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Abstract Background Infraocclusion of deciduous teeth is a frequent dental anomaly caused by ankylosis accompanied by local growth disturbance. During puberal growth spurt an increasing progression of infraocclusion is detected. The clinical classification of ankylosed deciduous teeth varies considerably among scientific studies. The aim of this paper is to present an up-to-date overview of the variety of methods. Methods The systematic literature search followed the PRISMA guidelines and included the analysis of the following databases and study registries: PubMed (MEDLINE), the Cochrane Library, Web of Science, Embase.com and ClinicalTrials.gov from database inception until September 23, 2024. Studies that investigated at least one ankylosed deciduous tooth per participant in a quantitative or qualitative manner were included. Studies that evaluated only histological data were excluded. Controlled and uncontrolled clinical studies, retrospective studies, observational studies and cross-sectional studies were included. The studies were restricted to English and German languages. Case reports, case series, comments, expert opinions, letters to the editor, literature reviews and studies enrolling less than 10 patients or 10 infraoccluded teeth in total were excluded. Results Of 5645 records, 42 papers qualified for the final analysis. The evaluation of infraoccluded deciduous teeth was mainly (n = 37) performed by quantitative and semiquantitative assessment of the extent of infraposition at the occlusal level. The measurement reference differed considerably. Fewer studies have analyzed ankylosed deciduous teeth at the alveolar level by examining the contour of the alveolar ridge (n = 7) or the height of the alveolar process (n = 5). Even fewer studies (n = 4) have performed qualitative analysis at the skeletal level by evaluating the influence of the vertical skeletal growth pattern on the incidence of ankylosed deciduous teeth. Conclusions To carry out a comprehensive evaluation of infraoccluded deciduous teeth, an assessment of the occlusal, alveolar and potentially skeletal levels is advisable. Radiographic investigations i.e. panoramic radiographs are therefore essential as a supplement to clinical examination. There is a need for standardization and objectification of the methods for the classification of infraoccluded deciduous teeth to give a general recommendation of clinical performance. Registration This systematic review has been registered in the international prospective register of systematic reviews (PROSPERO) under the registration number: CRD42024555842.

Abstract Providing a better understanding of what makes a compound a successful drug candidate is crucial for reducing the high attrition rates in drug discovery. Analyses of the differences between active compounds, clinical candidates and drugs require high-quality datasets. However, most datasets of drug discovery programs are not openly available. This work introduces a dataset of compound-target pairs extracted from the open-source bioactivity database ChEMBL (release 32). Compound-target pairs in the dataset either have at least one measured activity or are part of the manually curated set of known interactions in ChEMBL. Known interactions between drugs or clinical candidates and targets are specifically annotated to facilitate analyses of differences between drugs, clinical candidates, and other active compounds. In total, the dataset comprises 614,594 compound-target pairs, 5,109 (3,932) of which are known interactions between drugs (clinical candidates) and targets. The extraction is performed in an automated manner and fully reproducible. We are providing not only the datasets but also the code to rerun the analyses with other ChEMBL releases.

Abstract Purpose More accurate prediction of phenotype traits can increase the success of genomic selection in both plant and animal breeding studies and provide more reliable disease risk prediction in humans. Traditional approaches typically use regression models based on linear assumptions between the genetic markers and the traits of interest. Non-linear models have been considered as an alternative tool for modeling genomic interactions (i.e. non-additive effects) and other subtle non-linear patterns between markers and phenotype. Deep learning has become a state-of-the-art non-linear prediction method for sound, image and language data. However, genomic data is better represented in a tabular format. The existing literature on deep learning for tabular data proposes a wide range of novel architectures and reports successful results on various datasets. Tabular deep learning applications in genome-wide prediction (GWP) are still rare. In this work, we perform an overview of the main families of recent deep learning architectures for tabular data and apply them to multi-trait regression and multi-class classification for GWP on real gene datasets. Methods The study involves an extensive overview of recent deep learning architectures for tabular data learning: NODE, TabNet, TabR, TabTransformer, FT-Transformer, AutoInt, GANDALF, SAINT and LassoNet. These architectures are applied to multi-trait GWP. Comprehensive benchmarks of various tabular deep learning methods are conducted to identify best practices and determine their effectiveness compared to traditional methods. Results Extensive experimental results on several genomic datasets (three for multi-trait regression and two for multi-class classification) highlight LassoNet as a standout performer, surpassing both other tabular deep learning models and the highly efficient tree based LightGBM method in terms of both best prediction accuracy and computing efficiency. Conclusion Through series of evaluations on real-world genomic datasets, the study identifies LassoNet as a standout performer, surpassing decision tree methods like LightGBM and other tabular deep learning architectures in terms of both predictive accuracy and computing efficiency. Moreover, the inherent variable selection property of LassoNet provides a systematic way to find important genetic markers that contribute to phenotype expression.

High-resolution paleoclimate records from tropical continental settings are greatly needed to advance understanding of global climate dynamics. The International Continental Scientific Drilling Program (ICDP) project DeepCHALLA recovered a 214.8 m long sediment sequence from Lake Chala, a deep and permanently stratified (meromictic) crater lake in eastern equatorial Africa, covering the past ca. 250 000 years (250 kyr) of continuous lacustrine deposition since the earliest phase of lake-basin development. Lipid biomarker analyses on the sediments of Lake Chala can provide quantitative records of past variation in temperature and moisture balance from this poorly documented region. However, the degree to which climate proxies derived from aquatically produced biomarkers are affected by aspects of lake developmental history is rarely considered, even though it may critically influence their ability to consistently register a particular climate variable through time. Modern-system studies of Lake Chala revealed crucial information about the mechanisms underpinning relationships between proxies based on isoprenoid (iso-) and branched (br-) glycerol dialkyl glycerol tetraethers (GDGTs) and the targeted climate variables, but the persistence of these relationships in the past remains unclear. Here we assess the reliability of long-term climate signals registered in the sediments of Lake Chala by comparing downcore variations in GDGT distributions with major phases in lake-system evolution as reflected by independent proxies of lake depth, mixing regime and nutrient dynamics: seismic reflection data, lithology and fossil diatom assemblages. Together, these records suggest that during early lake history (before ca. 180–200 ka) the distinct mixing-related depth zones with which specific GDGT producers are associated in the modern-day lake were not yet formed, likely due to more open lake hydrology and absence of chemical water-column stratification. Consequently absolute GDGT concentrations dating to this period are relatively low, proxies sensitive to water-column stratification (e.g., branched versus isoprenoid tetraether (BIT) index) display highly irregular temporal variability, and correlations between proxies are dissimilar to expectations based on modern-system understanding. A sequence of lake-system changes between ca. 180–200 and ca. 80 ka first established and then strengthened the chemical density gradient, promoting meromictic conditions despite the overall decrease in lake depth due to the basin gradually being filled up with sediments. From ca. 180 ka onward some GDGTs and derived proxies (e.g., crenarchaeol concentration, BIT index and IR6Me) display strong ∼ 23 kyr periodicity, likely reflecting the predominantly precession-driven insolation forcing of Quaternary climate variability in low-latitude regions. Our results suggest that GDGT-based temperature and moisture-balance proxies in Lake Chala sediments reflect the climate history of eastern equatorial Africa from at least ca. 160 ka onwards, i.e., covering the complete last glacial–interglacial cycle and the penultimate glacial maximum. This work confirms the potential of lacustrine GDGTs for elucidating the climate history of tropical regions at Quaternary timescales, provided they are applied to suitably high-quality sediment archives. Additionally, their interpretation should incorporate a broader understanding of the extent to which lake-system evolution limits the extrapolation back in time of proxy-climate relationships established in the modern system.

