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An appropriately designed pharmacokinetic (PK) assay that is sensitive for anti-drug antibody (ADA) impact on relevant exposure is an alternative strategy to understand the neutralizing potential of ADAs. However, guidance on how to develop such PK assays and how to confirm the functional ADA impact on exposure is missing. Here, the PK assay of a T-cell-engaging bispecific antibody, cibisatamab, was developed based on its mechanism of action (MoA). Using critical monoclonal anti-idiotypic (anti-ID) antibody positive controls as ADA surrogates, the impact on exposure was evaluated pre-clinically. In a phase I clinical trial (NCT02324257), initial data suggest that the combination of ADA and PK assays for correlation of the ADA response with cibisatamab exposure. To understand the neutralizing potential of patient-derived ADAs on drug activity, advanced ADA characterization has been performed. Structural binding analysis of ADAs to antibody domains of the drug and its impact on targeting were assessed. For this purpose, relevant patient ADA binding features were identified and compared with the specific monoclonal anti-ID antibody-positive controls. Comparable results of target binding inhibition and similar impacts on exposure suggest that the observed reduction of Cmax and Ctrough levels in patients is caused by the neutralizing potential of ADAs and allows a correlation between ADA response and loss of exposure. Therefore, the described study provides important functional aspects for the development of an appropriately designed PK assay for bispecific antibodies as an alternative option towards understanding the neutralizing ADA impact on exposure.

Las actividades mineras y demás actividades económicas se realizan sobre el territorio; por ende, influyen en el ambiente y el entorno humano en el que se desenvuelven. Por ello, es trascendental garantizar que estas actividades humanas sean ejecutadas de forma respetuosa con el ambiente y la sociedad para así evitar futuros y eventuales conflictos socioambientales. Una de las herramientas más poderosas para lograr este equilibrio entre actividades humanas y desarrollo sostenible es el ordenamiento territorial (OT), entendido como la institución encargada de organizar las actividades humanas para lograr dicho equilibrio. Con base en esta premisa, este artículo tiene un triple objetivo: a) complementa la literatura sobre OT, explicando la interconexión entre esta institución y el régimen de concesiones mineras; b) identifica y analiza los principales problemas del procedimiento de otorgamiento de concesiones mineras en el Perú; y c) propone los fundamentos de un futuro sistema integrado de concesiones mineras y OT que contiene principios comunes y mecanismos participativos para conciliar las tensiones entre los intereses y valores de todos los interesados, además de brindar alternativas de solución a los problemas actuales del régimen de concesiones mineras. Para ello, se adopta una metodología cualitativa que combina análisis documental, revisión de reportes oficiales y entrevistas semiestructuradas con actores clave. Teniendo en cuenta los objetivos planteados, esta investigación concluye que: a) para lograr el desarrollo sostenible y evitar la futura aparición de conflictos, las concesiones mineras deben ser otorgadas con base en una planificación del territorio que el Estado (a nivel nacional, regional y local) debe realizar previa y conjuntamente con la sociedad civil; b) el procedimiento de concesiones mineras carece de mecanismos de buena gobernanza, sostenibilidad ambiental y justicia social; y c) como alternativa de solución a dichos problemas, se sugiere la creación de un sistema integrado de OT y concesiones mineras que sea vinculante, eficiente, escalonado, amigable con los inversionistas e intercultural.

Background Data on impact of COVID‐19 vaccination and outcomes of patients with COVID‐19 and acute ischemic stroke undergoing mechanical thrombectomy are scarce. Addressing this subject, we report our multicenter experience. Methods and Results This was a retrospective analysis of patients with COVID‐19 and known vaccination status treated with mechanical thrombectomy for acute ischemic stroke at 20 tertiary care centers between January 2020 and January 2023. Baseline demographics, angiographic outcome, and clinical outcome evaluated by the modified Rankin Scale score at discharge were noted. A multivariate analysis was conducted to test whether these variables were associated with an unfavorable outcome, defined as modified Rankin Scale score >3. A total of 137 patients with acute ischemic stroke (48 vaccinated and 89 unvaccinated) with acute or subsided COVID‐19 infection who underwent mechanical thrombectomy attributable to vessel occlusion were included in the study. Angiographic outcomes between vaccinated and unvaccinated patients were similar (modified Thrombolysis in Cerebral Infarction ≥2b: 85.4% in vaccinated patients versus 86.5% in unvaccinated patients; P=0.859). The rate of functional independence (modified Rankin Scale score, ≤2) was 23.3% in the vaccinated group and 20.9% in the unvaccinated group (P=0.763). The mortality rate was 30% in both groups. In the multivariable analysis, vaccination status was not a significant predictor for an unfavorable outcome (P=0.957). However, acute COVID‐19 infection remained significant (odds ratio, 1.197 [95% CI, 1.007–1.417]; P=0.041). Conclusions Our study demonstrated no impact of COVID‐19 vaccination on angiographic or clinical outcome of COVID‐19–positive patients with acute ischemic stroke undergoing mechanical thrombectomy, whereas worsening attributable to COVID‐19 was confirmed.

As numerous studies on highly efficient perovskite solar cells have been conducted on lead‐based light absorbers, such as MAPbI3 and FAPbI3, increasing concerns are rising regarding toxicity and stability issues. One of the most prominent and promising lead‐free alternatives is the double‐perovskite Cs2AgBiBr6, which is well‐suited for multi‐junction solar cells considering its relatively large indirect bandgap of around 1.95–2.05 eV. Despite distinctive reports on its performance under ambient conditions, the demonstrated stability has not yet been conclusively clarified. Within this study, the degradation behavior of Cs2AgBiBr6 single crystals is investigated under different ambient environments, such as AM1.5g solar irradiation, aquatic conditions, and humidity. The corresponding samples are analyzed by using Raman, UV–vis, energy‐dispersive X‐Ray, and micro‐photoluminescence spectroscopies together with X‐Ray diffraction. High intrinsic stability of Cs2AgBiBr6 in ambient conditions and severe degradation in aquatic conditions are observed. Furthermore, surface morphology alterations are found during the simulated solar irradiation indicating photo‐accelerated degradation behavior. In the results of this study, it is clearly implied that intense research efforts need to be put into sealing the Cs2AgBiBr6 layer in solar cells with the goal of protecting it from humidity and water intrusion simultaneously, therefore avoiding photo‐accelerated degradation.

Objectives To investigate the impact of disease activity and treatment with disease-modifying antirheumatic drugs (DMARDs) on all-cause mortality in patients with rheumatoid arthritis and prevalent interstitial lung disease (RA-ILD).Methods Patients with RA-ILD were selected from the biologics register Rheumatoid Arthritis: Observation of Biologic Therapy (RABBIT). Using time-varying Cox regression, the association between clinical measures and mortality was investigated. The impact of DMARDs was analysed by (1) Cox regression considering cumulative exposure (ie, treatment months divided by total months) and (2) time-varying Cox regression as main approach (treatment exposures at monthly level).Results Out of 15 566 participants, 381 were identified as RA-ILD cases with 1258 person-years of observation and 2.6 years median length of follow-up. Ninety-seven patients (25.5%) died and 34 (35.1%) of these were not receiving DMARD therapy at the time of death. Higher inflammatory biomarkers but not swollen and tender joint count were significantly associated with mortality. Compared with tumour necrosis factor inhibitors (TNFi), non-TNFi biologic DMARDs (bDMARDs) exhibited adjusted HRs (aHRs) for mortality below 1, lacking statistical significance. This finding was stable in various sensitivity analyses. Joint aHR for non-TNFi biologics and JAKi versus TNFi was 0.56 (95% CI 0.33 to 0.97). Receiving no DMARD treatment was associated with a twofold higher mortality risk compared with receiving any DMARD treatment, aHR 2.03 (95% CI 1.23 to 3.35).Conclusions Inflammatory biomarkers and absence of DMARD treatment were associated with increased risk of mortality in patients with RA-ILD. Non-TNFi bDMARDs may confer enhanced therapeutic benefits in patients with RA-ILD.

