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Background When more patients with congenital heart disease reach adult age, increased incidence of long‐term complications, including ischemic stroke, are expected. The aim of this study was to analyze cumulative incidence of ischemic stroke, associated factors, and case fatality in adult congenital heart disease. Methods and Results The study is based on Swedish national registers on congenital heart disease and stroke. Patients with congenital heart disease were followed between 2001 and 2018 for first‐ever ischemic stroke events (ischemic stroke due to patent foramen ovale excluded). Factors possibly associated with ischemic stroke were analyzed using Cox regression models. Out of 8914 adult patients with congenital heart disease, 108 suffered ischemic stroke over a mean period of 7.6±4.7 years. The mean age at ischemic stroke was 53.8 years, and the cumulative incidence was 0.15% at 1 year, 0.5% at 5 years, and 1.5% at 10 years. In multivariable analysis, age (hazard ratio [HR], 1.04 [95% CI, 1.03–1.06]), diabetes (HR, 2.9 [95% CI, 1.3–6.4]), ejection fraction

Background: The benefit of prophylactic whole pelvis radiation therapy (WPRT) in prostate cancer has been debated for decades, with evidence based mainly on conventional fractionation targeting pelvic nodes. Aim: This retrospective cohort study aimed to explore the impact of adding moderately hypofractionated pelvic radiotherapy to prostate-only irradiation (PORT) on prognosis, toxicity, and quality of life in real-world settings. Materials and methods: Patients with high-risk and conventionally staged prostate cancer (cT1-3N0M0) treated with moderately hypofractionated WPRT or PORT, using external beam radiotherapy alone or combined with high-dose-rate brachytherapy, at Örebro University Hospital between 2008 and 2021 were identified. Biochemical failure-free survival (BFFS), metastasis-free survival (MFS), prostate cancer-specific survival (PCSS), and overall survival (OS) were compared using Kaplan-Meier method and Cox proportional hazards. Toxicity and quality of life measures were also analysed. Results: Among 516 patients (227 PORT, 289 WPRT), 5-year BFFS rates were 77 % (PORT) and 74 % (WPRT), adjusted HR=1.50 (95 % CI=0.88–2.55). No significant differences were found in MFS, PCSS, or OS in main analyses. WPRT was associated with a higher risk of acute grade ≥ 2 and 3 genitourinary toxicities whereas no differences in late toxicities or quality of life between PORT and WPRT were observed. Conclusion: We found no significant differences in oncological outcomes or quality of life when comparing moderately hypofractionated PORT to WPRT. Some differences in toxicity patterns were observed. Despite caveats related to study design, our findings support the need for further research on WPRT’s impact on treatment-related and patient-reported outcomes.

Background Young people with congenital heart disease (CHD) are frequently affected by discontinued follow-up when transferring from paediatric to adult care. Identified predictors for discontinuation include mostly patient-related factors, and further knowledge of hospital and healthcare system factors is needed.Aim This study aims to explore patient-related, hospital-related and healthcare system-related factors affecting continued follow-up care after transfer, as perceived and experienced by paediatric cardiology and adult CHD (ACHD) healthcare providers (HCPs) in Sweden and Belgium.Methods This descriptive qualitative study included individual interviews with cardiologists, nurses and administrative staff, subjected to qualitative content analysis. A total of 30 HCPs from 13 specialist care outpatient clinics at 8 different centres in Sweden and Belgium were interviewed. HCPs were included if they had direct contact with patients and had at least 1 year of work experience.Findings The findings illuminate three main categories of factors perceived by HCPs to affect continued follow-up care after transfer, including ‘care structure’, ‘care processes’ and ‘patient characteristics and circumstances’. Success was described as multifactorial, emphasising processes and structures of care, with a focus on collaboration, organisation, joint responsibility, resources, care relationships and transitional care interventions. Few differences appeared between paediatric and ACHD HCPs and between Swedish and Belgian HCPs.Conclusion HCPs perceived factors on patient, hospital and healthcare system levels to influence continued follow-up. Process-related and structure-related aspects of care were perceived as more influential than individual patient characteristics. Hence, future research on discontinued follow-up care should focus on process-related and structure-related aspects of care delivery.