Introductionβ-TCP ceramics are bone replacement materials that have recently been tested as a drug delivery system that can potentially be applied to endogenous substances like growth factors found in blood platelets to facilitate positive attributes.MethodsIn this work, we used flow chamber loading to load β-TCP dowels with blood suspensions of platelet-rich plasma (PRP), platelet-poor plasma (PPP), or buffy coat (BC) character. PRP and BC platelet counts were adjusted to the same level by dilution. Concentrations of TGF-β1, PDGF-AB, and IGF-1 from dowel-surrounding culture medium were subsequently determined using ELISA over 5 days. The influence of alginate was additionally tested to modify the release.ResultsConcentrations of TGF-β1 and PDGF-AB increased and conclusively showed a release from platelets in PRP and BC compared to PPP. The alginate coating reduced the PDGF-AB release but did not reduce TGF-β1 and instead even increased TGF-β1 in the BC samples. IGF-1 concentrations were highest in PPP, suggesting circulating levels rather than platelet release as the driving factor. Alginate samples tended to have lower IGF-1 concentrations, but the difference was not shown to be significant.DiscussionThe release of growth factors from different blood suspensions was successfully demonstrated for β-TCP as a drug delivery system with release patterns that correspond to PRP activation after Ca2+-triggered activation. The release pattern was partially modified by alginate coating.

Abstract β-TCP ceramics are versatile bone substitute materials and show many interactions with cells of the monocyte-macrophage-lineage. The possibility of monocytes entering microporous β-TCP ceramics has however not yet been researched. In this study, we used a model approach to investigate whether monocytes might enter β-TCP, providing a possible explanation for the origin of CD68-positive osteoclast-like giant cells found in earlier works. We used flow chambers to unidirectionally load BC, PRP, or PPP into slice models of either 2 mm or 6 mm β-TCP. Immunofluorescence for CD68 and live/dead staining was performed after the loading process. Our results show that monocytes were present in a relevant number of PRP and BC slices representing the inside of our 2 mm slice model and also present on the actual inside of our 6 mm model. For PPP, monocytes were not found beyond the surface in either model. Our results indicate the possibility of a new and so far neglected constituent in β-TCP degradation, perhaps causing the process of ceramic degradation also starting from inside the ceramics as opposed to the current understanding. We also demonstrated flow chambers as a possible new in vitro model for interactions between blood and β-TCP.

Abstract Fluorescence analysis of β-TCP ceramics is often used to describe cells found on said ceramics. However, we found, to our knowledge, so far undescribed artifacts which might sometimes be hard to differentiate from cells due to shape and fluorescence behavior. We tried prolonged ultrasound washing as well as Technovit 9100 fixation to reduce these artifacts. While untreated dowels showed no reduction in artifacts no matter the further treatment, Technovit fixation reduced the artifacts with even further reduction achieved by mechanical cleaning. As a consequence, scientists working with these dowels and likely even other types should try to avoid creating false positive results by considering the existence of these artifacts, checking additional filters for unusual fluorescence and by reducing them by using Technovit fixation when possible.

Lernende Algorithmen gelten aufgrund ihrer irreduziblen Opazität als eigenständige Akteure/Performanzen, die bestehende soziale Gefälle digital amplifizieren, neue Barrieren in technisierten sozialen Ordnungen erzeugen oder Grenzen verschieben können, die den Zugang zu gesellschaftlichen Ressourcen beschränken. Der Artikel vergleicht die beiden dominierenden Ansätze miteinander, die sich mit Entstehung und Effekten dieser automatisierten Mechanismen kritisch auseinandersetzen. Auf Basis der Gegenüberstellung werden schliesslich unterschiedliche reflexive Implikationen und eine diffraktive Lesart medienbildungstheoretischer Interventionen ausgelotet.

Abstract The pseudo‐natural product (pseudo‐NP) concept aims to combine NP fragments in arrangements that are not accessible through known biosynthetic pathways. The resulting compounds retain the biological relevance of NPs but are not yet linked to bioactivities and may therefore be best evaluated by unbiased screening methods resulting in the identification of unexpected or unprecedented bioactivities. Herein, various NP fragments are combined with a tricyclic core connectivity via interrupted Fischer indole and indole dearomatization reactions to provide a collection of highly three‐dimensional pseudo‐NPs. Target hypothesis generation by morphological profiling via the cell painting assay guides the identification of an unprecedented chemotype for Aurora kinase inhibition with both its relatively highly 3D structure and its physicochemical properties being very different from known inhibitors. Biochemical and cell biological characterization indicate that the phenotype identified by the cell painting assay corresponds to the inhibition of Aurora kinase B.

Recently, the first sodium-ion cells have been commercialized and have become available for consumers. Given, moreover, the exciting announcements by several producers of such battery cells, it is of great interest to analyze these first commercial cells in order to understand which materials are used and how these cells are designed. Herein, two types of commercially available sodium-ion battery cells (cylindrical 1.5 Ah 18650 and 3.5 Ah 26700 cells) are investigated regarding (i) their electrode chemistry, (ii) their thermal properties upon discharge as a function of the applied C rate, (iii) the available specific energy, and (iv) their cell impedance. The data are correlated with the electrode thickness and electrode area obtained from an ex situ (ante-mortem) analysis of the 18650 cells, and discussed in comparison with the performance metrics reported for commercial lithium-ion cells. This comparison reveals that the herein studied 18650 sodium-ion cells (hard carbon⎪⎪NaxNiyFezMn1-y-zO2) provide a comparable or even higher specific energy (∼128 Wh kg−1) than that of graphite⎪⎪LiFePO4 lithium-ion cells.

Multi-task learning (MTL) is a learning paradigm whose aim is to leverage information shared across related tasks to improve the generalization of models. Motivated by the success of proximal optimization algorithms and single-task learning regression models, sparse proximal multi-task learning (SPMTL) for genome-wide prediction (GWP) should be explored. This study investigates proximal gradient descent splitting algorithms with five non-smooth sparsity-inducing norm regularizers, including the novel $L_{2,\frac {1}{2}}$ norm for GWP. Additionally, two popular methods based on Markov chain Monte Carlo (MCMC) are examined. To improve the computational efficiency, parallel Bayesian optimization strategy is employed for efficient hyperparameter tuning. Evaluation is conducted on three different real-world genomic datasets from mice, pigs and wheat, each associated with two, five, and four traits, respectively. Performance is assessed using mean squared error (MSE) and correlation coefficient between predicted and observed trait values in test sets. Experimental results reveal that the $L_{2,\frac {1}{2}}$ regularizer consistently achieves the best out-of-sample prediction across all datasets, demonstrating the effectiveness of SPMTL in leveraging shared information for improved GWP accuracy. Furthermore, the influence of different regularizers on sparsity and other properties of the SPMTL model are also explored.