In our study, we use the post-hypnotic suggestion of easy remembering to improve memory with long-lasting effects. We tested 24 highly suggestible participants in an online study. Participants learned word lists and recalled them later in a recognition memory task. At the beginning of the study, participants were hypnotized and the post-hypnotic suggestion to remember easily was associated with a cue that participants used during the recognition memory task. In a control condition, the same participants used a neutral cue. One week later, participants repeated both conditions with new word lists.Participants were significantly faster and more confident in their recognition ratings in the easy-remembering condition compared to the control condition, and this effect persisted over one week. Crucially, the increased speed and confidence in the easy-remembering condition did not affect memory accuracy. That makes our hypnosis intervention promising for patients experiencing subjective memory impairments. APA PsycINFO codes: 2343 (Learning and Memory), 2380 (Consciousness States), 3351 (Clinical Hypnosis)

Summary: Background: The COVID-19 pandemic heightened risks for individuals with hematological malignancies due to compromised immune systems, leading to more severe outcomes and increased mortality. While interventions like vaccines, targeted antivirals, and monoclonal antibodies have been effective for the general population, their benefits for these patients may not be as pronounced. Methods: The EPICOVIDEHA registry (National Clinical Trials Identifier, NCT04733729) gathers COVID-19 data from hematological malignancy patients since the pandemic's start worldwide. It spans various global locations, allowing comprehensive analysis over the first three years (2020–2022). Findings: The EPICOVIDEHA registry collected data from January 2020 to December 2022, involving 8767 COVID-19 cases in hematological malignancy patients from 152 centers across 41 countries, with 42% being female. Over this period, there was a significant reduction in critical infections and an overall decrease in mortality from 29% to 4%. However, hospitalization, particularly in the ICU, remained associated with higher mortality rates. Factors contributing to increased mortality included age, multiple comorbidities, active malignancy at COVID-19 onset, pulmonary symptoms, and hospitalization. On the positive side, vaccination with one to two doses or three or more doses, as well as encountering COVID-19 in 2022, were associated with improved survival. Interpretation: Patients with hematological malignancies still face elevated risks, despite reductions in critical infections and overall mortality rates over time. Hospitalization, especially in ICUs, remains a significant concern. The study underscores the importance of vaccination and the timing of COVID-19 exposure in 2022 for enhanced survival in this patient group. Ongoing monitoring and targeted interventions are essential to support this vulnerable population, emphasizing the critical role of timely diagnosis and prompt treatment in preventing severe COVID-19 cases. Funding: Not applicable.

Introduction: Patients with metastatic NSCLC (mNSCLC) treated with immune checkpoint inhibitors in clinical practice may often not meet the strict inclusion criteria of clinical trials. Our aim was to assess the trial eligibility of patients with mNSCLC treated with pembrolizumab monotherapy in real-world and to compare the outcome of “trial-ineligible” and “potentially trial-eligible” patients. Methods: Data from the prospective, clinical research platform CRISP were used to compare patient characteristics, treatment, and outcome of patients with programmed cell death-ligand 1 tumor proportion score greater than or equal to 50% tumors treated with pembrolizumab monotherapy who are deemed either “potentially trial-eligible” or “trial-ineligible” according to inclusion and exclusion criteria of the registrational studies (KEYNOTE-024 and -042). Results: Of 746 patients included, 343 patients (46.0%) were classified as “trial-ineligible” and had significantly worse outcomes compared with “potentially trial-eligible” patients (n = 403, 54.0%): median progression-free survival: 6.2 (95% confidence interval [CI]: 5.2–8.4) versus 10.3 (95% CI: 8.4–13.8) months, hazard ratio (trial-ineligible versus potentially trial-eligible) of 1.43 (95% CI: 1.19–1.72), p less than 0.001; median overall survival: 15.9 (95% CI: 11.4–20.3) versus 25.3 (95% CI: 19.8–30.4) months, hazard ratio of 1.36 (95% CI: 1.10–1.67), p equals 0.004. Conclusions: Our data reveal that a considerable proportion of patients with mNSCLC are not eligible to participate in a clinical trial and were found to have worse outcomes than potentially trial-eligible patients, whose outcomes were comparable with those obtained from pivotal clinical trials. This is of substantial clinical relevance for physicians discussing outcomes to be expected with their patients and stresses the need for real-world effectiveness analyses.

Background The International Olympic Committee (IOC) Medical and Scientific Commission has supported collating and sharing evidence globally by developing sports medicine consensus statements (‘Statements’'). Publishing the Statements requires substantial resources that must be balanced by use and impact on policy and practice. This study aimed to gain a better understanding of awareness and uptake of the Statements globally through a survey of the National Olympic Committees (NOC), National Paralympic Committees (NPC) and International Federations (IF).Method A cross-sectional survey of medical commission representatives from NOCs/NPCs/IFs. A structured questionnaire was distributed through the IOC head office, informed by prior research. Questions comprised a mix of closed and open-text responses with results presented descriptively by organisation type and total.Results 55 responses were included: 29 (52%) from NOC/NPC representatives (response rate 14%) and 26 (47%) from IF representatives (response rate 63%). All Statements had been used by at least one respondent, with the Statement addressing concussion ranked highest (used by 33/55). The main barriers to use were financial limitations (n=21), club/sport culture and behaviours (n=19) and lack of understanding from coaches/team sport personnel (n=19). Participants believed the Statements were a successful strategy for improving athlete health (n=39/51 agree or strongly agree).Conclusion There was clear support for the continued development of sports medicine guidance, including in the format of these Statements. To ensure Statements lead to demonstrable health benefits for athletes, input from athletes, coaches and supporting staff is needed, as well as clearer identification of the purpose and audience of each topic developed.

BackgroundAs depression is highly heterogenous, an increasing number of studies investigate person-specific associations of depressive symptoms in longitudinal data. However, most studies in this area of research conceptualize symptom interrelations to be static and time invariant, which may lead to important temporal features of the disorder being missed. ObjectiveTo reveal the dynamic nature of depression, we aimed to use a recently developed technique to investigate whether and how associations among depressive symptoms change over time. MethodsUsing daily data (mean length 274, SD 82 d) of 20 participants with depression, we modeled idiographic associations among depressive symptoms, rumination, sleep, and quantity and quality of social contacts as dynamic networks using time-varying vector autoregressive models. ResultsThe resulting models showed marked interindividual and intraindividual differences. For some participants, associations among variables changed in the span of some weeks, whereas they stayed stable over months for others. Our results further indicated nonstationarity in all participants. ConclusionsIdiographic symptom networks can provide insights into the temporal course of mental disorders and open new avenues of research for the study of the development and stability of psychopathological processes.

Abstract Background Despite multiple therapeutic modalities, the overall survival of patients with gastric adenocarcinoma remains poor, especially for advanced tumor stages. Although the tyrosine kinase MerTK has shown therapeutic relevance in several tumor entities, its potential effects in gastric adenocarcinoma have not yet been sufficiently characterized. Methods MerTK expression and its influence on patient survival were evaluated by immunohistochemistry in a cohort of 140 patients with gastric adenocarcinoma. CRISPR/Cas9 knockout and siRNA knockdown of MerTK in the gastric cancer cell lines SNU1, SNU5, and MKN45 was used to analyze protein expression, growth, migration, and invasion properties in vitro and in a murine xenograft model. MerTK was pharmacologically targeted with the small molecule inhibitor UNC2025 in vitro and in vivo. Results In patients, high MerTK expression was associated with decreased overall survival (OS) and lymph node metastasis especially in patients without neoadjuvant therapy (p

Particle-based systems have immense potential for combining thermal energy storage (TES) with renewable energy sources. The so-called sandTES system, which is an active TES system, utilizes sand or other small particles as a storage material and consists of a hot tank, a cold tank, and a reversible fluidized bed heat exchanger. In the preferred design, the tubes are arranged in horizontal serpentine tube bundles; thus, the headers are positioned vertically, for one phase subcritical, two-phase and supercritical water/steam conditions. So far, no design principles have been published for macro-sized vertical headers and horizontal tube bundles. This paper investigates the unbalance in flow distribution and other flow instabilities of such an unusual heat exchanger and its scale-up using APROS simulations.The steady-state simulations of the tallest investigated heat exchanger show a strong unbalance in the mass flows between individual heat exchanger tubes: the smallest mass flow was only 55% of the largest one when generating steam. Smaller heat exchangers experience less pronounced unbalance factors in the order of 88%. When steam is condensed, the unbalance is insignificant. Dynamic simulations of start-up and shutdown revealed instabilities and that the flow maldistributions even lead to flow reversals in most investigated cases although neither last for stationary operation. Part-load cases show higher unbalances than their respective full-load case by 9 to 17 percentage points. Header design modifications – secondary headers with submodules and orifices – improve the unbalance factor from 55% to 88%.

