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Ion trajectories have been simulated for an assembly of a linear quadrupole ion-filter and a linear Paul trap with additional pin electrodes for MS SPIDOC, a project in preparation for the study of biomolecules by single-particle imaging with X-ray pulses. The ion-optical components are based on digital RF guiding and trapping fields. In order to carefully handle biomolecules over a wide mass-over-charge range, the module presented consists of separate components for filtering and accumulation/trapping in order to select the ions of interest and to convert the beam from a continuous ion source to ion bunches, respectively, as required for the experiments downstream. The present analysis focuses on the transmission efficiency and mass resolving power of the filter, as well as the buffer-gas-pressure-dependent ion capture and thermalization in the trap for the example of a mass-to-charge ratio equivalent to hemoglobin 15+ ions. The resulting optimized ion bunch delivered by the assembly is characterized.
Abstract
This brief discussion paper is concerned with the sequence [have NP Vpp] and its distinction into a causative and a passive construction, which hinges on the (non-)agentivity of the subject participant, so that the sequence can be seen as ambiguous in that respect. Instead of analyzing these uses as two different constructions, I propose a unified analysis as instances of the affactive construction. This construction has the functional potential of putting primary focus on secondary participants, so-called afficiary participants. The potential ambiguity with regard to the agentivity of these participants is not an issue in usage, as it is only evoked as part of the conceptual content in the background.
Late to bed, late to rise—Warmer autumn temperatures delay spring phenology by delaying dormancy
(2021)
Abstract
Spring phenology of temperate forest trees has advanced substantially over the last decades due to climate warming, but this advancement is slowing down despite continuous temperature rise. The decline in spring advancement is often attributed to winter warming, which could reduce chilling and thus delay dormancy release. However, mechanistic evidence of a phenological response to warmer winter temperatures is missing. We aimed to understand the contrasting effects of warming on plants leaf phenology and to disentangle temperature effects during different seasons. With a series of monthly experimental warming by ca. 2.4°C from late summer until spring, we quantified phenological responses of forest tree to warming for each month separately, using seedlings of four common European tree species. To reveal the underlying mechanism, we tracked the development of dormancy depth under ambient conditions as well as directly after each experimental warming. In addition, we quantified the temperature response of leaf senescence. As expected, warmer spring temperatures led to earlier leaf‐out. The advancing effect of warming started already in January and increased towards the time of flushing, reaching 2.5 days/°C. Most interestingly, however, warming in October had the opposite effect and delayed spring phenology by 2.4 days/°C on average; despite six months between the warming and the flushing. The switch between the delaying and advancing effect occurred already in December. We conclude that not warmer winters but rather the shortening of winter, i.e., warming in autumn, is a major reason for the decline in spring phenology.
Introduction: To maintain a sufficient donor pool, deferred first-time donors (FTD) should be motivated to return for blood donation. This pilot study investigates how deferral affects momentary mood, satisfaction with the donation process, and subsequent return behavior to examine their potential for motivating (deferred) FTD. Methods: All of the subjects (n = 96) completed a first questionnaire (A1) before pre-donation assessment. Deferred FTD (n = 22) were asked to complete a second questionnaire (A2) immediately after deferral, while non-deferred FTD (n = 74) filled in the second questionnaire (A3) after blood donation. The impact of deferral, momentary mood, and satisfaction with the donation process on return behavior within 12 months was tested by calculating two path analyses, controlling for sex and age. Results: Mood (p < 0.001) and satisfaction with social aspects of the donation process (p = 0.01) were decreased after deferral. Deferred FTD were less likely than non-deferred FTD to return to the blood donation center within 12 months (60.8 vs. 36.4%; p = 0.043). However, path analyses revealed that deferral effects on mood and satisfaction were not connected to return behavior. Instead, age had a significant influence on return behavior (p < 0.05) such that, overall, non-returning FTD were older than returning FTD, regardless of their deferral status. Conclusion: Our findings suggest that mood and satisfaction with the donation process are directly affected by deferral but not clearly responsible for low return rates. It seems promising to embed these variables in established health behavior models in further studies to increase the return rates of deferred FTD.
Introduction: Patients who are overweight or obese have an increased risk of developing type 2 diabetes mellitus (T2DM). Weight loss can have a positive effect on glycemic control. Objective: We aimed to investigate glycemic control in patients with T2DM and overweight or obesity during a structured weight-loss program. Methods: This was a prospective, interventional study. We recruited 36 patients (14 men and 22 women) with a median age of 58.5 years and median body mass index (BMI) of 34.1, to a 15-week structured weight-loss program with a low-calorie (800 kcal) formula diet for 6 weeks. The primary end point, HbA<sub>1c</sub> level, and secondary end points, anthropometric data, medication, and safety, were assessed weekly. Laboratory values and quality of life were assessed at baseline and after 15 weeks. Results: HbA<sub>1c</sub> decreased from 7.3% at baseline to 6.5% at 15 weeks (p < 0.001), median body weight by 11.9 kg (p < 0.001), median BMI by 4.3 (p < 0.001) and median waist circumference by 11.0 cm (p < 0.001). Two participants discontinued insulin therapy, 4 could reduce their dosage of oral antidiabetic agents, and 6 completely discontinued their antidiabetic medication. Insulin dose decreased from 0.63 (0.38–0.89) to 0.39 (0.15–0.70) units/kg body weight (p < 0.001). No patient experienced hypoglycemic episodes or hospital emergency visits. Triglycerides and total cholesterol decreased as well as surrogate markers of liver function. However, the levels of high-density and low-density lipoprotein cholesterol (HDL-C and LDL-C) as well as uric acid remain unchanged. Regarding quality of life, the median physical health score increased from 44.5 (39.7–51.4) at baseline to 48.0 (43.1–55.3; p = 0.007), and the median mental health score decreased from 42.1 (36.1–46.7) to 37.4 (30.3–43.7; p = 0.004). Conclusions: A structured weight-loss program is effective in the short term in reducing HbA<sub>1c</sub>, weight, and antidiabetic medication in patients with T2DM who are overweight or obese. Levels of HDL-C and LDL-C were not affected by short-term weight loss. The decline in mental health and the long-term effects of improved glycemic control require further trials.
Abstract
Social organisation in species with fluctuating population sizes can change with density. Therefore, information on (future) density obtained during early life stages may be associated with social behaviour. Olfactory cues may carry important social information. We investigated whether early life experience of different experimental densities was subsequently associated with differences in attraction to adult conspecific odours. We used common voles (Microtus arvalis), a rodent species undergoing extreme density fluctuations. We found that individuals originating from high experimental density populations kept in large outdoor enclosures invested more time in inspecting conspecific olfactory cues than individuals from low‐density populations. Generally, voles from both treatments spent more time with the olfactory cues than expected by chance and did not differ in their latency to approach the odour samples. Our findings indicate either that early experience affects odour sensitivity or that animals evaluate the social information contained in conspecific odours differently, depending on their early life experience of conspecific density.
Introduction: In the light of the ongoing SARS-CoV-2 pandemic, convalescent plasma is a treatment option for COVID-19. In contrast to usual therapeutic plasma, the therapeutic agents of convalescent plasma do not represent clotting factor activities, but immunoglobulins. Quarantine storage of convalescent plasma as a measure to reduce the risk of pathogen transmission is not feasible. Therefore, pathogen inactivation (e.g., Theraflex®-MB, Macopharma, Mouvaux, France) is an attractive option. Data on the impact of pathogen inactivation by methylene blue (MB) treatment on antibody integrity are sparse. Methods: Antigen-specific binding capacity was tested before and after MB treatment of plasma (n = 10). IgG and IgM isoagglutinin titers were tested by agglutination in increasing dilutions. Furthermore, the binding of anti-EBV and anti-tetanus toxin IgG to their specific antigens was assessed by ELISA, and IgG binding to Fc receptors was assessed by flow cytometry using THP-1 cells expressing FcRI and FcRII. Results: There was no significant difference in the isoagglutinin titers, the antigen binding capacity of anti-EBV and anti-tetanus toxin IgG, as well as the Fc receptor binding capacity before and after MB treatment of plasma. Conclusion: MB treatment of plasma does not inhibit the binding capacity of IgM and IgG to their epitopes, or the Fc receptor interaction of IgG. Based on these results, MB treatment of convalescent plasma is appropriate to reduce the risk of pathogen transmission if quarantine storage is omitted.
Non-carious dental lesions such as developmental defects of enamel (DDE) and erosive tooth wear (ETW) are the subject of intensive research. This paper aims to give perspectives on both DDE, including dental fluorosis and molar incisor hypomineralization (MIH), and ETW, presenting epidemiological data from the Americas and associated diagnostic aspects. Besides, it is important to present evidence to guide the clinical assessment process, supporting the clinicians’ management decisions towards better oral health of their patients. The overall increase in the worldwide prevalence of non-carious lesions discussed in this this paper may reflect the need of perceptual changes. Although the number of publications related to these conditions has been increasing in the last years, there is still a need for clinical diagnostic and management awareness to include these conditions in routine dental practice. Besides, it is important to provide recommendations for standardized clinical assessment criteria, improving the process and helping clinicians’ adherence. In this sense, this paper discusses the most commonly implemented indices for each condition. Thus, despite the wide range of diagnostic indices, BEWE is proposed to be the index recommended for ETW assessment, Dean or Thylstrup & Fejerskov indices for fluorosis and preferably the EAPD criteria (or modified DDE index) for MIH. Overall, non-carious lesions are a growing concern, and it is important to implement preventive measures that control their severity and progression, and accurate diagnosis by the dental clinician.
Abstract
The two important mechanisms influencing the response of phytoplankton communities to alterations of abiotic factors in their environment are difficult to distinguish: species sorting resulting from a change in interspecific competitive pressure, and phenotypic plasticity (here explicitly physiological plasticity i.e. species‐specific physiological adjustment). A shift in species composition as well as physiological adjustments in species can lead to changes in fatty acid composition that determine the food quality for zooplankton consumers.
We used phytoplankton communities consisting of five species and exposed them to two different light intensities, two light conditions (constant and variable), and two levels of phosphorus supply. Changes in fatty acid and species composition were analyzed. We compared community pairs differing in one factor by calculating the Bray‐Curtis similarity index for the composition of both variables. Comparing the Bray‐Curtis similarity index of the species composition with the index of the fatty acid composition was used to estimate the effects of species sorting and physiological plasticity.
Changes in nutrient supply influenced fatty acid responses based on species sorting and physiological plasticity the most. On one hand, the relevance of physiological plasticity was highest at cultivation in different nutrient supplies but the same light environment. Conversely with low nutrients species sorting appeared to dominate the response to changes in light, while at high nutrients physiological plasticity appeared to influence the response. Overall, under low phosphorus supply the communities showed a lower total fatty acid content per carbon and had increased proportions of saturated and monounsaturated fatty acids. Instead, communities in low light produced more of eicosapentaenoic acid.
Our results suggest that the relevance of species sorting and physiological plasticity in shaping the community response highly depends on the environmental factors that influence the system. Nutrient supply had the largest effect, while light had more limited conditional effects. However, all of these factors are important in shaping the food quality of the phytoplankton community for higher trophic levels.
Are old regions less attractive? Interregional labour migration in a context of population ageing
(2021)
Abstract
Regional demographic change is often conceptualized as a circular process, where out‐migration continuously worsens conditions of population ageing and shrinkage. Thus, if migration acts as a consequence as well as cause of ageing, migration patterns should be influenced by the age structure of origin and destination regions. This paper analyses individual‐level migration decisions of full‐time employees across 326 German regions between 1997 and 2013 using binary choice models. The results show that individuals are more likely to migrate out of and less likely to migrate towards ageing regions. Moreover, the identified patterns are consistent with age‐selective migration reinforcing ageing processes and polarization of demographic structure.
Abstract
Introduced populations of invasive organisms have to cope with novel environmental challenges, while having reduced genetic variation caused by founder effects. The mechanisms associated with this “genetic paradox of invasive species” has received considerable attention, yet few studies have examined the genomic architecture of invasive species. Populations of the heart node ant Cardiocondyla obscurior belong to two distinct lineages, a New World lineage so far only found in Latin America and a more globally distributed Old World lineage. In the present study, we use population genomic approaches to compare populations of the two lineages with apparent divergent invasive potential. We find that the strong genetic differentiation of the two lineages began at least 40,000 generations ago and that activity of transposable elements (TEs) has contributed significantly to the divergence of both lineages, possibly linked to the very unusual genomic distribution of TEs in this species. Furthermore, we show that introgression from the Old World lineage is a dominant source of genetic diversity in the New World lineage, despite the lineages' strong genetic differentiation. Our study uncovers mechanisms underlying novel genetic variation in introduced populations of C. obscurior that could contribute to the species' adaptive potential.
Abstract
Saliva is an attractive sampling matrix for measuring various endogenous and exogeneous substances but requires sample treatment prior to chromatographic analysis. Exploiting supercritical CO2 for both extraction and chromatography simplifies sample preparation, reduces organic solvent consumption, and minimizes exposure to potentially infectious samples, but has not yet been applied to oral fluid. Here, we demonstrate the feasibility and benefits of online supercritical fluid extraction coupled to supercritical fluid chromatography and single‐quadrupole mass spectrometry for monitoring the model salivary tracer caffeine. A comparison of 13C‐ and 32S‐labeled internal standards with external standard calibration confirmed the superiority of stable isotope‐labeled caffeine over nonanalogous internal standards. As proof of concept, the validated method was applied to saliva from a magnetic resonance imaging study of gastric emptying. After administration of 35 mg caffeine via ice capsule, salivary levels correlated with magnetic resonance imaging data, corroborating caffeine's usefulness as tracer of gastric emptying (R2 = 0.945). In contrast to off‐line methods, online quantification required only minute amounts of organic solvents and a single manual operation prior to online bioanalysis of saliva, thus demonstrating the usefulness of CO2‐based extraction and separation techniques for potentially infective biomatrices.
Abstract
Halide methyltransferases (HMTs) enable the enzymatic synthesis of S‐adenosyl‐l‐methionine (SAM) from S‐adenosyl‐l‐homocysteine (SAH) and methyl iodide. Characterisation of a range of naturally occurring HMTs and subsequent protein engineering led to HMT variants capable of synthesising ethyl, propyl, and allyl analogues of SAM. Notably, HMTs do not depend on chemical synthesis of methionine analogues, as required by methionine adenosyltransferases (MATs). However, at the moment MATs have a much broader substrate scope than the HMTs. Herein we provide an overview of the discovery and engineering of promiscuous HMTs and how these strategies will pave the way towards a toolbox of HMT variants for versatile chemo‐ and regioselective biocatalytic alkylations.
Abstract
Myxomycetes are terrestrial protists with many presumably cosmopolitan species dispersing via airborne spores. A truly cosmopolitan species would suffer from outbreeding depression hampering local adaptation, while locally adapted species with limited distribution would be at a higher risk of extinction in changing environments. Here, we investigate intraspecific genetic diversity and phylogeography of Physarum albescens over the entire Northern Hemisphere. We sequenced 324 field collections of fruit bodies for 1–3 genetic markers (SSU, EF1A, COI) and analysed 98 specimens with genotyping by sequencing. The structure of the three‐gene phylogeny, SNP‐based phylogeny, phylogenetic networks, and the observed recombination pattern of three independently inherited gene markers can be best explained by the presence of at least 18 reproductively isolated groups, which can be seen as cryptic species. In all intensively sampled regions and in many localities, members of several phylogroups coexisted. Some phylogroups were found to be abundant in only one region and completely absent in other well‐studied regions, and thus may represent regional endemics. Our results demonstrate that the widely distributed myxomycete species Ph. albescens represents a complex of at least 18 cryptic species, and some of these seem to have a limited geographical distribution. In addition, the presence of groups of presumably clonal specimens suggests that sexual and asexual reproduction coexist in natural populations of myxomycetes.
