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Abstract Deterministic photon sources allow long-term advancements in quantum optics. A single quantum emitter embedded in a photonic resonator or waveguide may be triggered to emit one photon at a time into a desired optical mode. By coherently controlling a single spin in the emitter, multi-photon entanglement can be realized. We demonstrate a deterministic source of three-qubit entanglement based on a single electron spin trapped in a quantum dot embedded in a planar nanophotonic waveguide. We implement nuclear spin narrowing to increase the spin dephasing time to $${T}_{2}^{*}\simeq 33$$ T 2 * ≃ 33 ns, which enables high-fidelity coherent optical spin rotations, and realize a spin-echo pulse sequence for sequential generation of spin-photon and spin-photon-photon entanglement. The emitted photons are highly indistinguishable, which is a key requirement for scalability and enables subsequent photon fusions to realize larger entangled states. This work presents a scalable deterministic source of multi-photon entanglement with a clear pathway for further improvements, offering promising applications in photonic quantum computing or quantum networks.

We propose a type of phase transition in quantum many-body systems that occurs in highly excited quantum many-body scar states while most of the spectrum is largely unaffected. Such scar-state phase transitions can be realized by embedding a matrix product state, known to undergo a phase transition, as a scar state into the thermal spectrum of a parent Hamiltonian. We find numerically that the mechanism for the scar-state phase transition involves the formation or presence of low-entropy states at energies similar to the scar state in the vicinity of the phase transition point.

Abstract Organic mixed ionic‐electronic conductors (OMIECs) have emerged as promising materials for biological sensing, owing to their electrochemical activity, stability in an aqueous environment, and biocompatibility. Yet, OMIEC‐based sensors rely predominantly on the use of composite matrices to enable stimuli‐responsive functionality, which can exhibit issues with intercomponent interfacing. In this study, an approach is presented for non‐enzymatic glucose detection by harnessing a newly synthesized functionalized monomer, EDOT‐PBA. This monomer integrates electrically conducting and receptor moieties within a single organic component, obviating the need for complex composite preparation. By engineering the conditions for electrodeposition, two distinct polymer film architectures are developed: pristine PEDOT‐PBA and molecularly imprinted PEDOT‐PBA. Both architectures demonstrated proficient glucose binding and signal transduction capabilities. Notably, the molecularly imprinted polymer (MIP) architecture demonstrated faster stabilization upon glucose uptake while it also enabled a lower limit of detection, lower standard deviation, and a broader linear range in the sensor output signal compared to its non‐imprinted counterpart. This material design not only provides a robust and efficient platform for glucose detection but also offers a blueprint for developing selective sensors for a diverse array of target molecules, by tuning the receptor units correspondingly.

Background/Objectives: Genicular artery embolization (GAE) has demonstrated potential as a treatment for knee osteoarthritis by targeting inflammation and pain, although current evidence remains limited. This study used imaging biomarkers to objectively assess synovitis and possible ischemic complications following GAE. Methods: This was a prospective, single-center trial including participants with mild-to-moderate knee osteoarthritis. Ultrasound, contrast-enhanced (CE), and non-CE-MRI were performed two days before and one and six months after GAE. Ultrasound biomarkers included synovial hypertrophy, effusion, and Doppler activity. A combined effusion-synovitis score was assessed on non-CE-MRI, while CE-MRI allowed differentiation between synovium and effusion and was used to calculate whole-joint and local synovitis scores. The post-GAE MRIs were reviewed for ischemic complications. Results: Seventeen participants (aged 43–71) were treated. Significant reductions were observed in ultrasound-assessed synovial hypertrophy and Doppler activity, as well as in CE-MRI local and whole-joint synovitis scores. While reductions in effusion were noted in both ultrasound and MRI, these changes did not reach statistical significance. At one month, MRI revealed three cases of nonspecific osteonecrosis-like areas, which resolved completely by six months. Conclusions: This study demonstrated a reduction in synovitis and no permanent ischemic complication following GAE in knee osteoarthritis. Larger studies with longer follow-up are needed to confirm the long-term efficacy and safety of the procedure.

Background: Oxygen supplementation is ubiquitous in intensive care unit (ICU) patients with chronic obstructive pulmonary disease (COPD) and acute hypoxaemia, but the optimal oxygenation target has not been established. Methods: This was a pre-planned subgroup analysis of the Handling Oxygenation Targets in the ICU (HOT-ICU) trial, which allocated patients with acute hypoxaemia to a lower oxygenation target (partial pressure of arterial oxygen [Pao2] of 8 kPa) vs a higher target (Pao2 of 12 kPa) during ICU admission, for up to 90 days; the allocation was stratified for presence or absence of COPD. Here, we report key outcomes for patients with COPD. Results: The HOT-ICU trial enrolled 2928 patients of whom 563 had COPD; 277 were allocated to the lower and 286 to the higher oxygenation group. After allocation, the median Pao2 was 9.1 kPa (inter-quartile range 8.7–9.9) in the lower group vs 12.1 kPa (11.2–12.9) in the higher group. Data for arterial carbon dioxide (Paco2) were available for 497 patients (88%) with no between-group difference in time-weighted average; median Paco2 6.0 kPa (5.2–7.2) in the lower group vs 6.2 kPa (5.4–7.3) in the higher group. At 90 days, 122/277 patients (44%) in the lower oxygenation group had died vs 132/285 patients (46%) in the higher (relative risk 0.98; 95% confidence interval 0.82–1.17; P=0.67). No statistically significant differences were found in any secondary outcome. Conclusions: In ICU patients with COPD and acute hypoxaemia, a lower vs a higher oxygenation target did not reduce mortality. There were no between-group differences in Paco2 or in secondary outcomes. Clinical trial registration: NCT 03174002, EudraCT number 2017-000632-34.

