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Abstract The intensive nutrient requirements needed to sustain T cell activation and proliferation, combined with competition for nutrients within the tumor microenvironment, raise the prospect that glucose availability may limit CAR-T cell function. Here, we seek to test the hypothesis that stable overexpression (OE) of the glucose transporter GLUT1 in primary human CAR-T cells would improve their function and antitumor potency. We observe that GLUT1OE in CAR-T cells increases glucose consumption, glycolysis, glycolytic reserve, and oxidative phosphorylation, and these effects are associated with decreased T cell exhaustion and increased Th17 differentiation. GLUT1OE also induces broad metabolic reprogramming associated with increased glutathione-mediated resistance to reactive oxygen species, and increased inosine accumulation. When challenged with tumors, GLUT1OE CAR-T cells secrete more proinflammatory cytokines and show enhanced cytotoxicity in vitro, and demonstrate superior tumor control and persistence in mouse models. Our collective findings support a paradigm wherein glucose availability is rate limiting for effector CAR-T cell function and demonstrate that enhancing glucose availability via GLUT1OE could augment antitumor immune function.

Background: Tissue factor (TF), encoded by the F3 gene, is the main initiator of blood coagulation. The molecular epidemiology of the F3 gene and the relation to venous thromboembolism (VTE) remains to be determined. Objectives: The aim was to determine the molecular epidemiology and the importance of F3 variants for incident VTE by analysis of the population-based MDC study (Malmö Diet and Cancer), consisting of unselected middle-aged and older individuals. Methods: The exons of F3 were analyzed in a total of 28,794 individuals from the MDC cohort, and of these, 2584 (9 %) were affected by VTE during follow‐up (1991–2018). Qualifying variants used in gene-collapsing analysis were defined as loss-of-function or non-benign (PolyPhen-2) missense variants with minor allele frequency less than 0.1 %. Results: Exon sequencing of the F3 gene identified 61 different variants, 3′ UTR variants (n = 5), 5′ UTR variants (n = 9) synonymous (n = 10), in frame insertion (n = 1), splice region variants (n = 2), missense (n = 33) or loss-of-function variants (n = 1). No associations between common F3 gene variants and incident VTE were found. Seventeen rare variants were classified as qualifying and included in collapsing analysis (16 non-benign missense and 1 loss-of-function variants). The prevalence of F3 qualifying variants was 0.14 %. Seven individuals with F3 qualifying variants had VTE, while 34 individuals had no VTE. The adjusted VTE model was significant (hazard ratio = 2.1 [95 % confidence interval, 1.02–4.48], P-value = 0.045). Conclusions: Qualifying F3 gene variants are very rare, indicating a constrained gene. Rare but not common variation in the F3 gene may be involved in VTE.

Abstract Peptide hormones and neuropeptides are signaling molecules that control diverse aspects of mammalian homeostasis and physiology. Here we provide evidence for the endogenous presence of a sequence diverse class of blood-borne peptides that we call “capped peptides.” Capped peptides are fragments of secreted proteins and defined by the presence of two post-translational modifications – N-terminal pyroglutamylation and C-terminal amidation – which function as chemical “caps” of the intervening sequence. Capped peptides share many regulatory characteristics in common with that of other signaling peptides, including dynamic physiologic regulation. One capped peptide, CAP-TAC1, is a tachykinin neuropeptide-like molecule and a nanomolar agonist of mammalian tachykinin receptors. A second capped peptide, CAP-GDF15, is a 12-mer peptide cleaved from the prepropeptide region of full-length GDF15 that, like the canonical GDF15 hormone, also reduces food intake and body weight. Capped peptides are a potentially large class of signaling molecules with potential to broadly regulate cell-cell communication in mammalian physiology.

Abstract Background The development of entrustable professional activities (EPAs) as a framework for work-based training and assessment in undergraduate medical education has become popular. EPAs are defined as units of a professional activity requiring adequate knowledge, skills, and attitudes, with a recognized output of professional labor, independently executable within a time frame, observable and measurable in its process and outcome, and reflecting one or more competencies. Before a new framework is implemented in a specific context, it is valuable to explore social validity, that is, the acceptability by relevant stakeholders. Aim The aim of our work was to define Core EPAs for undergraduate medical education and further explore the social validity of the constructs. Method and material In a nationwide collaboration, EPAs were developed using a modified Delphi procedure and validated according to EQual by a group consisting of teachers nominated from each of the seven Swedish medical schools, two student representatives, and an educational developer (n = 16). In the next step, social validity was explored in a nationwide survey. The survey introduced the suggested EPAs. For each EPA, the importance of the EPA was rated, as was the rater’s perception of the present graduates’ required level of supervision when performing the activity. Free-text comments were also included and analyzed. Results Ten Core EPAs were defined and validated. The validation scores for EQual ranged from 4.1 to 4.9. The nationwide survey had 473 responders. All activities were rated as “important” by most responders, ranging from 54 to 96%. When asked how independent current graduates were in performing the ten activities, 6 to 35% reported “independent”. The three themes of the free text comments were: ‘relevant target areas and content’; ‘definition of the activities’; and ‘clinical practice and learning’. Conclusion Ten Core EPAs were defined and assessed as relevant for Swedish undergraduate medical education. There was a consistent gap between the perceived importance and the certainty that the students could perform these professional activities independently at the time of graduation. These results indicate that the ten EPAs may have a role in undergraduate education by creating clarity for all stakeholders.

Abstract Dr. Reddy's Laboratories rituximab (DRL_RI; Dr. Reddy's Laboratories SA, Basel, Switzerland) is under development as a rituximab biosimilar. Study RI‐01‐002 (Clinical Trials Registry ‐ India/2012/11/003129), comparing DRL_RI to the reference medicinal product (RMP) MabThera® (Roche, Grenzach‐Wyhlen, Germany), demonstrated pharmacokinetic (PK) equivalence and showed comparable pharmacodynamic, efficacy, safety, and immunogenicity profiles. We used data from the same study to perform population PK and PK–pharmacodynamic analyses: first exploring possible factors influencing the PK similarity assessment between products and then performing simulations to investigate the impact of tumor size on rituximab PK. Nonlinear mixed‐effects models for PK, tumor size, tumor size–PK, and tumor response were developed independently. The final PK model included drug product as a dose‐scaling parameter and predicted a 6.75% higher dose reaching the system in RMP‐treated patients. However, when tumor size was included in the tumor size–PK model, the drug product effect was no longer observed. The model rather indicated that patients with larger tumor size have higher clearance. Further simulations confirmed that higher baseline tumor size is associated to slightly lower rituximab exposure. Tumor response, described by a continuous‐time Markov model, did not differ between drug products. Both had higher effects during the first 20 weeks of treatment. Also, the model described a subpopulation of nonresponders to treatment (42%) with faster transitions to a worse state. The different rituximab exposure initially detected between drug products (6.75%) was shown using PK/PK–pharmacodynamic analysis to be attributed to a tumor size imbalance between treatment groups. PK/PK–pharmacodynamic analyses may contribute to PK similarity assessments.

Rare variants in the G-protein coupled receptor 151 (GPR151) gene in humans are associated with lower odds ratio for type 2 diabetes, but the mechanism behind this association has remained elusive. Here, the authors show that GPR151 regulates the process of hepatic gluconeogenesis and affects whole-body glucose metabolism.