Abstract
This work presents the reactivity and dissolution of an as‐polished and electrochemically pre‐treated polycrystalline Au electrode, which is used as a model system. The effect of the electrochemical pre‐treatment in corrosive 0.37 M HCl solutions on the Au surface roughness and dissolution is investigated by varying the number of pre‐treatment steps at 1.16 V against the reversible hydrogen electrode. It is shown that the first 10 s pre‐treatment of the as‐polished Au results in a higher surface roughness and thus higher electrochemically active surface area (ECSA) than that of the as‐polished Au. With the subsequent pre‐treatments, however, the ECSA is gradually decreasing reaching a steady value. The dissolution rate of the pre‐treated Au electrodes upon potential cycling in 0.1 M H2SO4 is determined by in situ inductively coupled plasma mass spectrometry. A non‐linear dependence of Au dissolution amount is found with respect to the number of pre‐treatments. The overall total Au dissolution rate follows a similar trend as ECSA/roughness. However, an important difference in the dissolution behavior is identified with respect to dissolution processes during Au oxidation (anodic dissolution) and Au reduction (cathodic dissolution): the former is more sensitive to the surface roughness. Thus, the ratio between Au anodic and cathodic dissolution amounts decreases substantially with decrease in surface roughness. This finding is explained by the slow and fast dissolution kinetics for anodic and cathodic processes, respectively. Current work further advances our understanding of the complex Au dissolution mechanism.
Abstract
Aim
Species ranges are highly dynamic, shifting in space and time as a result of complex ecological and evolutionary processes. Disentangling the relative contribution of both processes is challenging but of primary importance for forecasting species distributions under climate change. Here, we use the spectacular range expansion (ca. 1000 km poleward shift within 10 years) of the butterfly Pieris mannii to unravel the factors underlying range dynamics, specifically the role of (i) niche evolution (changes in host‐plant preference and acceptance) and (ii) ecological processes (climate change).
Location
Provence‐Alpes‐Côte d’Azur, France; North Rhine‐Westphalia, Rhineland‐Palatinate and Hesse, Germany.
Taxon
Insect and angiosperms.
Methods
We employed a combination of (i) common garden experiments, based on replicated populations from the species’ historical and newly established range and host‐plant species representative for each distribution range, co‐occurrence analyses and (ii) grid‐based correlative species distribution modelling (SDM) using Maxent.
Results
We observed changes in oviposition preference, with females from the newly established populations showing reduced host‐plant specialization and also an overall increased fecundity. These changes in behaviour and life history may have enabled using a broader range of habitats and thus facilitated the recent range expansion. In contrast, our results indicate that the range expansion is unlikely to be directly caused by anthropogenic climate change, as the range was not constrained by climate in the first place.
Main conclusions
We conclude that evolution of a broader dietary niche rather than climate change is associated with the rapid range expansion, and discuss potential indirect consequences of climate change as trigger for the genetic differences found. Our study thus illustrates the importance of species interactions in shaping species distributions and range shifts, and draws attention to indirect effects of climate change. Embracing this complexity is likely the key to a better understanding of range dynamics.
Abstract
Nervous system development has been intensely studied in insects (especially Drosophila melanogaster), providing detailed insights into the genetic regulatory network governing the formation and maintenance of the neural stem cells (neuroblasts) and the differentiation of their progeny. Despite notable advances over the last two decades, neurogenesis in other arthropod groups remains by comparison less well understood, hampering finer resolution of evolutionary cell type transformations and changes in the genetic regulatory network in some branches of the arthropod tree of life. Although the neurogenic cellular machinery in malacostracan crustaceans is well described morphologically, its genetic molecular characterization is pending. To address this, we established an in situ hybridization protocol for the crayfish Procambarus virginalis and studied embryonic expression patterns of a suite of key genes, encompassing three SoxB group transcription factors, two achaete–scute homologs, a Snail family member, the differentiation determinants Prospero and Brain tumor, and the neuron marker Elav. We document cell type expression patterns with notable similarities to insects and branchiopod crustaceans, lending further support to the homology of hexapod–crustacean neuroblasts and their cell lineages. Remarkably, in the crayfish head region, cell emigration from the neuroectoderm coupled with gene expression data points to a neuroblast‐independent initial phase of brain neurogenesis. Further, SoxB group expression patterns suggest an involvement of Dichaete in segmentation, in concordance with insects. Our target gene set is a promising starting point for further embryonic studies, as well as for the molecular genetic characterization of subregions and cell types in the neurogenic systems in the adult crayfish brain.
Abstract
Background
The need to optimize exposure treatments for anxiety disorders may be addressed by temporally intensified exposure sessions. Effects on symptom reduction and public health benefits should be examined across different anxiety disorders with comorbid conditions.
Methods
This multicenter randomized controlled trial compared two variants of prediction error‐based exposure therapy (PeEx) in various anxiety disorders (both 12 sessions + 2 booster sessions, 100 min/session): temporally intensified exposure (PeEx‐I) with exposure sessions condensed to 2 weeks (n = 358) and standard nonintensified exposure (PeEx‐S) with weekly exposure sessions (n = 368). Primary outcomes were anxiety symptoms (pre, post, and 6‐months follow‐up). Secondary outcomes were global severity (across sessions), quality of life, disability days, and comorbid depression.
Results
Both treatments resulted in substantial improvements at post (PeEx‐I: dwithin = 1.50, PeEx‐S: dwithin = 1.78) and follow‐up (PeEx‐I: dwithin = 2.34; PeEx‐S: dwithin = 2.03). Both groups showed formally equivalent symptom reduction at post and follow‐up. However, time until response during treatment was 32% shorter in PeEx‐I (median = 68 days) than PeEx‐S (108 days; TRPeEx‐I = 0.68). Interestingly, drop‐out rates were lower during intensified exposure. PeEx‐I was also superior in reducing disability days and improving quality of life at follow‐up without increasing relapse.
Conclusions
Both treatment variants focusing on the transdiagnostic exposure‐based violation of threat beliefs were effective in reducing symptom severity and disability in severe anxiety disorders. Temporally intensified exposure resulted in faster treatment response with substantial public health benefits and lower drop‐out during the exposure phase, without higher relapse. Clinicians can expect better or at least comparable outcomes when delivering exposure in a temporally intensified manner.
Abstract
G‐quadruplexes have attracted growing interest in recent years due to their occurrence in vivo and their possible biological functions. In addition to being promising targets for drug design, these four‐stranded nucleic acid structures have also been recognized as versatile tools for various technological applications. Whereas a large number of studies have yielded insight into their remarkable structural diversity, our current knowledge on G‐quadruplex stabilities as a function of sequence and environmental factors only gradually emerges with an expanding collection of thermodynamic data. This minireview provides an overview of general rules that may be used to better evaluate quadruplex thermodynamic stabilities but also discusses present challenges in predicting most stable folds for a given sequence and environment.
Abstract
Neutrophils are the most abundant leukocytes in circulation playing a key role in acute inflammation during microbial infections. Phagocytosis, one of the crucial defence mechanisms of neutrophils against pathogens, is amplified by chemotactic leukotriene (LT)B4, which is biosynthesized via 5‐lipoxygenase (5‐LOX). However, extensive liberation of LTB4 can be destructive by over‐intensifying the inflammatory process. While enzymatic biosynthesis of LTB4 is well characterized, less is known about molecular mechanisms that activate 5‐LOX and lead to LTB4 formation during host–pathogen interactions. Here, we investigated the ability of the common opportunistic fungal pathogen Candida albicans to induce LTB4 formation in neutrophils, and elucidated pathogen‐mediated drivers and cellular processes that activate this pathway. We revealed that C. albicans‐induced LTB4 biosynthesis requires both the morphological transition from yeast cells to hyphae and the expression of hyphae‐associated genes, as exclusively viable hyphae or yeast‐locked mutant cells expressing hyphae‐associated genes stimulated 5‐LOX by [Ca2+]i mobilization and p38 MAPK activation. LTB4 biosynthesis was orchestrated by synergistic activation of dectin‐1 and Toll‐like receptor 2, and corresponding signaling via SYK and MYD88, respectively. Conclusively, we report hyphae‐specific induction of LTB4 biosynthesis in human neutrophils. This highlights an expanding role of neutrophils during inflammatory processes in the response to C. albicans infections.
Abstract
Background
Twenty five‐hydroxy vitamin D (25OHD) levels have been proposed to protect against periodontitis based on in vitro and observational studies but evidence from long‐term randomized controlled trials (RCTs) is lacking. This study tested whether genetically proxied 25OHD is associated with periodontitis using Mendelian randomization (MR).
Methods
Genetic variants strongly associated with 25OHD in a genome‐wide association study (GWAS) of 417,580 participants of European ancestry were used as instrumental variables, and linked to GWAS summary data of 17,353 periodontitis cases and 28,210 controls. In addition to the main analysis using an inverse variance weighted (IVW) model, we applied additional robust methods to control for pleiotropy. We also undertook sensitivity analyses excluding single nucleotide polymorphisms (SNPs) used as instruments with potential pleiotropic effects and used a second 25OHD GWAS for replication. We identified 288 SNPs to be genome‐wide significant for 25OHD, explaining 7.0% of the variance of 25OHD levels and providing ≥90% power to detect an odds ratio (OR) of ≤ 0.97.
Results
MR analysis suggested that a 1 standard deviation increase in natural log‐transformed 25OHD was not associated with periodontitis risk (IVW OR = 1.04; 95% confidence interval (CI): 0.97–1.12; P‐value = 0.297). The robust models, replication, and sensitivity analyses were coherent with the primary analysis.
Conclusions
Collectively, our findings suggest that 25OHD levels are unlikely to have a substantial effect on the risk of periodontitis, but large long‐term RCTs are needed to derive definitive evidence on the causal role of 25OHD in periodontitis.
Objective
To evaluate the efficacy of tooth splinting (TS) and occlusal adjustment (OA) compared to no TS or OA in patients with periodontitis exhibiting masticatory dysfunction.
Material
The primary outcome criterion was tooth loss (TL), and the secondary outcome parameters were change in probing pocket depth (PPD), change in clinical attachment level (CAL), tooth mobility (TM), and patient‐reported outcome measures (PROMs). Literature search was performed on three electronic databases (from 01/1965 to 04/2021) and focused on clinical studies with at least 12 months follow‐up.
Results
From a total of 1515 publications, 51 articles were identified for full‐text reading, of which 2 retrospective case series on TS with low risk of bias and 1 randomized and 2 prospective studies on OA with unclear risk of bias were included. For TS, synthesis of data showed that in 72 patients, 26 out of 311 teeth (weighted mean incidence of TL 8.4%) and 156 out of 1541 teeth with no TS (weighted mean incidence of TL 10.1%) were lost over 2 years following non‐surgical periodontal therapy. The randomized controlled clinical trial (RCT) indicated CAL gain for teeth with OA compared to no OA. For the effect of OA on TL, PPD, and TM, heterogeneous data were retrieved from the included studies.
Conclusions
Within the limitations of this review and based on a low level of evidence, it is concluded that TS does not improve survival of mobile teeth in patients with advanced periodontitis. OA on teeth with mobility and/or premature contacts may lead to improved CAL, while the effect of OA on the remaining periodontal parameters remains unclear.
Abstract
We investigated four subaerial (paleo)lacustrine landforms at the north‐eastern shoreline of Schweriner See, north‐eastern Germany. These included two beach ridges, one subaerial nearshore bar and a silting up sequence located close to a fossil cliff, which marks the former maximum extent of Schweriner See. We used luminescence profiling with a SUERC portable OSL device (POSL) on all four sediment sequences in combination with sedimentological investigations such as grain size, loss‐on‐ignition and magnetic susceptibility to provide information on the various formations in a lacustrine depositional environment. The POSL reader was used on pre‐treated polymineral samples to gain an insight into luminescence distribution within the individual sediment sequences, but also among the four sequences. POSL proved valuable to understand depositional processes, which were not visible in lithology or sedimentological parameters. With somewhat larger uncertainty this method provides relative chronologies of the sediment sequences. Additionally, we carried out radiocarbon dating and full optical stimulated luminescence (OSL) dating to establish a chronological framework. OSL ages proved to be more reliable to date beach ridges in this setting than radiocarbon samples, which were severely influenced by sediment reworking. This combined approach of sedimentological analyses, luminescence profiling and absolute age determinations revealed details in depositional processes at Schweriner See which otherwise would have remained undetected. Furthermore, it helped to set these subaerial (paleo)lacustrine landforms in a chronological framework.
Currently, poleward range expansions are observed in many taxa, often in response to anthropogenic climate change. At the expanding front, populations likely face cooler and more variable temperature conditions, imposing thermal selection. This may result in changes in trait means or plasticity, the relative contribution of which is not well understood. We, here, investigate evolutionary change in range‐expanding populations of the butterfly Pieris mannii, by comparing populations from the core and the newly established northern range under laboratory conditions. We observed both changes in trait means and in thermal reaction norms. Range‐expanding populations showed a more rapid development, potentially indicative of counter‐gradient variation and an increased cold tolerance compared with core populations. Genotype‐environment interactions prevailed in all associated traits, such that the above differences were restricted to cooler environmental conditions. In range‐expanding populations, plasticity was decreased in developmental traits enabling relatively rapid growth even under cooler conditions but increased in cold tolerance arguably promoting higher activity under thermally challenging conditions. Notably, these changes must have occurred within a time period of ca. 10 years only. Our results suggest, in line with contemporary theory, that the evolution of plasticity may play a hitherto underestimated role for adaptation to climatic variation. However, rather than generally increased or decreased levels of plasticity, our results indicate fine‐tuned, trait‐specific evolutionary responses to increase fitness in novel environments.
Objective
To evaluate individual and group long-term efficacy and safety of erenumab in individuals with episodic migraine (EM) for whom 2–4 prior preventatives had failed.
Methods
Participants completing the 12-week double-blind treatment phase (DBTP) of the LIBERTY study could continue into an open-label extension phase (OLEP) receiving erenumab 140 mg monthly for up to 3 years. Main outcomes assessed at week 112 were: ≥50%, ≥75% and 100% reduction in monthly migraine days (MMD) as group responder rate and individual responder rates, MMD change from baseline, safety and tolerability.
Results
Overall 240/246 (97.6%) entered the OLEP (118 continuing erenumab, 122 switching from placebo). In total 181/240 (75.4%) reached 112 weeks, 24.6% discontinued, mainly due to lack of efficacy (44.0%), participant decision (37.0%) and adverse events (AEs; 12.0%). The ≥50% responder rate was 57.2% (99/173) at 112 weeks. Of ≥50% responders at the end of the DBTP, 36/52 (69.2%) remained responders at ≥50% and 22/52 (42.3%) at >80% of visits. Of the non-responders at the end of the DBTP, 60/185 (32.4%) converted to ≥50% responders in at least half the visits and 24/185 (13.0%) converted to ≥50% responders in >80% of visits. Change from baseline at 112 weeks in mean (SD) MMD was −4.2 (5.0) days. Common AEs (≥10%) were nasopharyngitis, influenza and back pain.
