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Abstract Trauma teams handle severely injured patients under high temporal demands and need to coordinate and achieve collaborative decision-making and task execution through communication. Specific coordination and communication behaviours are taught in simulation training to enhance team performance. An examination of the role and nature of communication could increase the understanding of educational possibilities and assess the validity of in situ simulation on behalf of communication. Our study aim was to describe the relative use of communication within information and task management, the use of coordinating behaviours, and the use of talking to the room and closed-loop communication in in-real-life trauma assessment and in the simulated domain. We video-recorded all verbal communicative events in four real-world trauma teams and four teams during simulation training. The analysis showed that although the teamwork was task-oriented, information management dominated task management at 64% of all the utterances in-real-life and 68% during simulation. In-real-life, information management was dominated by the codes “request information” (24%) and “confirmation” (21%), whereas “task distribution” (43%) was most frequently used for task management. The only difference between domains was that “give information after request” represented a smaller proportion of the utterances in-real-life compared to simulation (p ≤ 0.001). Talking to the room was primarily used by the teams in both domains to provide information without request and to delegate tasks. Closed-loop communication was used at a low frequency, 3.6% in-real-life, but was significantly higher, 7.7%, in simulation training. We suspect that this outcome reflects the Hawthorne effect. In the simulations, greater information delivery was provided in response to questions, probably accounting for instructor information. Our results may be valuable for research on trauma team behaviour in a simulated environment to draw conclusions about similar activities in-real-life.

Abstract Background Pseudomonas aeruginosa (PA) bloodstream infection (BSI) is a common healthcare-associated complication linked to antimicrobial resistance and high mortality. Ongoing clinical trials are exploring novel anti-virulence agents, yet studies on how bacterial virulence affects PA infection outcomes is conflicting and data from real-world clinical populations is limited. Methods We studied a multicentre cohort of 773 adult patients with PA BSI consecutively collected during 7-years from sites in Europe and Australia. Comprehensive clinical data and whole-genome sequencing of all bacterial strains were obtained. Results Based on the virulence genotype, we identify several virulence clusters, each showing varying proportions of multidrug-resistant phenotypes. Genes tied to biofilm synthesis and epidemic clones ST175 and ST235 are associated with mortality, while the type III secretion system is associated with septic shock. Adding genomic biomarkers to machine learning models based on clinical data indicates improved prediction of severe outcomes in PA BSI patients. Conclusions These findings suggest that virulence markers provide prognostic information with potential applications in guiding adjuvant sepsis treatments.

Sexuella trakasserier har under senare år uppmärksammats som ett stort problem, inte bara i arbetslivet utan även bland skolungdomar. Syftet med den här studien är att bidra med kunskap om fenomenet dickpics genom att undersöka ungas tal om dickpics som skickas till någon som inte har samtyckt till det. Det empiriska materialet utgörs av parintervjuer med elever i årskurs 5, 6, och 8 i en grundskola samt årskurs 1 och 3 i en gymnasieskola. Sammanlagt intervjuades 28 tjejer och 22 killar. När ungdomarna diskuterar ovälkomna dickpics navigerar de i ett könat sammanhang där de könsnormer som de måste förhålla sig till ger mycket olika villkor för killar och tjejer. I många av de ungas resonemang återskapas en hierarkisk heteronormativ genusordning. För tjejer beskrivs att det kan vara förenat med stor skam att få bilder på killars genitalier skickade till sig. Killar beskriver skam om en dickpic av misstag skulle sändas till en annan kille. Killar beskriver även skam i relation till om bilder skickade till tjejer skulle skickas vidare av sina mottagare och därmed avslöja avsändaren. Ungdomarnas resonemang tyder på att killars skickande av dickpics till tjejer som inte har samtyckt till det är en praktik som har blivit normaliserad.

Abstract Background Assessment of Rehabilitation Needs Checklist (ARNC), has been developed to assess rehabilitation need in cancer patients and is recommended by the Confederation of Regional Cancer Centres in Sweden, known as Hälsoskattningen. The aim of the study was to test the reliability and validity of the ARNC, mainly by comparing it with the Distress thermometer and EORTC QLQ-C30. Methodology A sample of 993 persons identified in the Swedish cancer register. The study participants were diagnosed with cancer in 2021 in the Mid Sweden region. The psychometric methods tested reliability and validity including factor analysis. Results The response rate was 38%. The test-retest analysis showed that ICC was 0.80 or higher for 12 of the ARNC items. A strong or modarete correlation between ARNC and the other instruments was found in all functional scales and for most items. CFA of the 13-item two-factor model showed a RMSEA value of 0.04, CFI and TLI values of 0.97 and 0.96, and a SRMR value of 0.05, indicating a satisfactory model fit. Conclusion The evaluation of the ARNC suggests that it is an acceptable and reliable screening instrument for detecting symptoms and signs indicating a possible need of rehabilitation. The medium to strong correlations between ARNC items and the EORTC QLQ- C30 items and scales suggest that ARNC could be an alternative also for research purposes when a shorter and less comprehensive instrument is needed. The simple design could be an advantage as it lowers the burden on cancer patients.

Objectives: Despite clinical relevance, commercially available molecular tools for accurate β-lactamase detection are limited. In this study, we evaluated the performance of the ARM-DⓇ Kit, β-Lactamase, a commercially available multiplex PCR assay designed to detect nine β-lactamase genes, including the five major plasmid-mediated carbapenemases, ESBL and AmpC genes circulating in the United States. Methods: A diverse collection of 113 Gram-negative isolates, including 42 with multiple β-lactamases genes, was selected from the U.S. Centers for Disease Control and Prevention (CDC) & Food and Drug Administration (FDA) Antimicrobial Resistance Isolate Bank, to represent the most frequently detected bacterial species carrying plasmid-mediated β-lactam resistance genes. Results: Results were compared with whole genome sequence data. Of 164 β-lactamase gene targets with 49 unique variants, all were detected correctly without any cross-reactivity. The sensitivity and specificity were 100% (164/164) and 99.9% (852/853), respectively. Conclusion: The ARM-DⓇ Kit, β-Lactamase detected a wide range of β-lactamase genotypes at a low upfront cost. The Streck assay represents a suitable, comprehensive tool for the detection of key β-lactamase resistance genes of public health concern in the United States.

