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Circulating proteomes provide a snapshot of the physiological state of a human organism responding to pathogenic challenges and drug interventions. The outcomes of patients with COVID-19 and acute respiratory distress syndrome triggered by the SARS-CoV2 virus remain uncertain. Tocilizumab is an anti-interleukin-6 treatment that exerts encouraging clinical activity by controlling the cytokine storm and improving respiratory distress in patients with COVID-19. We investigate the biological determinants of therapeutic outcomes after tocilizumab treatment. Overall, 28 patients hospitalized due to severe COVID-19 who were treated with tocilizumab intravenously were included in this study. Sera were collected before and after tocilizumab, and the patient’s outcome was evaluated until day 30 post-tocilizumab infusion for favorable therapeutic response to tocilizumab and mortality. Hyperreaction monitoring measurements by liquid chromatography–mass spectrometry-based proteomic analysis with data-independent acquisition quantified 510 proteins and 7019 peptides in the serum of patients. Alterations in the serum proteome reflect COVID-19 outcomes in patients treated with tocilizumab. Our results suggested that circulating proteins associated with the most significant prognostic impact belonged to the complement system, platelet degranulation, acute-phase proteins, and the Fc-epsilon receptor signaling pathway. Among these, upregulation of the complement system by activation of the classical pathway was associated with poor response to tocilizumab, and upregulation of Fc-epsilon receptor signaling was associated with lower mortality.

La visión multidimensional de la enfermedad es fundamental en la atención de patologías complejas como la enfermedad renal crónica (ERC). Es oportuno definir y unificar conceptos que permitan que los diferentes profesionales encargados de la atención ofrezcan una atención multidisciplinar, alineados a las necesidades de cada persona.

Postoperative atrial fibrillation (POAF) is associated with increased morbidity and mortality. Epicardial injection of botulinum toxin may suppress POAF.

Although advances in deep learning systems for image-based medical diagnosis demonstrate their potential to augment clinical decision-making, the effectiveness of physician–machine partnerships remains an open question, in part because physicians and algorithms are both susceptible to systematic errors, especially for diagnosis of underrepresented populations. Here we present results from a large-scale digital experiment involving board-certified dermatologists (n= 389) and primary-care physicians (n= 459) from 39 countries to evaluate the accuracy of diagnoses submitted by physicians in a store-and-forward teledermatology simulation. In this experiment, physicians were presented with 364 images spanning 46 skin diseases and asked to submit up to four differential diagnoses. Specialists and generalists achieved diagnostic accuracies of 38% and 19%, respectively, but both specialists and generalists were four percentage points less accurate for the diagnosis of images of dark skin as compared to light skin. Fair deep learning system decision support improved the diagnostic accuracy of both specialists and generalists by more than 33%, but exacerbated the gap in the diagnostic accuracy of generalists across skin tones. These results demonstrate that well-designed physician–machine partnerships can enhance the diagnostic accuracy of physicians, illustrating that success in improving overall diagnostic accuracy does not necessarily address bias.

Inflammation is characterized by a biphasic cycle consisting initially of a proinflammatory phase that is subsequently resolved by anti-inflammatory processes. Interleukin-1β (IL-1β) is a master regulator of proinflammation and is encoded within the same topologically associating domain (TAD) as IL-37, which is an anti-inflammatory cytokine that opposes the function of IL-1β. Within this TAD, we identified a long noncoding RNA called AMANZI, which negatively regulates IL-1β expression and trained immunity through the induction of IL37transcription. We found that the activation of IL37occurs through the formation of a dynamic long-range chromatin contact that leads to the temporal delay of anti-inflammatory responses. The common variant rs16944 present in AMANZI augments this regulatory circuit, predisposing individuals to enhanced proinflammation or immunosuppression. Our work illuminates a chromatin-mediated biphasic circuit coordinating expression of IL-1β and IL-37, thereby regulating two functionally opposed states of inflammation from within a single TAD.