Conclusions
Efficacy was sustained over 112 weeks in individuals with difficult-to-treat EM for whom 2–4 prior migraine preventives had failed. Erenumab treatment was safe and well tolerated, in-line with previous studies.
Trial registration number NCT03096834
Abstract
Body weight loss is frequently regarded as negatively related to outcomes in patients with malignancies. This retrospective analysis of the FIRE‐3 study evaluated the evolution of body weight in patients with metastatic colorectal cancer (mCRC). FIRE‐3 evaluated first‐line FOLFIRI (folinic acid, fluorouracil and irinotecan) plus cetuximab or bevacizumab in mCRC patients with RAS‐WT tumors (ie, wild‐type in KRAS and NRAS exons 2‐4). The prognostic and predictive relevance of early weight loss (EWL) regarding patient outcomes and treatment side effects were evaluated. Retrospective data on body weight during first 6 months of treatment were evaluated (N = 326). To correlate with efficacy endpoints and treatment side effects, patients were grouped according to clinically significant EWL ≥5% and <5% at Month 3. Age constituted the only significant predictor of EWL following a linear relationship with the corresponding log odds ratio (P = .016). EWL was significantly associated with the incident frequencies of diarrhea, edema, fatigue, nausea and vomiting. Further, a multivariate analysis revealed EWL to be an independent negative prognostic factor for overall survival (32.4 vs 21.1 months; hazard ratio [HR]: 1.64; 95% confidence interval [CI] = 1.13‐2.38; P = .0098) and progression‐free survival (11.8 vs 9.0 months; HR: 1.72; 95% CI = 1.18‐2.5; P = .0048). In conclusion, EWL during systemic treatment against mCRC is significantly associated with patient age. Patients exhibiting EWL had worse survival and higher frequencies of adverse events. Early preventative measures targeted at weight maintenance should be evaluated, especially in elderly patients being at highest risk of EWL.
Rice husk, one of the main side products in the rice production, and its sustainable management represent a challenge in many countries. Herein, we describe the use of this abundant agricultural bio‐waste as feedstock for the preparation of silver‐containing carbon/silica nano composites with antimicrobial properties. The synthesis was performed using a fast and cheap methodology consisting of wet impregnation followed by pyrolysis, yielding C/SiO2 composite materials doped with varying amounts of silver from 28 to 0.001 wt %. The materials were fully characterized and their antimicrobial activity against ESKAPE pathogens, namely E. faecium, S. aureus, K. pneumoniae, A. baumannii, P. aeruginosa, and E. coli, and the pathogenic yeast C. albicans was investigated. Sensitivities of these strains against the prepared materials were demonstrated, even with exceptional low amounts of 0.015 m% silver. Hence, we report a straightforward method for the synthesis of antimicrobial agents from abundant sources which addresses urgent questions like bio‐waste valorization and affordable alternatives to increasingly fewer effective antibiotics.
Bioinformatics Algorithms and Predictive Models: The Grand Challenge in Computational Virology
(2021)
Never in the past has the relevance of bioinformatic and predictive tools been more central
in the field of virology as today. SARS-CoV-2 has brought along a huge health burden, but also
a deeper awareness that scientific progress can no longer be effective without extensive systems
for data storage, sharing and analysis, as well as computational tools dedicated to molecular
epidemiology, NGS data analysis, prediction of drug targets, multi-OMIC data integration, and
many other applications.
Objectives: An inverse relationship between education and cardiovascular risk has been described, however, the combined association of education, income, and neighborhood socioeconomic status with macrovascular disease is less clear. The aim of this study was to evaluate the association of educational level, equivalent household income and area deprivation with macrovascular disease in Germany.
Methods: Cross-sectional data from two representative German population-based studies, SHIP-TREND (n = 3,731) and KORA-F4 (n = 2,870), were analyzed. Multivariable logistic regression models were applied to estimate odds ratios and 95% confidence intervals for the association between socioeconomic determinants and macrovascular disease (defined as self-reported myocardial infarction or stroke).
Results: The study showed a higher odds of prevalent macrovascular disease in men with low and middle educational level compared to men with high education. Area deprivation and equivalent income were not related to myocardial infarction or stroke in any of the models.
Conclusion: Educational level, but not income or area deprivation, is significantly related to the macrovascular disease in men. Effective prevention of macrovascular disease should therefore start with investing in individual education.
Although the nose, as a gateway for organism–environment interactions, may have a key role in asthmatic exacerbation, the rhinobiome of exacerbated children with asthma was widely neglected to date. The aim of this study is to understand the microbiome, the microbial immunology, and the proteome of exacerbated children and adolescents with wheeze and asthma. Considering that a certain proportion of wheezers may show a progression to asthma, the comparison of both groups provides important information regarding clinical and phenotype stratification. Thus, deep nasopharyngeal swab specimens, nasal epithelial spheroid (NAEsp) cultures, and blood samples of acute exacerbated wheezers (WH), asthmatics (AB), and healthy controls (HC) were used for culture (n = 146), 16 S-rRNA gene amplicon sequencing (n = 64), and proteomic and cytokine analyses. Interestingly, Proteobacteria were over-represented in WH, whereas Firmicutes and Bacteroidetes were associated with AB. In contrast, Actinobacteria commonly colonized HCs. Moreover, Staphylococcaceae, Enterobacteriaceae, Burkholderiaceae, Xanthobacteraceae, and Sphingomonadaceae were significantly more abundant in AB compared to WH and HC. The α-diversity analyses demonstrated an increase of bacterial abundance levels in atopic AB and a decrease in WH samples. Microbiome profiles of atopic WH differed significantly from atopic AB, whereby atopic samples of WH were more homogeneous than those of non-atopic subjects. The NAEsp bacterial exposure experiments provided a disrupted epithelial cell integrity, a cytokine release, and cohort-specific proteomic differences especially for Moraxella catarrhalis cultures. This comprehensive dataset contributes to a deeper insight into the poorly understood plasticity of the nasal microbiota, and, in particular, may enforce our understanding in the pathogenesis of asthma exacerbation in childhood.
Respiratory infection caused by Streptococcus pneumoniae is a leading cause of morbidity and mortality in older adults. Acquired CD4+ T cell mechanism are essential for the protection against colonization and subsequent development of infections by S. pneumoniae. In this study, we hypothesized that age-related changes within the CD4+ T-cell population compromise CD4+ T-cell specific responses to S. pneumoniae, thereby contributing to increased susceptibility at older age. To this end, we interrogated the CD4+ T-cell response against the immunogenic pneumococcal protein AliB, part of the unique oligopeptide ABC transporter system responsible for the uptake of nutrients for the bacterium and crucial for the development of pneumococcal meningitis, in healthy young and older adults. Specifically, proliferation of CD4+ T cells as well as concomitant cytokine profiles and phenotypic markers implied in immunosenescence were studied. Older adults showed decreased AliB-induced CD4+ T-cell proliferation that is associated with an increased frequency of regulatory T cells and lower levels of active CD25+CD127+CTLA-4−TIGIT-CD4+T cells. Additionally, levels of pro-inflammatory cytokines IFNy and IL-17F were decreased at older age. Our findings indicate that key features of a pneumococcal-specific CD4+ T-cell immune response are altered at older age, which may contribute to enhanced susceptibility for pneumococcal infections.
Food craving (FC) peaks are highly context-dependent and variable. Accurate prediction of FC might help preventing disadvantageous eating behavior. Here, we examine whether data from 2 weeks of ecological momentary assessment (EMA) questionnaires on stress and emotions (active EMA, aEMA) alongside temporal features and smartphone sensor data (passive EMA, pEMA) are able to predict FCs ~2.5 h into the future in N = 46 individuals. A logistic prediction approach with feature dimension reduction via Best Item Scale that is Cross-Validated, Weighted, Informative and Transparent (BISCWIT) was performed. While overall prediction accuracy was acceptable, passive sensing data alone was equally predictive to psychometric data. The frequency of which single predictors were considered for a model was rather balanced, indicating that aEMA and pEMA models were fully idiosyncratic.
Within the last decades cancer treatment improved by the availability of more specifically
acting drugs that address molecular target structures in cancer cells. However, those target-sensitive
drugs suffer from ongoing resistances resulting from mutations and moreover they are affected
by the cancer phenomenon of multidrug resistance. A multidrug resistant cancer can hardly be
treated with the common drugs, so that there have been long efforts to develop drugs to combat
that resistance. Transmembrane efflux pumps are the main cause of the multidrug resistance in
cancer. Early inhibitors disappointed in cancer treatment without a proof of expression of a respective
efflux pump. Recent studies in efflux pump expressing cancer show convincing effects of those
inhibitors. Based on the molecular symmetry of the efflux pump multidrug resistant protein (MRP) 4
we synthesized symmetric inhibitors with varied substitution patterns. They were evaluated in a
MRP4-overexpressing cancer cell line model to prove structure-dependent effects on the inhibition
of the efflux pump activity in an uptake assay of a fluorescent MRP4 substrate. The most active
compound was tested to resentisize the MRP4-overexpressing cell line towards a clinically relevant
anticancer drug as proof-of-principle to encourage for further preclinical studie
Contaminated surfaces have been discussed as a possible source of severe acute respiratory
syndrome coronavirus-2 (SARS-CoV-2). Under experimental conditions, SARS-CoV-2 can remain
infectious on surfaces for several days. However, the frequency of SARS-CoV-2 detection on surfaces
in healthcare settings and the public is currently not known. A systematic literature review was
performed. On surfaces around COVID-19 cases in healthcare settings (42 studies), the SARS-CoV2 RNA detection rates mostly were between 0% and 27% (Ct values mostly > 30). Detection of
infectious SARS-CoV-2 was only successful in one of seven studies in 9.2% of 76 samples. Most of the
positive samples were obtained next to a patient with frequent sputum spitting during sampling.
Eight studies were found with data from public surfaces and RNA detection rates between 0% and
22.1% (Ct values mostly > 30). Detection of infectious virus was not attempted. Similar results
were found in samples from surfaces around confirmed COVID-19 cases in non-healthcare settings
(7 studies) and from personal protective equipment (10 studies). Therefore, it seems plausible to
assume that inanimate surfaces are not a relevant source for transmission of SARS-CoV-2. In public
settings, the associated risks of regular surface disinfection probably outweigh the expectable health
benefit
With more than 25 million people affected, heart failure (HF) is a global threat. As energy
production pathways are known to play a pivotal role in HF, we sought here to identify key metabolic
changes in ischemic- and non-ischemic HF by using a multi-OMICS approach. Serum metabolites and
mRNAseq and epigenetic DNA methylation profiles were analyzed from blood and left ventricular
heart biopsy specimens of the same individuals. In total we collected serum from n = 82 patients
with Dilated Cardiomyopathy (DCM) and n = 51 controls in the screening stage. We identified
several metabolites involved in glycolysis and citric acid cycle to be elevated up to 5.7-fold in DCM
(p = 1.7 × 10−6
). Interestingly, cardiac mRNA and epigenetic changes of genes encoding rate-limiting
enzymes of these pathways could also be found and validated in our second stage of metabolite
assessment in n = 52 DCM, n = 39 ischemic HF and n = 57 controls. In conclusion, we identified a
new set of metabolomic biomarkers for HF. We were able to identify underlying biological cascades
that potentially represent suitable intervention targets.
Cold physical plasma is a partially ionized gas expelling many reactive oxygen and nitrogen
species (ROS/RNS). Several plasma devices have been licensed for medical use in dermatology, and
recent experimental studies suggest their putative role in cancer treatment. In cancer therapies with
an immunological dimension, successful antigen presentation and inflammation modulation is a
key hallmark to elicit antitumor immunity. Dendritic cells (DCs) are critical for this task. However,
the inflammatory consequences of DCs following plasma exposure are unknown. To this end,
human monocyte-derived DCs (moDCs) were expanded from isolated human primary monocytes;
exposed to plasma; and their metabolic activity, surface marker expression, and cytokine profiles
were analyzed. As controls, hydrogen peroxide, hypochlorous acid, and peroxynitrite were used.
Among all types of ROS/RNS-mediated treatments, plasma exposure exerted the most notable
increase of activation markers at 24 h such as CD25, CD40, and CD83 known to be crucial for T cell
costimulation. Moreover, the treatments increased interleukin (IL)-1α, IL-6, and IL-23. Altogether,
this study suggests plasma treatment augmenting costimulatory ligand and cytokine expression in
human moDCs, which might exert beneficial effects in the tumor microenvironment.
Unveiling the N-Terminal Homodimerization of BCL11B by Hybrid Solvent Replica-Exchange Simulations
(2021)
Transcription factors play a crucial role in regulating biological processes such as cell
growth, differentiation, organ development and cellular signaling. Within this group, proteins
equipped with zinc finger motifs (ZFs) represent the largest family of sequence-specific DNA-binding
transcription regulators. Numerous studies have proven the fundamental role of BCL11B for a
variety of tissues and organs such as central nervous system, T cells, skin, teeth, and mammary
glands. In a previous work we identified a novel atypical zinc finger domain (CCHC-ZF) which
serves as a dimerization interface of BCL11B. This domain and formation of the dimer were shown
to be critically important for efficient regulation of the BCL11B target genes and could therefore
represent a promising target for novel drug therapies. Here, we report the structural basis for
BCL11B–BCL11B interaction mediated by the N-terminal ZF domain. By combining structure
prediction algorithms, enhanced sampling molecular dynamics and fluorescence resonance energy
transfer (FRET) approaches, we identified amino acid residues indispensable for the formation of
the single ZF domain and directly involved in forming the dimer interface. These findings not only
provide deep insight into how BCL11B acquires its active structure but also represent an important
step towards rational design or selection of potential inhibitors.
COVID-19 Vaccinated Individuals Can Be a Source of SARS-CoV-2 Transmission—A Systematic Review
(2021)
Fundamental rights are probably given back earlier to COVID-19 vaccinated individuals
assuming that they cannot spread SARS-CoV-2 anymore. The objective of the study was to determine
if COVID-19 vaccinated individuals can still be the source of SARS-CoV-2 transmission. PubMed
was searched for studies on 4 April 2021. All studies with original data on COVID-19 cases among
vaccinated individuals (phase III RCTs) and on viral load in the upper respiratory tract of vaccinated
macaques after a SARS-CoV-2 challenge were included. Symptomatic COVID-19 cases were found
in four trials among vaccinated participants although less frequently than among control subjects.
One study revealed asymptomatic COVID-19 cases in a similar frequency among 2.168 AZD1222-
vaccinated subjects (1.0%) compared to 2.223 control subjects (1.0%). In 15 studies with vaccinated
macaques, it was found that the load of SARS-CoV-2 RNA, subgenomic RNA and infectious virus
in the upper respiratory tract is variable. Sterilizing immunity was found in none of the animal
studies. Major limitations of the animal studies are that the SARS-CoV-2 challenge took place within
a few weeks of the final or only vaccine dose, that the viral challenge was often high and, in some
studies, administered by up to four routes. Based on current knowledge it seems clear that COVID-19
vaccinated individuals can still be the source of SARS-CoV-2 transmission.