ABSTRACTThe species- and clone-specific susceptibility of Staphylococcus cells for bacteriophages is governed by the structures and glycosylation patterns of wall teichoic acid (WTA) glycopolymers. The glycosylation-dependent phage-WTA interactions in the opportunistic pathogen Staphylococcus epidermidis and in other coagulase-negative staphylococci (CoNS) have remained unknown. We report a new S. epidermidis WTA glycosyltransferase TagE whose deletion confers resistance to siphoviruses such as ΦE72 but enables binding of otherwise unbound podoviruses. S. epidermidis glycerolphosphate WTA was found to be modified with glucose in a tagE-dependent manner. TagE is encoded together with the enzymes PgcA and GtaB providing uridine diphosphate-activated glucose. ΦE72 transduced several other CoNS species encoding TagE homologs, suggesting that WTA glycosylation via TagE is a frequent trait among CoNS that permits interspecies horizontal gene transfer. Our study unravels a crucial mechanism of phage-Staphylococcus interaction and horizontal gene transfer, and it will help in the design of anti-staphylococcal phage therapies.IMPORTANCEPhages are highly specific for certain bacterial hosts, and some can transduce DNA even across species boundaries. How phages recognize cognate host cells remains incompletely understood. Phages infecting members of the genus Staphylococcus bind to wall teichoic acid (WTA) glycopolymers with highly variable structures and glycosylation patterns. How WTA is glycosylated in the opportunistic pathogen Staphylococcus epidermidis and in other coagulase-negative staphylococci (CoNS) species has remained unknown. We describe that S. epidermidis glycosylates its WTA backbone with glucose, and we identify a cluster of three genes responsible for glucose activation and transfer to WTA. Their inactivation strongly alters phage susceptibility patterns, yielding resistance to siphoviruses but susceptibility to podoviruses. Many different CoNS species with related glycosylation genes can exchange DNA via siphovirus ΦE72, suggesting that glucose-modified WTA is crucial for interspecies horizontal gene transfer. Our finding will help to develop antibacterial phage therapies and unravel routes of genetic exchange.

Ambient noise correlation analyses are largely used to monitor temporal medium changes generally associated with stress field variations and/or fluid movement. Here, we analyze the 2021 eruption of La Palma, the most active island in the Canary archipelago, to study its effects on the structure in a post-eruptive stage. To date, most of the studies, whether in volcanic environments or other geological systems, focus on determining seismic velocity changes that can be associated with precursory signals. In our study, we are interested in localizing the medium changes that permit constraining the depth of the most affected structure and suggesting possible mechanisms capable of inducing such alterations. The auto- and cross-correlation functions were computed using the phase cross-correlation strategy. The correlations were linearly stacked using a 3-day sliding window. The combination of these two approaches proved to render the best results. The analysis of 3 years of data resulted in the detection of occasional decorrelation before the eruption, followed by a well-defined decoherence period after the eruption. In addition, the relationship between the waveform correlation and lag time, using autocorrelations from before and after the eruption, permits identifying phase shifts and waveform distortion, which are sensitive to different parameters and, thus, have great importance in inferring the possible mechanism. Phase shifts occur when there is only velocity change without changing the structure, whereas waveform distortion is caused by a structural (geological) change. We also inferred the depths at which the most significant medium alterations occur. We observed that the decorrelation occurs at lag times corresponding to changes localized in depth. The surface structure appears to not have undergone significant medium changes for depths until approximately 8 km, either before or after the eruption.

BackgroundAmyotrophic lateral sclerosis (ALS) is a fatal disorder, which imposes a severe emotional burden on patients. Appropriate coping mechanisms may alleviate this burden and facilitate wellbeing, with social support known to be a successful coping strategy. This observational study aimed to determine the interplay of general coping traits of hope for success and fear of failure, coping behavior of social activity, and patients' wellbeing.MethodsIn this cross-sectional study, patients with ALS from a clinical-epidemiological registry in Southwestern Germany were interviewed regarding coping traits (achievement-motivated behavior: hope for success and fear of failure), coping behavior of social activity, and psychosocial adjustment, determined using measures of depressiveness, anxiety [both measured by Hospital Anxiety and Depression Scale (HADS)], and quality of life [Anamnestic Comparative Self-Assessment (ACSA)]. Demographics, clinical [ALS Functional Rating Scale revised version (ALSFRS-R)], and survival data were recorded.ResultsA total of 868 patients [60.70% male patients, mean age: 64.70 (±10.83) years, mean ALSFRS-R: 37.36 ± 7.07] were interviewed. Anxiety in patients was found to be associated with a high fear of failure. In contrast, a generally positive attitude in patients exemplified in high hopes for success was associated with better wellbeing. Finally, coping behavior of social activity explained up to 65% of the variance of depressiveness among the patients with ALS.ConclusionIn this study, we present evidence that the wellbeing of patients with ALS is not an immediate fatalistic consequence of physical degradation but rather determined by coping traits and behavior, which may be trained to substantially increase the wellbeing of patients with ALS.

Background and objective: Forests play a crucial role throughout the world as highly productive ecosystems, serving approximately a quarter of the human population by providing valuable services. However, these ecosystems are subject to various natural and human-induced disturbances such as insect outbreaks, fires, windthrow, snow damage, selective logging, and harvest, which significantly influence the composition and structure of forests. Recent studies have observed a notable increase in both natural and anthropogenic disturbances on a global scale. The availability of free Earth observation (EO) archives alongside the maturation of algorithms for analysing time series data have opened new opportunities to detect and understand forest disturbances in a vast spatio-temporal context. Over the past few decades, numerous EO-based approaches have been proposed to monitor forest ecosystems, benefiting from the open-data policies of multiple satellite constellations. This study conducted a mapping review to shed light on the state-of-the-art in forest disturbance characterization using EO big data. Study design: We searched major online databases, including Scopus, the Web of Science, MDPI, Science Direct and IEEE Xplore, extensively in order to identify scientific literature published from 1995 to 2023. Of the more than 2000 records screened, 104 publications met the specific inclusion criteria and were included in the review. The selected studies were categorized based on the type of spatial and spectral-temporal patterns used to characterize forest disturbances, the predictors employed to classify the target disturbances, the data fusion methods applied when using multisource EO data, the classification algorithms employed and the accessibility of the reference data used in the studies. Results: Our findings reveal that temporal patterns derived from spectral reflectance have been used three times more frequently than spatial patterns. The most common predictors were the spectral change magnitude and timing of disturbances derived from the short-wave infrared (SWIR) spectral region, along with measures of disturbed patch dimensions and elevation. The random forest emerged as the most used algorithm for classification. Furthermore, it was observed that less than 10% of the studies provided or made available the datasets used for their analyses. Conclusion: Although significant progress has been made in characterizing forest disturbances, the validity and credibility of results were found to be highly variable and much dependent on the choice of change detection methods, predictors and classification algorithms. The scarcity of research studies that provide access to their data poses a significant obstacle to the advancement of current methodologies and the development of novel approaches.

In intensively managed forests in Europe, where forests are divided into stands of small size and may show heterogeneity within stands, a high spatial resolution (10–––20 m) is needed to capture the differences in canopy height. In this work, we developed a deep learning model based on multi-sensor remote sensing measurements to create a high-resolution canopy height map over the “Landes de Gascogne” forest in France, a large maritime pine plantation of 13,000 km2 with flat terrain and intensive management. This area is characterized by even-aged and mono-specific stands, of a typical length of a few hundred meters, harvested every 35 to 50 years. Our deep learning U-Net model uses multi-band images from Sentinel-1 and Sentinel-2 with composite time averages as input to predict tree height derived from GEDI waveforms. The evaluation is performed with external validation data from forest inventory plots and a stereo 3D reconstruction model based on Skysat imagery available at specific locations. We trained seven different U-Net models based on combinations of Sentinel-1 and Sentinel-2 bands to evaluate the importance of each sensor in the dominant height retrieval. The model outputs allow us to generate a 10 m resolution canopy height map of the whole “Landes de Gascogne” forest area for 2020 with a mean absolute error of 2.02 m on the test dataset. The best predictions were obtained using all available bands from Sentinel-1 and Sentinel-2 but using only one satellite source also provided good predictions. For all validation datasets in coniferous forests, our model showed better metrics than previous canopy height models available in the same region.