Background In older adults, obstructive sleep apnea (OSA) has been associated with several cardiovascular complications. Whether young patients diagnosed with OSA also are at higher risk of developing subsequent cardiovascular disease is uncertain. We aimed to estimate the risk of developing an incident cardiovascular event among young patients diagnosed with OSA. Methods and Results We linked nationwide Danish health registries to identify a cohort of patients aged ≤50 years with OSA using data from 2010 through 2018. Cases without OSA from the general population were matched as controls (1:5). The main outcome was any cardiovascular event (including hypertension, diabetes, atrial fibrillation, ischemic heart disease, ischemic stroke, heart failure, and venous thromboembolism). All‐cause mortality was a secondary outcome. The study included 20 240 patients aged ≤50 years with OSA (19.6% female; mean±SD age 39.9±7.7 years) and 80 314 controls. After 5‐year follow‐up, 31.8% of the patients with OSA developed any cardiovascular event compared with 16.5% of the controls, with a corresponding relative risk (RR) of 1.96 (95% CI, 1.90–2.02). At 5‐year follow‐up, 27.3% of patients with OSA developed incident hypertension compared with 15.0% of the controls (RR, 1.84 [95% CI, 1.78–1.90]). Incident diabetes occurred in 6.8% of the patients with OSA and 1.4% of controls (RR, 5.05 [95% CI, 4.60–5.54]). Conclusions Similar to older adults, young adults with OSA demonstrate increased risk of developing cardiovascular events. To prevent cardiovascular disease progression, accumulation of cardiovascular risk factors, and mortality, risk stratification and prevention strategies should be considered for these patients.

Abstract Single nucleotide polymorphism (SNP) markers are powerful tools for investigating population structures, linkage analysis, and genome-wide association studies, as well as for breeding and population management. The availability of SNP markers has been limited to the most commercially important timber species, primarily due to the cost of genome sequencing required for SNP discovery. In this study, a combination of reference-based and reference-free approaches were used to identify SNPs in Nordmann fir (Abies nordmanniana), a species previously lacking genomic sequence information. Using a combination of a genome assembly of the closely related Silver fir (Abies alba) species and a de novo assembly of low-copy regions of the Nordmann fir genome, we identified a high density of reliable SNPs. Reference-based approaches identified two million SNPs in common between the Silver fir genome and low-copy regions of Nordmann fir. A combination of one reference-free and two reference-based approaches identified 250 shared SNPs. A subset of 200 SNPs were used to genotype 342 individuals and thereby tested and validated in the context of identity analysis and/or clone identification. The tested SNPs successfully identified all ramets per clone and five mislabeled individuals via identity and genomic relatedness analysis. The identified SNPs will be used in ad hoc breeding of Nordmann fir in Denmark.

Abstract Despite the growing interest in dynamic behaviors at the frequency domain, there exist very few studies on molecular orientation-dependent transient responses of organic mixed ionic–electronic conductors. In this research, we investigated the effect of ion injection directionality on transient electrochemical transistor behaviors by developing a model mixed conductor system. Two polymers with similar electrical, ionic, and electrochemical characteristics but distinct backbone planarities and molecular orientations were successfully synthesized by varying the co-monomer unit (2,2’-bithiophene or phenylene) in conjunction with a novel 1,4-dithienylphenylene-based monomer. The comprehensive electrochemical analysis suggests that the molecular orientation affects the length of the ion-drift pathway, which is directly correlated with ion mobility, resulting in peculiar OECT transient responses. These results provide the general insight into molecular orientation-dependent ion movement characteristics as well as high-performance device design principles with fine-tuned transient responses.

This review article provides a comprehensive overview of recent advancements in electron transport materials derived from quinoxaline, along with their applications in various electronic devices. We focus on their utilization in organic solar cells (OSCs), dye-sensitized solar cells (DSSCs), organic field-effect transistors (OFETs), organic-light emitting diodes (OLEDs) and other organic electronic technologies. Notably, the potential of quinoxaline derivatives as non-fullerene acceptors in OSCs, auxiliary acceptors and bridging materials in DSSCs, and n-type semiconductors in transistor devices is discussed in detail. Additionally, their significance as thermally activated delayed fluorescence emitters and chromophores for OLEDs, sensors and electrochromic devices is explored. The review emphasizes the remarkable characteristics and versatility of quinoxaline derivatives in electron transport applications. Furthermore, ongoing research efforts aimed at enhancing their performance and addressing key challenges in various applications are presented.

With our very limited memories, we provide a brief review of Paul Frampton’s memories of the discovery of the Veneziano model, with this indeed being string theory, with Y. Nambu, and, secondly, his 3-3-1 theory. The latter is, indeed, a non-excluded replacement for the Standard Model with triangle anomalies being cancelled, as they must in a truly viable theory. It even needs (essentially) three as the family number! Moreover, primordial black holes as dark matter is mentioned. We end with a review of my own very speculative, utterly recent idea that for the purpose of the classical approximation, we could, using the functional integral as our rudimentary assumption taken over from quantum mechanics, obtain the equations of motion without the, in our opinion, very mysterious imaginary unit i, which usually occurs as a factor in the exponent of the functional integrand, which is this i times the action. The functional integral without the mysterious i leads to the prediction of some of the strongest features in cosmology, and also seems to argue for as few black holes as possible and for the cosmological constant being zero.

Knee osteoarthritis (OA) affects millions worldwide, leading to pain and reduced quality of life. Conventional treatments often fail to provide adequate relief, necessitating new therapeutic approaches. This study evaluated the efficacy and safety of genicular artery embolization (GAE) using permanent microspheres in patients with mild-to-moderate knee OA. In this prospective, single-center study, 17 participants underwent GAE. KOOS (Knee injury and Osteoarthritis Outcome Score), WOMAC (The Western Ontario and McMaster Universities Arthritis Index), and IPAQ (International Physical Activity Questionnaire) scores, along with physical performance tests, medication use, and dual-energy X-ray absorptiometry (DEXA) scans, were assessed at baseline and at multiple follow-up points over six months. The primary endpoint, VAS at six months, showed significant improvement (median reduction from 66 mm to 40 mm, p = 0.0004). All pain and function scores, as well as physical performance tests, improved significantly. No clinically relevant changes in medication use or DEXA parameters were observed after six months. Only minor, self-limiting adverse events occurred. This study indicates that GAE is a promising minimally invasive treatment for knee OA, providing significant pain relief and functional improvement. However, further long-term, randomized trials are needed to confirm these findings and establish optimal patient selection criteria.