The adequate assessment of the quality of parts produced by additive manufacturing is crucial for their application in the aviation industry. Therefore, parameters of the manufacturing process, which influence the part quality, have to be identified and quantified to reveal existing correlations. Besides, it is essential to gain an overall understanding of the influence of each step in the additive manufacturing chain, including also post-process treatments and inspection methods, on the data, which is used to develop a statement about the additively manufactured parts’ quality. The present study aims on forming such a comprehensive picture. For this purpose, 120 test specimens from AlSi10Mg were manufactured on an EOS M 290. Four different surface treatments (centrifugal blasting, barrel finishing, abrasive flow machining and turning & polishing) were applied to the specimens and compared to the as-built condition regarding the resulting material properties. The relative density, surface roughness, surface hardness, ultimate tensile strength, yield strength, Young’s modulus and the fatigue properties were determined and analysed especially for correlations with the surface treatment and specimen positions in the build space. The surface roughness, fatigue properties and static tensile properties showed to be dependent on the applied surface treatment, while fewer correlations could be found regarding the surface hardness and relative part density. No clear indication was found relating one of the mentioned properties to certain areas in the build space.

We examined human deepfake detection performance (DDP) in relation to face identity processing ability among Berlin Police officers, including Super-Recognizers (SRs). While we find no relationship, further research into human DDP using state-of-the-art static deepfakes is needed to establish the potential value of SR-deployment.

The more than 20 extant members of the genus Canariella Hesse, 1918 are all endemic to the Canary Islands. From the largest island of the Canarian Archipelago, Tenerife, only 5 species of the genus are currently recognised as valid species. This comparatively low number of species is surprising when compared with the diversity of other endemic genera of the Canary Islands and when compared with the diversity of Canariella on other large, high islands of this archipelago. We critically review the diversity of the Canariella hispidula (Lamarck, 1822) group on the basis of the available published data, as well as on the basis of materials in museum collections and the collections of the authors. Of the 9 previously described taxa belonging to this species complex we recognise 6 as valid species, namely C. hispidula, C. berthelotii (d’Orbigny, 1836), C. leprosa (Shuttleworth, 1852), C. lanosa (Mousson, 1872), C. subhispidula (Mousson, 1872), and C. everia (Mabille, 1882). The nominal taxon Helix (Gonostoma) beata Wollaston, 1878 is considered as a subspecies of C. berthelotii, while the nominal taxa Helix fortunata Shuttleworth, 1852 and Helicodonta salteri Gude, 1911 are considered synonyms of C. berthelotii and C. hispidula, respectively. The taxon from the southern and south-eastern parts of Tenerife previously considered to represent “C. bertheloti (Férussac, 1835)” is described as a new species, Canariella hartmuti sp. nov. The designation of a “lectotype” by Ibánez et al. (1995) for this unavailable name is withdrawn. The taxa C. leprosa and C. everia are placed in an undescribed subgenus, while the remaining taxa are placed in the nominate subgenus Canariella s. str.

Pollution by chemicals and waste impacts human and ecosystem health on regional, national, and global scales, resulting, together with climate change and biodiversity loss, in a triple planetary crisis. Consequently, in 2022, countries agreed to establish an intergovernmental science–policy panel (SPP) on chemicals, waste, and pollution prevention, complementary to the existing intergovernmental science–policy bodies on climate change and biodiversity. To ensure the SPP’s success, it is imperative to protect it from conflicts of interest (COI). Here, we (i) define and review the implications of COI, and its relevance for the management of chemicals, waste, and pollution; (ii) summarize established tactics to manufacture doubt in favor of vested interests, i.e., to counter scientific evidence and/or to promote misleading narratives favorable to financial interests; and (iii) illustrate these with selected examples. This analysis leads to a review of arguments for and against chemical industry representation in the SPP’s work. We further (iv) rebut an assertion voiced by some that the chemical industry should be directly involved in the panel’s work because it possesses data on chemicals essential for the panel’s activities. Finally, (v) we present steps that should be taken to prevent the detrimental impacts of COI in the work of the SPP. In particular, we propose to include an independent auditor’s role in the SPP to ensure that participation and processes follow clear COI rules. Among others, the auditor should evaluate the content of the assessments produced to ensure unbiased representation of information that underpins the SPP’s activities.

Ali Cosmic Microwave Background (CMB) Polarization Telescope (AliCPT-1) will be the first large-scale microwave focal plane polarimeter, with $>\!10^{4}$ detectors, dedicated to ground-based CMB observations in the Northern Hemisphere. The observatory is on the Tibetan plateau. AliCPT-1 will observe the sky with polarization sensitive Transition-Edge Sensors (TESes) in two frequency bands centered at 90 and 150 GHz. A 72 cm aperture refracting cryogenic telescope, cooled down to 4 K, will focus the sky radiation on a focal plane unit designed to host up to 32,376 detectors in 19 detector modules cooled down to 280 mK. The TESes will be read out with a microwave multiplexing architecture with a multiplexing factor up to 1,820 and a RFSoC-based room temperature readout electronics. The first detector and cryogenic multiplexer unit have been separately assembled and characterized under dark conditions. The cryostat has been successfully characterized at cryogenic temperatures, and the basic operation of the warm RFSoC system for a single detector unit has been demonstrated. Here we present the performance of the receiver before the integration of the first detector module. AliCPT-1 is a unique and powerful degree-scale CMB experiment through its combination of a unique site, large focal plane, and new enabling readout technologies.