Abstract Tuberculosis (TB) poses a significant global health threat, with high mortality rates if left untreated. Current sputum-based TB treatment monitoring methods face numerous challenges, particularly in relation to sample collection and analysis. This pilot study explores the potential of TB status assessment using DNA methylation (DNAm) signatures, which are gaining recognition as diagnostic and predictive tools for various diseases. We collected buccal swab samples from pulmonary TB patients at the commencement of TB treatment (n = 10), and at one, two, and six-month follow-up intervals. We also collected samples from healthy controls (n = 10) and individuals exposed to TB (n = 10). DNAm patterns were mapped using the Illumina Infinium Methylation EPIC 850 K platform. A DNAm profile distinct from controls was discovered in the oral mucosa of TB patients at the start of treatment, and this profile changed throughout the course of TB treatment. These findings were corroborated in a separate validation cohort of TB patients (n = 41), monitored at two and six months into their TB treatment. We developed a machine learning model to predict symptom scores using the identified DNAm TB profile. The model was trained and evaluated on the pilot, validation, and two additional independent cohorts, achieving an R2 of 0.80, Pearson correlation of 0.90, and mean absolute error of 0.13. While validation is needed in larger cohorts, the result opens the possibility of employing DNAm-based diagnostic and prognostic tools for TB in future clinical practice.

Abstract To investigate if salivary O-linked glycans are altered in primary Sjögren’s syndrome (pSS), and thus contributing to explain symptoms of oral dryness, and an impaired oral mucosal barrier function leading to changes in microbial metabolism and colonization by both pathogenic and commensal microorganisms and increased prevalence of oral diseases. O-linked oligosaccharides from stimulated whole saliva (SWS) samples from 24 patients with pSS, 38 patients with non-pSS sicca, and 23 healthy controls were analyzed using liquid chromatography mass spectrometer (LC-MS). Non-fractionated reduced and alkylated saliva was dot-blotted to PVDF-membrane and O-linked oligosaccharides were released using reductive beta-elimination. The 50 most abundant glycans were identified and their intensity compared for each sample, reflecting the relative abundance of individual monosaccharide residues. Comparison of the compositions of O-glycans in SWS samples revealed higher relative levels of sialic acid (NeuAc) and lower levels of neutral amino-monosaccharides (HexNAc) in pSS and non-pSS sicca patients than in the healthy controls. MS2 fragmentation analysis of salivary O-glycans suggests that altered sulfation, fucosylation, sialylation and distribution of core types may all contribute to the observed alteration, directly or indirectly. Additionally, the short disaccharide sialyl-Tn was most abundant in the saliva samples from patients with pSS. Our findings indicate that the salivary mucin-type O-glycan profile is altered in pSS, reflecting a dysfunction of the post-translational modification of salivary mucins leading to rheological changes of saliva, oral dryness symptoms, and impaired oral mucosal barrier function. The pathophysiological significance of the aberrant O-glycosylation needs further elucidation.

Abstract Circulating tumor DNA (ctDNA) has shown potential as a non-invasive tumor biomarker in neuroblastoma. Previous studies used generic assays for detection of selected predefined oncogenic variants as markers of ctDNA, which limits the sensitivity and excludes a subset of patients from analysis. Here we assessed patient-specific ctDNA analysis for treatment evaluation and detection of relapse in neuroblastoma. We generated personalized sequencing panels targeting 10 tumor-specific single nucleotide variants (SNVs) for each patient and performed ctDNA analysis of 136 plasma samples collected longitudinally in 13 children with neuroblastoma. ctDNA was detected using ultra-deep next generation sequencing with unique molecular identifiers to eliminate polymerase-induced errors. We found that the levels of ctDNA at diagnosis correlated with risk group and decreased gradually during effective treatment. All samples collected during follow-up in patients without disease relapse were ctDNA-negative. All four relapses were associated with elevated ctDNA levels, and a majority of the analyzed SNVs were detected at time of relapse. In one case, ctDNA became positive 78 days before the relapse was diagnosed with routine assessment and increased by over a thousandfold before the start of additional treatment. Overall, ctDNA was more uniformly elevated at diagnosis, showed less putative false positive results, and was more sensitive for detection of relapse compared to five serum or urine tumor markers used in clinical routine. In conclusion, personalized ctDNA analysis is suitable for clinical monitoring of tumor burden and may be used in all neuroblastoma patients regardless of risk group or tumor genetics.

Abstract Background Tracking the emergence, introduction and spread of SARS-CoV-2 variants of concern are essential for informing public health strategies. In 2021, Cambodia faced two major epidemic waves of SARS-CoV-2 triggered by the successive rise of the Alpha and Delta variants. Methods Phylodynamic analysis of 1,163 complete SARS-CoV-2 genomes from Cambodia, along with global sequences, were conducted between February and September 2021 to infer viral introductions, molecular epidemiology and population dynamics. The relationship between epidemic trends and control strategies were evaluated. Bayesian phylogeographic reconstruction was employed to estimate and contrast the spatiotemporal dynamics of the Alpha and Delta variants over time. Results Here we reveal that the Alpha variant displays rapid lineage diversification, accompanied by the acquisition of a spike E484K mutation that coincides with the national implementation of mass COVID-19 vaccination. Despite nationwide control strategies and increased vaccination coverage, the Alpha variant was quickly displaced by Delta variants that exhibits a higher effective reproductive number. Phylogeographic inference indicates that the Alpha variant was introduced through south-central region of Cambodia, with strong diffusion rates from the capital of Phnom Penh to other provinces, while the Delta variant likely entered the country via the northern border provinces. Conclusions Continual genomic surveillance and sequencing efforts, in combination with public health strategies, play a vital role in effectively tracking and responding to the emergence, evolution and dissemination of future emerging variants.

