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Multiple sclerosis (MS) is a chronic autoimmune and neurodegenerative disease that results in immune cell infiltration of the central nervous system (CNS) and demyelination in young adults. Substantial progress has been made in developing disease modifying therapies for people with relapsing-remitting MS, but options remain limited for people with primary progressive MS (PPMS). PPMS accounts for ∼15% of MS diagnoses. Herein, we generated a human induced pluripotent stem cell line (hiPSC) from a person with clinically definite PPMS. This disease-specific hiPSC line will be useful for studying PPMS in vitro, allowing the generation of immune and CNS cell types.

Regular population monitoring of imperilled charismatic species such as large carnivores is critical for conservation. However, the role of monitoring in conservation is frequently diminished due to: 1) surveys being implemented in isolation, 2) limited on-ground-capacity leading to infrequent monitoring, and 3) inappropriate methods being applied. Wildlife monitoring is often resource-intensive and the utility and cost of different field protocols is rarely reported. In this study we deployed two standard field protocols aimed at collecting data on African lions within a spatial capture-recapture framework. For our first protocol, we trained Uganda Wildlife Authority rangers in search-encounter techniques, the industry gold standard for monitoring lions. The second protocol involved deploying 32 paired stations of state-of-the-art infra-red camera traps. During the search-encounter protocol, two rangers covered 2939 km in 76 days, recording 102 detections (30 individuals) in a ~ 256 km2 area. The resulting density estimates (13.91 lions/100 km2, posterior SD = 2.34) yielded acceptable precision. Conversely, 64 camera traps over 1601 trap nights yielded two usable lion detections. We argue that where wildlife tourism rangers exist, they could be a powerful addition to future lion and wildlife census attempts across the continent. Our results confirm that the current technology of store-bought infra-red camera traps is not suitable for individual identification of lions, and therefore cannot be applied to analytical models that require unambiguous individual identities. However, we encourage the continued testing and advancement of infra-red camera trap technology since in many instances, this may be preferable to white-flash camera traps, which can yield individual identities for lions. Our study also shows the immense importance of the Nile Delta for African lions in Uganda’s Murchison Falls National Park, a protected area with both oil extraction and high rates of anthropogenic snaring pressure.

ABSTRACT: Dietary carbohydrate manipulation can be used to reduce enteric CH4 emission, but few studies have focused on the interaction of the different types of carbohydrates that can affect feed intake and ruminal fermentation. Understanding this interaction is necessary to make the most out of CH4 mitigation feeding strategies using different dietary carbohydrates. The aim of this study was to test the effect on enteric CH4 emission, feed intake, and milk production response when cows were fed either grass-clover silage (GCS) or corn silage (CS) as the sole forage source (55% of dry matter, DM), in combination with either barley (BAR) or dried beet pulp (DBP) as a concentrate (21.5% of DM). A total of 24 (half first-parity and half second-parity) cows were used in a crossover design with 2 periods of 21 d each, receiving 2 of 4 diets obtained from a 2 × 2 factorial arrangement of the experimental diet. Feed intake, CH4 emission metrics, and milk production were recorded at the end of the experimental periods. The diets had NDF concentrations between 258 and 340 g/kg of DM and starch concentrations between 340 and 7.45 g/kg of DM (CS-BAR and GCS-DBP, respectively). The effects of silage and concentrate on dry matter intake (DMI) were additive, with the highest feed intake in cows fed CS-BAR, followed by cows fed CS-DBP, GCS-BAR, and GCS-DBP (21.2, 19.9, 19.1, and 18.3 kg/d, respectively). Energy corrected milk (ECM) yield was not affected by silage source in first parity cows, but it was higher for cows fed CS than cows fed GCS in second parity. The effects of silage and concentrate on CH4 production (g/d), yield (g/kg of DMI), and intensity (g/kg of ECM) were not additive, as cows fed GCS had similar responses regardless of the concentrate used, but cows fed CS had lower CH4 production, yield, and intensity when fed BAR instead of DBP. The lower CH4 production, yield, and intensity in cows fed CS-BAR compared with other diets could be partially explained by the nonlinear relationship between ruminal VFA and carbohydrates (NDF and starch) concentration reported in the literature; however, we observed a linear relationship between the acetate/propionate ratio and CH4 yield, suggesting possible other effects. The effects of silage and concentrate on the ruminal VFA were additive in first parity cows, but not in second parity cows. The interaction between dietary carbohydrate type and parity might indicate an effect of feed intake or the energy balance of the cow. Feeding cows silage and concentrate both rich in starch can result in the lowest enteric CH4 emission.

Abstract Caves represent a specific environment with a special microclimate and fauna adapted to it. However, we have still a restricted knowledge on soil fauna communities in an environments with a marked microclimate gradient at the interface between cave and surface habitats. In the present study, we investigated the community patterns of dominant soil microarthropod group, oribatid mites, and their relationship to environmental factors across the microclimate gradient along a transect with seven study sites from cold and wet cave entrance zone to warm and drier deciduous forest. The cold and wet sites showed low oribatid abundances and a high spatial clustering of individuals in comparison to the warm sites. The oribatid mites showed significantly higher abundance and species richness at warm forest sites. Indicator species analysis indicated specific cold-tolerant species that dominated at cold sites of the gradient, but which were absent at the warmest sites. Variance analysis clarified that community composition at sites were significantly driven by environmental factors: temperature, soil moisture, pH and C/N ratio. The study underlines the importance of ice cave entrances as sources of high α-diversity of soil mesofauna and thus the conservation priority of these valuable habitats.