IMPORTANCE: The increasing use of neoadjuvant systemic therapy (NST) has led to substantial pathological complete response rates in patients with initially node-positive, early breast cancer, thereby questioning the need for axillary lymph node dissection (ALND). Targeted axillary dissection (TAD) is feasible for axillary staging; however, data on oncological safety are scarce. OBJECTIVE: To assess 3-year clinical outcomes in patients with node-positive breast cancer who underwent TAD alone or TAD with ALND. DESIGN, SETTING, AND PARTICIPANTS: The SenTa study is a prospective registry study and was conducted between January 2017 and October 2018. The registry includes 50 study centers in Germany. Patients with clinically node-positive breast cancer underwent clipping of the most suspicious lymph node (LN) before NST. After NST, the marked LNs and sentinel LNs were excised (TAD) followed by ALND according to the clinician’s choice. Patients who did not undergo TAD were excluded. Data analysis was performed in April 2022 after 43 months of follow-up. EXPOSURE: TAD alone vs TAD with ALND. MAIN OUTCOMES AND MEASURES: Three-year clinical outcomes were evaluated. RESULTS: Of 199 female patients, the median (IQR) age was 52 (45-60) years. A total of 182 patients (91.5%) had 1 to 3 suspicious LNs; 119 received TAD alone and 80 received TAD with ALND. Unadjusted invasive disease-free survival was 82.4% (95% CI, 71.5-89.4) in the TAD with ALND group and 91.2% (95% CI, 84.2-95.1) in the TAD alone group (P = .04); axillary recurrence rates were 1.4% (95% CI, 0-54.8) and 1.8% (95% CI, 0-36.4), respectively (P = .56). Adjusted multivariate Cox regression indicated that TAD alone was not associated with an increased risk of recurrence (hazard ratio [HR], 0.83; 95% CI, 0.34-2.05; P = .69) or death (HR, 1.07; 95% CI, 0.31-3.70; P = .91). Similar results were obtained for 152 patients with clinically node-negative breast cancer after NST (invasive disease-free survival: HR, 1.26; 95% CI, 0.27-5.87; P = .77; overall survival: HR, 0.81; 95% CI, 0.15-3.83; P = .74). CONCLUSIONS AND RELEVANCE: These results suggest that TAD alone in patients with mostly good clinical response to NST and at least 3 TAD LNs may confer survival outcomes and recurrence rates similar to TAD with ALND.

Current debates on threats to social integration in times of multiple crises call for a better understanding of the relationship between socioeconomic inequality and sociocultural value conflicts. The aim of this article is to (re)introduce the concept of social milieus as a promising approach to capture the complexity of this relationship at the group level. We offer a theoretical extension of the concept of social milieus, which has so far been limited to the German discourse, by linking it to the international debate on sociocultural “cleavages” and cultural value conflicts. Social milieus are defined as large latent groups with similar socioeconomic positions and cultural values. Accordingly, they develop milieu-specific forms of social integration in potentially conflictual demarcation from other milieus. This conceptualization offers a theoretical framework for analyzing social integration from the perspective of social groups in terms of social integration within social milieus and relationships between milieus. In order to illustrate the capabilities of this theoretical approach, we develop a first empirical model of social milieus in Germany based on a Latent Class Analysis of socioeconomic indicators and Schwartz’ basic human values. With this theoretical concept and empirical model, we put social milieus on the international research agenda for the analysis of social integration within and between social groups.

La cellulite à éosinophiles (syndrome de Wells) est une entité clinico-histologique rare et polymorphe. L’objectif de cette étude était, à partir d’une série de cas, de fournir des données actuelles cliniques et paracliniques, d’identifier des facteurs pronostiques, d’évaluer la réponse aux traitements et in finede proposer un algorithme de décision.