Abstract To evaluate the hemostatic system with ROTEM in patients undergoing surgery for acute type aortic dissection (ATAAD) using elective aortic procedures as controls. This was a prospective, controlled, observational study. The study was performed at a tertiary referral center and university hospital. Twenty-three patients with ATAAD were compared to 20 control patients undergoing elective surgery of the ascending aorta or the aortic root. ROTEM (INTEM, EXTEM, HEPTEM and FIBTEM) was tested at 6 points in time before, during and after surgery for ATAAD or elective aortic surgery. The ATAAD group had an activated coagulation coming into the surgical theatre. The two groups showed activation of both major coagulation pathways during surgery, but the ATAAD group consistently had larger deficiencies. Reversal of the coagulopathy was successful, although none of the groups reached elective baseline until postoperative day 1. ROTEM did not detect low levels of clotting factors at heparin reversal nor low levels of platelets. This study demonstrated that ATAAD is associated with a coagulopathic state. Surgery causes additional damage to the hemostatic system in ATAAD patients as well as in patients undergoing elective surgery of the ascending aorta or the aortic root. ROTEM does not adequately catch the full coagulopathy in ATAAD. A transfusion protocol in ATAAD should be specifically created to target this complex coagulopathic state and ROTEM does not negate the need for routine laboratory tests.

Abstract Mercury’s southern inner magnetosphere is an unexplored region as it was not observed by earlier space missions. In October 2021, BepiColombo mission has passed through this region during its first Mercury flyby. Here, we describe the observations of SERENA ion sensors nearby and inside Mercury’s magnetosphere. An intermittent high-energy signal, possibly due to an interplanetary magnetic flux rope, has been observed downstream Mercury, together with low energy solar wind. Low energy ions, possibly due to satellite outgassing, were detected outside the magnetosphere. The dayside magnetopause and bow-shock crossing were much closer to the planet than expected, signature of a highly eroded magnetosphere. Different ion populations have been observed inside the magnetosphere, like low latitude boundary layer at magnetopause inbound and partial ring current at dawn close to the planet. These observations are important for understanding the weak magnetosphere behavior so close to the Sun, revealing details never reached before.

Background: Chronic obstructive pulmonary disease (COPD) and infections are risk factors for venous thromboembolism (VTE), but the reasons behind the associations are not fully known. Few studies have investigated whether lung function and respiratory symptoms in individuals without COPD are associated with VTE. Objectives: To study the incidence of VTE in individuals without COPD and other major VTE risk factors, in relation to baseline lung function and respiratory symptoms, through a 44-year follow-up prospective cohort study. Methods: As part of a health screening program, a total of 20,253 men and 7361 women underwent a baseline examination from 1974 to 1992, including a spirometry test and a self-administered questionnaire about respiratory symptoms, e.g., chronic bronchitis, cough, phlegm, and dyspnoea. Lung function was assessed through quartiles of forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC). Through linkage with national registers, all individuals were followed for incidence of VTE. Results: Respiratory symptoms (cough and dyspnoea) at baseline were associated with an increased risk of incident VTE in women after adjustments for age, height, BMI, smoking status, varicose veins, and FEV1/FVC. The adjusted hazard ratio in relation to chronic bronchitis was 1.57 (95% confidence interval 1.17–2.11). Poor lung function was not associated with an increased risk of VTE after adjustments for potential confounders. Conclusion: Women with respiratory symptoms of cough and dyspnoea without COPD have an increased risk of VTE, independent of lung function and major VTE risk factors. Further studies are needed to confirm the association and to study the clinical applicability of the results.

Abstract Covariate modeling is an important opportunity for pharmacometrics to influence decision making in drug development. The stepwise covariate model (SCM) building procedure is the most common method for covariate model development. Despite its advantages, the traditional SCM method is known to have long runtimes and the suboptimal ability to select relevant covariates, especially in more complex phase III settings. In this work, two alternative approaches are presented: SCM+, which introduces the “adaptive scope reduction” and changes to general estimation settings, and “stage‐wise filtering,” which groups covariates into categories based on their importance (mechanistic, structural, and exploratory). The three methods (SCM, SCM+, and SCM+ with stage‐wise filtering) are applied to data from a simulated phase III population pharmacokinetic study and are compared in terms of efficiency and relevance. The two SCM+ methods were considerably more efficient than the traditional SCM: the number of function evaluations was reduced by 70% for SCM+ and by 76% for SCM+ with stage‐wise filtering compared to SCM; the corresponding number of executed models was reduced by 44% for SCM+ and 70% for SCM+ with stage‐wise filtering. In addition, among the three methods, SCM+ with stage‐wise filtering selected the highest number of relevant covariates. Given the improved efficiency and ability to select relevant covariates shown in this work, the use of SCM+ and stage‐wise filtering can greatly increase the efficiency of covariate modeling in drug development, which will ultimately facilitate more timely support for decision making.

Summary: Here, we present an in vivo protocol for measuring basal and insulin-stimulated glucose uptake in tissues from mice. We describe steps for administering 2-deoxy-D-[1,2–3H]glucose in the presence or absence of insulin via intraperitoneal injections. We then detail tissue collection, tissue processing to measure 3H counts on a scintillation counter, and data interpretation. This protocol can be applied to other glucoregulatory hormones, genetic mouse models, and other species.For complete details on the use and execution of this protocol, please refer to Jiang et al. (2021).1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Abstract Objective measures, such as activity monitoring, can potentially complement clinical assessment for psychiatric patients. Alterations in rest–activity patterns are commonly encountered in patients with major depressive disorder. The aim of this study was to investigate whether features of activity patterns correlate with severity of depression symptoms (evaluated by Montgomery–Åsberg Rating Scale (MADRS) for depression). We used actigraphy recordings collected during ongoing major depressive episodes from patients not undergoing any antidepressant treatment. The recordings were acquired from two independent studies using different actigraphy systems. Data was quality-controlled and pre-processed for feature extraction following uniform procedures. We trained multiple regression models to predict MADRS score from features of activity patterns using brute-force and semi-supervised machine learning algorithms. The models were filtered based on the precision and the accuracy of fitting on training dataset before undergoing external validation on an independent dataset. The features enriched in the models surviving external validation point to high depressive symptom severity being associated with less complex activity patterns and stronger coupling to external circadian entrainers. Our results bring proof-of-concept evidence that activity patterns correlate with severity of depressive symptoms and suggest that actigraphy recordings may be a useful tool for individual evaluation of patients with major depressive disorder.

In 2021 JET exploited its unique capabilities to operate with T and D–T fuel with an ITER-like Be/W wall (JET-ILW). This second major JET D–T campaign (DTE2), after DTE1 in 1997, represented the culmination of a series of JET enhancements—new fusion diagnostics, new T injection capabilities, refurbishment of the T plant, increased auxiliary heating, in-vessel calibration of 14 MeV neutron yield monitors—as well as significant advances in plasma theory and modelling in the fusion community. DTE2 was complemented by a sequence of isotope physics campaigns encompassing operation in pure tritium at high T-NBI power. Carefully conducted for safe operation with tritium, the new T and D–T experiments used 1 kg of T (vs 100 g in DTE1), yielding the most fusion reactor relevant D–T plasmas to date and expanding our understanding of isotopes and D–T mixture physics. Furthermore, since the JET T and DTE2 campaigns occurred almost 25 years after the last major D–T tokamak experiment, it was also a strategic goal of the European fusion programme to refresh operational experience of a nuclear tokamak to prepare staff for ITER operation. The key physics results of the JET T and DTE2 experiments, carried out within the EUROfusion JET1 work package, are reported in this paper. Progress in the technological exploitation of JET D–T operations, development and validation of nuclear codes, neutronic tools and techniques for ITER operations carried out by EUROfusion (started within the Horizon 2020 Framework Programme and continuing under the Horizon Europe FP) are reported in (Litaudon et al Nucl. Fusion accepted), while JET experience on T and D–T operations is presented in (King et al Nucl. Fusion submitted).

