottle-fed infants. More importantly, the data convincingly show that the Sr isotope composition of the prepared milk is determined by that of the formula and not the (local) tap water, thereby limiting the potential of Sr isotope analysis for determining the geological or geographical origin in formula-fed babies in medico-legal cases.

Sea urchin eggs are covered with layers of extracellular matrix, namely, the vitelline layer (VL) and jelly coat (JC). It has been shown that sea urchin eggs’ JC components serve as chemoattractants or ligands for the receptor on the fertilizing sperm to promote the acrosome reaction. Moreover, the egg’s VL provides receptors for conspecific sperm to bind, and, to date, at least two sperm receptors have been identified on the surface of sea urchin eggs. Interestingly, however, according to our previous work, denuded sea urchin eggs devoid of the JC and VL do not fail to become fertilized by sperm. Instead, they are bound and penetratedby multiple sperm, raising the possibility that an alternative pathway independent of the VL-residing sperm receptor may be at work. In this research, we studied the roles of the JC and VL using intact and denuded eggs and the synthetic polyamine BPA-C8. BPA-C8 is known to bind to the negatively charged macromolecular complexes in the cells, such as the JC, VL, and the plasma membrane of echinoderm eggs, as well as to the actin filaments in fibroblasts. Our results showed that, when added to seawater, BPA-C8 significantly repressed the Ca2+ wave in the intact P. lividus eggs at fertilization. In eggs deprived of the VL and JC, BPA-C8 binds to the plasma membrane and increases fibrous structures connecting microvilli, thereby allowing the denuded eggs to revert towards monospermy at fertilization. However, the reduced Ca2+ signal in denuded eggs was nullified compared to the intact eggs because removing the JC and VL already decreased the Ca2+ wave. BPA-C8 does not cross the VL and the cell membrane of unfertilized sea urchin eggs to diffuse into the cytoplasm at variance with the fibroblasts. Indeed, the jasplakinolide-induced polymerization of subplasmalemmal actin filaments was inhibited in the eggs microinjected with BPA-C8, but not in the ones bath-incubated with the same dose of BPA-C8.

Introduction The incidence of type 2 diabetes is increasing globally. Recent research suggests that loneliness could be a potential risk factor for the development of type 2 diabetes. We aimed to investigate the association between loneliness and type 2 diabetes and the modifying effect of mental disorders.Research design and methods We conducted a prospective study including 465 290 adults (aged ≥16 years) who participated in either the Danish Health and Morbidity Survey or the Danish National Health Survey between 2000 and 2017. Loneliness was based on self-report, while type 2 diabetes was measured using an algorithm combining several health registers including type 2 diabetes patients treated both within the hospital sector and general practice. Cox proportional hazards regressions were used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs).Results During a mean follow-up time of 6.3 years, 13 771 individuals (3%) developed type 2 diabetes. Feeling lonely once in a while was associated with a 14% increased risk of type 2 diabetes (95% CI 1.09 to 1.20), while feeling lonely often was associated with a 24% increased risk (95% CI 1.14 to 1.34), independent of sociodemographic factors and body mass index. The association was stronger among individuals without a mental disorder (HR 1.21, 95% CI 1.10 to 1.34 among those feeling lonely often) compared with those with a mental disorder (HR 1.07, 95% CI 0.93 to 1.23).Conclusions Loneliness independently increased the risk of type 2 diabetes. The effect was more pronounced in individuals without a mental disorder, as having a mental disorder itself likely increases the risk of type 2 diabetes. These findings emphasize the importance of addressing loneliness as a modifiable risk factor in preventing type 2 diabetes.

Abstract Background Mild memory impairment, termed amnestic mild cognitive impairment (aMCI), is associated with rapid progression towards dementia in Parkinson’s disease (PD). Studies have shown hyperactivation of hippocampal DG/CA3 subfields during an episodic memory task as a biomarker of aMCI related to Alzheimer’s disease. This project investigates the feasibility of a trial to establish the efficacy of a repurposed antiepileptic drug, levetiracetam, in low doses as a putative treatment to target DG/CA3 hyperactivation and improve episodic memory deficits in aMCI in PD. Based on previous work, it is hypothesized that levetiracetam will normalize DG/CA3 overactivation in PD-aMCI participants and improve memory performance. Methods Twenty-eight PD-aMCI participants, 28 PD participants without memory impairment (PD-nMI), and 28 healthy controls will be recruited. PD-aMCI participants will undertake a 12-week randomized, placebo-controlled, double-blind cross-over trial with a 14-day treatment of 125 mg levetiracetam or placebo twice daily, separated by a 4-week washout period. After each treatment period, participants will complete an episodic memory task designed to tax hippocampal subregion-specific function during high-resolution functional magnetic resonance imaging (fMRI). PD-nMI and healthy controls will undergo the fMRI protocol only, to compare baseline DG/CA3 subfield activity. Results Episodic memory task performance and functional activation in the DG/CA3 subfield during the fMRI task will be primary outcome measures. Global cognition, PD severity, and adverse events will be measured as secondary outcomes. Recruitment, eligibility, and study completion rates will be explored as feasibility outcomes. Conclusions This study, the first of its kind, will establish hippocampal subregion functional impairment and proof of concept of levetiracetam as an early therapeutic option to reduce dementia risk in PD. Trial registration ClinicalTrials.gov, NCT04643327 . Registered on 25 November 2020.