Abstract Background A national colorectal cancer (CRC) screening programme was launched in 2002 in Germany. A comprehensive evaluation of the programme effectiveness using real-world data is still lacking. In addition, there are regional reports on increasing colorectal cancer incidence in younger populations. Therefore, we aimed to describe and compare the overall, age- and stage-specific incidence trends for colorectal, colon and rectal cancer. Methods We used data from seven population-based cancer registries in Germany. We report absolute and relative changes in incidence rates between the early screening phase (2003–2005) and the most recent time period available (2015–2017), as well as annual percent changes. We analysed incidences according to tumour site (colorectum, colon, and rectum) and to six age groups (young adults: 15–34, 35–39, 40–49, screening-entitled/older adults: 50–54, 55–69 and 70 + years old). Results In our sample of 271,011 colorectal adenocarcinomas, about two-thirds were located in the colon and 95% of them occurred in the age group 50+ (50–54: 5%, 55–69: 32.8%, 70+: 57.2%). For the time period 2003–2005 the age-specific incidence rates of individuals in the age group 55–69 were about 76/100,00 for colon and 54/100,000 for rectal cancer (age group 70 + colon: 179/100,000; rectum: 84/100,000). The incidence rates in young adults were less than 13% of that of individuals in the age group 55–69 (

Abstract Background Children of families with a parent with a mental illness have an increased risk of developing social and mental health problems resulting in decreased quality of life. Therefore, children and adolescents living in families with a parent with mental illness are regarded as a target group for preventive interventions. To date, only a few economic evaluation studies for interventions directed at preventing the intergenerational transmission of mental health problems exist. In this investigation we estimated the cost utility of an intervention for the support of children and adolescents with a parent having a mental illness from the perspective of the German health and social care system. Methods We randomly assigned a total of 214 families with 337 children and adolescents to the intervention (INT) group (108/170) or the control (TAU) group (106/167). Families in the intervention group received on average eight intervention sessions (50–90 min) over 6 months. We estimated total cost of illness by means of the Children and Adolescent Mental Health Service Receipt Inventory (CAMHSRI) over 24 months. For the estimation of Quality-Adjusted Live Years (QALYs) we applied the KIDSCREEN-10. For estimating the incremental cost-utility of the intervention compared to treatment as usual we used the net-benefit approach. Results We estimated the annual cost of illness amounting to € 3784.59 (SD € 8581.11) in the TAU group and € 3264.44 (SD € 9431.89) in the INT group. The annual cost difference between INT and TAU was € − 516.14 (SE 1124.95) which was not significant (p ≤ 0.05). We estimated the average QALY to be 0.759 (SD 0.073) in the TAU group and 0.763 (SD 0.072). The QALY difference between INT and TAU was 0.0037 (SE 0.0092) which was not significant (p ≤ 0.05). The incremental cost utility ratio (ICUR) indicated that the gain of one additional year in full health by means of the intervention was associated with the saving of € 139.49. However, the stochastic insecurity of the ICUR did not allow a unique decision about the cost-utility of the intervention. Conclusions More information on the economic value of the intervention for families with a parent with mental illness in comparison to treatment as usual in Germany is needed. Trial registration: ClinicalTrials.gov, identifier NCT02308462; German Clinical Trials Register: DRKS00006806.

Development of urban green areas and awareness of their value among citizens and local authorities is rapidly growing. This trend is not only the result of the coronavirus pandemic, but also reflects a belief in the role of green areas in reducing the negative effects of climate change and supporting overall well-being. As a consequence, more and more local governments are promoting local policies focused on the development of urban green areas with the participation of citizens. Using data collected in Zielona Góra, Poland, this study explores the gender patterns and differences in use and preferences according to the development of urban green areas. The main goals of the study were (1) to evaluate the possible relationship between gender and preferred types of visited green areas and transport modes used to reach them and (2) to explore the differences in expectations regarding the spatial development of green areas among men and women. The result of the study shows that women more often than men visit green areas closer to their place of residence and more often indicate playgrounds and other forms of greenery of an aesthetic function as proposed green areas. Furthermore, there are also differences regarding the means of transport used and preferable distance to green areas. Women visibly prefer green areas within the city centre, mostly use individual means of transport, and are more likely to travel on foot than men. Men prefer more distant green areas and mostly travel longer distances.

External Quality Assessment schemes (EQAS) are mandatory to ensure quality standards in diagnostic methods and achieve laboratory accreditation. As host institution for two German culture-based bacteriology EQAS (RV-A and RV-B), we investigated the obtained data of 590 up to 720 surveys per year in RV-A and 2,151 up to 2,929 in RV-B from 2006 to 2023. As educational instruments, they function to review applied methodology and are valuable to check for systemic- or method-dependent failures in microbiology diagnostics or guidelines. Especially, containment of multi-resistant bacteria in times of rising antibiotic resistance is one major point to assure public health. The correct identification and reporting of these strains is therefore of high importance to achieve this goal. Moreover, correct antimicrobial susceptibility testing (AST) per se is important for selecting appropriate therapy, to restrict broad-spectrum antibiotics and minimize resistance development. The reports of participating laboratories displayed a high level of correct identification results in both schemes with mostly consistent failure rates around 2.2% (RV-A) and 3.9% (RV-B) on average. In contrast, results in AST revealed increasing failure rates upon modification of AST requirements concerning adherence to standards and subsequent bacterial species-specific evaluation. Stratification on these periods revealed in RV-A a moderate increase from 1.3% to 4.5%, while in RV-B failure rates reached 14% coming from 4.3% on average. Although not mandatory, subsequent AST evaluation and consistent reporting are areas of improvement to benefit public health.

Background A risk model has been proposed to provide a patient individualized estimation of risk for major clinical events (heart failure events, ventricular arrhythmia, all‐cause mortality) in patients with transposition of the great arteries and atrial switch surgery. We aimed to externally validate the model. Methods and Results A retrospective, multicentric, longitudinal cohort of 417 patients with transposition of the great arteries (median age, 24 years at baseline [interquartile range, 18–30]; 63% men) independent of the model development and internal validation cohort was studied. The performance of the prediction model in predicting risk at 5 years was assessed, and additional predictors of major clinical events were evaluated separately in our cohort. Twenty‐five patients (5.9%) met the major clinical events end point within 5 years. Model validation showed good discrimination between high and low 5‐year risk patients (Harrell C index of 0.73 [95% CI, 0.65–0.81]) but tended to overestimate this risk (calibration slope of 0.20 [95% CI, 0.03–0.36]). In our population, the strongest independent predictors of major clinical events were a history of heart failure and at least mild impairment of the subpulmonary left ventricle function. Conclusions We reported the first external validation of a major clinical events risk model in a large cohort of adults with transposition of the great arteries. The model allows for distinguishing patients at low risk from those at intermediate to high risk. Previous episode of heart failure and subpulmonary left ventricle dysfunction appear to be key markers in the prognosis of patients. Further optimizing risk models are needed to individualize risk predictions in patients with transposition of the great arteries.