The innate immune system relies on families of pattern recognition receptors (PRRs)
that detect distinct conserved molecular motifs from microbes to initiate antimicrobial responses.
Activation of PRRs triggers a series of signaling cascades, leading to the release of pro-inflammatory
cytokines, chemokines and antimicrobials, thereby contributing to the early host defense against
microbes and regulating adaptive immunity. Additionally, PRRs can detect perturbation of cellular
homeostasis caused by pathogens and fine-tune the immune responses. Among PRRs, nucleotide
binding oligomerization domain (NOD)-like receptors (NLRs) have attracted particular interest in the
context of cellular stress-induced inflammation during infection. Recently, mechanistic insights into
the monitoring of cellular homeostasis perturbation by NLRs have been provided. We summarize
the current knowledge about the disruption of cellular homeostasis by pathogens and focus on NLRs
as innate immune sensors for its detection. We highlight the mechanisms employed by various
pathogens to elicit cytoskeleton disruption, organelle stress as well as protein translation block, point
out exemplary NLRs that guard cellular homeostasis during infection and introduce the concept of
stress-associated molecular patterns (SAMPs). We postulate that integration of information about
microbial patterns, danger signals, and SAMPs enables the innate immune system with adequate
plasticity and precision in elaborating responses to microbes of variable virulence.
The thyroid gland is both a thyroid hormone (TH) generating as well as a TH responsive
organ. It is hence crucial that cathepsin-mediated proteolytic cleavage of the precursor thyroglobulin
is regulated and integrated with the subsequent export of TH into the blood circulation, which is
enabled by TH transporters such as monocarboxylate transporters Mct8 and Mct10. Previously, we
showed that cathepsin K-deficient mice exhibit the phenomenon of functional compensation through
cathepsin L upregulation, which is independent of the canonical hypothalamus-pituitary-thyroid axis,
thus, due to auto-regulation. Since these animals also feature enhanced Mct8 expression, we aimed
to understand if TH transporters are part of the thyroid auto-regulatory mechanisms. Therefore,
we analyzed phenotypic differences in thyroid function arising from combined cathepsin K and
TH transporter deficiencies, i.e., in Ctsk-/-/Mct10-/-
, Ctsk-/-/Mct8-/y, and Ctsk-/-/Mct8-/y/Mct10-/-
.
Despite the impaired TH export, thyroglobulin degradation was enhanced in the mice lacking Mct8,
particularly in the triple-deficient genotype, due to increased cathepsin amounts and enhanced cysteine peptidase activities, leading to ongoing thyroglobulin proteolysis for TH liberation, eventually
causing self-thyrotoxic thyroid states. The increased cathepsin amounts were a consequence of
autophagy-mediated lysosomal biogenesis that is possibly triggered due to the stress accompanying
intrathyroidal TH accumulation, in particular in the Ctsk-/-/Mct8-/y/Mct10-/- animals. Collectively,
our data points to the notion that the absence of cathepsin K and Mct8 leads to excessive thyroglobulin
degradation and TH liberation in a non-classical pathway of thyroid auto-regulation.
: Platelets are components of the blood that are highly reactive, and they quickly respond
to multiple physiological and pathophysiological processes. In the last decade, it became clear that
platelets are the key components of circulation, linking hemostasis, innate, and acquired immunity.
Protein composition, localization, and activity are crucial for platelet function and regulation. The
current state of mass spectrometry-based proteomics has tremendous potential to identify and quantify thousands of proteins from a minimal amount of material, unravel multiple post-translational
modifications, and monitor platelet activity during drug treatments. This review focuses on the role
of proteomics in understanding the molecular basics of the classical and newly emerging functions
of platelets. including the recently described role of platelets in immunology and the development
of COVID-19.The state-of-the-art proteomic technologies and their application in studying platelet
biogenesis, signaling, and storage are described, and the potential of newly appeared trapped ion
mobility spectrometry (TIMS) is highlighted. Additionally, implementing proteomic methods in
platelet transfusion medicine, and as a diagnostic and prognostic tool, is discussed.
Harmonization of Biobank Education for Biobank Technicians: Identification of Learning Objectives
(2021)
: The quality of biospecimens stored in a biobank depends tremendously on the technical
personnel responsible for processing, storage, and release of biospecimens. Adequate training of
these biobank employees would allow harmonization of correct sample handling and thus ensure a
high and comparable quality of samples across biobank locations. However, in Germany there are no
specific training opportunities for technical biobank staff. To understand the educational needs of
the technical personnel a web-based survey was sent to all national biobanks via established e-mail
registers. In total, 79 biobank employees completed the survey, including 43 technicians. The majority
of the participating technical personnel stated that they had worked in a biobank for less than three
years and had never participated in an advanced training. Three-quarters of the technicians indicated
that they were not able to understand English content instantly. Based on these results and the results
of a workshop with 16 biobank technicians, 41 learning objectives were formulated. These learning
objectives can be used as a basis for advanced training programs for technical personnel in biobanks.
Setting up courses based on the identified learning objectives for this group of biobank staff could
contribute to harmonization and sustainability of biospecimen quality.
Myocardial infarction is a leading cause for morbidity and mortality worldwide. The only
viable treatment for the ischemic insult is timely reperfusion, which further exacerbates myocardial
injury. Maintaining mitochondrial function is crucial in preserving cardiomyocyte function in
ischemia reperfusion (IR) injury. Poloxamer (P) 188 has been shown to improve cardiac IR injury
by improving cellular and mitochondrial function. The aim of this study was to show if P188
postconditioning has direct protective effects on mitochondrial function in the heart. Langendorff
prepared rat hearts were subjected to IR injury ex-vivo and reperfused for 10 min with 1 mM P188
vs. vehicle. Cardiac mitochondria were isolated with 1 mM P188 vs. 1 mM polyethylene glycol
(PEG) vs. vehicle by differential centrifugation. Mitochondrial function was assessed by adenosine
triphosphate synthesis, oxygen consumption, and calcium retention capacity. Mitochondrial function
decreased significantly after ischemia and showed mild improvement with reperfusion. P188 did
not improve mitochondrial function in the ex-vivo heart, and neither further P188 nor PEG induced
direct mitochondrial protection after IR injury in this model.
Background: Klebsiella pneumoniae causes severe diseases including sepsis, pneumonia
and wound infections and is differentiated into hypervirulent (hvKp) and classic (cKp) pathotypes.
hvKp isolates are characterized clinically by invasive and multiple site infection and phenotypically
in particular through hypermucoviscosity and increased siderophore production, enabled by the
presence of the respective virulence genes, which are partly carried on plasmids. Methods: Here, we
analyzed two K. pneumoniae isolates of a human patient that caused severe multiple site infection.
By applying both genomic and phenotypic experiments and combining basic science with clinical
approaches, we aimed at characterizing the clinical background as well as the two isolates in-depth.
This also included bioinformatics analysis of a chromosomal virulence plasmid integration event.
Results: Our genomic analysis revealed that the two isolates were clonal and belonged to sequence
type 420, which is not only the first description of this K. pneumoniae subtype in Germany but also
suggests belonging to the hvKp pathotype. The latter was supported by the clinical appearance and
our phenotypic findings revealing increased siderophore production and hypermucoviscosity similar
to an archetypical, hypervirulent K. pneumoniae strain. In addition, our in-depth bioinformatics
analysis suggested the insertion of a hypervirulence plasmid in the bacterial chromosome, mediated
by a new IS5 family sub-group IS903 insertion sequence designated ISKpn74. Conclusion: Our study
contributes not only to the understanding of hvKp and the association between hypervirulence and
clinical outcomes but reveals the chromosomal integration of a virulence plasmid, which might lead
to tremendous public health implications.
Reactive oxygen species (ROS) have been subject of increasing interest in the pathophysiology and therapy of cancers in recent years. In skin cancer, ROS are involved in UV-induced tumorigenesis and its targeted treatment via, e.g., photodynamic therapy. Another recent technology for topical ROS generation is cold physical plasma, a partially ionized gas expelling dozens of reactive species onto its treatment target. Gas plasma technology is accredited for its wound-healing abilities in Europe, and current clinical evidence suggests that it may have beneficial effects against actinic keratosis. Since the concept of hormesis dictates that low ROS levels perform signaling functions, while high ROS levels cause damage, we investigated herein the antitumor activity of gas plasma in non-melanoma skin cancer. In vitro, gas plasma exposure diminished the metabolic activity, preferentially in squamous cell carcinoma cell (SCC) lines compared to non-malignant HaCaT cells. In patient-derived basal cell carcinoma (BCC) and SCC samples treated with gas plasma ex vivo, increased apoptosis was found in both cancer types. Moreover, the immunomodulatory actions of gas plasma treatment were found affecting, e.g., the expression of CD86 and the number of regulatory T-cells. The supernatants of these ex vivo cultured tumors were quantitatively screened for cytokines, chemokines, and growth factors, identifying CCL5 and GM-CSF, molecules associated with skin cancer metastasis, to be markedly decreased. These findings suggest gas plasma treatment to be an interesting future technology for non-melanoma skin cancer topical therapy.
The early-life microbiome (ELM) interacts with the psychosocial environment, in particular during early-life adversity (ELA), defining life-long health trajectories. The ELM also plays a significant role in the maturation of the immune system. We hypothesised that, in this context, the resilience of the oral microbiomes, despite being composed of diverse and distinct communities, allows them to retain an imprint of the early environment. Using 16S amplicon sequencing on the EpiPath cohort, we demonstrate that ELA leaves an imprint on both the salivary and buccal oral microbiome 24 years after exposure to adversity. Furthermore, the changes in both communities were associated with increased activation, maturation, and senescence of both innate and adaptive immune cells, although the interaction was partly dependent on prior herpesviridae exposure and current smoking. Our data suggest the presence of multiple links between ELA, Immunosenescence, and cytotoxicity that occur through long-term changes in the microbiome.
Neutrophils in Tuberculosis: Cell Biology, Cellular Networking and Multitasking in Host Defense
(2021)
Neutrophils readily infiltrate infection foci, phagocytose and usually destroy microbes. In
tuberculosis (TB), a chronic pulmonary infection caused by Mycobacterium tuberculosis (Mtb),
neutrophils harbor bacilli, are abundant in tissue lesions, and their abundances in blood correlate
with poor disease outcomes in patients. The biology of these innate immune cells in TB is complex.
Neutrophils have been assigned host-beneficial as well as deleterious roles. The short lifespan of
neutrophils purified from blood poses challenges to cell biology studies, leaving intracellular
biological processes and the precise consequences of Mtb–neutrophil interactions ill-defined. The
phenotypic heterogeneity of neutrophils, and their propensity to engage in cellular cross-talk and
to exert various functions during homeostasis and disease, have recently been reported, and such
observations are newly emerging in TB. Here, we review the interactions of neutrophils with Mtb,
including subcellular events and cell fate upon infection, and summarize the cross-talks between
neutrophils and lung-residing and -recruited cells. We highlight the roles of neutrophils in TB
pathophysiology, discussing recent findings from distinct models of pulmonary TB, and emphasize
technical advances that could facilitate the discovery of novel neutrophil-related disease
mechanisms and enrich our knowledge of TB pathogenesis
: Background: High-impact trauma frequently leads to injuries of the orbit, but literature
focusing on the viscerocranium rather than the neurocranium is underrepresented. Methods: Retrospective cohort study (2006–2014) at an urban level 1 trauma center assessing the frequency and
typical patterns of orbital injuries on whole-body computed tomography (WBCT) with maxillofacial
multi-slice CT (MSCT) after severe trauma. (1) Screening of consecutive WBCT cases for dedicated
maxillofacial MSCT. (2) Examination by two independent experts’ radiologists for (peri-/)orbital
injuries. (3) Case review for trauma mechanisms. Results: 1061 WBCT were included revealing 250
(23.6%) patients with orbital injuries. Less than one-quarter (23.3%) of patients showed osseous
and 9.5% showed soft tissue injuries. Combined osseous and soft tissue lesions were present in
39.2% of orbital injuries, isolated soft tissue injuries were rare. Single- or two-wall fractures of the
orbit were prevalent, and the orbital floor was affected in 67% of fractures. Dislocated extraocular
muscles (44.6%), deformation of the ocular globe (23.8%), and elongation of the optic nerve (12.9%)
were the most frequently soft tissue findings. Vascular trauma was suspected in 15.8% of patients.
Conclusions: Orbital trauma was confirmed in 23.6% of cases with suspected facial injuries after severe
trauma. Concomitant soft tissue injuries should be excluded explicitly in cases with orbital fractures
to prevent loss of vision or ocular motility.
Background: Gram-negative infections of the peritoneal cavity result in profound modifications of peritoneal B cell populations and induce the migration of peritoneal B cells to distant
secondary lymphoid organs. However, mechanisms controlling the egress of peritoneal B cells from
the peritoneal cavity and their subsequent trafficking remain incompletely understood. Sphingosine1-phosphate (S1P)-mediated signaling controls migratory processes in numerous immune cells. The
present work investigates the role of S1P-mediated signaling in peritoneal B cell trafficking under
inflammatory conditions. Methods: Differential S1P receptor expression after peritoneal B cell activation was assessed semi-quantitatively using RT-PCR in vitro. The functional implications of
differential S1P1 and S1P4 expression were assessed by transwell migration in vitro, by adoptive
peritoneal B cell transfer in a model of sterile lipopolysaccharide (LPS)-induced peritonitis and in
the polymicrobial colon ascendens stent peritonitis (CASP) model. Results: The two sphingosine-1-
phosphate receptors (S1PRs) expressed in peritoneal B cell subsets S1P1 and S1P4 are differentially
regulated upon stimulation with the TLR4 agonist LPS, but not upon PMA/ionomycin or B cell receptor (BCR) crosslinking. S1P4 deficiency affects both the trafficking of activated peritoneal B cells
to secondary lymphoid organs and the positioning of these cells within the functional compartments of the targeted organ. S1P4 deficiency in LPS-activated peritoneal B cells results in significantly reduced numbers of splenic innate response activator B cells. Conclusions: The S1P-S1PR system is implicated in the trafficking of LPS-activated peritoneal B cells. Given the protective role of peritoneal B1a B cells in peritoneal sepsis, further experiments to investigate the impact of S1P4 mediated signaling on the severity and mortality of peritoneal sepsis are warranted.
Fibroblasts contribute to approximately 20% of the non-cardiomyocytic cells in the heart. They play important roles in the myocardial adaption to stretch, inflammation, and other pathophysiological conditions. Fibroblasts are a major source of extracellular matrix (ECM) proteins whose production is regulated by cytokines, such as TNF-α or TGF-β. The resulting myocardial fibrosis is a hallmark of pathological remodeling in dilated cardiomyopathy (DCM). Therefore, in the present study, the secretome and corresponding transcriptome of human cardiac fibroblasts from patients with DCM was investigated under normal conditions and after TNF-α or TGF-β stimulation. Secreted proteins were quantified via mass spectrometry and expression of genes coding for secreted proteins was analyzed via Affymetrix Transcriptome Profiling. Thus, we provide comprehensive proteome and transcriptome data on the human cardiac fibroblast’s secretome. In the secretome of quiescent fibroblasts, 58% of the protein amount belonged to the ECM fraction. Interestingly, cytokines were responsible for 5% of the total protein amount in the secretome and up to 10% in the corresponding transcriptome. Furthermore, cytokine gene expression and secretion were upregulated upon TNF-α stimulation, while collagen secretion levels were elevated after TGF-β treatment. These results suggest that myocardial fibroblasts contribute to pro-fibrotic and to inflammatory processes in response to extracellular stimuli.