A spontaneous reduction in anomalous particle transport in the plasma core is seen experimentally in reproducible, purely neutral beam heated plasma phases at Wendelstein 7-X (W7-X). Heating and fueling the plasma exclusively with the neutral beam injection system for several seconds leads to continuously peaking plasma density profiles with strong gradients inside mid minor radius. A significant acceleration of the density peaking occurs after a certain onset time and is examined with a detailed particle transport analysis in several discharges. By invoking the particle continuity equation, the total experimental radial electron flux is deduced from the time evolution of the electron density profile and the radially resolved particle sources. Subtracting the modeled neoclassical particle flux contribution gives the anomalous particle flux. Exploiting the evolving plasma conditions, anomalous diffusion and convection coefficients are computed from the flux variation with density and density gradients. In several discharges a significant and consistent change of the anomalous transport coefficients is seen when crossing a specific normalized density gradient length.

Inference of electron density and temperature has been performed using multiple, diverse sets of plasma diagnostic data at Wendelstein 7-X. Predictive models for the interferometer, Thomson scattering and helium beam emission spectroscopy (He-BES) systems have been developed within the Minerva framework and integrated into a unified model. Electron density and temperature profiles are modelled using Gaussian processes. Calibration factors for the Thomson scattering system and predictive uncertainties are considered as additional unknown parameters. The joint posterior probability distribution for the electron density and temperature profiles as well as Gaussian process hyperparameters and model parameters is explored through a Markov chain Monte Carlo algorithm. Samples from this distribution are numerically marginalised over the hyperparameters and model parameters to yield marginal posterior distributions for the electron density and temperature profiles. The profile inferences incorporate various data combinations from the interferometer and Thomson scattering as well as constraints at the limiter/divertor positions through virtual observations or edge data from He-BES. Additionally, the integration of x-ray imaging crystal spectrometer data into the model for ion temperature profiles is presented. All profiles presented in this study are inferred with optimally selected hyperparameters and model parameters by exploring the joint posterior distribution, inherently applying Bayesian Occam’s razor.

Biomarkers are quantifiable characteristics of biological processes. In Mycobacterium tuberculosis, common biomarkers used in clinical drug development are colony forming unit (CFU) and time-to-positivity (TTP) from sputum samples. This analysis aimed to develop a combined quantitative tuberculosis biomarker model for CFU and TTP biomarkers for assessing drug efficacy in early bactericidal activity studies. Daily CFU and TTP observations in 83 previously patients with uncomplicated pulmonary tuberculosis after 7 days of different rifampicin monotherapy treatments (10–40 mg/kg) from the HIGHRIF1 study were included in this analysis. The combined quantitative tuberculosis biomarker model employed the Multistate Tuberculosis Pharmacometric model linked to a rifampicin pharmacokinetic model in order to determine drug exposure-response relationships on three bacterial sub-states using both the CFU and TTP data simultaneously. CFU was predicted from the MTP model and TTP was predicted through a time-to-event approach from the TTP model, which was linked to the MTP model through the transfer of all bacterial sub-states in the MTP model to a one bacterial TTP model. The non-linear CFU-TTP relationship over time was well predicted by the final model. The combined quantitative tuberculosis biomarker model provides an efficient approach for assessing drug efficacy informed by both CFU and TTP data in early bactericidal activity studies and to describe the relationship between CFU and TTP over time.

Background Whether sex‐specific differences exist for risk factors for pulmonary embolism (PE) and deep venous thrombosis (DVT), with the exception of pregnancy and estrogen therapy, has been sparsely studied. We aimed to study whether sex‐specific differences of risk factors exist for noncancer‐related DVT and PE in middle‐aged and older individuals without cardiovascular history or previous diagnosis in a population‐based historical (retrospective) cohort. Methods and Results Potential venous thromboembolism (VTE) risk factors were registered at baseline in 15 807 women and 9996 men aged 44 to 74 years, who participated in the Malmö Diet and Cancer study (1991–1996). We excluded subjects with a previous history of VTE, cancer, a diagnosis of cardiovascular disease, or a diagnosis of cancer‐associated VTE during follow‐up. Patients were followed up from baseline until the first event of PE or DVT, death, or December 31, 2018. During the follow‐up period, 365 (2.3%) women and 168 (1.7%) men were affected by first DVT, and 309 (2.0%) women and 154 (1.5%) men were affected by first PE. In the multivariable Cox regression models, the anthropometric obesity markers of weight, body mass index, waist and hip circumference, fat percentage, and muscle weight were in a dose‐dependent way associated with DVT and PE among women but not men. In an analysis that included patients with cardiovascular disease and cancer‐related VTE, the results were similar for women. For men, several obesity measures became significantly associated with PE or DVT but were weaker than in women, especially for DVT. Conclusions Anthropometric obesity measures are more important risk factors for both DVT and PE among women than men, especially for individuals without cardiovascular history or previous diagnosis or cancer‐related VTE.

Pain signals are relayed to the brain via a nociceptive system, and in rare cases, this nociceptive system contains genetic variants that can limit the pain response. Here, we questioned whether a human transient receptor potential vanilloid 1 (TRPV1) missense variant causes a resistance to noxious stimuli and, further, whether we could target this region with a cell-permeable peptide as a pain therapeutic. Initially using a computational approach, we identified a human K710N TRPV1 missense variant in an otherwise highly conserved region of mammalian TRPV1. After generating a TRPV1K710N-knockin mouse using CRISPR/Cas9, we discovered that the K710N variant reduced capsaicin-induced calcium influx in dorsal root ganglion neurons. The TRPV1K710N rodents also had less acute behavioral responses to noxious chemical stimuli and less hypersensitivity to nerve injury, while their response to noxious heat remained intact. Furthermore, blocking this K710 region in WT rodents using a cell-penetrating peptide limited acute behavioral responses to noxious stimuli and returned pain hypersensitivity induced by nerve injury to baseline levels. These findings identify K710 TRPV1 as a discrete site that is crucial for the control of nociception and provide insights into how to leverage rare genetic variants in humans to uncover fresh strategies for developing pain therapeutics.

Summary: Non-alcoholic fatty liver disease is a heterogeneous disease with unclear underlying molecular mechanisms. Here, we perform single-cell RNA sequencing of hepatocytes and hepatic non-parenchymal cells to map the lipid signatures in mice with non-alcoholic fatty liver disease (NAFLD). We uncover previously unidentified clusters of hepatocytes characterized by either high or low srebp1 expression. Surprisingly, the canonical lipid synthesis driver Srebp1 is not predictive of hepatic lipid accumulation, suggestive of other drivers of lipid metabolism. By combining transcriptional data at single-cell resolution with computational network analyses, we find that NAFLD is associated with high constitutive androstane receptor (CAR) expression. Mechanistically, CAR interacts with four functional modules: cholesterol homeostasis, bile acid metabolism, fatty acid metabolism, and estrogen response. Nuclear expression of CAR positively correlates with steatohepatitis in human livers. These findings demonstrate significant cellular differences in lipid signatures and identify functional networks linked to hepatic steatosis in mice and humans.