The applicability of electrical impedance tomography (EIT) in birds is unknown. This study aimed to evaluate the use of EIT in anaesthetised chickens in four recumbency positions. Four adult Hyline chickens were anaesthetised with isoflurane in oxygen, and intubated endotracheally for computed tomography (CT). A rubber belt was placed around the coelom caudal to the shoulder joint. A chicken-specific finite element (FE) model, which is essential to generate anatomically accurate functional EIT images for analysis, was constructed based on the CT images obtained at the belt level. Ten additional chickens were anaesthetised with the same protocol. An EIT electrode belt was placed at the same location. The chickens were breathing spontaneously and positioned in dorsal, ventral, right and left lateral recumbency in a randomised order. For each recumbency, raw EIT data were collected over 2 min after 13 min of stabilisation. The data were reconstructed into functional EIT images. EIT variables including tidal impedance variation (TIV), centre of ventilation right to left (CoVRL) and ventral to dorsal (CoVVD), right to left (RL) ratio, impedance change (ΔZ) and eight regional impedance changes including the dorsal, central-dorsal, central-ventral and ventral regions of the right and left regions were analysed. Four breathing patterns (BrP) were observed and categorised based on the expiratory curve. A linear mixed model was used to compare EIT variables between recumbencies. Fisher's exact test was used to compare the frequencies of breathing patterns for each recumbency. The ΔZ observed was synchronous to ventilation, and represented tidal volume of the cranial air sacs as confirmed by CT. Significant differences were found in CoVVD and regional impedance changes between dorsal and ventral recumbencies (P < 0.05), and in CoVRL, RL ratio and regional impedance changes between right and left recumbencies (P < 0.05), which suggested a tendency for the distribution of ventilation to shift towards non-dependent air sacs. No differences were found for TIV and respiratory rate between recumbencies. Recumbency had a significant effect on the frequencies of each of the four BrPs (P = 0.001). EIT can monitor the magnitude and distribution of ventilation of the cranial air sacs in different recumbencies in anaesthetised chickens.

Abstract Endotracheal suctioning is a widely used procedure to remove secretions from the airways of ventilated patients. Despite its prevalence, regional effects of this maneuver have seldom been studied. In this study, we explore its effects on regional lung aeration in neonates and young infants using electrical impedance tomography (EIT) as part of the large EU-funded multicenter observational study CRADL. 200 neonates and young infants in intensive care units were monitored with EIT for up to 72 h. EIT parameters were calculated to detect changes in ventilation distribution, ventilation inhomogeneity and ventilation quantity on a breath-by-breath level 5–10 min before and after suctioning. The intratidal change in aeration over time was investigated by means of regional expiratory time constants calculated from all respiratory cycles using an innovative procedure and visualized by 2D maps of the thoracic cross-section. 344 tracheal suctioning events from 51 patients could be analyzed. They showed no or very small changes of EIT parameters, with a dorsal shift of the center of ventilation by 0.5% of the chest diameter and a 7% decrease of tidal impedance variation after suctioning. Regional time constants did not change significantly. Routine suctioning led to EIT-detectable but merely small changes of the ventilation distribution in this study population. While still a measure requiring further study, the time constant maps may help clinicians interpret ventilation mechanics in specific cases.

Abstract Targeted proteasomal and autophagic protein degradation, often employing bifunctional modalities, is a new paradigm for modulation of protein function. In an attempt to explore protein degradation by means of autophagy we combine arylidene-indolinones reported to bind the autophagy-related LC3B-protein and ligands of the PDEδ lipoprotein chaperone, the BRD2/3/4-bromodomain containing proteins and the BTK- and BLK kinases. Unexpectedly, the resulting bifunctional degraders do not induce protein degradation by means of macroautophagy, but instead direct their targets to the ubiquitin-proteasome system. Target and mechanism identification reveal that the arylidene-indolinones covalently bind DCAF11, a substrate receptor in the CUL4A/B-RBX1-DDB1-DCAF11 E3 ligase. The tempered α, β-unsaturated indolinone electrophiles define a drug-like DCAF11-ligand class that enables exploration of this E3 ligase in chemical biology and medicinal chemistry programs. The arylidene-indolinone scaffold frequently occurs in natural products which raises the question whether E3 ligand classes can be found more widely among natural products and related compounds.

Background: Approximately 27% of female breast cancer patients are diagnosed before the age of 55, a group often comprising mothers with young children. Maternal psychosocial well-being significantly impacts these children’s psychosocial well-being. This study assesses the well-being of children with mothers who have early-onset breast cancer. Methods: We examined the eldest child (up to 15 years old) of women with nonmetastatic breast cancer (

Polyphosphate (polyP) is an evolutionary ancient inorganic molecule widespread in biology, exerting a broad range of biological activities. The intracellular polymer serves as an energy storage pool and phosphate/calcium ion reservoir with implications for basal cellular functions. Metabolisms of the polymer are well understood in procaryotes and unicellular eukaryotic cells. However, functions, regulation, and association with disease states of the polymer in higher eukaryotic species such as mammalians are just beginning to emerge. The review summarises our current understanding of polyP metabolism, the polymer’s functions, and methods for polyP analysis. In-depth knowledge of the pathways that control polyP turnover will open future perspectives for selective targeting of the polymer.

The building sector's significant greenhouse gas emissions and energy consumption present added challenges to meeting European climate commitments amidst rapid population growth. In Luxembourg, single-family houses dominate the residential buildings, noticeably contributing to construction waste and CO2 emissions. This study compares the environmental impacts of a three-story reinforced concrete masonry single-family house and an identical timber building in Luxembourg, emphasizing greenhouse gas emissions and embodied energy. A cradle-to-grave life cycle assessment was conducted using Building Information Modelling (BIM) models to analyze the global warming potential and primary energy requirements. Environmental product declarations from the producers and the ÖKOBAUDAT German database were used to determine the environmental impacts of the materials. The results show that the timber building outperforms the concrete building with a 43.5% lower global warming potential, while the concrete building demonstrates a 15.6% reduction in primary energy demand. This aligns with the average outcomes of seven similar studies discussed in this paper, at 33.2% and 4.7%, respectively. Moreover, the timber building is 78.6% lighter than the concrete one. When evaluating benefits and loads beyond the system boundary, the timber building provides 3.6 and 4 times greater advantages in terms of global warming potential and primary energy, respectively, compared to the reinforced concrete masonry building. Additionally, the study explores the impact of reusing the floors in the timber building. The cradle-to-grave LCA reveals that reusing the timber slabs improves the building's global warming potential and primary energy by 2.4% and 1.2%, respectively. However, when considering the benefits and loads beyond the system boundary, floor system reuse exhibits a 38.9% surge in global warming advantages while reducing primary energy benefits by 28.1%. The findings advocate for a policy promoting timber construction and reuse in Luxembourg, aiming to achieve the net-zero emission target by 2050.