Background: Electrogram dispersion identifies putative atrial fibrillation (AF) drivers in first time ablation procedures, with high acute termination rates and long-term outcomes akin to extensive ablation approaches. Its use in a population that had undergone repeat ablation is unknown, particularly where the pulmonary veins are already isolated. Objective: This purpose of this study was to assess electrogram dispersion mapping during repeat ablation procedures for persistent AF. Methods: One hundred sixty-seven patients from the United Kingdom and Denmark, all with persistent AF recurrence after prior ablation procedure(s), were mapped using a five splined catheter for electrogram dispersion before ablation. Areas were manually tagged on biatrial electroanatomic maps and ablated once pulmonary vein isolation was confirmed or reisolated if required. All patients had 12-month continuous monitoring, with most of the cohort having follow-up beyond 24 months. Results: Of the 167 patients [53 (32%) female; mean age 66 ± 8 years; mean left atrial (LA) diameter 4.8 cm; mean ejection fraction 53%], 108 had pulmonary veins already isolated. Dispersion sites occurred in both atria (3.2 LA, 1.4 right atrium). Acute termination to sinus rhythm occurred in 71 (42%) of the cohort patients, with a further 73 (44%) terminating to atrial tachycardia/flutter. At 12-month follow-up, 95% of patients were free of AF, with 74% overall freedom from all atrial arrhythmias. Heart failure and severely enlarged LA predicted recurrence, and termination to sinus improved freedom from all atrial arrhythmias. Conclusion: Dispersion mapping is a promising approach at repeat ablation procedures for persistent AF, with high acute termination rates and good clinical outcomes. Further prospective randomized trials are needed to evaluate this approach in a population that had undergone repeat ablation.

ABSTRACT: Enteric CH4 produced from dairy cows contributes to the emission of greenhouse gases from anthropogenic sources. Recent studies have shown that the selection of lower CH4-emitting cows is possible, but doing so would be simpler if performance measures already recorded on farm could be used, instead of measuring gas emissions from individual cows. These performance measures could be used for selection of low emitting cows. The aim of this analysis was to quantify how much of the between-cow variation in CH4 production can be explained by variation in performance measures. A dataset with 3 experiments and a total of 149 lactating dairy cows with repeated measures was used to estimate the between-cow variation (the variation between cow estimates) for performance and gas measures from GreenFeed (C-Lock, Rapid City, SD). The cow estimates were obtained with a linear mixed model with the diet within period effect as a fixed effect and the cow within experiment as a random effect. The cow estimates for CH4 production were first regressed on the performance and gas measures individually, and then performance and CO2 production measures were grouped in 3 subsets for principal component analysis and principal component regression. The variables that explained most of the between-cow variation in CH4 production were DMI (R2 = 0.44), among the performance measures, and CO2 production (R2 = 0.61), among gas measures. Grouping the measures increased the R2 to 0.53 when only performance measures were used, and to 0.66 when CO2 production was added to the significant performance measures. We found the marginal improvement to be insufficient to justify the use of grouped measures rather than an individual measure because the latter simplifies the model and avoids over-fitting. Investigation of other measures that can be explored to increase explanatory power of between-cow variation in CH4 production is briefly discussed. Finally, the use of residual CH4 as a measure for CH4 efficiency could be considered by using either DMI or CO2 production as the sole predicting variables.

Background Elevated troponin levels are a sensitive biomarker for cardiac injury. The quick and reliable prediction of troponin elevation for patients with chest pain from readily available ECGs may pose a valuable time-saving diagnostic tool during decision-making concerning this patient population.Methods and results The data used included 15 856 ECGs from patients presenting to the emergency rooms with chest pain or dyspnoea at two centres in Sweden from 2015 to June 2023. All patients had high-sensitivity troponin test results within 6 hours after 12-lead ECG. Both troponin I (TnI) and TnT were used, with biomarker-specific cut-offs and sex-specific cut-offs for TnI. On this dataset, a residual convolutional neural network (ResNet) was trained 10 times, each on a unique split of the data. The final model achieved an average area under the curve for the receiver operating characteristic curve of 0.7717 (95% CI±0.0052), calibration curve analysis revealed a mean slope of 1.243 (95% CI±0.075) and intercept of −0.073 (95% CI±0.034), indicating a good correlation between prediction and ground truth. Post-classification, tuned for F1 score, accuracy was 71.43% (95% CI±1.28), with an F1 score of 0.5642 (95% CI±0.0052) and a negative predictive value of 0.8660 (95% CI±0.0048), respectively. The ResNet displayed comparable or surpassing metrics to prior presented models.Conclusion The model exhibited clinically meaningful performance, notably its high negative predictive accuracy. Therefore, clinical use of comparable neural networks in first-line, quick-response triage of patients with chest pain or dyspnoea appears as a valuable option in future medical practice.

IntroductionGiven a high amount of workplace stressors, burnout syndrome, as a depression-related syndrome, is highly relevant for medical service soldiers. This study aims to examine their effects with regard to moral injuries and personal values following foreign deployment.Materials and methodsThis longitudinal study included 91 soldiers of the German Armed Forces Medical Service. Participants completed the Maslach Burnout Inventory (MBI) and the Portrait-Value-Questionnaire (PVQ) before and after a foreign deployment as well as the Moral Injury Scale (SMBE) after deployment. Analysis has been conducted using t-tests to assess potential changes in MBI and PVQ scales between pre-test - t1 (2-4 weeks before deployment) and post-test – t2 (up to 6 months after deployment). In addition, correlations were examined between moral injuries (MI) after deployment and MBI scores at t1 and t2 as well as between personal values (PVQ t1) and MBI scores at t1 and t2.ResultsThe MBI subscales showed mild to moderate burnout symptoms at both pre- and post-tests, with a slight deterioration during the study period, albeit not significant. There were no significant mean differences in PVQ between measurement points. Nevertheless, PVQ self-direction and tradition at t1 correlated negatively with MBI INV at t2 (PVQ SD r = -.21, p = .043) and MBI PA at t2 (PVQ TR r = -.23, p = .027). Furthermore, the subscale PVQ power at t1 correlated positively with MBI PA at t2 (PVQ PO r = .28, p = .006), meanwhile PVQ universalism at t1 correlated positively with MBI INV at t1 (PVQ UN r = .25, p = .018). Furthermore, positive correlations were found between moral injuries at t2 (SMBE total score, SMBE_Sub1, SMBE_Sub2) and MBI subscales Emotional Exhaustion (EE; r = -.54, p = .001), Depersonalization (DP; r = .38, p = .001), and Involvement (INV; r = .30, p = .004) before and after the deployment period. No correlation was found between MI and MBI subscale Personal Accomplishment (PA).ConclusionThe results indicate that medical service soldiers exhibit mild to moderate burnout symptoms even before deployment. Significant associations between moral injuries and burnout were found in 3 out of 4 MBI subscales (EE, DP, INV). There was a significant association with a stronger moral injury and higher burnout levels, persisting both before and after the study period. Furthermore, our results suggest that personal value orientations might be meaningful predictors of burnout. Hence, causal questions regarding general work stress among medical service soldiers should be further explored in more detailed studies. Further research could lay the foundation for future approaches in psychotherapy as well as primary and secondary prevention in this field.