Abstract Background The deteriorating psychosocial work environment among healthcare workers in Sweden, influenced by demanding working conditions and resource constraints, affects individual well-being and patient care quality. Healthcare workers, including physicians, registered nurses, and nursing assistants, often work interdependently and share workplaces, yet are three completely different professions. Nonetheless, comprehensive studies comparing their psychosocial work environments are scarce; often focusing on healthcare workers either separately or as a homogenous group, but rarely comparative. Aim Utilising the job demands–resources model, this study investigated variations in the psychosocial work environment among Swedish healthcare workers. We wanted to identify how the antecedents of individual well-being, in the form of demands and resources, differed between healthcare workers. Method Data from the 2022 Longitudinal Occupational Health Survey for Health Care in Sweden were analysed; the participants included 7589 physicians, registered nurses, and nursing assistants. The analysis involved descriptive statistics, including measures of means and analysis of covariance (ANCOVA), employing the Bonferroni correction for multiple post hoc comparisons. The ANCOVA was also stratified by working factors, including years of work experience and employment within the private/public sector. Results The study revealed significant variations in how healthcare workers perceive their psychosocial work environment. Physicians faced the highest level of Quantitative Demands (mean (x̄) 3.15; 95% CI 3.11–3.19), while registered nurses reported the most Emotional Demands (x̄ 3.37; 95% CI 3.32–3.41). Nursing assistants had the highest grand means for the imbalance between Efforts and Rewards (Effort Reward Imbalance) (x̄ 1.49; 95% CI 1.49–1.49) and an imbalance between Work and Private Life (Work–Life Interference) (x̄ 3.20, 95% CI 3.15–3.25), along with limited resources. The stratified analysis showed that years of experience and the sector affected healthcare workers' perceptions of their psychosocial working environment. For example, registered nurses working in the private sector reported better working conditions than registered nurses working in the public sector. The situation for nursing assistants was reversed. Conclusion Psychosocial work environments are experienced differently between and within healthcare professions in Sweden. This study provides crucial insights for improving workplace conditions and consequently enhancing healthcare professionals’ well-being and quality of patient care.

Abstract Increasing biological nitrogen (N) fixation (BNF) in maize production could reduce the environmental impacts of N fertilizer use, but reactive N in the rhizosphere of maize limits the BNF process. Using non-transgenic methods, we developed gene-edited strains of Klebsiella variicola (Kv137-2253) and Kosakonia sacchari (Ks6-5687) bacteria optimized for root-associated BNF and ammonium excretion in N-rich conditions. The aim of this research was to elucidate the mechanism of action of these strains. We present evidence from in vitro, in planta and field experiments that confirms that our genetic remodeling strategy derepresses BNF activity in N-rich systems and increases ammonium excretion by orders of magnitude above the respective wildtype strains. BNF is demonstrated in controlled environments by the transfer of labeled 15N2 gas from the rhizosphere to the chlorophyll of inoculated maize plants. This was corroborated in several 15N isotope tracer field experiments where inoculation with the formulated, commercial-grade product derived from the gene-edited strains (PIVOT BIO PROVEN® 40) provided on average 21 kg N ha-1 to the plant by the VT-R1 growth stages. Data from small-plot and on-farm trials suggest that this technology can improve crop N status pre-flowering and has potential to mitigate the risk of yield loss associated with a reduction in synthetic N fertilizer inputs.

Societal Impact Statement Can modern breeding technologies, such as genome editing, contribute to reduced pesticide usage? This question has been accentuated by a recent legal proposal to exempt genome‐edited plants from the strict regulations applied to classical genetically modified (GM) crops within the European Union (EU). Using official statistics on crop cultivation and pesticide usage for two example crops commonly grown in Sweden, we calculate that cereal farmers collectively could save up to 70 million € in pesticide usage for wheat alone and that a late blight‐resistant potato could reduce pesticide usage by over 80% provided that the EU legislation is amended. Summary The European Commission has set goals to reduce the use of chemical pesticides, and one way to meet these goals in the agricultural sector is to breed disease‐resistant crops. Here, we ask whether modern breeding technologies, for example, genome editing using site‐directed nucleases, can contribute to these goals. This question has been accentuated by recent legal proposals in the European Union (EU) and several other jurisdictions worldwide to exempt genome‐edited plants from the strict regulations often applied to classical genetically modified (GM) crops. Using official statistics on crop cultivation and pesticide usage for two example crops commonly grown in Sweden (wheat and potato), we show that cereal farmers collectively could potentially save up to 70 million € in pesticide usage for wheat alone and that a late blight‐resistant potato could reduce pesticide usage by over 80% provided that the EU legislation is amended. Given the immense potential of genome‐edited crops, we further discuss details in the legal proposal currently being negotiated in the EU on the so‐called new genomic techniques that includes both genome editing and targeted insertions of cisgenes. Although promising, we argue that several technical limitations in the legal proposal will, if implemented, hamper the development of disease‐resistant crops and make the suggested legislation less future‐proof.