IntroductionWe examined the concurrent language and cognitive abilities in a group of Swedish students with different reading profiles in secondary school, and the retrospective (primary school) and prospective (upper-secondary school) reading skills of each reading profile.MethodsSeventy-nine students participated in data collections in primary (grade 2: age 8), secondary (grade 8: age 14) and upper-secondary school (year 2: age 17). Independent variables included measures of word recognition, and vocabulary and text comprehension in secondary school. Dependent variables included measures of phonemic awareness, verbal fluency, listening comprehension, spelling, verbal working memory and nonverbal reasoning skills in secondary school, and word recognition and reading comprehension in primary and upper-secondary school.ResultsWhen exploring the concurrent language and cognitive abilities of the reading profiles in secondary school, spelling emerged as a weakness and listening comprehension as a strength for students with poor decoding. Students with poor comprehension experienced weaknesses in spelling, and non-verbal reasoning. Students with both poor decoding and comprehension displayed a multi-deficit profile in language and cognition. As regards the retrospective and prospective reading skills, the relative ranking of the reading profiles was rather consistent in both primary and upper-secondary school.DiscussionThe findings suggest that limitations in phonological awareness may not be a prominent feature of secondary school students with poor decoding in more transparent orthographies. From an educational perspective, spoken sources may support learning among students with poor decoding, whereas students with poor comprehension or combined difficulties in decoding and comprehension need support when learning from both spoken and written sources.

Clavicle fractures combined with sternoclavicular joint dislocations are very rare injuries that need to be addressed quickly and treated effectively due to the altered biomechanics of the shoulder girdle as well as to the potential damages to the surrounding “noble” anatomical structures.A diagnostic and therapeutic algorithm for such injuries has not yet been established. Computer Tomography with 3D reconstruction should be the diagnostic gold standard. In case of a highly displaced fracture and/or dislocation in an active patient, surgical treatment is advised in order to obtain proper bone and joint healing with satisfactory functional outcomes as well as to protect the surrounding anatomical structures from potential damages.We present the case of an 18-year-old male, skeletally mature patient, who had a fall while snowboarding. Subsequently he was diagnosed with a very uncommon combination of a displaced medial clavicle fracture and complete posterior Sterno-Clavicular dislocation with 111° rotation of the sternoclavicular fragment. We opted for surgery, decided to use “off-label” a 2.5 V-plate Ulna plate long (Medartis®) and to associate this procedure with a Sterno-Clavicular arthrodesis with tape-augmentation to stabilize the SC joint; this treatment strategy resulted in a good clinical outcome without any remaining instability and satisfactory ROM.We collected this case to describe this seldom combination, to show our treatment strategy and to advocate the creation of a standardized diagnostic and therapeutic algorithm. X-rays, Computer Tomography images and intraoperative photos are presented.

(1) Background: The health-related quality of life (HRQOL) of colorectal cancer (CRC) survivors >10 years post-diagnosis is understudied. We aimed to compare the HRQOL of CRC survivors 14–24 years post-diagnosis to that of age- and sex-matched non-cancer controls, stratified by demographic and clinical factors. (2) Methods: We used data from 506 long-term CRC survivors and 1489 controls recruited from German population-based multi-regional studies. HRQOL was assessed with the European Organization for Research and Treatment of Cancer Quality of Life Core-30 (EORTC QLQ-C30) questionnaire. We estimated differences in the HRQOL of CRC survivors and controls with multiple regression, adjusted for age at survey, sex, and education, where appropriate. (3) Results: CRC survivors reported poorer social functioning but better health status/QOL than controls. CRC survivors, in general, had higher levels of symptom burden, and in particular diarrhea and constipation, regardless of demographic or clinical factors. In stratified analyses, HRQOL differed by age, sex, cancer type, and having a permanent stoma. (4) Conclusions: Although CRC survivors may have a comparable health status/QOL to controls 14–24 years after diagnosis, they still live with persistent bowel dysfunction that can negatively impact aspects of functioning. Healthcare providers should provide timely and adapted follow-up care to ameliorate potential long-term suffering.

Cow uterine infections pose a challenge in dairy farming, resulting in reproductive disorders. Uterine fluid extracellular vesicles (UF-EVs) play a key role in cell-to-cell communication in the uterus, potentially holding the signs of aetiology for endometritis. We used mass spectrometry-based quantitative shotgun proteomics to compare UF-EV proteomic profiles in healthy cows (H), cows with subclinical (SE) or clinical endometritis (CLE) sampled at 28–35 days postpartum. Functional analysis was performed on embryo cultures with the exposure to different EV types. A total of 248 UF-EV proteins exhibited differential enrichment between the groups. Interestingly, in SE, EV protein signature suggests a slight suppression of inflammatory response compared to CLE-UF-EVs, clustering closer with healthy cows’ profile. Furthermore, CLE-UF-EVs proteomic profile highlighted pathways associated with cell apoptosis and active inflammation aimed at pathogen elimination. In SE-UF-EVs, the regulation of normal physiological status was aberrant, showing cell damage and endometrial repair at the same time. Serine peptidase HtrA1 (HTRA1) emerged as a potential biomarker for SE. Supplementation of CLE- and SE-derived UF-EVs reduced the embryo developmental rates and quality. Therefore, further research is warranted to elucidate the precise aetiology of SE in cattle, and HTRA1 should be further explored as a potential diagnostic biomarker.

Ventricular arrhythmias (VAs) in heart failure are enhanced by sympathoexcitation. However, radiotracer studies of catecholamine uptake in failing human hearts demonstrate a proclivity for VAs in patients with reduced cardiac sympathetic innervation. We hypothesized that this counterintuitive finding is explained by heterogeneous loss of sympathetic nerves in the failing heart. In a murine model of dilated cardiomyopathy (DCM), delayed PET imaging of sympathetic nerve density using the catecholamine analog [11C]meta-Hydroxyephedrine demonstrated global hypoinnervation in ventricular myocardium. Although reduced, sympathetic innervation in 2 distinct DCM models invariably exhibited transmural (epicardial to endocardial) gradients, with the endocardium being devoid of sympathetic nerve fibers versus controls. Further, the severity of transmural innervation gradients was correlated with VAs. Transmural innervation gradients were also identified in human left ventricular free wall samples from DCM versus controls. We investigated mechanisms underlying this relationship by in silico studies in 1D, 2D, and 3D models of failing and normal human hearts, finding that arrhythmogenesis increased as heterogeneity in sympathetic innervation worsened. Specifically, both DCM-induced myocyte electrical remodeling and spatially inhomogeneous innervation gradients synergistically worsened arrhythmogenesis. Thus, heterogeneous innervation gradients in DCM promoted arrhythmogenesis. Restoration of homogeneous sympathetic innervation in the failing heart may reduce VAs.