Sal (Shorea robusta) forests, a dominant forest type in Nepal, experience different disturbance intensities depending on management regimes. This study compares the impact of disturbance on Nepalese Sal forests, which are managed on three major management regimes: protected area, state-managed forest, and buffer zone community forest. Using a systematic sampling approach, we sampled 20 plots, each covering 500 square meters, and nested plots within each main plot to measure pole and regeneration for each management regime. We recorded forest characteristics including tree species, counts, diameter, height, crown cover, and disturbance indicators. We compared forest attributes such as diversity indices, species richness, and stand structure by management regime using analysis of variance and regression analysis. The forest management regimes were classified into three disturbance levels based on disturbance factor bundles, and the buffer zone community forest was found to have the highest disturbance while the protected forest had the lowest disturbance. Species richness, diversity, evenness, abundance, density and basal area were higher, but regeneration was lower in protected area and state-managed forest compared to the buffer zone community forests. This suggests positive impacts of moderate disturbance on regeneration. The management plan should prioritize the minimization of excessive disturbance to balance forest conservation and provide forest resources to local users.
Endothelial dysfunction (ED) comes with age, even without overt vessel damage such as that which occurs in atherosclerosis and diabetic vasculopathy. We hypothesized that aging would affect the downstream signalling of the endothelial nitric oxide (NO) system in the vascular smooth muscle (VSM). With this in mind, resistance mesenteric arteries were isolated from 13-week (juvenile) and 40-week-old (aged) mice and tested under isometric conditions using wire myography. Acetylcholine (ACh)-induced relaxation was reduced in aged as compared to juvenile vessels. Pretreatment with L-NAME, which inhibits nitrix oxide synthases (NOS), decreased ACh-mediated vasorelaxation, whereby differences in vasorelaxation between groups disappeared. Endothelium-independent vasorelaxation by the NO donor sodium nitroprusside (SNP) was similar in both groups; however, SNP bolus application (10−6 mol L−1) as well as soluble guanylyl cyclase (sGC) activation by runcaciguat (10−6 mol L−1) caused faster responses in juvenile vessels. This was accompanied by higher cGMP concentrations and a stronger response to the PDE5 inhibitor sildenafil in juvenile vessels. Mesenteric arteries and aortas did not reveal apparent histological differences between groups (van Gieson staining). The mRNA expression of the α1 and α2 subunits of sGC was lower in aged animals, as was PDE5 mRNA expression. In conclusion, vasorelaxation is compromised at an early age in mice even in the absence of histopathological alterations. Vascular smooth muscle sGC is a key element in aged vessel dysfunction.
The therapeutic efficacy of a cardiovascular device after implantation is highly dependent on the host-initiated complement and coagulation cascade. Both can eventually trigger thrombosis and inflammation. Therefore, understanding these initial responses of the body is of great importance for newly developed biomaterials. Subtle modulation of the associated biological processes could optimize clinical outcomes. However, our failure to produce truly blood compatible materials may reflect our inability to properly understand the mechanisms of thrombosis and inflammation associated with biomaterials. In vitro models mimicking these processes provide valuable insights into the mechanisms of biomaterial-induced complement activation and coagulation. Here, we review (i) the influence of biomaterials on complement and coagulation cascades, (ii) the significance of complement-coagulation interactions for the clinical success of cardiovascular implants, (iii) the modulation of complement activation by surface modifications, and (iv) in vitro testing strategies.
EGFR is overexpressed in the majority of clear cell renal cell carcinomas (CCRCCs). Although EGFR deregulation was found to be of great significance in CCRCC biology, the EGFR
overexpression is not associated with EGFR-targeted therapy responsiveness. Moreover, the prognostic role of EGFR expression remains controversial. In the present study, we evaluated the role
played by EGFR overexpression in CCRCC and its prognostic significance associated with different
immunohistochemical localization patterns. In our study, the Total Score (TS) related to membranouscytoplasmic EGFR expression showed a significant correlation with grade, pathologic stage (pT),
and Stage, Size, Grade, and Necrosis (SSIGN) score, and a negative correlation with nuclear EGFR
expression. No significant correlations were shown between nuclear EGFR and clinic-pathological
features. Additionally, a correlation between SGLT1 expression levels and pT was described. Multivariate analysis identifies pT and SSIGN score as independent prognostic factors for CCRCC. A
significantly increased survival rate was found in the case of positive expression of nuclear EGFR
and SGLT1. Based on our findings, SGLT1 and nuclear EGFR overexpression defines a subgroup of
CCRCC patients with good prognosis. Membranous-cytoplasmic EGFR expression was shown to be
a poor prognostic factor and could define a CCRCC subgroup with poor prognosis that should be
responsive to anti-EGFR therapies
FAM159B is a so-called adaptor protein. These proteins are essential components in numerous cell signalling pathways. However, little is known regarding FAM159B expression in normal and neoplastic human tissues. The commercially available rabbit polyclonal anti-human FAM159B antibody HPA011778 was initially characterised for its specificity using Western blot analyses and immunocytochemistry and then applied to a large series of formalin-fixed, paraffin-embedded normal and neoplastic human tissue samples. Confirmation of FAM159B’s predicted size and antibody specificity was achieved in BON-1 cells, a neuroendocrine tumour cell line endogenously expressing FAM159B, using targeted siRNA. Immunocytochemical experiments additionally revealed cytoplasmic expression of the adaptor protein. Immunohistochemical staining detected FAM159B expression in neuronal and neuroendocrine tissues such as the cortex, the trigeminal ganglia, dorsal root and intestinal ganglia, the pancreatic islets and the neuroendocrine cells of the bronchopulmonary and gastrointestinal tract, but also in the syncytiotrophoblasts of the placenta. FAM159B was also expressed in many of the 28 tumour entities investigated, with high levels in medullary and anaplastic thyroid carcinomas, parathyroid adenomas, lung and ovarian carcinomas, lymphomas and neuroendocrine tumours of different origins. The antibody HPA011778 can act as a useful tool for basic research and identifying FAM159B expression in tissue samples.
Extracellular vesicles (EVs) are reminiscent of their cell of origin and thus represent a
valuable source of biomarkers. However, for EVs to be used as biomarkers in clinical practice, simple,
comparable, and reproducible analytical methods must be applied. Although progress is being
made in EV separation methods for human biofluids, the implementation of EV assays for clinical
diagnosis and common guidelines are still lacking. We conducted a comprehensive analysis of
established EV separation techniques from human serum and plasma, including ultracentrifugation
and size exclusion chromatography (SEC), followed by concentration using (a) ultracentrifugation,
(b) ultrafiltration, or (c) precipitation, and immunoaffinity isolation. We analyzed the size, number,
protein, and miRNA content of the obtained EVs and assessed the functional delivery of EV cargo.
Our results demonstrate that all methods led to an adequate yield of small EVs. While no significant
difference in miRNA content was observed for the different separation methods, ultracentrifugation
was best for subsequent flow cytometry analysis. Immunoaffinity isolation is not suitable for
subsequent protein analyses. SEC + ultracentrifugation showed the best functional delivery of
EV cargo. In summary, combining SEC with ultracentrifugation gives the highest yield of pure
and functional EVs and allows reliable analysis of both protein and miRNA contents. We propose
this combination as the preferred EV isolation method for biomarker studies from human serum
or plasma.
PIM1 Inhibition Affects Glioblastoma Stem Cell Behavior and Kills Glioblastoma Stem-like Cells
(2021)
Despite comprehensive therapy and extensive research, glioblastoma (GBM) still represents the most aggressive brain tumor in adults. Glioma stem cells (GSCs) are thought to play a major role in tumor progression and resistance of GBM cells to radiochemotherapy. The PIM1 kinase has become a focus in cancer research. We have previously demonstrated that PIM1 is involved in survival of GBM cells and in GBM growth in a mouse model. However, little is known about the importance of PIM1 in cancer stem cells. Here, we report on the role of PIM1 in GBM stem cell behavior and killing. PIM1 inhibition negatively regulates the protein expression of the stem cell markers CD133 and Nestin in GBM cells (LN-18, U-87 MG). In contrast, CD44 and the astrocytic differentiation marker GFAP were up-regulated. Furthermore, PIM1 expression was increased in neurospheres as a model of GBM stem-like cells. Treatment of neurospheres with PIM1 inhibitors (TCS PIM1-1, Quercetagetin, and LY294002) diminished the cell viability associated with reduced DNA synthesis rate, increased caspase 3 activity, decreased PCNA protein expression, and reduced neurosphere formation. Our results indicate that PIM1 affects the glioblastoma stem cell behavior, and its inhibition kills glioblastoma stem-like cells, pointing to PIM1 targeting as a potential anti-glioblastoma therapy.
Doxorubicin is a frequently used anticancer drug to treat many types of tumors, such as breast cancer or bronchial carcinoma. The clinical use of doxorubicin is limited by its poorly predictable cardiotoxicity, the reasons of which are so far not fully understood. The drug is a substrate of several efflux transporters such as P-gp or BCRP and was recently reported to be a substrate of cation uptake transporters. To evaluate the potential role of transporter proteins in the accumulation of doxorubicin at its site of action (e.g., mammary carcinoma cells) or adverse effects (e.g., heart muscle cells), we studied the expression of important uptake and efflux transporters in human breast cancer and cardiac tissue, and investigated the affinity of doxorubicin to the identified transporters. The cellular uptake studies on doxorubicin were performed with OATP1A2*1, OATP1A2*2, and OATP1A2*3-overexpressing HEK293 cells, as well as OCT1-, OCT2-, and OCT3- overexpressing MDCKII cells. To assess the contribution of transporters to the cytotoxic effect of doxorubicin, we determined the cell viability in the presence and absence of transporter inhibitors in different cell lines. Several transporters, including P-gp, BCRP, OCT1, OCT3, and OATP1A2 were expressed in human heart and/or breast cancer tissue. Doxorubicin could be identified as a substrate of OCT1, OCT2, OCT3, and OATP1A2. The cellular uptake into cells expressing genetic OATP1A2 variants was markedly reduced and correlated well with the increased cellular viability. Inhibition of OATP1A2 (naringin) and OCT transporters (1-methyl-4-phenylpyridinium) resulted in a significant decrease of doxorubicin-mediated cytotoxicity in cell lines expressing the respective transporters. Similarly, the excipient Cremophor EL significantly inhibited the OCT1-3- and OATP1A2-mediated cellular uptake and attenuated the cytotoxicity of doxorubicin. In conclusion, genetic and environmental-related variability in the expression and function of these transporters may contribute to the substantial variability seen in terms of doxorubicin efficacy and toxicity.
Background/Aims
Prematurely born infants undergo costly, stressful eye examinations to uncover the small fraction with retinopathy of prematurity (ROP) that needs treatment to prevent blindness. The aim was to develop a prediction tool (DIGIROP-Screen) with 100% sensitivity and high specificity to safely reduce screening of those infants not needing treatment. DIGIROP-Screen was compared with four other ROP models based on longitudinal weights.
Methods
Data, including infants born at 24–30 weeks of gestational age (GA), for DIGIROP-Screen development (DevGroup, N=6991) originate from the Swedish National Registry for ROP. Three international cohorts comprised the external validation groups (ValGroups, N=1241). Multivariable logistic regressions, over postnatal ages (PNAs) 6–14 weeks, were validated. Predictors were birth characteristics, status and age at first diagnosed ROP and essential interactions.
Results
ROP treatment was required in 287 (4.1%)/6991 infants in DevGroup and 49 (3.9%)/1241 in ValGroups. To allow 100% sensitivity in DevGroup, specificity at birth was 53.1% and cumulatively 60.5% at PNA 8 weeks. Applying the same cut-offs in ValGroups, specificities were similar (46.3% and 53.5%). One infant with severe malformations in ValGroups was incorrectly classified as not needing screening. For all other infants, at PNA 6–14 weeks, sensitivity was 100%. In other published models, sensitivity ranged from 88.5% to 100% and specificity ranged from 9.6% to 45.2%.
Conclusions
DIGIROP-Screen, a clinical decision support tool using readily available birth and ROP screening data for infants born GA 24–30 weeks, in the European and North American populations tested can safely identify infants not needing ROP screening. DIGIROP-Screen had equal or higher sensitivity and specificity compared with other models. DIGIROP-Screen should be tested in any new cohort for validation and if not validated it can be modified using the same statistical approaches applied to a specific clinical setting.
Introduction
Stroke is the leading neurological cause of adult long-term disability in Europe. Even though functional consequences directly related to neurological impairment are well studied, post-stroke trajectories of functional health according to the International Classification of Functioning, Disability and Health are poorly understood. Particularly, no study investigated the relationship between post-stroke trajectories of activities of daily living (ADL) and self-rated health (SRH). However, such knowledge is of major importance to identify patients at risk of unfavourable courses. This prospective observational study aims to investigate trajectories of ADL and SRH, and their modifying factors in the course of the first year after stroke.
Methods and analysis
The study will consecutively enrol 300 patients admitted to a tertiary care hospital with acute ischaemic stroke or transient ischaemic attack (TIA; Age, Blood Pressure, Clinical Features, Duration of symptoms, Diabetes score ≥3). Patient inclusion is planned from May 2021 to September 2022. All participants will complete an interview assessing ADL, SRH, mental health, views on ageing and resilience-related concepts. Participants will be interviewed face-to-face 1–5 days post-stroke/TIA in the hospital; and will be followed up after 6 weeks, 3 months, 6 months and 12 months via telephone. The 12-month follow-up will also include a neurological assessment. Primary endpoints are ADL operationalised by modified Rankin Scale scores and SRH. Secondary outcomes are further measures of ADL, functional health, physical activity, falls and fatigue. Views on ageing, social support, resilience-related concepts, affect, frailty, illness perceptions and loneliness will be examined as modifying factors. Analyses will investigate the bidirectional relationship between SRH and ADL using bivariate latent change score models.
Ethics and dissemination
The study has been approved by the institutional review board of the University Medicine Greifswald (Ref. BB 237/20). The results will be disseminated through scientific publications, conferences and media. Moreover, study results and potential implications will be discussed with patient representatives.
Trial registration number NCT04704635.
AbstractWe propose a new scattering mechanism of Rydberg excitons, i.e., those with high principal quantum numbers, namely scattering by coupled LO phonon-plasmon modes, which becomes possible due to small differences in energies of the states due to different quantum defects. Already in very low-density electron–hole plasmas these provide a substantial contribution to the excitonic linewidth. This effect should allow determining plasma densities by a simple line shape analysis. Whenever one expects that low-density electron–hole plasma is present the plasmon induced broadening is of high significance and must be taken into account in the interpretation.
