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Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice. Neither the natural history of AF nor its response to therapy are sufficiently predictable by clinical and echocardiographic parameters. Atrial fibrillatory frequency (or rate) can reliably be assessed from the surface electrocardiogram (ECG) using digital signal processing (filtering, subtraction of averaged QRST complexes, and power spectral analysis) and shows large inter-individual variability. This measurement correlates well with intraatrial cycle length, a parameter which appears to have primary importance in AF domestication and response to therapy. AF with a low fibrillatory rate is more likely to terminate spontaneously, and responds better to antiarrhythmic drugs or cardioversion while high rate AF is more often persistent and refractory to therapy. In conclusion, frequency analysis of AF seems to be useful for non-invasive assessment of electrical remodeling in AF and may subsequently be helpful for guiding AF therapy.

Azole resistance in Aspergillus fumigatus fungi has increased during the past 25 years. Increasing evidence documents that selection of azole-resistant A. fumigatus (ARAf) takes place in the environment (1,2). Investigations [...]

Abstract Background Activated fibroblast-like synoviocytes (FLS) are drivers of synovitis and structural joint damage in rheumatoid arthritis (RA). Despite the use of disease-modifying drugs, only about 50% of RA patients reach remission in real-world settings. We used an unbiased approach to investigate the effects of standard-of-care methotrexate (MTX) and a Janus kinase inhibitor, tofacitinib (TOFA), on gene expression in RA-FLS, in order to identify untargeted disease mediators. Methods Primary RA-FLS were activated by stimulation with interleukin-1β (IL-1β) or platelet-derived growth factor + IL-1β in the presence or absence of MTX or TOFA, with or without additional inhibitors. Co-cultures of synovial cells were performed in direct and indirect systems. Cells were collected for RNA sequencing or qPCR, and supernatants were analyzed for protein concentrations. Results Six thousand three hundred fifty genes were differentially expressed, the majority being upregulated, in MTX-treated activated RA-FLS and 970 genes, the majority being downregulated, in TOFA-treated samples. Pathway analysis showed that MTX had largest effects on ‘Molecular mechanisms of cancer’ and TOFA on ‘Interferon signaling’. Targeted analysis of disease-associated genes revealed that MTX increased the expression of cell cycle-regulating genes but also of pro-inflammatory mediators like IL-1α (IL1A) and granulocyte–macrophage colony-stimulating factor, GM-CSF (CSF2). The MTX-promoted expression of CSF2 in activated RA-FLS peaked at 48 h, could be mediated via either NF-κB or AP-1 transcription factors, and was abrogated by IL-1 inhibitors (IRAK4 inhibitor and anakinra). In a co-culture setting, MTX-treatment of activated RA-FLS induced IL1B expression in macrophages. Conclusions MTX treatment induces secretion of IL-1 from activated RA-FLS which by autocrine signaling augments their release of GM-CSF. This unexpected effect of MTX might contribute to the persistence of synovitis.

Abstract Aims Heart failure (HF) and chronic kidney disease (CKD) place significant challenges on the healthcare system, and their co‐existence is associated with shared adverse outcomes. The multinational CaReMe project was initiated to provide contemporary, real‐world epidemiological data on cardiovascular and reno‐metabolic diseases. Utilizing data from the German CaReMe cohort, we characterize a multicentric HF population and describe in‐hospital outcomes stratified for co‐morbid CKD. Methods and results This retrospective, observational study analysed administrative data from inpatient cases hospitalized in 87 German Helios hospitals between 1 January 2016 and 31 August 2022. The first hospitalization of patients aged ≥18 years with a primary discharge diagnosis of HF, based on ICD‐10 codes, were considered the index cases, and subsequent hospitalizations were considered as readmissions. Baseline characteristics and outcomes were stratified for co‐morbid CKD using ICD‐10‐encoding from the index cases. Cox regression was utilized for readmission endpoints and in‐hospital mortality. In total, 174 829 index cases (mean age 79 ± 15 years, 49.9% female) were included; of these, 55.0% had coexisting CKD. Patients with CKD were older, suffered from worse HF‐related symptoms, had a higher co‐morbidity burden, and in‐hospital mortality was increased at index and during follow‐up. Prevalent CKD was associated with higher rehospitalization rates and was an independent predictor for in‐hospital death. Conclusions Within this HF inpatient cohort from a multicentric German database, CKD was diagnosed in more than half of the patients and was associated with increased in‐hospital mortality at baseline and during follow‐up. Rehospitalizations were observed earlier and more frequently in patients with HF and co‐morbid CKD.