Abstract Background A growing body of evidence suggests that the gut microbiota is strongly linked to general human health. Microbiome-directed interventions, such as diet and exercise, are acknowledged as a viable and achievable strategy for preventing disorders and improving human health. However, due to the significant inter-individual diversity of the gut microbiota between subjects, lifestyle recommendations are expected to have distinct and highly variable impacts to the microbiome structure. Results Here, through a large-scale meta-analysis including 1448 shotgun metagenomics samples obtained longitudinally from 396 individuals during lifestyle studies, we revealed Bacteroides stercoris, Prevotella copri, and Bacteroides vulgatus as biomarkers of microbiota’s resistance to structural changes, and aromatic and non-aromatic amino acid biosynthesis as important regulator of microbiome dynamics. We established criteria for distinguishing between significant compositional changes from normal microbiota fluctuation and classified individuals based on their level of response. We further developed a machine learning model for predicting “responders” and “non-responders” independently of the type of intervention with an area under the curve of up to 0.86 in external validation cohorts of different ethnicities. Conclusions We propose here that microbiome-based stratification is possible for identifying individuals with highly plastic or highly resistant microbial structures. Identifying subjects that will not respond to generalized lifestyle therapeutic interventions targeting the restructuring of gut microbiota is important to ensure that primary end-points of clinical studies are reached. Video Abstract

Objective: Developmental dysplasia of the hip (DDH) is a congenital condition affecting 2–3% of all infants. DDH increases the risk of osteoarthritis, is the cause of 30 ​% of all total hip arthroplasties (THAs) in adults

Abstract Background It is not clearly known how well Danes estimate their chances of reaching the average life expectancy and whether identifiable population subgroups misestimate their life expectancy, and potentially also investments and savings in health and pensions. Therefore, in this study, we examined on the individual level whether subjective life expectancy is in line with the statistically calculated chance of reaching age 85, and further explored the psychological and behavioral factors associated with under or overestimation. Methods We opted for a cross-sectional survey design based on a sample of 5,379 Danish citizens aged 50–70 years, returning a web-based questionnaire with socio-demographic data supplemented from a national registry. Average participant estimates of their chance of reaching age 85 for each age range and sex group were compared with actuarial data. We then performed multiple linear regression analyses to examine factors associated with the subjective expectancy of reaching age 85 years. Results We found that 32% of females and 23% of males reported 100% certainty of reaching age 85, and average expected survival chance exceeded the statistically predicted survival chance for 23% of males and 16% for females in age-ranges 50–60 and 61–70. Our multivariable analysis found that health literacy, internal health locus of control, willingness to take health risks, self-rated health, and health and life satisfaction all showed a significant positive association with expectation of reaching age 85. Moreover, those on daily medications, ex- or current smokers, and heavy drinkers were significantly less optimistic about reaching age 85. Conclusions Particularly for the population groups with inaccurate life expectancies, the significant associations with psychological and behavioral factors open a way for initiatives based on behavior change theories to reach a better agreement between subjective and statistical life expectancy.

Abstract A new species of cloud fish of the genus Hypsolebias is described from a temporary pool in the rio Trairi basin, Rio Grande do Norte State, Brazil. It is the first record of the genus Hypsolebias for the basin. The new speciesbelongs to the H. flammeus species-group, which is composed of the species H. alternatus, H. brunoi, H. delucai, H. fasciatus, H. longignatus, H. marginatus, H. multiradiatus, and H. flammeus. The new species differs from all other species of the group, except H. flammeus, H. multiradiatus,and H. brunoi, by male color pattern and the presence of a metallic blue sheen surrounding the black spots of females. It differs from H. flammeus, H. multiradiatus and H. brunoi by dorsal and anal fin shape (both rounded vs. pointed) and by the orientation of the reddish-brown bars on the body and anal fin of males (diagonal vs. vertical). The new species differs from its congeners of Northeast Brazil mainly by the higher number of dorsal fin rays in males and the higher number of scales in the longitudinal series.

Abstract Background On 1 January 2018 a four-year test scheme concerning use of medicinal cannabis (MC) was enacted. It has recently been extended for four more years by the Danish Parliament permitting all Danish physicians to prescribe MC to their patients. Previous studies have shown that general practitioners (GPs) have varying prescription experience, little knowledge, and mixed attitudes about MC. However, the present evidence is still limited, and no studies exist about Danish GPs’ prescription experience, knowledge, and attitudes towards MC. Therefore, our aim was to examine Danish GPs’ prescription experience, knowledge, and attitudes towards MC. Methods A national online survey-based study addressing Danish GPs was performed from September 2018 to July 2019. We performed separate multivariable logistic regression analyses including GPs’ prescription experience, knowledge, and attitudes towards MC as outcome variables. Results A total of 427 (38.4%) of 1112 GPs completed the questionnaire. Of these, 37 (8.7%) had experience in prescribing MC. The majority had little or no knowledge about MC (80.6%) as well as a negative view on prescription of MC (71.4%) to patients. Factors associated with prescribing MC to patients were: Single-handed practices (OR = 1.6, 95% CI 1.1;1.8) and perception of having quite some knowledge about MC (OR = 4.8, 95% CI 2.2;10.4). Factors associated with having quite some knowledge about MC were: having a positive attitude towards prescribing MC (OR = 5.2, 95% CI 1.9;14.0), being male (OR = 1.7, 95% CI 1.4;1.8), and being at least 60 years of age (OR = 2.8, 95% CI 1.3;6.0). Factors associated with having a positive attitude towards prescribing MC were: having quite some knowledge about MC (OR = 5.2, 95% CI 2.2;12.5) and GPs being male (OR = 1.7, 95% CI 1.1;1.9). Conclusion In this first study on prescription experience, knowledge, and attitudes about MC among Danish GPs, conducted one year after the Danish test scheme was enacted, we find a very low proportion of prescribers, little knowledge, and an overall negative attitude towards MC. Among the prescribing GPs, four in ten have little to no knowledge and a negative attitude towards MC. We stress that prescribing patterns, knowledge, and attitudes may change throughout the remaining time of the test scheme.