Abstract Thermal seed treatment can be used as an alternative method to prevent infection by seed-borne diseases, but exposure duration and temperature during thermal treatment are important to maintain high seed viability and emergence whilst decreasing infection rate. A method for predicting suitable treatment parameters to maintain viability and eliminate seed-borne pathogens is therefore needed. Seeds of winter wheat were subjected to thermal treatment at four levels of intensity and pre-treatments with or without imbibition. Treatment impact was measured by metabolome analysis using LC-MS and GC-MS, analysis of spermosphere bacterial and fungal metagenomes using Illumina MiSeq, and detection of presence of Fusarium spp. and Microdochium spp. using ddPCR. The results showed that moderate treatment intensity reduced signs of infection and increased seedling emergence. In imbibed samples, myo-inositol concentration and myo-inositol: glucose ratio were positively correlated with treatment intensity, whereas concentrations of glucose and citric acid were negatively correlated. No correlations were found for non-imbibed samples. Imbibition had a large significant impact on microbial community composition of the wheat spermosphere. Imbibition of wheat seeds prior to thermal treatment altered wheat spermosphere microbiota. The concentration of myo-inositol, potentially in combination with glucose, could be a candidate predictor for suitable thermal treatment intensity of wheat seeds.

Abstract Sepsis continues to be a major cause of death and illness globally, posing significant challenges for healthcare professionals. In the pursuit of more accurate and timely monitoring tools, the concept of capnodynamically derived mixed venous oxygen saturation (Capno-SvO2) has emerged as a promising method. Capno-SvO2 provides a non-invasive way to assess and track SvO2 and could serve as an additional tool alongside more invasive methods like the pulmonary artery catheter. This could potentially be of great value in the care of critically ill patients with sepsis, where alternative minimal invasive monitoring methods may vary in reliability. The aim of the current study was to compare capno-SvO2 against values obtained through pulmonary artery blood sample CO-oximetry and continuous fiberoptic SvO2 monitoring, using a well-established porcine experimental sepsis model. Anesthetized pigs were exposed to a standardized endotoxin infusion sepsis protocol, followed by a series of maneuvers typically applied in sepsis care. Simultaneous recordings were done throughout the experiment for all three monitoring methods. Bland–Altman analysis corrected for repeated measurements was used to assess the agreement of absolute values between the paired recording of CO-oximetry and Capno-SvO2 as well as between CO-oximetry and fiberoptic SvO2. The ability of Capno-SvO2 and fiberoptic SvO2 to track changes was assessed by concordance rate. A total of 10 animals and 275 paired datapoints were included in the study. The majority of the animals displayed pronounced hemodynamical instability in response to endotoxin exposure and subsequent treatment interventions. Analysis of all paired data points showed a bias between Capno-SvO2 and CO-oximetry SvO2 of + 1% with 95% limits of agreement of -14% to + 17%. The corresponding numbers for fiberoptic SvO2 and CO-oximetry SvO2 were -4% and -15% to + 8%. The concordance rate as compared to CO-oximetry, were 97% and 93% for Capno-SvO2 and fiberoptic SvO2, respectively. In this experimental sepsis model, continuous, non-invasive Capno-SvO2 generates average absolute values comparable to the gold standard CO-oximetry albeit with relatively wide limits of agreement. Capno-SvO2 displayed a concordance rate of 97% against CO-oximetry and exhibits better trending ability compared to invasive fiberoptic SvO2.

Abstract Quantifying fair national shares of the remaining global carbon budget has proven challenging. Here, we propose an indicator—additional carbon accountability—that quantifies countries’ responsibility for mitigation and CO2 removal in addition to achieving their own targets. Considering carbon debts since 1990 and future claims based on countries’ emission pathways, the indicator uses an equal cumulative per capita emissions approach to allocate accountability for closing the mitigation gap among countries with a positive total excessive carbon claim. The carbon budget is exceeded by 576 Gigatonnes of fossil CO2 when limiting warming below 1.5 °C (50% probability). Additional carbon accountability is highest for the United States and China, and highest per capita for the United Arab Emirates and Russia. Assumptions on carbon debts strongly impact the results for most countries. The ability to pay for this accountability is challenging for Iran, Kazakhstan and several BRICS+ members, in contrast to the G7 members.

Abstract Access to defined glycans and glycoconjugates is pivotal for discovery, dissection, and harnessing of a range of biological functions orchestrated by cellular glycosylation processes and the glycome. We previously employed genetic glycoengineering by nuclease-based gene editing to develop sustainable production of designer glycoprotein therapeutics and cell-based glycan arrays that display glycans in their natural context at the cell surface. However, access to human glycans in formats and quantities that allow structural studies of molecular interactions and use of glycans in biomedical applications currently rely on chemical and chemoenzymatic syntheses associated with considerable labor, waste, and costs. Here, we develop a sustainable and scalable method for production of glycans in glycoengineered mammalian cells by employing secreted Glycocarriers with repeat glycosylation acceptor sequence motifs for different glycans. The Glycocarrier technology provides a flexible production platform for glycans in different formats, including oligosaccharides, glycopeptides, and multimeric glycomodules, and offers wide opportunities for use in bioassays and biomedical applications.

Abstract Background Problem-solving interventions with workplace involvement (PSI-WPI) have been shown to reduce sick leave and increase return to work in an occupational health services context. However, many employees struggle with reduced work functioning, anxiety-, and depressive symptoms up to 12 months after a sick leave episode, and it is unclear if the intervention affects outcomes other than sick leave. The aim of this study is to investigate if a PSI-WPI added to care as usual (CAU) is superior to CAU with respect to self-reported sick leave, psychological symptoms, work ability, work performance, and health after RTW when provided in primary care. Methods Employed individuals aged 18–59 years on sick leave (2 to 12 weeks) diagnosed by a physician at a primary care center with mild to moderate depression, anxiety, or adjustment disorder were enrolled in a two-armed cluster-randomised trial evaluating the effectiveness of a PSI-WPI. Multiple outcomes were recorded at baseline, six months, 12 months, and every fourth week during the study period. Outcomes were categorised into psychological symptoms, health, work ability, work performance, and self-reported sick leave. Data were analysed using MANOVA, GEE (Generalized Estimating Equations), and cox regression. Results One hundred ninety-nine individuals responded to the invitation to participate; one participant withdrew, one was excluded as the employment ended, nine did not answer the baseline survey, and three were removed from the analysis due to missing data. The analysis included 81 subjects who received the intervention and 104 subjects who received the control. Baseline characteristics were similar across both groups. No differences between the groups were found among either variables except one. There was a significant difference between the groups in self-rated health (EQ5D) in favour of the CAU group from baseline to six-month follow-up, with a mean difference of -8.44 (-14.84, -2.04). Conclusions A problem-solving intervention with workplace involvement added to CAU did not result in statistically significant reductions in outcomes. Further research is needed to understand why problem-solving interventions appear to have an effect on sick leave in an occupational health services context and not in a primary care context. Trial registration NCT3346395, registration date 2017–11-17.