Vaccine-induced immune thrombotic thrombocytopenia (VITT) and cerebral venous sinus thrombosis (CVST) have been recently described as rare complications following vaccination against SARS-CoV-2 with vector vaccines. We report a case of a young woman who presented with VITT and cerebral CVST 7 days following vaccination with ChAdOx1 nCov-19 (AstraZeneca). While the initial MRI was considered void of pathological findings, MRI 3 days later revealed extensive CVST of the transversal and sigmoidal sinus with intracerebral haemorrhage. Diagnostic tests including a platelet-factor-4-induced platelet activation assay confirmed the diagnosis of VITT. Treatment with intravenous immunoglobulins and argatroban resulted in a normalisation of platelet counts and remission of CVST.
AbstractThe performance of a positively biased external ring anode in combination with a hollow cathode (HC) discharge or a magnetron sputtering (MS) discharge, both with a Ti cathode and with Ar as working gas, is investigated. Plasma and floating potential increase as function of anode voltage. Energy-resolved mass spectrometry reveals that the kinetic energy of argon and titanium ions is enhanced by a positive anode voltage allowing for an effective energy control of plasma ions.
AbstractInfrared IR absorption spectra of melamine-formaldehyde (MF) microparticles confined in an rf plasma are studied at different plasma conditions. Several absorption peaks have been analysed in dependence of plasma power and their temporal evolution. For comparison, the IR absorption spectra of heated MF microparticles without plasma exposition are used to determine the general influence of the temperature on the IR spectra. Measuring the temperature of the particles inside the plasma shows that the temperature is not the only process changing the particles’ IR spectra. Chemical changes of the MF particles with increasing plasma power influence the absorption peak structure.
AbstractThe efficient operation of a tokamak is limited by several constraints, such as the transition to high confinement or the density limits occurring in both confinement regimes. These particular boundaries of operation are derived in terms of a combination of dimensionless parameters describing interchange-drift-Alfvén turbulence without any free adjustable parameter. The derived boundaries describe the operational space at the separatrix of the ASDEX Upgrade tokamak, which is presented in terms of an electron density and temperature existence diagram. The derived density limits are compared against Greenwald scaling. The power threshold and role of ion heat flux for the transition to high confinement are discussed.
Fast 3D particle reconstruction using a convolutional neural network: application to dusty plasmas
(2021)
AbstractWe present an algorithm to reconstruct the three-dimensional positions of particles in a dense cloud of particles in a dusty plasma using a convolutional neural network. The approach is found to be very fast and yields a relatively high accuracy. In this paper, we describe and examine the approach regarding the particle number and the reconstruction accuracy using synthetic data and experimental data. To show the applicability of the approach the 3D positions of particles in a dense dust cloud in a dusty plasma under weightlessness are reconstructed from stereoscopic camera images using the prescribed neural network.
AbstractAnalytical results for the dielectric function in RPA are derived for three-, two-, and one-dimensional semiconductors in the weakly-degenerate limit. Based on this limit, quantum corrections are derived. Further attention is devoted to systems with linear carrier dispersion and the resulting Dirac-cone physics.
Background and aim
To report the six-month safety analyses among patients enrolled in the “Physical Fitness Training in Subacute Stroke—PHYS-STROKE” trial and identify underlying risk factors associated with serious adverse events.
Methods
We performed a pre-specified safety analysis of a multicenter, randomized controlled, endpoint-blinded trial comprising 200 patients with moderate to severe subacute stroke (days 5–45 after stroke) that were randomly assigned (1:1) to receive either aerobic, bodyweight supported, treadmill-based training (n = 105), or relaxation sessions (n = 95, control group). Each intervention session lasted for 25 min, five times weekly for four weeks, in addition to standard rehabilitation therapy. Serious adverse events defined as cerebro- and cardiovascular events, readmission to hospital, and death were assessed during six months of follow-up. Incident rate ratios (IRR) were calculated, and Poisson regression analyses were conducted to identify risk factors for serious adverse events and to test the association with aerobic training.
Results
Six months after stroke, 50 serious adverse events occurred in the trial with a higher incidence rate (per 100 patient-months) in the training group compared to the relaxation group (6.31 vs. 3.22; IRR 1.70, 95% CI 0.96 to 3.12). The association of aerobic training with serious adverse events incidence rates were modified by diabetes mellitus (IRR for interaction: 7.10, 95% CI 1.56 to 51.24) and by atrial fibrillation (IRR for interaction: 4.37, 95% CI 0.97 to 31.81).
Conclusions
Safety analysis of the PHYS-STROKE trial found a higher rate of serious adverse events in patients randomized to aerobic training compared to control within six months after stroke. Exploratory analyses found an association between serious adverse events occurrence in the aerobic training group with pre-existing diabetes mellitus and atrial fibrillation which should be further investigated in future trials.
Data access statement
The raw data and analyses scripts are provided by the authors on a secure online repository for reproduction of reported findings.
Sturgeons are among the most ancient linages of actinopterygians. At present, many sturgeon species are critically endangered. Surrogate production could be used as an affordable and a time-efficient method for endangered sturgeons. Our study established a method for identifying and isolating type A spermatogonia from different developmental stages of testes using flow cytometric cell sorting (FCM). Flow cytometric analysis of a whole testicular cell suspension showed several well-distinguished cell populations formed according to different values of light scatter parameters. FCM of these different cell populations was performed directly on glass slides for further immunocytochemistry to identify germ cells. Results showed that the cell population in gate P1 on a flow cytometry plot (with high forward scatter and high side scatter parameter values) contains the highest amount of type A spermatogonia. The sorted cell populations were characterized by expression profiles of 10 germ cell specific genes. The result confirmed that setting up for the P1 gate could precisely sort type A spermatogonia in all tested testicular developmental stages. The P2 gate, which was with lower forward scatter and side scatter values mostly, contained type B spermatogonia at a later maturing stage. Moreover, expressions of plzf, dnd, boule, and kitr were significantly higher in type A spermatogonia than in later developed germ cells. In addition, plzf was firstly found as a reliable marker to identify type A spermatogonia, which filled the gap of identification of spermatogonial stem cells in sterlet. It is expected to increase the efficiency of germ stem cell culture and transplantation with plzf identification. Our study thus first addressed a phenotypic characterization of a pure type A spermatogonia population in sterlet. FCM strategy can improve the production of sturgeons with surrogate broodstock and further the analysis of the cellular and molecular mechanisms of sturgeon germ cell development.
Do Belonging and Social Exclusion at School Affect Structural Brain Development During Adolescence?
(2021)
Students’ sense of belonging presents an essential resource for academic and health outcomes, whereas social exclusion at school negatively impacts students’ well‐being and academic performance. Aiming to understand how feelings of school‐related belonging and exclusion shape the structural brain development, this study applied longitudinal questionnaire‐based data and MRI data from 71 adolescent students (37 females, Mage at t1 = 15.0; t2 = 16.1 years). All were white participants from Germany. Voxel‐based morphometry revealed only an association of social exclusion (and not of belonging) and gray matter volume in the left anterior insula: From t1 to t2, there was less gray matter decrease, the more social exclusion students perceived. School‐related social exclusion and disturbed neurodevelopment are thus significantly associated.
Abstract
Climate change will lead to more frequent and severe drought periods which massively reduce crop production worldwide. Besides drought, nitrogen (N)‐deficiency is another critical threat to crop yield production. Drought and N‐deficiency both decrease photosynthesis and induce similar adaptive strategies such as longer roots, reduction of biomass, induction of reactive oxygen species (ROS), and antioxidative enzymes. Due to the overlapping response to N‐deficiency and drought, understanding the physiological and molecular mechanisms involved in cross‐stresses tolerance is crucial for breeding strategies and achieving multiple stress resistance and eventually more sustainable agriculture. The objective of this study was to investigate the effect of a mild N‐deficiency on drought stress tolerance of tomato plants (Solanum lycopersicum L., cv. Moneymaker). Various morphological and physiological parameters such as dry biomass, root length, water potential, SPAD values, stomatal conductance, and compatible solutes accumulation (proline and sugar) were analyzed. Moreover, the expression of ROS scavenging marker genes, cytosolic ASCORBATE PEROXIDASES (cAPX1, cAPX2, and cAPX3), were investigated. Our results showed that a former mild N‐deficiency (2 mM NO3−) enhances plant adaptive response to drought stress (4 days) when compared to the plants treated with adequate N (5 mM NO3−). The improved adaptive response was reflected in higher aboveground biomass, longer root, increased specific leaf weight, enhanced stomatal conductance (without reducing water content), and higher leaf sugar content. Moreover, the APX1 gene showed a higher expression level compared to control under N‐deficiency and in combination with drought in the leaf, after a one‐week recovery period. Our finding highlights a potentially positive link between a former mild N‐deficiency and subsequent drought stress response in tomato. Combining the morphological and physiological response with underlying gene regulatory networks under consecutive stress, provide a powerful tool for improving multiple stress resistance in tomato which can be further transferred to other economically important crops.
Polyethylene terephthalate (PET) is a mass-produced petroleum-based non-biodegradable plastic that contributes to the global plastic pollution. Recently, biocatalytic degradation has emerged as a viable recycling approach for PET waste, especially with thermophilic polyester hydrolases such as a cutinase (LCC) isolated from a leaf-branch compost metagenome and its variants. To improve the enzymatic PET hydrolysis performance, we fused a chitin-binding domain (ChBD) from Chitinolyticbacter meiyuanensis SYBC-H1 to the C-terminus of the previously reported LCCICCG variant, demonstrating higher adsorption to PET substrates and, as a result, improved degradation performance by up to 19.6% compared to with its precursor enzyme without the binding module. For compare hydrolysis with different binding module, the catalytic activity of LCCICCG-ChBD, LCCICCG-CBM, LCCICCG-PBM and LCCICCG-HFB4 were further investigated with PET substrates of various crystallinity and it showed measurable activity on high crystalline PET with 40% crystallinity. These results indicated that fusing a polymer-binding module to LCCICCG is a promising method stimulating the enzymatic hydrolysis of PET.
Vaccine-induced immune thrombotic thrombocytopenia (VITT) and cerebral venous sinus thrombosis (CVST) have been recently described as rare complications following vaccination against SARS-CoV-2 with vector vaccines. We report a case of a young woman who presented with VITT and cerebral CVST 7 days following vaccination with ChAdOx1 nCov-19 (AstraZeneca). While the initial MRI was considered void of pathological findings, MRI 3 days later revealed extensive CVST of the transversal and sigmoidal sinus with intracerebral haemorrhage. Diagnostic tests including a platelet-factor-4-induced platelet activation assay confirmed the diagnosis of VITT. Treatment with intravenous immunoglobulins and argatroban resulted in a normalisation of platelet counts and remission of CVST.
Ongoing resistance developments against antibiotics that also affect last-resort antibiotics require novel antibacterial compounds. Strategies to discover such novel structures have been dimerization or hybridization of known antibacterial agents. We found novel antibacterial agents by dimerization of indols and hybridization with carbazoles. They were obtained in a simple one-pot reaction as bisindole tetrahydrocarbazoles. Further oxidation led to bisindole carbazoles with varied substitutions of both the indole and the carbazole scaffold. Both the tetrahydrocarbazoles and the carbazoles have been evaluated in various S. aureus strains, including MRSA strains. Those 5-cyano substituted derivatives showed best activities as determined by MIC values. The tetrahydrocarbazoles partly exceed the activity of the carbazole compounds and thus the activity of the used standard antibiotics. Thus, promising lead compounds could be identified for further studies.
Zinc finger proteins play pivotal roles in health and disease and exert critical functions in various cellular processes. A majority of zinc finger proteins bind DNA and act as transcription factors. B-cell lymphoma/leukemia 11B (BCL11B) represents one member of the large family of zinc finger proteins. The N-terminal domain of BCL11B was shown to be crucial for BCL11B to exert its proper function by homodimerization. Here, we describe an easy and fast preparation protocol to yield the fluorescently tagged protein of the recombinant N-terminal BCL11B zinc finger domain (BCL11B42-94) for in vitro studies. First, we expressed fluorescently tagged BCL11B42-94 in E. coli and described the subsequent purification utilizing immobilized metal ion affinity chromatography to achieve very high yields of a purified fusion protein of 200 mg/L culture. We proceeded with characterizing the atypical zinc finger domain using circular dichroism and size exclusion chromatography. Validation of the functional fluorescent pair CyPet-/EYFP-BCL11B42-94 was achieved with Förster resonance energy transfer. Our protocol can be utilized to study other zinc finger domains to expand the knowledge in this field.
The Study of Health in Pomerania (SHIP), a population-based study from a rural state in northeastern Germany with a relatively poor life expectancy, supplemented its comprehensive examination program in 2008 with whole-body MR imaging at 1.5 T (SHIP-MR). We reviewed more than 100 publications that used the SHIP-MR data and analyzed which sequences already produced fruitful scientific outputs and which manuscripts have been referenced frequently. Upon reviewing the publications about imaging sequences, those that used T1-weighted structured imaging of the brain and a gradient-echo sequence for R2* mapping obtained the highest scientific output; regarding specific body parts examined, most scientific publications focused on MR sequences involving the brain and the (upper) abdomen. We conclude that population-based MR imaging in cohort studies should define more precise goals when allocating imaging time. In addition, quality control measures might include recording the number and impact of published work, preferably on a bi-annual basis and starting 2 years after initiation of the study. Structured teaching courses may enhance the desired output in areas that appear underrepresented.
Background: Tissue-resident macrophages have mixed developmental origins. They derive in variable extent from yolk sac (YS) hematopoiesis during embryonic development. Bone marrow (BM) hematopoietic progenitors give rise to tissue macrophages in postnatal life, and their contribution increases upon organ injury. Since the phenotype and functions of macrophages are modulated by the tissue of residence, the impact of their origin and developmental paths has remained incompletely understood. Methods: In order to decipher cell-intrinsic macrophage programs, we immortalized hematopoietic progenitors from YS and BM using conditional HoxB8, and carried out an in-depth functional and molecular analysis of differentiated macrophages. Results: While YS and BM macrophages demonstrate close similarities in terms of cellular growth, differentiation, cell death susceptibility and phagocytic properties, they display differences in cell metabolism, expression of inflammatory markers and inflammasome activation. Reduced abundance of PYCARD (ASC) and CASPASE-1 proteins in YS macrophages abrogated interleukin-1β production in response to canonical and non-canonical inflammasome activation. Conclusions: Macrophage ontogeny is associated with distinct cellular programs and immune response. Our findings contribute to the understanding of the regulation and programming of macrophage functions.
Background: Protease-activated receptor 1 (PAR1) and toll-like receptors (TLRs) are inflammatory mediators contributing to atherogenesis and atherothrombosis. Vorapaxar, which selectively antagonizes PAR1-signaling, is an approved, add-on antiplatelet therapy for secondary prevention. The non-hemostatic, platelet-independent, pleiotropic effects of vorapaxar have not yet been studied. Methods and Results: Cellular targets of PAR1 signaling in the vasculature were identified in three patient cohorts with atherosclerotic disease. Evaluation of plasma biomarkers (n = 190) and gene expression in endomyocardial biopsies (EMBs) (n = 12) revealed that PAR1 expression correlated with endothelial activation and vascular inflammation. PAR1 colocalized with TLR2/4 in human carotid plaques and was associated with TLR2/4 gene transcription in EMBs. In addition, vorapaxar reduced atherosclerotic lesion size in apolipoprotein E–knock out (ApoEko) mice. This reduction was associated with reduced expression of vascular adhesion molecules and TLR2/4 presence, both in isolated murine endothelial cells and the aorta. Thrombin-induced uptake of oxLDL was augmented by additional TLR2/4 stimulation and abrogated by vorapaxar. Plaque-infiltrating pro-inflammatory cells were reduced in vorapaxar-treated ApoEko mice. A shift toward M2 macrophages paralleled a decreased transcription of pro-inflammatory cytokines and chemokines. Conclusions: PAR1 inhibition with vorapaxar may be effective in reducing residual thrombo-inflammatory event risk in patients with atherosclerosis independent of its effect on platelets.