The solar-type subgiant β Hyi has long been studied as an old analog of the Sun. Although the rotation period has never been measured directly, it was estimated to be near 27 days. As a Southern Hemisphere target, it was not monitored by long-term stellar activity surveys, but archival International Ultraviolet Explorer data revealed a 12 yr activity cycle. Previous ground-based asteroseismology suggested that the star is slightly more massive and substantially larger and older than the Sun, so the similarity of both the rotation rate and the activity cycle period to solar values is perplexing. We use two months of precise time-series photometry from the Transiting Exoplanet Survey Satellite to detect solar-like oscillations in β Hyi and determine the fundamental stellar properties from asteroseismic modeling. We also obtain a direct measurement of the rotation period, which was previously estimated from an ultraviolet activity–rotation relation. We then use rotational evolution modeling to predict the rotation period expected from either standard spin-down or weakened magnetic braking (WMB). We conclude that the rotation period of β Hyi is consistent with WMB and that changes in stellar structure on the subgiant branch can reinvigorate the large-scale dynamo and briefly sustain magnetic activity cycles. Our results support the existence of a “born-again” dynamo in evolved subgiants—previously suggested to explain the cycle in 94 Aqr Aa—which can best be understood within the WMB scenario.

Abstract Prediction of survival for patients in intensive care units (ICUs) has been subject to intense research. However, no models exist that embrace the multiverse of data in ICUs. It is an open question whether deep learning methods using automated data integration with minimal pre-processing of mixed data domains such as free text, medical history and high-frequency data can provide discrete-time survival estimates for individual ICU patients. We trained a deep learning model on data from patients admitted to ten ICUs in the Capital Region of Denmark and the Region of Southern Denmark between 2011 and 2018. Inspired by natural language processing we mapped the electronic patient record data to an embedded representation and fed the data to a recurrent neural network with a multi-label output layer representing the chance of survival at different follow-up times. We evaluated the performance using the time-dependent concordance index. In addition, we quantified and visualized the drivers of survival predictions using the SHAP methodology. We included 37,355 admissions of 29,417 patients in our study. Our deep learning models outperformed traditional Cox proportional-hazard models with concordance index in the ranges 0.72–0.73, 0.71–0.72, 0.71, and 0.69–0.70, for models applied at baseline 0, 24, 48, and 72 h, respectively. Deep learning models based on a combination of entity embeddings and survival modelling is a feasible approach to obtain individualized survival estimates in data-rich settings such as the ICU. The interpretable nature of the models enables us to understand the impact of the different data domains.

Fat distribution is associated with cardiometabolic disease, although it has been less well studied than overall obesity. In a multiancestry exome-sequencing study, the authors identified predicted loss-of-function mutations in INHBE associated with favorable fat distribution and protection from type 2 diabetes.

Abstract Background People experiencing homelessness (PEH) and associated shelter workers may be at higher risk of infection with “Severe acute respiratory syndrome coronavirus 2” (SARS-CoV-2). The aim of this study was to determine the prevalence of SARS-CoV-2 among PEH and shelter workers in Denmark. Design and methods In November 2020, we conducted a nationwide cross-sectional seroprevalence study among PEH and shelter workers at 21 recruitment sites in Denmark. The assessment included a point-of-care test for antibodies against SARS-CoV-2, followed by a questionnaire. The seroprevalence was compared to that of geographically matched blood donors considered as a proxy for the background population, tested using a total Ig ELISA assay. Results We included 827 participants in the study, of whom 819 provided their SARS-CoV-2 antibody results. Of those, 628 were PEH (median age 50.8 (IQR 40.9–59.1) years, 35.5% female) and 191 were shelter workers (median age 46.6 (IQR 36.1–55.0) years and 74.5% female). The overall seroprevalence was 6.7% and was similar among PEH and shelter workers (6.8% vs 6.3%, p = 0.87); and 12.2% among all participants who engaged in sex work. The overall participant seroprevalence was significantly higher than that of the background population (2.9%, p

A GWAS on the four major iron-related biomarkers is conducted using data from the Trøndelag Health Study (HUNT), Michigan Genomics Initiative (MGI), and SardiNIA study, to identify 123 loci associated with iron homeostasis and effect on all-cause mortality.

Quantitative reconstructions of past land cover are necessary to determine the processes involved in climate–human–land-cover interactions. We present the first temporally continuous and most spatially extensive pollen-based land-cover reconstruction for Europe over the Holocene (last 11 700 cal yr BP). We describe how vegetation cover has been quantified from pollen records at a 1∘ × 1∘ spatial scale using the “Regional Estimates of VEgetation Abundance from Large Sites” (REVEALS) model. REVEALS calculates estimates of past regional vegetation cover in proportions or percentages. REVEALS has been applied to 1128 pollen records across Europe and part of the eastern Mediterranean–Black Sea–Caspian corridor (30–75∘ N, 25∘ W–50∘ E) to reconstruct the percentage cover of 31 plant taxa assigned to 12 plant functional types (PFTs) and 3 land-cover types (LCTs). A new synthesis of relative pollen productivities (RPPs) for European plant taxa was performed for this reconstruction. It includes multiple RPP values (≥2 values) for 39 taxa and single values for 15 taxa (total of 54 taxa). To illustrate this, we present distribution maps for five taxa (Calluna vulgaris, Cerealia type (t)., Picea abies, deciduous Quercus t. and evergreen Quercus t.) and three land-cover types (open land, OL; evergreen trees, ETs; and summer-green trees, STs) for eight selected time windows. The reliability of the REVEALS reconstructions and issues related to the interpretation of the results in terms of landscape openness and human-induced vegetation change are discussed. This is followed by a review of the current use of this reconstruction and its future potential utility and development. REVEALS data quality are primarily determined by pollen count data (pollen count and sample, pollen identification, and chronology) and site type and number (lake or bog, large or small, one site vs. multiple sites) used for REVEALS analysis (for each grid cell). A large number of sites with high-quality pollen count data will produce more reliable land-cover estimates with lower standard errors compared to a low number of sites with lower-quality pollen count data. The REVEALS data presented here can be downloaded from https://doi.org/10.1594/PANGAEA.937075 (Fyfe et al., 2022).

