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In many parts of the world, researchers and policymakers alike report possible threats to democracy and its institutions. Accounts in the media of hatred and threats aimed at people taking part in public discourse, and of a polarized political debate, raise general questions about the current state and future of democratic dialogue and processes. Solutions are sought, by both research and policy, in the educational context. Some researchers have turned to the agonistic theory proposed by Chantal Mouffe, highlighting the democratic role of conflict and dissent. Empirical research on agonism in education is, however, scarce. In this article, we explore agonistic democratic theory in educational practice, more precisely in a conversation about a literary classic in an upper-secondary Swedish L1 classroom. Based on the analysis of data generated through a teacher-researcher collaboration, we propose six didactic conditions that are fruitful for what we call agonistic literary discussions. Contributing to the debate on how education could meet a possible threat to democracy, we argue that an agonistic approach is a productive path. This approach views democracy as an ongoing process, and it views the classroom as a place where the meaning of democracy can be negotiated.

ABSTRACTIntroduction Different COVID-19 vaccines are being utilized as boosters. This systematic review and meta-analysis aims to evaluate the reactogenicity of COVID-19 vaccines given as booster doses, according to vaccine type, dose, timing, participant characteristics and primary immunization regimen received.Methods Four databases (MEDLINE, Embase, Web of Science and CENTRAL) were searched for randomized controlled trials between 1 January 2020 and 1 January 2023 according to predetermined criteria.Results Twenty-eight studies describing 19 vaccines of four different types (viral vector, inactivated, mRNA and protein sub-unit) were identified. BNT162b2 vaccine (Pfizer-BioNTech) was selected as the control as it was most often compared with other vaccines. Fever, fatigue, headache, injection-site pain, redness, and swelling were the most frequently reported solicited events. mRNA vaccines were the most reactogenic, followed by viral vector vaccines and protein sub-unit vaccines, while inactivated vaccines were the least reactogenic. Full-dose vaccines were more reactogenic than half-dose vaccines. Heterologous BNT162b2 boosters were more reactogenic than boosters with the same vaccine used for primary immunization.Conclusions COVID-19 vaccine booster schedules have distinct reactogenicity profiles, dependent on dose and vaccine type, which may allow targeted recommendations and provide choice for specific populations. Greater standardization of adverse event reporting will aid future studies.

Abstract Background The question of whether antibiotic prophylaxis should be administered routinely for dental implant surgery is unresolved. Despite the lack of conclusive supportive evidence, antibiotics are often administered to reduce the risk of infection, which could lead to early implant failure. Increasing antibiotic resistance is a major concern and it is therefore important to reduce the overall use of antibiotics, including in dentistry. The aim of the present systematic review and meta-analysis was to evaluate the efficacy of preoperative antibiotics in preventing early implant failure, in overall healthy patients undergoing dental implant surgery. Methods An electronic search was undertaken of PubMed (Medline), Web of Science and the Cochrane Library up to October 1st, 2023, to identify randomized clinical trials (RCTs). All RCTs comparing antibiotic prophylaxis with no antibiotics/placebo in overall healthy patients receiving dental implants were included. The primary outcome was patients with early implant failure. Risk of bias was assessed, data were extracted, a meta-analysis was done, and GRADE certainty-of-evidence ratings were determined. The risk ratio (RR), the risk difference (RD) and 95% confidence intervals (CI) were estimated. Results After removal of duplicates, 1086 abstracts were screened, and 17 articles were reviewed in full text. Seven RCTs with moderate or low risk of bias and with a total of 1859 patients and 3014 implants were included in the meta-analysis. With reference to early implant failure at patient level, the meta-analysis failed to disclose any statistically significant difference (RR: 0.66, 95% CI: 0.30-1.47) between antibiotic prophylaxis and a placebo. The risk difference was -0.007 (95% CI: -0.035-0.020) leading to a number needed to treat (NNT) of 143. Conclusion Antibiotic prophylaxis for dental implant surgery does not seem to have any substantial effect on early implant failure ( ). The results do not support routine antibiotic prophylaxis for dental implant surgery.

Abstract Background The ongoing global migration has led to multicultural societies, with many migrants who do not speak the official language in the host country. This could contribute to communication problems with staff in healthcare and a risk to patient safety. Research on patient safety in medication use in migrants is an under-researched area. The aim was to explore diverse foreign-born people’s experiences and perceptions of self-management of medication and determine if home-based practice patterns have implications on medication safety, and what factors may support safe medication use. Methods A qualitative explorative study, with individual semi-structured interviews and participant observations in the patients’ home. Qualitative content analysis was applied. Results A purposeful sample of 15 foreign-born persons identified by healthcare staff as having language difficulties in Swedish that may pose a safety risk in connection with medication use at home, was selected. Three categories were identified. The first category showed respondents being dependent on another person, having experiences of not receiving information about their medications due to language barriers, having difficulties getting access to the healthcare centre and feeling distrusted/misunderstood. The second category showed respondents being independent and self-motivated Although they struggled, they managed to get access/contact with the healthcare centre themselves and felt understood/listened to by the staff. The last category concerned factors that facilitating medication use; such as having a medication list in the respondents’ own language and offering a choice of language on the answering machine at the healthcare centre. Although they knew it was impossible to get an interpreter at the pharmacy, they felt safe knowing there was always a solution for receiving understandable information. Conclusion The findings highlighted that language barriers can complicate the communication between migrants and the healthcare, which can affect the medication safety. Understanding of this group is essential to improve the cooperation between patients and staff, leading to culturally congruent care. This knowledge should be used in healthcare to understand the gap in communication to increase patient safety. Further research from other angles, e.g. pharmacy/healthcare staff and relatives is needed to identify and evaluate facilitation to improve the outcome of the intended medication treatment.