Abstract Identification of covariates, including biomarkers, spirometry, and diaries/questionnaires, that predict asthma exacerbations would allow better clinical predictions, shorter phase II trials and inform decisions on phase III design, and/or initiation (go/no‐go). The objective of this work was to characterize asthma‐exacerbation hazard as a function of baseline and time‐varying covariates. A repeated time‐to‐event (RTTE) model for exacerbations was developed using data from a 52‐week phase IIb trial, including 502 patients with asthma randomized to placebo or 70 mg, 210 mg, or 490 mg astegolimab every 4 weeks. Covariate analysis was performed for 20 baseline covariates using the full random effects modeling approach, followed by time‐varying covariate analysis of nine covariates using the stepwise covariate model (SCM) building procedure. Following the SCM, an astegolimab treatment effect was explored. Diary‐based symptom score (difference in objective function value [dOFV] of −83.7) and rescue medication use (dOFV = −33.5), and forced expiratory volume in 1 s (dOFV = −14.9) were identified as significant time‐varying covariates. Of note, time‐varying covariates become more useful with more frequent measurements, which should favor the daily diary scores over others. The most influential baseline covariates were exacerbation history and diary‐based symptom score (i.e., symptom score was important as both time‐varying and baseline covariate). A (nonsignificant) astegolimab treatment effect was included in the final model because the limited data set did not allow concluding the remaining effect size as irrelevant. Without time‐varying covariates, the treatment effect was statistically significant (p

Thermal helium beam diagnostics using the line ratio spectroscopy method are widely used to infer temperature and density in fusion-relevant edge plasmas. These diagnostics consist of an observational system which measures emitted line radiation from either intrinsic or injected helium plasma impurities. These spectral features are then compared to the output of a collisional-radiative model to infer plasma parameters (Te, ne) from the observed helium radiation. In order to investigate the systematic uncertainties of such a diagnostic, we present the results of a Bayesian treatment of a helium collisional-radiative model (Schmitz et al., 2008) using synthetic data modeled after an existing system on the plasma experiment Wendelstein 7-X (Barbui et al. 2016). From this study, we present a new method for comprehensively combining measurement uncertainties with underlying atomic rate parameter uncertainties in the inference of plasma parameters. Finally, we also demonstrate the utility of this Bayesian approach in targeting sensitivities within the model, allowing determination of high-priority atomic data for future refinement and comparison between differing atomic models.

Abstract Background Tissue factor is the main initiator of blood coagulation, and tissue factor pathway inhibitor (TFPI) is the primary inhibitor of the initiation of blood coagulation. The genetic variation of TFPI and the relation to venous thromboembolism (VTE), that is, venous thrombosis and pulmonary embolism, remains to be clarified. This exome sequencing study aimed to determine the molecular epidemiology of the TFPI gene and the relation to VTE in a large population‐based cohort of middle‐aged and older adults. Methods The exomes of TFPI were analyzed for variants in 28,794 subjects without previous VTE (born 1923–1950, 60% women), who participated in the Malmö Diet and Cancer Study (1991–1996). Patients were followed until the first event of VTE, death, or 2018. Qualifying variants were defined as loss‐of‐function or nonbenign (PolyPhen‐2) missense variants with minor allele frequency less than 0.1%. Results No common variant was associated with VTE. Nine rare variants (two loss‐of‐function and seven nonbenign missense) were classified as qualifying and included in collapsing analysis. Prevalence of qualifying variants was 0.09%. Five individuals with VTE compared to 17 individuals without VTE carried one qualifying variant. Cox multivariate regression analysis adjusted for age, sex, body mass index, systolic blood pressure, smoking and alcohol consumption, rs6025, rs1799963, and ancestry showed a hazard ratio of 2.9 (95% CI, 1.2–7.1) for rare qualifying variants. Conclusion Rare qualifying TFPI variants were associated with VTE, suggesting that rare variants in TFPI contribute to the development of VTE. The qualifying TFPI gene variants were very rare, suggesting a constrained gene.

The secreted protein isthmin-1 (Ism1) mitigates diabetes by increasing adipocyte and skeletal muscle glucose uptake by activating the PI3K-Akt pathway. However, while both Ism1 and insulin converge on these common targets, Ism1 has distinct cellular actions suggesting divergence in downstream intracellular signaling pathways. To understand the biological complexity of Ism1 signaling, we performed phosphoproteomic analysis after acute exposure, revealing overlapping and distinct pathways of Ism1 and insulin. We identify a 53% overlap between Ism1 and insulin signaling and Ism1-mediated phosphoproteome-wide alterations in ~450 proteins that are not shared with insulin. Interestingly, we find several unknown phosphorylation sites on proteins related to protein translation, mTOR pathway, and, unexpectedly, muscle function in the Ism1 signaling network. Physiologically, Ism1 ablation in mice results in altered proteostasis, including lower muscle protein levels under fed and fasted conditions, reduced amino acid incorporation into proteins, and reduced phosphorylation of the key protein synthesis effectors Akt and downstream mTORC1 targets. As metabolic disorders such as diabetes are associated with accelerated loss of skeletal muscle protein content, these studies define a non-canonical mechanism by which this antidiabetic circulating protein controls muscle biology.

Anthropogenic activities on the Indo-Gangetic Plain emit vast amounts of light-absorbing particles (LAPs) into the atmosphere, modifying the atmospheric radiation state. With transport to the nearby Himalayas and deposition to its surfaces the particles contribute to glacier melt and snowmelt via darkening of the highly reflective snow. The central Himalayas have been identified as a region where LAPs are especially pronounced in glacier snow but still remain a region where measurements of LAPs in the snow are scarce. Here we study the deposition of LAPs in five snow pits sampled in 2016 (and one from 2015) within 1 km from each other from two glaciers in the Sunderdhunga Valley, in the state of Uttarakhand, India, in the central Himalayas. The snow pits display a distinct enriched LAP layer interleaved by younger snow above and older snow below. The LAPs exhibit a distinct vertical distribution in these different snow layers. For the analyzed elemental carbon (EC), the younger snow layers in the different pits show similarities, which can be characterized by a deposition constant of about 50 µg m−2 mm−1 snow water equivalent (SWE), while the old-snow layers also indicate similar values, described by a deposition constant of roughly 150 µg m−2 mm−1 SWE. The enriched LAP layer, contrarily, displays no similar trends between the pits. Instead, it is characterized by very high amounts of LAPs and differ in orders of magnitude for concentration between the pits. The enriched LAP layer is likely a result of strong melting that took place during the summers of 2015 and 2016, as well as possible lateral transport of LAPs. The mineral dust fractional absorption is slightly below 50 % for the young- and old-snow layers, whereas it is the dominating light-absorbing constituent in the enriched LAP layer, thus, highlighting the importance of dust in the region. Our results indicate the problems with complex topography in the Himalayas but, nonetheless, can be useful in large-scale assessments of LAPs in Himalayan snow.

Abstract Background It has been proposed, and preclinically demonstrated, that 161Tb is a better alternative to 177Lu for the treatment of small prostate cancer lesions due to its high emission of low-energy electrons. 161Tb also emits photons suitable for single-photon emission computed tomography (SPECT) imaging. This study aims to establish a SPECT protocol for 161Tb imaging in the clinic. Materials and methods Optimal settings using various γ-camera collimators and energy windows were explored by imaging a Jaszczak phantom, including hollow-sphere inserts, filled with 161Tb. The collimators examined were extended low-energy general purpose (ELEGP), medium-energy general purpose (MEGP), and low-energy high resolution (LEHR), respectively. In addition, three ordered subset expectation maximization (OSEM) algorithms were investigated: attenuation-corrected OSEM (A-OSEM); attenuation and dual- or triple-energy window scatter-corrected OSEM (AS-OSEM); and attenuation, scatter, and collimator-detector response-corrected OSEM (ASC-OSEM), where the latter utilized Monte Carlo-based reconstruction. Uniformity corrections, using intrinsic and extrinsic correction maps, were also investigated. Image quality was assessed by estimated recovery coefficients (RC), noise, and signal-to-noise ratio (SNR). Sensitivity was determined using a circular flat phantom. Results The best RC and SNR were obtained at an energy window between 67.1 and 82.1 keV. Ring artifacts, caused by non-uniformity, were removed with extrinsic uniformity correction for the energy window between 67.1 and 82.1 keV, but not with intrinsic correction. Analyzing the lower energy window between 48.9 and 62.9 keV, the ring artifacts remained after uniformity corrections. The recovery was similar for the different collimators when using a specific OSEM reconstruction. Recovery and SNR were highest for ASC-OSEM, followed by AS-OSEM and A-OSEM. When using the optimized parameter setting, the resolution of 161Tb was higher than for 177Lu (8.4 ± 0.7 vs. 10.4 ± 0.6 mm, respectively). The sensitivities for 161Tb and 177Lu were 7.41 and 8.46 cps/MBq, respectively. Conclusion SPECT with high resolution is feasible with 161Tb; however, extrinsic uniformity correction is recommended to avoid ring artifacts. The LEHR collimator was the best choice of the three tested to obtain a high-resolution image. Due to the complex emission spectrum of low-energy photons, window-based scatter correction had a minor impact on the image quality compared to using attenuation correction only. On the other hand, performing attenuation, scatter, and collimator-detector correction clearly improved image quality. Based on these data, SPECT-based dosimetry for 161Tb-labeled radiopharmaceuticals is feasible.