Abstract Delayed graft function after kidney transplantation is common and increases morbidity and health care costs. There is evidence that endotrophin, a specific fragment of pro-collagen type VI, promotes the inflammatory response in kidney diseases. We tested the hypothesis that pretransplant endotrophin in kidney transplant recipients may be associated with the risk of delayed graft function. Pretransplant plasma endotrophin was assessed using an enzyme-linked immunosorbent assay in three independent cohorts with 806 kidney transplant recipients. The primary outcome was delayed graft function, i.e., the necessity of at least one dialysis session within one-week posttransplant. In the discovery cohort median pretransplant plasma endotrophin was higher in 32 recipients (12%) who showed delayed graft function when compared to 225 recipients without delayed graft function (58.4 ng/mL [IQR 33.4–69.0]; N = 32; vs. 39.5 ng/mL [IQR 30.6–54.5]; N = 225; P = 0.009). Multivariable logistic regression, fully adjusted for confounders showed, that pretransplant plasma endotrophin as a continuous variable was independently associated with delayed graft function in both validation cohorts, odds ratio 2.09 [95% CI 1.30–3.36] and 2.06 [95% CI 1.43–2.97]. Pretransplant plasma endotrophin, a potentially modifiable factor, was independently associated with increased risk of delayed graft function and may be a new avenue for therapeutic interventions.

Abstract To provide novel data on surfactant levels in adult COVID-19 patients, we collected bronchoalveolar lavage fluid less than 72 h after intubation and used Fourier Transform Infrared Spectroscopy to measure levels of dipalmitoylphosphatidylcholine (DPPC). A total of eleven COVID-19 patients with moderate-to-severe ARDS (CARDS) and 15 healthy controls were included. CARDS patients had lower DPPC levels than healthy controls. Moreover, a principal component analysis was able to separate patient groups into distinguishable subgroups. Our findings indicate markedly impaired pulmonary surfactant levels in COVID-19 patients, justifying further studies and clinical trials of exogenous surfactant.

Abstract Background In Denmark emergency medical technicians transport patients with acute COPD exacerbations to the nearest emergency department. From a clinical and economic perspective, this transport and assessment at the hospital may be inconvenient if the patient is immediately discharged from the emergency department. We established an emergency technical technicians point-of-care diagnostics and treatment program of patients with COPD with use of ultrasound and blood analysis. Patients' perspectives on treatment at home and sense of security are important to qualify clinical practice at home with patients with acute exacerbation. Aim and objectives To explore patient's and relatives' experience of treatment at home during emergency calls due to COPD in exacerbation and to investigate their attitude to avoid hospitalization as well as experience of stress during point-of-care diagnostics in their own home. Method A qualitative study comprising semi-structured interviews with 16 patients carried out from April 1st, 2019 to March 31st, 2020 in Denmark. Data was analysed inspired by Malteruds’ text condensation and informed by Critical Psychology with first person perspective focusing on the patient's views on point-of-care diagnostics and treatment of their COPD in acute exacerbation. Results The interviews revealed that in order to ensure an experience of quality in the assessment and treatment of patients in their own homes, it was important that the ambulance staff showed great safety and experience in the use of the technical equipment and treatment of dyspnea. It was also of importance that the patients felt confident that their general practitioner followed up on the home treatment initiated. Conclusion Patients’ perspectives showed that point-of-care diagnostics and treatment of acute COPD in exacerbation was considered a qualitative offer by the patients and their relatives. At the same time, it was crucial that the emergency medical technicians showed experience and safety in handling shortness of breath as well as the technical equipment. Trial registration: Approved by the Danish Data Protection Agency Project-ID: 20/24845.

People with kidney disease are disproportionately affected by atherosclerosis for unclear reasons. Soluble urokinase plasminogen activator receptor (suPAR) is an immune-derived mediator of kidney disease, levels of which are strongly associated with cardiovascular outcomes. We assessed suPAR’s pathogenic involvement in atherosclerosis using epidemiologic, genetic, and experimental approaches. We found serum suPAR levels to be predictive of coronary artery calcification and cardiovascular events in 5,406 participants without known coronary disease. In a genome-wide association meta-analysis including over 25,000 individuals, we identified a missense variant in the plasminogen activator, urokinase receptor (PLAUR) gene (rs4760), confirmed experimentally to lead to higher suPAR levels. Mendelian randomization analysis in the UK Biobank using rs4760 indicated a causal association between genetically predicted suPAR levels and atherosclerotic phenotypes. In an experimental model of atherosclerosis, proprotein convertase subtilisin/kexin–9 (Pcsk9) transfection in mice overexpressing suPAR (suPARTg) led to substantially increased atherosclerotic plaques with necrotic cores and macrophage infiltration compared with those in WT mice, despite similar cholesterol levels. Prior to induction of atherosclerosis, aortas of suPARTg mice excreted higher levels of CCL2 and had higher monocyte counts compared with WT aortas. Aortic and circulating suPARTg monocytes exhibited a proinflammatory profile and enhanced chemotaxis. These findings characterize suPAR as a pathogenic factor for atherosclerosis acting at least partially through modulation of monocyte function.