Abstract Key Message Medetera (Fischer von Waldheim) flies, natural enemies of the spruce bark beetle Ips typographus (L.), were attracted to synthetic blends of compounds produced by infested spruce trees. A subset of trapped specimens revealed sixteen Medetera species. Most abundant were M. signaticornis, M. infumata, and M. prjachinae. Only blends containing beetle-produced compounds significantly attracted Medetera spp. and I. typographus. Context Fly species of the genus Medetera (Fischer von Waldheim) (Diptera: Dolichopodidae) represent one of the most important groups of natural enemies of the Eurasian bark beetle Ips typographus (L.), which infests Norway spruce Picea abies (L.) Karst. In a previous study, we showed that adult Medetera flies exploit semiochemicals to find beetle-infested trees however, the exact nature of those attractive compounds has not yet been determined. Aims The aim of this follow-up study was to investigate the behavioral responses of Medetera spp. and I. typographus, to different combinations of semiochemicals. Methods In this study, 22 volatile compounds identified from I. typographus-infested Norway spruce were divided into five groups (A–E) based on being primarily produced by the bark beetle I. typographus (group A), bark beetle-associated microorganisms (groups B and C), or spruce tree (groups D and E). The effect of the compounds in these groups in the attraction of Medetera species and I. typographus was tested in two different subtractive field trapping assays. Results In the first subtractive assay, the full blend (ABCDE), and the blends lacking microbial compounds of group C, or spruce tree compounds of group D led to significant attraction of Medetera flies. Morphological identification of a subset of the specimens collected revealed that sixteen species were attracted to the synthetic blends, with M. signaticornis Loew being the most abundant. In the second subtractive assay, high attraction of Medetera flies and I. typographus was found for a 12-component synthetic blend. Conclusion The insights gained provide a basis for developing synthetic attractants to facilitate monitoring of Medetera flies. Future testing and optimization of these attractants will enhance our ability to monitor, conserve and utilize Medetera flies, thereby enabling us to better protect forests from the damaging effects of spruce bark beetles.

Abstract The recovery process after tibial plateau fractures varies, with some patients experiencing persistent gait asymmetries for a long period of time. The aim of this study is to analyse knee joint kinematics and kinetics post-fracture using a linear mixed-effects model, assessing 26 participants over 24 months (aged 45, range 26–63), and an age-matched control group (aged 47, range 26–62). Participants underwent three-dimensional gait analysis at 6-, 12- and 24-months post-injury. Controls participated in the gait analysis on one occasion. Six gait variables related to knee joint kinematics and kinetics were analysed with a linear mixed-effects model. The model was constructed to determine if there was a differential improvement over time between the injured and the non-injured legs across the six variables, referred to as an interaction effect. If no interaction effect was observed, the model assessed whether there was a side difference between the legs and if there was any improvement over time in both legs. Additionally, non-parametric tests were performed to assess differences between the non-injured leg and the control group across the six variables 24 months after injury. The findings revealed an interaction effect in terms of cumulative absorbed power (p = 0.02, side difference p = 0.06). Other variables showed no interaction effects. Although a side difference between legs was observed for all variables (p

Abstract Neuroblastoma (NB) is one of the most lethal childhood cancers due to its propensity to become treatment resistant. By spatial mapping of subclone geographies before and after chemotherapy across 89 tumor regions from 12 NBs, we find that densely packed territories of closely related subclones present at diagnosis are replaced under effective treatment by islands of distantly related survivor subclones, originating from a different most recent ancestor compared to lineages dominating before treatment. Conversely, in tumors that progressed under treatment, ancestors of subclones dominating later in disease are present already at diagnosis. Chemotherapy treated xenografts and cell culture models replicate these two contrasting scenarios and show branching evolution to be a constant feature of proliferating NB cells. Phylogenies based on whole genome sequencing of 505 individual NB cells indicate that a rich repertoire of parallel subclones emerges already with the first oncogenic mutations and lays the foundation for clonal replacement under treatment.

Abstract By applying nonlinear mixed‐effect (NLME) models, model‐integrated evidence (MIE) approaches are able to analyze bioequivalence (BE) data with pharmacokinetic end points that have sparse sampling, which is problematic for non‐compartmental analysis (NCA). However, MIE approaches may suffer from inflation of type I error due to underestimation of parameter uncertainty and to the assumption of asymptotic normality. In this study, we developed a MIE BE analysis method that is based on a pre‐defined model and consists of several steps including model fitting, uncertainty assessment, simulation, and BE determination. The presented MIE approach has several improvements compared with the previously reported model‐integrated methods: (1) treatment, sequence, and period effects are only added to absorption parameters (such as relative bioavailability and rate of absorption) instead of all PK parameters; (2) a simulation step is performed to generate confidence intervals of the pharmacokinetic metrics for BE assessment; and (3) in an effort to maintain type I error, two more advanced parameter uncertainty evaluation approaches are explored, a nonparametric (case resampling) bootstrap, and sampling importance resampling (SIR). To evaluate the developed method and compare the uncertainty assessment methods, simulation experiments were performed for BE studies using a two‐way crossover design with different amounts of information (sparse to rich designs) and levels of variability. Based on the simulation results, the method using SIR for parameter uncertainty quantification controls type I error at the nominal level of 0.05 (i.e., the significance level set for BE evaluation) even for studies with small sample size and/or sparse sampling. As expected, our MIE approach for BE assessment exhibited higher power than the NCA‐based method, especially as the data becomes sparser and/or more variable.