Hemoglobinopathies including thalassemias are among the most frequent genetic disorders worldwide. Primarily, these entities result from germline variants in the globin gene clusters and their cis-acting regulatory elements, and thus the WHO classifies thalassemias as inherited diseases. Non-inherited disorders of globin chain synthesis mimicking the phenotype of thalassemias have also been described and are referred to as acquired thalassemias. These forms mainly affect the alpha-globin genes and are observed at much lower frequencies...

In the vast abyssal plains northwest of Iceland, white glass sponges of the genus Caulophacus Schulze, 1886 were inhabited by reddish Bythocaris G.O. Sars, 1870 shrimps and pinkish amphipods. After in situ observations at 3700 m depth, in -1°C waters by a remotely operated vehicle, members of this assemblage were collected and preserved for molecular studies. Based on integrative taxonomic analyses, the amphipods were identified as a new species of the genus Halirages Boeck, 1871 – Halirages spongiae sp. nov. Lörz, Nack & Tandberg –, as described in detail below. Part of our integrative approach was to establish reference DNA barcodes for known species of Halirages. However, our investigation of material of Calliopiidae G.O. Sars, 1895 collected around Iceland and Norway revealed slight morphological discrepancies in all the described species of Halirages. Except for Halirages fulvocinctus (M. Sars, 1858), none of the encountered specimens of Calliopiidae fully matched a current species description. We illuminate the morphological characteristics of nine operational taxonomic units, which also represented clades in COI and 28S. We set the Icelandic samples in the context of Halirages from Canada and Norway. A key to the world species of Halirages is provided.

The effects of stress factors associated with climate change and agricultural management practices on microorganisms are often studied separately, and it remains to be determined how these factors impact the soil microbiome and, subsequently, plant growth characteristics. The aim of this study was to understand how the historical climate and agriculture to which soil microbes have been exposed can influence the growth characteristics of wheat seedlings and their associated bacterial communities. We collected soil from organic and conventional fields with different histories of climate conditions to extract microbes to inoculate wheat seeds under agar-based cultivation conditions. Within a growth period of 8 days, we monitored germination rates and time as well as seedling above-ground biomass and their associated bacterial communities. The results showed a positive interaction between conventional farming practices and an ambient climate for faster and higher germination rates. We demonstrate that soil microbial extracts from organic farming with experience of the future climate significantly enhanced above-ground biomass along with the diversity of bacterial communities associated with seedlings than other treatments. Such findings support the idea that organic agricultural practices not only mitigate the adverse effects of climate change but also promote the diversity of seedling-associated bacteria.

IntroductionThe fact that the daily lives of billions of people were affected by the medical, social, and political aspects of the SARS-CoV-2 pandemic shows the need to anchor the understanding of One Health in society. Hence, promoting awareness and deepening the understanding of the interrelation between human health, animal health, and ecosystems must be accomplished through quality education, as advocated by UN Sustainable Development Goal 4. The often-questioned and discussed measures taken by governments to control the global pandemic between 2020 and 2023 can be seen as an opportunity to meet the educational needs of civil society solutions in multi-stakeholder settings between public, universities, and schools.MethodsThis paper focuses on the integration of One Health principles in educational frameworks, particularly within the context of the higher education teaching framework “Teaching Clinic.” This master-level course in the domain of pre-service teacher education serves as a potent vehicle for facilitating One Health Education, bridging the gap between research, higher education, and schools. Through the presentation of two case studies, this article demonstrates how the Teaching Clinic approach fosters interdisciplinary perspectives and provides a dynamic learning environment for pre-service teachers, as well as for pupils involved in the educational process.ResultsIn both cases, the integration of educational One Health school teaching-learning settings effectively enhanced pupils’ understanding of complex topics and engaged them in active learning experiences. Pre-service teachers played a crucial role in developing, implementing, and evaluating these interventions. In Case I, pupils demonstrated proficiency in analyzing data and evaluating mathematical models, while in Case II, the chosen instructional approach facilitated One Health knowledge acquisition and enjoyment among pupils. These results underscore the potential of the One Health Teaching Clinic as a valuable educational framework for enhancing teaching and learning outcomes for pre-service teachers and fostering pupil engagement in socio-scientific One Health-related topics.DiscussionThe discussion delves into the significance of breaking down disciplinary silos and the crucial role of teacher education in promoting a holistic approach to education, emphasizing the intersectionality of One Health Education and Education for Sustainable Development. This article underpins the significance of collaborative efforts across multiple (scientific) disciplines and across secondary and tertiary education levels to reach a nexus. Moreover, it emphasizes the alignment of this approach with the 2030 Agenda, Education for Sustainable Development, and Sustainable Development Goals, highlighting the potential for collective action toward a more sustainable future.

A total of 48 CharAM-specimens were manufactured by four partners in three specimen configurations. Thermal post-processing and testing was conducted at a single partner to minimize other processing variation. The geometry and strength of more than 2000 cantilevers (48 cantilevers per CharAM-specimen) were analyzed. It is shown that each partner managed to fabricate specimens with exceptional geometrical consistency, even though significant differences were present between partners. Likewise, the strength of each configuration was alike for several specimens of one partner but deviated from that of other partners. Thus, it is demonstrated that the CharAM-methodology is sufficiently accurate to determine differences between specimens manufactured with slightly varying manufacturing processes or specimens manufactured at different production sites. Through the introduction of an automated geometry evaluation, a large amount of strength and geometry data for additively manufactured materials can be obtained with comparatively low effort.

IntroductionTreating major depressive disorder (MDD) with transcranial direct current stimulation (tDCS) devices at home has various logistic advantages compared to tDCS treatment in the clinic. However, preliminary (controlled) studies showed side effects such as skin lesions and difficulties in the implementation of home-based tDCS. Thus, more data are needed regarding the feasibility and possible disadvantages of home-based tDCS.MethodsTen outpatients (23–69 years) with an acute depressive episode were included for this one-arm feasibility study testing home-based tDCS. All patients self-administered prefrontal tDCS (2 mA, 20 min, anodal left, cathodal right) at home on 30 consecutive working days supported by video consultations. Correct implementation of the home-based treatment was analyzed with tDCS recordings. Feasibility was examined by treatment compliance. For additional analyses of effectiveness, three depression scores were used: Hamilton depression rating scale (HDRS-21), Major Depression Inventory (MDI), and the subscale depression of the Depression-Anxiety-Stress Scale (DASS). Furthermore, usability was measured with the user experience questionnaire (UEQ). Tolerability was analyzed by the number of reported adverse events (AEs).ResultsEight patients did not stick to the protocol. AEs were minimal. Four patients responded to the home treatment according to the MDI. Usability was judged positive by the patients.ConclusionsRegular video consultations or other safety concepts are recommended regardless of the number of video sessions actually conducted. Home-based tDCS seems to be safe and handy in our feasibility study, warranting further investigation.

Introduction: Recurrent pyloric stenosis poses unique diagnostic challenges, particularly in discerning authentic recurrence from post-pyloromyotomy scarring on ultrasound imaging. Case presentation: A male infant began experiencing projectile non bilious vomiting nine days following birth. Upon initial clinical examination, no evidence of pyloric olive or signs of dehydration were detected. However, an abdominal ultrasound examination unveiled a thickened pyloric wall measuring 4.5 mm, along with a pyloric canal length of 17 mm, indicating the presence of pyloric stenosis. Consequently, an uncomplicated supra-umbilical open pyloromyotomy was performed when the patient was 20 days old. Twenty-three days after being discharged, the patient presented to the emergency for a 24-h history of vomiting after every third bottle. On physical exam, a palpable pyloric olive was discovered. The patient had gained 410 g in 23 days (about 18 g/day). An abdominal ultrasound showed a pyloric muscle length of 21 mm and a muscle thickness of 4.5 mm. A multidisciplinary reunion was conducted between the pediatric gastroenterology and pediatric surgery department deciding to perform a second pyloromyotomy. This was executed through the same supra-umbilical incision. A healed incision scar was found along the complete length of the pyloric muscle on the anterior side. The decision was made to perform a second pyloromyotomy approximately 5 mm more dorsal from the first myotomy. There was a small perforation of the mucosa on the duodenal side which was sutured with a PDS 6/0. The progression unfolded without incident, with an improvement in symptoms and weight gain. Follow-up ultrasounds showed a gradual decrease in the length of the pyloric muscle. Conclusion: Recurrent pyloric stenosis is challenging to differentiate from postoperative edema. Particularly, the pyloric length on ultrasound can help distinguish and indicate whether a second pyloromyotomy should be performed or not.