Background Five classic thrombophilias have been recognized: factor V Leiden (rs6025), the prothrombin G20210A variant (rs1799963), and protein C, protein S, and antithrombin deficiencies. This study aimed to determine the thrombotic risk of classic thrombophilias in a cohort of middle‐aged and older adults. Methods and Results Factor V Leiden, prothrombin G20210A and protein‐coding variants in the PROC (protein C), PROS1 (protein S), and SERPINC1 (antithrombin) anticoagulant genes were determined in 29 387 subjects (born 1923–1950, 60% women) who participated in the Malmö Diet and Cancer study (1991–1996). The Human Gene Mutation Database was used to define 68 disease‐causing mutations. Patients were followed up from baseline until the first event of venous thromboembolism (VTE), death, or Dec 31, 2018. Carriership (n=908, 3.1%) for disease‐causing mutations in the PROC, PROS1, and SERPINC1 genes was associated with incident VTE: Hazard ratio (HR) was 1.6 (95% CI, 1.3–1.9). Variants not in Human Gene Mutation Database were not linked to VTE (HR, 1.1; 95% CI, 0.8–1.5). Heterozygosity for rs6025 and rs1799963 was associated with incident VTE: HR, 1.8 (95% CI, 1.6–2.0) and HR, 1.6 (95% CI, 1.3–2.0), respectively. The HR for carrying 1 classical thrombophilia variant was 1.7 (95% CI, 1.6–1.9). HR was 3.9 (95% CI, 3.1–5.0) for carriers of ≥2 thrombophilia variants. Conclusions The 5 classic thrombophilias are associated with a dose‐graded risk of VTE in middle‐aged and older adults. Disease‐causing variants in the PROC, PROS1, and SERPINC1 genes were more common than the rs1799963 variant but the conferred genetic risk was comparable with the rs6025 and rs1799963 variants.

Objectives: Estimating blood loss is an important factor in several surgical procedures. The accuracy of blood loss measurements in situations where blood is mixed with saliva and saline is however uncertain. The purpose of this laboratory study was to ascertain if blood loss measurements in mixtures of blood, saline, and saliva are reliable and could be applicable in a clinical setting. Material and Methods: Venous blood and resting saliva were collected from six volunteers. Saliva, saline, and combinations thereof were mixed with blood to obtain different concentrations. A portable spectrophotometer was first used to measure the haemoglobin concentration in undiluted venous blood followed by measurements of the haemoglobin concentration after each dilution. To examine the strength of linear relationships, linear regression and Pearson correlations were used. Results: The measurements of haemoglobin concentrations in mixtures of blood, saline, and saliva were proven to be accurate for haemoglobin measurements > 0.3 g/dl (correlation = 0.986 to 1). For haemoglobin measurements < 0.3 g/dl, a small increase in haemoglobin values were reported, which was directly associated to the saliva concentration in the solution (correlation = 0.983 to 1). This interference of saliva was significantly eliminated by diluting the samples with saline, mimicking the clinical situation. Conclusions: The results suggest that a portable spectrophotometer can be used clinically to preoperatively measure the haemoglobin value of a venous blood sample and postoperatively measure the haemoglobin value of the collected liquids, including shed blood, thereby achieving a highly accurate method of measuring blood loss during oral and maxillofacial surgery.

Background This is the first nationwide segregation analysis that aimed to determine whether familial venous thromboembolism (VTE) is attributable to inheritance and/or shared environment, and the possible mode of inheritance. Methods and Results The Swedish Multi‐Generation Register was linked to the Swedish patient register for the period 1964 to 2015. Three generational families of Swedish‐born individuals were identified. Heritability was examined using Falconer regression. Complex segregation analysis was conducted using the Statistical Analysis for Genetic Epidemiology software (version 6.4, 64‐bit Linux). Among the 4 301 174 relatives from 450 558 pedigrees, 177 865 (52% women) individuals were affected with VTE. VTE occurred in 2 or more affected relatives in 61 217 (13.6%) of the pedigrees. Heritability showed age and sex dependence with higher heritability for men and young individuals. In 18 933 pedigrees, VTE occurred only in the first generation and was not inherited. Segregation analysis was performed in the remaining 42 284 pedigrees with inherited VTE and included 939 192 individuals. Prevalence constraints were imposed in the models to allow for the selection of the pedigrees analyzed. The sporadic nongenetic model could be discarded. The major‐type‐only model, with a correlation structure compatible with some polygenic effects, was the preferred model. Among the Mendelian models, the mixed codominant (plus polygenic) model was preferred. Conclusions This nationwide segregation analysis of VTE supports a genetic cause of the familial aggregation of VTE. Heritability was higher for men and younger individuals, suggesting a Carter effect, in agreement with a multifactorial threshold inheritance.

The deposition of light-absorbing aerosol (LAA) onto snow initiates processes that lead to increased snowmelt. Measurements of LAA, such as black carbon (BC) and mineral dust, have been observed globally to darken snow. Several measurement techniques of LAA in snow collect the particulates on filters for analysis. Here we investigate micro-quartz filters' optical response to BC experiments in which the particles are initially suspended in air or in a liquid. With particle soot absorption photometers (PSAPs) we observed a 20 % scattering enhancement for quartz filters compared to the standard PSAP Pallflex filters. The multiple-scattering correction factor (Cref) of the quartz filters for airborne soot aerosol is estimated to be ∼3.4. In the next stage correction factors were determined for BC particles mixed in water and also for BC particles both mixed in water and further treated in an ultrasonic bath. Comparison of BC collected from airborne particles with BC mixed in water filters indicated a higher mass absorption cross section by approximately a factor of 2 for the liquid-based filters, which is probably due to the BC particles penetrating deeper in the filter matrix. The ultrasonic bath increased absorption still further, roughly by a factor of 1.5, compared to only mixing in water. Application of the correction functions to earlier published field data from the Himalaya and Finnish Lapland yielded mass absorption coefficient (MAC) values of ∼7–10 m2 g−1 at λ=550 nm, which is in the range of the published MAC of airborne BC aerosol.