IntroductionSelf-efficacy for writing (SEW) and reading ability are some of several factors that may be related to the quality of written text that students produce. The aim of the current study was (1) to explore the variation in SEW and written text quality in L1-Swedish and L2-English among upper secondary students with different reading profiles in L1 (typical reading vs. reading difficulties) and with different study backgrounds (SB1year or SB2years = one or two years of studies of Swedish and English, respectively), and in the next step (2) to explore if individual variations in L1-reading and SEW may explain variation in written text quality.MethodsParticipants were 100 upper secondary students (aged 17–18) with different reading profiles operationalized as typical reading and reading difficulties. Data consisted of screening for word recognition and reading comprehension, text quality results from argumentative L1- and L2-writing tasks, school information on study background in Swedish/English, and students’ responses from an online survey about SEW.ResultsAs to SEW results, an ANOVA revealed significant main effects for reading profile and study background in L1, but in L2 there was only a significant main effect for reading profile. Written text quality results indicated that there was a significant interaction effect between reading profile and study background in L1, indicating that the significant main effect for reading profile on written text quality was influenced by the group of students with reading difficulties and SB1year. There was a significant main effect for reading profile and study background on written text quality in L2. Students with reading difficulties and SB1year were the most vulnerable group, and they had the lowest scores in L1/L2 SEW and written text quality in L1 and L2. Multiple regression results indicated that word recognition and SEW contributed significantly to L1-text quality, and word recognition, reading comprehension, and SEW contributed significantly to L2-text quality. Thus, this study sheds light on the under-researched area of L1/L2 SEW and text quality of students with reading difficulties at the level of upper secondary school.DiscussionPedagogical implications are discussed and highlight the need for writing instruction across subjects in upper secondary school and for extra writing support/scaffolding for students with reading difficulties and shorter study background in the language subjects L1 (Swedish) and L2 (English).

Congenital heart disease (CHD) often involves the systemic right ventricle (SRV), which is the morphological right ventricle that supports systemic circulation. SRV patients are at a higher risk of sudden cardiac death (SCD) than other adult CHD patients and continues to be a significant cause of death in this aging population. However, the pathophysiology of ventricular arrhythmias in SRV is still not fully understood, and there may be differences between subtypes of CHD. Although these events are rare, predicting them is challenging. This review discusses contemporary strategies for assessing and preventing the risk of ventricular arrhythmias in SRV patients. Several risk factors have been identified to be associated with ventricular arrhythmias in patients with SRV. A recent risk stratification model combines independently associated factors into a risk score, and subpulmonary left ventricle dysfunction is emerging as a critical factor in risk assessment. Cardiac magnetic resonance imaging, biomarkers, and genetic data may refine the ability to predict ventricular arrhythmias in SRV. However, the question of whether implantable cardioverter-defibrillators (ICDs) should be used as a preventive measure in this cohort remains unanswered. Multicenter studies are needed to evaluate risk models and ICD use in this aging population. Given that ICDs have drawbacks, such as a high rate of inappropriate shocks and late lead-related complications, shared clinical decision-making is crucial when considering their use. The review emphasizes the need for further research in this area to improve the identification of patients at risk of clinical ventricular arrhythmias and to develop effective prevention strategies.

Modern missiles must deal with stringent performance requirements and ensure robustness across a wide range of operating conditions during flight time. Classic gain-scheduling designs have been successful in practice, but do not provide theoretically ensured bounds on both performance and robustness. Controllers are interpolated at intermediate operating conditions and switching them may cause instability. On the other hand, polytopic linear parameter-varying (LPV) controllers avert this switching and use real-time information about the plant, in order to smooth out the gain scheduling. We hereby propose a novel procedure to yield an output feedback LPV controller that ensures robust $\text{H}_{\infty} $ performance to a missile longitudinal autopilot. Our novel approach considers the four-block loop-shaping $\text{H}_{\infty} $ control theory with polytopic LPV weights that use polytopic coordinates of the LPV plant. One is capable of adjusting the singular values of the open-loop plant individually at the polytope vertices, and benefits from a trade-off between linear matrix inequalities (LMI) based optimization tools and the designer experience. This can be construed as a natural extension of the traditional $\text{H}_{\infty} $ loop-shaping method that uses linear time-invariant (LTI) weights. Assuming the scheduling variables are frozen, we also include LMI conditions for assigning closed-loop poles and hence circumvent controller order reduction. Nonlinear simulations assess the proposed autopilot, and results show an improved robust stability margin, in addition to an improved response to the acceleration command, concerning the LTI-based approach.

Bioelectrical signals are often pulse-shaped with superimposed interference signals. In this context, accurate identification of features such as pulse onsets, peaks, amplitudes, and duration is a frequent problem. In this paper, we present a versatile method of rather low computational complexity to robustly identify such features in real-world signals. For that, we take use of two straight-line models fit to the observations by minimizing a quadratic cost term, and then identify desired features by tweaked likelihood measures. To demonstrate the idea and facilitate access to the method, we provide examples from the field of cardiology.

Objectives: Avoiding inadvertent hypothermia during surgery is important. Intravenous fluid warmers used intraoperatively are critical for maintaining euthermia. We sought to prospectively evaluate the performance of the parylene-coated enFlow™ intravenous fluid warmer in patients undergoing surgery. Methods: This was a prospective two-center observational clinical trial performed in inpatient surgical services of two large academic hospital systems. After written informed consent, patients were enrolled in the trial. All patients were adults scheduled for a surgery that was expected to last for at least 1 h with the administration of at least 1 L of fluid warmed prior to infusion. Patient temperature was recorded in the preoperative unit, at the induction of anesthesia, and then every 15 or 30 min until the end of surgery. Temperature monitoring continued in the recovery unit. The parylene-coated enFlow™ intravenous fluid warmer was used in addition to the usual patient warming techniques. The primary outcome was the average core temperature, and secondary analyses assessed individual temperature measurements, temperature measurements during specific time periods, and rate of hypothermic events. Results: In all, 50 patients (29 males) with a mean age of 64 years were included in the analysis. The mean surgical time was 195 min and patients received an average of 1142 mL of fluids. Core temperature dropped by only 0.3°C approximately 60 min after induction and recovered back to the baseline level approximately 60 min later. There was no correlation between flow rate and measured core body temperature. Conclusions: The parylene-coated enFlow intravenous fluid warmer was able to warm fluids at all flow rates during prolonged surgery. The results showed that enFlow performed as expected.

We present a comprehensive analysis of the Hubble Space Telescope observations of the atmosphere of WASP-121 b, an ultra-hot Jupiter. After reducing the transit, eclipse, and phase-curve observations with a uniform methodology and addressing the biases from instrument systematics, sophisticated atmospheric retrievals are used to extract robust constraints on the thermal structure, chemistry, and cloud properties of the atmosphere. Our analysis shows that the observations are consistent with a strong thermal inversion beginning at ∼10 ^4 Pa on the dayside, solar to subsolar metallicity Z (i.e., $-0.77\lt \mathrm{log}({\text{}}Z)\lt 0.05$ ), and supersolar C/O ratio (i.e., 0.59 < C/O < 0.87). More importantly, utilizing the high signal-to-noise ratio and repeated observations of the planet, we identify the following unambiguous time-varying signals in the data: (i) a shift of the putative hotspot offset between the two phase curves and (ii) varying spectral signatures in the transits and eclipses. By simulating the global dynamics of WASP-121 b's atmosphere at high resolution, we show that the identified signals are consistent with quasiperiodic weather patterns, hence atmospheric variability, with signatures at the level probed by the observations (∼5% to ∼10%) that change on a timescale of ∼5 planet days; in the simulations, the weather patterns arise from the formation and movement of storms and fronts, causing hot (as well as cold) patches of atmosphere to deform, separate, and mix in time.