Abstract Alcohol consumption is associated with a wide variety of preventable health complications and is a major risk factor for all-cause mortality in the age group 15-47 years. To reduce dangerous drinking behavior, eHealth applications have shown promise. A particularly interesting potential lies in the combination of eHealth apps with mathematical models. However, existing mathematical models do not consider real-life situations, such as combined intake of meals and beverages, and do not connect drinking to clinical markers, such as phosphatidylethanol (PEth). Herein, we present such a model which can simulate real-life situations and connect drinking to long-term markers. The new model can accurately describe both estimation data according to a χ2 -test (187.0

Abstract Background Accidental hypothermia is common in all trauma patients and contributes to the lethal diamond, increasing both morbidity and mortality. In hypotensive shock, fluid resuscitation is recommended using fluids with a temperature of 37–42°, as fluid temperature can decrease the patient’s body temperature. In Sweden, virtually all prehospital services use preheated fluids. The aim of the present study was to investigate how the temperature of preheated infusion fluids is affected by the ambient temperatures and flow rates relevant for prehospital emergency care. Methods In this experimental simulation study, temperature changes in crystalloids preheated to 39 °C were evaluated. The fluid temperature changes were measured both in the infusion bag and at the patient end of the infusion system. Measurements were conducted in conditions relevant to prehospital emergency care, with ambient temperatures varying between − 4 and 28 °C and flow rates of 1000 ml/h and 6000 ml/h, through an uninsulated infusion set at a length of 175 cm. Results The flow rate and ambient temperature affected the temperature in the infusion fluid both in the infusion bag and at the patient end of the system. A lower ambient temperature and lower flow rate were both associated with a greater temperature loss in the infusion fluid. Conclusion This study shows that both a high infusion rate and a high ambient temperature are needed if an infusion fluid preheated to 39 °C is to remain above 37 °C when it reaches the patient using a 175-cm-long uninsulated infusion set. It is apparent that the lower the ambient temperature, the higher the flow rate needs to be to limit temperature loss of the fluid.

Abstract Ultrasonic imaging, using ultrasonic phased arrays, has an enormous impact in science, medicine and society and is a widely used modality in many application fields. The maximum amount of information which can be captured by an array is provided by the data acquisition method capturing the complete data set of signals from all possible combinations of ultrasonic generation and detection elements of a dense array. However, capturing this complete data set requires long data acquisition time, large number of array elements and transmit channels and produces a large volume of data. All these reasons make such data acquisition unfeasible due to the existing phased array technology or non-applicable to cases requiring fast measurement time. This paper introduces the concept of an adaptive data acquisition process, the Selective Matrix Capture (SMC), which can adapt, dynamically, to specific imaging requirements for efficient ultrasonic imaging. SMC is realised experimentally using Laser Induced Phased Arrays (LIPAs), that use lasers to generate and detect ultrasound. The flexibility and reconfigurability of LIPAs enable the evolution of the array configuration, on-the-fly. The SMC methodology consists of two stages: a stage for detecting and localising regions of interest, by means of iteratively synthesising a sparse array, and a second stage for array optimisation to the region of interest. The delay-and-sum is used as the imaging algorithm and the experimental results are compared to images produced using the complete generation-detection data set. It is shown that SMC, without a priori knowledge of the test sample, is able to achieve comparable results, while preforming $$\sim$$ ∼ 10 times faster data acquisition and achieving $$\sim$$ ∼ 10 times reduction in data size.

ABSTRACT: Fat in the form of cracked rapeseed and 3-nitrooxypropanol (3-NOP, market as Bovaer) were fed alone or in combination to 4 Danish Holstein multicannulated dairy cows, with the objective to investigate effects on gas exchange, dry matter intake (DMI), nutrient digestion, and nutrient metabolism. The study design was a 4 × 4 Latin square with a 2 × 2 factorial treatment arrangement with 2 levels of fat supplementation; 33 g of crude fat per kg of dry matter (DM) or 64 g of crude fat per kg of DM for low and high fat diets, respectively, and 2 levels of 3-NOP; 0 mg/kg DM or 80 mg/kg DM. In total, 4 diets were formulated: low fat (LF), high fat (HF), 3-NOP and low fat (3LF), and 3-NOP and high fat (3HF). Cows were fed ad libitum and milked twice daily. The adaptation period lasted 11 d, followed by 5 d with 12 diurnal sampling times of digesta and ruminal fluid. Thereafter, gas exchange was measured for 5 d in respiration chambers. Chromic oxide and titanium dioxide were used as external flow markers to determine intestinal nutrient flow. No interactions between fat supplementation and 3-NOP were observed for methane yield (g/kg DM), total-tract digestibility of nutrients or total volatile fatty acid (VFA) concentration in the rumen. Methane yield (g/kg DMI) was decreased by 24% when cows were fed 3-NOP. In addition, 3-NOP increased carbon dioxide and hydrogen yield (g/kg DM) by 6% and 3,500%, respectively. However, carbon dioxide production was decreased when expressed on a daily basis. Fat supplementation did not affect methane yield but tended to reduce methane in percent of gross energy intake. A decrease (11%) in DMI was observed, when cows were fed 3-NOP. Likely, the lower DMI mediated a lower passage rate causing the tendency to higher rumen and total-tract neutral detergent fiber digestibility, when the cows were fed 3-NOP. Total VFA concentrations in the rumen were negatively affected both by 3-NOP and fat supplementation. Furthermore, 3-NOP caused a shift in the VFA fermentation profile, with decreased acetate proportion and increased butyrate proportion, whereas propionate proportion was unaffected. Increased concentrations of the alcohols methanol, ethanol, propanol, butanol, and 2-butanol were observed in the ruminal fluid when cows were fed 3-NOP. These changes in rumen metabolites indicate partial re-direction of hydrogen into other hydrogen sinks, when methanogenesis is inhibited by 3-NOP. In conclusion, fat supplementation did not reduce methane yield, whereas 3-NOP reduced methane yield, irrespective of fat level. However, the concentration of 3-NOP and diet composition and resulting desired mitigation effect must be considered before implementation. The observed reduction in DMI with 80 mg 3-NOP/kg DM was intriguing and may indicate that a lower dose should be applied in a Northern European context; however, the mechanism behind needs further investigation.