Aimed at fundamental understanding and design of advanced magnetic resonance experiments on basis of Hamiltonians, we describe highly convergent and exact effective Hamiltonian methods which alleviate important deficits of current less accurate methods. This involves single-spin vector effective Hamiltonian theory (SSV-EHT) to first order in the interaction frame of rf and chemical shift offsets as well as exact effective Hamiltonian theory (EEHT) being an exact approach to average Hamiltonian theory not relying on interaction frame transformations. Bringing these methods together, we present tools to analyze challenging experiments in need of considering large static components in Hamiltonian (e.g., offsets) while economizing with radiofrequency irradiation power. It is demonstrated how the two complementary tools may provide important new insight into the detailed effective Hamiltonians of advanced NMR experiments, noting that the methods are by no means restricted to NMR. This is demonstrated for isotropic mixing in liquid-state NMR and dipolar recoupling in solid-state NMR where insight into the delicate interplay between bilinear two-spin and linear single-spin terms in the effective Hamiltonian may increase understanding of determinants for broadband excitation and the formation of recoupling resonances. Furthermore, we demonstrate how simple products single-spin effective Hamiltonians may be used as generators of multiple-spin effective Hamiltonians and though this a new approach to density operator calculations for large multiple-spin systems.

Odor-active volatile sulfur compounds are formed in heated food protein systems. In the present study, hydrogen sulfide (H2S) was found to be the most abundant sulfur volatile in whey protein solutions (whey protein isolate [WPI], a whey model system and single whey proteins) by gas chromatography-flame photometric detector (GC-FPD) analysis after heat treatments (60–90 °C for 10 min, 90 °C for 120 min and UHT-like treatment). H2S was detected in WPI after heating at 90 °C for 10 min, and was significantly increased at higher heat load (90 °C for 120 min and the UHT-like treatment). Site-specific LC-MS/MS-based proteomic analysis was conducted, monitoring desulfurization reactions in these protein systems to investigate the mechanism of H2S formation in heated WPI. Cysteine residues from beta-lactoglobulin were found to be responsible for the formation of H2S in heated WPI, presumably via beta-elimination.

Postweaning diarrhoea caused by Enterotoxigenic Escherichia coli (ETEC) is a threat to the pig industry. With an intensified focus on finding alternatives to the use of medical zinc oxide and antibiotics in newly weaned pigs, the objective of this study was to investigate the effect of early inoculation of probiotics to suckling piglets on subsequently ETEC faecal shedding and immune parameters in ETEC F18-challenged weaned piglets. Sixty pigs weaned on day 28 of age were assigned to three treatment groups: (i) Negative Control (non-challenged), (ii) Positive Control (challenged) and (iii) Probiotic (challenged and inoculated with a multi-species probiotic product during suckling). On days 1 and 2 postweaning, pigs in the Positive Control and Probiotic groups were challenged with 5 × 108 colony-forming unit ETEC F18/pig/day, whereas pigs in the Negative Control group were provided with NaCl. Growth and diarrhoea incidence were not significantly affected by ETEC challenge or probiotic administration. ETEC F18 shedding and C-reactive protein concentration in plasma were significantly lower in the Negative Control group, confirming a successful challenge model. Pigs in the Probiotic group had a significantly reduced number of pigs shedding ETEC F18 and STb toxin in faeces compared with the Positive Control group. Probiotic application did not significantly impact the concentration of C-reactive protein, haptoglobin and cytokines in plasma nor haematology numbers. In conclusion, weaned pigs administered with a multi-species probiotic product early in life had a more rapid response towards the pathogen challenge and a faster clearance of ETEC compared with the Positive Control group. Administration of a multi-species probiotic to newborn piglets may thus promote resilience in the newly weaned pig. However, further studies with pigs subjected to a more severe pathogen challenge are needed to confirm these results and to investigate the mechanism of action of the probiotic intervention.

Topological phases have been reported on self-similar structures in the presence of a perpendicular magnetic field. Here, we present an understanding of these phases from a perspective of spectral flow and charge pumping. We study the Harper-Hofstadter model on self-similar structures constructed from the Sierpinski gasket. We numerically investigate the spectral flow and the associated charge pumping when a flux tube is inserted through the structure and the flux through the tube is varied adiabatically. We find that the nature of the spectral flow is qualitatively different from that of translationally invariant noninteracting systems with a perpendicular magnetic field. We show that the instantaneous eigenspectra can be used to understand the quantization of the charge pumped over a cycle, and hence to understand the topological character of the system. We show the correspondence between the local contributions to the Hall conductivity and the spectral flow of the edgelike states. We also show that the edgelike states can be approximated by eigenstates of the discrete angular-momentum operator, their chiral nature being a consequence of this.

Abstract Streptomyces griseofuscus DSM 40191 is a fast growing Streptomyces strain that remains largely underexplored as a heterologous host. Here, we report the genome mining of S. griseofuscus, followed by the detailed exploration of its phenotype, including the production of native secondary metabolites and ability to utilise carbon, nitrogen, sulphur and phosphorus sources. Furthermore, several routes for genetic engineering of S. griseofuscus were explored, including use of GusA-based vectors, CRISPR-Cas9 and CRISPR-cBEST-mediated knockouts. Two out of the three native plasmids were cured using CRISPR-Cas9 technology, leading to the generation of strain S. griseofuscus DEL1. DEL1 was further modified by the full deletion of a pentamycin BGC and an unknown NRPS BGC, leading to the generation of strain DEL2, lacking approx. 500 kbp of the genome, which corresponds to a 5.19% genome reduction. DEL2 can be characterized by faster growth and inability to produce three main native metabolites: lankacidin, lankamycin, pentamycin and their derivatives. To test the ability of DEL2 to heterologously produce secondary metabolites, the actinorhodin BGC was used. We were able to observe a formation of a blue halo, indicating a potential production of actinorhodin by both DEL2 and a wild type.

Abstract Aims To explore Registered Nurses' experiences and perceptions with National Early Warning Score and Individual Early Warning Score to identify patient deterioration. Design A qualitative exploratory design. Methods Six focus groups were conducted at six Danish hospitals from February to June 2019. Registered Nurses from both medical, surgical and emergency departments participated. The focus groups were analysed using content analysis. Results One theme and four categories were identified. Theme: Meaningful in identifying patient deterioration but causing frustration due to lack of flexibility. Categories: (a) Inter‐professional collaboration strengthened through the use of Early Warning Score systems, (b) Enhanced professional development and communication among nurses when using Early Warning Score systems, (c) Detecting patient deterioration by integrating nurses' clinical gaze with Early Warning Score systems and (d) Modification and fear of making mistakes when using Early Warning Score systems.