Current endeavours in exoplanet characterization rely on atmospheric retrieval to quantify crucial physical properties of remote exoplanets from observations. However, the scalability and efficiency of said technique are under strain with increasing spectroscopic resolution and forward model complexity. The situation has become more acute with the recent launch of the James Webb Space Telescope and other upcoming missions. Recent advances in machine learning provide optimization-based variational inference as an alternative approach to perform approximate Bayesian posterior inference. In this investigation we developed a normalizing-flow-based neural network, combined with our newly developed differentiable forward model, Diff - τ , to perform Bayesian inference in the context of atmospheric retrievals. Using examples from real and simulated spectroscopic data, we demonstrate the advantages of our proposed framework: (1) training our neural network does not require a large precomputed training set and can be trained with only a single observation; (2) it produces high-fidelity posterior distributions in excellent agreement with sampling-based retrievals; (3) it requires up to 75% fewer forward model calls to converge to the same result; and (4) this approach allows formal Bayesian model selection. We discuss the computational efficiencies of Diff - τ in relation to TauREx3 's nominal forward model and provide a “lessons learned” account of developing radiative transfer models in differentiable languages. Our proposed framework contributes toward the latest development of neural network–powered atmospheric retrieval. Its flexibility and significant reduction in forward model calls required for convergence holds the potential to be an important addition to the retrieval tool box for large and complex data sets along with sampling-based approaches.

IntroductionElectrical impedance tomography (EIT) allows assessment of ventilation and aeration homogeneity which may be associated with respiratory outcomes in preterm infants.MethodsThis was a secondary analysis to a recent randomized controlled trial in very preterm infants in the delivery room (DR). The predictive value of various EIT parameters assessed 30 min after birth on important respiratory outcomes (early intubation

Snakebite envenoming (SBE) is a grossly neglected tropical disease (NTD) that predominantly affects those living in rural settings in low-and-middle income countries. South Asia currently accounts for the highest global SBE-related mortality, and substantial morbidity rates. To alleviate the high burden in the region, community engagement (CE) is considered to be an integral component for optimizing SBE prevention and control. To better understand existing CE practices for SBE in the region, the experiences of SBE-CE actors concerning the barriers to, and enablers of CE practices were captured through semi-structured interviews. Fifteen key informants from India, Bangladesh and Nepal participated in the study. Important enablers included providing innovative, inclusive and continuous methods and materials, carefully planning of programs, performing monitoring and evaluation, SBE data availability, motivated and trained staff members, good organizational reputations, communication with other SBE-actors, collaborations, and the involvement of the government. Substantial barriers comprised a lack of SBE data, lack of innovative methods and materials for educational purposes, a shortage of human and physical resources, community resistance, untrained health care workers (HCWs), and ineffective traditional healing practices. In order to optimize and sustain SBE-CE practices, context-sensitive, multi-faceted approaches are needed that incorporate all these factors which influence its sustainable implementation.

Abstract Giant seafloor craters are known along many a continental margin with recurrent mass-wasting deposits. However, the impact of breakup-related magmatism on the evolution of such craters is barely understood. Using high-quality geophysical datasets, this work examines the genetic relationship among the location of magmatic sills, forced folds and the formation of giant paleo-seafloor craters underneath an ancient mass-transport complex in the Møre and Vøring basins, offshore Norway. The data reveal that forced folding of near-seafloor strata occurred because of the intrusion of several interconnected magmatic sills. Estimates of 1-dimensional uplift based on well data show that uplift occurred due to the intrusion of magma in Upper Cretaceous to Lower Eocene strata. Our findings also prove that subsurface fluid plumbing associated with the magmatic sills was prolonged in time and led to the development of several vertical fluid flow conduits, some of which triggered mass wasting in Neogene to Recent times. The repeated vertical expulsion of subsurface fluids weakened the strata on the continental slope, thereby promoting mass wasting, the selective cannibalization of the paleo-seafloor, and the formation of elongated craters at the basal shear zone of the mass-transport complex. Significantly, the model presented here proves a close link between subsurface magmatic plumbing systems and mass wasting on continental margins.

In this study, in operandi SAXS experiments were conducted on samples of human hair with a varying degree of strain (2% within the elastic region and 10% beyond). Four different features in the SAXS patterns were evaluated: The intermediate filament distance perpendicular to and the distance from the meridional arc in the load direction, as well as the distances of the lipid bilayer peak in and perpendicular to the load direction. From the literature, one concludes that polar lipids in the cuticle are the origin of the lipid peak in the SAXS pattern, and this study shows that the observed strain in the lipids is much lower than in the intermediate filaments. We support these findings with SEM micrographs, which show that the scales in the cuticle deform much less than the cortex. The observed deformation of the intermediate filaments is very high, about 70% of the macrostrain, and the ratio of the transverse strain to the longitudinal strain at the nanoscale gives a Poisson ratio of νnano = 0.44, which is typical for soft matter. This work also finds that by varying the time period between two strain cycles, the typical strain recovery time is about 1000 min, i.e., one day. After this period, the structure is nearly identical to the initial structure, which suggests an interpretation that this is the typical time for the self-healing of hair after mechanical treatment.

This study determined the impact of subclinical intramammary infections (IMIs), such as the major and minor udder pathogens (MaPs and MiPs), on the somatic cell count (SCC) in cow milk and investigated the possibilities of indirect sensing of the udder pathogens using the mastitis detection index (MDi) (DeLaval, Tumba, Sweden). The MDi incorporates quarter-level milk electrical conductivity, blood in milk, and milking interval. The case group (n = 21; MDi ≥ 1.4) was compared with the control group (n = 24; MDi < 1.4) for the presence of IMIs. The microbiological investigation of udder quarter foremilk samples was performed two times with an interval of 10 to 14 days. The case and control groups differed in terms of the occurrence of MaPs and MiPs in milk. During the continuous subclinical IMI and the episodic MaP infection, a higher SCC was detected compared with the episodic MiP infection or quarters without IMI. The novel finding of this study was that by using the milk quality sensor for the sensing of subclinical IMIs, there was an indication for the successful detection of episodic MaPs. However, the sensing of the continuous subclinical IMIs was not possible in the current study and still needs to be investigated.

Abstract Background Perioperative hypothermia is a common occurrence, particularly with the elderly and pediatric age groups. Hypothermia is associated with an increased risk of perioperative complications. One method of preventing hypothermia is warming the infused fluids given during surgery. The enFlow™ intravenous fluid warmer has recently been reintroduced with a parylene coating on its heating blocks. In this paper, we evaluated the impact of the parylene coating on the new enFlow’s fluid warming capacity. Methods Six coated and six uncoated enFlow cartridges were used. A solution of 10% propylene glycol and 90% distilled H2O was infused into each heating cartridge at flow rates of 2, 10, 50, 150, and 200 ml/min. The infused fluid temperature was set at 4 °C, 20 °C, and 37 °C. Output temperature was recorded at each level. Data for analysis was derived from 18 runs at each flow rate (six cartridges at three temperatures). Results The parylene coated fluid warming cartridge delivered very stable output of 40 °C temperatures at flow rates of 2, 10, and 50 ml/min regardless of the temperature of the infusate. At higher flow rates, the cartridges were not able to achieve the target temperature with the colder fluid. Both cartridges performed with similar efficacy across all flow rates at all temperatures. Conclusions At low flow rates, the parylene coated enFlow cartridges was comparable to the original uncoated cartridges. At higher flow rates, the coated and uncoated cartridges were not able to achieve the target temperature. The parylene coating on the aluminum heating blocks of the new enFlow intravenous fluid warmer does not negatively affect its performance compared to the uncoated model.

