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Medieval texts reveal the normalised presence of Saami peoples in medieval Fennoscandia, suggesting close interactions involving trade, relationships, rituals, and magic. Despite growing recognition of these relations, the Saami remain overlooked in general studies of the Middle Ages, often relegated to symbolic roles or footnotes. As a result, Saami characters are typically depicted as the exotic Other within Norse society, often being stripped of agency and humanity in historical narratives. To counter these biases and distorted narratives, an essential step is analysing exclusionary structures in medieval literature and critically reviewing existing research on Saami representation. This process challenges dehumanising portrayals and confronts present-day stereotypes. The present study aims to ‘re-humanize’ (as Paulette F. C. Steeves puts it) the medieval Saami past by using decolonising frameworks and perspectives offered by the so-called ‘Indigenous turn’ of medieval studies, bridging medieval studies and Indigenous studies within a Norse context.
Numerous insertions of mitochondrial DNA in the genome of the northern mole vole, Ellobius talpinus
(2024)
Background
Ellobius talpinus is a subterranean rodent representing an attractive model in population ecology studies due to its highly special lifestyle and sociality. In such studies, mitochondrial DNA (mtDNA) is widely used. However, if nuclear copies of mtDNA, aka NUMTs, are present, they may co-amplify with the target mtDNA fragment, generating misleading results. The aim of this study was to determine whether NUMTs are present in E. talpinus.
Methods and results
PCR amplification of the putative mtDNA CytB-D-loop fragment using ‘universal’ primers from 56 E. talpinus samples produced multiple double peaks in 90% of the sequencing chromatograms. To reveal NUMTs, molecular cloning and sequencing of PCR products of three specimens was conducted, followed by phylogenetic analysis. The pseudogene nature of three out of the seven detected haplotypes was confirmed by their basal positions in relation to other Ellobius haplotypes in the phylogenetic tree. Additionally, ‘haplotype B’ was basal in relation to other E. talpinus haplotypes and found present in very distant sampling sites. BLASTN search revealed 195 NUMTs in the E. talpinus nuclear genome, including fragments of all four PCR amplified pseudogenes. Although the majority of the NUMTs studied were short, the entire mtDNA had copies in the nuclear genome. The most numerous NUMTs were found for rrnL, COXI, and D-loop.
Conclusions
Numerous NUMTs are present in E. talpinus and can be difficult to discriminate against mtDNA sequences. Thus, in future population or phylogenetic studies in E. talpinus, the possibility of cryptic NUMTs amplification should always be taken into account.
Changes in the microcirculation of the skin are a frequently observed accompanying phenomenon of many diseases, far beyond the spectrum of dermatological diseases. Not all of these changes are pathological, many are transient and have no serious consequences. This is true for many inflammatory diseases such as psoriasis vulgaris or atopic eczema.
However, there are also diseases in which functionally and morphologically recognizable microangiopathies lead to severe disease consequences. One of the most important diseases in this context is systemic sclerosis, an autoimmune systemic disease with multiple organ manifestations. Investigations of the cutaneous microcirculation are of great importance for the initial diagnosis as well as for prognosis and assessment of disease progression.
In peripheral hemodynamic disorders such as peripheral arterial disease (PAD) and chronic venous insufficiency (CVI), understanding microcirculatory disturbances also plays an important role in therapy and in monitoring the success of therapeutic interventions.
Background and Objectives: Alzheimer’s disease (AD) stands as a pervasive neurodegenerative ailment of global concern, necessitating a relentless pursuit of remedies. This study aims to furnish a comprehensive exposition, delving into the intricate mechanistic actions of medicinal herbs and phytochemicals. Furthermore, we assess the potential of these compounds in inhibiting human acetylcholinesterase through molecular docking, presenting encouraging avenues for AD therapeutics. Materials and Methods: Our approach entailed a systematic exploration of phytochemicals like curcumin, gedunin, quercetin, resveratrol, nobiletin, fisetin, and berberine, targeting their capability as human acetylcholinesterase (AChE) inhibitors, leveraging the PubChem database. Diverse bioinformatics techniques were harnessed to scrutinize molecular docking, ADMET (absorption, distribution, metabolism, excretion, and toxicity), and adherence to Lipinski’s rule of five. Results: Results notably underscored the substantial binding affinities of all ligands with specific amino acid residues within AChE. Remarkably, gedunin exhibited a superior binding affinity (−8.7 kcal/mol) compared to the reference standard. Conclusions: These outcomes accentuate the potential of these seven compounds as viable candidates for oral medication in AD treatment. Notably, both resveratrol and berberine demonstrated the capacity to traverse the blood-brain barrier (BBB), signaling their aptitude for central nervous system targeting. Consequently, these seven molecules are considered orally druggable, potentially surpassing the efficacy of the conventional drug, donepezil, in managing neurodegenerative disorders.
Despite recent advances in the treatment of non-small cell lung cancer (NSCLC), acquired drug resistance to targeted therapy remains a major obstacle. Epithelial-mesenchymal transition (EMT) has been identified as a key resistance mechanism in NSCLC. Here, we investigated the mechanistic role of key EMT-regulating small non-coding microRNAs (miRNAs) in sublines of the NSCLC cell line HCC4006 adapted to afatinib, erlotinib, gefitinib, or osimertinib. The most differentially expressed miRNAs derived from extracellular vesicles were associated with EMT, and their predicted target ZEB1 was significantly overexpressed in all resistant cell lines. Transfection of a miR-205-5p mimic partially reversed EMT by inhibiting ZEB1, restoring CDH1 expression, and inhibiting migration in erlotinib-resistant cells. Gene expression of EMT-markers, transcription factors, and miRNAs were correlated during stepwise osimertinib adaptation of HCC4006 cells. Temporally relieving cells of osimertinib reversed transition trends, suggesting that the implementation of treatment pauses could provide prolonged benefits for patients. Our results provide new insights into the contribution of miRNAs to drug-resistant NSCLC harboring EGFR-activating mutations and highlight their role as potential biomarkers and therapeutic targets.
Background
The Earth Biogenome Project has rapidly increased the number of available eukaryotic genomes, but most released genomes continue to lack annotation of protein-coding genes. In addition, no transcriptome data is available for some genomes.
Results
Various gene annotation tools have been developed but each has its limitations. Here, we introduce GALBA, a fully automated pipeline that utilizes miniprot, a rapid protein-to-genome aligner, in combination with AUGUSTUS to predict genes with high accuracy. Accuracy results indicate that GALBA is particularly strong in the annotation of large vertebrate genomes. We also present use cases in insects, vertebrates, and a land plant. GALBA is fully open source and available as a docker image for easy execution with Singularity in high-performance computing environments.
Conclusions
Our pipeline addresses the critical need for accurate gene annotation in newly sequenced genomes, and we believe that GALBA will greatly facilitate genome annotation for diverse organisms.
Mixotrophic and heterotrophic protists hold a key position in aquatic microbial food webs. Whereas they can account for the bulk of bacterivory in pelagic systems, the potential structuring effect of these consumers on bacterial communities is far from clear. We conducted short-term grazing experiments to test for the overall impact on bacterial community structure and possible prey preferences of phagotrophic protists. The protist taxa selected for this study include three mixotrophic flagellates, comprising two obligate- and one facultative mixotroph, and one phagoheterotrophic flagellate lacking phototrophic capacity. Bacterioplankton from seven different lakes were enriched and used to represent semi-natural prey communities. Our study demonstrated protist strain specific impacts on bacterial community composition linked to grazing. The three mixotrophs had variable impacts on bacterial communities where the two obligate mixotrophs exhibited lower grazing rates, while showing a tendency to promote higher bacterial diversity. The phagoheterotroph displayed the highest grazing rates and structured the bacterial communities via apparent selective grazing. Consistent selectivity trends were observed throughout the experiments, such as the apparent avoidance of all flagellates of Actinobacteria, and high grazing on dominant Burkholderiales taxa. However, there was no consistent “fingerprint” of mixotrophic grazing on prey communities, but the structuring impact rather seemed to depend on the trophic mode of the individual protist taxa, i.e. their dependence on phototrophy vs. phagotrophy. Our findings highlight the differential structuring impact of protist taxa on bacterial communities which may have important ecological implications, for example during periodic dominance of obligate mixotrophic bacterivores in changing lake ecosystems.
Copulatory mechanics of ghost spiders reveals a new self-bracing mechanism in entelegyne spiders
(2023)
Spiders evolved a distinctive sperm transfer system, with the male copulatory organs located on the tarsus of the pedipalps. In entelegyne spiders, these organs are usually very complex and consist of various sclerites that not only allow the transfer of the sperm themselves but also provide a mechanical interlock between the male and female genitalia. This interlocking can also involve elements that are not part of the copulatory organ such as the retrolateral tibial apophysis (RTA)—a characteristic of the most diverse group of spiders (RTA clade). The RTA is frequently used for primary locking i.e., the first mechanical engagement between male and female genitalia. Despite its functional importance, some diverse spider lineages have lost the RTA, but evolved an apophysis on the femur instead. It can be hypothesized that this femoral apophysis is a functional surrogate of the RTA during primary locking or possibly serves another function, such as self-bracing, which involves mechanical interaction between male genital structures themselves to stabilize the inserted pedipalp. We tested these hypotheses using ghost spiders of the genus Josa (Anyphaenidae). Our micro-computed tomography data of cryofixed mating pairs show that the primary locking occurs through elements of the copulatory organ itself and that the femoral apophysis does not contact the female genitalia, but hooks to a projection of the copulatory bulb, representing a newly documented self-bracing mechanism for entelegyne spiders. Additionally, we show that the femoral self-bracing apophysis is rather uniform within the genus Josa. This is in contrast to the male genital structures that interact with the female, indicating that the male genital structures of Josa are subject to different selective regimes.
Dermatophytosis, the most prevalent fungal infection, is witnessing a rising incidence annually. To address this challenge, we developed a terbinafine-loaded oil-in-water nanoemulsion (TH-NE) through the aqueous microtitration method. The formulation comprised olive oil (oil phase), Span 80 (surfactant), and propylene glycol (co-surfactant). Pseudo-phase ternary diagrams and thermodynamic studies underscored the stability of TH-NE. Employing the Box–Behnken design (BBD), we optimized TH-NE, which resulted in a remarkable particle size of 28.07 nm ± 0.5, a low polydispersity index (PDI) of 0.1922 ± 0.1, and a substantial negative zeta potential of −41.87 mV ± 1. Subsequently, TH-NE was integrated into a 1.5% carbopol matrix, yielding a nanoemulgel (TH-NEG). Texture analysis of TH-NEG demonstrated a firmness of 168.00 g, a consistency of 229.81 g/s, negative cohesiveness (−83.36 g), and a work of cohesion at −107.02 g/s. In vitro drug release studies revealed an initial burst effect followed by sustained release, with TH-NEG achieving an impressive 88% release over 48 h, outperforming TH-NE (74%) and the marketed formulation (66%). Ex vivo release studies mirrored these results, with TH-NEG (86%) and TH-NE (71%) showcasing sustained drug release in comparison to the marketed formulation (67%). Confocal microscopy illustrated that TH-NEG and TH-NE penetrated to depths of 30 µm and 25 µm, respectively, into the epidermal layer. Furthermore, dermatokinetic studies highlighted the enhanced drug penetration of TH-NEG compared to TH-NE through mouse skin. In summary, our study establishes TH-NEG as a promising carrier for terbinafine in treating dermatophytosis, offering improved drug delivery and sustained release potential.
Synthesis of Quercetin-Loaded Silver Nanoparticles and Assessing Their Anti-Bacterial Potential
(2023)
The study delves into the multifaceted potential of quercetin (Qu), a phytoconstituent found in various fruits, vegetables, and medicinal plants, in combination with silver nanoparticles (AgNPs). The research explores the synthesis and characterization of AgNPs loaded with Qu and investigates their pharmaceutical applications, particularly focusing on antibacterial properties. The study meticulously evaluates Qu’s identity, and physicochemical properties, reaffirming its suitability for pharmaceutical use. The development of Qu-loaded AgNPs demonstrates their high drug entrapment efficiency, ideal particle characteristics, and controlled drug release kinetics, suggesting enhanced therapeutic efficacy and reduced side effects. Furthermore, the research examines the antibacterial activity of Qu in different solvents, revealing distinct outcomes. Qu, both in methanol and water formulations, exhibits antibacterial activity against Escherichia coli, with the methanol formulation displaying a slightly stronger efficacy. In conclusion, this study successfully synthesizes AgNPs loaded with Qu and highlights their potential as a potent antibacterial formulation. The findings underscore the influence of solvent choice on Qu’s antibacterial properties and pave the way for further research and development in drug delivery systems and antimicrobial agents. This innovative approach holds promise for addressing microbial resistance and advancing pharmaceutical formulations for improved therapeutic outcomes.
Biological invasions pose global threats to biodiversity and ecosystem functions. Invasive species often display a high degree of phenotypic plasticity, enabling them to adapt to new environments. This study examines plasticity to water stress in native and invasive Opuntia ficus-indica populations, a prevalent invader in arid and semi-arid ecosystems. Through controlled greenhouse experiments, we evaluated three native and nine invasive populations. While all plants survived the dry treatment, natives exhibited lower plasticity to high water availability with only a 36% aboveground biomass increase compared to the invasives with a greater increase of 94%. In terms of belowground biomass, there was no significant response to increased water availability for native populations, but plants from the invasive populations showed a 75% increase from the dry to the wet treatment. Enhanced phenotypic plasticity observed in invasive populations of O. ficus-indica is likely a significant driver of their success and invasiveness across different regions, particularly with a clear environmental preference towards less arid conditions. Climate change is expected to amplify the invasion success due to the expansion of arid areas and desertification. Opuntia ficus-indica adapts to diverse environments, survives dry spells, and grows rapidly in times of high-water supply, making it a candidate for increased invasion potential with climate change.
Background
Haemosporidian parasites of the genus Polychromophilus infect bats worldwide. They are vectored by obligate ectoparasitic bat flies of the family Nycteribiidae. Despite their global distribution, only five Polychromophilus morphospecies have been described to date. The two predominant species, Polychromophilus melanipherus and Polychromophilus murinus, are broadly distributed and mainly infect miniopterid and vespertilionid bats, respectively. In areas where species from different bat families aggregate together, the infection dynamics and ability of either Polychromophilus species to infect other host families is poorly characterized.
Methods
We collected 215 bat flies from two bat species, Miniopterus schreibersii and Rhinolophus ferrumequinum, which sometimes form mixed clusters in Serbia. Miniopterus schreibersii is known to be frequently infected with P. melanipherus, whereas R. ferrumequinum has been observed to be incidentally infected with both Polychromophilus species. All flies were screened for Polychromophilus infections using a PCR targeting the haemosporidian cytb gene. Positive samples were subsequently sequenced for 579 bp of cytochrome b (cytb) and 945 bp of cytochrome oxidase subunit 1 (cox1).
Results
Polychromophilus melanipherus DNA was detected at six out of nine sampling locations and in all three examined bat fly species collected from M. schreibersii (Nycteribia schmidlii, n = 21; Penicillidia conspicua, n = 8; Penicillidia dufourii, n = 3). Four and five haplotypes were found for cytb and cox1, respectively. Evidence for multiple Polychromophilus haplotypes was found in 15 individual flies. These results point to a high diversity of P. melanipherus parasites in Miniopterus hosts and efficient transmission throughout the study area. A single Phthiridium biarticulatum bat fly collected from R. ferrumequinum screened positive for P. melanipherus, but only yielded a partial cox1 sequence fragment. Nevertheless, this result suggests that secondary hosts (both bat and fly species) are regularly confronted with this parasite.
Conclusions
The results of this study provide new insights into the prevalence and distribution of Polychromophilus parasites in European bats and their nycteribiid vectors. The use of bat flies for the non-invasive investigation of Polychromophilus infections in bat populations has proven to be efficient and thus represents an alternative for large-scale studies of infections in bat populations without the need to invasively collect blood from bats.
Background
Medical research is increasingly interdisciplinary. However, not all projects are successful and cooperation is not always sustained beyond the end of funding. This study empirically assesses the effect of control and trust on the sustainability of interdisciplinary medical research in terms of its performance and satisfaction.