This study aims to evaluate the clinical outcome of stereotactic radiosurgery as the sole treatment for brain metastases and to assess prognostic factors influencing survival. A total of 108 consecutive patients with 213 metastases were retrospectively analyzed. Treatment was determined with close-meshed MRI follow-up. Various prognostic factors were assessed, and several prognostic indices were compared regarding their reliability to estimate overall survival. Median overall survival was 15 months; one-year overall survival was 50.5%. Both one- and two-year local controls were 90.9%. The rate of new metastases after SRS was 49.1%. Multivariate analysis of prognostic factors revealed that the presence of extracranial metastases, male sex, lower KPI, and progressive extracranial disease were significant risk factors for decreased survival. Of all evaluated prognostic indices, the Basic Score for Brain Metastases (BSBMs) showed the best correlation with overall survival. A substantial survival advantage was found for female patients after SRS when compared to male patients (18 versus 9 months, p = 0.003). SRS of brain metastasis is a safe and effective treatment option when frequent monitoring for new metastases with MRI is performed. Common prognostic scores lack reliable estimation of survival times. Female sex should be considered as an additional independent positive prognostic factor influencing survival.

Abstract For generations researchers have been observing the dynamic processes of life through the lens of a microscope. This has offered tremendous insights into biological phenomena that span multiple orders of time- and length-scales ranging from the pure magic of molecular reorganization at the membrane of immune cells, to cell migration and differentiation during development or wound healing. Standard fluorescence microscopy techniques offer glimpses at such processes in vitro, however, when applied in intact systems, they are challenged by reduced signal strengths and signal-to-noise ratios that result from deeper imaging. As a remedy, two-photon excitation (TPE) microscopy takes a special place, because it allows us to investigate processes in vivo, in their natural environment, even in a living animal. Here, we review the fundamental principles underlying TPE aimed at basic and advanced microscopy users interested in adopting TPE for intravital imaging. We focus on applications in neurobiology, present current trends towards faster, wider and deeper imaging, discuss the combination with photon counting technologies for metabolic imaging and spectroscopy, as well as highlight outstanding issues and drawbacks in development and application of these methodologies.

Mixed ionic-electronic conductors (MIECs) play a crucial role in the landscape of energy conversion and storage technologies, with a pronounced focus on electrode materials’ application in solid oxide fuel cells (SOFCs) and proton-conducting ceramic fuel cells (PCFCs). In parallel, the emergence of semiconductor ionic materials (SIMs) has introduced a new paradigm in the field of functional materials, particularly for both electrode and electrolyte development for low-temperature, 300–550 ​°C, SOFCs, and PCFCs. This review article critically delves into the intricate mechanisms underpinning the synergistic relationship between MIECs and SIMs, with a particular emphasis on elucidating the fundamental working principles of semiconductor ionic membrane fuel cells (SIMFCs). By exploring critical facets such as ion-coupled electron transfer/transport, junction effect, energy bands alignment, and theoretical computations, it casts an illuminating spotlight on the transformative potential of MIECs, also involving triple charge conducting oxides (TCOs) in the context of SIMs and advanced fuel cells (FCs). The insights and findings articulated herein contribute substantially to the advancement of SIMs and SIMFCs by tailoring MIECs (TCOs) as promising avenues toward the emergence of high-performance SIMFCs. This scientific quest not only addresses the insistent challenges surrounding efficient charge transfer, ionic transport and power output but also unlocks the profound potential for the widespread commercialization of FC technology.

Objective Fluoropyrimidine chemotherapy is a first-line treatment for many gastrointestinal (GI) cancers, however, cardiotoxicity concerns may limit administration in patients with pre-existing cardiovascular disease (CVD). This study investigated the association of pre-existing CVD with use of fluoropyrimidine chemotherapy in tumour-eligible GI cancer patients.Methods and analysis National cancer registry data from the Virtual Cardio-Oncology Research Initiative from England between 2014 and 2018 was used to identify GI cancer patients eligible to receive fluoropyrimidine chemotherapy. Linkage to Hospital Episode Statistics and CVD registry data were used to ascertain prior CVD and outcomes. Primary outcome was first administration of fluoropyrimidine chemotherapy following cancer diagnosis. Cox proportional hazard models determined HR and 95% CIs for the association between initiation of fluoropyrimidine treatment and prior CVD.Results 112 726 eligible patients were identified (median age 71 years (IQR 62–80), 39.7% female). 33 026 (29.3%) had pre-existing CVD. 73 392 (65.1%) patients had a diagnosis of colorectal, 23 208 (20.6%) oesophageal, 14 788 (13.1%) gastric and 1338 (1.2%) small bowel cancer. Individuals with pre-existing CVD had a 27% reduced rate of receiving fluoropyrimidine chemotherapy (HR, 0.73; 95% CI 0.70 to 0.75) on multivariable analysis. Significantly reduced rates of fluoropyrimidine administration were found across all subtypes of pre-existing CVD.Conclusions GI cancer patients with all types of pre-existing CVD are less likely to receive fluoropyrimidine chemotherapy despite eligibility. This suggests widespread caution regarding administration of fluoropyrimidines across this population; further research is needed to assess whether such conservatism is justified.