In contemporary media environments, mainstream news media have become increasingly challenged by political alternative media. Even though research on how political alternative media cover politics and society has increased, there is still limited research comparing how political alternative media and mainstream news media cover key political events, such as election campaigns. To fill this gap, the purpose of this study is to compare election news coverage in political alternative and mainstream news media, drawing theoretically on theories related to mediatization and structural bias on the one hand, and politicization and political bias on the other. Empirically, the overarching research question is how election coverage in left- and right-wing political alternative and mainstream media differs. Findings suggest that political alternative media do function as an alternative to mainstream news media in that they offer more politicized coverage of election campaigns. However, left-wing, and right-wing political alternative media also constitute alternatives to each other in how the election campaigns are covered.

Abstract Background The number of pregnant women with congenital heart disease (CHD) is rising, and the disease poses increased risks of cardiovascular and obstetric complications during pregnancy, potentially impacting breastfeeding success. This study aimed to investigate breastfeeding in primiparous women with CHD compared to primiparous women without CHD, and to examine potential hindering factors for breastfeeding in women with CHD. Methods The data were gathered between 2014 and 2019 and obtained by merging the Swedish Congenital Heart Disease Register (SWEDCON) with the Swedish Pregnancy Register. Primiparous women ≥ 18 years of age with CHD (n = 578) were matched by age and municipality to 3049 women without CHD, giving birth after 22 gestational weeks. Multivariable logistic regression analysis was used to identify factors associated with non-breastfeeding in women with CHD. Results Fewer women with CHD breastfed than women without CHD two days (94% vs. 97%, p = 0.001) and four weeks after birth (84% vs. 89%, p = 0.006). When all women were analysed, having CHD was associated with non-breastfeeding at both two days and four weeks after birth. For women with CHD, body mass index (BMI) ≥ 30 (OR 3.1; 95% CI 1.4, 7.3), preterm birth (OR 6.4; 95% CI 2.1, 19.0), self-reported history of psychiatric illness (OR 2.4; 95% CI 1.2, 5.1), small for gestational age (OR 4.2; 95% CI 1.4, 12.2), and New York Heart Association Stages of Heart Failure class II − III (OR 6.0; 95% CI 1.4, 26.7) were associated with non-breastfeeding two days after birth. Four weeks after birth, factors associated with non-breastfeeding were BMI ≥ 30 (OR 4.3; 95% CI 2.1, 9.0), self-reported history of psychiatric illness (OR 2.2; 95% CI 1.2, 4.2), and preterm birth (OR 8.9; 95% CI 2.8, 27.9). Conclusions The study shows that most women with CHD breastfeed, however, at a slightly lower proportion compared to women without CHD. In addition, factors related to the heart disease were not associated with non-breastfeeding four weeks after birth. Since preterm birth, BMI ≥ 30, and psychiatric illness are associated with non-breastfeeding, healthcare professionals should provide greater support to women with CHD having these conditions.

Objective To investigate the time to first childbirth and to compare the prevalence of assisted reproductive treatment (ART) in women with congenital heart disease (CHD) compared with women without CHD.Methods All women in the national register for CHD who had a registered first childbirth in the Swedish Pregnancy Register between 2014 and 2019 were identified. These individuals (cases) were matched by birth year and municipality to women without CHD (controls) in a 1:5 ratio. The time from the 18th birthday to the first childbirth and the prevalence of ART was compared between cases and controls.Results 830 first childbirths in cases were identified and compared with 4137 controls. Cases were slightly older at the time for first childbirth (28.9 vs 28.5 years, p=0.04) and ART was more common (6.1% vs 4.0%, p

Abstract Background Dynamic spirometry is an important investigation to differentiate between impaired and normal lung function. This study aimed to evaluate the results of lung function testing in a cohort of subjects from Northern Sweden without any known heart or pulmonary disease. Our focus was to compare with two reference materials that have showed differences in the age-dependency of lung function in Swedish subjects. Methods The study population consisted of 285 healthy adults (148 males, 52%) between 20–90 years of age. The subjects had been randomly selected from the population register for inclusion in a study investigating cardiac function in heart-healthy subjects, but were also assessed with dynamic spirometry. At least seven percent reported smoking. Sixteen subjects presented with pulmonary functional impairments and were excluded from the current study. The sex-specific age-dependency in lung volumes was estimated using the LMS model, where non-linear equations were derived for the mean value (M), the location (L) or skewness, and the scatter (S) or coefficient of variation. This model of the observed lung function data was compared with reference values given by the original LMS model published by the Global Lung Initiative (GLI), and with the model from the recent Obstructive Lung Disease In Norrbotten (OLIN) study, where higher reference values were presented for Swedish subjects than those given by the GLI model. Results No differences were found in the age-dependency of pulmonary function between the LMS model developed in the study and the OLIN model. Although the study group included smokers, the original GLI reference values suggested significantly lower normal values of FEV1 (forced expiratory volume) and FVC (forced vital capacity), and consequently fewer subjects below the lower limit of normality, than both the rederived LMS and OLIN models. Conclusions Our results are in line with previous reports and support that the original GLI reference values underestimate pulmonary function in the adult Swedish population. This underestimation could be reduced by updating the coefficients in the underlying LMS model based on a larger cohort of Swedish citizens than was available in this study.