Abstract Background Tralokinumab is an anti–interleukin (IL)-13 monoclonal antibody investigated for the treatment of severe, uncontrolled asthma in two Phase III clinical trials, STRATOS 1 and 2. The STRATOS 1 biomarker analysis plan was developed to identify biomarker(s) indicative of IL-13 activation likely to predict tralokinumab efficacy and define a population in which there was an enhanced treatment effect; this defined population was then tested in STRATOS 2. Methods The biomarkers considered were blood eosinophil counts, fractional exhaled nitric oxide (FeNO), serum dipeptidyl peptidase-4, serum periostin and total serum immunoglobulin E. Tralokinumab efficacy was measured as the reduction in annualised asthma exacerbation rate (AAER) compared with placebo (primary endpoint measure of STRATOS 1 and 2). The biomarker analysis plan included negative binomial and generalised additive models, and the Subgroup Identification based on Differential Effect Search (SIDES) algorithm, supported by robustness and sensitivity checks. Effects on the key secondary endpoints of STRATOS 1 and 2, which included changes from baseline in standard measures of asthma outcomes, were also investigated. Prior to the STRATOS 1 read-out, numerous simulations of the methodology were performed with hypothetical data. Results FeNO and periostin were identified as the only biomarkers potentially predictive of treatment effect, with cut-offs chosen by the SIDES algorithm of > 32.3 ppb and > 27.4 ng/ml, respectively. The FeNO > 32.3 ppb subgroup was associated with greater AAER reductions and improvements in key secondary endpoints compared with the periostin > 27.4 ng/ml subgroup. Upon further evaluation of AAER reductions at different FeNO cut-offs, ≥37 ppb was chosen as the best cut-off for predicting tralokinumab efficacy. Discussion A rigorous statistical approach incorporating multiple methods was used to investigate the predictive properties of five potential biomarkers and to identify a participant subgroup that demonstrated an enhanced tralokinumab treatment effect. Using STRATOS 1 data, our analyses identified FeNO at a cut-off of ≥37 ppb as the best assessed biomarker for predicting enhanced treatment effect to be tested in STRATOS 2. Our findings were inconclusive, which reflects the complexity of subgroup identification in the severe asthma population. Trial registration STRATOS 1 and 2 are registered on ClinicalTrials.gov (NCT02161757 registered on June 12, 2014, and NCT02194699 registered on July 18, 2014).

Abstract Background Patients with unprovoked first venous thromboembolism (VTE) are at a high risk of recurrence. Although circulating microRNAs (miRNAs) have been found to be associated with VTE and are markers of hypercoagulability, this study is the first to examine whether circulating miRNAs are associated with the risk of VTE recurrence. Results A nested case-control study design was used where plasma samples were obtained from 78 patients with unprovoked VTE from the Malmö Thrombophilia Study (MATS). A total of 39 VTE patients with recurrent VTE (cases) were matched with 39 VTE patients without recurrent VTE (controls) defined by age and sex (MATS population). Plasma levels of 179 different miRNAs were evaluated in the 78 samples (after anticoagulant treatment was stopped) using qPCR. A total of 110 miRNAs were detected in all samples. Among those, 12 miRNAs (miR-15b-5p, miR-106a-5p, miR-197-3p, miR-652-3p, miR-361-5p, miR-222-3p, miR-26b-5p, miR-532-5p, miR-27b-3p, miR-21-5p, miR-103a-3p, and miR-30c-5p) were found to be associated with recurrent VTE after multiple correction test and conditional logistic regression analysis. A further analysis showed that miR-15b-5p, miR-197-3p, miR-27b-3p, and miR-30c-5p exhibited a trend over time, with a larger difference in miRNA levels between cases and controls for earlier recurrence. Of these 12 miRNAs, 8 miRNAs significantly correlated with circulating transforming growth factor β1/2 (TGFβ1/2). Three of them correlated with platelet count. Conclusion We have identified 12 plasma miRNAs that may have the potential to serve as novel, non-invasive predictive biomarkers for VTE recurrence.

The Nordic Centre of Excellence CRAICC (Cryosphere–Atmosphere Interactions in a Changing Arctic Climate), funded by NordForsk in the years 2011–2016, is the largest joint Nordic research and innovation initiative to date, aiming to strengthen research and innovation regarding climate change issues in the Nordic region. CRAICC gathered more than 100 scientists from all Nordic countries in a virtual centre with the objectives of identifying and quantifying the major processes controlling Arctic warming and related feedback mechanisms, outlining strategies to mitigate Arctic warming, and developing Nordic Earth system modelling with a focus on short-lived climate forcers (SLCFs), including natural and anthropogenic aerosols. The outcome of CRAICC is reflected in more than 150 peer-reviewed scientific publications, most of which are in the CRAICC special issue of the journal Atmospheric Chemistry and Physics. This paper presents an overview of the main scientific topics investigated in the centre and provides the reader with a state-of-the-art comprehensive summary of what has been achieved in CRAICC with links to the particular publications for further detail. Faced with a vast amount of scientific discovery, we do not claim to completely summarize the results from CRAICC within this paper, but rather concentrate here on the main results which are related to feedback loops in climate change–cryosphere interactions that affect Arctic amplification.

Abstract Introduction To evaluate the usefulness of the 2018 NIA‐AA (National Institute on Aging and Alzheimer's Association) research framework in a longitudinal memory clinic study with different clinical outcomes and underlying disorders. Methods We included 420 patients with mild cognitive impairment or subjective cognitive impairment. During the follow up, 27% of the patients converted to dementia, with the majority converting to Alzheimer's disease (AD) or mixed dementia. Based on the baseline values of the cerebrospinal fluid biomarkers, the patients were classified into one of the eight possible ATN groups (amyloid beta [Aβ] aggregation [A], tau aggregation reflecting neurofibrillary tangles [T], and neurodegeneration [N]). Results The majority of the patients converting to AD and mixed dementia were in ATN groups positive for A (71%). The A+T+N+ group was highly overrepresented among converters to AD and mixed dementia. Patients converting to dementias other than AD or mixed dementia were evenly distributed across the ATN groups Discussion Our findings provide support for the usefulness of the ATN system to detect incipient AD or mixed dementia.

Summary: We present a protocol for isolating hepatocytes from mice with established non-alcoholic fatty liver disease. This protocol consists of liver perfusion using a peristaltic pump, followed by a modified 25% and 90% Percoll gradient centrifugation protocol to capture lipid-laden hepatocytes that are usually lost using traditional isolation protocols. This protocol enables simultaneous isolation of normal and lipid-filled hepatocytes. Lipid-filled hepatocytes can be used in cell culture systems to study drug metabolism, hepatotoxicity, or glucose and lipid metabolism.For complete details on the use and execution of this protocol, please refer to Sharabi et al. (2017) and Kegel et al. (2016).

Metabolic diseases, such as diabetes, obesity, and fatty liver disease, have now reached epidemic proportions. Receptor tyrosine kinases (RTKs) are a family of cell surface receptors responding to growth factors, hormones, and cytokines to mediate a diverse set of fundamental cellular and metabolic signaling pathways. These ligands signal by endocrine, paracrine, or autocrine means in peripheral organs and in the central nervous system to control cellular and tissue-specific metabolic processes. Interestingly, the expression of many RTKs and their ligands are controlled by changes in metabolic demand, for example, during starvation, feeding, or obesity. In addition, studies of RTKs and their ligands in regulating energy homeostasis have revealed unexpected diversity in the mechanisms of action and their specific metabolic functions. Our current understanding of the molecular, biochemical and genetic control of energy homeostasis by the endocrine RTK ligands insulin, FGF21 and FGF19 are now relatively well understood. In addition to these classical endocrine signals, non-endocrine ligands can govern local energy regulation, and the intriguing crosstalk between the RTK family and the TGFβ receptor family demonstrates a signaling network that diversifies metabolic process between tissues. Thus, there is a need to increase our molecular and mechanistic understanding of signal diversification of RTK actions in metabolic disease. Here we review the known and emerging molecular mechanisms of RTK signaling that regulate systemic glucose and lipid metabolism, as well as highlighting unexpected roles of non-classical RTK ligands that crosstalk with other receptor pathways.