Abstract Background Patient-reported outcome measures (PROM) provide clinicians with information about patients’ perceptions of distress. When linked with treatment and diagnostic registers, new information on common mental health disorders (CMHD) and service use, may be obtained, which might be useful clinically and for policy decision-making. This study reports the prevalence of CMHD and their association with PROM severity. Further, subgroups of self-reported symptoms of depression and anxiety were examined, and their association with clinician-assessed mental disorders, functional impairment, and service use. Methods In a cohort study of 2473 (63% female) outpatients, CMHD was examined with pre-treatment scores of self-reported depression and anxiety, and the number of assessments and psychotherapy appointments one year after treatment start. Factor mixture modelling (FMM) of anxiety and depression was used to examine latent subgroups. Results Overall, 22% of patients with a CMHD had an additional comorbid mood/anxiety disorder, making the prevalence lower than expected. This comorbid group reported higher symptoms of anxiety and depression compared to patients with non-comorbid disorders. FMM revealed three classes: “anxiety and somatic depression” (33%), “mixed depression and anxiety” (40%), and “cognitive depression” (27%). The anxiety and somatic depression class was associated with older age, being single and on sick leave, higher probability of depressive-, anxiety-, and comorbid disorders, having more appointments and higher functional impairment. Although the cognitive depression class had less somatic distress than the mixed depression and anxiety class, they reported more functional impairment and had higher service use. Conclusion The results show that higher levels of somatic symptoms of depression could both indicate higher and lower levels of functional impairment and service use. A group of patients with high somatic depression and anxiety was identified, with severe impairment and high service needs. By gaining insights into CMHD factors’ relation with clinical covariates, self-reported risk factors of depression and anxiety could be identified for groups with different levels of aggravating life circumstances, with corresponding service needs. These could be important symptom targets in different groups of patients.

Abstract Kidney function as part of metabolic changes could be associated with amyotrophic lateral-sclerosis (ALS). We investigated the associations between estimated chronic kidney disease (CKD), based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) cystatin C equation, and the risk at onset and prognostic value of CKD for ALS. Between October 2010 and June 2014, 362 ALS cases (59.4% men, mean age 65.7 years) and 681 controls (59.5% men, means age 66.3 years) were included in a population-based case–control study based on the ALS registry Swabia in Southern Germany. All ALS cases were followed-up (median 89.7 months), 317 died. Serum samples were measured for cystatin C to estimate the glomerular filtration rate (eGFR) according to the CKD-EPI equation. Information on covariates were assessed by an interview-based standardized questionnaire. Conditional logistic regression models were applied to calculate odds ratios (OR) for risk of ALS associated with eGFR/CKD stages. Time-to-death associated with renal parameters at baseline was assessed in ALS cases only. ALS cases were characterized by lower body mass index, slightly lower smoking prevalence, more intense occupational work and lower education than controls. Median serum cystatin-C based eGFR concentrations were lower in ALS cases than in controls (54.0 vs. 59.5 mL/min pro 1.73 m2). The prevalence of CKD stage ≥ 3 was slightly higher in ALS cases than in controls (14.1 vs. 11.0%). In the adjusted models, CKD stage 2 (OR 1.82, 95% CI 1.32, 2.52) and stage 3 (OR 2.34, 95% CI 1.38, 3.96) were associated with increased ALS risk. In this cohort of ALS cases, eGFR and CKD stage ≥ 3 (HR 0.94; 95% CI 0.64, 1.38) were not associated with prognosis. In this case–control study, higher CKD stages were associated with increased ALS risk, while in the prospective cohort of ALS cases, no indication of an association of CysC-based CKD on mortality was seen. In addition, our work strengthens the importance to evaluate renal function using a marker independent of muscle mass in ALS patients.

Abstract Background The clinical spectrum of acute SARS-CoV-2 infection ranges from an asymptomatic to life-threatening disease. Considering the broad spectrum of severity, reliable biomarkers are required for early risk stratification and prediction of clinical outcomes. Despite numerous efforts, no COVID-19-specific biomarker has been established to guide further diagnostic or even therapeutic approaches, most likely due to insufficient validation, methodical complexity, or economic factors. COVID-19-associated coagulopathy is a hallmark of the disease and is mainly attributed to dysregulated immunothrombosis. This process describes an intricate interplay of platelets, innate immune cells, the coagulation cascade, and the vascular endothelium leading to both micro- and macrothrombotic complications. In this context, increased levels of immunothrombotic components, including platelet and platelet-leukocyte aggregates, have been described and linked to COVID-19 severity. Methods Here, we describe a label-free quantitative phase imaging approach, allowing the identification of cell-aggregates and their components at single-cell resolution within 30 min, which prospectively qualifies the method as point-of-care (POC) testing. Results We find a significant association between the severity of COVID-19 and the amount of platelet and platelet-leukocyte aggregates. Additionally, we observe a linkage between severity, aggregate composition, and size distribution of platelets in aggregates. Conclusions This study presents a POC-compatible method for rapid quantitative analysis of blood cell aggregates in patients with COVID-19.

Abstract Epithelial membrane protein 3 (EMP3) is an N-glycosylated tetraspanin with a putative trafficking function. It is highly expressed in isocitrate dehydrogenase-wild-type glioblastoma (IDH-wt GBM), and its high expression correlates with poor survival. However, the exact trafficking role of EMP3 and how it promotes oncogenic signaling in GBM remain unclear. Here, we show that EMP3 promotes EGFR/CDK2 signaling by regulating the trafficking and enhancing the stability of EGFR. BioID2-based proximity labeling revealed that EMP3 interacts with endocytic proteins involved in the vesicular transport of EGFR. EMP3 knockout (KO) enhances epidermal growth factor (EGF)-induced shuttling of EGFR into RAB7 + late endosomes, thereby promoting EGFR degradation. Increased EGFR degradation is rescued by the RAB7 negative regulator and novel EMP3 interactor TBC1D5. Phosphoproteomic and transcriptomic analyses further showed that EMP3 KO converges into the inhibition of the cyclin-dependent kinase CDK2 and the repression of EGFR-dependent and cell cycle transcriptional programs. Phenotypically, EMP3 KO cells exhibit reduced proliferation rates, blunted mitogenic response to EGF, and increased sensitivity to the pan-kinase inhibitor staurosporine and the EGFR inhibitor osimertinib. Furthermore, EGFR-dependent patient-derived glioblastoma stem cells display a transcriptomic signature consistent with reduced CDK2 activity, as well as increased susceptibility to CDK2 inhibition upon EMP3 knockdown. Lastly, using TCGA data, we showed that GBM tumors with high EMP3 expression have increased total and phosphorylated EGFR levels. Collectively, our findings demonstrate a novel EMP3-dependent mechanism by which EGFR/CDK2 activity is sustained in GBM. Consequently, EMP3’s stabilizing effect provides an additional layer of tumor cell resistance against targeted kinase inhibition.