Abstract HPV vaccination with concomitant HPV-based screening of young women has been proposed for faster cervical cancer elimination. We describe the baseline results of a population-based trial of this strategy to reduce the incidence of HPV. All 89,547 women born 1994-1999 and resident in the capital region of Sweden were personally invited to concomitant HPV vaccination and HPV screening with 26,125 women (29.2%) enrolled between 2021-05-03 and 2022-12-31. Baseline HPV genotyping of cervical samples from the study participants finds, compared to pre-vaccination prevalences, a strong decline of HPV16 and 18 in birth cohorts previously offered vaccination, some decline for cross-protected HPV types but no decline for HPV types not targeted by vaccines. Our dynamic transmission modelling predicts that the trial could reduce the incidence of high-risk HPV infections among the 1994-1998 cohorts by 62-64% in 3 years. Baseline results are prevalences of HPV infection, validated transmission model projections, and power estimates for evaluating HPV incidence reductions at follow-up (+/−0.1% with 99.9% confidence). In conclusion, concomitant HPV vaccination and HPV screening appears to be a realistic option for faster cervical cancer elimination. Clinicaltrials.gov identifier: NCT04910802; EudraCT number: 2020-001169-34.

Introduction Syndromic panel assays, that is, using one test to simultaneously target multiple pathogens with overlapping signs and symptoms, have been integrated into routine paediatric care over the past decade, mainly for more severely ill and hospitalised patients. Their wider availability and short turnaround times open the possibility to apply them to non-hospitalised patients as well. In this context, it is important to trial how clinicians make use of pathogen detection data and if their early availability influences management decisions, particularly antibiotic use and hospitalisation.Methods and analysis Advanced Diagnostics for Enhanced QUality of Antibiotic prescription in respiratory Tract infections in Emergency rooms is an individually randomised, controlled, open-label effectiveness trial comparing the impact of a respiratory pathogen panel assay (BIOFIRE Respiratory Panel 2.1plus) used as a rapid syndromic test on nasopharyngeal swabs in addition to the standard of care versus standard of care alone. The trial will 1:1 randomise 520 participants under the age of 18 at 7 paediatric emergency departments in 5 European countries. Inclusion criteria for the trial consist of two sets, with the first describing respiratory tract infections in paediatric patients and the second describing the situation of potential management uncertainty in which test results may immediately affect management decisions. Enrolment started in July 2021 and is expected to be completed in early 2024. We will perform a two-sample t-test assuming a pooled variance estimate to compare the log-transformed mean time on antibiotic treatment (in hours) and number of days alive out of the hospital within 14 days after study enrolment between the control and intervention arms.Ethics and dissemination The trial protocol and materials were approved by research ethics committees in all participating countries. The respiratory pathogen panel assay is CE marked (assessed to meet European regulations) and FDA (United States Food and Drug Administration) cleared for diagnostic use. Participants and caregivers provide informed consent prior to study procedures commencing. The trial results will be published in peer-reviewed journals and at national and international conferences. Key messages will also be disseminated via press and social media where appropriate.Trial registration number NCT04781530.

Abstract Background Adherence to antibiotic recommendations and safety aspects of restrictive use are important components when combating antibiotic resistance. The primary aim of this study was to assess the impact of national guidelines on antibiotic prescriptions for bone augmentation procedures among dentists working at three specialized clinics. The secondary aim was to assess the occurrence of postoperative infections. Methods Medical charts of 400 patients treated with bone augmentation were reviewed: 200 in the years 2010–2011 and 200 in 2014–2015. The Swedish national recommendations for antibiotic prophylaxis were published in 2012. Results There was a wide variation in antibiotic regiments prescribed throughout the study. The number of patients treated with antibiotic prophylaxis in a single dose of 2 g amoxicillin, and treated as advocated in the national recommendations, was low and decreasing between the two time periods from 25% (n = 50/200) in 2010–2011 to 18.5% (n = 37/200) in 2014–2015. The number of patients not given any antibiotics either as a prophylactic single dose or during the postoperative phase increased (P

Abstract Background Colorectal cancer (CRC) is known to present a distinct microbiome profile compared to healthy mucosa. Non‐targeted deep‐sequencing strategies enable nowadays full microbiome characterization up to species level. Aim We aimed to analyze both bacterial and viral communities in CRC using these strategies. Materials & Methods We analyzed bacterial and viral communities using both DNA and RNA deep‐sequencing (Novaseq) in colorectal tissue specimens from 10 CRC patients and 10 matched control patients. Following taxonomy classification using Kraken 2, different metrics for alpha and beta diversities as well as relative and differential abundance were calculated to compare tumoral and healthy samples. Results No viral differences were identified between tissue types, but bacterial species Polynucleobacter necessarius had a highly increased presence for DNA in tumors (p = 0.001). RNA analyses showed that bacterial species Arabia massiliensis had a highly decreased transcription in tumors (p = 0.002) while Fusobacterium nucleatum transcription was highly increased in tumors (p = 0.002). Discussion Sequencing of both DNA and RNA enables a wider perspective of micriobiome profiles. Lack of RNA transcription (Polynucleobacter necessarius) casts doubt on possible role of a microorganism in CRC. The association of F. nucleatum mainly with transcription, may provide further insights on its role in CRC. Conclusion Joint assessment of the metagenome (DNA) and the metatranscriptome (RNA) at the species level provided a huge coverage for both bacteria and virus and identifies differential specific bacterial species as tumor associated.