Clavicle injuries are common, but only few case reports describe combined clavicular injuries (CCI). CCI include combinations between clavicular fractures and acromioclavicular/sternoclavicular joint dislocations (SCJD). We present the first general therapeutic recommendations for CCI based on a new classification and their distribution. A retrospective, epidemiological, big data analysis was based on ICD-10 diagnoses from 2012 to 2014 provided by the German Federal Statistical Office. CCI represent 0.7% of all clavicle-related injuries (n = 814 out of 114,003). SCJD show by far the highest proportion of combination injuries (13.2% of all SCJD were part of CCI) while the proportion of CCI in relation to the other injury entities was significantly less (p < 0.023). CCIs were classified depending on (1) the polarity (monopolar type I, 92.2% versus bipolar type II, 7.8%). Monopolar type I was further differentiated depending on (2) the positional relationship between the combined injuries: Ia two injuries directly at the respective pole versus Ib with an injury at one end plus an additional midshaft clavicle fracture. Type II was further differentiated depending on (3) the injured structures: IIa ligamento-osseous, type IIb purely ligamentous (rarest with 0.6%). According to our classification, the CCI severity increases from type Ia to IIb. CCI are more important than previously believed and seen as an indication for surgery. The exclusion of further, contra-polar injuries in the event of a clavicle injury is clinically relevant and should be focused.
Growth, ageing and atherosclerotic plaque development alter the biomechanical forces acting on the vessel wall. However, monitoring the detailed local changes in wall shear stress (WSS) at distinct sites of the murine aortic arch over time has been challenging. Here, we studied the temporal and spatial changes in flow, WSS, oscillatory shear index (OSI) and elastic properties of healthy wildtype (WT, n = 5) and atherosclerotic apolipoprotein E-deficient (Apoe−/−, n = 6) mice during ageing and atherosclerosis using high-resolution 4D flow magnetic resonance imaging (MRI). Spatially resolved 2D projection maps of WSS and OSI of the complete aortic arch were generated, allowing the pixel-wise statistical analysis of inter- and intragroup hemodynamic changes over time and local correlations between WSS, pulse wave velocity (PWV), plaque and vessel wall characteristics. The study revealed converse differences of local hemodynamic profiles in healthy WT and atherosclerotic Apoe−/− mice, and we identified the circumferential WSS as potential marker of plaque size and composition in advanced atherosclerosis and the radial strain as a potential marker for vascular elasticity. Two-dimensional (2D) projection maps of WSS and OSI, including statistical analysis provide a powerful tool to monitor local aortic hemodynamics during ageing and atherosclerosis. The correlation of spatially resolved hemodynamics and plaque characteristics could significantly improve our understanding of the impact of hemodynamics on atherosclerosis, which may be key to understand plaque progression towards vulnerability.
Introduction: With the increased emergence of SARS-CoV-2 variants, the impact on schools and preschools remains a matter of debate. To ensure that schools and preschools are kept open safely, the identification of factors influencing the extent of outbreaks is of importance.
Aim: To monitor dynamics of COVID-19 infections in schools and preschools and identify factors influencing the extent of outbreaks.
Methods: In this prospective observational study we analyzed routine surveillance data of Mecklenburg-Western Pomerania, Germany, from calendar week (CW) 32, 2020 to CW19, 2021 regarding SARS-CoV-2 infection events in schools and preschools considering changes in infection control measures over time. A multivariate linear regression model was fitted to evaluate factors influencing the number of students, teachers and staff tested positive following index cases in schools and preschools. Due to an existing multicollinearity in the common multivariate regression model between the variables “face mask obligation for children” and “face mask obligation for adults”, two further separate regression models were set up (Multivariate Model Adults and Multivariate Model Children).
Results: We observed a significant increase in secondary cases in preschools in the first quarter of 2021 (CW8 to CW15, 2021), and simultaneously a decrease in secondary cases in schools. In multivariate regression analysis, the strongest predictor of the extent of the outbreaks was the teacher/ caregiver mask obligation (B = −1.9; 95% CI: −2.9 to −1.0; p < 0.001). Furthermore, adult index cases (adult only or child+adult combinations) increased the likelihood of secondary cases (B = 1.3; 95% CI: 0.9 to 1.8; p < 0.001). The face mask obligation for children also showed a significant reduction in the number of secondary cases (B = −0.6; 95% CI: −0.9 to −0.2; p = 0.004.
Conclusion: The present study indicates that outbreak events at schools and preschools are effectively contained by an obligation for adults and children to wear face masks.
Following the relational-developmental systems approach, this three-wave study examines whether acute stress (T2) mediates the relationship between the development of personality traits from the beginning of 8th grade (T1, Mage = 15.63, SD = 0.59; 22 girls) to the end of 9th grade (T3). Using the Montréal Imaging Stress Task, which is a task that provokes acute social stress by negative social feedback, this study combined the functional magnetic resonance imaging (fMRI), heart rate, and longitudinal survey data of 41 adolescents. Mediation analysis revealed that stress-induced left insula activation partially mediates the longitudinal stability of conscientiousness. These results highlight the impact of negative social feedback during stress on students’ personality development.
Cold physical plasmas, especially noble gas driven plasma jets, emit considerable amounts of ultraviolet radiation (UV). Given that a noble gas channel is present, even the energetic vacuum UV can reach the treated target. The relevance of UV radiation for antimicrobial effects is generally accepted. It remains to be clarified if this radiation is relevant for other biomedical application of plasmas, e.g., in wound care or cancer remediation. In this work, the role of (vacuum) ultraviolet radiation generated by the argon plasma jet kINPen for cysteine modifications was investigated in aqueous solutions and porcine skin. To differentiate the effects of photons of different wavelength and complete plasma discharge, a micro chamber equipped with a MgF2, Suprasil, or Borosilicate glass window was used. In liquid phase, plasma-derived VUV radiation was effective and led to the formation of cysteine oxidation products and molecule breakdown products, yielding sulfite, sulfate, and hydrogen sulfide. At the boundary layer, the impact of VUV photons led to water molecule photolysis and formation of hydroxyl radicals and hydrogen peroxide. In addition, photolytic cleavage of the weak carbon-sulfur bond initiated the formation of sulfur oxy ions. In the intact skin model, protein thiol modification was rare even if a VUV transparent MgF2 window was used. Presumably, the plasma-derived VUV radiation played a limited role since reactions at the boundary layer are less frequent and the dense biomolecules layers block it effectively, inhibiting significant penetration. This result further emphasizes the safety of physical plasmas in biomedical applications.
The Coronavirus disease 2019 (COVID-19) pandemic is affecting many areas of life and has led to major changes in undergraduate medical education. Even before the COVID-19 pandemic, high mental burden of medical students has frequently been reported in the literature. Additional pandemic-specific stressors could exacerbate this situation. This study aimed to assess mental health outcomes among medical students during the first semester after the COVID-19 outbreak and perception of the students on how the learning environment has changed. In May 2020, we conducted a cross-sectional survey among undergraduate medical students at a large medical school in Germany. The survey included validated mental health instruments (Distress Thermometer, Patient Health Questionnaire 4) and self-developed items to examine the perception of the study situation during the COVID-19 pandemic. Open-ended questions were analyzed by conventional content analyses. The response rate was 59.2% (914/1,545). Overall, 61.9% of the students reported distress levels above the cutoff. Year 1 students reported significantly higher levels of distress, anxiety and depression than students during their second to fourth year of studies. 48.3% of the students indicated a decrease in their study motivation since the beginning of the COVID-19 pandemic with significant differences between study years. The binary logistic regression model showed that male gender, being in study year 2, higher distress scores and higher symptoms of depression were significantly associated with a higher likelihood for experiencing serious worries. In the open-ended questions on current concerns related to the impact of the COVID-19 pandemic on their studies, students most frequently reported concerns about missing relevant practical learning experience, difficulties with self-regulated learning and self motivation as well as study-related worries. Year 4 students reported significantly more worries about the lack of practical training than students from study years 1 to 3. Analysis of gender differences showed that female students reported more frequently diverse worries. In contrast, female students shared more frequently helpful strategies in all the categories compared to male students. Our findings suggest that medical students experience significant levels of distress and mental burden during the COVID-19 pandemic and highlight the need for ongoing psychological and educational support for medical students during the COVID-19 pandemic and after.
Objectives
To give an overview over the associations between self-reported health literacy and medication adherence in older adults.
Design
A systematic literature review of quantitative studies published in English and German.
Data sources
MEDLINE via PubMed, CINAHL, Cochrane Library, Epistemonikos and LIVIVO were searched.
Eligibility criteria
Included studies had to examine the associations between self-reported health literacy and medication adherence in the elderly (samples including ≥66% of ≥60 years old) and had to use a quantitative methodology and had to be written in English or German.
Data extraction and synthesis
All studies were screened for inclusion criteria by two independent reviewers. A narrative synthesis was applied to analyse all included studies thematically. Quality assessment was conducted using the NIH Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies.
Results
We found 2313 studies, of which nine publications from eight studies were included in this review. Five studies reported a majority of participants with limited health literacy, one study reported a majority of participants with adequate health literacy, and three publications from two studies only reported mean levels of health literacy. Eight publications from seven studies used self-reports to measure medication adherence, while one study used the medication possession ratio. Overall, six publications from five studies reported significantly positive associations between health literacy and medication adherence while two studies reported positive but non-significant associations between both constructs and one study reported mixed results.
Conclusion
In this review, associations between self-reported health literacy and medication adherence are rather consistent, indicating positive associations between both constructs in older adults. However, concepts and measures of health literacy and medication adherence applied in the included studies still show a noteworthy amount of heterogeneity (eg, different use of cutoffs). These results reveal the need for more differentiated research in this area.
PROSPERO registration number CRD42019141028.
Objectives
To investigate levels of distress, depression, anxiety, stress and perception of their current study situation during the COVID-19 pandemic among undergraduate dental and medical students.
Design
Observational, cross-sectional study including two consecutive surveys (May and July 2020).
Setting
A large medical school in Germany.
Participants
All first year dental and medical students were invited. 132 participating first year students (44 dental, 88 medical) from the first survey and 150 students (50 dental, 100 medical) from the second were included in our analyses.
Primary and secondary outcome measures
Mental burden (distress thermometer, Patient Health Questionnaire-4, Perceived Stress Scale-4) and self-reported changes in mental health and perception of study situation during the COVID-19 pandemic (self-developed items) were compared. Open-ended questions were analysed by conventional content analyses.
Results
A considerable proportion of students (t1: May 2020: 84.1%; t2: July 2020: 77.3%) reported distress levels above cut-off. In July 2020, dental students reported significantly higher distress scores than medical students (dental: M=7.0, SD=2.3; medical: M=5.7; SD=2.1; p<0.001). More dental than medical students reported mild, moderate and severe levels of anxiety and depression symptoms. The majority stated that their mental health and study motivation had not changed during the pandemic. Logistic regression showed that being a dental student was significantly associated with a higher likelihood for serious worries regarding the study situation during COVID-19 at t1 (OR 4.0; 95% CI 1.1 to 14.2). At t2 higher distress was significantly associated with a higher likelihood for experiencing serious worries (OR 1.8; 95% CI 1.3 to 2.5). Regarding current concerns related to the pandemic, students most frequently reported difficulties with self-regulated learning (15.2%), study-related worries and uncertainty (14.4%), missing feedback of students and lecturers (11.4%) and lack of practical training (9.8%).
Conclusion
The results suggest that high mental burden and the lack of practical training among medical and dental students is an increasing problem, with a possibly even higher urgency in dental students. Tailored psychological and educational support offers during and after the COVID-19 pandemic might help them as they progress through (medical and) dental school.
Parents, peers, and teachers provide a powerful context for school students’ well-being. However, a detailed and systematic analysis of how parental, peer, and teacher support relate to students’ well-being, measured by the dimensions self-worth, psychological and physical well-being, is still missing. To address this research gap, the following study investigates 733 adolescent German students from grades 7 and 8 (Mage = 13.97, SD = 0.41, 52% girls) with respect to their perceived supportive relationships at home and within the school context. The study considers gender, socioeconomic status, and school form as potential confounders. The results of the structural equation model, analyzed with the statistical software R, indicate that perceived teacher support was positively related to students’ self-worth and physical well-being, while peer support was related to psychological well-being. Students who perceived their parents as supportive reported higher well-being with respect to all three dimensions investigated.
MRI-based vessel size imaging (VSI) allows for in-vivo assessment of cerebral microvasculature and perfusion. This exploratory analysis of vessel size (VS) and density (Q; both assessed via VSI) in the subacute phase of ischemic stroke involved sixty-two patients from the BAPTISe cohort (‘Biomarkers And Perfusion--Training-Induced changes after Stroke’) nested within a randomized controlled trial (intervention: 4-week training vs. relaxation). Relative VS, Q, cerebral blood volume (rCBV) and –flow (rCBF) were calculated for: ischemic lesion, perilesional tissue, and region corresponding to ischemic lesion on the contralateral side (mirrored lesion). Linear mixed-models detected significantly increased rVS and decreased rQ within the ischemic lesion compared to the mirrored lesion (coefficient[standard error]: 0.2[0.08] p = 0.03 and −1.0[0.3] p = 0.02, respectively); lesion rCBF and rCBV were also significantly reduced. Mixed-models did not identify time-to-MRI, nor training as modifying factors in terms of rVS or rQ up to two months post-stroke. Larger lesion VS was associated with larger lesion volumes (β 34, 95%CI 6.2–62; p = 0.02) and higher baseline NIHSS (β 3.0, 95%CI 0.49–5.3;p = 0.02), but was not predictive of six-month outcome. In summary, VSI can assess the cerebral microvasculature and tissue perfusion in the subacute phases of ischemic stroke, and may carry relevant prognostic value in terms of lesion volume and stroke severity.
Aging is an independent risk factor for hypertension, cardiovascular morbidity, and mortality. However, detailed mechanisms linking aging to cardiovascular disease are unclear. We studied the aging effects on the role of perivascular adipose tissue and downstream vasoconstriction targets, voltage-dependent KV7 channels, and their pharmacological modulators (flupirtine, retigabine, QO58, and QO58-lysine) in a murine model. We assessed vascular function of young and old mesenteric arteries in vitro using wire myography and membrane potential measurements with sharp electrodes. We also performed bulk RNA sequencing and quantitative reverse transcription-polymerase chain reaction tests in mesenteric arteries and perivascular adipose tissue to elucidate molecular underpinnings of age-related phenotypes. Results revealed impaired perivascular adipose tissue-mediated control of vascular tone particularly via KV7.3–5 channels with increased age through metabolic and inflammatory processes and release of perivascular adipose tissue-derived relaxation factors. Moreover, QO58 was identified as novel pharmacological vasodilator to activate XE991-sensitive KCNQ channels in old mesenteric arteries. Our data suggest that targeting inflammation and metabolism in perivascular adipose tissue could represent novel approaches to restore vascular function during aging. Furthermore, KV7.3–5 channels represent a promising target in cardiovascular aging.