The common pathogen Group A Streptococcus (GAS, Streptococcus pyogenes) is an extracellular bacterium that is associated with a multitude of infectious syndromes spanning a wide range of severity. The surface-exposed M protein is a major GAS virulence factor that is also target for protective antibody responses. In this study, we use a murine immunization model to investigate aspects of the cellular and molecular foundation for protective adaptive immune responses generated against GAS. We show that a wild type M1 GAS strain induces a non-protective antibody response, while an isogenic strain carrying the immunodominant 2W T helper cell epitope within the M protein elicits an immune response that is protective against the parental non-recombinant M1 GAS strain. Although the two strains induce total anti-GAS IgG levels of similar magnitude, only the 2W-carrying strain promotes elevated titers of the complement-fixing IgG2c subclass. Protection is dependent on IFN-γ, and IFN-γ-deficient mice show a specific reduction in IgG2c levels. Our findings suggest that inclusion of the 2W T cell epitope in the M protein confers essential qualitative alterations in the adaptive immune response against GAS, and that sparsity in IFN-γ-promoting Th cell epitopes in the M protein may constitute an immune evasion mechanism, evolved to allow the pathogen to avoid attack by complement-fixing antibodies.

Summary: Group B streptococcus (GBS) is a leading cause of life-threatening neonatal infections and subsets of adverse pregnancy outcomes. Essentially all GBS strains possess one allele of the alpha-like protein (Alp) family. A maternal GBS vaccine, consisting of the fused N-terminal domains of the Alps αC and Rib (GBS-NN), was recently demonstrated to be safe and immunogenic in healthy adult women. To enhance antibody responses to all clinically relevant Alps, a second-generation vaccine has been developed (AlpN), also containing the N-terminal domain of Alp1 and the one shared by Alp2 and Alp3. In this study, the safety and immunogenicity of AlpN is assessed in a randomized, double-blind, placebo-controlled, and parallel-group phase I study, involving 60 healthy non-pregnant women. AlpN is well tolerated and elicits similarly robust and persistent antibody responses against all four Alp-N-terminal domains, resulting in enhanced opsonophagocytic killing of all Alp serotypes covered by the vaccine.

Background and aimAlkaline sphingomyelinase (NPP7) is expressed by intestinal epithelial cells and is crucial for the digestion of dietary sphingomyelin. NPP7 also inactivates proinflammatory mediators including platelet-activating factor and lysophosphatidylcholine. The aim of this study was to examine a potential role for NPP7 in the homeostasis of the intestinal immune system.MethodsWe quantified the numbers of B-lymphocytes, plasma cells, T-lymphocytes including regulatory T-lymphocytes (Tregs), natural killer cells, dendritic cells, macrophages, and neutrophils, in the small and large intestines, the mesenteric lymph nodes and the spleens of heterozygous and homozygous NPP7 knockout (KO) and wildtype (WT) mice. Tissues were examined by immunohistochemistry and stainings quantified using computerized image analysis.ResultsThe numbers of both small and large intestinal CD3ε+, CD4+, and CD8α+ T-lymphocytes were significantly higher in NPP7 KO compared to WT mice (with a dose-response relationship in the large intestine), whereas Treg numbers were unchanged, and dendritic cell numbers reduced. In contrast, the numbers of CD3ε+ and CD4+ T-lymphocytes in mesenteric lymph nodes were significantly reduced in NPP7 KO mice, while no differences were observed in spleens. The numbers of B-lymphocytes, plasma cells, natural killer cells, macrophages, and neutrophils were similar between genotypes.ConclusionNPP7 contributes to the regulation of dendritic cell and T-lymphocyte numbers in mesenteric lymph nodes and both the small and large intestines, thus playing a role in the homeostasis of gut immunity. Although it is likely that the downstream effects of NPP7 activity involve the sphingomyelin metabolites ceramide and spingosine-1-phosphate, the exact mechanisms behind this regulatory function of NPP7 need to be addressed in future studies.