Light-absorbing impurities (LAIs) deposited in snow have the potential to substantially affect the snow radiation budget, with subsequent implications for snow melt. To more accurately quantify the snow albedo, the contribution from different LAIs needs to be assessed. Here we estimate the main LAI components, elemental carbon (EC) (as a proxy for black carbon) and mineral dust in snow from the Indian Himalayas and paired the results with snow samples from Arctic Finland. The impurities are collected onto quartz filters and are analyzed thermal–optically for EC, as well as with an additional optical measurement to estimate the light-absorption of dust separately on the filters. Laboratory tests were conducted using substrates containing soot and mineral particles, especially prepared to test the experimental setup. Analyzed ambient snow samples show EC concentrations that are in the same range as presented by previous research, for each respective region. In terms of the mass absorption cross section (MAC) our ambient EC surprisingly had about half of the MAC value compared to our laboratory standard EC (chimney soot), suggesting a less light absorptive EC in the snow, which has consequences for the snow albedo reduction caused by EC. In the Himalayan samples, larger contributions by dust (in the range of 50 % or greater for the light absorption caused by the LAI) highlighted the importance of dust acting as a light absorber in the snow. Moreover, EC concentrations in the Indian samples, acquired from a 120 cm deep snow pit (possibly covering the last five years of snow fall), suggest an increase in both EC and dust deposition. This work emphasizes the complexity in determining the snow albedo, showing that LAI concentrations alone might not be sufficient, but additional transient effects on the light-absorbing properties of the EC need to be considered and studied in the snow. Equally as imperative is the confirmation of the spatial and temporal representativeness of these data by comparing data from several and deeper pits explored at the same time.

Abstract Background Full Monte Carlo (MC)-based SPECT reconstructions have a strong potential for correcting for image degrading factors, but the reconstruction times are long. The objective of this study was to develop a highly parallel Monte Carlo code for fast, ordered subset expectation maximum (OSEM) reconstructions of SPECT/CT images. The MC code was written in the Compute Unified Device Architecture language for a computer with four graphics processing units (GPUs) (GeForce GTX Titan X, Nvidia, USA). This enabled simulations of parallel photon emissions from the voxels matrix (1283 or 2563). Each computed tomography (CT) number was converted to attenuation coefficients for photo absorption, coherent scattering, and incoherent scattering. For photon scattering, the deflection angle was determined by the differential scattering cross sections. An angular response function was developed and used to model the accepted angles for photon interaction with the crystal, and a detector scattering kernel was used for modeling the photon scattering in the detector. Predefined energy and spatial resolution kernels for the crystal were used. The MC code was implemented in the OSEM reconstruction of clinical and phantom 177Lu SPECT/CT images. The Jaszczak image quality phantom was used to evaluate the performance of the MC reconstruction in comparison with attenuated corrected (AC) OSEM reconstructions and attenuated corrected OSEM reconstructions with resolution recovery corrections (RRC). Result The performance of the MC code was 3200 million photons/s. The required number of photons emitted per voxel to obtain a sufficiently low noise level in the simulated image was 200 for a 1283 voxel matrix. With this number of emitted photons/voxel, the MC-based OSEM reconstruction with ten subsets was performed within 20 s/iteration. The images converged after around six iterations. Therefore, the reconstruction time was around 3 min. The activity recovery for the spheres in the Jaszczak phantom was clearly improved with MC-based OSEM reconstruction, e.g., the activity recovery was 88% for the largest sphere, while it was 66% for AC-OSEM and 79% for RRC-OSEM. Conclusion The GPU-based MC code generated an MC-based SPECT/CT reconstruction within a few minutes, and reconstructed patient images of 177Lu-DOTATATE treatments revealed clearly improved resolution and contrast.

Abstract Background Genome-wide association studies are useful for discovering genotype–phenotype associations but are limited because they require large cohorts to identify a signal, which can be population-specific. Mapping genetic variation to genes improves power and allows the effects of both protein-coding variation as well as variation in expression to be combined into “gene level” effects. Methods Previous work has shown that warfarin dose can be predicted using information from genetic variation that affects protein-coding regions. Here, we introduce a method that improves dose prediction by integrating tissue-specific gene expression. In particular, we use drug pathways and expression quantitative trait loci knowledge to impute gene expression—on the assumption that differential expression of key pathway genes may impact dose requirement. We focus on 116 genes from the pharmacokinetic and pharmacodynamic pathways of warfarin within training and validation sets comprising both European and African-descent individuals. Results We build gene-tissue signatures associated with warfarin dose in a cohort-specific manner and identify a signature of 11 gene-tissue pairs that significantly augments the International Warfarin Pharmacogenetics Consortium dosage-prediction algorithm in both populations. Conclusions Our results demonstrate that imputed expression can improve dose prediction and bridge population-specific compositions. MATLAB code is available at https://github.com/assafgo/warfarin-cohort

The climate impact of black carbon (BC) is notably amplified in the Arctic by its deposition, which causes albedo decrease and subsequent earlier snow and ice spring melt. To comprehensively assess the climate impact of BC in the Arctic, information on both atmospheric BC concentrations and deposition is essential. Currently, Arctic BC deposition data are very scarce, while atmospheric BC concentrations have been shown to generally decrease since the 1990s. However, a 300-year Svalbard ice core showed a distinct increase in EC (elemental carbon, proxy for BC) deposition from 1970 to 2004 contradicting atmospheric measurements and modelling studies. Here, our objective was to decipher whether this increase has continued in the 21st century and to investigate the drivers of the observed EC deposition trends. For this, a shallow firn core was collected from the same Svalbard glacier, and a regional-to-meso-scale chemical transport model (SILAM) was run from 1980 to 2015. The ice and firn core data indicate peaking EC deposition values at the end of the 1990s and lower values thereafter. The modelled BC deposition results generally support the observed glacier EC variations. However, the ice and firn core results clearly deviate from both measured and modelled atmospheric BC concentration trends, and the modelled BC deposition trend shows variations seemingly independent from BC emission or atmospheric BC concentration trends. Furthermore, according to the model ca. 99 % BC mass is wet-deposited at this Svalbard glacier, indicating that meteorological processes such as precipitation and scavenging efficiency have most likely a stronger influence on the BC deposition trend than BC emission or atmospheric concentration trends. BC emission source sectors contribute differently to the modelled atmospheric BC concentrations and BC deposition, which further supports our conclusion that different processes affect atmospheric BC concentration and deposition trends. Consequently, Arctic BC deposition trends should not directly be inferred based on atmospheric BC measurements, and more observational BC deposition data are required to assess the climate impact of BC in Arctic snow.

In order to quantify the effects of absorbing contaminants on snow, a series of spectral reflectance measurements were conducted. Chimney soot, volcanic sand, and glaciogenic silt were deposited on a natural snow surface in a controlled way as a part of the Soot on Snow (SoS) campaign. The bidirectional reflectance factors of these soiled surfaces and untouched snow were measured using the Finnish Geodetic Institute's Field Goniospectropolariradiometer, FIGIFIGO. A remarkable feature is the fact that the absorbing contaminants on snow enhanced the metamorphism of snow under strong sunlight in our experiments. Immediately after deposition, the contaminated snow surface appeared darker than the natural snow in all viewing directions, but the absorbing particles sank deep into the snow in minutes. The nadir measurement remained the darkest, but at larger zenith angles, the surface of the contaminated snow changed back to almost as white as clean snow. Thus, for a ground observer the darkening caused by impurities can be completely invisible, overestimating the albedo, but a nadir-observing satellite sees the darkest points, underestimating the albedo. Through a reciprocity argument, we predict that at noon, the albedo perturbation should be lower than in the morning or afternoon. When sunlight stimulates sinking more than melting, the albedo should be higher in the afternoon than in the morning, and vice versa when melting dominates. However, differences in the hydrophobic properties, porosity, clumping, or size of the impurities may cause different results than observed in these measurements.