Human milk is the ideal source of nutrition for most infants, but significant gaps remain in our understanding of human milk biology. As part of addressing these gaps, the Breastmilk Ecology: Genesis of Infant Nutrition (BEGIN) Project Working Groups 1–4 interrogated the state of knowledge regarding the infant–human milk–lactating parent triad. However, to optimize the impact of newly generated knowledge across all stages of human milk research, the need remained for a translational research framework specific to the field. Thus, with inspiration from the simplified environmental sciences framework of Kaufman and Curl, Working Group 5 of the BEGIN Project developed a translational framework for science in human lactation and infant feeding, which includes 5 nonlinear, interconnected translational stages, T1: Discovery; T2: Human health implications; T3: Clinical and public health implications; T4: Implementation; and T5: Impact. The framework is accompanied by 6 overarching principles: 1) Research spans the translational continuum in a nonlinear, nonhierarchical manner; 2) Projects engage interdisciplinary teams in continuous collaboration and cross talk; 3) Priorities and study designs incorporate a diverse range of contextual factors; 4) Research teams include community stakeholders from the outset through purposeful, ethical, and equitable engagement; 5) Research designs and conceptual models incorporate respectful care for the birthing parent and address implications for the lactating parent; 6) Research implications for real-world settings account for contextual factors surrounding the feeding of human milk, including exclusivity and mode of feeding. To demonstrate application of the presented translational research framework and its overarching principles, 6 case studies are included, each illustrating research gaps across all stages of the framework. Applying a translational framework approach to addressing gaps in the science of human milk feeding is an important step toward the aligned goals of optimizing infant feeding across diverse contexts as well as optimizing health for all.

Introduction: Cardiovascular diseases (CVD) are the leading cause of death globally. Inflammation is an important driver of CVD where tissue damage may lead to the formation of deadly thrombi. Therefore, antithrombotic drugs, such as platelet inhibitors, are crucial for secondary risk prevention in coronary artery disease (CAD) and peripheral artery disease (PAD). For severe forms of the disease, dual-pathway inhibition (DPI) where low-dose aspirin is combined with rivaroxaban has shown improved efficacy in reducing cardiovascular mortality. Methods: Given this greater improvement in mortality, and the importance of inflammation in driving atherosclerosis, the potential for off-target inflammation-lowering effects of these drugs was evaluated by looking at the change in immune cell distribution and responsiveness to ex vivo lipopolysaccharide (LPS) stimulation after 3 months of DPI in patients with CAD. Results: We observed no changes in whole blood or peripheral blood mononuclear cell (PBMC) immune cell responsiveness to LPS after 3 months of DPI. Additionally, we did not observe any changes in the distribution of total white blood cells, monocytes, neutrophils, lymphocytes, or platelets during the study course. Signs of systemic inflammation were studied using Olink proteomics in 33 patients with PAD after 3 months of DPI. No changes were observed in any of the inflammatory proteins measured after the treatment period, suggesting that the state of chronic inflammation was not altered in these subjects. Conclusion: Three months of DPI does not result in any meaningful change in immune cell responsiveness and distribution in patients with CAD or PAD. Trial Registration: ClinicalTrials.gov ID: NCT05210725

Iron-bound cyclic tetrapyrroles (hemes) are redox-active cofactors in bioenergetic enzymes. However, the mechanisms of heme transport and insertion into respiratory chain complexes remain unclear. Here, we used cellular, biochemical, structural and computational methods to characterize the structure and function of the heterodimeric bacterial ABC transporter CydDC. We provide multi-level evidence that CydDC is a heme transporter required for functional maturation of cytochrome bd, a pharmaceutically relevant drug target. Our systematic single-particle cryogenic-electron microscopy approach combined with atomistic molecular dynamics simulations provides detailed insight into the conformational landscape of CydDC during substrate binding and occlusion. Our simulations reveal that heme binds laterally from the membrane space to the transmembrane region of CydDC, enabled by a highly asymmetrical inward-facing CydDC conformation. During the binding process, heme propionates interact with positively charged residues on the surface and later in the substrate-binding pocket of the transporter, causing the heme orientation to rotate 180°.