Azole-resistant Aspergillus fumigatus (ARAf) fungi have been found inconsistently in the environment in Denmark since 2010. During 2018–2020, nationwide surveillance of clinical A. fumigatus fungi reported environmental TR34/L98H or TR46/Y121F/T289A resistance mutations in 3.6% of isolates, prompting environmental sampling for ARAf and azole fungicides and investigation for selection of ARAf in field and microcosmos experiments. ARAf was ubiquitous (20% of 366 samples; 16% TR34/L98H- and 4% TR46/Y121F/T289A-related mechanisms), constituting 4.2% of 4,538 A. fumigatus isolates. The highest proportions were in flower- and compost-related samples but were not correlated with azole-fungicide application concentrations. Genotyping showed clustering of tandem repeat–related ARAf and overlaps with clinical isolates in Denmark. A. fumigatus fungi grew poorly in the field experiment with no postapplication change in ARAf proportions. However, in microcosmos experiments, a sustained complete (tebuconazole) or partial (prothioconazole) inhibition against wild-type A. fumigatus but not ARAf indicated that, under some conditions, azole fungicides may favor growth of ARAf in soil.

Johannes Leiner,1,2 Vincent Pellissier,2 Sebastian König,1,2 Lars Stellmacher,2 Sven Hohenstein,2 Carolin Schanner,2 Stefan Kwast,2 Ralf Kuhlen,3,4 Andreas Bollmann1– 3 1Department of Electrophysiology, Heart Center Leipzig at University of Leipzig, Leipzig, Saxony, Germany; 2Real World Evidence and Health Technology Assessment, Helios Health Institute, Berlin, Germany; 3Helios Health Institute, Berlin, Germany; 4Helios Health, Berlin, GermanyCorrespondence: Johannes Leiner, Heart Centre Leipzig at University of Leipzig, Department of Electrophysiology, Struempellstrasse 39, Leipzig, 04289, Germany, Tel +49 341 865 251573, Email johannes.leiner@helios-gesundheit.deIntroduction: Type 2 diabetes mellitus (T2DM) is a leading cause of chronic kidney disease (CKD) globally. Both conditions substantially worsen patients’ prognosis. Current data on German in-hospital CKD cohorts are scarce. The multinational CaReMe study was initiated to evaluate the current epidemiology and healthcare burden of cardiovascular, renal and metabolic diseases. In this substudy, we share real-world data on CKD inpatients stratified for coexisting T2DM derived from a large German hospital network.Methods: This study used administrative data of inpatient cases from 89 Helios hospitals from 01/01/2016 to 28/02/2022. Data were extracted from ICD-10-encoded discharge diagnoses and OPS-encoded procedures. The first case meeting a previously developed CKD definition (defined by ICD-10- and OPS-codes) was considered the index case for a particular patient. Subsequent hospitalizations were analysed for readmission statistics. Patient characteristics and pre-defined endpoints were stratified for T2DM at index case.Results: In total, 48,011 patients with CKD were included in the present analysis (mean age ± standard deviation, 73.8 ± 13.1 years; female, 44%) of whom 47.9% had co-existing T2DM. Patients with T2DM were older (75 ± 10.6 vs 72.7 ± 14.9 years, p < 0.001), but gender distribution was similar to patients without T2DM. The burden of cardiovascular disease was increased in patients with T2DM, and index and follow-up in-hospital mortality rates were higher. Non-T2DM patients were characterised by more advanced CKD at baseline. Patients with T2DM had consistently higher readmission numbers for all events of interest, except for readmissions due to kidney failure/dialysis, which were more common in non-T2DM patients.Conclusion: In this study, we present recent data on hospitalized patients with CKD in Germany. In this CKD cohort, nearly half had T2DM, which substantially affected cardiovascular disease burden, rehospitalization frequency and mortality. Interestingly, non-diabetic patients had more advanced underlying renal disease, which affected renal outcomes. Keywords: chronic kidney disease, type 2 diabetes mellitus, administrative data, in-hospital mortality, kidney failure, rehospitalization