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

Abstract Rickets is a disorder of bone development and can be the result of either dietary or genetic causes. Here, related pugs from 2 litters were included. Three pugs had clinical signs including, lameness, bone deformities, and dyspnea. One other pug was found dead. Radiographs of 2 affected pugs, 5 and 6 months old, showed generalized widening, and irregular margination of the physes of both the appendicular and the axial skeleton with generalized decrease in bone opacity and bulbous swelling of the costochondral junctions. Two pugs had low serum calcium and 1,25 (OH)2D3 concentrations. Test results further indicated secondary hyperparathyroidism with adequate concentrations of 25‐hydroxyvitamin D. Necropsy revealed tongue‐like projections of cartilage extending into the metaphysis consistent with rickets, loss of metaphyseal mineralization and lung pathology. Vitamin D‐dependent rickets was diagnosed. A truncating mutation in the 1α‐hydroxylase gene (CYP27B1) was identified by genome sequence analysis of the pugs with VDDR type 1A. Vitamin D‐dependent rickets type 1A can occur in young pugs, and if left untreated is a life‐threatening condition. Early medical intervention can reverse clinical signs and should be instituted as soon as possible.

Background: Diabetic foot ulcers (DFU) pose a significant health risk in diabetic patients, with insufficient revascularization during wound healing being the primary cause. This study aimed to assess microvessel sprouting and wound healing capabilities using vascular endothelial growth factor (VEGF-A) and a modified fibroblast growth factor (FGF1). Methods: An ex vivo aortic ring rodent model and an in vivo wound healing model in diabetic mice were employed to evaluate the microvessel sprouting and wound healing capabilities of VEGF-A and a modified FGF1 both as monotherapies and in combination. Results: The combination of VEGF-A and FGF1 demonstrated increased vascular sprouting in the ex vivo mouse aortic ring model, and topical administration of a combination of VEGF-A and FGF1 mRNAs formulated in lipid nanoparticles (LNPs) in mouse skin wounds promoted faster wound closure and increased neovascularization seven days post-surgical wound creation. RNA-sequencing analysis of skin samples at day three post-wound creation revealed a strong transcriptional response of the wound healing process, with the combined treatment showing significant enrichment of genes linked to skin growth. Conclusion: f-LNPs encapsulating VEGF-A and FGF1 mRNAs present a promising approach to improving the scarring process in DFU.

Summary: Background: It is not clear whether Viridans Group Streptococcal Infective Endocarditis (VGS-IE) among individuals at high risk is more frequent following bacteraemia caused by invasive dental procedures (IDPs) than after daily bacteraemia caused by chewing and tooth brushing. The aim of this nested study was to assess if VGS-IE was temporally associated with IDPs in a national cohort of individuals at high risk. Methods: This nested case-control and case-crossover study was based on a Swedish national cohort study of 76,762 individuals at high risk of IE due to complex congenital heart disease, prosthetic heart valve or previous IE. Participants were living in Sweden between July 1st, 2008 and January 1st, 2018. The frequency of IDPs during the 3 months before VGS-IE was calculated and compared to controls (sampled 1:10). A case-crossover study was conducted to account for residual confounders. Participants were identified using the national patient register, and IDPs were identified using the national dental health register. Findings: 98,247 IDPs were carried out in the cohort during the study period: 624 occasions of oral surgery, 44,190 extractions and 53,433 sessions of subgingival scaling. The study could not confirm that IDPs were more common among cases (4.6%) than controls (4.1%), OR = 1.22 [95% Confidence Interval (CI) 0.64–2.3], or during case- (3.3%) than reference periods (3.8%), OR = 0.89 [95% CI: 0.68–1.17]. Restricting the analysis to the period when cessation of antibiotic prophylaxis for the prevention of IE in Swedish dentistry was recommended, from the 1st of October 2012 to the 1st of January 2018, did not alter the results of the case-control study: OR 0.64, 95% CI: 0.20–2.09, or the case-crossover study: OR 0.58, 95% CI: 0.15–2.19. Interpretation: The study could not confirm that VGS-IE is associated with IDPs among individuals at high risk. A study with larger sample size could clarify whether there is a lack of association. The finding of a small (

Introduction Incontinence-associated dermatitis (IAD) is irritant contact dermatitis and skin damage associated with prolonged skin contact with urine and/or faeces. Identifying prognostic factors for the development of IAD may improve management, facilitate prevention and inform future research.Methods and analysis This protocol follows the guidelines of the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols. Prospective and retrospective observational studies or clinical trials in which prognostic factors associated with the development of IAD are described are eligible. There are no restrictions on study setting, time, language, participant characteristics or geographical regions. Reviews, editorials, commentaries, methodological articles, letters to the editor, cross-sectional and case–control studies, and case reports are excluded. MEDLINE, CINAHL, EMBASE and The Cochrane Library will be searched from inception until May 2023. Two independent reviewers will independently evaluate studies. The Quality in Prognostic Studies tool will be used to assess the risk of bias, and the Checklist for Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies-Prognostic Factors checklist will be used for data extraction of the included studies. Separate analyses will be conducted for each identified prognostic factor, with adjusted and unadjusted estimated measures analysed separately. Evidence will be summarised with a meta-analysis when possible, and narratively otherwise. The Q and I2 statistics will be calculated in order to quantify heterogeneity. The quality of the evidence obtained will be evaluated according to the Grades of Recommendation Assessment, Development and Evaluation guidance.Ethics and dissemination No ethical approval is needed since all data is already publicly accessible. The results of this work will be published in a peer-reviewed scientific journal.