Abstract Background A substantial proportion of young people with Complex Chronic Conditions (CCCs) experience some degree of discontinuation of follow-up care, which is an umbrella term to describe a broken chain of follow-up. Discontinuation of follow-up care is not clearly defined, and the great plethora of terms used within this field cannot go unnoticed. Terms such as “lost to follow-up”, “lapses in care” and “care gaps”, are frequently used in published literature, but differences between terms are unclear. Lack of uniformity greatly affects comparability of study findings. The aims of the present study were to (i) provide a systematic overview of terms and definitions used in literature describing discontinuation of follow-up care in young people with CCC’s; (ii) to clarify operational components of discontinuation of follow-up care (iii); to develop conceptual definitions and suggested terms to be used; and (iv) to perform an expert-based evaluation of terms and conceptual definitions. Methods A systematic literature search performed in PubMed was used to provide an overview of current terms used in literature. Using a modified summative content analysis, operational components were analysed, and conceptual definitions were developed. These conceptual definitions were assessed by an expert panel using a survey. Results In total, 47 terms and definitions were retrieved, and a core set of operational components was identified. Three main types of discontinuation of follow-up care emerged from the analysis and expert evaluation, conceptually defined as follows: Lost to follow-up care : “No visit within a defined time period and within a defined context, and the patient is currently no longer engaged in follow-up care”; Gap in follow-up care: “Exceeded time interval between clinic visits within a defined context, and the patient is currently engaged in follow-up care”; and Untraceability: “Failure to make contact due to lack of contact information”. Conclusion By creating a common vocabulary for discontinuation of follow-up care, the quality of future studies could improve. The conceptual definitions and operational components provide guidance to both researchers and healthcare professionals focusing on discontinuation of follow-up care for young people with CCCs.

Background Coarctation of the aorta coexists with other cardiac anomalies and has long‐term complications, including recoarctation, which may require intervention after the primary coarctation repair. This study aims to clarify the prevalence of and risk factors for interventions related to the coarctation complex as well as late mortality in a large contemporary patient population. Methods and Results The Swedish National Register of Congenital Heart Disease was used, which comprised 683 adults with repaired coarctation of the aorta. Analysis was performed on freedom from intervention thereafter at the coarctation site, aortic valve, left ventricular outflow tract, or ascending aorta. One hundred ninety‐six (29%) patients had at least 1 of these interventions. Estimated freedom from either of these interventions was 60% after 50 years. The risk of undergoing such an intervention was higher among men (hazard ratio, 1.6 [95% CI, 1.2–2.2]). Estimated freedom from another intervention at the coarctation site was 75% after 50 years. In women, there was an increase in interventions at the coarctation site after 45 years. Patients who underwent one of the previously mentioned interventions after the primary coarctation repair had poorer left ventricular function. Eighteen patients (3%) died during follow‐up in the register. The standardized mortality ratio was 2.9 (95% CI, 1.7–4.3). Conclusions Interventions are common after coarctation repair. The risk for and time of interventions are affected by sex. Our results have implications for planning follow‐up and giving appropriate medical advice to the growing population of adults with repaired coarctation of the aorta.

Background Little is known about the cause of death (CoD) in patients with transposition of the great arteries palliated with a Mustard or Senning procedure. The aim was to describe the CoD for patients with the Mustard and Senning procedure during short‐ (20 years) follow‐up after the operation. Methods and Results This is a retrospective, descriptive multicenter cohort study including all Nordic patients (Denmark, Finland, Norway, and Sweden) who underwent a Mustard or Senning procedure between 1967 and 2003. Patients who died within 30 days after the index operation were excluded. Among 968 patients with Mustard/Senning palliated transposition of the great arteries, 814 patients were eligible for the study, with a mean follow‐up of 33.6 years. The estimated risk of all‐cause mortality reached 36.0% after 43 years of follow‐up, and the risk of death was highest among male patients as compared with female patients (P=0.004). The most common CoD was sudden cardiac death (SCD), followed by heart failure/heart transplantation accounting for 29% and 27%, respectively. During short‐, mid‐, and long‐term follow‐up, there was a change in CoD with SCD accounting for 23.7%, 46.6%, and 19.0% (P=0.002) and heart failure/heart transplantation 18.6%, 22.4%, and 46.6% (P=0.0005), respectively. Conclusions Among patients corrected with Mustard or Senning transposition of the great arteries, the most common CoD is SCD followed by heart failure/heart transplantation. The CoD changes as the patients age, with SCD as the most common cause in adolescence and heart failure as the dominant cause in adulthood. Furthermore, the risk of all‐cause mortality, SCD, and death attributable to heart failure or heart transplantation was increased in men >10 years after the Mustard/Senning operation.