The marine coccolithophore species Emiliania huxleyi tolerates a broad range of salinity conditions over its near-global distribution, including the relatively stable physiochemical conditions of open-ocean environments and nearshore environments with dynamic and extreme short-term salinity fluctuations. Previous studies show that salinity impacts the physiology and morphology of E. huxleyi, suggesting that salinity stress influences the calcification of this globally important species. However, it remains unclear how rapidly E. huxleyi responds to salinity changes and therefore whether E. huxleyi morphology is sensitive to short-term transient salinity events (such as occur on meteorological timescales) in addition to longer-duration salinity changes. Here, we investigate the real-time growth and calcification response of two E. huxleyi strains isolated from shelf sea environments to the abrupt onset of hyposaline and hypersaline conditions over a time period of 156 h (6.5 d). Morphological responses in the size of the cell covering (coccosphere) and the calcium carbonate plates (coccoliths) that form the coccosphere occurred as rapidly as 24–48 h following the abrupt onset of salinity 25 (hyposaline) and salinity 45 (hypersaline) conditions. Generally, cells tended towards smaller coccospheres (−24 %) with smaller coccoliths (−7 % to −11 %) and reduced calcification under hyposaline conditions, whereas cells growing under hypersaline conditions had either relatively stable coccosphere and coccolith sizes (Mediterranean strain RCC1232) or larger coccospheres (+35 %) with larger coccoliths (+13 %) and increased calcification (Norwegian strain PLYB11). This short-term response is consistent with reported coccolith size trends with salinity over longer durations of low- and high-salinity exposure in culture and under natural-salinity gradients. The coccosphere size response of PLYB11 to salinity stress was greater in magnitude than was observed in RCC1232 but occurred after a longer duration of exposure to the new salinity conditions (96–128 h) compared to RCC1232. In both strains, coccosphere size changes were larger and occurred more rapidly than changes in coccolith size, which tended to occur more gradually over the course of the experiments. Variability in the magnitude and timing of rapid morphological responses to short-term salinity stress between these two strains supports previous suggestions that the response of E. huxleyi to salinity stress is strain specific. At the start of the experiments, the light condition was also switched from a light : dark cycle to continuous light, with the aim of desynchronising cell division. As cell density and mean cell size data sampled every 4 h showed regular periodicity under all salinity conditions, the cell division cycle retained its entrainment to pre-experiment light : dark conditions for the entire experiment duration. Extended acclimation periods to continuous light are therefore advisable for E. huxleyi to ensure successful desynchronisation of the cell division cycle. When working with phased or synchronised populations, data should be compared between samples taken from the same phase of the cell division cycle to avoid artificially distorting the magnitude or even direction of physiological or biogeochemical response to the environmental stressor.

ObjectivesThe COVID-19 pandemic affected patients’ access to health services, including patients with severe chronic pain. Since limited data on pandemic-caused changes in pain therapy is available, we analyzed its effect on hospital-based pain treatment.MethodsFor this retrospective claims data analysis conducted in n = 37 hospitals, we included patients treated for a chronic pain-related diagnosis. Discharge rates stratified by region and pain unit size were analyzed for different time periods between January 2019 and June 2022.ResultsThere was a significant decrease in day-care, inpatient interdisciplinary multimodal pain management, from a total of 5,533 hospital pre-pandemic treatments in 2019, to 3,942 in 2020 and 4,262 in 2021, with a slight increase in the first half of 2022. The extent of COVID-19-related changes differed depending on region and pain unit size.ConclusionThe decreased number of hospital pain treatments during the pandemic implies a relevant analgesic undertreatment. During future pandemics, the ethical dimension of potentially non-sufficient pain treatment should be weighted against social, medical and hygienic restrictions influencing the hospitalization rate.

The quickly developing drone technology can be used efficiently in the field of pipeline leak detection. The aim of this article is to provide drone mission concepts for detecting releases from pipelines. It provides an overview of the current applications of natural gas pipeline surveys, it considers environmental conditions by plume modelling, it discusses suitable commercially available sensors, and develops concepts for routine monitoring of pipelines and short term missions for localising and identifying a known leakage. Suitable platforms depend on the particular mission and requirements concerning sensors and legislation. As an illustration, a feasibility study during a release experiment is introduced. The main challenge of this study was the variability of wind direction on a time scale of minutes, which produces considerable differences to the plume simulations. Nevertheless, the leakage rates derived from the observations are in the same order of magnitude as the emission rates. Finally the results from the modeling, the release experiment and possible drone scenarios are combined and requirements for future application derived.