Background: Bullying is a public health issue with long-term effects for victims. This study investigated if there was an association between pedagogical and social school climate and student-reported bullying victimization, which dimensions of pedagogical and social school climate were associated with bullying, and if these associations were modified by individual-level social factors. Methods: The study had a cross-sectional multilevel design with individual-level data on bullying from 3311 students nested in 94 schools over 3 consecutive school years. School climate was measured with student and teacher questionnaires, aggregated at the school level. The association between school climate and bullying victimization was estimated with multilevel mixed-model logistic regression. Results: In schools with the most favorable school climate, fewer students reported being bullied. This was especially evident when school climate was measured with the student instrument. Students in schools with favorable climate had an adjusted odds ratio of bullying of 0.74 (95% CI: 0.55-1.00) compared to students in schools with the worst climate. Results from the teacher instrument were in the same direction, but less consistent. Conclusions: Improvement in school climate has the potential to affect students both academically, and socially, as well as decrease the prevalence of bullying.

Abstract Automated segmentation of human cardiac magnetic resonance datasets has been steadily improving during recent years. Similar applications would be highly useful to improve and speed up the studies of cardiac function in rodents in the preclinical context. However, the transfer of such segmentation methods to the preclinical research is compounded by the limited number of datasets and lower image resolution. In this paper we present a successful application of deep architectures 3D cardiac segmentation for rats in preclinical contexts which to our knowledge has not yet been reported. We developed segmentation models that expand on the standard U-Net architecture and evaluated models separately trained for systole and diastole phases (2MSA) and a single model trained for all phases (1MSA). Furthermore, we calibrated model outputs using a Gaussian process (GP)-based prior to improve phase selection. The resulting models approach human performance in terms of left ventricular segmentation quality and ejection fraction (EF) estimation in both 1MSA and 2MSA settings (Sørensen-Dice score 0.91 ± 0.072 and 0.93 ± 0.032, respectively). 2MSA achieved a mean absolute difference between estimated and reference EF of 3.5 ± 2.5%, while 1MSA resulted in 4.1 ± 3.0%. Applying GPs to 1MSA enabled automating systole and diastole phase selection. Both segmentation approaches (1MSA and 2MSA) were statistically equivalent. Combined with a proposed cardiac phase selection strategy, our work presents an important first step towards a fully automated segmentation pipeline in the context of rat cardiac analysis.

Abstract Lipid nanoparticles (LNPs) are currently used to transport functional mRNAs, such as COVID‐19 mRNA vaccines. The delivery of angiogenic molecules, such as therapeutic VEGF‐A mRNA, to ischemic tissues for producing new blood vessels is an emerging strategy for the treatment of cardiovascular diseases. Here, the authors deliver VEGF‐A mRNA via LNPs and study stoichiometric quantification of their uptake kinetics and how the transport of exogenous LNP‐mRNAs between cells is functionally extended by cells’ own vehicles called extracellular vesicles (EVs). The results show that cellular uptake of LNPs and their mRNA molecules occurs quickly, and that the translation of exogenously delivered mRNA begins immediately. Following the VEGF‐A mRNA delivery to cells via LNPs, a fraction of internalized VEGF‐A mRNA is secreted via EVs. The overexpressed VEGF‐A mRNA is detected in EVs secreted from three different cell types. Additionally, RNA‐Seq analysis reveals that as cells’ response to LNP‐VEGF‐A mRNA treatment, several overexpressed proangiogenic transcripts are packaged into EVs. EVs are further deployed to deliver VEGF‐A mRNA in vitro and in vivo. Upon equal amount of VEGF‐A mRNA delivery via three EV types or LNPs in vitro, EVs from cardiac progenitor cells are the most efficient in promoting angiogenesis per amount of VEGF‐A protein produced. Intravenous administration of luciferase mRNA shows that EVs could distribute translatable mRNA to different organs with the highest amounts of luciferase detected in the liver. Direct injections of VEGF‐A mRNA (via EVs or LNPs) into mice heart result in locally produced VEGF‐A protein without spillover to liver and circulation. In addition, EVs from cardiac progenitor cells cause minimal production of inflammatory cytokines in cardiac tissue compared with all other treatment types. Collectively, the data demonstrate that LNPs transform EVs as functional extensions to distribute therapeutic mRNA between cells, where EVs deliver this mRNA differently than LNPs.

Medical multi-professional teams are increasingly collaborating via telemedicine. In distributed team settings, members are geographically separated and collaborate through technology. Developing improved training strategies for distributed teams and finding appropriate instruments to assess team performance is necessary. The Team Emergency Assessment Measure (TEAM), an instrument validated in traditional collocated acute-care settings, was tested for validity and reliability in this study when used for distributed teams. Three raters assessed video recordings of simulated team training scenarios (n = 18) among teams with varying levels of proficiency working with a remotely located physician via telemedicine. Inter-rater reliability, determined by intraclass correlation, was 0.74–0.92 on the TEAM instrument’s three domains of leadership, teamwork, and task management. Internal consistency (Cronbach’s alpha) ranged between 0.89–0.97 for the various domains. Predictive validity was established by comparing scores with proficiency levels. Finally, concurrent validity was established by high correlations, >0.92, between scores in the three TEAM domains and the teams’ overall performance. Our results indicate that TEAM can be used in distributed acute-care team settings and consequently applied in future-directed learning and research on distributed healthcare teams.