Abstract Background Understanding behavioral factors associated with low health literacy (HL) is relevant for health care providers to better support their patients’ health and adherence to preventive treatment. In this study, we aim to study associations between low HL and socio-demographic characteristics, medication-related perceptions and experience, as well as general psychological factors among patients aged 50–80 years. Methods We used a cross-sectional survey design based on a representative group of 6,871 Danish citizens aged 50–80 years returning a web-based questionnaire with socio-demographic data added from a national registry. Chi-square tests were conducted to analyze associations between low HL and daily use of medication and self-rated health. Chi-square tests and binary logistic regression were conducted for analyzing data from respondents using prescribed medicines daily (N = 4,091). Results Respondents with low HL were more often on daily medications (19 % [777/4,091] vs. 16 % [436/2,775]; P

Abstract Background Lifestyle intervention, i.e. diet and physical activity, forms the basis for care of type 2 diabetes (T2D). The current physical activity recommendation for T2D is aerobic training for 150 min/week of moderate to vigorous intensity, supplemented with resistance training 2–3 days/week, with no more than two consecutive days without physical activity. The rationale for the recommendations is based on studies showing a reduction in glycated haemoglobin (HbA1c). This reduction is supposed to be caused by increased insulin sensitivity in muscle and adipose tissue, whereas knowledge about effects on abnormalities in the liver and pancreas are scarce, with the majority of evidence stemming from in vitro and animal studies. The aim of this study is to investigate the role of the volume of exercise training as an adjunct to dietary therapy in order to improve the pancreatic β-cell function in T2D patients less than 7 years from diagnosis. The objective of this protocol for the DOSE-EX trial is to describe the scientific rationale in detail and to provide explicit information about study procedures and planned analyses. Methods/design In a parallel-group, 4-arm assessor-blinded randomised clinical trial, 80 patients with T2D will be randomly allocated (1:1:1:1, stratified by sex) to 16 weeks in either of the following groups: (1) no intervention (CON), (2) dietary intervention (DCON), (3) dietary intervention and supervised moderate volume exercise (MED), or (4) dietary intervention and supervised high volume exercise (HED). Enrolment was initiated December 15th, 2018, and will continue until N = 80 or December 1st, 2021. Primary outcome is pancreatic beta-cell function assessed as change in late-phase disposition index (DI) from baseline to follow-up assessed by hyperglycaemic clamp. Secondary outcomes include measures of cardiometabolic risk factors and the effect on subsequent complications related to T2D. The study was approved by The Scientific Ethical Committee at the Capital Region of Denmark (H-18038298). Trial registration: The Effects of Different Doses of Exercise on Pancreatic β-cell Function in Patients With Newly Diagnosed Type 2 Diabetes (DOSE-EX), NCT03769883, registered 10 December 2018 https://clinicaltrials.gov/ct2/show/NCT03769883 ). Any modification to the protocol, study design, and changes in written participant information will be approved by The Scientific Ethical Committee at the Capital Region of Denmark before effectuation. Discussion The data from this study will add knowledge to which volume of exercise training in combination with a dietary intervention is needed to improve β-cell function in T2D. Secondarily, our results will elucidate mechanisms of physical activity mitigating the development of micro- and macrovascular complications correlated with T2D.

Reliable quantitative vegetation reconstructions for Europe during the Holocene are crucial to improving our understanding of landscape dynamics, making it possible to assess the past effects of environmental variables and land-use change on ecosystems and biodiversity, and mitigating their effects in the future. We present here the most spatially extensive and temporally continuous pollen-based reconstructions of plant cover in Europe (at a spatial resolution of 1° × 1°) over the Holocene (last 11.7 ka BP) using the ‘Regional Estimates of VEgetation Abundance from Large Sites’ (REVEALS) model. This study has three main aims. First, to present the most accurate and reliable generation of REVEALS reconstructions across Europe so far. This has been achieved by including a larger number of pollen records compared to former analyses, in particular from the Mediterranean area. Second, to discuss methodological issues in the quantification of past land cover by using alternative datasets of relative pollen productivities (RPPs), one of the key input parameters of REVEALS, to test model sensitivity. Finally, to validate our reconstructions with the global forest change dataset. The results suggest that the RPPs.st1 (31 taxa) dataset is best suited to producing regional vegetation cover estimates for Europe. These reconstructions offer a long-term perspective providing unique possibilities to explore spatial-temporal changes in past land cover and biodiversity.

Abstract Introduction Crowding of the emergency departments is an increasing problem. Many patients with an exacerbation of chronic obstructive pulmonary disease (COPD) are often treated in the emergency departments for a very short period before discharged to their homes. It is possible that this treatment could take place in the patients’ homes with sufficient diagnostics supporting the treatment. In an effort to keep the diagnostics and treatment of some of these patients in their homes and thus to reduce the patient load at the emergency departments, we implemented a prehospital treat-and-release strategy based on ultrasonography and blood testing performed by emergency medical technicians (EMT) or paramedics (PM) in patients with acute exacerbation of COPD. Method EMTs and PMs were enrolled in a six-hour educational program covering ultrasonography of the lungs and point of care blood tests. During the seasonal peak of COPD exacerbations (October 2018 – May 2019) all patients who were treated by the ambulance crews for respiratory insufficiency were screened in the ambulances. If the patient had uncomplicated COPD not requiring immediate transport to the hospital, ultrasonographic examination of the lungs, measurements of C-reactive protein and venous blood gases analyses were performed. The response to the initial treatment and the results obtained were discussed via telemedical consultation with a prehospital anaesthesiologist who then decided to either release the patient at the scene or to have the patient transported to the hospital. The primary outcome was strategy feasibility. Results We included 100 EMTs and PMs in the study. During the study period, 771 patients with respiratory insufficiency were screened. Uncomplicated COPD was rare as only 41patients were treated according to the treat-and-release strategy. Twenty of these patients (49%) were released at the scene. In further ten patients, technical problems were encountered hindering release at the scene. Conclusion In a few selected patients with suspected acute exacerbations of COPD, it was technically and organisationally feasible for EMTs and PMs to perform prehospital POCT-ultrasound and laboratory testing and release the patients following treatment. None of the patients released at the scene requested a secondary ambulance within the first 48 h following the intervention.