Abstract Conventional approaches for establishing bioequivalence (BE) between test and reference formulations using non‐compartmental analysis (NCA) may demonstrate low power in pharmacokinetic (PK) studies with sparse sampling. In this case, model‐integrated evidence (MIE) approaches for BE assessment have been shown to increase power, but may suffer from selection bias problems if models are built on the same data used for BE assessment. This work presents model averaging methods for BE evaluation and compares the power and type I error of these methods to conventional BE approaches for simulated studies of oral and ophthalmic formulations. Two model averaging methods were examined: bootstrap model selection and weight‐based model averaging with parameter uncertainty from three different sources, either from a sandwich covariance matrix, a bootstrap, or from sampling importance resampling (SIR). The proposed approaches increased power compared with conventional NCA‐based BE approaches, especially for the ophthalmic formulation scenarios, and were simultaneously able to adequately control type I error. In the rich sampling scenario considered for oral formulation, the weight‐based model averaging method with SIR uncertainty provided controlled type I error, that was closest to the target of 5%. In sparse‐sampling designs, especially the single sample ophthalmic scenarios, the type I error was best controlled by the bootstrap model selection method.

Abstract Population pharmacokinetic (PK) models are widely used to inform drug development by pharmaceutical companies and facilitate drug evaluation by regulatory agencies. Developing a population PK model is a multi‐step, challenging, and time‐consuming process involving iterative manual model fitting and evaluation. A tool for fully automatic model development (AMD) of common population PK models is presented here. The AMD tool is implemented in Pharmpy, a versatile open‐source library for pharmacometrics. It consists of different modules responsible for developing the different components of population PK models, including the structural model, the inter‐individual variability (IIV) model, the inter‐occasional variability (IOV) model, the residual unexplained variability (RUV) model, the covariate model, and the allometry model. The AMD tool was evaluated using 10 real PK datasets involving the structural, IIV, and RUV modules in three sequences. The different sequences yielded generally consistent structural models; however, there were variations in the results of the IIV and RUV models. The final models of the AMD tool showed lower Bayesian Information Criterion (BIC) values and similar visual predictive check plots compared with the available published models, indicating reasonable quality, in addition to reasonable run time. A similar conclusion was also drawn in a simulation study. The developed AMD tool serves as a promising tool for fast and fully automatic population PK model building with the potential to facilitate the use of modeling and simulation in drug development.

Abstract We aimed to evaluate short-term effects of a web-based self-management support on objectively measured physical activity (PA) compared to usual care in people with chronic obstructive pulmonary disease (COPD). We conducted a pragmatic randomised controlled trial including people with stable COPD within primary healthcare. Participants were randomised to intervention group, IG (access to the COPD Web, an interactive website to support self-management with focus on PA), or to control group, CG (usual care). Primary outcome at 3 months was change in accelerometry-measured daily steps analysed with ANCOVA, and secondary outcomes were self-reported PA, disease-related symptoms, and quality of life. Missing data in intention-to-treat (ITT) analyses were multiply imputed. One hundred and forty-six participants (n = 73/group), mean (SD) age 69.5 (6.7) years, FEV1pred 60.7 (19.1)% were included. The ITT analysis showed no significant difference in steps between the groups: 1295 steps (95% CI: [−365, 2955], p = 0.12), while the complete case analysis (n = 98) revealed a significant difference of 1492 steps (95% CI: [374, 2609], p = 0.01) in favour of IG. A significant increase in self-reported PA was seen in IG in both the ITT and complete case analysis. In summary, access to the COPD Web was insufficient to increase short-term PA level compared to usual care. However, among participants with complete step data, a clinically relevant effect on daily steps exceeding the minimal important difference was observed, partly explained by higher baseline PA than among dropouts. This indicates that access to the COPD Web may increase PA levels for some people with COPD.

Abstract Left atrial (LA) epicardial adipose tissue (EAT) and wall fibrosis are both proven to contribute to the pathogenesis and progression of atrial fibrillation (AF). The theory of LA wall fibrosis induction by local EAT infiltration, paracrine secretions, and activation of the inflammatory process is strongly advocated, but the imaging evidence for anatomical proximity of the two tissue types and its association to AF stage is lacking. Accordingly, the aim of the study was to analyse the spatial overlap between LA EAT and adjacent wall fibrosis using 3D Dixon water-fat separated late gadolinium enhancement (LGE-Dixon) MRI and correlate the findings with the clinical AF stage. Forty-two AF patients (18 paroxysmal, 10 persistent, and 14 permanent) and nine non-AF patients were scanned. The permanent AF patients had greater LA volume and EAT than the paroxysmal group. The LA fibrosis area showed the same trend. The LA EAT-fibrosis overlap area was small and there was no significant difference between the three AF stages. There was no significant relationship between LA EAT- fibrosis overlap area and AF type. The findings shed light on the complex interplay between LA fibrosis and EAT during the progression from paroxysmal to permanent AF.