Abstract Background Left ventricular (LV) diastolic dysfunction is an acknowledged peri-operative risk factor that should be identified before surgery. This study aimed to evaluate a simplified echocardiographic method using e’ and E/e’ for identification and grading of diastolic dysfunction pre-operatively. Methods Ninety six ambulatory surgical patients were consecutively included to this prospective observational study. Pre-operative transthoracic echocardiography was conducted prior to surgery, and diagnosis of LV diastolic dysfunction was established by comprehensive and simplified assessment, and the results were compared. The accuracy of e’-velocities in order to discriminate patients with diastolic dysfunction was established by calculating accuracy, efficiency, positive (PPV) and negative predictive (NPV) values, and area under the receiver operating characteristic curve (AUROC). Results Comprehensive assessment established diastolic dysfunction in 77% (74/96) of patients. Of these, 22/74 was categorized as mild dysfunction, 43/74 as moderate dysfunction and 9/74 as severe dysfunction. Using the simplified method with e’ and E/e’, diastolic dysfunction was established in 70.8% (68/96) of patients. Of these, 8/68 was categorized as mild dysfunction, 36/68 as moderate dysfunction and 24/68 as severe dysfunction. To discriminate diastolic dysfunction of any grade, e’-velocities (mean

Abstract Background In order to assess left atrial contractile function in disturbed circulatory conditions, it is necessary to have a clear understanding of how it behaves in a normal resting state with changes in loading conditions. However, currently the understanding of this relationship is incomplete. We hypothesize that in healthy individuals, left atrial contraction strain and its peak strain rate are increased or decreased by increasing or decreasing preload, respectively. Methods Controlled maneuvers used to change preload included continuous positive airway pressure by mask (CPAP 20 cmH2O) for preload decrease, and passive leg raise (15 degrees angle) for preload increase. Cardiac ultrasound 4-chamber views of the left atria and left ventricle were acquired at baseline and during maneuver. Acquired images were post processed and analyzed offline. Comparisons were made using paired t-test and means with 95% confidence interval. Results There were 38 participants, complete results were obtained from 23 in the CPAP maneuver and 27 in the passive leg raise maneuver. For the CPAP group, left atrial contraction strain was 11.6% (10.1 to 13.1) at baseline and 12.8% (11.0 to 14.6) during the maneuver (p = 0.16). Left atrial contraction peak strain rate was − 1.7 s− 1 (− 1.8 to − 1.5) at baseline and − 1.8 s− 1 (− 2.0 to − 1.6) during the maneuver (p = 0.29). For the passive leg raise-group, left atrial contraction strain was 10.1% (9.0 to 11.2) at baseline and 10.8% (9.4 to 12.3) during the maneuver (p = 0.28). Left atrial contraction peak strain rate was − 1.5 s− 1 (− 1.6 to − 1.4) at baseline and − 1.6 s− 1 (− 1.8 to − 1.5) during the maneuver (p = 0.29). Left atrial area, an indicator of preload, increased significantly during passive leg raise and decreased during CPAP. Conclusion In healthy individuals, left atrial contraction strain and its peak strain rate seem to be preload-independent. Trial registration The study was 2018-02-19 registered at clinicaltrials.gov ( NCT03436030 ).

The accumulation of peripheral blood late-differentiated memory CD8 T cells with features of replicative (cellular) senescence, including inability to proliferate in vitro, has been extensively studied. Importantly, the abundance of these cells is directly correlated with increased morbidity and mortality in older persons. Of note, peripheral blood contains only 2% of the total body lymphocyte population. By contrast, the gut-associated lymphoid tissue (GALT) is the most extensive lymphoid organ, housing up to 60% of total body lymphocytes, but has never been assessed with respect to senescence profiles. We report here the development of a method for measuring and comparing proliferative capacity of peripheral blood and gut colorectal mucosa-derived CD8 T cells. The protocol involves a 5-day culture of mononuclear leukocyte populations, from blood and gut colorectal mucosa respectively, labeled with 5-(and 6)-carboxyfluorescein diacetate succinimidyl ester (CFSE) and 5-bromo-2'-deoxyuridine (BrdU) and stimulated with anti-CD2/3/28-linked microbeads. Variables tested and optimized as part of the protocol development include: mode of T cell stimulation, CFSE concentration, inclusion of a second proliferation marker, BrdU, culture duration, initial culture concentration, and inclusion of autologous irradiated feeder cells. Moving forward, this protocol demonstrates a significant advance in the ability of researchers to study compartment-specific differences of in vitro proliferative dynamics of CD8 T cells, as an indicator of replicative senescence and immunological aging. The study's two main novel contributions are (1) Optimization and adaptation of standard proliferative dynamics blood T cell protocols for T cells within the mucosal immune system. (2) Introduction of the novel technique of combining CFSE and BrdU staining to do so.

A hallmark of human immunosenescence is the accumulation of late-differentiated memory CD8+ T cells with features of replicative senescence, such as inability to proliferate, absence of CD28 expression, shortened telomeres, loss of telomerase activity, enhanced activation, and increased secretion of inflammatory cytokines. Importantly, oligoclonal expansions of these cells are associated with increased morbidity and mortality risk in elderly humans. Currently, most information on the adaptive immune system is derived from studies using peripheral blood, which contains approximately only 2% of total body lymphocytes. However, most lymphocytes reside in tissues. It is not clear how representative blood changes are of the total immune status. This is especially relevant with regard to the human gastrointestinal tract (GALT), a major reservoir of total body lymphocytes (approximately 60%) and an anatomical region of high antigenic exposure. To assess how peripheral blood T cells relate to those in other locations, we compare CD8+ T cells from peripheral blood and the GALT, specifically rectosigmoid colon, in young/middle age, healthy donors, focusing on phenotypic and functional alterations previously linked to senescence in peripheral blood. Overall, our results indicate that gut CD8+ T cells show profiles suggestive of greater differentiation and activation than those in peripheral blood. Specifically, compared to blood from the same individual, the gut contains significantly greater proportions of CD8+ T cells that are CD45RA- (memory), CD28-, CD45RA-CD28+ (early memory), CD45RA-CD28- (late memory), CD25-, HLA-DR+CD38+ (activated) and Ki-67+ (proliferating); ex vivo CD3+ telomerase activity levels are greater in the gut as well. However, gut CD8+ T cells may not necessarily be more senescent, since they expressed significantly lower levels of CD57 and PD-1 on CD45RO+ memory cells, and had in vitro proliferative dynamics similar to that of blood cells. Compartment-specific age-effects in this cohort were evident as well. Blood cells showed a significant increase with age in proportion of HLA-DR+38+, Ki-67+ and CD25+ CD8+ T cells; and an increase in total CD3+ ex-vivo telomerase activity that approached significance. By contrast, the only age-effect seen in the gut was a significant increase in CD45RA- (memory) and concurrent decrease in CD45RA+CD28+ (naïve) CD8+ T cells. Overall, these results indicate dynamics of peripheral blood immune senescence may not hold true in the gut mucosa, underscoring the importance for further study of this immunologically important tissue in evaluating the human immune system, especially in the context of chronic disease and aging.