Abstract Mechanical ventilation is a life-saving therapy in several clinical situations, promoting gas exchange and providing rest to the respiratory muscles. However, mechanical ventilation may cause hemodynamic instability and pulmonary structural damage, which is known as ventilator-induced lung injury (VILI). The four main injury mechanisms associated with VILI are as follows: barotrauma/volutrauma caused by overstretching the lung tissues; atelectrauma, caused by repeated opening and closing of the alveoli resulting in shear stress; and biotrauma, the resulting biological response to tissue damage, which leads to lung and multi-organ failure. This narrative review elucidates the mechanisms underlying the pathogenesis, progression, and resolution of VILI and discusses the strategies that can mitigate VILI. Different static variables (peak, plateau, and driving pressures, positive end-expiratory pressure, and tidal volume) and dynamic variables (respiratory rate, airflow amplitude, and inspiratory time fraction) can contribute to VILI. Moreover, the potential for lung injury depends on tissue vulnerability, mechanical power (energy applied per unit of time), and the duration of that exposure. According to the current evidence based on models of acute respiratory distress syndrome and VILI, the following strategies are proposed to provide lung protection: keep the lungs partially collapsed (SaO2 > 88%), avoid opening and closing of collapsed alveoli, and gently ventilate aerated regions while keeping collapsed and consolidated areas at rest. Additional mechanisms, such as subject-ventilator asynchrony, cumulative power, and intensity, as well as the damaging threshold (stress–strain level at which tidal damage is initiated), are under experimental investigation and may enhance the understanding of VILI.

Abstract Background Due to the growing economic pressure, there is an increasing interest in the optimization of operational processes within surgical operating rooms (ORs). Surgical departments are frequently dealing with limited resources, complex processes with unexpected events as well as constantly changing conditions. In order to use available resources efficiently, existing workflows and processes have to be analyzed and optimized continuously. Structural and procedural changes without prior data-driven analyses may impair the performance of the OR team and the overall efficiency of the department. The aim of this study is to develop an adaptable software toolset for surgical workflow analysis and perioperative process optimization in arthroscopic surgery. Methods In this study, the perioperative processes of arthroscopic interventions have been recorded and analyzed subsequently. A total of 53 arthroscopic operations were recorded at a maximum care university hospital (UH) and 66 arthroscopic operations were acquired at a special outpatient clinic (OC). The recording includes regular perioperative processes (i.a. patient positioning, skin incision, application of wound dressing) and disruptive influences on these processes (e.g. telephone calls, missing or defective instruments, etc.). For this purpose, a software tool was developed (‘s.w.an Suite Arthroscopic toolset’). Based on the data obtained, the processes of the maximum care provider and the special outpatient clinic have been analyzed in terms of performance measures (e.g. Closure-To-Incision-Time), efficiency (e.g. activity duration, OR resource utilization) as well as intra-process disturbances and then compared to one another. Results Despite many similar processes, the results revealed considerable differences in performance indices. The OC required significantly less time than UH for surgical preoperative (UH: 30:47 min, OC: 26:01 min) and postoperative phase (UH: 15:04 min, OC: 9:56 min) as well as changeover time (UH: 32:33 min, OC: 6:02 min). In addition, these phases result in the Closure-to-Incision-Time, which lasted longer at the UH (UH: 80:01 min, OC: 41:12 min). Conclusion The perioperative process organization, team collaboration, and the avoidance of disruptive factors had a considerable influence on the progress of the surgeries. Furthermore, differences in terms of staffing and spatial capacities could be identified. Based on the acquired process data (such as the duration for different surgical steps or the number of interfering events) and the comparison of different arthroscopic departments, approaches for perioperative process optimization to decrease the time of work steps and reduce disruptive influences were identified.

Abstract Hepatocellular carcinoma (HCC) has high recurrence rates exceeding 50% despite curative resection. The serum biomarker alpha-fetoprotein (AFP) is a well-known prognostic marker for HCC. EpCAM-positive circulating tumor cells (CTC) have a high predictive value for early HCC recurrence after curatively intended resection, most likely indicating micro-metastases at the time of resection. However, sensitivity remains low. The objective of this study was to evaluate a composite test comprising both CTC and AFP to identify patients at high risk for early HCC recurrence. We prospectively enrolled 58 patients undergoing curative intended resection for HCC at a tertiary referral center. Blood specimens were obtained prior to resection and analyzed for EpCAM-positive CTC and serum AFP levels. A positive result was defined as either detection of CTC or AFP levels ≥ 400 ng/ml. Eight patients tested positive for CTC, seven for AFP, and two for both markers. A positive composite test was significantly associated with shorter early recurrence-free survival (5 vs. 16 months, p = 0.005), time to recurrence (5 vs. 16 months, p = 0.011), and overall survival (37 vs. not reached, p = 0.034). Combining CTC and AFP identified patients with poor outcome after surgical resection, for whom adjuvant or neoadjuvant therapies may be particularly desirable.

Titanium alloys have been gaining importance in various industries due to their advantageous combination of strength, low density, excellent corrosion/oxidation resistance, and superior mechanical properties at elevated temperatures. Recently, eutectoid Ti–Cu alloys have been explored as promising candidates for advanced processes. This work investigates the effects of Fe and Al on a Ti-5.9Cu alloy using multi-scale characterization techniques. While Fe acts as a β-stabilizing element (despite being a sluggish eutectoid former), Al acts as an α-stabilizer. This work focuses on the effects of combined addition of these elements, studied in different heat treatment conditions. The results show that a fine, equiaxed microstructure is obtained in the binary Ti-5.9Cu alloy, whereas the addition of 2 wt% Fe, or 2 wt% Fe combined with 2 wt% Al to the Ti-5.9Cu alloy deteriorates the effect of grain refinement and coarse, columnar grains result and a small amount of β-phase is retained. Further, the microstructure resulting from the eutectoid decomposition is altered dramatically from a lamellar pearlitic in the binary alloy to a lath-like α-phase with diverse decomposition products in the ternary and quaternary alloys accompanied by increasing hardness values. Evaluation of the α misorientation suggests that a substantial amount of non-Burgers α is present in the Ti-Cu alloy in contrast to the results of the ternary and quaternary alloys. The observed Cu-rich intermetallic compound was identified as Ti2Cu phase with off-stoichiometric composition. Results obtained explain how adding either Fe or Fe and Al leads to substantial hardening.

Background: Duplex kidneys may be associated with additional pathologies with an indication for surgery. Various surgical approaches have been described. However, little is known about long-term outcomes and quality of life (QoL) for these patients. Objective: To present long-term outcomes and QoL data up to 30 yr after surgical treatment of duplex kidneys and associated pathologies. Design, setting, and participants: We collected clinical and operative data for all patients who underwent surgery for complicated duplex kidney at our institution from 1990 to 2018. All patients were invited for a follow-up examination or telephone interview. Outcome measurements and statistical analysis: We evaluated renal function, clinical outcomes, residual dilation of the upper urinary tract, and health-related QoL. Results and limitations: Of the 176 patients included, 173 were available for follow-up (mean 140.5 mo). Surgical treatment involved an upper-tract, lower-tract, or combined approach in 11%, 56%, and 33% of cases, respectively. Rates of perioperative complications (8%) and secondary surgery (10%) were low. Overall, 95% of our patients achieved full restitution. Renal function was preserved in all cases, with recurrent urinary tract infections reported by just 2% and urinary incontinence by 1%. Good health-related QoL was reported by 98% of patients. Those without full restitution included six patients who underwent total nephrectomy and two boys who underwent multiple surgeries and urinary diversion. Our results are limited by their retrospective nature, including partly incomplete data sets. Conclusions: Management of duplex kidneys and associated pathologies is complex and highly individual. By planning a personal approach for each patient it is possible to achieve full bodily integrity and good QoL for most of these patients. Patient summary: Almost all patients undergoing surgery for duplex kidneys and associated pathologies will lead a life without body impairment and good quality of life.This trial is registered in the German Clinical Trials Register as DRKS00022542.

Textile-reinforced concrete (TRC) is a composite material consisting of a concrete matrix with a high-performance reinforcement made of technical textiles. TRC offers unique mechanical properties for the construction industry, enabling the construction of lightweight, material-minimized structures with high load-bearing potential. In addition, compared with traditional concrete design, TRC offers unique possibilities to realize free-form, double-curved structures. After more than 20 years of research, TRC is increasingly entering the market, with several demonstrator elements and buildings completed and initial commercialization successfully finished. Nevertheless, research into this highly topical area is still ongoing. In this paper, the authors give an overview of the current and future trends in the research and application of textiles in concrete construction applications. These trends include topics such as maximizing the textile utilization rate by improving the mechanical load-bearing performance (e.g., by adapting bond behavior), increasing design freedom by utilizing novel manufacturing methods (e.g., based on robotics), adding further value to textile reinforcements by the integration of additional functions in smart textile solutions (e.g., in textile sensors), and research into increasing the sustainability of TRC (e.g., using recycled fibers).