Well-aligned food policies are needed at both national and international level to guide food system transformation towards sustainability. Rigorous indicator frameworks are essential in order to facilitate discussion of priorities, enable comparisons, assessment and progress monitoring, and ensure accountability. In this study, we develop a national framework for a sustainable food system, using Sweden as a case. Our framework, the Food System Sustainability House, advances the literature on sustainable food system frameworks in three distinct ways. Firstly, it is tailored to a specific national context (Sweden in our case); secondly, it distinguishes between impacts of domestic production arising within territorial boundaries and impacts related to Swedish consumption independent of country of origin; and thirdly, to facilitate policy priorities, it suggests how different dimensions of sustainability are interlinked at a conceptual level. From a scientific perspective, the Food System Sustainability House postulates the interlinkages between the societal objectives of the food system, the environmental foundations on which production takes place, and the economic system and governance which in the framework are suggested to function as enablers for an overall sustainable system. From a policy perspective, the framework provides a much-needed basis for assessing food system sustainability by suggesting indicators within a comprehensive set of sustainability themes at national level for monitoring distinct perspectives. It also provides the necessary basis for a discussion on how sustainability dimensions are interlinked.

Background: No previous study has evaluated patients attitudes towards inclusion in an ongoing cardiac arrest clinical trial. The aim of this study was to assess patientś willingness and motives to participate in the ongoing randomized controlled drug trial “Vasopressin and Steroids in addition to Adrenaline in cardiac arrest” (VAST-A trial) in case of an in-hospital cardiac arrest (IHCA). Objectives: Hospitalized patients, men ≥ 18 and women ≥ 50 years, were asked for informed consent for inclusion in the VAST-A trial in case of an IHCA, the reason for approving or declining inclusion in the trial and baseline characteristics. Methods: Patients admitted to hospital were asked to give informed consent of inclusion in VAST-A in case of an IHCA during their hospital stay. Patients were also asked why they approved or declined inclusion as well as baseline characteristics questions. Results: 1,064 patients were asked about willingness to participate in the VAST-A trial, of these 902 (84.8%) patients approved inclusion. A subgroup of 411 patients were, except willingness, also asked about motives to participate or not and basic characteristics. The main reason for approving inclusion was to contribute to research (n = 328, 83.9%). The main reason for declining inclusion was concerns regarding testing the drug treatment (n = 6, 30%). Conclusion: Among hospitalized patients the vast majority gave informed consent to inclusion in an ongoing randomized cardiac arrest drug trial. The main reason for approving inclusion was to contribute to research.

Abstract Background Children are spending less leisure time with their friends in person and an increasing amount of time with digital screens. These changes may negatively affect children’s physical and mental health. The Screen-Free Time with Friends Feasibility Trial will test the feasibility, including acceptability and compliance, of an intervention designed to reduce screen media usage and encourage physical interaction with friends during leisure time in 9–11-year-old children. Methods A non-randomized single-group feasibility trial will be conducted from March to October 2023 including approximately 75 children (aged 9–11 years) and 75 parents (at least 1 per child) from 3 different schools recruited from 3 different municipalities in Denmark. The Screen-Free Time with Friends intervention is a multicomponent intervention targeting families, afterschool clubs, and local communities. It has been developed using a systematic process guided by the Medical Research Council UK’s framework for developing and evaluating complex interventions. With a systems perspective in mind, the intervention and implementation approach has been designed to facilitate adaptation to the specific needs of diverse local communities while maintaining the core components of the intervention. Feasibility and acceptability of the intervention will be assessed during the intervention using process evaluation inspired by the RE-AIM framework including questionnaires and interviews with the municipality project managers, research team members, local ambassadors and stakeholders, parents and school, and afterschool club personnel. In addition, participation, recruitment, retention rate, and compliance to the outcome measurements will be investigated and presented. Discussion The trial will investigate the feasibility and acceptability of the Screen-Free Time with Friends intervention, the recruitment strategy, and the planned outcome measurements. This feasibility study will investigate necessary refinements before the implementation of the intervention program in a larger cluster randomized controlled trial to evaluate its impact. Trial registration. ClinicalTrials.gov, ID: NCT05480085. Registered 29 July 2022. https://clinicaltrials.gov/ct2/show/NCT05480085?cond=Screen+free+time+with+friends&draw=2&rank=1

Abstract Purpose One major risk factor for breast cancer is high mammographic density. It has been estimated that dense breast tissue contributes to ~ 30% of all breast cancer. Prevention targeting dense breast tissue has the potential to improve breast cancer mortality and morbidity. Anti-estrogens, which may be associated with severe side-effects, can be used for prevention of breast cancer in women with high risk of the disease per se. However, no preventive therapy targeting dense breasts is currently available. Inflammation is a hallmark of cancer. Although the biological mechanisms involved in the increased risk of cancer in dense breasts is not yet fully understood, high mammographic density has been associated with increased inflammation. We investigated whether low-dose acetylsalicylic acid (ASA) affects local breast tissue inflammation and/or structural and dynamic changes in dense breasts. Methods Postmenopausal women with mammographic dense breasts on their regular mammography screen were identified. A total of 53 women were randomized to receive ASA 160 mg/day or no treatment for 6 months. Magnetic resonance imaging (MRI) was performed before and after 6 months for a sophisticated and continuous measure breast density by calculating lean tissue fraction (LTF). Additionally, dynamic quantifications including tissue perfusion were performed. Microdialysis for sampling of proteins in vivo from breasts and abdominal subcutaneous fat, as a measure of systemic effects, before and after 6 months were performed. A panel of 92 inflammatory proteins were quantified in the microdialysates using proximity extension assay. Results After correction for false discovery rate, 20 of the 92 inflammatory proteins were significantly decreased in breast tissue after ASA treatment, whereas no systemic effects were detected. In the no-treatment group, protein levels were unaffected. Breast density, measured by LTF on MRI, were unaffected in both groups. ASA significantly decreased the perfusion rate. The perfusion rate correlated positively with local breast tissue concentration of VEGF. Conclusions ASA may shape the local breast tissue microenvironment into an anti-tumorigenic state. Trials investigating the effects of low-dose ASA and risk of primary breast cancer among postmenopausal women with maintained high mammographic density are warranted. Trial registration EudraCT: 2017-000317-22.