Abstract The beneficial effects of exercise are partly mediated via local or systemic functions of the insulin-like growth factor-1 (IGF-1) system. As IGF-1 increases local brain hemoglobin beta (Hbb) transcripts, we hypothesized that exercise could have similar effects. Mice were single-housed with free access to running wheels for seven days. After sacrifice and saline perfusion, the expression of 13 genes was quantified using real-time quantitative polymerase chain reaction (RT-qPCR) in three brain regions: the prefrontal cortex, motor cortex, and hippocampus. In addition, plasma insulin, glucose, homeostatic model assessment of IR (HOMA-IR), C-peptide, and IGF-1 were investigated. We show that hemoglobin-related transcripts (Hbb and 5’-aminolevulinate synthase 2 [Alas2]) increased 46–63% in the running group, while IGF-1-related genes [Igf1 / growth hormone receptor (Ghr)] decreased slightly (7%). There were also moderate to large correlations between Hbb- and IGF-1-related genes in the running group but not in the sedentary group. HOMA-IR, plasma glucose, and insulin changed marginally and non-significantly, but there was a trend toward an increase in plasma-IGF-1 in the running group. In conclusion, seven days of running increased Hbb-related transcripts in three brain regions. Hbb-related transcripts correlated with components of the brain IGF-1 system only in the running group.

Abstract Measuring disease progression in clinical trials for testing novel treatments for multifaceted diseases as progressive supranuclear palsy (PSP), remains challenging. In this study we assess a range of statistical approaches to compare outcomes as measured by the items of the progressive supranuclear palsy rating scale (PSPRS). We consider several statistical approaches, including sum scores, a modified PSPRS rating scale that had been recommended by FDA in a pre-IND meeting, multivariate tests, and analysis approaches based on multiple comparisons of the individual items. In addition, we propose two novel approaches which measure disease status based on Item Response Theory models. We assess the performance of these tests under various scenarios in an extensive simulation study and illustrate their use with a re-analysis of the ABBV-8E12 clinical trial. Furthermore, we discuss the impact of the FDA-recommended scoring of item scores on the power of the statistical tests. We find that classical approaches as the PSPRS sum score demonstrate moderate to high power when treatment effects are consistent across the individual items. The tests based on Item Response Theory (IRT) models yield the highest power when the simulated data are generated from an IRT model. The multiple testing based approaches have a higher power in settings where the treatment effect is limited to certain domains or items. The study demonstrates that there is no one-size-fits-all testing procedure for evaluating treatment effects using PSPRS items; the optimal method varies based on the specific effect size patterns. The efficiency of the PSPRS sum score, while generally robust and straightforward to apply, varies depending on the specific patterns of effect sizes encountered and more powerful alternatives are available in specific settings. These findings can have important implications for the design of future clinical trials in PSP and similar multifaceted diseases.

Abstract Background Physical activity is thought to be a key component in reducing postoperative complications following major abdominal surgery. The available literature on exercise interventions following radical cystectomy in patients with bladder cancer is scarce but suggests that physical activity and exercise might improve physical function and health-related quality of life, thus calling for further investigation. The CanMoRe-trial is a single-blinded randomised controlled trial (Clinicals Trials NCT03998579 25/06/2019), aimed at evaluating the impact of an exercise intervention in primary care following robot-assisted radical cystectomy. This study seeks to explore patients’ experiences of the exercise intervention in the CanMoRe-trial to gain a better understanding of facilitating aspects and potential barriers. Methods A qualitative study was conducted involving 20 patients from the intervention group of the CanMoRe-trial who were interviewed individually between October 2020 and March 2023 using a semi-structured interview guide. The interviews were recorded and transcribed verbatim and reflexive thematic analysis was used to analyse the data. Results Four main themes were identified: Having to adapt to new circumstances, describing the challenges regarding physical activity patients face after discharge. Optimising conditions for rehabilitation, describing how practical conditions affect patients’ ability to exercise. Motivated to get back to normal, describing patients´ desire to get back to normal life and factors influencing motivation. Importance of a supportive environment, describing the impact of social support, support from physiotherapists, and how the environment where exercise takes place impacts patients’ ability to exercise. Conclusion This study found that patients participating in the CanMoRe-trial are positive towards physical exercise in PC following radical RARC. They are motivated to get back to normal life but face major challenges when arriving home following surgery, which affect their ability to perform physical activity and engage in exercise. Conditions need to be optimised to support patients’ ability to engage in exercise by providing an accessible PC location to perform exercise in. A supportive environment is also needed, including guidance from healthcare professionals regarding which type of exercise, intensity and amount of exercise that should be performed, enabling patients gradually to develop self-efficacy regarding exercise and focusing on goals related to patients’ normal lives before surgery.

Abstract Background This study aimed to examine the social gradient in self-reported alcohol-related harm (ARH) among young alcohol consumers by including a largely overlooked group of adolescents. We also explored the extent to which such a gradient could be attributed to differential exposure or differential vulnerability to risk factors. Method Cross-sectional survey of upper-secondary students (n = 2996) in Sweden. Negative binomial regressions estimated the relationship between academic orientation (higher education preparatory; HEP, vocational; VP and introductory; IP) and ARH. To assess the contribution of explanatory factors, we estimated models that included risk factors such as heavy episodic drinking (HED). Results A graded association was observed between academic orientation and ARH, with more ARH among students in IP (IRR = 1.79) and VP (IRR = 1.43) than in HEP. Adjustments for risk factors attenuated the estimates by approximately half, but there was still 14% more ARH in VP and 50% more in IP than in HEP. The additive interaction test indicated a positive and significant interaction for students in VP who engaged in HED, versus students in HEP, who did not. Conclusion The findings suggest a negative gradient in the association between academic orientation and ARH, where the students in IP experienced the highest levels of ARH. While differential exposure and vulnerability to HED account for a significant proportion of the excess risk among VP students, HED seems to be less important relative to other risk factors among IP students. More research is needed to identify the mechanisms underlying the elevated levels of ARH among the most disadvantaged group—students enrolled in IP.