Type I interferons (IFNs) are essential for antiviral immunity, appear to represent a key component of mRNA vaccine-adjuvanticity, and correlate with severity of systemic autoimmune disease. Relevant to all, type I IFNs can enhance germinal center (GC) B cell responses but underlying signaling pathways are incompletely understood. Here, we demonstrate that a succinct type I IFN response promotes GC formation and associated IgG subclass distribution primarily through signaling in cDCs and B cells. Type I IFN signaling in cDCs, distinct from cDC1, stimulates development of separable Tfh and Th1 cell subsets. However, Th cell-derived IFN-γ induces T-bet expression and IgG2c isotype switching in B cells prior to this bifurcation and has no evident effects once GCs and bona fide Tfh cells developed. This pathway acts in synergy with early B cell-intrinsic type I IFN signaling, which reinforces T-bet expression in B cells and leads to a selective amplification of the IgG2c+ GC B cell response. Despite the strong Th1 polarizing effect of type I IFNs, the Tfh cell subset develops into IL-4 producing cells that control the overall magnitude of the GCs and promote generation of IgG1+ GC B cells. Thus, type I IFNs act on B cells and cDCs to drive GC formation and to coordinate IgG subclass distribution through divergent Th1 and Tfh cell-dependent pathways.

Abstract Objective To derive cluster analysis-based groupings for adults with congenital heart disease (ACHD) when it comes to perceived health, psychological functioning, health behaviours and quality of life (QoL). Methods This study was part of a larger worldwide multicentre study called APPROACH-IS; a cross sectional study which recruited 4028 patients (2013–2015) from 15 participating countries. A hierarchical cluster analysis was performed using Ward's method in order to group patients with similar psychological characteristics, which were defined by taking into consideration the scores of the following tests: Sense Of Coherence, Health Behavior Scale (physical exercise score), Hospital Anxiety Depression Scale, Illness Perception Questionnaire, Satisfaction with Life Scale and the Visual Analogue Scale scores of the EQ-5D perceived health scale and a linear analogue scale (0–100) measuring QoL. Results 3768 patients with complete data were divided into 3 clusters. The first and second clusters represented 89.6% of patients in the analysis who reported a good health perception, QoL, psychological functioning and the greatest amount of exercise. Patients in the third cluster reported substantially lower scores in all PROs. This cluster was characterised by a significantly higher proportion of females, a higher average age the lowest education level, more complex forms of congenital heart disease and more medical comorbidities. Conclusions This study suggests that certain demographic and clinical characteristics may be linked to less favourable health perception, quality of life, psychological functioning, and health behaviours in ACHD. This information may be used to improve psychosocial screening and the timely provision of psychosocial care.

Hydrogen (H2) is currently a highly attractive fuel for internal combustion engines (ICEs) owing to the prospects of potentially near-zero emissions. However, the production emissions and cost of H2 fuel necessitate substantial improvements in ICE thermal efficiency. This work aims to investigate a potential implementation of H2 combustion in a highly efficient double compression-expansion engine (DCEE). DICI nonpremixed H2 combustion mode is used for its superior characteristics, as concluded in previous studies. The analysis is performed using a 1D GT-Power software package, where different variants of the DICI H2 and diesel combustion cycles, obtained experimentally and numerically (3D CFD) are imposed in the combustion cylinder of the DCEE. The results show that the low jet momentum, free jet mixing dominated variants of the DICI H2 combustion concept are preferred, owing to the lower heat transfer losses and relaxed requirements on the fuel injection system. Insulation of the expander and removal of the intercooling improve the engine efficiency by 1.3 and 0.5%-points, respectively, but the latter leads to elevated temperatures in the high-pressure tank, which makes the selection of its materials harder but allows the use of cheaper oxidation catalysts. The results also show that the DCEE performance is insensitive to combustion cylinder temperatures, making it potentially suitable for other high-octane fuels, such as methane, methanol, ammonia, etc. Finally, a brake thermal efficiency of 56% is achieved with H2 combustion, around 1%-point higher than with diesel. Further efficiency improvements are also possible with a fully optimized H2 combustion system.