Background: Pneumonectomy is a major surgical resection that still remains a high-risk operation. The current study aims to investigate perioperative risk factors for postoperative morbidity and early mortality after pneumonectomy for thoracic malignancies. Methods: We retrospectively analyzed all patients who underwent pneumonectomy for thoracic malignancies at our institution between 2014 and 2022. Complications were assessed up to 30 days after the operation. Mortality for any reason was recorded after 30 days and 90 days. Results: A total of 145 out of 169 patients undergoing pneumonectomy were included in this study. The postoperative 30-day complication rate was 41.4%. The 30-day-mortality was 8.3%, and 90-day-mortality 17.2%. The presence of cardiovascular comorbidities was a risk factor for major cardiopulmonary complications (54.2% vs. 13.2%, p < 0.01). Postoperative bronchus stump insufficiency (OR: 11.883, 95% CI: 1.288–109.591, p = 0.029) and American Society of Anesthesiologists (ASA) score 4 (OR: 3.023, 95% CI: 1.028–8.892, p = 0.044) were independent factors for early mortality. Conclusion: Pneumonectomy for thoracic malignancies remains a high-risk major lung resection with significant postoperative morbidity and mortality. Attention should be paid to the preoperative selection of patients.

Abstract Background In Germany, homeless people are entitled to health care within the regular health care system. However, due to their specific living conditions they make little use of these services. In 2013, three Medical centres for the homeless (MCH) were opened in Hamburg to provide general health care. This study aims to analyse the consultation reasons and diagnoses prevalent among the homeless in comparison to regular primary care patients. It also examines the means and obstacles of integrating the homeless into Germany’s regular health care system. Methods From 2013 to 2014, routine medical data of all patients of the MCH consenting to participate in the study were analysed descriptively, in particular consultation reasons (categorised by ICPC-2), ICD-10 diagnoses and data on health insurance status and the use of the regular health care system. Consultation reasons and diagnoses of homeless patients were compared descriptively with data from regular general practices. Additionally, anonymous data on patient numbers, gender and insurance status was exported from the MCH’s software and analysed descriptively for the years 2013 to 2020. Results A total of 840 homeless patients in 2013 and 2014 gave consent to the evaluation of consultation reasons and diagnoses. The most frequent consultation reasons in the MCH in 2013 were skin conditions (24%), musculoskeletal conditions (16%) and psychological disorders (14%), in GP practices these were musculoskeletal conditions (22%), conditions affecting the digestive system (14%) and skin conditions (12%). Essential (primary) hypertension, diabetes mellitus type 2 and back pain are among the top-10-diagnoses in GP practices, as well as in MCH. With regard to the other top-10-diagnoses, there are clear differences between GP practices and MCH: “Psychological behavioural disorder due to alcohol” and diagnoses in connection with trauma, skin infections and acute respiratory infections stand out in MCH. 35% of the homeless patients reported a lack of health insurance as the reason for “not making use of” the regular health care system, while 10% reported they were unable to visit a regular general practitioner due to physical or psychological reasons. In the years 2013–2020 46% to 73% of the 8.380 MCH patients had no health care insurance. Conclusion Patients consulting the MCH suffer from medical conditions typical for the homeless, namely skin diseases, wounds, injuries and behavioural disorders due to alcohol abuse, but also from “typical” symptoms in regular GP care as cough or lower back symptoms. Consultation reasons mostly are acute illnesses. Chronic diseases are equally present in regular GP and MCH patients, but pose a great challenge for the homeless among other things due to their irregular contact with the health care system. The lack of health insurance poses the greatest hurdle to the integration of the homeless into the regular health care system.

Abstract A positron emission tomography (PET) tracer detecting α-synuclein pathology will improve the diagnosis, and ultimately the treatment of α-synuclein-related diseases. Here we show that the PET ligand, [18F]ACI-12589, displays good in vitro affinity and specificity for pathological α-synuclein in tissues from patients with different α-synuclein-related disorders including Parkinson’s disease (PD) and Multiple-System Atrophy (MSA) using autoradiography and radiobinding techniques. In the initial clinical evaluation we include 23 participants with α-synuclein related disorders, 11 with other neurodegenerative disorders and eight controls. In vivo [18F]ACI-12589 demonstrates clear binding in the cerebellar white matter and middle cerebellar peduncles of MSA patients, regions known to be highly affected by α-synuclein pathology, but shows limited binding in PD. The binding statistically separates MSA patients from healthy controls and subjects with other neurodegenerative disorders, including other synucleinopathies. Our results indicate that α-synuclein pathology in MSA can be identified using [18F]ACI-12589 PET imaging, potentially improving the diagnostic work-up of MSA and allowing for detection of drug target engagement in vivo of novel α-synuclein targeting therapies.

Abstract Alzheimer’s disease (AD) is characterized by the accumulation of β-amyloid peptide (Aβ). It affects cognition and leads to memory impairment. The mitochondrial translocator protein (TSPO) plays an essential role in maintaining mitochondrial homeostasis and has been implicated in several neuronal disorders or neuronal injuries. Ligands targeting the mitochondrial translocator protein (18 kDa), promote neurosteroidogenesis and may be neuroprotective. To study whether the TSPO ligand XBD173 may exert early neuroprotective effects in AD pathology we investigated the impact of XBD173 on amyloid toxicity and neuroplasticity in mouse models of AD. We show that XBD173 (emapunil), via neurosteroid-mediated signaling and delta subunit-containing GABAA receptors, prevents the neurotoxic effect of Aβ on long-term potentiation (CA1-LTP) in the hippocampus and prevents the loss of spines. Chronic but not acute administration of XBD173 ameliorates spatial learning deficits in transgenic AD mice with arctic mutation (ArcAβ). The heterozygous TSPO-knockout crossed with the transgenic arctic mutation model of AD mice (het TSPOKO X ArcAβ) treated with XBD173 does not show this improvement in spatial learning suggesting TSPO is needed for procognitive effects of XBD173. The neuroprotective profile of XBD173 in AD pathology is further supported by a reduction in plaques and soluble Aβ levels in the cortex, increased synthesis of neurosteroids, rescued spine density, reduction of complement protein C1q deposits, and reduced astrocytic phagocytosis of functional synapses both in the hippocampus and cortex. Our findings suggest that XBD173 may exert therapeutic effects via TSPO in a mouse model of AD.

Abstract Soils provide essential ecosystem functions that are threatened by climate change and intensified land use. We explore how climate and land use impact multiple soil function simultaneously, employing two datasets: (1) observational – 456 samples from the European Land Use/Land Cover Area Frame Survey; and (2) experimental – 80 samples from Germany’s Global Change Experimental Facility. We aim to investigate whether manipulative field experiment results align with observable climate, land use, and soil multifunctionality trends across Europe, measuring seven ecosystem functions to calculate soil multifunctionality. The observational data showed Europe-wide declines in soil multifunctionality under rising temperatures and dry conditions, worsened by cropland management. Our experimental data confirmed these relationships, suggesting that changes in climate will reduce soil multifunctionality across croplands and grasslands. Land use changes from grasslands to croplands threaten the integrity of soil systems, and enhancing soil multifunctionality in arable systems is key to maintain multifunctionality in a changing climate.

Abstract We describe a solution for secure and verifiable handling of energy certificates. Such certificates are increasingly used to claim and prove responsible use of green energy, and there is a strong need for transparency and public verifiability. While the proposed solution is designed for handling electricity it applies to different types of energy as well and the concepts may also be applied to other domains. Transmission System Operators are trusted to record consumption and production of electricity. The movement from volume-based MWh yearly certificates to spot-market aligned hourly or 15 min time-volume based intervals, creates challenges in relation to handling large amounts of data and subsequent transactions. Small discrete intervals gives the certification increased accuracy of energy consumption, as a means to prevent greenwashing, with the cost of higher amounts of transactional data and complexity. To ensure trust in the certification, these certificates must in addition be unique and publicly verifiable. This paper describes how blockchain technology can be used to create the required transparency and public verifiability. We show how large amounts of data can be efficiently handled on blockchains and how confidential data such as the amount of used energy in the certificates can be protected, ensuring privacy and correctness of the certificates.