Abstract The forthcoming generation of materials, including artificial muscles, recyclable and healable systems, photochromic heterogeneous catalysts, or tailorable supercapacitors, relies on the fundamental concept of rapid switching between two or more discrete forms in the solid state. Herein, we report a breakthrough in the “speed limit” of photochromic molecules on the example of sterically-demanding spiropyran derivatives through their integration within solvent-free confined space, allowing for engineering of the photoresponsive moiety environment and tailoring their photoisomerization rates. The presented conceptual approach realized through construction of the spiropyran environment results in ~1000 times switching enhancement even in the solid state compared to its behavior in solution, setting a record in the field of photochromic compounds. Moreover, integration of two distinct photochromic moieties in the same framework provided access to a dynamic range of rates as well as complementary switching in the material’s optical profile, uncovering a previously inaccessible pathway for interstate rapid photoisomerization.

Increasing patient safety during operations is an inevitable topic in anaesthesiology. The cockpit strategy presented by Vogelsang et al. addresses this issue with elements such as closed loop communication and the use of checklists. In this paper, the use of checklists is taken up further. An AR application is presented that augments checklists for anaesthesia induction into the user’s field of view. The application is to be implemented in teaching and help prospective physicians to internalise the workflows in anaesthesiology more quickly and sustainably. A working prototype has been created and loaded onto the HoloLens 2. The prototype is being assessed and evaluated by an anaesthetist. The feedback will be included into the following development steps. The application will be further adapted to the needs and requirements of the users. In order to evaluate the usability and the user experience, students and medical professionals should test and evaluate the application repeatedly.

Introduction: The ongoing COVID-19 pandemic is placing an extraordinary burden on our health care system with its limited resources. Accurate triage of patients is necessary to ensure medical care for those most severely affected. In this regard, biomarkers could contribute to risk evaluation. The aim of this prospective observational clinical study was to assess the relationship between urinary N-terminal pro-brain natriuretic peptide (NT-proBNP) and acute kidney injury (AKI) as well as severe disease in patients with COVID-19. Methods: 125 patients treated with an acute respiratory infection in the emergency department of the University Hospital Regensburg were analyzed. These patients were divided into a COVID-19 cohort (n = 91) and a cohort with infections not caused by severe acute respiratory syndrome-coronavirus-2 (n = 34). NT-proBNP was determined from serum and fresh urine samples collected in the emergency department. Clinical endpoints were the development of AKI and a composite one consisting of AKI, intensive care unit admission, and in-hospital death. Results: 11 (12.1%) COVID-19 patients developed AKI during hospitalization, whereas 15 (16.5%) reached the composite endpoint. Urinary NT-proBNP was significantly elevated in COVID-19 patients who suffered AKI or reached the composite endpoint (each p < 0.005). In a multivariate regression analysis adjusted for age, chronic kidney disease, chronic heart failure, and arterial hypertension, urinary NT-proBNP was identified as independent predictor of AKI (p = 0.017, OR = 3.91 [CI: 1.28–11.97] per standard deviation [SD]), as well as of the composite endpoint (p = 0.026, OR 2.66 [CI: 1.13–6.28] per SD). Conclusion: Urinary NT-proBNP might help identify patients at risk for AKI and severe disease progression in COVID-19.

Introduction: Congenital pouch colon (CPC) is a rare intestinal anomaly usually associated with an anorectal malformation (ARM). Because of its low incidence, there are no guidelines on the correct treatment. We report the step-by-step management and challenging surgery of a newborn with CPC and cloaca to ensure the patient's best quality of life possible. Case presentation: We describe a case of type II CPC associated with a complex cloaca with a retro-vesical didelphus uterus in a 1530g preterm syndromic female. A preoperative cystoscopy identified a urogenital sinus with an anterior bladder and a posterior vagina. The abdominal exploration done on day 1 showed a dilated CPC with the cecum ending in a large structure extending toward the bladder, and a proximal diverting ileostomy was created. Eight months later, the CPC was mobilized, and the common wall of the bladder and the pouch colon was excised. The 8-cm colonic pouch was tabularized by a triangle resection resulting in a colonic tube used to create a colostomy. Because of the syndromic nature of the patient, the consensus has been not to proceed with the urogenital reconstruction and the ileo-anal pull-through. Conclusion: CPC malformations should be suspected in the case of a single perineal orifice. There is no consensus about the best surgical approach to CPC. The operative reconstruction must be tailored to each patient in order to ensure the best possible quality of life.

Abstract This article describes a teaching strategy that synergizes computing and management, aimed at the running of complex projects in industry and academia, in the areas of civil engineering, physics, geosciences, and a number of other related fields. The course derived from this strategy includes four parts: (a) Computing with a selected set of modern paradigms—the stress is on Control Flow and Data Flow computing paradigms, but paradigms conditionally referred to as Energy Flow and Diffusion Flow are also covered; (b) Project management that is holistic—the stress is on the wide plethora of issues spanning from the preparation of project proposals, all the way to incorporation activities to follow after the completion of a successful project; (c) Examples from past research and development experiences—the stress is on experiences of leading experts from academia and industry; (d) Student projects that stimulate creativity—the stress is on methods that educators could use to induce and accelerate the creativity of students in general. Finally, the article ends with selected pearls of wisdom that could be treated as suggestions for further elaboration.