Bariatric procedures are associated with nutrient deficiencies. Studies show an association between gastric bypass (Roux-en-Y gastric bypass [RYGB]) and hypovitaminosis D as well as hyperparathyroidism, yet few compare RYGB to sleeve gastrectomy (SG), and large long-term analyses are scarce. Evaluate trends of vitamin D and parathyroid hormone (PTH) levels in RYGB and SG. National quality register. The Scandinavian Obesity Surgery Registry records all bariatric surgeries in Sweden. Data from 2008 to 2021 on primary RYGB or SG with reported 25-hydroxy vitamin D (25-OH-D) and/or PTH levels were included. Individuals with an estimated glomerular filtration rate of <60 mL/min/1.73 m2 were excluded, leaving a study population of 25,385 RYGB and 5073 SG patients. A decrease in 25-OH-D, mirrored by an increase in PTH, was observed after the first year for both procedures, but more pronounced in RYGB. At 5 years, 25-OH-D levels were still higher than at baseline. Regular supplementation resulted in better 25-OH-D and PTH levels. Linear regression found that procedure type (RYGB versus SG), 25-OH-D levels, and time since surgery were significant factors in predicting PTH levels. The risk of pathologic PTH levels (>7 pmol/L) at 2 and 5 years postoperatively was roughly three times higher in RYGB (odds ratios = 3.41 and 2.84, respectively). Previous studies alongside these results suggest that RYGB, more so than SG, may cause hypovitaminosis D and thereby hyperparathyroidism, which could lead to osteopenia. The threshold for 25-OH-D should be >75 nmol/L, and despite higher levels, current vitamin D supplementation may not be sufficient. Follow-up should include screening for hyperparathyroidism and hypovitaminosis D. • In both RYGBP and sleeve, 25-OH D decreased, mirrored by increased PTH. • At five years, 25-OH D levels were still higher than at baseline. • Regular supplementation resulted in better 25-OH D and PTH levels. • The risk of pathological PTH levels (>7 pmol/L) was roughly tripled in RYGBP. [ABSTRACT FROM AUTHOR]

Abstract Although metagenomics and metatranscriptomics are commonly used to identify bacteria and viruses in human samples, few studies directly compare these strategies. We wished to compare DNA and RNA sequencing of bacterial and viral metagenomes and metatranscriptomes in the human cervix. Total nucleic acids from six human cervical samples were subjected to DNA and RNA sequencing. The effect of DNase-treatment before reverse transcription to cDNA were also analyzed. Similarities and differences in the metagenomic findings with the three different sequencing approaches were evaluated. A higher proportion of human sequences were detected by DNA sequencing (93%) compared to RNA sequencing without (76%) and with prior DNase-treatment (11%). On the contrary, bacterial sequences increased 17 and 91 times. However, the number of detected bacterial genera were less by RNA sequencing, suggesting that only a few contribute to most of the bacterial transcripts. The viral sequences were less by RNA sequencing, still twice as many virus genera were detected, including some RNA viruses that were missed by DNA sequencing. Metatranscriptomics of total cDNA provided improved detection of mainly transcribed bacteria and viruses in cervical swabs as well as detection of RNA viruses, compared to metagenomics.

Objectives Early mobilisation and effective pain management after open nephrectomy for renal cell carcinoma often include epidural analgesia (EDA), requiring an infusion pump and a urinary catheter, thus impeding mobilisation. Spinal anaesthesia (SpA) may be an alternative. This randomised clinical trial evaluated whether SpA improves analgesia and facilitates mobilisation over EDA and which factors influence mobilisation and length of stay (LOS). Methods Between 2012 and 2015, 135 patients were randomised and stratified by surgical method to either SpA with clonidine or EDA. Mobility index score (MobIs), pain scale, patient satisfaction questionnaire, and LOS were the main outcome measures. Results SpA patients exhibited an increase in MobIs significantly earlier than EDA patients. Among SpA patients >50% reached MobIs ≥13 by postoperative day 3, while 29% of EDA patients never reached MobIs ≥13 before discharge. SpA patients had higher maximum pain scores on postoperative days 1 and 2, but both groups had similar patient satisfaction. One day before discharge, 36/64 SpA versus 22/67 EDA patients (56% and 33%, respectively) were opioid-free. SpA patients were discharged significantly earlier than EDA patients. Conclusions SpA facilitates postoperative pain management and is associated with faster mobilisation and shorter LOS. The trial was registered at ClinicalTrials.org (ID-NCT02030717).