ABSTRACT: The objective of the present study was to investigate the effect of individual and combined use of dietary fat, nitrate, and 3-nitrooxypropanol (3-NOP) on dairy cows' enteric methane (CH4) emission and production performance. Twenty-four primiparous and 24 multiparous Danish Holstein cows (111 ± 44.6 d in milk; mean ± standard deviation) were included in an incomplete 8 × 8 Latin square design with six 21-d periods. Dietary treatments were organized in a 2 × 2 × 2 factorial arrangement aiming for 2 levels of FAT (30 or 63 g of crude fat/kg of dry matter [DM]; LF or HF, respectively), 2 levels of NITRATE (0 or 10 g of nitrate/kg of DM; UREA or NIT, respectively), and 2 levels of 3-NOP (0 or 80 mg/kg DM; BLANK or NOP, respectively). Treatments were included in ad libitum-fed partial mixed rations in bins that automatically measured feed intake and eating behavior. Additional concentrate was offered as bait in GreenFeed units used for measurement of gas emission. For total DM intake (DMI), a FAT × NITRATE interaction showed that DMI, across parities and levels of 3-NOP, was unaffected by separate fat supplementation, but reduced by nitrate with 4.6% and synergistically decreased (significant 2-way interaction) with 13.0% when fat and nitrate were combined. Additionally, 3-NOP decreased DMI by 13.4% and the combination of 3-NOP with fat and nitrate decreased DMI in an additive way (no significant 3-way interaction). The decreasing effects on DMI were more pronounced in multiparous cows than in primiparous cows. For treatments with largest reductions in DMI, eating behavior was altered toward more frequent, but smaller meals, a slower eating rate and increased attempts to visit unassigned feed bins. Energy-corrected milk (ECM) yield increased by 6.3% with fat supplementation, whereas ECM yield did not differ among diets including nitrate (FAT × NITRATE interaction). Cows supplemented with 3-NOP had 9.0% lower ECM yield than cows fed no 3-NOP. Based on three 2-way interactions including FAT, NITRATE, and 3-NOP, the combined use of the additives resulted in antagonistic effects on CH4 reduction. A 6% to 7% reduction in CH4 yield (CH4/kg of DMI) could be ascribed to the effect of fat, a 12% to 13% reduction could be ascribed to the effect of nitrate and an 18% to 23% reduction could be ascribed to the effect of 3-NOP. Hence, no combinations of additives resulted in CH4 yield-reductions that were greater than what was obtained by separate supplementation of the most potent additive within the combination. The CH4 yield reduction potential of additives was similar between parities. Increased apparent total-tract digestibility of organic matter (OM) in cows fed combinations including nitrate or 3-NOP was a result of a NITRATE × 3-NOP interaction. Apparent total-tract digestibility of OM was also increased by fat supplementation. These increases reflected observed decreases in DMI. In conclusion, combined use of fat, nitrate, and 3-NOP in all combinations did not result in CH4 reductions that were greater than separate supplementation of the most potent additive within the combination (3-NOP > nitrate > fat). Additionally, separate supplementation of some additives and combined use of all additives reduced DMI.

Abstract Background Liver cirrhosis, the advanced stage of many chronic liver diseases, is associated with escalated risks of liver-related complications like decompensation and hepatocellular carcinoma (HCC). Morbidity and mortality in cirrhosis patients are linked to portal hypertension, sarcopenia, and hepatocellular carcinoma. Although conventional cirrhosis management centered on treating complications, contemporary approaches prioritize preemptive measures. This study aims to formulate novel blood- and imaging-centric methodologies for monitoring liver cirrhosis patients. Methods In this prospective study, 150 liver cirrhosis patients will be enrolled from three Swedish liver clinics. Their conditions will be assessed through extensive blood-based markers and magnetic resonance imaging (MRI). The MRI protocol encompasses body composition profile with Muscle Assement Score, portal flow assessment, magnet resonance elastography, and a abbreviated MRI for HCC screening. Evaluation of lifestyle, muscular strength, physical performance, body composition, and quality of life will be conducted. Additionally, DNA, serum, and plasma biobanking will facilitate future investigations. Discussion The anticipated outcomes involve the identification and validation of non-invasive blood- and imaging-oriented biomarkers, enhancing the care paradigm for liver cirrhosis patients. Notably, the temporal evolution of these biomarkers will be crucial for understanding dynamic changes. Trial registration Clinicaltrials.gov, registration identifier NCT05502198. Registered on 16 August 2022. Link: https://classic.clinicaltrials.gov/ct2/show/NCT05502198 .

This paper examines the work of Immanuel Kant in the light of a new theory on the nature of truth, knowledge and falsehood (the Inversion Theory of Truth). Kant’s idea that knowledge could be absolutely certain, and that its truth must correspond with reality, is discredited by a dissection of the Correspondence Theory of Truth. This examination of the nature of truth, as well as knowledge and falsehood, is conducted with reference to Sir Karl Popper’s writings on regulative ideas, the criterion of demarcation and the principle of falsifiability. It is argued that if truth is to be regarded as certain, it should be used to describe objects and events in the objective (noumenal) state, and that subjective knowledge must contain (and is improved by) falsehood. Perceptions and knowledge are obtained by the biological and evolutionary process of Active Subjectivism. Ideas we have knowledge of can be metaphysical or scientific, according to Popper’s Criterion of Demarcation. Kant’s “Copernican revolution” claim that our intellect imposes absolutely true laws on nature could not allow for the possibility that ideas might be constructed from fallible perceptions, and hence that all knowledge is uncertain. Instead, he developed a Critique of Practical Reason in which religion, though not provable through logical reasoning, could be proved by our innate moral sense, giving us a Categorical Imperative that could lead to perverse results. By rejecting the absolute certainty of a priori knowledge, and admitting a degree of essential falsehood, we arrive at a more reasonable grounding for moral behavior.