A saturated riparian buffer (SRB) is an edge‐of‐field conservation practice that intercepts tile drainage and reduces nitrate flux to nearby streams by redistributing the flow as shallow groundwater. In this study, a three‐dimensional, finite‐difference groundwater model representative of SRBs in central Iowa was developed to assess the flow of groundwater and implications for nitrate removal during spring conditions, when flow to the SRB is highest. The model reproduces field observations of water level with Nash–Sutcliffe efficiency of 0.68, which is deemed acceptable for hydrologic models. The modeling shows that groundwater flow is three‐dimensional near the distribution pipe and the stream and primarily one‐dimensional in the rest of the buffer. The path the water takes in flowing toward the stream depends on where it exits the distribution pipe. When nitrate is not limiting, the potential for nitrate removal depends on the length of the path—and thus travel time—and depth because denitrification potential varies with depth. Travel time Ttcan be estimated well with slight modifications to a one‐dimensional approximation: Tt= 1.11Lx/vx, where Lxis the buffer width and vxis a one‐dimensional approximation of the average linear velocity of groundwater. Refining knowledge of SRB function is an important step toward enhancing design for improving water quality. The model reproduces field observations of water level acceptably.Groundwater flow is one‐dimensional in most of the modeled saturated riparian buffer.Potential for N removal is greatest in flow that exits via the top perforations.Modeled travel time in SRBs is 11% larger than predicted by the one‐dimensional formula.

Fresh water is increasingly limited due to climate change. One way to reduce fresh water use by irrigated agriculture is to breed plants that can produce adequate yields with less water. A wild tomato, Solanum habrochaites, is more water stress tolerant than cultivated tomato, S. lycopersicumL. Our study aimed to fine map quantitative trait loci (QTL) for maturity, yield, and water use efficiency (WUE)‐related traits (shoot dry weight and carbon isotope discrimination, ∆13C) on chromosome 9 in S. habrochaitesusing a set of 21 sub‐near isogenic lines (sub‐NILs). These sub‐NILs and controls were evaluated in field experiments grown under full and reduced irrigation treatments across 2 yr. Genotype × environment interactions were significant, so the data was separated into subsets of environments for further analyses. Significant QTL were detected for 20 trait–environment combinations. All QTL were partially or completely coincident. The presence of the S. habrochaitesallele at QTL was associated with later maturity, lower yields, and greater WUE. However, yield and ∆13C exhibited no or low correlations with each other, suggesting these traits could be selected for improvement independently during breeding. Two of 21 sub‐NILs showed superior performance for WUE and yield compared to controls. These two genotypes may prove useful in breeding programs to improve the WUE of tomato cultivars without negative effects on yield. Water use efficiency‐related and horticultural quantitative trait locus mapped on S. habrochaiteschromosome 9.Quantitative trait locus for horticultural and water use efficiency‐related traits were coincident.Solanum habrochaitesalleles were associated with positive water use efficiency‐related traits.Genotype × environment and quantitative trait locus × environment interactions were detected.Two sub‐near isogenic lines performed well for yield and Δ13C and may prove useful for breeding.

AbstractSeveral studies have investigated the relationship between the energy performance of buildings and housing prices. First, this paper identifies a price premium for energy efficiency within the German rental market. Then, the indexed price differences and associated marginal benefits are compared with the marginal costs of energy retrofits. An extensive database of Germany’s largest online platform for housing over a time span from 2016 to 2020 is used in a hedonic regression approach. In addition, to extract the marginal costs of energy consumption abatement, a dataset of 1048 rental units regarding green-retrofit measures is utilized. Although a significant green premium is identified in the rental market, the findings suggest that it is not high enough to compensate landlords for the money they have to spend to retrofit. The marginal costs exceed the marginal benefits by far. Furthermore, it is found that the German government’s recent plans to split the carbon tax between landlords and tenants do not change this because the price per metric ton of carbon is insufficiently high. Limitations with respect to the data basis and consequently to the interpretation of the results exist. Nevertheless, the findings can help both tenants and landlords in their decision-making, as well as policy makers in the implementation of decarbonization efforts.

•Mortality rate in patients with hematologic malignancy with breakthrough COVID-19 is ∼9%, lower than in the prevaccination era.•Patients who received monoclonal antibodies, alone or combined with antivirals, showed a better clinical outcome.

The first Neogene deposits from Fuerteventura (Canary Islands, Spain) containing fossil landsnail shells were already described in the mid-19th century, and additional sites with a rich terrestrial gastropod fauna of Late Miocene and Early Pliocene age have been discovered since then. However, few species from these deposits have been scientifically named and described. Here we describe 2 Tudorella Fischer, 1885 species, T. rothei sp. nov. and T. lenneae sp. nov., from Early Pliocene deposits in Fuerteventura. We compare the new species with extant and fossil members of the genus, as well as with other representatives of the Pomatiidae from the Western Palaearctic region. The 2 new species represent the first records of the genus Tudorella from the Canary Islands, from where only endemic species belonging to the genus Pomatias Studer, 1789 had been known until now.