Methods
The sample consists of 100 German publicly funded medical research collaborations with scientists from medicine, natural and social sciences (N = 364). We develop a system model to analyze the influence of trust and control on performance and satisfaction of the cooperation.
Findings
Both control and trust are important prerequisites for sustainability, control mainly for the performance of the collaboration, and trust primarily for its satisfaction. While the level of interdisciplinarity is a positive moderator for performance, expectation of continuity is a negative intervening variable for the effect of trust and control on satisfaction. Moreover, trust principally adds to the positive impact of control on sustainability.
Conclusions
Interdisciplinary medical research requires a participative but systematic management of the respective consortium.
Introduction
Proteasome inhibition is first line therapy in multiple myeloma (MM). The immunological potential of cell death triggered by defects of the ubiquitin-proteasome system (UPS) and subsequent perturbations of protein homeostasis is, however, less well defined.
Methods
In this paper, we applied the protein homeostasis disruptors bortezomib (BTZ), ONX0914, RA190 and PR619 to various MM cell lines and primary patient samples to investigate their ability to induce immunogenic cell death (ICD).
Results
Our data show that while BTZ treatment triggers sterile type I interferon (IFN) responses, exposure of the cells to ONX0914 or RA190 was mostly immunologically silent. Interestingly, inhibition of protein de-ubiquitination by PR619 was associated with the acquisition of a strong type I IFN gene signature which relied on key components of the unfolded protein and integrated stress responses including inositol-requiring enzyme 1 (IRE1), protein kinase R (PKR) and general control nonderepressible 2 (GCN2). The immunological relevance of blocking de-ubiquitination in MM was further reflected by the ability of PR619-induced apoptotic cells to facilitate dendritic cell (DC) maturation via type I IFN-dependent mechanisms.
Conclusion
Altogether, our findings identify de-ubiquitination inhibition as a promising strategy for inducing ICD of MM to expand current available treatments.
The aim of this study was to compare three sensorimotor training forms in patients with chronic low back pain to determine their effects on the reduction of pain-related impairment and changes in posturography. Over two weeks, during the multimodal pain therapy (MMPT) period, six sessions of sensorimotor physiotherapy or training in the Galileo® or Posturomed® (n = 25 per group) were performed. A significant reduction in pain-related impairment after the intervention phase was shown across all groups (time effect: p < 0.001; ηp2 = 0.415). There was no change in postural stability (time effect: p = 0.666; ηp2 = 0.003), but there was a significant improvement in the peripheral vestibular system (time effect: p = 0.014; ηp2 = 0.081). An interaction effect was calculated for the forefoot-hindfoot ratio (p = 0.014; ηp2 = 0.111). Only the Posturomed® group showed an improvement in anterior-posterior weight distribution (heel load: 47% vs. 49%). These findings suggest that these forms of sensorimotor training in the context of MMPT are suitable for reducing pain-related impairment. Posturography demonstrated stimulation of a subsystem, but no improvement in postural stability.
Geometric regularity of spider webs has been intensively studied in orb‐weaving spiders, although it is not exclusive of orb weavers. Here, we document the geometrically regular, repetitive elements in the webs of the non‐orb‐weaving groups Leptonetidae and Telemidae for the first time. Similar to orb weavers, we found areas with regularly spaced parallel lines in the webs of Calileptoneta helferi, Sulcia sp., and cf. Pinelema sp. Furthermore, we provide a detailed account of the regular webs of Ochyrocera (Ochyroceratidae). The sections of the web with regularly disposed parallel lines are built as U‐shaped modules reminiscent of orb webs. It has been suggested that the regularly spaced parallel lines in the webs of Ochyroceratidae and Psilodercidae may be produced in a single sweep of their posterior lateral spinnerets, which have regularly spaced aciniform gland spigots, perhaps involving expansion of the spinnerets. To test this hypothesis, we compared the spacing between parallel lines with the spacing between spigots, searched for expansible membranes in the spinnerets, and examined the junctions of regularly spaced lines. The distance between parallel lines was 10–20 times the distance between spigots, and we found no expansible membranes, and the intersection of parallel lines are cemented, which opposes the single sweep hypothesis. Furthermore, we found cues of viscid silk in the parallel lines of the psilodercid Althepus and broadened piriform gland spigots that may be responsible of its production. Finally, we evaluated the presence or absence of geometrically regular web elements across the spider tree of life. We found reports of regular webs in 31 spider families, including 20 families that are not orb weavers and hypothesize that the two basic aspects of regularity (parallel lines spaced at regular intervals, and radial lines spaced at regular angles) probably appeared many times in the evolution of spiders.
Background: Fatigue, dyspnea, and lack of energy and concentration are commonly interpreted as indicative of symptomatic anemia and may thus play a role in diagnostic and therapeutic decisions. Objective: To investigate the association between symptoms commonly attributed to anemia and the actual presence of anemia. Methods: Data from two independent cohorts of the Study of Health in Pomerania (SHIP) were analyzed. Interview data, laboratory data, and physical examination were individually linked with claims data from the Association of Statutory Health Insurance Physicians. A complete case analysis using logistic regression models was performed to evaluate the association of anemia with symptoms commonly attributed to anemia. The models were adjusted for confounders such as depression, medication, insomnia, and other medical conditions. Results: A total of 5979 participants (53% female, median age 55) were included in the analysis. Of those, 30% reported fatigue, 16% reported lack of energy, 16% reported lack of concentration, and 29% reported dyspnea and/or weakness. Anemia was prevalent in about 6% (379). The symptoms were more prevalent in participants with anemia. However, participants with anemia were older and had a poorer health status. There was no association in multivariate logistic regression models between the symptoms fatigue, lack of concentration, dyspnea, and/or weakness and anemia. Anemia was associated (OR: 1.45; 95% CI: 1.13–1.86) with lack of energy in the multivariate analysis. Other factors such as depression, insomnia, and medication were more strongly associated with the symptoms. Conclusion: The clinical symptoms commonly attributed to anemia are unspecific and highly prevalent both in non-anemic and anemic persons. Even in the presence of anemia, other diagnoses should be considered as causes such as depression, heart failure, asthma, and COPD, which are more closely associated with the symptoms. Further diagnostic research is warranted to explore the association of symptoms in different subgroups and settings in order to help clinical decision making.
Background: Uterine leiomyosarcoma (LMS) is a rare entity amongst malignant gynaecological tumours and is mostly diagnosed after surgery for benign leiomyoma (LM) of the uterus. As minimal invasive surgery is widely used, the morcellation of LM and the uterus is rather common. As there is little known about the impact of the morcellation of LMS on local and distant metastases, as well as overall survival, we carried out a large-scale retrospective study. Methods: A total of 301 LMS cases from the German Clinical Competence Centre for Genital Sarcomas and Mixed Tumours were analysed. We distinguished morcellated and non-morcellated LMS from pT1 and >pT1 tumours. Fine–Gray competing risks regressions and cumulative incidence rates were computed for the time to local recurrence, distant metastases, and patient death. Results: The recurrence free interval in pT1 LMS was significantly lower in the morcellation group with a 2-year cumulative incidence rate of 49% vs. 26% in non-morcellated LMS (p = 0.001). No differences were seen in >pT1 tumours. Distant metastases were more frequently found in non-morcellated pT1 LMS compared to the morcellated cases (5-year cumulative incidence: 54% vs. 29%, p < 0.001). There was no significant difference in time to death between both groups neither in the pT1 stages nor in >pT1 disease. Subdistribution hazard ratios estimated by multivariable competing risks regressions for the morcellation of pT1 LMS were 2.11 for local recurrence (95% CI 1.41–3.16, p < 0.001) and 0.52 for distant metastases (95% CI 0.32–0.84, p = 0.008). Conclusions: Tumour morcellation is not associated with OS for pT1 tumours. The morcellation of pT1 LMS seems to prolong the time to distant metastases whereas local recurrence is more likely to occur after the morcellation of pT1 LMS.
Bone generally displays a high intrinsic capacity to regenerate. Nonetheless, large osseous defects sometimes fail to heal. The treatment of such large segmental defects still represents a considerable clinical challenge. The regeneration of large bone defects often proves difficult, since it relies on the formation of large amounts of bone within an environment impedimental to osteogenesis, characterized by soft tissue damage and hampered vascularization. Consequently, research efforts have concentrated on tissue engineering and regenerative medical strategies to resolve this multifaceted challenge. In this review, we summarize, critically evaluate, and discuss present approaches in light of their clinical relevance; we also present future advanced techniques for bone tissue engineering, outlining the steps to realize for their translation from bench to bedside. The discussion includes the physiology of bone healing, requirements and properties of natural and synthetic biomaterials for bone reconstruction, their use in conjunction with cellular components and suitable growth factors, and strategies to improve vascularization and the translation of these regenerative concepts to in vivo applications. We conclude that the ideal all-purpose material for scaffold-guided bone regeneration is currently not available. It seems that a variety of different solutions will be employed, according to the clinical treatment necessary.
In the current era of precision oncology, it is widely acknowledged that CRC is a heterogeneous disease entity. Tumor location (right- or left-sided colon cancer or rectal cancer) is a crucial factor in determining disease progression as well as prognosis and influences disease management. In the last decade, numerous works have reported that the microbiome is an important element of CRC carcinogenesis, progression and therapy response. Owing to the heterogeneous nature of microbiomes, the findings of these studies were inconsistent. The majority of the studies combined colon cancer (CC) and rectal cancer (RC) samples as CRC for analysis. Furthermore, the small intestine, as the major site for immune surveillance in the gut, is understudied compared to the colon. Thus, the CRC heterogeneity puzzle is far from being solved, and more research is necessary for prospective trials that separately investigate CC and RC. Our prospective study aimed to map the colon cancer landscape using 16S rRNA amplicon sequencing in biopsy samples from the terminal ileum, healthy colon tissue, healthy rectal tissue and tumor tissue as well as in preoperative and postoperative stool samples of 41 patients. While fecal samples provide a good approximation of the average gut microbiome composition, mucosal biopsies allow for detecting subtle variations in local microbial communities. In particular, the small bowel microbiome has remained poorly characterized, mainly because of sampling difficulties. Our analysis revealed the following: (i) right- and left-sided colon cancers harbor distinct and diverse microbiomes, (ii) the tumor microbiome leads to a more consistent cancer-defined microbiome between locations and reveals a tumor microbiome–ileal microbiome association, (iii) the stool only partly reflects the microbiome landscape in patients with CC, and (iv) mechanical bowel preparation and perioperative antibiotics together with surgery result in major changes in the stool microbiome, characterized by a significant increase in the abundance of potentially pathogenic bacteria, such as Enterococcus. Collectively, our results provide new and valuable insights into the complex microbiome landscape in patients with colon cancer.
Background: The use of cold atmospheric plasma (CAP) in oncology has been intensively investigated over the past 15 years as it inhibits the growth of many tumor cells. It is known that reactive oxidative species (ROS) produced in CAP are responsible for this effect. However, to translate the use of CAP into medical practice, it is essential to know how CAP treatment affects non-malignant cells. Thus, the current in vitro study deals with the effect of CAP on human bone cancer cells and human osteoblasts. Here, identical CAP treatment regimens were applied to the malignant and non-malignant bone cells and their impact was compared. Methods: Two different human bone cancer cell types, U2-OS (osteosarcoma) and A673 (Ewing’s sarcoma), and non-malignant primary osteoblasts (HOB) were used. The CAP treatment was performed with the clinically approved kINPen MED. After CAP treatment, growth kinetics and a viability assay were performed. For detecting apoptosis, a caspase-3/7 assay and a TUNEL assay were used. Accumulated ROS was measured in cell culture medium and intracellular. To investigate the influence of CAP on cell motility, a scratch assay was carried out. Results: The CAP treatment showed strong inhibition of cell growth and viability in bone cancer cells. Apoptotic processes were enhanced in the malignant cells. Osteoblasts showed a higher potential for ROS resistance in comparison to malignant cells. There was no difference in cell motility between benign and malignant cells following CAP treatment. Conclusions: Osteoblasts show better tolerance to CAP treatment, indicated by less affected viability compared to CAP-treated bone cancer cells. This points toward the selective effect of CAP on sarcoma cells and represents a further step toward the clinical application of CAP.
Inflammasome activation and formation of ASC specks in patients with juvenile idiopathic arthritis
(2023)
Objective
The formation of large intracellular protein aggregates of the inflammasome adaptor ASC is a hallmark of inflammasome activation and characteristic of autoinflammation. Inflammasome activated cells release the highly proinflammatory cytokine IL-1β in addition to ASC specks into the extracellular space. Autoinflammatory activity has been demonstrated in systemic JIA, however minimal data exist on the role of inflammasomes in other JIA subtypes. We therefore investigated, if pyroptotic cells are present in the circulation of oligo- and poly-articular JIA.
Methods
Peripheral blood of JIA patients (n = 46) was investigated for ASC speck formation, a key step in inflammasome activation, by flow cytometry and immunofluorescence. Free ASC and proinflammatory cytokine levels were determined by ELISA and multiplex assay.
Results
Oligo-articular JIA patients showed a significantly increased proportion of ASC speck+ monocytes compared to poly-articular JIA patients. In serum free ASC alone is not sufficient to assess inflammasome activity and does not correlate with ASC speck+ monocytes. Compared to control several cytokines were significantly elevated in samples of JIA patients. JIA serum containing antinuclear antibodies, incubated with ASC specks boosts a secondary inflammation by IL-1β production in macrophages.
Conclusion
For the first time, we detect ex vivo inflammasome activation by ASC speck formation in oligo- and poly-articular JIA patients. Most notably, inflammasome activation was significantly higher in oligo- compared to poly-articular JIA patients. This data suggests that inflammasome derived autoinflammation may have a greater influence in the previously thought autoimmune oligo-articular JIA patients.
Predicting complications in pediatric Crohn's disease patients followed in CEDATA-GPGE registry
(2023)
Background
Complications of Crohn's disease (CD) often impair patients' quality of life. It is necessary to predict and prevent these complications (surgery, stricturing [B2]/penetrating [B3] disease behavior, perianal disease, growth retardation and hospitalization). Our study investigated previously suggested and additional predictors by analyzing data of the CEDATA-GPGE registry.
Methods
Pediatric patients (< 18 years) diagnosed with CD with follow up data in the registry were included in the study. Potential risk factors for the selected complications were evaluated by performing Kaplan-Meier survival curves and cox regression models.
Results
For the complication surgery, the potential risk factors older age, B3 disease, severe perianal disease and initial therapy with corticosteroids at the time of diagnosis were identified. Older age, initial therapy with corticosteroids, low weight-for-age, anemia and emesis predict B2 disease. Low weight-for-age and severe perianal disease were risk factors for B3 disease. Low weight-for-age, growth retardation, older age, nutritional therapy, and extraintestinal manifestations (EIM) of the skin were identified as risk factors for growth retardation during the disease course. High disease activity and treatment with biologicals were predictors for hospitalization. As risk factors for perianal disease, the factors male sex, corticosteroids, B3 disease, a positive family history and EIM of liver and skin were identified.
Conclusion
We confirmed previously suggested predictors of CD course and identified new ones in one of the largest registries of pediatric CD patients. This may help to better stratify patients’ according to their individual risk profile and choose appropriate treatment strategies.
Non-coding RNA (ncRNA) classes take over important housekeeping and regulatory functions and are quite heterogeneous in terms of length, sequence conservation and secondary structure. High-throughput sequencing reveals that the expressed novel ncRNAs and their classification are important to understand cell regulation and identify potential diagnostic and therapeutic biomarkers. To improve the classification of ncRNAs, we investigated different approaches of utilizing primary sequences and secondary structures as well as the late integration of both using machine learning models, including different neural network architectures. As input, we used the newest version of RNAcentral, focusing on six ncRNA classes, including lncRNA, rRNA, tRNA, miRNA, snRNA and snoRNA. The late integration of graph-encoded structural features and primary sequences in our MncR classifier achieved an overall accuracy of >97%, which could not be increased by more fine-grained subclassification. In comparison to the actual best-performing tool ncRDense, we had a minimal increase of 0.5% in all four overlapping ncRNA classes on a similar test set of sequences. In summary, MncR is not only more accurate than current ncRNA prediction tools but also allows the prediction of long ncRNA classes (lncRNAs, certain rRNAs) up to 12.000 nts and is trained on a more diverse ncRNA dataset retrieved from RNAcentral.