Forest steppes are dynamic ecosystems, highly susceptible to changes in climate, disturbances and land use. Here we examine the Holocene history of the European forest steppe ecotone in the lower Danube Plain to better understand its sensitivity to climate fluctuations, fire and human impact, and the timing of its transition into a cultural forest steppe. We used multi-proxy analyses (pollen, n-alkanes, coprophilous fungi, charcoal and geochemistry) of a 6000-year sequence from Lake Oltina (southeastern Romania) combined with a REVEALS (Regional Estimates of Vegetation Abundance from Large Sites) model of quantitative vegetation cover. We found a greater tree cover, composed of xerothermic (Carpinus orientalis and Quercus) and temperate (Carpinus betulus, Tilia, Ulmus and Fraxinus) tree taxa, between 6000 and 2500 cal yr BP. Maximum tree cover ( ∼  50 %), dominated by C. orientalis occurred between 4200 and 2500 cal yr BP at a time of wetter climatic conditions and moderate fire activity. Compared to other European forest steppe areas, the dominance of C. orientalis represents the most distinct feature of the woodland's composition at this time. Tree loss was underway by 2500 yr BP (Iron Age), with the REVEALS model indicating a fall to ∼  20 % tree cover from the Late Holocene forest maximum, linked to clearance for agriculture, while climate conditions remained wet. Biomass burning increased markedly at 2500 cal yr BP, suggesting that fire was regularly used as a management tool until 1000 cal yr BP when woody vegetation became scarce. A sparse tree cover, with only weak signs of forest recovery, then became a permanent characteristic of the lower Danube Plain, highlighting more or less continuous anthropogenic pressure. The timing of anthropogenic ecosystem transformation here (2500 cal yr BP) falls between that in central-eastern (between 3700 and 3000 cal yr BP) and eastern (after 2000 cal yr BP) Europe. Our study is the first quantitative land cover estimate at the forest steppe ecotone in southeastern Europe spanning 6000 years. It provides critical empirical evidence that, at a broad spatial scale, the present-day forest steppe and woodlands reflect the potential natural vegetation in this region under current climate conditions. However, the extent of tree cover and its composition have been neither stable in time nor shaped solely by the climate. Consequently, vegetation change must be seen as dynamic and reflecting wider changes in environmental conditions including natural disturbances and human impact.

Drugs targeting cardiovascular disease (CVD) can have negative consequences for liver function. Here, the authors combine genome wide analyses on 69,479 individuals to identify loss-of-function variants with beneficial effects on CVD-related traits without negative impacts on liver function.

Bone mineral density (BMD) is associated with fracture risk and many genetic loci with small effect sizes have been discovered by genome-wide association studies (GWAS). Here, the authors discover a large-effect rare loss-of-function genetic variant for BMD in the MEPE gene in the Norwegian HUNT study which replicates in the UK Biobank.

The Eurasian (née European) Modern Pollen Database (EMPD) was established in 2013 to provide a public database of high-quality modern pollen surface samples to help support studies of past climate, land cover, and land use using fossil pollen. The EMPD is part of, and complementary to, the European Pollen Database (EPD) which contains data on fossil pollen found in Late Quaternary sedimentary archives throughout the Eurasian region. The EPD is in turn part of the rapidly growing Neotoma database, which is now the primary home for global palaeoecological data. This paper describes version 2 of the EMPD in which the number of samples held in the database has been increased by 60 % from 4826 to 8134. Much of the improvement in data coverage has come from northern Asia, and the database has consequently been renamed the Eurasian Modern Pollen Database to reflect this geographical enlargement. The EMPD can be viewed online using a dedicated map-based viewer at https://empd2.github.io and downloaded in a variety of file formats at https://doi.pangaea.de/10.1594/PANGAEA.909130 (Chevalier et al., 2019).

Abstract Background The impact of neutropenia in critically ill immunocompromised patients admitted in a context of acute respiratory failure (ARF) remains uncertain. The primary objective was to assess the prognostic impact of neutropenia on outcomes of these patients. Secondary objective was to assess etiology of ARF according to neutropenia. Methods We performed a post hoc analysis of a prospective multicenter multinational study from 23 ICUs belonging to the Nine-I network. Between November 2015 and July 2016, all adult immunocompromised patients with ARF admitted to the ICU were included in the study. Adjusted analyses included: (1) a hierarchical model with center as random effect; (2) propensity score (PS) matched cohort; and (3) adjusted analysis in the matched cohort. Results Overall, 1481 patients were included in this study of which 165 had neutropenia at ICU admission (11%). ARF etiologies distribution was significantly different between neutropenic and non-neutropenic patients, main etiologies being bacterial pneumonia (48% vs 27% in neutropenic and non-neutropenic patients, respectively). Initial oxygenation strategy was standard supplemental oxygen in 755 patients (51%), high-flow nasal oxygen in 165 (11%), non-invasive ventilation in 202 (14%) and invasive mechanical ventilation in 359 (24%). Before adjustment, hospital mortality was significantly higher in neutropenic patients (54% vs 42%; p = 0.006). After adjustment for confounder and center effect, neutropenia was no longer associated with outcome (OR 1.40, 95% CI 0.93–2.11). Similar results were observed after matching (52% vs 46%, respectively; p = 0.35) and after adjustment in the matched cohort (OR 1.04; 95% CI 0.63–1.72). Conclusion Neutropenia at ICU admission is not associated with hospital mortality in this cohort of critically ill immunocompromised patients admitted for ARF. In neutropenic patients, main ARF etiologies are bacterial and fungal infections.

Thyroid stimulating hormone (TSH) is critical for normal development and metabolism. Here, the authors conduct a GWAS and suggest protective effect of higher TSH on risk of thyroid cancer and goitre.