Objectives To describe changes in Swedish primary care physicians’ use of, attitudes and intentions toward digital tools in patient care between 2019 and 2022.Design A survey using a validated questionnaire measuring physician’s intentions to use digital tools based on the theory of planned behavior.Setting Sample of primary health care centers in southern Sweden.Subjects Primary care physicians.Main outcome measures Self-reported use and intentions to use, digital tools including digital consultations by text or video, chronic disease monitoring and artificial intelligence (AI) and the associations between attitudes, subjective norms, perceived behavioral control and behavioral intentions to use digital tools, in 2019 compared to 2022.Results In both 2019 (n = 198) and 2022 (n = 93), physicians reported high intentions to use digital tools. Self-reported use of video was slightly higher in 2022 (p = .03). No other changes were seen in the self-reported use or behavioral intentions to use digital tools.Conclusion The slow adoption of patient-related digital tools in Swedish primary health care does not seem to be explained by a low intention to use them among physicians. Future research on implementation of digital tools should include a focus on contextual factors such as organizational, technical and cultural barriers.

This study investigates the development of literary competences among EFL preservice teachers (PSTs) through their engagement with picturebooks in an EFL teacher education program in Santiago, Chile. Using qualitative content analysis, the study examines the pedagogical proposals and reading sessions of 12 PSTs to identify the types of literary competences they developed. The findings reveal that while PSTs demonstrated strengths in plot and character analysis competence and subjective and emotional competence, they showed less proficiency in thematic and symbolic competence, esthetic and stylistic competence and cultural competence. However, the results highlight the potential of integrating picturebooks into EFL classrooms to foster diverse literary competences. The paper concludes suggesting that EFL teacher education programs should adopt a balanced approach, incorporating both text-oriented and reader-oriented activities to better prepare English teachers for effective literary instruction.

Purpose: This study aims to analyse student and teaching staff views on how higher education (HE) can contribute to sustainable development, and to provide examples of how a medical university has adopted the sustainable development goals (SDGs) as part of its institutional strategies and practises. Design/methodology/approach: The study is based on participant views from a conference, which aimed to identify actions needed for HE to contribute to the SDGs. More than 500 students, teachers and academic leaders participated at workshops to discuss and reflect on the role of higher education institutions (HEIs) in sustainable development. The discussion key points were recorded on flipcharts, and the analysis builds on all written statements from the nine workshops. Based on the findings from the workshop, steering documents and activities of a medical university were identified as examples of implementation. Findings: Two overarching interdependent themes were identified and indicated a need to rethink the role not only of HE per se but also that of HEIs at large, to meet the challenges of sustainable development. The study also provides an example of how such organizational change can be practically implemented at a medical university, through the establishment of overarching institutional strategies, funding opportunities and external collaborations. Practical implications: The findings reflect a "bottom-up" call from students and educational staff for HEIs to step up and contribute to systems change - both through a change in pedagogies, as well as through an institution-wide approach and a shift in the role of HEIs in society. Originality/value: The study is unique in providing an exemplar of the implementation of sustainable development in HE at a specific medical university.

Similar to many countries in the Western world, educational reforms in Sweden have dramatically changed the educational system in the last few decades. The two reforms that we address in this paper concern "The Career Services for Teachers Reform" and "Teachers Salary Boost" which were implemented at the national level in Sweden in 2013 and 2017, respectively. In this ethnographic study we focus on the design features of these two contemporary reforms and how they impact on both the social and educational life of teachers and school leaders at a secondary high school. However, this change in organisational logic was not only a major digression from the academic tradition and its traditional character of "merit before birth". Due to design features within these reforms, the door to nepotism, real or imagined, was now wide open. Moreover, in the same way as these reforms represent something new to Swedish education, and to the teaching profession in particular, it is just one more step on a road already mapped out via the ongoing neo-liberalisation of society at large.

Academic Literacies elucidates how undergraduate students with diverse skillsets can effectively engage with socially constructed and discipline-specific knowledge(s) "through" writing. Over the last two decades, language specialists and education researchers have developed a robust, student-focused epistemology. However, it remains unclear how lecturers understand and teach Academic Literacies in their courses. This article shifts the focus by exploring how we -- a teaching team in International Relations at a Swedish university -- translated the knowledge claims and ideological commitments of Academic Literacies into an applied pedagogy. We employ collaborative, reflective practice to investigate how we progressively integrated Academic Literacies in an introductory, bachelor's level course from 2010-2019. Specifically, we illustrate how we used formative feedback, peer assessment, and reflective journaling to teach International Relations "through" academic writing. We conclude with a discussion of the best practices and unresolved challenges of our evolving pedagogical design.

The aim of this study is to examine what it means to be a student in a vocational education and training programme in the municipal adult education system in Sweden and how the interplay between school and working life affects students' identity formation. To achieve this, 12 students from two different programmes have been interviewed at the end of their education: one group of assistant nurses and one group of floor layers. The results show that learning a vocation and developing a vocational identity is a journey through different practices with whom students both identify and dis-identify themselves. In these processes of identification, students can also undergo personal development in a broader sense or develop an identity as an adult. Understanding adult student identities, in particular how they see themselves as learners, can be beneficial for those working with and in adult learning. Furthermore, what the school teaches may conflict with the expectations and daily demands of working life, creating a divide between practices. Understanding the divide between school and working life, and how students are affected by this divide, can also facilitate the understanding of their vocational identity development process.

This paper describes the process of developing classroom culture that promotes reciprocal intercultural encountering in the primary school. Storycrafting, an oral storytelling method used for democratic encounters between participants, was used to connect classes in Scotland, Finland and Belgium over three cycles of design-based research. Abductive analysis produced a theoretical framework of seven key dimensions that influence the learning space for reciprocal encounters: power, knowledge, relatedness, purpose, structure, continuity and meaningfulness. These dimensions were used to identify four kinds of learning spaces that occurred during the implementation of the story exchange: the ambivalent space, the space of information, the transitional space and the space of reciprocal encountering. The intervention created a platform for children's encounters that reinforced mutuality and reciprocal interactions rather than Othering the exchange partners.