Introduction: The topics of bullying, school anxiety and school absenteeism are of steady interest for the scientific community in recent decades. However, it seems surprising that investigations into the combination of these constructs are rare, especially considering their interconnectedness. Due to the lack of joint investigation of these factors, it is hardly possible to compare results of these related, yet distinct factors across other studies, let alone the predictive power of specific factors. The goal of the current study is to investigate how bullying, school anxiety and school absenteeism are related, considering the variables gender and grade level.
Methods: For this purpose, N = 195 secondary school children in the 7th–9th grades in northern Germany were surveyed via self-report questionnaires and additionally collecting their school records. We present complex descriptive analyses with scales and subscales of bullying, anxiety and absenteeism. Further, a structural equation modelling (SEM) approach is utilized to discover the interconnectedness of the constructs.
Results: On the one hand, the descriptive statistics show significant gender and grade level differences regarding bullying and anxiety. On the other hand, the SEM reveals that high values on the bullying victim scale are accompanied by significantly higher school displeasure (anxiety). School displeasure—as well as high bullying offender values—are associated with significantly more days of absence from school.
Discussion: We discuss how school environment improvement through specific interventions such as the cognitive-behavioral approach, could aid to ameliorate this issue.
Simple Summary
This German multicenter study investigated the importance of different supportive measures offered to patients with prostate cancer who undergo surgery (radical prostatectomy). A number of these supportive measures are required during the certification of a urologic hospital as prostate cancer center. However, a broad scientific basis evaluating these measures from the patient’s perspective is still lacking. In this study, patients were asked to rate the relevance of several supportive measures and to estimate the effective availability of these different supportive measures at their urologic clinic about 15 months after surgery. Our study highlights that only six of fifteen different supportive measures were rated as very relevant by patients. None of these six supportive measures were offered more intensively at the certified clinics compared to the non-certified clinics according to the patients. Our study helps to identify those supportive measures with the highest subjective impact on patients in this setting.
Abstract
Certification as a prostate cancer center requires the offer of several supportive measures to patients undergoing radical prostatectomy (RP). However, it remains unclear how patients estimate the relevance of these measures and whether the availability of these measures differs between certified prostate cancer centers (CERTs) and non-certified centers (NCERTs). In 20 German urologic centers, a survey comprising questions on the relevance of 15 supportive measures was sent to 1000 patients at a median of 15 months after RP. Additionally, patients were asked to rate the availability of these measures using a four-item Likert scale. The aim of this study was to compare these ratings between CERTs and NCERTs. The response rate was 75.0%. In total, 480 patients underwent surgery in CERTs, and 270 in NCERTs. Patients rated 6/15 supportive measures as very relevant: preoperative medical counselling concerning treatment options, a preoperative briefing answering last questions, preoperative pelvic floor exercises (PFEs), postoperative PFEs, postoperative social support, and postoperative rehabilitation addressing physical fitness recovery. These ratings showed no significant difference between CERTs and NCERTs (p = 0.133–0.676). In addition, 4/9 of the remaining criteria were rated as more detailed by patients in CERTs. IMPROVE represents the first study worldwide to evaluate a patient-reported assessment of the supportive measures accompanying RP. Pertinent offers vary marginally between CERTs and NCERTs.
Background: Clinical practice guidelines are systematically developed statements intended to optimize patient care. However, a gapless implementation of guideline recommendations requires health care personnel not only to be aware of the recommendations and to support their content but also to recognize every situation in which they are applicable. To not miss situations in which recommendations should be applied, computerized clinical decision support can be provided through a system that allows an automated monitoring of adherence to clinical guideline recommendations in individual patients.
Objective: This study aims to collect and analyze the requirements for a system that allows the monitoring of adherence to evidence-based clinical guideline recommendations in individual patients and, based on these requirements, to design and implement a software prototype that integrates guideline recommendations with individual patient data, and to demonstrate the prototype’s utility in treatment recommendations.
Methods: We performed a work process analysis with experienced intensive care clinicians to develop a conceptual model of how to support guideline adherence monitoring in clinical routine and identified which steps in the model could be supported electronically. We then identified the core requirements of a software system to support recommendation adherence monitoring in a consensus-based requirements analysis within the loosely structured focus group work of key stakeholders (clinicians, guideline developers, health data engineers, and software developers). On the basis of these requirements, we designed and implemented a modular system architecture. To demonstrate its utility, we applied the prototype to monitor adherence to a COVID-19 treatment recommendation using clinical data from a large European university hospital.
Results: We designed a system that integrates guideline recommendations with real-time clinical data to evaluate individual guideline recommendation adherence and developed a functional prototype. The needs analysis with clinical staff resulted in a flowchart describing the work process of how adherence to recommendations should be monitored. Four core requirements were identified: the ability to decide whether a recommendation is applicable and implemented for a specific patient, the ability to integrate clinical data from different data formats and data structures, the ability to display raw patient data, and the use of a Fast Healthcare Interoperability Resources–based format for the representation of clinical practice guidelines to provide an interoperable, standards-based guideline recommendation exchange format.
Conclusions: Our system has advantages in terms of individual patient treatment and quality management in hospitals. However, further studies are needed to measure its impact on patient outcomes and evaluate its resource effectiveness in different clinical settings. We specified a modular software architecture that allows experts from different fields to work independently and focus on their area of expertise. We have released the source code of our system under an open-source license and invite for collaborative further development of the system.
Burnout among high school students is linked to their telomere length and relatedness with peers
(2023)
School burnout is a serious concern, as it impairs students’ health and academic success. According to the Conservation of Resources Theory, burnout results from the depletion of personal coping resources and can be counteracted by supportive social relationships. However, it is not yet clear how students’ relatedness with their peers is linked to their burnout. Next to students’ self-reported fatigue, biomarkers such as telomere length (TL), which presents an indicator of aging, complement stress research. To identify school-related factors that may prevent students from experiencing burnout and to link TL to students’ self-reported burnout, the current study investigated how relatedness with peers as well as TL at the beginning of the school year explained students’ burnout at the end of the school year. The sample included 78 students (Mage = 13.7 ± 0.7 years; 48% girls). Results of multilevel analysis in Mplus indicate that, over the school year, students with higher TL and those who experienced relatedness with their peers reported lower levels of burnout. Moreover, students who felt related to their peers exhibited a longer TL. The study implies that students’ relatedness with their peers may be a promising setscrew to prevent students’ burnout and support their physical health. This is one of the first studies to link TL with school-related variables such as burnout and relatedness to peers in a non-clinical student sample, providing a baseline for interventions and future interdisciplinary studies in the field of education and stress.
Background
Elective surgeries are among the most common health stressors in later life and put a significant risk at functional and mental health, making them an important target of research into healthy aging and physical resilience. Large-scale longitudinal research mostly conducted in non-clinical samples provided support of the predictive value of self-rated health (SRH) for both functional and mental health. Thus, SRH may have the potential to predict favorable adaptation processes after significant health stressors, that is, physical resilience. So far, a study examining the interplay between SRH, functional and mental health and their relative importance for health changes in the context of health stressors was missing. The present study aimed at addressing this gap.
Methods
We used prospective data of 1,580 inpatients (794 complete cases) aged 70 years or older of the PAWEL study, collected between October 2017 and May 2019 in Germany. Our analyses were based on SRH, functional health (Barthel Index) and self-reported mental health problems (PHQ-4) before and 12 months after major elective surgery. To examine changes and interrelationships in these health indicators, bivariate latent change score (BLCS) models were applied.
Results
Our analyses provided evidence for improvements of SRH, functional and mental health from pre-to-post surgery. BLCS models based on complete cases and the total sample pointed to a complex interplay of SRH, functional health and mental health with bidirectional coupling effects. Better pre-surgery SRH was associated with improvements in functional and mental health, and better pre-surgery functional health and mental health were associated with improvements in SRH from pre-to-post surgery. Effects of pre-surgery SRH on changes in functional health were smaller than those of functional health on changes in SRH.
Conclusions
Meaningful changes of SRH, functional and mental health and their interplay could be depicted for the first time in a clinical setting. Our findings provide preliminary support for SRH as a physical resilience factor being associated with improvements in other health indicators after health stressors. Longitudinal studies with more timepoints are needed to fully understand the predictive value of SRH for multidimensional health.
Trial registration
PAWEL study, German Clinical Trials Register, number DRKS00013311. Registered 10 November 2017 – Retrospectively registered, https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00013311.
Endoscopic and Histopathological Characteristics of Gastrointestinal Lymphoma: A Multicentric Study
(2023)
Background: Extranodal non-Hodgkin lymphoma (NHL) is more prevalent in the gastrointestinal (GI) tract than in other sites. This study aimed to determine the endoscopic characteristics of primary gastrointestinal non-Hodgkin lymphomas. Methods: We investigated 140 patients from three tertiary referral hospitals with primary malignant lymphoma of the gastrointestinal tract. Characteristics of the lesions were evaluated and analyzed using image-enhanced endoscopy, endoscopic ultrasound, and histopathology. Results: The median age was 60.5 (range: 11–99), and 59 (42.1%) were female. The most frequent complaint was abdominal pain (74.3%), followed by bloody feces (10%) and diarrhea (2.9%). B symptoms were observed in 15 (10.7%) patients. GI obstruction was the most common complication (10.0%), followed by hemorrhage (7.9%) and perforation (1.5%). Regarding endoscopic findings, the identified sites were the following: the stomach (61.4%), colon (10%), small intestine (10%), ileocecum (8.6%), rectum (6.4%), and duodenum (3.6%). Diffuse large B-cell lymphoma (DLBCL) and mucosa-associated lymphoid tissue (MALT) lymphoma are most prevalent in the stomach. Helicobacter pylori was identified in 46 cases (39.0%), with MALT lymphoma being the most infected subtype. Nearly all gastrointestinal non-Hodgkin lymphomas manifested as superficial type (25–59.6%) and ulcer type (15.6–50%) under endoscopy. We found that fungating type and protruding with ulcer type were more frequent types of aggressive lymphomas (diffuse large B-cell lymphoma, mantle cell lymphoma, and T-cell lymphoma) compared to the indolent types (MALT lymphoma, follicular lymphoma, duodenal-type follicular lymphoma, and small lymphocytic lymphoma) (p < 0.05). Conclusions: This study showed that most subtypes of gastrointestinal non-Hodgkin lymphomas exhibited same endoscopic features (superficial type and ulcer type). Aggressive gastrointestinal non-Hodgkin lymphomas (diffuse large B-cell lymphoma, mantle cell lymphoma, and T-cell lymphoma) were highly suspected when fungating lesions and protruding with ulcer lesions were encountered under endoscopy. Endoscopists should be aware of the connection between enhanced endoscopic characteristics and histological varieties of gastrointestinal lymphoma to improve diagnosis.
Facial expressions play a crucial role in human interactions. Typically, a positive (negative) expression evokes a congruent positive (negative) reaction within the observer. This congruent behavior is inverted, however, when the same positive (negative) expression is displayed by an outgroup member. Two approaches provide an explanation for this phenomenon. The social intentions account proposes underlying social messages within the facial display, whereas the processing conflict account assumes an affective conflict triggered by incongruent combinations of emotion and the affective connotation of group membership. In three experiments, we aimed at further substantiating the processing conflict account by separating the affective conflict from potential social intentions. For this, we created a new paradigm, in which the participant was an outside observer of a social interaction scene between two faces. Participants were required to respond to the emotional target person that could represent an ingroup or outgroup member. In all three experiments, irrespective of any social intention, responses were consistently affected by the group relation between participant and emotional target, i.e., the affective (in)congruency of the target seen by participants. These results further support the processing conflict account. The implications for the two theoretical accounts are discussed.
Psychological Factors as Risk Contributors for Poor Hip Function after Periacetabular Osteotomy
(2023)
Psychologic comorbidities have been identified as risk factors for poor outcomes in orthopedic procedures, but their influence on the outcome of hip-preserving periacetabular osteotomy (PAO) remains uncertain. This retrospective cohort study aimed to assess the impact of patients’ psychological health on the outcome of PAO in patients with hip dysplasia (HD) and acetabular retroversion (AR). The study included 110 patients undergoing PAO for HD or AR between 2019 and 2021. Standardized questionnaires were administered to assess psychological factors, postoperative hip function, and activity level (mean follow-up: 25 months). Linear regression analyses were used to examine the associations between psychological factors and postoperative hip function and activity level. Both HD and AR patients showed improved postoperative hip function and activity levels. Linear regression analyses revealed that depression significantly impaired postoperative outcomes in both groups, whereas somatization negatively influenced the outcome in AR patients. General health perceptions significantly contributed to an improved postoperative outcome. These findings highlight the importance of concomitantly addressing psychologically relevant factors in order to improve patient outcomes after PAO procedures. Future prospective studies should continue to investigate the impact of various psychological factors and explore possibilities of incorporating psychological support into routine postoperative care for these patient cohorts.
There is a current need for developing improved synthetic porous materials for better constraining the dynamic and coupled processes relevant to the geotechnical use of underground reservoirs. In this study, a low temperature preparation method for making synthetic rocks is presented that uses a geopolymer binder cured at 80 °C based on alkali-activated metakaolin. For the synthesised sandstone, the key rock properties permeability, porosity, compressive strength, and mineralogical composition, are determined and compared against two natural reservoir rocks. In addition, the homogeneity of the material is analysed structurally by micro-computed tomography and high-resolution scanning electron microscopy, and chemically by energy dispersive X-ray spectroscopy. It is shown that simple, homogenous sandstone analogues can be prepared that show permeability-porosity values in the range of porous reservoir rocks. The advance in using geopolymer binders to prepare synthetic sandstones containing thermally sensitive minerals provides materials that can be easily adapted to specific experimental needs. The use of such material in flow-through experiments is expected to help bridge the gap between experimental observations and numerical simulations, leading to a more systematic understanding of the physio-chemical behaviour of porous reservoir rocks.
Plant roots influence many ecological and biogeochemical processes, such as carbon, water and nutrient cycling. Because of difficult accessibility, knowledge on plant root growth dynamics in field conditions, however, is fragmentary at best. Minirhizotrons, i.e. transparent tubes placed in the substrate into which specialized cameras or circular scanners are inserted, facilitate the capture of high-resolution images of root dynamics at the soil-tube interface with little to no disturbance after the initial installation. Their use, especially in field studies with multiple species and heterogeneous substrates, though, is limited by the amount of work that subsequent manual tracing of roots in the images requires. Furthermore, the reproducibility and objectivity of manual root detection is questionable. Here, we use a Convolutional Neural Network (CNN) for the automatic detection of roots in minirhizotron images and compare the performance of our RootDetector with human analysts with different levels of expertise. Our minirhizotron data come from various wetlands on organic soils, i.e. highly heterogeneous substrates consisting of dead plant material, often times mainly roots, in various degrees of decomposition. This may be seen as one of the most challenging soil types for root segmentation in minirhizotron images. RootDetector showed a high capability to correctly segment root pixels in minirhizotron images from field observations (F1 = 0.6044; r2 compared to a human expert = 0.99). Reproducibility among humans, however, depended strongly on expertise level, with novices showing drastic variation among individual analysts and annotating on average more than 13-times higher root length/cm2 per image compared to expert analysts. CNNs such as RootDetector provide a reliable and efficient method for the detection of roots and root length in minirhizotron images even from challenging field conditions. Analyses with RootDetector thus save resources, are reproducible and objective, and are as accurate as manual analyses performed by human experts.
Background: General clinical perception suggests a decline in the diagnosis and treatment of lung cancer during the SARS-CoV-2 pandemic. Early diagnosis of non-small cell lung cancer (NSCLC) is crucial in therapeutic regimes as early stages are potentially curable by operation alone or with combined therapy. Pandemic-triggered overload of the healthcare system may have prolonged the diagnosis of NSCLC, possibly leading to higher tumor stages at first diagnosis. This study aims to identify how COVID-19 affected the distribution of the Union for International Cancer Control (UICC) stage in NSCLC at first diagnosis.