Lipid nanoparticles (LNPs) are the most clinically advanced delivery system for RNA-based drugs but have predominantly been investigated for intravenous and intramuscular administration. Subcutaneous administration opens the possibility of patient self-administration and hence long-term chronic treatment that could enable messenger RNA (mRNA) to be used as a novel modality for protein replacement or regenerative therapies. In this study, we show that subcutaneous administration of mRNA formulated within LNPs can result in measurable plasma exposure of a secreted protein. However, subcutaneous administration of mRNA formulated within LNPs was observed to be associated with dose-limiting inflammatory responses. To overcome this limitation, we investigated the concept of incorporating aliphatic ester prodrugs of anti-inflammatory steroids within LNPs, i.e., functionalized LNPs to suppress the inflammatory response. We show that the effectiveness of this approach depends on the alkyl chain length of the ester prodrug, which determines its retention at the site of administration. An unexpected additional benefit to this approach is the prolongation observed in the duration of protein expression. Our results demonstrate that subcutaneous administration of mRNA formulated in functionalized LNPs is a viable approach to achieving systemic levels of therapeutic proteins, which has the added benefits of being amenable to self-administration when chronic treatment is required.

Abstract Background When working in complex environments with critically ill patients, team performance is influenced by situation awareness in teams. Moreover, improved situation awareness in the teams will probably improve team and task performance. The aim of this study is to evaluate an educational programme on situation awareness for interprofessional teams at the intensive care units using team and task performance as outcomes. Method Twenty interprofessional teams from the northern part of Sweden participated in this randomized controlled intervention study conducted in situ in two intensive care units. The study was based on three cases (cases 0, 1 and 2) with patients in a critical situation. The intervention group (n = 11) participated in a two-hour educational programme in situation awareness, including theory, practice, and reflection, while the control group (n = 9) performed the training without education in situation awareness. The outcomes were team performance (TEAM instrument), task performance (ABCDE checklist) and situation awareness (Situation Awareness Global Assessment Technique (SAGAT)). Generalized estimating equation were used to analyse the changes from case 0 to case 2, and from case 1 to case 2. Results Education in situation awareness in the intervention group improved TEAM leadership (p = 0.003), TEAM task management (p = 0.018) and TEAM total (p = 0.030) when comparing cases 1 and 2; these significant improvements were not found in the control group. No significant differences were observed in the SAGAT or the ABCDE checklist. Conclusions This intervention study shows that a 2-h education in situation awareness improved parts of team performance in an acute care situation. Team leadership and task management improved in the intervention group, which may indicate that the one or several of the components in situation awareness (perception, comprehension and projection) were improved. However, in the present study this potential increase in situation awareness was not detected with SAGAT. Further research is needed to evaluate how educational programs can be used to increase situation awareness in interprofessional ICU teams and to establish which components that are essential in these programs. Trial registration This randomized controlled trial was not registered as it does not report the results of health outcomes after a health care intervention on human participants.

Abstract Background Bariatric surgery, Roux-en-Y gastric bypass (RYGBP) in particular, is associated with weight loss as well as low bone mineral density. Bone mineral density relies upon multiple factors, some of which are lifestyle factors. The aim of this study was to compare lifestyle factors in order to eliminate them as culprits of the suspected difference in BMD in RYGBP operated and controls. Materials and methods Study participants included 71 RYGBP-operated women (42.3 years, BMI 33.1 kg/m2) and 94 controls (32.4 years, BMI 23.9 kg/m2). Each completed a DEXA scan, as well as survey of lifestyle factors (e.g. physical activity in daily life, corticosteroid use, and calcium intake). All study participants were premenopausal Caucasian women living in the same area. Blood samples were taken in RYGBP-patients. Results BMD was significantly lower in RYGBP, femoral neck 0.98 vs. 1.04 g/cm2 compared to controls, despite higher BMI (present and at 20 years of age) and similar physical activity and calcium intake. In a multivariate analysis, increased time since surgery and age were negatively associated with BMD of the femoral neck and total hip in RYGBP patients. Conclusion Despite similar lifestyle, RYGBP was followed by a lower BMD compared to controls. Thus, the reduced BMD in RYGBP cannot be explained, seemingly nor prevented, by lifestyle factors. As the reduction in BMD was associated with time since surgery, strict follow-up is a lifelong necessity after bariatric surgery, and especially important in younger bariatric patients.

Patients with treated HIV-1-infection experience earlier occurrence of aging-associated diseases, raising speculation that HIV-1-infection, or antiretroviral treatment, may accelerate aging. We recently described an age-related co-methylation module comprised of hundreds of CpGs; however, it is unknown whether aging and HIV-1-infection exert negative health effects through similar, or disparate, mechanisms. We investigated whether HIV-1-infection would induce age-associated methylation changes. We evaluated DNA methylation levels at >450,000 CpG sites in peripheral blood mononuclear cells (PBMC) of young (20-35) and older (36-56) adults in two separate groups of participants. Each age group for each data set consisted of 12 HIV-1-infected and 12 age-matched HIV-1-uninfected samples for a total of 96 samples. The effects of age and HIV-1 infection on methylation at each CpG revealed a strong correlation of 0.49, p