Abstract Background Only two-thirds of patients admitted to psychiatric wards return to their previous jobs. Return-to-work interventions in Germany are investigated for their effectiveness, but information regarding cost-effectiveness is lacking. This study investigates the cost-utility of a return-to-work intervention for patients with mental disorders compared to treatment as usual (TAU). Methods We used data from a cluster-randomised controlled trial including 166 patients from 28 inpatient psychiatric wards providing data at 6- and 12-month follow-ups. Health and social care service use was measured with the Client Sociodemographic and Service Receipt Inventory. Quality of life was measured with the EQ-5D-3L questionnaire. Cost-utility analysis was performed by calculating additional costs per one additional QALY (Quality-Adjusted Life Years) gained by receiving the support of return-to-work experts, in comparison to TAU. Results No significant cost or QALY difference between the intervention and control groups has been detected. The return-to-work intervention cannot be identified as cost-effective in comparison to TAU. Conclusions The employment of return-to-work experts could not reach the threshold of providing good value for money. TAU, therefore, seems to be sufficient support for the target group.

Abstract Background If people with episodic mental-health conditions lose their job due to an episode of their mental illness, they often experience personal negative consequences. Therefore, reintegration after sick leave is critical to avoid unfavorable courses of disease, longer inability to work, long payment of sickness benefits, and unemployment. Existing return-to-work (RTW) programs have mainly focused on “common mental disorders” and often used very elaborate and costly interventions without yielding convincing effects. It was the aim of the RETURN study to evaluate an easy-to-implement RTW intervention specifically addressing persons with mental illnesses being so severe that they require inpatient treatment. Methods The RETURN study was a multi-center, cluster-randomized controlled trial in acute psychiatric wards addressing inpatients suffering from a psychiatric disorder. In intervention wards, case managers (RTW experts) were introduced who supported patients in their RTW process, while in control wards treatment, as usual, was continued. Results A total of 268 patients were recruited for the trial. Patients in the intervention group had more often returned to their workplace at 6 and 12 months, which was also mirrored in more days at work. These group differences were statistically significant at 6 months. However, for the main outcome (days at work at 12 months), differences were no longer statistically significant (p = 0.14). Intervention patients returned to their workplace earlier than patients in the control group (p = 0.040). Conclusions The RETURN intervention has shown the potential of case-management interventions when addressing RTW. Further analyses, especially the qualitative ones, may help to better understand limitations and potential areas for improvement.

Abstract Background The genetic basis of phenotypic traits is highly variable and usually divided into mono-, oligo- and polygenic inheritance classes. Relatively few traits are known to be monogenic or oligogeneic. The majority of traits are considered to have a polygenic background. To what extent there are mixtures between these classes is unknown. The rapid advancement of genomic techniques makes it possible to directly map large amounts of genomic markers (GWAS) and predict unknown phenotypes (GWP). Most of the multi-marker methods for GWAS and GWP falls into one of two regularization frameworks. The first framework is based on $$\ell _1$$ ℓ 1 -norm regularization (e.g. the LASSO) and is suitable for mono- and oligogenic traits, whereas the second framework regularize with the $$\ell _2$$ ℓ 2 -norm (e.g. ridge regression; RR) and thereby is favourable for polygenic traits. A general framework for mixed inheritance is lacking. Results We have developed a proximal operator algorithm based on the recent LAVA regularization method that jointly performs $$\ell _1$$ ℓ 1 - and $$\ell _2$$ ℓ 2 -norm regularization. The algorithm is built on the alternating direction method of multipliers and proximal translation mapping (LAVA ADMM). When evaluated on the simulated QTLMAS2010 data, it is shown that the LAVA ADMM together with Bayesian optimization of the regularization parameters provides an efficient approach with lower test prediction mean-squared-error (65.89) than the LASSO (66.11), Ridge regression (83.41) and Elastic net (66.11). For the real pig data the test MSE of the LAVA ADMM is 0.850 compared to the LASSO, RR and EN with 0.875, 0.853 and 0.853, respectively. Conclusions This study presents the LAVA ADMM that is capable of joint modelling of monogenic major genetic effects and polygenic minor genetic effects which can be used for both genome-wide assoiciation and prediction purposes. The statistical evaluations based on both simulated and real pig data set shows that the LAVA ADMM has better prediction properies than the LASSO, RR and EN. Julia code for the LAVA ADMM is available at: https://github.com/patwa67/LAVAADMM .

The important increase in life expectancy of adult patients with congenital heart disease (ACHD) has generated new challenges, including arrhythmias that represent one of the main late complications. Reentrant atrial arrhythmias are by far the main mechanism encountered, and catheter ablation has been now presented as a first-line therapy in this patient population. The number of procedures is expected to continuously increase year after year. The heterogeneity and complexity of phenotypes encountered require these cases to be performed by highly experienced operators, in specialized centers with multidisciplinary competencies. A thorough knowledge and understanding of anatomic specificities, vascular access issues, and main circuits encountered according to underlying phenotype is essential. Acute success rates have significantly improved and are now excellent, but recurrences remain a common issue, with different mechanisms or circuits frequently encountered. Observational data have suggested the interest of systematically targeting all inducible atrial arrhythmias, whether previously documented or not, and a lot of hope and research is based on the prediction of arrhythmia substrate before arrhythmia development by imaging or electroanatomic mapping to deliver a prophylactic patient tailored ablation approach. In this review, we summarize those different points in the most common or distinctive defects to offer a didactic overview of atrial flutter catheter ablation in ACHD patients.

Abstract Background Equine asthma (EA) causes airflow impairment, which increases in severity with exercise. Electrical impedance tomography (EIT) is an imaging technique that can detect airflow changes in standing healthy horses during a histamine provocation test. Objectives To explore EIT‐calculated flow variables before and after exercise in healthy horses and horses with mild‐to‐moderate (MEA) and severe equine asthma (SEA). Animals Nine healthy horses 9 horses diagnosed with MEA and 5 with SEA were prospectively included. Methods Recordings were performed before and after 15 minutes of lunging. Absolute values from global and regional peak inspiratory (PIF, positive value) and expiratory (PEF, negative value) flows were calculated. Data were analyzed using a mixed model analysis followed by Bonferroni's multiple comparisons test to evaluate the impact of exercise and diagnosis on flow indices. Results Control horses after exercise had significantly lower global PEF and PIF compared to horses with SEA (mean difference [95% confidence interval, CI]: 0.0859 arbitrary units [AU; 0.0339‐0.1379], P