Methods: A retrospective case-control study was conducted, including all patients receiving their first diagnosis of NSCLC in the regions of Leipzig and Mecklenburg-Vorpommern (MV) between January 2019 and March 2021. Patient data were retrieved from the clinical cancer registries of the city of Leipzig and the federal state of MV. Ethical approval for this retrospective evaluation of archived, anonymized patient data was waived by the Scientific Ethical Committee at the Medical Faculty, Leipzig University. Three investigation periods were defined to study the effects of high incidences of SARS-COV-2: the curfew period as an enacted security measure, the period of high incidence rates and the period of the aftermath of high incidences. Differences in the UICC stages between these pandemic periods were studied by Mann-Whitney-U-Test. Pearson’s correlation was calculated to examine changes in operability.
Results: The number of patients diagnosed with NSCLC dropped substantially during investigation periods. There was a significant difference in the UICC status in the aftermath of high incidences and imposed security measures in Leipzig (P=0.016). N-status differed significantly in the aftermath of high incidences and imposed security measures (P=0.022) with a decrease of N0- and an increase of N3-status, respectively, while N1- and N2-status remained relatively unaffected. No pandemic phase showed a significant difference in operability.
Conclusions: The pandemic led to a delay in the diagnosis of NSCLC in the two examined regions. This resulted in higher UICC stages upon diagnosis. However, no increase in inoperable stages was shown. It remains to be seen, how this will affect the overall prognosis of the involved patients.
Guidelines and Standard Frameworks for AI in Medicine: Protocol for a Systematic Literature Review
(2023)
Background: Applications of artificial intelligence (AI) are pervasive in modern biomedical science. In fact, research results suggesting algorithms and AI models for different target diseases and conditions are continuously increasing. While this situation undoubtedly improves the outcome of AI models, health care providers are increasingly unsure which AI model to use due to multiple alternatives for a specific target and the “black box” nature of AI. Moreover, the fact that studies rarely use guidelines in developing and reporting AI models poses additional challenges in trusting and adapting models for practical implementation.
Objective: This review protocol describes the planned steps and methods for a review of the synthesized evidence regarding the quality of available guidelines and frameworks to facilitate AI applications in medicine.
Methods: We will commence a systematic literature search using medical subject headings terms for medicine, guidelines, and machine learning (ML). All available guidelines, standard frameworks, best practices, checklists, and recommendations will be included, irrespective of the study design. The search will be conducted on web-based repositories such as PubMed, Web of Science, and the EQUATOR (Enhancing the Quality and Transparency of Health Research) network. After removing duplicate results, a preliminary scan for titles will be done by 2 reviewers. After the first scan, the reviewers will rescan the selected literature for abstract review, and any incongruities about whether to include the article for full-text review or not will be resolved by the third and fourth reviewer based on the predefined criteria. A Google Scholar (Google LLC) search will also be performed to identify gray literature. The quality of identified guidelines will be evaluated using the Appraisal of Guidelines, Research, and Evaluation (AGREE II) tool. A descriptive summary and narrative synthesis will be carried out, and the details of critical appraisal and subgroup synthesis findings will be presented.
Results: The results will be reported using the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analyses) reporting guidelines. Data analysis is currently underway, and we anticipate finalizing the review by November 2023.
Conclusions: Guidelines and recommended frameworks for developing, reporting, and implementing AI studies have been developed by different experts to facilitate the reliable assessment of validity and consistent interpretation of ML models for medical applications. We postulate that a guideline supports the assessment of an ML model only if the quality and reliability of the guideline are high. Assessing the quality and aspects of available guidelines, recommendations, checklists, and frameworks—as will be done in the proposed review—will provide comprehensive insights into current gaps and help to formulate future research directions.
International Registered Report Identifier (IRRID): DERR1-10.2196/47105
Background: Thorough data stewardship is a key enabler of comprehensive health research. Processes such as data collection, storage, access, sharing, and analytics require researchers to follow elaborate data management strategies properly and consistently. Studies have shown that findable, accessible, interoperable, and reusable (FAIR) data leads to improved data sharing in different scientific domains.
Objective: This scoping review identifies and discusses concepts, approaches, implementation experiences, and lessons learned in FAIR initiatives in health research data.
Methods: The Arksey and O’Malley stage-based methodological framework for scoping reviews was applied. PubMed, Web of Science, and Google Scholar were searched to access relevant publications. Articles written in English, published between 2014 and 2020, and addressing FAIR concepts or practices in the health domain were included. The 3 data sources were deduplicated using a reference management software. In total, 2 independent authors reviewed the eligibility of each article based on defined inclusion and exclusion criteria. A charting tool was used to extract information from the full-text papers. The results were reported using the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) guidelines.
Results: A total of 2.18% (34/1561) of the screened articles were included in the final review. The authors reported FAIRification approaches, which include interpolation, inclusion of comprehensive data dictionaries, repository design, semantic interoperability, ontologies, data quality, linked data, and requirement gathering for FAIRification tools. Challenges and mitigation strategies associated with FAIRification, such as high setup costs, data politics, technical and administrative issues, privacy concerns, and difficulties encountered in sharing health data despite its sensitive nature were also reported. We found various workflows, tools, and infrastructures designed by different groups worldwide to facilitate the FAIRification of health research data. We also uncovered a wide range of problems and questions that researchers are trying to address by using the different workflows, tools, and infrastructures. Although the concept of FAIR data stewardship in the health research domain is relatively new, almost all continents have been reached by at least one network trying to achieve health data FAIRness. Documented outcomes of FAIRification efforts include peer-reviewed publications, improved data sharing, facilitated data reuse, return on investment, and new treatments. Successful FAIRification of data has informed the management and prognosis of various diseases such as cancer, cardiovascular diseases, and neurological diseases. Efforts to FAIRify data on a wider variety of diseases have been ongoing since the COVID-19 pandemic.
Conclusions: This work summarises projects, tools, and workflows for the FAIRification of health research data. The comprehensive review shows that implementing the FAIR concept in health data stewardship carries the promise of improved research data management and transparency in the era of big data and open research publishing.
International Registered Report Identifier (IRRID): RR2-10.2196/22505
Introduction: At the cellular level, acute temperature changes alter ionic conductances, ion channel kinetics, and the activity of entire neuronal circuits. This can result in severe consequences for neural function, animal behavior and survival. In poikilothermic animals, and particularly in aquatic species whose core temperature equals the surrounding water temperature, neurons experience rather rapid and wide-ranging temperature fluctuations. Recent work on pattern generating neural circuits in the crustacean stomatogastric nervous system have demonstrated that neuronal circuits can exhibit an intrinsic robustness to temperature fluctuations. However, considering the increased warming of the oceans and recurring heatwaves due to climate change, the question arises whether this intrinsic robustness can acclimate to changing environmental conditions, and whether it differs between species and ocean habitats.
Methods: We address these questions using the pyloric pattern generating circuits in the stomatogastric nervous system of two crab species, Hemigrapsus sanguineus and Carcinus maenas that have seen a worldwide expansion in recent decades.
Results and discussion: Consistent with their history as invasive species, we find that pyloric activity showed a broad temperature robustness (>30°C). Moreover, the temperature-robust range was dependent on habitat temperature in both species. Warm-acclimating animals shifted the critical temperature at which circuit activity breaks down to higher temperatures. This came at the cost of robustness against cold stimuli in H. sanguineus, but not in C. maenas. Comparing the temperature responses of C. maenas from a cold latitude (the North Sea) to those from a warm latitude (Spain) demonstrated that similar shifts in robustness occurred in natural environments. Our results thus demonstrate that neuronal temperature robustness correlates with, and responds to, environmental temperature conditions, potentially preparing animals for changing ecological conditions and shifting habitats.
Extra-organismal DNA (eoDNA) from material left behind by organisms (noninvasive DNA, e.g., feces, hair) or from environmental samples (eDNA, e.g., water, soil) is a valuable source of genetic information. However, the relatively low quality and quantity of eoDNA, which can be further degraded by environmental factors, results in reduced amplification and sequencing success. This is often compensated for through cost- and time-intensive replications of genotyping/sequencing procedures. Therefore, system- and site-specific quantifications of environmental degradation are needed to maximize sampling efficiency (e.g., fewer replicates, shorter sampling durations), and to improve species detection and abundance estimates. Using 10 environmentally diverse bat roosts as a case study, we developed a robust modeling pipeline to quantify the environmental factors degrading eoDNA, predict eoDNA quality, and estimate sampling-site-specific ideal exposure duration. Maximum humidity was the strongest eoDNA-degrading factor, followed by exposure duration and then maximum temperature. We also found a positive effect when hottest days occurred later. The strength of this effect fell between the strength of the effects of exposure duration and maximum temperature. With those predictors and information on sampling period (before or after offspring were born), we reliably predicted mean eoDNA quality per sampling visit at new sites with a mean squared error of 0.0349. Site-specific simulations revealed that reducing exposure duration to 2–8 days could substantially improve eoDNA quality for future sampling. Our pipeline identified high humidity and temperature as strong drivers of eoDNA degradation even in the absence of rain and direct sunlight. Furthermore, we outline the pipeline's utility for other systems and study goals, such as estimating sample age, improving eDNA-based species detection, and increasing the accuracy of abundance estimates.
Metabarcoding of invertebrate-derived DNA (iDNA) is increasingly used to describe vertebrate diversity in terrestrial ecosystems. Fly iDNA has also shown potential as a tool for detecting pathogens. Combining these approaches makes fly iDNA a promising tool for understanding the ecology and distribution of novel pathogens or emerging infectious diseases. Here, we use fly iDNA to explore the geographic distribution of Bacillus cereus biovar anthracis (Bcbva) along a gradient from the forest within Taï National Park, Côte d'Ivoire, out to surrounding villages. We tested fly pools (N = 100 pools of 5 flies) collected in the forest (N = 25 pools), along the forest edge (N = 50 pools), and near surrounding villages (N = 25 pools) for Bcbva. Using the same iDNA, we sought to reconstruct fly and mammal communities with metabarcoding, with the aim of investigating potential links with Bcbva detection. We detected Bcbva in 5/100 fly pools and positivity varied significantly across the habitat types (forest = 4/25, edge = 1/50, village = 0/25). It was possible to culture Bcbva from all positive fly pools, confirming their positivity, while sequencing of their whole genomes revealed a considerable portion of known genomic diversity for this pathogen. iDNA generated data about the mammal and fly communities in these habitats, revealing the highest mammal diversity in the forest and considerable changes in fly community composition along the gradient. Bcbva host range estimates from fly iDNA were largely identical to the results of long-term carcass monitoring efforts in the region. We show that fly iDNA can generate data on the geographic distribution and host range of a pathogen at kilometer scales, as well as reveal the pathogen's phylogenetic diversity. Our results highlight the power of fly iDNA for mammal biomonitoring and pathogen surveillance.
BatNet: a deep learning-based tool for automated bat species identification from camera trap images
(2023)
Automated monitoring technologies can increase the efficiency of ecological data collection and support data-driven conservation. Camera traps coupled with infrared light barriers can be used to monitor temperate-zone bat assemblages at underground hibernacula, where thousands of individuals of multiple species can aggregate in winter. However, the broad-scale adoption of such photo-monitoring techniques is limited by the time-consuming bottleneck of manual image processing. Here, we present BatNet, an open-source, deep learning-based tool for automated identification of 13 European bat species from camera trap images. BatNet includes a user-friendly graphical interface, where it can be retrained to identify new bat species or to create site-specific models to improve detection accuracy at new sites. Model accuracy was evaluated on images from both trained and untrained sites, and in an ecological context, where community- and species-level metrics (species diversity, relative abundance, and species-level activity patterns) were compared between human experts and BatNet. At trained sites, model performance was high across all species (F1-score: 0.98–1). At untrained sites, overall classification accuracy remained high (96.7–98.2%), when camera placement was comparable to the training images (<3 m from the entrance; <45° angle relative to the opening). For atypical camera placements (>3 m or >45° angle), retraining the detector model with 500 site-specific annotations achieved an accuracy of over 95% at all sites. In the ecological case study, all investigated metrics were nearly identical between human experts and BatNet. Finally, we exemplify the ability to retrain BatNet to identify a new bat species, achieving an F1-score of 0.99 while maintaining high classification accuracy for all original species. BatNet can be implemented directly to scale up the deployment of camera traps in Europe and enhance bat population monitoring. Moreover, the pretrained model can serve as a baseline for transfer learning to automatize the image-based identification of bat species worldwide.
Humans consume snail flesh as part of their diet. To assess its nutritional value and toxicity, chemical analyses were conducted to confirm the presence of protein, total and reduced carbohydrates, fat, fatty acid composition and mineral components. Furthermore, an acute toxicity study was carried out to determine the safety of Helix aspersa Müller snail flesh. H. aspersa Müller snail flesh exhibits a high nutritional content, a good ω3/ω6 ratio and higher levels of unsaturated fatty acids. Various minerals have been found in the flesh of H. aspersa Müller. Around 76.91 kcal, or 3.84% of the energy of a daily meal of 2000 kcal, are present in 100 g of this flesh. The evaluation of the antioxidant capacity indicated that the flesh’s extracts contained a large quantity of antioxidant biomolecules. Administration of the aqueous extract of H. aspersa Müller flesh didn’t cause death in laboratory rats, indicating that the lethal dose 50 is greater than 2000 mg·kg−1 body weight. The consumption of the flesh of H. aspersa Müller is highly recommended for human consumption due to its high concentration of nutrients and essential elements, as well as unsaturated fats, and due to its safety.
Mutations in genes coding for proteasome subunits and/or proteasome assembly helpers typically cause recurring autoinflammation referred to as chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures (CANDLE) or proteasome-associated autoinflammatory syndrome (PRAAS). Patients with CANDLE/PRAAS present with mostly chronically elevated type I interferon scores that emerge as a consequence of increased proteotoxic stress by mechanisms that are not fully understood. Here, we report on five unrelated patients with CANDLE/PRAAS carrying novel inherited proteasome missense and/or nonsense variants. Four patients were compound heterozygous for novel pathogenic variants in the known CANDLE/PRAAS associated genes, PSMB8 and PSMB10, whereas one patient showed additive loss-of-function mutations in PSMB8. Variants in two previously not associated proteasome genes, PSMA5 and PSMC5, were found in a patient who also carried the PSMB8 founder mutation, p.T75M. All newly identified mutations substantially impact the steady-state expression of the affected proteasome subunits and/or their incorporation into mature 26S proteasomes. Our observations expand the spectrum of PRAAS-associated genetic variants and improve a molecular diagnosis and genetic counseling of patients with sterile autoinflammation.
Objectives: Several clinical disease activity indices (DAIs) have been developed to noninvasively assess mucosal healing in pediatric Crohn’s disease (CD). However, their clinical application can be complex. Therefore, we present a new way to identify the most informative biomarkers for mucosal inflammation from current markers in use and, based on this, how to obtain an easy-to-use DAI for clinical practice. A further aim of our proof-of-concept study is to demonstrate how the performance of such a new DAI can be compared to that of existing DAIs.
Methods: The data of two independent study cohorts, with 167 visits from 109 children and adolescents with CD, were evaluated retrospectively. A variable selection based on a Bayesian ordinal regression model was applied to select clinical or standard laboratory parameters as predictors, using an endoscopic outcome. The predictive performance of the resulting model was compared to that of existing pediatric DAIs.
Results: With our proof-of-concept dataset, the resulting model included C-reactive protein (CRP) and fecal calprotectin (FC) as predictors. In general, our model performed better than the existing DAIs. To show how our Bayesian approach can be applied in practice, we developed a web application for predicting disease activity for a new CD patient or visit.
Conclusions: Our work serves as a proof-of-concept, showing that the statistical methods used here can identify biomarkers relevant for the prediction of a clinical outcome. In our case, a small number of biomarkers is sufficient, which, together with the web interface, facilitates the clinical application. However, the retrospective nature of our study, the rather small amount of data, and the lack of an external validation cohort do not allow us to consider our results as the establishment of a novel DAI for pediatric CD. This needs to be done with the help of a prospective study with more data and an external validation cohort in the future.