The Na+/taurocholate cotransporting polypeptide (NTCP) is located in the basolateral membrane of hepatocytes, where it transports bile acids from the portal blood back into hepatocytes. Furthermore, NTCP has a role for the hepatic transport of some drugs. Extrapolation of drug transport data from rodents to humans is not always possible, because species differences in the expression level, localization, affinity, and substrate selectivity of relevant transport proteins must be considered. In the present study, a functional comparison of human NTCP (hNTCP) and mouse Ntcp (mNtcp) showed similar Km values of 67 ± 10 µM and 104 ± 9 µM for the probe substrate estrone-3-sulfate as well as of 258 ± 42 µM and 199 ± 13 µM for the drug rosuvastatin, respectively. IC50 values for the probe inhibitor cyclosporine A were 3.1 ± 0.3 µM for hNTCP and 1.6 ± 0.4 µM for mNtcp. In a drug and pesticide inhibitory screening on both transporters, 4 of the 15 tested drugs (cyclosporine A, benzbromarone, MK571, and fluvastatin) showed high inhibitory potency, but only slight inhibition was observed for the 13 tested pesticides. Among these compounds, only four drugs and three pesticides showed significant differences in their inhibition pattern on hNTCP and mNtcp. Most pronounced was the difference for benzbromarone with a fivefold higher IC50 for mNtcp (27 ± 10 µM) than for hNTCP (5.5 ± 0.6 µM).
In conclusion, we found a strong correlation between the transport kinetics and inhibition pattern among hNTCP and mNtcp. However, specific compounds, such as benzbromarone, showed clear species differences. Such species differences have to be considered when pharmacokinetic data are transferred from rodent to humans.
This review assessed population-based estimate rates of cancer patients with minor and young adult children (≤ 25 years), children and young adults having a parent with cancer as well as the psychosocial situation and well-being of children and young adults affected by parental cancer. Eighteen publications on population-based studies were included. Studies varied in the age ranges of both cancer patients and children. The prevalence rates of cancer patients having children ranged from 14 to 24.7% depending on the sample structure (e.g., age, gender). Studies reported that between 1.6 and 8.4% of children resp. young adult children have a parent with a history of cancer. Seven publications reported on the psychosocial situation or well-being in children and young adults affected by parental cancer. Estimate rates of psychosocial problems, psychiatric diagnoses or distress ranged between 2.5 and 34% of children depending on the method of measurement and outcome. The differences in the sample structure between the studies impeded the comparison of prevalence rates. However, the findings help to determine the need for specific support services and health care planning. The results emphazise the importance to routinely include issues on the parental role of patients and questions on the well-being and coping of children into psychooncological care. If necessary, support should be provided to families living with a cancer diagnosis.
Rewetting is the most effective way to reduce greenhouse gas (GHG) emissions from drained peatlands and must significantly contribute to the implementation of the Paris Agreement on Climate within the land sector. In 2010–2013, more than 73 thousand hectares of fire-prone peatlands were rewetted in the Moscow Region (the hitherto largest rewetting program in the Northern Hemisphere). As the Russian Federation has no national accounting of rewetted areas yet, this paper presents an approach to detect them based on multispectral satellite data verified by ground truthing. We propose that effectively rewetted areas should minimally include areas with wet grasslands and those covered with water (cf. the IPCC categories “rewetted organic soils” and “flooded lands”). In 2020, these lands amounted in Moscow Region to more than 5.3 and 3.6 thousand hectares, respectively. Assuming that most rewetted areas were former peat extraction sites and using IPCC default GHG emission factors, an overall GHG emission reduction of over 36,000 tCO2-eq year−1 was calculated. We furthermore considered the uncertainty of calculations. With the example of a 1535 ha large rewetted peatland, we illustrate the estimation of GHG emission reductions for the period up to 2050. The approach presented can be used to estimate GHG emission reductions by peatland rewetting on the national, regional, and object level.
Controlling the time point and site of the release of active ingredients within the gastrointestinal tract after administration of oral delivery systems is still a challenge. In this study, the effect of the combination of small capsules (size 3) and large capsules (size 00) on the disintegration site and time was investigated using magnetic resonance imaging (MRI) in combination with a salivary tracer technique. As capsule shells, Vcaps® HPMC capsules, Vcaps® Plus HPMC capsules, gelatin and DRcaps® designed release capsules were used. The three HPMC-based capsules (Vcaps®, Vcaps® Plus and DRcaps® capsules) were tested as single capsules; furthermore, seven DUOCAP® capsule-in-capsule combinations were tested in a 10-way crossover open-label study in six healthy volunteers. The capsules contained iron oxide and hibiscus tea powder as tracers for visualization in MRI, and two different caffeine species (natural caffeine and 13C3) to follow caffeine release and absorption as measured by salivary levels. Results showed that the timing and location of disintegration in the gastrointestinal tract can be measured and differed when using different combinations of capsule shells. Increased variability among the six subjects was observed in most of the capsule combinations. The lowest variability in gastrointestinal localization of disintegration was observed for the DUOCAP® capsule-in-capsule configuration using a DRcaps® designed release capsule within a DRcaps® designed release outer capsule. In this combination, the inner DRcaps® designed release capsule always opened reliably after reaching the ileum. Thus, this combination enables targeted delivery to the distal small intestine. Among the single capsules tested, Vcaps® Plus HPMC capsules showed the fastest and most consistent disintegration.
Background and Objectives: Vaccine induced thrombotic thrombocytopenia (VITT) may occur after COVID-19 vaccination with recombinant adenoviral vector-based vaccines. VITT can present as cerebral sinus and venous thrombosis (CSVT), often complicated by intracranial hemorrhage. Today it is unclear, how long symptomatic VITT can persist. Here, we report the complicated long-term course of a VITT patient with extremely high titers of pathogenic anti-platelet factor 4 (PF4)-IgG antibodies. Methods: Clinical and laboratory findings are presented, including the course of platelet counts, D-Dimer levels, clinical presentation, imaging, SARS-CoV-2-serological and immunological, platelet activating anti-PF4-IgG, as well as autopsy findings. Results: The patient presented with extended superior sagittal sinus thrombosis with accompanying bifrontal intracerebral hemorrhage. Repeated treatment with intravenous immune globuline (IVIG) resolved recurrent episodes of thrombocytopenia. Moreover, the patient’s serum remained strongly positive for platelet-activating anti-PF4-IgG over three months. After a period of clinical stabilization, the patient suffered a recurrent and fatal intracranial hemorrhage. Conclusions: Complicated VITT with extremely high anti-PF4-IgG titers over three months can induce recurrent thrombocytopenia despite treatment with IVIG and anticoagulation. Plasma exchange, immunoadsorption, and /or immunosuppressive treatment may be considered in complicated VITT to reduce extraordinarily high levels of anti-PF4-IgG. Long-term therapy in such cases must take the individual bleeding risk and CSVT risk into account.
Free light chains (FLC) are a promising biomarker to detect intrathecal inflammation in patients with inflammatory central nervous system (CNS) diseases, including multiple sclerosis (MS). The diagnostic use of this biomarker, in particular the kappa isoform of FLC (“KFLC”), has been investigated for more than 40 years. Based on an extensive literature review, we found that an agreement on the correct method for evaluating KFLC concentrations has not yet been reached. KFLC indices with varying cut-off values and blood-CSF-barrier (QAlbumin) related non-linear formulas for KFLC interpretation have been investigated in several studies. All approaches revealed high diagnostic sensitivity and specificity compared with the oligoclonal bands, which are considered the gold standard for the detection of intrathecally synthesized immunoglobulins. Measurement of KFLC is fully automated, rater-independent, and has been shown to be stable against most pre-analytic influencing factors. In conclusion, the determination of KFLC represents a promising diagnostic approach to show intrathecal inflammation in neuroinflammatory diseases. Multicenter studies are needed to show the diagnostic sensitivity and specificity of KFLC in MS by using the latest McDonald criteria and appropriate, as well as standardized, cut-off values for KFLC concentrations, preferably considering non-linear formulas such as Reiber’s diagram.
OBJECTIVES: Internal tandem duplications (ITDs) of the Fms-like tyrosine kinase 3 (FLT3) represent the most frequent molecular aberrations in acute myeloid leukemia (AML) and are associated with an inferior prognosis. The pattern of downstream activation by this constitutively activated receptor tyrosine kinase is influenced by the localization of FLT3-ITD depending on its glycosylation status. Different pharmacological approaches can affect FLT3-ITD-driven oncogenic pathways by the modulation of FLT3-ITD localization. AIMS: The objective of this study was to investigate the effects of N-glycosylation inhibitors (tunicamycin or 2-deoxy-D-glucose) or the histone deacetylase inhibitor valproic acid (VPA) on FLT3-ITD localization and downstream activity. We sought to determine the potential differences between the distinct FLT3-ITD variants, particularly concerning their susceptibility towards combined treatment by addressing either N-glycosylation and the heat shock protein 90 (HSP90) by 17-AAG, or by targeting the PI3K/AKT/mTOR pathway by rapamycin after treatment with VPA. METHODS: Murine Ba/F3 leukemia cell lines were stably transfected with distinct FLT3-ITD variants resulting in IL3-independent growth. These Ba/F3 FLT3-ITD cell lines or FLT3-ITD-expressing human MOLM13 cells were exposed to tunicamycin, 2-deoxy-D-glucose or VPA, and 17-AAG or rapamycin, and characterized in terms of downstream signaling by immunoblotting. FLT3 surface expression, apoptosis, and metabolic activity were analyzed by flow cytometry or an MTS assay. Proteome analysis by liquid chromatography–tandem mass spectrometry was performed to assess differential protein expression. RESULTS: The susceptibility of FLT3-ITD-expressing cells to 17-AAG after pre-treatment with tunicamycin or 2-deoxy-D-glucose was demonstrated. Importantly, in Ba/F3 cells that were stably expressing distinct FLT3-ITD variants that were located either in the juxtamembrane domain (JMD) or in the tyrosine kinase 1 domain (TKD1), response to the sequential treatments with tunicamycin and 17-AAG varied between individual FLT3-ITD motifs without dependence on the localization of the ITD. In all of the FLT3-ITD cell lines that were investigated, incubation with tunicamycin was accompanied by intracellular retention of FLT3-ITD due to the inhibition of glycosylation. In contrast, treatment of Ba/F3-FLT3-ITD cells with VPA was associated with a significant increase of FLT3-ITD surface expression depending on FLT3 protein synthesis. The allocation of FLT3 to different cellular compartments that was induced by tunicamycin, 2-deoxy-D-glucose, or VPA resulted in the activation of distinct downstream signaling pathways. Whole proteome analyses of Ba/F3 FLT3-ITD cells revealed up-regulation of the relevant chaperone proteins (e.g., calreticulin, calnexin, HSP90beta1) that are directly involved in the stabilization of FLT3-ITD or in its retention in the ER compartment. CONCLUSION: The allocation of FLT3-ITD to different cellular compartments and targeting distinct downstream signaling pathways by combined treatment with N-glycosylation and HSP90 inhibitors or VPA and rapamycin might represent new therapeutic strategies to overcome resistance towards tyrosine kinase inhibitors in FLT3-ITD-positive AML. The treatment approaches addressing N-glycosylation of FLT3-ITD appear to depend on patient-specific FLT3-ITD sequences, potentially affecting the efficacy of such pharmacological strategies.
Functional connectivity studies have demonstrated that creative thinking builds upon an interplay of multiple neural networks involving the cognitive control system. Theoretically, cognitive control has generally been discussed as the common basis underlying the positive relationship between creative thinking and intelligence. However, the literature still lacks a detailed investigation of the association patterns between cognitive control, the factors of creative thinking as measured by divergent thinking (DT) tasks, i.e., fluency and originality, and intelligence, both fluid and crystallized. In the present study, we explored these relationships at the behavioral and the neural level, based on N = 77 young adults. We focused on brain-signal complexity (BSC), parameterized by multi-scale entropy (MSE), as measured during a verbal DT and a cognitive control task. We demonstrated that MSE is a sensitive neural indicator of originality as well as inhibition. Then, we explore the relationships between MSE and factor scores indicating DT and intelligence. In a series of across-scalp analyses, we show that the overall MSE measured during a DT task, as well as MSE measured in cognitive control states, are associated with fluency and originality at specific scalp locations, but not with fluid and crystallized intelligence. The present explorative study broadens our understanding of the relationship between creative thinking, intelligence, and cognitive control from the perspective of BSC and has the potential to inspire future BSC-related theories of creative thinking.
(1) Background: Predicting chronic low back pain (LBP) is of clinical and economic interest as LBP leads to disabilities and health service utilization. This study aims to build a competitive and interpretable prediction model; (2) Methods: We used clinical and claims data of 3837 participants of a population-based cohort study to predict future LBP consultations (ICD-10: M40.XX-M54.XX). Best subset selection (BSS) was applied in repeated random samples of training data (75% of data); scoring rules were used to identify the best subset of predictors. The rediction accuracy of BSS was compared to randomforest and support vector machines (SVM) in the validation data (25% of data); (3) Results: The best subset comprised 16 out of 32 predictors. Previous occurrence of LBP increased the odds for future LBP consultations (odds ratio (OR) 6.91 [5.05; 9.45]), while concomitant diseases reduced the odds (1 vs. 0, OR: 0.74 [0.57; 0.98], >1 vs. 0: 0.37 [0.21; 0.67]). The area-under-curve (AUC) of BSS was acceptable (0.78 [0.74; 0.82]) and comparable with SVM (0.78 [0.74; 0.82]) and randomforest (0.79 [0.75; 0.83]); (4) Conclusions: Regarding prediction accuracy, BSS has been considered competitive with established machine-learning approaches. Nonetheless, considerable misclassification is inherent and further refinements are required to improve predictions.
(1) Background: Sepsis is a leading cause of death and a global public health problem. Accordingly, deciphering the underlying molecular mechanisms of this disease and the determinants of its morbidity and mortality is pivotal. This study examined the effect of the rs951818 SNP of the negative costimulatory lymphocyte-activation gene 3 (LAG-3) on sepsis mortality and disease severity. (2) Methods: 707 consecutive patients with sepsis were prospectively enrolled into the present study from three surgical ICUs at University Medical Center Goettingen. Both 28- and 90-day mortality were analyzed as the primary outcome, while parameters of disease severity served as secondary endpoints. (3) Results: In the Kaplan–Meier analysis LAG-3 rs951818 AA-homozygote patients showed a significantly lower 28-day mortality (17.3%) compared to carriers of the C-allele (23.7%, p = 0.0476). In addition, these patients more often received invasive mechanical ventilation (96%) during the course of disease than C-allele carriers (92%, p = 0.0466). (4) Conclusions: Genetic profiling of LAG-3 genetic variants alone or in combination with other genetic biomarkers may represent a promising approach for risk stratification of patients with sepsis. Patient-individual therapeutic targeting of immune checkpoints, such as LAG-3, may be a future component of sepsis therapy. Further detailed investigations in clinically relevant sepsis models are necessary.