Abstract Agriculturally important crop plants emit a multitude of volatile organic compounds (VOCs), which are excellent indicators of their health status and their interactions with pathogens and pests. In this study, we have developed a novel cellular olfactory panel for detecting fungal pathogen-related VOCs we had identified in the field, as well as during controlled inoculations of several crop plants. The olfactory panel consists of seven stable HEK293 cell lines each expressing a functional Drosophila olfactory receptor as a biosensing element along with GCaMP6, a fluorescent calcium indicator protein. An automated 384-well microplate reader was used to characterize the olfactory receptor cell lines for their sensitivity to reference VOCs. Subsequently, we profiled a set of 66 VOCs on all cell lines, covering a concentration range from 1 to 100 μM. Results showed that 49 VOCs (74.2%) elicited a response in at least one olfactory receptor cell line. Some VOCs activated the cell lines even at nanomolar (ppb) concentrations. The interaction profiles obtained here will support the development of biosensors for agricultural applications. Additionally, the olfactory receptor proteins can be purified from these cell lines with sufficient yields for further processing, such as structure determination or integration with sensor devices.

Abstract Co-assembly of the multilayered coat protein complex II (COPII) with the Sar1 GTPase at subdomains of the endoplasmic reticulum (ER) enables secretory cargoes to be concentrated efficiently within nascent transport intermediates, which subsequently deliver their contents to ER-Golgi intermediate compartments. Here, we define the spatiotemporal accumulation of native COPII subunits and secretory cargoes at ER subdomains under differing nutrient availability conditions using a combination of CRISPR/Cas9-mediated genome editing and live cell imaging. Our findings demonstrate that the rate of inner COPII coat recruitment serves as a determinant for the pace of cargo export, irrespective of COPII subunit expression levels. Moreover, increasing inner COPII coat recruitment kinetics is sufficient to rescue cargo trafficking deficits caused by acute nutrient limitation. Our findings are consistent with a model in which the rate of inner COPII coat addition acts as an important control point to regulate cargo export from the ER.

Abstract Background The increased prevalence of insulin resistance is one of the major health risks in society today. Insulin resistance involves both short-term dynamics, such as altered meal responses, and long-term dynamics, such as the development of type 2 diabetes. Insulin resistance also occurs on different physiological levels, ranging from disease phenotypes to organ-organ communication and intracellular signaling. To better understand the progression of insulin resistance, an analysis method is needed that can combine different timescales and physiological levels. One such method is digital twins, consisting of combined mechanistic mathematical models. We have previously developed a model for short-term glucose homeostasis and intracellular insulin signaling, and there exist long-term weight regulation models. Herein, we combine these models into a first interconnected digital twin for the progression of insulin resistance in humans. Methods The model is based on ordinary differential equations representing biochemical and physiological processes, in which unknown parameters were fitted to data using a MATLAB toolbox. Results The interconnected twin correctly predicts independent data from a weight increase study, both for weight-changes, fasting plasma insulin and glucose levels, and intracellular insulin signaling. Similarly, the model can predict independent weight-change data in a weight loss study with the weight loss drug topiramate. The model can also predict non-measured variables. Conclusions The model presented herein constitutes the basis for a new digital twin technology, which in the future could be used to aid medical pedagogy and increase motivation and compliance and thus aid in the prevention and treatment of insulin resistance.

Energy prices are usually determined by the marginal costs obtained by solving economic dispatch problems without considering commitment costs. Hence, generating units are compensated through uplift payments. However, uplift payments may undermine market transparency as they are not publicly disclosed. Alternatively, energy prices can be obtained from the unit commitment problem which considers commitment costs. But, due to non-convexity, prices may not monotonically increase with demand. To resolve this issue, convex hull pricing has been introduced. It is defined as the slope of the convex envelope of the total cost function over the convex hull of a unit commitment (UC) problem. Although several approaches have been developed, a relevant survey has not been found to aid the understanding of convex hull pricing from the current limited literature. This paper provides a systematic survey of convex hull pricing. It reviews, compares, and links various existing approaches, focusing on the modeling and computation of convex hull prices. Furthermore, this paper explores potential areas of improvement and future challenges due to the ongoing efforts for power system decarbonization.

Single molecular studies of photosensitized interfacial electron transfer (ET) processes in Coumarin 343 (C343)-TiO(sub 2) nanoparticles (NP) and cresyl violet (CV (super +))-TiO(sub 2) NP systems are reported. The fluorescence fluctuation dynamics were found to be inhomogeneous from molecule to molecule and from time to time, showing significant static and dynamic disorders in the interfacial ET reaction dynamics.

Across society, organisations find themselves challenged to address the climate and nature emergencies. Universities have a complex set of responsibilities given that they are preparing students for an uncertain future in which the very survival of life is in the balance. A characteristic of this complex challenge is the need to develop the necessary ecological and vertical literacy required to tackle the many aspects of fragmentation we are subject to. The 30x30 biodiversity challenge provides universities with an opportunity to address one particular form of fragmentation, that affecting habitats. The case study presented here explores how a Hedgehog Friendly Campus (HFC) initiative allowed awareness of hedgehog habitat needs and in particular the health of hedgerows to feed into campus environmental management. A surprising finding is that addressing the fragmentation of hedgerows highlights organisational fragmentation, with little communication between landscape managers, research and teaching. A collaborative systems approach to the biodiversity challenge is thus needed and realising this will challenge universities to build their capacity to embrace research and learning for sustainability through living lab projects. This requires a recognition of the responsibility universities have to enable action learning across disciplines in ways that will connect staff and students to, and bring them into relation with, the biodiversity crisis at a local level. The HFC initiative provides a rich opportunity for communities of inquiry and practice to be nurtured and for this process to inform the evolution of our understanding of habitat restoration on university campuses as a corporate responsibility.