Ocean literacies: the promise of regional approaches integrating ocean histories and psychologies
(2023)
The current concept of ocean literacy reflects a prerequisite for achieving ocean sustainability. Existing ocean literacy reflects a fundamentally western view of oceans that works in tension with ocean literacy goals. Although ocean literacy practitioners and researchers are, laudably, starting to incorporate Indigenous knowledges and perspectives from BIPOC communities, attention to historical change continues to be left out of ocean literacy, to the detriment of ocean literacy goals. This article points out that, given the reality that human-ocean relationships have changed over time, and differed among cultural groups in the past as well as in the present, ocean literacy needs to incorporate ocean history at a foundational level. Because there are historical differences in human relationships with oceans, it stands to reason that regional ocean literacies must be more effective than a universal and timeless ocean literacy framework. Following the logical efficacy of a regional approach to ocean literacy, this article further argues that regional ocean literacies should involve the systematic inclusion of emotional elements. Regional ocean literacies should be constructed through knowledge co-production, involving diverse types of expertise, knowledge and actors to produce context-specific knowledge and pathways towards a sustainable future. To fully exploit the potential of ocean literacy, there is a need for the UN Ocean Decade to work towards regional and place-based approaches that incorporate history as well as culture in an iterative and collaborative process involving diverse types of expertise, knowledge and actors.
The absorption of drugs with narrow absorption windows in the upper small intestine can be improved with a mucoadhesive drug delivery system such as enteric films. To predict the mucoadhesive behaviour in vivo, suitable in vitro or ex vivo methods can be performed. In this study, the influence of tissue storage and sampling site on the mucoadhesion of polyvinyl alcohol film to human small intestinal mucosa was investigated. Tissue from twelve human subjects was used to determine adhesion using a tensile strength method. Thawing of tissue frozen at −20 °C resulted in a significantly higher work of adhesion (p = 0.0005) when a low contact force was applied for one minute, whereas the maximum detachment force was not affected. When the contact force and time were increased, no differences were found for thawed tissue compared to fresh tissue. No change in adhesion was observed depending on the sampling location. Initial results from a comparison of adhesion to porcine and human mucosa suggest that the tissues are equivalent.
To evaluate the influence of the blood–brain barrier on neuronal gadolinium deposition in a mouse model after multiple intravenous applications of the linear contrast agent gadodiamide. The prospective study held 54 mice divided into three groups: healthy mice (A), mice with iatrogenic induced disturbance of the blood–brain barrier by glioblastoma (B) or cerebral infarction (C). In each group 9 animals received 10 iv-injections of gadodiamide (1.2 mmol/kg) every 48 h followed by plain T1-weighted brain MRI. A final MRI was performed 5 days after the last contrast injection. Remaining mice underwent MRI in the same time intervals without contrast application (control group). Signal intensities of thalamus, pallidum, pons, dentate nucleus, and globus pallidus-to-thalamus and dentate nucleus-to-pons ratios, were determined. Gadodiamide complex and total gadolinium amount were quantified after the last MR examination via LC–MS/MS and ICP-MS. Dentate nucleus-to-pons and globus pallidus-to-thalamus SI ratios showed no significant increase over time within all mice groups receiving gadodiamide, as well as compared to the control groups at last MR examination. Comparing healthy mice with group B and C after repetitive contrast administration, a significant SI increase could only be detected for glioblastoma mice in globus pallidus-to-thalamus ratio (p = 0.033), infarction mice showed no significant SI alteration. Tissue analysis revealed significantly higher gadolinium levels in glioblastoma group compared to healthy (p = 0.013) and infarction mice (p = 0.029). Multiple application of the linear contrast agent gadodiamide leads to cerebral gadolinium deposition without imaging correlate in MRI.
Objective: The instrument THERapy-related InterACTion (THER-I-ACT) was developed to document therapeutic interactions comprehensively in the human therapist–patient setting. Here, we investigate whether the instrument can also reliably be used to characterise therapeutic interactions when a digital system with a humanoid robot as a therapeutic assistant is used.
Methods: Participants and therapy: Seventeen stroke survivors receiving arm rehabilitation (i.e., arm basis training (ABT) for moderate-to-severe arm paresis [n = 9] or arm ability training (AAT) for mild arm paresis [n = 8]) using the digital therapy system E-BRAiN over a course of nine sessions. Analysis of the therapeutic interaction: A total of 34 therapy sessions were videotaped. All therapeutic interactions provided by the humanoid robot during the first and the last (9th) session of daily training were documented both in terms of their frequency and time used for that type of interaction using THER-I-ACT. Any additional therapeutic interaction spontaneously given by the supervising staff or a human helper providing physical assistance (ABT only) was also documented. All ratings were performed by two trained independent raters.
Statistical analyses: Intraclass correlation coefficients (ICCs) were calculated for the frequency of occurrence and time used for each category of interaction observed.
Results: Therapeutic interactions could comprehensively be documented and were observed across the dimensions provision of information, feedback, and bond-related interactions. ICCs for therapeutic interaction category assessments from 34 therapy sessions by two independent raters were high (ICC ≥0.90) for almost all categories of the therapeutic interaction observed, both for the occurrence frequency and time used for categories of therapeutic interactions, and both for the therapeutic interaction performed by the robot and, even though much less frequently observed, additional spontaneous therapeutic interactions by the supervisory staff and a helper being present. The ICC was similarly high for an overall subjective rating of the concentration and engagement of patients (0.87).
Conclusion: Therapeutic interactions can comprehensively and reliably be documented by trained raters using the instrument THER-I-ACT not only in the traditional patient–therapist setting, as previously shown, but also in a digital therapy setting with a humanoid robot as the therapeutic agent and for more complex therapeutic settings with more than one therapeutic agent being present.
The reduction of individual carbon consumption could make an important contribution to the worldwide effort to limit global warming. Based on Bandura’s theory of moral disengagement, we hypothesized that the propensity to morally disengage concerning high-carbon behaviors (e.g., eating meat or traveling by plane) is one important factor that prevents individuals from reducing their carbon footprint. To measure the propensity to morally disengage in high-carbon-related behavior contexts, a questionnaire (MD-HCB) was developed and psychometrically validated in an online study with a German sample (N = 220). Confirmatory factor analyses revealed that the final nine-item scale had a one-dimensional structure, as intended. The internal consistency of the scale was excellent (Cronbach’s α = 0.94) and the scale interpretation had predictive validity for both past low-carbon consumption behavior and the intention to engage in such behavior in the future. Correlational analyses with relevant existing instruments confirmed the construct validity of the interpretations that can be drawn from the MD-HCB, as its resulting score is related to, yet separable from, the general tendency to morally disengage and is meaningfully connected to related constructs. A pre-study with a student sample (N = 89) not only helped to identify limitations in the study design but also showed a weak predictive ability of moral competence concerning high-carbon consumption behavior and intention to change. Based on our findings, future media campaigns designed to increase people’s intention to reduce high-carbon behavior could focus on the modification of common cognitive disengagement strategies.
Overexpression of polo-like kinase 1 (PLK1) has been found in many different types of cancers. With its essential role in cell proliferation, PLK1 has been determined to be a broad-spectrum anti-cancer target. In this study, 3D-QSAR, molecular docking, and molecular dynamics (MD) simulations were applied on a series of novel pteridinone derivatives as PLK1 inhibitors to discover anti-cancer drug candidates. In this work, three models—CoMFA (Q² = 0.67, R² = 0.992), CoMSIA/SHE (Q² = 0.69, R² = 0.974), and CoMSIA/SEAH (Q² = 0.66, R² = 0.975)—of pteridinone derivatives were established. The three models that were established gave R²(pred) = 0.683, R²(pred) = 0.758, and R²(pred) = 0.767, respectively. Thus, the predictive abilities of the three proposed models were successfully evaluated. The relations between the different champs and activities were well-demonstrated by the contour chart of the CoMFA and CoMSIA/SEAH models. The results of molecular docking indicated that residues R136, R57, Y133, L69, L82, and Y139 were the active sites of the PLK1 protein (PDB code: 2RKU), in which the more active ligands can inhibit the enzyme of PLK1. The results of the molecular dynamic MD simulation diagram were obtained to reinforce the previous molecular docking results, which showed that both inhibitors remained stable in the active sites of the PLK1 protein (PDB code: 2RKU) for 50 ns. Finally, a check of the ADME-Tox properties of the two most active molecules showed that molecular N° 28 could represent a good drug candidate for the therapy of prostate cancer diseases.
Physiological and neural synchrony in emotional and neutral stimulus processing: A study protocol
(2023)
Background: As psychotherapy involves at least two individuals, it is essential to include the interaction perspective research. During interaction, synchrony, i.e., the occurrence of simultaneous responses, can be observed at the physiological, neural, and behavioral level. Physiological responses include heart rate and electrodermal activity; neural markers can be measured using electroencephalogram. Emotionally arousing stimuli are allocated more attentional resources (motivated attention), which is reflected in physiological activation and brain potentials. Here we present a protocol for a pilot study implementing a new research methodology, and replication of the motivated attention to emotion effect in in dyads. There is evidence that higher synchrony is associated with more positive (therapeutic) relationships. Thus, the secondary outcome will be the association between physiological and neural synchrony and subjective ratings.
Methods and design: Individuals (18−30 years) will participate in same-sex pairs in two experiments. In the first experiment (triadic interaction), both participants attentively watch unpleasant, neutral and pleasant pictures, and read/listen to standardized scripts (unpleasant, neutral, and pleasant, respectively) for the imagination task. In the second experiment, participants will read out three scripts (unpleasant, neutral, pleasant) to each other, followed by a joint imagination period. Stimuli will be presented in counterbalanced orders. After each picture and imagination, participants rate their subjective arousal and valence. In the beginning and in the end of the procedure, dyads rate their relationship, sympathy, and bonds (Working Alliance Inventory subscale). Heart rate, electrodermal activity and electroencephalogram will be continuously measured during both experiments using portable devices (EcgMove4 and EdaMove4, nine-channel B-Alert X-Series mobile-wireless EEG). Synchrony analyses will include the dual electroencephalography analysis pipeline, correlational analyses and Actor–Partner Interdependence Models.
Discussion: The present study protocol provides an experimental approach to investigate interpersonal synchrony during emotion processing, allowing for the establishment of research methods in a pilot study, which can later be translated into real-life psychotherapy research. In the future, fundamental understanding of such mechanisms in dyadic interactions is essential in order to promote therapeutic relationships, and thus, treatment effectiveness and efficiency.
Objective: To characterize a socially active humanoid robot’s therapeutic interaction as a therapeutic assistant when providing arm rehabilitation (i.e., arm basis training (ABT) for moderate-to-severe arm paresis or arm ability training (AAT) for mild arm paresis) to stroke survivors when using the digital therapeutic system Evidence-Based Robot-Assistant in Neurorehabilitation (E-BRAiN) and to compare it to human therapists’ interaction.
Methods: Participants and therapy: Seventeen stroke survivors receiving arm rehabilitation (i.e., ABT [n = 9] or AAT [n = 8]) using E-BRAiN over a course of nine sessions and twenty-one other stroke survivors receiving arm rehabilitation sessions (i.e., ABT [n = 6] or AAT [n = 15]) in a conventional 1:1 therapist–patient setting. Analysis of therapeutic interaction: Therapy sessions were videotaped, and all therapeutic interactions (information provision, feedback, and bond-related interaction) were documented offline both in terms of their frequency of occurrence and time used for the respective type of interaction using the instrument THER-I-ACT. Statistical analyses: The therapeutic interaction of the humanoid robot, supervising staff/therapists, and helpers on day 1 is reported as mean across subjects for each type of therapy (i.e., ABT and AAT) as descriptive statistics. Effects of time (day 1 vs. day 9) on the humanoid robot interaction were analyzed by repeated-measures analysis of variance (rmANOVA) together with the between-subject factor type of therapy (ABT vs. AAT). The between-subject effect of the agent (humanoid robot vs. human therapist; day 1) was analyzed together with the factor therapy (ABT vs. AAT) by ANOVA.
Main results and interpretation: The overall pattern of the therapeutic interaction by the humanoid robot was comprehensive and varied considerably with the type of therapy (as clinically indicated and intended), largely comparable to human therapists’ interaction, and adapted according to needs for interaction over time. Even substantially long robot-assisted therapy sessions seemed acceptable to stroke survivors and promoted engaged patients’ training behavior.
Conclusion: Humanoid robot interaction as implemented in the digital system E-BRAiN matches the human therapeutic interaction and its modification across therapies well and promotes engaged training behavior by patients. These characteristics support its clinical use as a therapeutic assistant and, hence, its application to support specific and intensive restorative training for stroke survivors.
The cortical silent period (CSP), assessed with transcranial magnetic stimulation (TMS), provides insights into motor cortex excitability. Alterations in the CSP have been observed in multiple sclerosis (MS), although a comparison of the sometimes contradictory results is difficult due to methodological differences. The aim of this study is to provide a more profound neurophysiological understanding of fatigue’s pathophysiology and its relationship to the CSP. Twenty-three patients with MS, along with a matched control group, underwent comprehensive CSP measurements at four intensities (125, 150, 175, and 200% resting motor threshold), while their fatigue levels were assessed using the Fatigue Scale for Motor and Cognitive Functions (FSMC) and its motor and cognitive subscore. MS patients exhibited a significantly increased CSP duration compared to controls (p = 0.02), but CSP duration was not associated with the total FSMC, or the motor or cognitive subscore. Our data suggest a systematic difference in MS patients compared to healthy controls in the CSP but no association with fatigue when measured with the FSMC. Based on these results, and considering the heterogeneous literature in the field, our study highlights the need for a more standardized approach to neurophysiological data collection and validation. This standardization is crucial for exploring the link between TMS and clinical impairments in diseases like MS.
The study of prostate cancer in vitro relies on established cell lines that lack important physiological characteristics, such as proper polarization and expression of relevant biomarkers. Microphysiological systems (MPS) can replicate cancer microenvironments and lead to cellular phenotypic changes that better represent organ physiology in vitro. In this study, we developed an MPS model comprising conventional prostate cancer cells to evaluate their activity under dynamic culture conditions. Androgen-sensitive (LNCaP) and androgen-insensitive (PC3) cells were grown in conventional and 3D cultures, both static and dynamic. Cell morphology, the secretion of prostate-specific antigen, and the expression of key prostate markers and microRNAs were analyzed. LNCaP formed spheroids in 3D and MPS cultures, with morphological changes supported by the upregulation of cytokeratins and adhesion proteins. LNCaP also maintained a constant prostate-specific antigen secretion in MPS. PC3 cells did not develop complex structures in 3D and MPS cultures. PSA expression at the gene level was downregulated in LNCaP-MPS and considerably upregulated in PC3-MPS. MicroRNA expression was altered by the 3D static and dynamic culture, both intra- and extracellularly. MicroRNAs associated with prostate cancer progression were mostly upregulated in LNCaP-MPS. Overall dynamic cell culture substantially altered the morphology and expression of LNCaP cells, arguably augmenting their prostate cancer phenotype. This novel approach demonstrates that microRNA expression in prostate cancer cells is sensitive to external stimuli and that MPS can effectively promote important physiological changes in conventional prostate cancer models.
Primary and acquired therapy resistance is a major problem in patients with BRAF-mutant melanomas being treated with BRAF and MEK inhibitors (BRAFI, MEKi). Therefore, development of alternative therapy regimes is still required. In this regard, new drug combinations targeting different pathways to induce apoptosis could offer promising alternative approaches. Here, we investigated the combination of proteasome and Kv1.3 potassium channel inhibition on chemo-resistant, BRAF inhibitor-resistant as well as sensitive human melanoma cells. Our experiments demonstrated that all analyzed melanoma cell lines were sensitive to proteasome inhibitor treatment at concentrations that are not toxic to primary human fibroblasts. To further reduce proteasome inhibitor-associated side effects, and to foster apoptosis, potassium channels, which are other targets to induce pro-apoptotic effects in cancer cells, were blocked. In support, combined exposure of melanoma cells to proteasome and Kv1.3 channel inhibitor resulted in synergistic effects and significantly reduced cell viability. On the molecular level, enhanced apoptosis correlated with an increase of intracellular Kv1.3 channels and pro-apoptotic proteins such as Noxa and Bak and a reduction of anti-apoptotic proteins. Thus, use of combined therapeutic strategies triggering different apoptotic pathways may efficiently prevent the outgrowth of drug-resistant and -sensitive BRAF-mutant melanoma cells. In addition, this could be the basis for an alternative approach to treat other tumors expressing mutated BRAF such as non-small-cell lung cancer.