Abstract Background Granulomatous myositis is a rare condition in both humans and dogs. In humans it is most frequently related to sarcoidosis, where a concurrent granulomatous neuritis has been reported occasionally. Simultaneous granulomatous myositis and neuritis have been diagnosed previously in dogs (unpublished observations), but have not been studied further. Additional investigations are therefore warranted to characterize this disorder. Here we present a detailed description of concurrent idiopathic granulomatous myositis and granulomatous neuritis in a dog with suspected immune-mediated aetiology. Case presentation The dog presented with dysphonia and paresis in the pelvic limbs and tail. In addition to muscle biopsies being taken for histopathology, magnetic resonance imaging, computed tomography and electrodiagnostics were performed. Muscle biopsies displayed granuloma formation with giant cells and epithelioid macrophages in muscle fibres and nerve branches. Microorganisms were not detected. Long-term treatment with glucocorticoids was clinically successful. Two years after the clinical signs started, the dog presented with signs of sepsis and died. Histopathologically, no granulomatous inflammation could be demonstrated in either muscles or nerves at that time. Conclusions This case illustrates a granulomatous interstitial polymyositis and intramuscular neuritis that improved clinically and resolved histologically with glucocorticoid treatment. Idiopathic granulomatous myositis and neuritis should be considered as a differential diagnosis in dogs with clinical signs of neuromuscular disorders.

Abstract The extent that antibodies to SARS-CoV-2 may protect against future virus-associated disease is unknown. We invited all employees (n = 15,300) at work at the Karolinska University Hospital, Stockholm, Sweden to participate in a study examining SARS-Cov-2 antibodies in relation to registered sick leave. For consenting 12,928 healthy hospital employees antibodies to SARS-CoV-2 could be determined and compared to participant sick leave records. Subjects with viral serum antibodies were not at excess risk for future sick leave (adjusted odds ratio (OR) controlling for age and sex: 0.85 [95% confidence interval (CI) (0.85 (0.43–1.68)]. By contrast, subjects with antibodies had an excess risk for sick leave in the weeks prior to testing [adjusted OR in multivariate analysis: 3.34 (2.98–3.74)]. Thus, presence of viral antibodies marks past disease and protection against excess risk of future disease. Knowledge of whether exposed subjects have had disease in the past or are at risk for future disease is essential for planning of control measures. Trial registration: First registered on 02/06/20, ClinicalTrials.gov NCT04411576.

Abstract Background Fms-related tyrosine kinase 3 (FLT3) receptor serves as a prognostic marker and therapeutic target in acute myeloid leukemia (AML). Approximately one-third of AML patients carry mutation in FLT3, associated with unfavourable prognosis and high relapse rate. The multitargeted kinase inhibitor midostaurin (PKC412) in combination with standard chemotherapy (daunorubicin and cytarabine) was recently shown to increase overall survival of AML patients. For that reason, PKC412 has been approved for treatment of AML patients with FLT3-mutation. PKC412 synergizes with standard chemotherapy, but the mechanism involved is not fully understood and the risk of relapse is still highly problematic. Methods By utilizing the unique nature of mass cytometry for single cell multiparameter analysis, we have explored the proteomic effect and intracellular signaling response in individual leukemic cells with internal tandem duplication of FLT3 (FLT3-ITD) after midostaurin treatment in combination with daunorubicin or cytarabine. Results We have identified a synergistic inhibition of intracellular signaling proteins after PKC412 treatment in combination with daunorubicin. In contrast, cytarabine antagonized phosphorylation inhibition of PKC412. Moreover, we found elevated levels of FLT3 surface expression after cytarabine treatment. Interestingly, the surface localization of FLT3 receptor increased in vivo on the blast cell population of two AML patients during day 3 of induction therapy (daunorubicin; once/day from day 1–3 and cytarabine; twice/day from day 1–7). We found FLT3 receptor expression to correlate with intracellular cytarabine (AraC) response. AML cell line cultured with AraC with or without PKC412 had an antagonizing phosphorylation inhibition of pAKT (p = 0.042 and 0.0261, respectively) and pERK1/2 (0.0134 and 0.0096, respectively) in FLT3high compared to FLT3low expressing cell populations. Conclusions Our study provides insights into how conventional chemotherapy affects protein phosphorylation of vital signaling proteins in human leukemia cells. The results presented here support further investigation of novel strategies to treat FLT3-mutated AML patients with PKC412 in combination with chemotherapy agents and the potential development of novel treatment strategies.

Previous studies indicate that school climate is important for student health and academic achievement. This study concerns the validity and reliability of the student edition a Swedish instrument for measuring pedagogical and social school climate (PESOC). Data were collected from 5,745 students at 97 Swedish secondary schools. Multilevel confirmatory factor analyses were conducted, and multilevel composite reliability estimates, as well as correlations with school-level achievement indicators, were calculated. The results supported an 8-factor structure at the student level and 1 general factor at the school level. Factor loadings and composite reliability estimates were acceptable at both levels. The school-level factor was moderately and positively correlated with school-level academic achievement. The student PESOC is a promising instrument for studying school climate.

The aim of this article is to explore how children use and reuse semiotic resources in their writing of hybrid genres in school. In focus are children's use and reuse of semiotic resources from both earlier literacy events at school and literacy events they have experienced at home or in their leisure time. This double focus is rare in previous studies and thus the study contributes new insights concerning how children's writing can be understood as a hybridization process in which semiotic resources from different literacy practices in school and out of school interplay. The theoretical framework of the study is based on New Literacy Studies, social semiotics and genre theories. The methodological approach is semiotic ethnography. The material is based on videotaped classroom observations of a particular writing process consisting of both collective and individual writing, as well as on the texts produced. A genre analysis is conducted in three steps, in order to explore the reuse of semiotic resources from literacy events in and out of school in five children's texts. The results of this analysis show children's creative ways of reusing semiotic resources, not only from literacy events and practices outside of school but also from previous literacy events in school. These creative ways of children engaging in hybridization processes while writing a narrative in sub-genres within an official literacy event in school can be understood as the children seizing agency in order to influence their own practice.