Objective Cholecystectomy is one of the most frequently performed surgeries in Germany and is performed as a treatment of acute cholecystitis (guideline S3 IIIB.8) and after endoscopic retrograde cholangiopancreatography for choledocholithiasis with simultaneous cholecystolithiasis (guideline S3 IIIC.6). This article examines the effects of a guideline update from 2017, which recommends prompt cholecystectomy within 24 hours of admission due to cholecystitis or within 72 hours after bile duct repair. In addition, it aims to identify reasons (eg, financial disincentives) and potential for improvement for non-adherence to the guidelines.Design Methodologically, a retrospective analysis based on routine billing data from 84 Helios Group hospitals from 2016 and 2022, with a total of 45 393 included cases, was applied. The guideline adherence rate is used as the main outcome measure.Results Results show the guideline updates led to a statistically significant increase in the proportion of cholecystectomy performed in a timely manner (guideline S3 IIIB.8: increase from 43% to 49%, p

Abstract Background Control and elimination of schistosomiasis is an arduous task, with current strategies proving inadequate to break transmission. Exploration of genetic approaches to interrupt Schistosoma mansoni transmission, the causative agent for human intestinal schistosomiasis in sub-Saharan Africa and South America, has led to genomic research of the snail vector hosts of the genus Biomphalaria. Few complete genomic resources exist, with African Biomphalaria species being particularly underrepresented despite this being where the majority of S. mansoni infections occur. Here we generate and annotate the first genome assembly of Biomphalaria sudanica sensu lato, a species responsible for S. mansoni transmission in lake and marsh habitats of the African Rift Valley. Supported by whole-genome diversity data among five inbred lines, we describe orthologs of immune-relevant gene regions in the South American vector B. glabrata and present a bioinformatic pipeline to identify candidate novel pathogen recognition receptors (PRRs). Results De novo genome and transcriptome assembly of inbred B. sudanica originating from the shoreline of Lake Victoria (Kisumu, Kenya) resulted in a haploid genome size of ~ 944.2 Mb (6,728 fragments, N50 = 1.067 Mb), comprising 23,598 genes (BUSCO = 93.6% complete). The B. sudanica genome contains orthologues to all described immune genes/regions tied to protection against S. mansoni in B. glabrata, including the polymorphic transmembrane clusters (PTC1 and PTC2), RADres, and other loci. The B. sudanica PTC2 candidate immune genomic region contained many PRR-like genes across a much wider genomic region than has been shown in B. glabrata, as well as a large inversion between species. High levels of intra-species nucleotide diversity were seen in PTC2, as well as in regions linked to PTC1 and RADres orthologues. Immune related and putative PRR gene families were significantly over-represented in the sub-set of B. sudanica genes determined as hyperdiverse, including high extracellular diversity in transmembrane genes, which could be under pathogen-mediated balancing selection. However, no overall expansion in immunity related genes was seen in African compared to South American lineages. Conclusions The B. sudanica genome and analyses presented here will facilitate future research in vector immune defense mechanisms against pathogens. This genomic/transcriptomic resource provides necessary data for the future development of molecular snail vector control/surveillance tools, facilitating schistosome transmission interruption mechanisms in Africa.

The escalating threat and impact of network-based attacks necessitate innovative intrusion detection systems. Machine learning has shown promise, with recent strides in quantum machine learning offering new avenues. However, the potential of quantum computing is tempered by challenges in current noisy intermediate-scale quantum era machines. In this article, we explore quantum neural networks (QNNs) for intrusion detection, optimizing their performance within current quantum computing limitations. Our approach includes efficient classical feature encoding, QNN classifier selection, and performance tuning leveraging current quantum computational power. This study culminates in an optimized multilayered QNN architecture for network intrusion detection. A small version of the proposed architecture was implemented on IonQ's Aria-1 quantum computer, achieving a notable 0.86 F1 score using the NF-UNSW-NB15 dataset. In addition, we introduce a novel metric, certainty factor, laying the foundation for future integration of uncertainty measures in quantum classification outputs. Moreover, this factor is used to predict the noise susceptibility of our quantum binary classification system.

Background Even after atrial fibrillation (AF) catheter ablation, many patients still experience relevant symptom burden. The objective of the MENTAL AF trial was to determine whether app‐based mental training (MT) during the 3 months following pulmonary vein isolation reduces AF‐related symptoms. Methods and Results Patients scheduled for pulmonary vein isolation were enrolled and randomized 1:1 to either app‐based MT or usual care. Of 174 patients, 76 in the MT and 75 in the usual care group were included in the final analysis. The intervention was delivered by a daily 10‐minute app‐based MT. The primary outcome was the intergroup difference of the mean AF6 sum score, an AF‐specific questionnaire, during the 3‐month study period. Secondary outcomes included quality‐of‐life measures such as the AFEQT (Atrial Fibrillation Effect on Quality of Life). Mean age (SD) was 61 (8.7) years and 61 (41%) were women. The mean AF6 sum score over the study period was 8.9 (6.9) points in the MT group and 12.5 (10.1) in the usual care group (P=0.011). This referred to a reduction in the AF6 sum score compared with baseline of 75% in MT and 52% for usual care (P