Organic anion transporters 1 and 3 (OAT1 and OAT3) play a crucial role in kidney function by regulating the secretion of multiple renally cleared small molecules and toxic metabolic by-products. Assessing the activity of these transporters is essential for drug development purposes as they can significantly impact drug disposition and safety. OAT1 and OAT3 are amongst the most abundant drug transporters expressed in human renal proximal tubules. However, their expression is lost when cells are isolated and cultured in vitro, which is a persistent issue across all human and animal renal proximal tubule cell models, including primary cells and cell lines. Although it is well known that the overall expression of drug transporters is affected in vitro, the underlying reasons for the loss of OAT1 and OAT3 are still not fully understood. Nonetheless, research into the regulatory mechanisms of these transporters has provided insights into the molecular pathways underlying their expression and activity. In this review, we explore the regulatory mechanisms that govern the expression and activity of OAT1 and OAT3 and investigate the physiological changes that proximal tubule cells undergo and that potentially result in the loss of these transporters. A better understanding of the regulation of these transporters could aid in the development of strategies, such as introducing microfluidic conditions or epigenetic modification inhibitors, to improve their expression and activity in vitro and to create more physiologically relevant models. Consequently, this will enable more accurate assessment for drug development and safety applications.
Mendelian randomization indicates causal effects of estradiol levels on kidney function in males
(2023)
Context: Chronic kidney disease (CKD) is a public health burden worldwide. Epidemiological studies observed an association between sex hormones, including estradiol, and kidney function.
Objective: We conducted a Mendelian randomization (MR) study to assess a possible causal effect of estradiol levels on kidney function in males and females.
Design: We performed a bidirectional two-sample MR using published genetic associations of serum levels of estradiol in men (n = 206,927) and women (n = 229,966), and of kidney traits represented by estimated glomerular filtration rate (eGFR, n = 567,460), urine albumin-to-creatinine ratio (UACR, n = 547,361), and CKD (n = 41,395 cases and n = 439,303 controls) using data obtained from the CKDGen Consortium. Additionally, we conducted a genome-wide association study using UK Biobank cohort study data (n = 11,798 men and n = 6,835 women) to identify novel genetic associations with levels of estradiol, and then used these variants as instruments in a one-sample MR.
Results: The two-sample MR indicated that genetically predicted estradiol levels are significantly associated with eGFR in men (beta = 0.077; p = 5.2E-05). We identified a single locus at chromosome 14 associated with estradiol levels in men being significant in the one-sample MR on eGFR (beta = 0.199; p = 0.017). We revealed significant results with eGFR in postmenopausal women and with UACR in premenopausal women, which did not reach statistical significance in the sensitivity MR analyses. No causal effect of eGFR or UACR on estradiol levels was found.
Conclusions: We conclude that serum estradiol levels may have a causal effect on kidney function. Our MR results provide starting points for studies to develop therapeutic strategies to reduce kidney disease.
Polypharmacy in patients with multiple sclerosis and the impact on levels of care and therapy units
(2023)
Background: The aim of this study was to examine the societal costs of polypharmacy in patients with multiple sclerosis (MS). We therefore focused on the association between the number of medications on the level of care (LOC), the German classification of the need for care, and the number of therapy sessions (TTU).
Methods: In addition to demographic information and medication, 101 MS patients performed the Multiple Sclerosis Health Resource Utilization Survey (MS-HRS). Medications were subdivided into a total number of medications (TD), MS-related medication [MSD, i.e., disease-modifying drugs (DMDs) and symptomatic treatment (SD)], and medication for comorbidities (CDs). Multivariate linear regression models were performed to estimate if the amount of each medication type affects LOC or TTU.
Results: Polypharmacy appeared in 54 patients at the time of the survey. The relative risk (RR) of LOC 1 increased significantly by 2.46 (p = 0.001) per TD and by 2.55 (p = 0.004) per MSD, but not per CD (RR 1.44; p = 0.092). The effect of RR on MSD was driven by SD (RR 2.2; p = 0.013) but not DMD (RR 2.6; p = 0.4). RR of MSD remained significant for LOC 2 (1.77; p = 0.009) and LOC 3/4 (1.91; p = 0.015), with a strong trend in RR of SD, but not DMD. TTU increased significantly per MSD (p = 0.012), but not per TD (p = 0.081) and CD (p = 0.724).
Conclusion: The number of MSDs is related to the likelihood of a higher level of care and the number of therapy sessions and is therefore a good indication of the extent of the societal costs.
Non-Floating Harbour Syndrome (FLHS) neurodevelopmental disorder (NDD) is a recently described disorder caused by mutations in certain regions of the SRCAP gene. We generated two iPSC lines that contain truncating mutation on both alleles at the 3′-end of SRCAP using CRISPR/Cas9 technology. Both cell lines are pluripotent, differentiate into the 3 germ layers and contain no genomic aberrations or off-target modifications. The cell lines form part of a human disease model to investigate the effects of truncating mutations in different regions of SRCAP.
Introduction: The environmental bacterium Burkholderia pseudomallei causes the often fatal and massively underreported infectious disease melioidosis. Antigens inducing protective immunity in experimental models have recently been identified and serodiagnostic tools have been improved. However, further elucidation of the antigenic repertoire of B. pseudomallei during human infection for diagnostic and vaccine purposes is required. The adaptation of B. pseudomallei to very different habitats is reflected by a huge genome and a selective transcriptional response to a variety of conditions. We, therefore, hypothesized that exposure of B. pseudomallei to culture conditions mimicking habitats encountered in the human host might unravel novel antigens that are recognized by melioidosis patients.
Methods and results: In this study, B. pseudomallei was exposed to various stress and growth conditions, including anaerobiosis, acid stress, oxidative stress, iron starvation and osmotic stress. Immunogenic proteins were identified by probing two-dimensional Western blots of B. pseudomallei intracellular and extracellular protein extracts with sera from melioidosis patients and controls and subsequent MALDI-TOF MS. Among B. pseudomallei specific immunogenic signals, 90 % (55/61) of extracellular immunogenic proteins were identified by acid, osmotic or oxidative stress. A total of 84 % (44/52) of intracellular antigens originated from the stationary growth phase, acidic, oxidative and anaerobic conditions. The majority of the extracellular and intracellular protein antigens were identified in only one of the various stress conditions. Sixty-three immunoreactive proteins and an additional 38 candidates from a literature screening were heterologously expressed and subjected to dot blot analysis using melioidosis sera and controls. Our experiments confirmed melioidosis-specific signals in 58 of our immunoproteome candidates. These include 15 antigens with average signal ratios (melioidosis:controls) greater than 10 and another 26 with average ratios greater than 5, including new promising serodiagnostic candidates with a very high signal-to-noise ratio.
Conclusion: Our study shows that a comprehensive B. pseudomallei immunoproteomics approach, using conditions which are likely to be encountered during infection, can identify novel antibody targets previously unrecognized in human melioidosis.
The male genitalia of pholcid spiders, which is one of the most species-rich spider families, are characterized by a procursus, which is a morphologically diverse projection of the copulatory organ. It has been shown that the procursus interacts with the female genitalia during copulation. Here, we investigate the function of the procursus in Gertschiola neuquena, a species belonging to the early branched and understudied subfamily Ninetinae, using behavioural and morphological data. Although many aspects of the copulatory behaviour of G. neuquena follow the general pattern described for the family, males use only one pedipalp during each copulation. Based on our micro-CT analysis of cryofixed mating pairs using virgin females, we can show that the long and filiform procursus is inserted deeply into the unpaired convoluted female spermatheca, and the intromittent sclerite, the embolus, is rather short and stout only reaching the most distal part of the female sperm storage organ. Histological data revealed that sperm are present in the most proximal part of the spermatheca, suggesting that the procursus is used to allocate sperm deeply into the female sperm storage organ. This represents the first case of a replacement of the sperm allocation function of the intromittent sclerite in spiders.
Colonic atresia (CA) is a rare disease with an incidence range between one of 20 000 and one of 66 000 live births. Most CA are located within the proximal colon; distal CA are even rarer. Because of its rarity, another case shall be described herewith. A 37th week of pregnancy born child was noticed occurring multiple vomiting, a distended abdomen and additional whitish-bloody stool shortly thereafter. In the first operation, a double-barrel stoma was created. After sufficient weight gain and alignment of the stoma ends, a secondary anastomosis was created in the child after 2 months. The diagnosis can be made reliably on the basis of an X-ray and leads to a good outcome with prompt surgical intervention. However, accompanying malformations should always be considered.
This article is the first to show that gender shapes the degree to which legislators use formal mechanisms to oversee government activities. Extensive scholarly work has analysed the use of oversight instruments, especially regarding who monitors whom. Whether, how, and why the conformity of men and women with institutional roles differs, has not yet received scholarly attention. We hypothesise that women become more active than men in overseeing the executive when in opposition while reducing their monitoring activities even more strongly than men when in government because of different social roles ascribed to men and women as well as differences in risk aversity between sexes. We analyse panel data for three oversight tools from the German Bundestag between 1949 and 2013 to test this proposition. Our findings imply that characteristics of political actors influence even a strongly institutionalised process as oversight and further clarify the gender bias in political representation.
The vast majority of RNA splicing in today‘s organisms is achieved by the highly regulated and precise removal of introns from pre-mRNAs via the spliceosome. Here we present a model of how RNA splicing may have occurred in earlier life forms. We have designed a hairpin ribozyme derived spliceozyme that mediates two RNA cleavages and one ligation event at specific positions and thus cuts a segment (intron) out of a parent RNA and ligates the remaining fragments (exons). The cut-out intron then performs a downstream function, acting as a positive regulator of the activity of a bipartite DNAzyme. This simple scenario shows how small RNAs can perform complex RNA processing dynamics, involving the generation of new phenotypes by restructuring segments of given RNA species, as well as delivering small RNAs that may play a functional role in downstream processes.
In future fusion reactors disruptions must be avoided at all costs. Disruptions due to the density limit (DL) are typically described by the power-independent Greenwald scaling. Recently, a power dependence of the disruptive DL was predicted by several authors (Zanca et al 2019 Nucl. Fusion 59 126011; Giacomin et al 2022 Phys. Rev. Lett. 128 185003; Singh and Diamond 2022 Plasma Phys. Control. Fusion 64 084004; Stroth et al 2022 Nucl. Fusion 62 076008; Brown and Goldston 2021 Nucl. Mater. Energy 27 101002). It is investigated whether this increases the operational range of the tokamak. Increasing the heating power in the L-mode can induce an L-H transition, and therefore a power-dependent DL and the L-H transition cannot be considered independently. The different models are tested on a data base for separatrix parameters at the separatrix of ASDEX Upgrade and compared with the concept (SepOS) presented in Eich and Manz (2021 Nucl. Fusion 61 086017). The disruptive separatrix density scales with the power ne ∝ P0.38±0.08 in good agreement to all models. Also the back transition from high to low (H-L) confinement shows an approximately Greenwald scaling with an additional power dependence ne ∝ P0.4 according to the SepOS concept. For future devices operating at much higher heating power such a power scaling may allow operation at much higher separatrix densities than are common in H-mode operation. Preconditions to extrapolation for future devices are discussed.
Peatlands contribute to a wide range of ecosystem services. They play an important role as carbon sinks in their natural state, but when they are drained, they cause carbon emissions. Rewetting drained peatlands is required to reduce carbon emissions and create new carbon sinks. However, drained peatlands are commonly used as grassland or croplands; therefore, alternative agriculture schemes are required following rewetting. Paludiculture, i.e., agriculture on wet and rewetted peatlands, is an option in these areas after rewetting to produce biomass sustainably. Monitoring of peatland management is challenging, yet needed to ensure a successful rewetting and plantation of, e.g., Phragmites australis and Typha spp., two plants which are commonly used in paludiculture. Remote sensing is an excellent tool for monitoring the vegetation composition of vast rewetted peatland regions. However, because many peatland species have similar spectral characteristics, such monitoring is ideally based on high-spatial, high-temporal hyperspectral images. Data that complies with all these requirements does not exist on a regular basis. Therefore, we assessed the potential for mapping peatland vegetation communities in the Peene and Trebel river basins of the federal state of Mecklenburg-Western Pomerania, Germany, using multi-date hyperspectral (PRISMA) data. We used regression-based unmixing to map fractions of different peatland vegetation classes. Results were analyzed with regard to the contribution of multi-date observations and, in comparison, to multispectral datasets (Landsat-8/Sentinel-2). Our results showed that different classes are best mapped at different observation dates. The multi-date hyperspectral datasets produced less Mean Absolute Error (MAE = 16.4%) than the single-date hyperspectral images (ΔMAE + 1%), with high accuracies for all classes of interest. Compared to the results obtained with multispectral data from similar acquisition dates and annual spectral-temporal metrics (STM), the results from hyperspectral data were always clearly superior (ΔMAE + 4%). Besides the superior performance during comparisons, our results also indicate that information that can be derived from the hyperspectral data with the regression-based unmixing goes clearly beyond that of discrete classification. With more hyperspectral sensors coming up and an expected higher availability of multi-data hyperspectral imagery, these data can be expected to play a bigger role in the future monitoring of peatlands.
The current study analyzes the trajectory of the goose vowel in Received Pronunciation (RP) over ten decades (1920s-2010s). Recordings of eighty-seven RP speakers were transcribed in ELAN, and vowel tokens were extracted by FAVE, measuring F1 and F2 values at the midpoint. Showing the life-cycle of a sound change from start to (almost) completion, the results confirm that goose-fronting has been an active sound change for many decades in RP, with F2 starting to increase in the middle of the twentieth century and accelerated changes in the 1970s and the 2010s. We observe similar predictor strengths of linguistic factors as in previous studies. The results are interpreted in light of the social changes in the social composition of the RP group in the second part of the twentieth century, involving increased dialect contact.
The controlled formation and adjustment of size and density of magnetic skyrmions in Ta/CoFeB/MgO trilayers with low Dzyaloshinskii–Moriya interaction is demonstrated. Close to the out-of-plane to in-plane magnetic spin reorientation transition, we find that small energy contributions enable skyrmion formation in a narrow window of 20 pm in CoFeB thickness. Zero-field stable skyrmions are established with proper magnetic field initialization within a 10 pm CoFeB thickness range. Using magneto-optical imaging with quantitative image processing, variations in skyrmion distribution and diameter are analyzed quantitatively, the latter for sizes well below the optical resolution limit. We demonstrate the controlled merging of individual skyrmions. The overall demonstrated degree of comprehension of skyrmion control aids to the development of envisioned skyrmion based magnetic memory devices.
Properties of self-excited dust acoustic waves under the influence of active compression of the dust particle system were experimentally studied in the laboratory and under microgravity conditions (parabolic flight). Ground based laboratory experiments clearly show that wave properties can be manipulated by changing the discharge volume, its aspect ratio, and thus the dust particle density. Complementary experiments under microgravity conditions, performed to exclude the effects of gravity inflicted sedimentation and anisotropic behavior, were less conclusive due to residual fluctuations in the planes acceleration indicating the need for a better microgravity environment. A theoretical model, using plasma parameters obtained from particle-in-cell simulations as input, supports the experimental findings. It shows that the waves can be described as a new observation of the dust acoustic mode, which demonstrates their generic character.
Minced Cartilage Implantation in Acetabular Cartilage Defects: Case Series with 2-Year Results
(2023)
Objective
The objective was to evaluate clinical outcome and safety of arthroscopic, autologous minced cartilage implantation for acetabular cartilage lesions observed during hip arthroscopy to treat femoroacetabular impingement syndrome (FAIS).
Design
Eleven male patients, average age: 29.4 ± 5.4 years, average body mass index (BMI): 24.2 ± 2.2 kg/m2, scheduled for hip arthroscopy due to FAIS accompanied by an acetabular cartilage lesion were included in the case series. Cartilage tissue was harvested and minced from the loose cartilage flap at the chondrolabral lesion by arthroscopic shaver, augmented with autologous conditioned plasma, implanted into the defect, and fixated by autologous thrombin. Concomitant interventions were performed as indicated. The patients were evaluated preoperatively and at 24-month follow-up, using the International Hip Outcome Tool-12 (iHOT-12) and Visual Analog Scale (VAS) pain score and by magnetic resonance imaging (MRI) using the Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) grading scale at the 2-year follow-up.