Atmospheric aerosol composition was measured using a Single Particle Soot Photometer (SP2) in the Finnish Arctic during winter 2011–2012. The Sammaltunturi measurement site at the Pallas GAW (Global Atmosphere Watch) station receives air masses from different source regions including the Arctic Ocean and continental Europe. The SP2 provides detailed information about mass distributions and mixing state of refractory black carbon (rBC). The measurements showed widely varying rBC mass concentrations (0–120 ng m−3), which were related to varying contributions of different source regions and aerosol removal processes. The rBC mass was log-normally distributed showing a relatively constant rBC core mass mean diameter with an average of 194 nm (75–655 nm sizing range). On average, the number fraction of particles containing rBC was 0.24 (integrated over 350–450 nm particle diameter range) and the average particle diameter to rBC core volume equivalent diameter ratio was 2.0 (averaged over particles with 150–200 nm rBC core volume equivalent diameters). These average numbers mean that the observed rBC core mass mean diameter is similar to those of aged particles, but the observed particles seem to have unusually high particle to rBC core diameter ratios. Comparison of the measured rBC mass concentration with that of the optically detected equivalent black carbon (eBC) using an Aethalometer and a MAAP showed that eBC was larger by a factor of five. The difference could not be fully explained without assuming that only a part of the optically detected light absorbing material is refractory and absorbs light at the wavelength used by the SP2. Finally, climate implications of five different black carbon mixing state representations were compared using the Mie approximation and simple direct radiative forcing efficiency calculations. These calculations showed that the observed mixing state means significantly lower warming effect or even a net cooling effect when compared with that of a homogenous aerosol containing the same amounts of black carbon and non-absorbing material.

A global heat flux model based on a fractional derivative of plasma pressure is proposed for the heat transport in fusion plasmas. The degree of the fractional derivative of the heat flux, α, is defined through the power balance analysis of the steady state. The model was used to obtain the experimental values of α for a large database of the Joint European Torus (JET) carbon-wall as well as ITER like-wall plasmas. The fractional degrees of the electron heat flux are found to be α

Black carbon (BC) is a light-absorbing particle that warms the atmosphere–Earth system. The climate effects of BC are amplified in the Arctic, where its deposition on light surfaces decreases the albedo and causes earlier melt of snow and ice. Despite its suggested significant role in Arctic climate warming, there is little information on BC concentrations and deposition in the past. Here we present results on BC (here operationally defined as elemental carbon (EC)) concentrations and deposition on a Svalbard glacier between 1700 and 2004. The inner part of a 125 m deep ice core from Holtedahlfonna glacier (79°8' N, 13°16' E, 1150 m a.s.l.) was melted, filtered through a quartz fibre filter and analysed for EC using a thermal–optical method. The EC values started to increase after 1850 and peaked around 1910, similar to ice core records from Greenland. Strikingly, the EC values again increase rapidly between 1970 and 2004 after a temporary low point around 1970, reaching unprecedented values in the 1990s. This rise is not seen in Greenland ice cores, and it seems to contradict atmospheric BC measurements indicating generally decreasing atmospheric BC concentrations since 1989 in the Arctic. For example, changes in scavenging efficiencies, post-depositional processes and differences in the vertical distribution of BC in the atmosphere are discussed for the differences between the Svalbard and Greenland ice core records, as well as the ice core and atmospheric measurements in Svalbard. In addition, the divergent BC trends between Greenland and Svalbard ice cores may be caused by differences in the analytical methods used, including the operational definitions of quantified particles, and detection efficiencies of different-sized BC particles. Regardless of the cause of the increasing EC values between 1970 and 2004, the results have significant implications for the past radiative energy balance at the coring site.

Climatic effects of black carbon (BC) deposition on snow have been proposed to result from reduced snow albedo and increased melt due to light-absorbing particles. In this study, we hypothesize that BC may decrease the liquid-water retention capacity of melting snow, and present our first data, where both the snow density and elemental carbon content were measured. In our experiments, artificially added light-absorbing impurities decreased the density of seasonally melting natural snow. No relationship was found in case of natural non-melting snow. We also suggest three possible processes that might lead to lower snow density.

We have measured spectral albedo, as well as ancillary parameters, of seasonal European Arctic snow at Sodankylä, Finland (67°22' N, 26°39' E). The springtime intensive melt period was observed during the Snow Reflectance Transition Experiment (SNORTEX) in April 2009. The upwelling and downwelling spectral irradiance, measured at 290–550 nm with a double monochromator spectroradiometer, revealed albedo values of ~0.5–0.7 for the ultraviolet and visible range, both under clear sky and variable cloudiness. During the most intensive snowmelt period of four days, albedo decreased from 0.65 to 0.45 at 330 nm, and from 0.72 to 0.53 at 450 nm. In the literature, the UV and VIS albedo for clean snow are ~0.97–0.99, consistent with the extremely small absorption coefficient of ice in this spectral region. Our low albedo values were supported by two independent simultaneous broadband albedo measurements, and simulated albedo data. We explain the low albedo values to be due to (i) large snow grain sizes up to ~3 mm in diameter; (ii) meltwater surrounding the grains and increasing the effective grain size; (iii) absorption caused by impurities in the snow, with concentration of elemental carbon (black carbon) in snow of 87 ppb, and organic carbon 2894 ppb, at the time of albedo measurements. The high concentrations of carbon, detected by the thermal–optical method, were due to air masses originating from the Kola Peninsula, Russia, where mining and refining industries are located.

Environment Climate Data Sweden (ECDS) is a new Swedish research infrastructure, furthering the reuse of scientific data in the domains of environment and climate. ECDS consists of a technical infrastructure and a service organization, supporting the management, exchange, and re-use of scientific data. The technical components of ECDS include a portal and an underlying data catalogue with information on datasets. The datasets are described using a metadata profile compliant with international standards. The datasets accessible through ECDS can be hosted by universities, institutes, or research groups or at the new Swedish federated data storage facility Swestore of the Swedish National Infrastructure for Computing (SNIC).

For patients with atrial fibrillation, non-vitamin K oral anticoagulants, or NOACs (dabigatran, rivaroxaban, edoxaban, and apixaban) have been proven non-inferior or superior to warfarin in preventing stroke and systemic embolism, and in risk of haemorrhage. In the pivotal NOAC studies, quality of warfarin treatment was poor with mean time in therapeutic range (TTR) 55-65%, compared with ≥70% in Swedish clinical practice.We compared NOACs (as a group) to warfarin in non-valvular atrial fibrillation, studying all 12,694 patients starting NOAC treatment within the Swedish clinical register and dosing system Auricula, from July 1, 2011 to December 31, 2014, and matching them to 36,317 patients starting warfarin using propensity scoring. Endpoints were thromboembolic events and major bleedings that were fatal or required hospital care. Outcome data were collected from validated Swedish hospital administrative and clinical registers.Mean age was 72.2 vs 72.3 years, proportion of males 58.2% vs 57.0%, and mean follow-up time 299 vs 283 days for NOACs and warfarin. Distribution of NOACs was: dabigatran 40.3%, rivaroxaban 31.2%, and apixaban 28.5%. Mean TTR was 70%. There were no significant differences in rates of thromboembolic/thrombotic events or gastrointestinal bleeding. NOAC treated patients had lower rates of major bleeding overall, hazard ratio 0.78 (95% confidence interval 0.67-0.92), intracranial bleeding 0.59 (0.40-0.87), haemorrhagic stroke 0.49 (0.28-0.86), and other major bleeding 0.71 (0.57-0.89).For patients with atrial fibrillation, NOACs are as effective for stroke prevention as well-managed warfarin but cause fewer major bleedings.