One of the general concepts underlying Waldorf education is that teaching is an art. Although this idea is certainly not unique to Waldorf education, what is unique is the way it has been integrated into Waldorf teacher education. While Waldorf teacher education programs are diverse, both in national and international contexts, one of the central elements which they share is the prominent role which different forms of artistic practice play throughout the course of pre-service and in-service programs. This article explores the reasons and aims behind the inclusion of subjects such as music, sculpture, and speech in Waldorf teacher education, at first within the larger context of viewing different perspectives and justifications for the inclusion of the arts in teacher education outside of Waldorf pedagogy. In light of the educational challenges posed by widespread sensory deficits among children and adolescents, viewed here as being connected to the extensive role/s which different forms of digital media play in their lives, the case is made for the potentials of the arts as a way to address those deficits. In examining both the arguments for arts-based courses in teacher education and the pedagogical challenges of our times I propose a concept for the inclusion of the arts in teacher education connected to the concept of aesthesis, from the Ancient Greek concept of aisthésis, understood here as the primary perceptual-sensory basis of aesthetic experience. The integration of scientific courses with arts-based practice in teacher education is seen as providing a fruitful basis for teachers to be able to take on these educational challenges.

Critical care cardiology (CCC) in the modern era is shaped by a multitude of innovative treatment options and an increasingly complex, ageing patient population. Generating high-quality evidence for novel interventions and devices in an intensive care setting is exceptionally challenging. As a result, formulating the best possible therapeutic approach continues to rely predominantly on expert opinion and local standard operating procedures. Fostering the full potential of CCC and the maturation of the next generation of decision-makers in this field calls for an updated training concept, that encompasses the extensive knowledge and skills required to care for critically ill cardiac patients while remaining adaptable to the trainee’s individual career planning and existing educational programs. In the present manuscript, we suggest a standardized training phase in preparation of the first ICU rotation, propose a modular CCC core curriculum, and outline how training components could be conceptualized within three sub-specialization tracks for aspiring cardiac intensivists.

Background: In neurologic prognostication of comatose survivors from cardiac arrest, two independent predictors of poor outcome are the loss of the Pupillary light reflex (PLR) and the loss of the N20 response from Somatosensory Evoked potentials (SSEP). The PLR can be quantitatively assessed by pupillometry. Both tests depend on the midbrain, in which a dysfunction reflects a severe hypoxic injury. We reasoned that a certain level of defective PLR would be predictive of a bilaterally absent SSEP N20 response. Method: Neurological Pupil index (NPi) from the pupillometry and the SSEP N20 response were registered >48 h after cardiac arrest in comatose survivors. Clinical data were retrospectively analyzed. A receiver operating characteristic curve was used to evaluate the capacity of NPi to predict bilaterally absent SSEP N20 response. An NPi threshold value resulting in 48 hours after cardiac arrest predicted bilateral loss of the SSEP N20 response with a FPR

In plants, an increasing number of traits and new characteristics are being developed using gene editing. Simple traits represented by a single gene can be managed through backcross breeding, but this is typically not the case for more complex traits which may result from the function of a large number of genes. Here, we demonstrate two case studies of improving oleic oil content and developing pod shatter reduction in Brassica napus by using gene editing tools on an industrial scale. There are four BnaFAD2 genes involved in oleic oil content and eight BnaSHP genes involved in pod shatter tolerance. In order to develop these two traits, we delivered nuclease ribonucleoproteins with Gene Repair OligoNucleotides (GRONs) into protoplasts, with subsequent regeneration into plants on an industrial scale, which encompassed robust tissue culture protocols, efficient gene editing, robotics sampling, and molecular screening, vigorous plant regeneration, growth, and phenotyping. We can produce precise loss-of-function-edited plants with two improved agronomically important complex traits, high oleic oil or pod shatter reduction, in elite canola varieties within 1–3 years, depending on the trait complexity. In the edited plants carrying loss of function of four BnaFAD2 genes, the seed fatty acid oleic acid content reached 89% compared to 61% in the non-edited wildtype control. The plants carrying eight edited BnaSHP genes achieved 51% pod shatter reduction in multiple year field testing in the target environment compared to the wildtype control.

Abstract Identification of ventilatory constraint is a key objective of clinical exercise testing. Expiratory flow-limitation (EFL) is a well-known type of ventilatory constraint. However, EFL is difficult to measure, and commercial metabolic carts do not readily identify or quantify EFL. Deep machine learning might provide a new approach for identifying EFL. The objective of this study was to determine if a convolutional neural network (CNN) could accurately identify EFL during exercise in adults in whom baseline airway function varied from normal to mildly obstructed. 2931 spontaneous exercise flow-volume loops (eFVL) were placed within the baseline maximal expiratory flow-volume curves (MEFV) from 22 adults (15 M, 7 F; age, 32 yrs) in whom lung function varied from normal to mildly obstructed. Each eFVL was coded as EFL or non-EFL, where EFL was defined by eFVLs with expired airflow meeting or exceeding the MEFV curve. A CNN with seven hidden layers and a 2-neuron softmax output layer was used to analyze the eFVLs. Three separate analyses were conducted: (1) all subjects (n = 2931 eFVLs, [GRALL]), (2) subjects with normal spirometry (n = 1921 eFVLs [GRNORM]), (3) subjects with mild airway obstruction (n = 1010 eFVLs, [GRLOW]). The final output of the CNN was the probability of EFL or non-EFL in each eFVL, which is considered EFL if the probability exceeds 0.5 or 50%. Baseline forced expiratory volume in 1 s/forced vital capacity was 0.77 (94% predicted) in GRALL, 0.83 (100% predicted) in GRNORM, and 0.69 (83% predicted) in GRLOW. CNN model accuracy was 90.6, 90.5, and 88.0% in GRALL, GRNORM and GRLOW, respectively. Negative predictive value (NPV) was higher than positive predictive value (PPV) in GRNORM (93.5 vs. 78.2% for NPV vs. PPV). In GRLOW, PPV was slightly higher than NPV (89.5 vs. 84.5% for PPV vs. NPV). A CNN performed very well at identifying eFVLs with EFL during exercise. These findings suggest that deep machine learning could become a viable tool for identifying ventilatory constraint during clinical exercise testing.