Results
The defect size was on average 3.5 cm2 (1.5-4.5 cm2). From preoperatively to 2 years postoperatively, the iHOT-12 significantly improved from 50.2 ± 18 to 86.5 ± 19 (P < 0.0001), and pain score decreased from 5.6 ± 1.8 to 1.0 ± 1.5 (P < 0.0001) on the Visual Analog Scale pain score. Regarding functional outcome and pain, 10 of the 11 patients and all patients reached the minimal clinically important difference (MCID), respectively. The postoperative average MOCART score was 87.2 (± 9.2). No adverse events or reoperations were observed.
Conclusions
Arthroscopic, autologous minced cartilage implantation for treating full-thickness acetabular cartilage lesions in FAIS shows statistically and clinically significant improvement at short-term follow-up.
Background:
Minced cartilage implantation (MCI) has seen a renaissance in recent years. In this evolved technique, human articular cartilage is harvested with an arthroscopic shaver, augmented with platelet-rich plasma (PRP), and implanted with autologous thrombin. This modified technique combines the possibility of cell-based surgical cartilage repair with a minimally invasive autologous 1-step procedure. However, evidence on cell survival and preserved function after shaver-based mincing and PRP supplementation is limited.
Purpose:
To evaluate the effects of arthroscopic shaver mincing and augmentation with PRP on human cartilage tissue.
Study Design:
Controlled laboratory study.
Methods:
Standardized samples were taken from 12 donors during autologous MCI. A comparison of cell outgrowth, cell viability, proliferation capacity, and ability to produce extracellular matrix–specific proteoglycans after chondrogenic redifferentiation was made between cartilage taken by curettage from the border of the cartilage defect, cartilage tissue minced by an arthroscopic shaver, and cartilage tissue minced by an arthroscopic shaver that was additionally augmented with autologous PRP.
Results:
There was no difference between all 3 groups in terms of cell outgrowth or proliferation capacity. Metabolic activity relative to the cell number of chondrocytes isolated from shaver-minced cartilage was higher compared with chondrocytes isolated from cartilage that was derived by curettage or shaver-minced cartilage that was augmented with PRP. After chondrogenic stimulation, the normalized proteoglycan content was higher in spheroids of cells derived from shaver-minced cartilage augmented with PRP than in spheroids of cells derived from curettage. A high correlation of cell outgrowth, proliferation capacity, and viability between isolated cells from all 3 groups taken from an individual donor was observed.
Conclusion:
Chondrocytes isolated from human cartilage tissue that was harvested and minced with an arthroscopic shaver remained viable and proliferative. The augmentation of shaver-minced cartilage with PRP led to the enhanced proteoglycan production of chondrogenic spheroids in vitro, pointing toward the development of a cartilage-specific extracellular matrix. This in vitro study yields promising results regarding the use of an arthroscopic shaver and augmentation with PRP in the context of MCI.
Clinical Relevance:
Knowledge that shaver mincing and augmentation with PRP are feasible for processing articular cartilage during MCI is highly relevant for surgical cartilage repair.
Aim
Climate change challenges temperate forest trees by increasingly irregular precipitation and rising temperatures. Due to long generation cycles, trees cannot quickly adapt genetically. Hence, the persistence of tree populations in the face of ongoing climate change depends largely on phenotypic variation, that is the capability of a genotype to express variable phenotypes under different environmental conditions, known as plasticity. We aimed to quantify phenotypic variation of central Europe's naturally dominant forest tree across various intraspecific scales (individuals, mother trees (families), populations) to evaluate its potential to respond to changing climatic conditions.
Location
Europe.
Time Period
2016–2019.
Major Taxa Studied
European beech (Fagus sylvatica L.).
Methods
We conducted a fully reciprocal transplantation experiment with more than 9000 beech seeds from seven populations across a Europe-wide gradient. We compared morphological (Specific Leaf Area), phenological (leaf unfolding) and fitness-related (growth, survival) traits across various biological scales: within single mother trees, within populations and across different populations under the contrasting climates of the translocation sites.
Results
The experiment revealed significant phenotypic variation within the offspring of each mother tree, regardless of geographic origin. Initially, seedling height growth varied among mother trees and populations, likely due to maternal effects. However, the growth performance successively aligned after the first year. In summary, we observed a consistent growth response in different beech populations to diverse environments after initial maternal effects.
Main Conclusions
The study strikingly demonstrates the importance of considering intraspecific variation. Given the surprisingly broad spectrum of phenotypes each mother tree holds within its juvenile offspring, we conclude that Fagus sylvatica might have the potential for medium-term population persistence in face of climate change, provided that this pattern persists into later life stages. Hence, we also suggest further investigating the inclusion of passive adaptation and natural dynamics in the adaptive management of forests.
Although serious accidents remain the leading cause of pediatric mortality, protocols to orient diagnostic procedures towards a certain type of initial imaging are widely needed. Since 2007, we have performed whole-body magnetic resonance imaging (WBMR) and whole-body computed tomography (WBCT) for diagnoses of severely injured children. We retrospectively reviewed 134 WBMR and 158 WBCT in patients younger than 16 years that were performed at two trauma centers between 2007 and 2018. A higher Injury Severity Score (ISS) was found in WBCT vs. WBMR (10.6 vs. 5.8; p = 0.001), but without any significant difference in mortality. The WBMR was significantly preferred at younger ages (9.6 vs. 12.8 years; p < 0.001). The time between patient’s arrival until diagnosis was 2.5 times longer for WBCT (92.1 vs. 37.1 min; p < 0.001). More patients in the CT group received analgesic sedation and/or intubation at 37.3% vs. 21.6% in the MRI group. Of these patients, 86.4% (CT) and 27.6% (MRI) were already preclinically sedated (p < 0.001). Correspondingly, 72.4% of the patients were first sedated in-hospital for MRIs. In conclusion, WBMR is an alternative and radiation-free imaging method for high-energy-traumatized children. Although the selected diagnostics seemed appropriate, limitations regarding longer duration or additional analgesic sedation are present, and further studies are needed.
We apply the charge simulation method (CSM) in order to compute the logarithmic capacity of compact sets consisting of (infinitely) many “small” components. This application allows to use just a single charge point for each component. The resulting method therefore is significantly more efficient than methods based on discretizations of the boundaries (for example, our own method presented in Liesen et al. (Comput. Methods Funct. Theory 17, 689–713, 2017)), while maintaining a very high level of accuracy. We study properties of the linear algebraic systems that arise in the CSM, and show how these systems can be solved efficiently using preconditioned iterative methods, where the matrix-vector products are computed using the fast multipole method. We illustrate the use of the method on generalized Cantor sets and the Cantor dust.
Hibernation is a widespread adaptation in animals to seasonally changing environmental conditions. In the face of global anthropogenic change, information about plastic adjustments to environmental conditions and associated mortality costs are urgently needed to assess population persistence of hibernating species. Here, we used a five-year data set of 1047 RFID-tagged individuals from two bat species, Myotis nattereri and Myotis daubentonii that were automatically recorded each time they entered or left a hibernaculum. Because the two species differ in foraging strategy and activity pattern during winter, we expected species–specific responses in the timing of hibernation relative to environmental conditions, as well as different mortality costs of early departure from the hibernaculum in spring. Applying mixed-effects modelling, we disentangled population-level and individual-level plasticity in the timing of departure. To estimate mortality costs of early departure, we used both a capture mark recapture analysis and a novel approach that takes into account individual exposure times to mortality outside the hibernaculum. We found that the timing of departure varied between species as well as among and within individuals, and was plastically adjusted to large-scale weather conditions as measured by the NAO (North Atlantic Oscillation) index. Individuals of M. nattereri, which can exploit milder temperatures for foraging during winter, tuned departure more closely to the NAO index than individuals of M. daubentonii, which do not hunt during winter. Both analytical approaches used to estimate mortality costs showed that early departing individuals were less likely to survive until the subsequent hibernation period than individuals that departed later. Overall, our study demonstrates that individuals of long-lived hibernating bat species have the potential to plastically adjust to changing climatic conditions, although the potential for adjustment differs between species.
Background
One of the main treatment goals in cochlear implant (CI) patients is to improve speech perception. One of the target parameters is speech intelligibility in quiet. However, treatment results show a high variability, which has not been sufficiently explained so far. The aim of this noninterventional retrospective study was to elucidate this variability using a selected population of patients in whom etiology was not expected to have a negative impact on postoperative speech intelligibility.
Materials and methods
Audiometric findings of the CI follow-up of 28 adult patients after 6 months of CI experience were evaluated. These were related to the preoperative audiometric examination and evaluated with respect to a recently published predictive model for the postoperative monosyllabic score.
Results
Inclusion of postoperative categorical loudness scaling and hearing loss for Freiburg numbers in the model explained 55% of the variability in fitting outcomes with respect to monosyllabic word recognition.
Conclusion
The results of this study suggest that much of the cause of variability in fitting outcomes can be captured by systematic postoperative audiometric checks. Immediate conclusions for CI system fitting adjustments may be drawn from these results. However, the extent to which these are accepted by individual patients and thus lead to an improvement in outcome must be subject of further studies, preferably prospective.
Purpose
The German Retina.net ROP registry and its Europe-wide successor, the EU-ROP registry, collect data from patients treated for ROP. This analysis compares input parameters of these two registries to establish a procedure for joint analyses of different registry data using exemplary datasets from the two registries.
Methods
Exemplary datasets from the two databases over a 1-year period each (German Retina.net ROP Registry, 2011, 22 infants; EU-ROP Registry, 2021, 44 infants) were compared. The parameters documented in the two databases were aligned and analysed regarding demographic parameters, treatment modalities, complications within first 24 h and retreatments.
Results
The current analysis showed that data can be aligned for joint analyses with some adjustments within the data structure. The registry with more detailed data collection (EU-ROP) needs to be reduced regarding granularity in order to align the different registries, as the registry with lower granularity determines the level of analyses that can be performed in a comparative approach. In the exemplary datasets, we observed that the overall most common ROP severity in both registries was zone II, 3+ (2011: 70.5%; 2021: 65%), with decreasing numbers of clock hours showing preretinal neovascularisations (2011: 10–12 clock hours in 29% of cases, 2021: 4–6 clock hours in 38%). The most prevalent treatment method was laser coagulation in 2011 (75%) and anti-VEGF therapy in 2021 (86.1%). Within the anti-VEGF group, all patients were treated with bevacizumab in 2011 and with ranibizumab in 2021. Retreatment rates were comparable in 2011 and 2021.
Conclusion
Data from two different ROP registries can be aligned and jointly analysed. The analysis reveals a paradigm shift in treatment modalities, from predominantly laser to anti-VEGF, and within the anti-VEGF group from bevacizumab to ranibizumab in Germany. In addition, there was a trend towards earlier treatment in 2021.
Thermal ablation offers a minimally invasive alternative in the treatment of hepatic tumours. Several types of ablation are utilised with different methods and indications. However, to this day, ablation size remains limited due to the formation of a central non-conductive boundary layer. In thermal ablation, this boundary layer is formed by carbonisation. Our goal was to prevent or delay carbonisation, and subsequently increase ablation size. We used bovine liver to compare ablation diameter and volume, created by a stand-alone laser applicator, with those created when utilising a spacer between laser applicator and hepatic tissue. Two spacer variants were developed: one with a closed circulation of cooling fluid and one with an open circulation into hepatic tissue. We found that the presence of a spacer significantly increased ablation volume up to 75.3 cm3, an increase of a factor of 3.19 (closed spacer) and 3.02 (open spacer) when compared to the stand-alone applicator. Statistical significance between spacer variants was also present, with the closed spacer producing a significantly larger ablation volume (p < 0.001, MDiff = 3.053, 95% CI[1.612, 4.493]) and diameter (p < 0.001, MDiff = 4.467, 95% CI[2.648, 6.285]) than the open spacer. We conclude that the presence of a spacer has the potential to increase ablation size.
An aneurysmal fibrous histiocytoma is a rare cutaneous soft-tissue tumour which accounts for approximately 0.06% of all dermatopathologies. Metastasis is exceedingly uncommon, to the point that there have only been eight reported cases in the scientific literature. We present the case of a 25-year-old male with a primary aneurysmal fibrous histiocytoma located in the nuchal region which exhibited rapid growth and abrupt ulceration over a short time span and showed signs of locoregional aggressive infiltration. A subsequent histopathological analysis confirmed the presence of diffuse solid and cystic pulmonary metastases. Further genetic sequencing verified LAMTOR1-PRKCD fusion. This case report seeks to review the existing literature on aneurysmal fibrous histiocytoma, discuss the challenges of differential diagnosis and propose standardised diagnostic criteria.
Marine algae produce complex polysaccharides, which can be degraded by marine heterotrophic bacteria utilizing carbohydrate-active enzymes. The red algal polysaccharide porphyran contains the methoxy sugar 6-O-methyl-D-galactose (G6Me). In the degradation of porphyran, oxidative demethylation of this monosaccharide towards D-galactose and formaldehyde occurs, which is catalyzed by a cytochrome P450 monooxygenase and its redox partners. In direct proximity to the genes encoding for the key enzymes of this oxidative demethylation, genes encoding for zinc-dependent alcohol dehydrogenases (ADHs) were identified, which seem to be conserved in porphyran utilizing marine Flavobacteriia. Considering the fact that dehydrogenases could play an auxiliary role in carbohydrate degradation, we aimed to elucidate the physiological role of these marine ADHs. Although our results reveal that the ADHs are not involved in formaldehyde detoxification, a knockout of the ADH gene causes a dramatic growth defect of Zobellia galactanivorans with G6Me as a substrate. This indicates that the ADH is required for G6Me utilization. Complete biochemical characterizations of the ADHs from Formosa agariphila KMM 3901T (FoADH) and Z. galactanivorans DsijT (ZoADH) were performed, and the substrate screening revealed that these enzymes preferentially convert aromatic aldehydes. Additionally, we elucidated the crystal structures of FoADH and ZoADH in complex with NAD+ and showed that the strict substrate specificity of these new auxiliary enzymes is based on a narrow active site.
Purpose
The significance of the underlying literature in clinical guidelines can be weakened by the risk of bias, which could negatively affect the recommendations. Especially in controversial matters, such as fluoride use for caries prevention in children, biased results may be not reliable and lead to incorrect conclusions. This study was performed to detect bias in underlying literature of the German guideline for caries prevention using fluoride in children, where no consensus was reached between paediatricians and paediatric dentists.
Methods
Three tools used for risk of bias assessments of different study designs were RoB 2 for RCTs, ROBINS-I for non-randomized studies, and ROBIS for systematic reviews. For each study cited in the guideline two independent risk of bias assessments were performed. Disagreements were resolved by consensus.
Results
Out of 58 papers, 48.3% (n = 28) showed high risk of bias, with the majority in sections regarding fluoride tablets, fluoridated toothpaste, and paediatricians’ recommendations. 9 out of 20 recommendations and statements were based on studies with high risk of bias, all of which were in these three controversial sections. 13 out of 29 RCTs showed high risk of bias (44.8%), as all 13 non-randomized trials did, while only 2 of 16 (12.5%) systematic reviews had high risk of bias.
Conclusion
Considering risk of bias of cited studies in clinical guidelines may result in substantial changes in its recommendations and aid in reaching consensus. Efforts should be made to assess risk of bias of underlying literature in future clinical guidelines.
This study investigated, if a mixed electroactive bacterial (EAB) culture cultivated heterotrophically at a positive applied potential could be adapted from oxidative to reductive or bidirectional extracellular electron transfer (EET). To this end, a periodic potential reversal regime between − 0.5 and 0.2 V vs. Ag/AgCl was applied. This yielded biofilm detachment and mediated electroautotrophic EET in combination with carbonate, i.e., dissolved CO2, as the sole carbon source, whereby the emerged mixed culture (S1) contained previously unknown EAB. Using acetate (S2) as well as a mixture of acetate and carbonate (S3) as the main carbon sources yielded primarily alternating electrogenic organoheterotropic metabolism with the higher maximum oxidation current densities recorded for mixed carbon media, exceeding on average 1 mA cm−2. More frequent periodic polarization reversal resulted in the increase of maximum oxidative current densities by about 50% for S2-BES and 80% for S3-BES, in comparison to half-batch polarization. The EAB mixed cultures developed accordingly, with S1 represented by mostly aerobes (84.8%) and being very different in composition to S2 and S3, dominated by anaerobes (96.9 and 96.5%, respectively). S2 and S3 biofilms remained attached to the electrodes. There was only minor evidence of fully reversible bidirectional EET. In conclusion the three triplicates fed with organic and/or inorganic carbon sources demonstrated two forms of diauxie: Firstly, S1-BES showed a preference for the electrode as the electron donor via mediated EET. Secondly, S2-BES and S3-BES showed a preference for acetate as electron donor and c-source, as long as this was available, switching to CO2 reduction, when acetate was depleted.