Abstract Background Heterogeneity in type 2 diabetes presentation and progression suggests that precision medicine interventions could improve clinical outcomes. We undertook a systematic review to determine whether strategies to subclassify type 2 diabetes were associated with high quality evidence, reproducible results and improved outcomes for patients. Methods We searched PubMed and Embase for publications that used ‘simple subclassification’ approaches using simple categorisation of clinical characteristics, or ‘complex subclassification’ approaches which used machine learning or ‘omics approaches in people with established type 2 diabetes. We excluded other diabetes subtypes and those predicting incident type 2 diabetes. We assessed quality, reproducibility and clinical relevance of extracted full-text articles and qualitatively synthesised a summary of subclassification approaches. Results Here we show data from 51 studies that demonstrate many simple stratification approaches, but none have been replicated and many are not associated with meaningful clinical outcomes. Complex stratification was reviewed in 62 studies and produced reproducible subtypes of type 2 diabetes that are associated with outcomes. Both approaches require a higher grade of evidence but support the premise that type 2 diabetes can be subclassified into clinically meaningful subtypes. Conclusion Critical next steps toward clinical implementation are to test whether subtypes exist in more diverse ancestries and whether tailoring interventions to subtypes will improve outcomes.

Abstract How far are species distributed on the abyssal plains? Spanning from 3000 to 6000 m below sea level, abyssal plains cover three-quarters of the ocean floor and are the largest but also least explored habitat on Earth. The question of vertical and horizontal distribution is central to understanding biogeographic and population genetic processes within species inhabiting the deep-sea benthos. Amphipod crustaceans are an important and dominant taxon in this ecosystem. As they are brooders, their dispersal capacities are more limited compared to species with free-swimming larvae, and with the exception of a few scavenging species deep-sea amphipods are restricted to a single ocean. Based on an integrative taxonomic approach (morphology, COI, 16S and 18S) we demonstrate the occurrence of a predatory amphipod species, Rhachotropis abyssalis, in three oceans: the Antarctic Ross Sea, the Northwest Pacific and the North Atlantic; regions more than 20,000 km apart. Although such extensive geographic distributions may represent a rare exception for brooding predators, these findings might also be no exception at all, but a reflection of the rare sampling and rare taxonomic investigation of invertebrate predators in the deep-sea. Our findings highlight our abysmal state of knowledge regarding biodiversity and biogeography on abyssal plains.

Abstract Background: Data on seroconversion rates after SARS-CoV-2 infection in young children (

In neuroimaging, there is no equivalent alternative to magnetic resonance imaging (MRI). However, image acquisitions are generally time-consuming, which may limit utilization in some cases, e.g., in patients who cannot remain motionless for long or suffer from claustrophobia, or in the event of extensive waiting times. For multiple sclerosis (MS) patients, MRI plays a major role in drug therapy decision-making. The purpose of this study was to evaluate whether an ultrafast, T2-weighted (T2w), deep learning-enhanced (DL), echo-planar-imaging-based (EPI) fluid-attenuated inversion recovery (FLAIR) sequence (FLAIRUF) that has targeted neurological emergencies so far might even be an option to detect MS lesions of the brain compared to conventional FLAIR sequences. Therefore, 17 MS patients were enrolled prospectively in this exploratory study. Standard MRI protocols and ultrafast acquisitions were conducted at 3 tesla (T), including three-dimensional (3D)-FLAIR, turbo/fast spin-echo (TSE)-FLAIR, and FLAIRUF. Inflammatory lesions were grouped by size and location. Lesion conspicuity and image quality were rated on an ordinal five-point Likert scale, and lesion detection rates were calculated. Statistical analyses were performed to compare results. Altogether, 568 different lesions were found. Data indicated no significant differences in lesion detection (sensitivity and positive predictive value [PPV]) between FLAIRUF and axially reconstructed 3D-FLAIR (lesion size ≥3 mm × ≥2 mm) and no differences in sensitivity between FLAIRUF and TSE-FLAIR (lesion size ≥3 mm total). Lesion conspicuity in FLAIRUF was similar in all brain regions except for superior conspicuity in the occipital lobe and inferior conspicuity in the central brain regions. Further findings include location-dependent limitations of signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) as well as artifacts such as spatial distortions in FLAIRUF. In conclusion, FLAIRUF could potentially be an expedient alternative to conventional methods for brain imaging in MS patients since the acquisition can be performed in a fraction of time while maintaining good image quality.

Herpesviral protein kinases, such as the therapy-relevant pUL97 of human cytomegalovirus (HCMV), are important for viral replication efficiency as well as pathogenesis, and represent key antiviral drug targets. HCMV pUL97 is a viral cyclin-dependent kinase (CDK) ortholog, as it shares functional and structural properties with human CDKs. Recently, the formation of vCDK/pUL97–cyclin complexes and the phosphorylation of a variety of viral and cellular substrate proteins has been demonstrated. Genetic mapping and structural modeling approaches helped to define two pUL97 interfaces, IF1 and IF2, responsible for cyclin binding. In particular, the regulatory importance of interactions between vCDK/pUL97 and host cyclins as well as CDKs has been highlighted, both as determinants of virus replication and as a novel drug-targeting option. This aspect was substantiated by the finding that virus replication was impaired upon cyclin type H knock-down, and that such host-directed interference also affected viruses resistant to existing therapies. Beyond the formation of binary interactive complexes, a ternary pUL97–cyclin H–CDK7 complex has also been described, and in light of this, an experimental trans-stimulation of CDK7 activity by pUL97 appeared crucial for virus–host coregulation. In accordance with this understanding, several novel antiviral targeting options have emerged. These include kinase inhibitors directed to pUL97, to host CDKs, and to the pUL97–cyclin H interactive complexes. Importantly, a statistically significant drug synergy has recently been reported for antiviral treatment schemes using combinations of pharmacologically relevant CDK7 and vCDK/pUL97 inhibitors, including maribavir. Combined, such findings provide increased options for anti-HCMV control. This review focuses on regulatory interactions of vCDK/pUL97 with the host cyclin–CDK apparatus, and it addresses the functional relevance of these key effector complexes for viral replication and pathogenesis. On this basis, novel strategies of antiviral drug targeting are defined.

In the present study with a novel two-chamber setup (TCS) for dustiness investigations, the relationship between pressure differences as well as air velocities and the resulting dust emissions is investigated. The dust emissions of six particle size fractions of acetaminophen at pressure differences between 0 and 12 Pa are examined. The results show that both simulated and measured air velocities increase with increasing pressure difference. Dust emissions decrease significantly with increasing pressure difference and air velocity. Fine particles cause higher dust emissions than coarse particles. A high goodness of fit is obtained with exponential and quadratic functions to describe the relationship between pressure difference and dust emission, indicating that even moderate increases in pressure may lead to a reduction in the emission. Average air velocities within the TCS simulated with Computational Fluid Dynamics are between 0.09 and 0.37 m/s, whereas those measured experimentally are between 0.09 and 0.41 m/s, both ranges corresponding to the recommended values for effective particle separation in containment systems. These results underline the ability of the novel TCS to control pressure and airflow, which is essential for reliable dust emission measurements and thus provide support for further scientific and industrial applications.

In this focused genetic case–control study, we analyzed two functional single-nucleotide variants (SNVs) associated with breast cancer risk (rs2046210, rs9383590) and one risk SNV for an implantation defect and infertility (rs9340799) for their association with endometriosis susceptibility, progression and ESR1 gene regulation in endometriosis patients. The rs2046210, rs9383590 and rs9340799 SNVs were genotyped in 153 endometriosis patients and 87 control subjects with Caucasian ancestry. We analyzed the association of all SNVs with endometriosis susceptibility in all patients and in subgroups and assessed the concordance between the SNVs. Quantitative reverse transcription PCR was used to determine ESR1 gene expression in the eutopic endometrial tissue of the controls and endometriosis patients. The heterozygous rs2046210 GA genotype was associated with significantly increased endometriosis risk, particularly in younger, leaner and infertile women and with an increased ESR1 gene expression in the eutopic endometrium of these patients, compared to controls. The minor AA genotype of rs2046210 was identified as a potential risk factor for endometriosis progression in women with mild endometriosis. The results from this analysis indicate that rs2046210 may be a functional genetic variant associated with endometriosis development and progression.