Plant-associated microbes play vital roles in promoting plant growth and health, with plants secreting root exudates into the rhizosphere to attract beneficial microbes. Exudate composition defines the nature of microbial recruitment, with different plant species attracting distinct microbiota to enable optimal adaptation to the soil environment. To more closely examine the relationship between plant genotype and microbial recruitment, we analysed the rhizosphere microbiomes of landrace (Chevallier) and modern (NFC Tipple) barley (Hordeum vulgare) cultivars. Distinct differences were observed between the plant-associated microbiomes of the 2 cultivars, with the plant-growth promoting rhizobacterial genus Pseudomonas substantially more abundant in the Tipple rhizosphere. Striking differences were also observed between the phenotypes of recruited Pseudomonas populations, alongside distinct genotypic clustering by cultivar. Cultivar-driven Pseudomonas selection was driven by root exudate composition, with the greater abundance of hexose sugars secreted from Tipple roots attracting microbes better adapted to growth on these metabolites and vice versa. Cultivar-driven selection also operates at the molecular level, with both gene expression and the abundance of ecologically relevant loci differing between Tipple and Chevallier Pseudomonas isolates. Finally, cultivar-driven selection is important for plant health, with both cultivars showing a distinct preference for microbes selected by their genetic siblings in rhizosphere transplantation assays.

As the global health crisis unfolded, many academic conferences moved online in 2020. This move has been hailed as a positive step towards inclusivity in its attenuation of economic, physical, and legal barriers and effectively enabled many individuals from groups that have traditionally been underrepresented to join and participate. A number of studies have outlined how moving online made it possible to gather a more global community and has increased opportunities for individuals with various constraints, e.g., caregiving responsibilities. Yet, the mere existence of online conferences is no guarantee that everyone can attend and participate meaningfully. In fact, many elements of an online conference are still significant barriers to truly diverse participation: the tools used can be inaccessible for some individuals; the scheduling choices can favour some geographical locations; the set-up of the conference can provide more visibility to well-established researchers and reduce opportunities for early-career researchers. While acknowledging the benefits of an online setting, especially for individuals who have traditionally been underrepresented or excluded, we recognize that fostering social justice requires inclusivity to actively be centered in every aspect of online conference design. Here, we draw from the literature and from our own experiences to identify practices that purposefully encourage a diverse community to attend, participate in, and lead online conferences. Reflecting on how to design more inclusive online events is especially important as multiple scientific organizations have announced that they will continue offering an online version of their event when in-person conferences can resume.

Abstract Background Automated feature selection methods such as the Least Absolute Shrinkage and Selection Operator (LASSO) have recently gained importance in the prediction of quality-related outcomes as well as the risk-adjustment of quality indicators in healthcare. The methods that have been used so far, however, do not account for the fact that patient data are typically nested within hospitals. Methods Therefore, we aimed to demonstrate how to account for the multilevel structure of hospital data with LASSO and compare the results of this procedure with a LASSO variant that ignores the multilevel structure of the data. We used three different data sets (from acute myocardial infarcation, COPD, and stroke patients) with two dependent variables (one numeric and one binary), on which different LASSO variants with and without consideration of the nested data structure were applied. Using a 20-fold sub-sampling procedure, we tested the predictive performance of the different LASSO variants and examined differences in variable importance. Results For the metric dependent variable Duration Stay, we found that inserting hospitals led to better predictions, whereas for the binary variable Mortality, all methods performed equally well. However, in some instances, the variable importances differed greatly between the methods. Conclusion We showed that it is possible to take the multilevel structure of data into account in automated predictor selection and that this leads, at least partly, to better predictive performance. From the perspective of variable importance, including the multilevel structure is crucial to select predictors in an unbiased way under consideration of the structural differences between hospitals.

Abstract In motor control, the brain not only sends motor commands to the periphery, but also generates concurrent internal signals known as corollary discharge (CD) that influence sensory information processing around the time of movement. CD signals are important for identifying sensory input arising from self-motion and to compensate for it, but the underlying mechanisms remain unclear. Using whole-cell patch clamp recordings from neurons in the zebrafish optic tectum, we discovered an inhibitory synaptic signal, temporally locked to spontaneous and visually driven locomotion. This motor-related inhibition was appropriately timed to counteract visually driven excitatory input arising from the fish’s own motion, and transiently suppressed tectal spiking activity. High-resolution calcium imaging revealed localized motor-related signals in the tectal neuropil and the upstream torus longitudinalis, suggesting that CD enters the tectum via this pathway. Together, our results show how visual processing is suppressed during self-motion by motor-related phasic inhibition. This may help explain perceptual saccadic suppression observed in many species.