Background and Aims
Hepatocellular ballooning is a common finding in chronic liver disease, mainly characterized by rarefied cytoplasm that often contains Mallory-Denk bodies (MDB). Ballooning has mostly been attributed to degeneration but its striking resemblance to glycogenotic/steatotic changes characterizing preneoplastic hepatocellular lesions in animal models and chronic human liver diseases prompts the question whether ballooned hepatocytes (BH) are damaged cells on the path to death or rather viable cells, possibly involved in neoplastic development.
Methods
Using specimens from 96 cirrhotic human livers, BH characteristics were assessed for their glycogen/lipid stores, enzyme activities, and proto-oncogenic signaling cascades by enzyme- and immunohistochemical approaches with serial paraffin and cryostat sections.
Results
BH were present in 43.8% of cirrhotic livers. Particularly pronounced excess glycogen storage of (glycogenosis) and/or lipids (steatosis) were characteristic, ground glass features and MDB were often observed. Decreased glucose-6-phosphatase, increased glucose-6-phosphate dehydrogenase activity and altered immunoreactivity of enzymes involved in glycolysis, lipid metabolism, and cholesterol biosynthesis were discovered. Furthermore, components of the insulin signaling cascade were upregulated along with insulin dependent glucose transporter glucose transporter 4 and the v-akt murine thymoma viral oncogene homolog/mammalian target of rapamycin signaling pathway associated with de novo lipogenesis.
Conclusions
BH are hallmarked by particularly pronounced glycogenosis with facultative steatosis, many of their features being reminiscent of metabolic aberrations documented in preneoplastic hepatocellular lesions in experimental animals and chronic human liver diseases. Hence, BH are not damaged entities facing death but rather viable cells featuring metabolic reprogramming, indicative of a preneoplastic nature.
Background
The ‘wallflower’ hypothesis proposes females mate indiscriminately to avoid reproductive delays. Post-copulatory mechanisms may then allow ‘trading up’, favouring paternity of future mates. We tested links between pre- and post-copulatory choice in Latrodectus geometricus female spiders paired sequentially with two males. These females copulate as adults or as subadults and store sperm in paired spermathecae. Choosy adults have a higher risk of delays to reproduction than subadults.
Results
We predicted low pre-copulatory, but high post-copulatory choice at first matings for adults and the opposite for subadults. At second matings, we expected all females would prefer males superior to their first. We found all females mated indiscriminately at their first pairing, but in contrast to subadults, adults usually allowed only a single insertion (leaving one of their paired spermatheca empty); a mechanism of post-copulatory choosiness. Adult-mated females were more likely to remate than subadult-mated females when they became adults, showing a preference for larger males, while subadult-mated females tended to prefer males of greater size-corrected mass.
Conclusions
Our results show that the ‘wallflower’ effect and ‘trading up’ tactics can be utilized at different life stages, allowing females to employ choice even if rejecting males is costly.
Chronic kidney disease is a major public health burden associated with a drastically reduced quality of living and life span that lacks suitable, individualized therapeutic strategies. Here we present a human induced pluripotent stem cell line (iPSC, UMGACBi001-A) reprogrammed from urine cells of an acute septic dialysis patient suffering from chronic kidney disease using non-integrating administration of RNAs. The generated iPSCs were positively characterized for typical morphology, pluripotency marker expression, directed differentiation potential, non-contamination, chromosomal consistency and donor identity. This iPSC-line can be a useful source for in vitro disease modelling and individualized therapeutic approaches.
Transcriptional corepressors Sin3, Cyc8 and Tup1 are important for downregulation of gene expression by recruiting various histone deacetylases once they gain access to defined genomic locations by interaction with pathway-specific repressor proteins. In this work we systematically investigated whether 17 yeast repressor proteins (Cti6, Dal80, Fkh1, Gal80, Mig1, Mot3, Nrg1, Opi1, Rdr1, Rox1, Sko1, Ume6, Ure2, Xbp1, Yhp1, Yox1 and Whi5) representing several unrelated regulatory pathways are able to bind to Sin3, Cyc8 and Tup1. Our results show that paired amphipathic helices 1 and 2 (PAH1 and PAH2) of Sin3 are functionally redundant for some regulatory pathways. WD40 domains of Tup1 proved to be sufficient for interaction with repressor proteins. Using length variants of selected repressors, we mapped corepressor interaction domains (CIDs) in vitro and assayed gene repression in vivo. Systematic comparison of CID minimal sequences allowed us to define several related positional patterns of hydrophobic amino acids some of which could be confirmed as functionally supported by site-directed mutagenesis. Although structural predictions indicated that certain CIDs may be α-helical, most repression domains appear to be randomly structured and must be considered as intrinsically disordered regions (IDR) adopting a defined conformation only by interaction with a corepressor.
Monitoring and assessing groundwater quality according to European directives and national regulations is usually based on interpolation techniques, e.g. Kriging. However, contour maps of hydrochemical parameters often suggest a spurious local accuracy and can therefore lead to inappropriate action measures. Here, the early concept of extension variance combined with the Voronoi tessellation regionalization is proposed. The mosaic-like representation of pollutant concentrations in Voronoi polygons avoids misinterpretations caused by interpolation. The additional calculation of the extension variance, which is based on fundamental geostatistical assumptions, allows for estimating the probability that a given threshold is exceeded. This concept is further extended to hydraulically delimitable groundwater bodies, thus ensuring that hydraulic boundaries are considered. A method is here described for the assessment of groundwater quality with respect to nitrate concentration in the principal aquifer of the state Mecklenburg-Western Pomerania in Germany.
The potential of several ion-sensitive electrodes responds to the incorporated cations and anions. This has led some authors to misinterpret the potential of metal salt membrane electrodes and of electrodes of the second kind. Neglecting the kinetics of potential establishment and interpreting the potentials solely based on thermodynamics produce completely irrelevant data and suggest that ion concentrations down to 10−45 mol L−1 are accessible by simple potentiometric measurements. The switching from cation to anion response mechanism cannot be derived from thermodynamic equations. It bears complete similarity to the switching of response in the case of foreign interfering ions.
Objectives
To investigate the effect of layer height of FFF-printed models on aligner force transmission to a second maxillary premolar during buccal torquing, distalization, extrusion, and rotation using differing foil thicknesses.
Materials and methods
Utilizing OnyxCeph3™ Lab (Image Instruments GmbH, Chemnitz, Germany, Release Version 3.2.185), the following movements were programmed for the second premolar: buccal torque (0.1–0.5 mm), distalization (0.1–0.4 mm), extrusion (0.1–0.4 mm), rotation (0.1–0.5 mm), and staging 0.1 mm. Via FFF, 91 maxillary models were printed for each staging at different layer heights (100 µm, 150 µm, 200 µm, 250 µm, 300 µm). Hence, 182 aligners, made of polyethylene terephthalate glycol (PET-G) with two thicknesses (0.5 mm and 0.75 mm), were prepared. The test setup comprised an acrylic maxillary model with the second premolar separated and mounted on a sensor, measuring initial forces and moments exerted by the aligners. A generalized linear model for the gamma distribution was applied, evaluating the significance of the factors layer height, type of movement, aligner thickness, and staging on aligner force transmission.
Results
Foil thickness and staging were found to have a significant influence on forces delivered by aligners, whereas no significance was determined for layer height and type of movement. Nevertheless, at a layer height of 150 µm, the most appropriate force transmission was observed.
Conclusions
Printing aligner models at particularly low layer heights leads to uneconomically high print time without perceptible better force delivery properties, whereas higher layer heights provoke higher unpredictability of forces due to scattering. A z-resolution of 150 µm appears ideal for in-office aligner production combining advantages of economic print time and optimal force transmission.
In teaching electrochemistry, it is of primary importance to make students always aware of the relations between electrochemistry and all the non-electrochemical topics, which are taught. The vast majority of students will not specialise in electrochemistry, but they all can very much benefit from the basics and concepts of electrochemistry. This paper is aimed to give suggestions how the teaching of electrochemistry can easily be interrelated to topics of inorganic, organic, analytical, environmental chemistry, biochemistry and biotechnology.
The classical Buscher rules d escribe T-duality for metrics and B-fields in a topologically trivial setting. On the other hand, topological T-duality addresses aspects of non-trivial topology while neglecting metrics and B-fields. In this article, we develop a new unifying framework for both aspects.
In general, concepts such as chemical equilibria and classical analytical chemistry, as well as instrumental methods such as potentiometry and flow injection analysis (FIA), are taught separately in the curricula of chemistry-related degree programs. However, FIA provides an opportunity to connect all of these important topics. This article shows how simple experiments can be used to link the fundamentals of FIA and potentiometry to the fundamentals of chemical equilibria and teach them in a sustainable way. The experiments were designed for undergraduate environmental science students with basic knowledge of chemical equilibria and classical analytical chemistry and minimal knowledge of electrochemistry. However, they can also be integrated into various courses on instrumental analysis in chemistry-related degree programs.
How can powerful states best extract domestic concessions from their junior allies? What are the conditions under which the powerful state is more likely to succeed in inducing such domestic policy change? This article explores the link between US security commitments and Washington’s ability to attain favourable policy outcomes within the allied domestic arena. It provides an illustrative case of how the USA, using security guarantees as leverage, can enter allied domestic space and shape its decision-making process. After it was revealed that Latvia had served as a key node through which North Korea attempted to evade the sanctions regime, the USA, by playing its security guarantor card, pressured Riga to carry out substantial policy reforms in relation to its financial system. This approach yielded considerable results. In order to preserve the existing security arrangements with the dominant alliance member, Latvia offered significant policy concessions. This finding demonstrates that US security alliances come with side benefits that are often underrated or neglected in the scholarly literature.
SLC35F1 is a member of the sugar-like carrier (SLC) superfamily that is expressed in the mammalian brain. Malfunction of SLC35F1 in humans is associated with neurodevelopmental disorders. To get insight into the possible roles of Slc35f1 in the brain, we generated Slc35f1-deficient mice. The Slc35f1-deficient mice are viable and survive into adulthood, which allowed examining adult Slc35f1-deficient mice on the anatomical as well as behavioral level. In humans, mutation in the SLC35F1 gene can induce a Rett syndrome-like phenotype accompanied by intellectual disability (Fede et al. Am J Med Genet A 185:2238–2240, 2021). The Slc35f1-deficient mice, however, display only a very mild phenotype and no obvious deficits in learning and memory as, e.g., monitored with the novel object recognition test or the Morris water maze test. Moreover, neuroanatomical parameters of neuronal plasticity (as dendritic spines and adult hippocampal neurogenesis) are also unaltered. Thus, Slc35f1-deficient mice display no major alterations that resemble a neurodevelopmental phenotype.
Animals often respond to climate change with changes in morphology, e.g., shrinking body size with increasing temperatures, as expected by Bergmann’s rule. Because small body size can have fitness costs for individuals, this trend could threaten populations. Recent studies, however, show that morphological responses to climate change and the resulting fitness consequences cannot be generalized even among related species. In this long-term study, we investigate the interaction between ambient temperature, body size and survival probability in a large number of individually marked wild adult female Natterer’s bats (Myotis nattereri). We compare populations from two geographical regions in Germany with a different climate. In a sliding window analysis, we found larger body sizes in adult females that were raised in warmer summers only in the northern population, but not in the southern population that experienced an overall warmer climate. With a capture-mark-recapture approach, we showed that larger individuals had higher survival rates, demonstrating that weather conditions in early life could have long-lasting fitness effects. The different responses in body size to warmer temperatures in the two regions highlight that fitness-relevant morphological responses to climate change have to be viewed on a regional scale and may affect local populations differently.
Background and objective
Political, economic, communicative and cultural borders still limit the accessibility of acute healthcare services for patients so that they frequently have to accept longer distances to travel to the next provider within their own country. In this paper, we analyze the impact of borders and opening of borders on acute medical care in hospitals and on patients in border regions.
Methods
We develop a conceptual framework model of cross-border healthcare and apply it to the Polish–German border area. The model combines the distance decay effect, a catchment area analysis, economies of scale and the learning curve.
Results
Borders have a major impact on acute medical care in hospitals and on patients. Setting of new borders will reduce the accessibility of health facilities for patients or require the establishment of new hospitals. Reopening borders might induce a vicious circle leading to the insolvency of a hospital which might result in poorer health for some patients.
Conclusion
Strong effort should be invested to overcome political and cultural borders to improve the health of the population in border regions. Similarly, increased cross-border acute healthcare must be seen in the context of rural health and the special situation of small rural hospitals in rural peripheral areas.
Parental gender preferences in Central and Eastern Europe and differential early life disadvantages
(2023)
Parental gender preferences may affect partnership decisions and as a result lead to early life disadvantages. We study these preferences in five post-communist countries of Central and Eastern Europe, a region with strong traditional gender norms and persisting inequalities between women and men in labour market outcomes. Using subsamples of census from Belarus, Hungary, Poland, Romania and Russia around 2000 and 2010, we follow Dahl and Moretti (2008), The demand for sons, to examine the effect of the gender of the first-born child(ren) on fertility decisions and relationship stability of their parents. We only find strong evidence of ‘boy preferences’ in fertility decisions in the cases of Romania and Russia. However, unlike Dahl and Moretti (2008), The demand for sons, for the US, we cannot confirm a relationship between the children's gender and parental partnership decisions. This is the case for all examined Central and Eastern European countries, as well as for a number of countries from Western Europe. The cases of Romania and Russia raise questions about other potential consequences of the documented gender preferences. We argue that our approach can be applied more broadly to identify other countries characterised by parental gender preferences, and to motivate further examination of different forms of gender driven early life disadvantages.
How well populations can cope with global warming will often depend on the evolutionary potential and plasticity of their temperature-sensitive, fitness-relevant traits. In Bechstein's bats (Myotis bechsteinii), body size has increased over the last decades in response to warmer summers. If this trend continues it may threaten populations as larger females exhibit higher mortality. To assess the evolutionary potential of body size, we applied a Bayesian ‘animal model’ to estimate additive genetic variance, heritability and evolvability of body size, based on a 25-year pedigree of 332 wild females. Both heritability and additive genetic variance were reduced in hot summers compared to average and cold summers, while evolvability of body size was generally low. This suggests that the observed increase in body size was mostly driven by phenotypic plasticity. Thus, if warm summers continue to become more frequent, body size likely increases further and the resulting fitness loss could threaten populations.
Background
Both vulnerability and integrity represent action-guiding concepts in nursing practice. However, they are primarily discussed regarding patients—not nurses—and considered independently from rather than in relation to each other.
Aim
The aim of this paper is to characterize the moral dimension of nurses' vulnerability and integrity, specify the concepts' relationship in nurses' clinical practice and, ultimately, allow a more fine-grained understanding.
Design
This discursive paper demonstrates how vulnerability and integrity relate to each other in nursing practice and carves out which types of vulnerability pose a threat to nurses' moral integrity. The concept of vulnerability developed by Mackenzie et al. (2014) is applied to the situation of nurses and expanded to include the concept of moral integrity according to Hardingham (2004). Four scenarios are used to demonstrate where and how nurses' vulnerabilities become particularly apparent in clinical practice. This leads to a cross-case discussion, in which the vulnerabilities identified are examined against the background of moral integrity and the relationship between the two concepts is determined in more detail.
Results and Conclusion
Vulnerability and integrity do not only form a conceptual pair but also represent complementary moral concepts. Their joint consideration has both a theoretical and practical added value. It is shown that only specific forms of vulnerability pose a threat to moral integrity and the vulnerability–integrity relationship is mediated via moral distress.
Implications for the Profession and/or Patient Care
The manuscript provides guidance on how the concrete threat(s) to integrity can be buffered and moral resilience can be promoted. Different types of threats also weigh differently and require specific approaches to assess and handle them at the micro-, meso- and macro-level of the healthcare system.