Background Heart failure (HF) is the leading cause of mortality and associated with significant morbidity in adults with congenital heart disease. We sought to assess the association between HF and patient‐report outcomes in adults with congenital heart disease. Methods and Results As part of the APPROACH‐IS (Assessment of Patterns of Patient‐Reported Outcomes in Adults with Congenital Heart disease—International Study), we collected data on HF status and patient‐reported outcomes in 3959 patients from 15 countries across 5 continents. Patient‐report outcomes were: perceived health status (12‐item Short Form Health Survey), quality of life (Linear Analogue Scale and Satisfaction with Life Scale), sense of coherence‐13, psychological distress (Hospital Anxiety and Depression Scale), and illness perception (Brief Illness Perception Questionnaire). In this sample, 137 (3.5%) had HF at the time of investigation, 298 (7.5%) had a history of HF, and 3524 (89.0%) had no current or past episode of HF. Patients with current or past HF were older and had a higher prevalence of complex congenital heart disease, arrhythmias, implantable cardioverter‐defibrillators, other clinical comorbidities, and mood disorders than those who never had HF. Patients with HF had worse physical functioning, mental functioning, quality of life, satisfaction with life, sense of coherence, depressive symptoms, and illness perception scores. Magnitudes of differences were large for physical functioning and illness perception and moderate for mental functioning, quality of life, and depressive symptoms. Conclusions HF in adults with congenital heart disease is associated with poorer patient‐reported outcomes, with large effect sizes for physical functioning and illness perception. Registration URL: https://clinicaltrials.gov; Unique identifier: NCT02150603.

Abstract Background The relationship between healthcare system inputs (e.g., human resources and infrastructure) and mortality has been extensively studied. However, the association between healthcare system inputs and patient-reported outcomes remains unclear. Hence, we explored the predictive value of human resources and infrastructures of the countries’ healthcare system on patient-reported outcomes in adults with congenital heart disease. Methods This cross-sectional study included 3588 patients with congenital heart disease (median age = 31y; IQR = 16.0; 52% women; 26% simple, 49% moderate, and 25% complex defects) from 15 countries. The following patient-reported outcomes were measured: perceived physical and mental health, psychological distress, health behaviors, and quality of life. The assessed inputs of the healthcare system were: (i) human resources (i.e., density of physicians and nurses, both per 1000 people) and (ii) infrastructure (i.e., density of hospital beds per 10,000 people). Univariable, multivariable, and sensitivity analyses using general linear mixed models were conducted, adjusting for patient-specific variables and unmeasured country differences. Results Sensitivity analyses showed that higher density of physicians was significantly associated with better self-reported physical and mental health, less psychological distress, and better quality of life. A greater number of nurses was significantly associated with better self-reported physical health, less psychological distress, and less risky health behavior. No associations between a higher density of hospital beds and patient-reported outcomes were observed. Conclusions This explorative study suggests that density of human resources for health, measured on country level, are associated with patient-reported outcomes in adults with congenital heart disease. More research needs to be conducted before firm conclusions about the relationships observed can be drawn. Trial registration ClinicalTrials.gov: NCT02150603 . Registered 30 May 2014,

B cells interact with T follicular helper (Tfh) cells in germinal centers (GCs) to generate high-affinity antibodies. Much less is known about how cognate T–B-cell interactions influence Th cells that enter circulation and peripheral tissues. Therefore, we generated mice lacking MHC-II expressing B cells and, by thoracic duct cannulation, analyzed Th cells in the efferent lymph at defined intervals post-immunization. Focusing on gut-draining mesenteric lymph nodes (MLNs), we show that antigen-specific α4β7+ gut-homing effector Th cells enter the circulation prior to CXCR5+PD-1+ Tfh-like cells. B cells appear to have no or limited impact on the early generation and egress of gut-homing Th cells but are critical for the subsequent appearance of Tfh-like cells that peak in the lymph before GCs have developed. At this stage, antigen-presenting B cells also reduce the proportion of α4β7+ Th cells in the MLN and efferent lymph. Furthermore, cognate B-cell interaction drives a broad transcriptional program in Th cells, including IL-4 that is confined to the Tfh cell lineage. The IL-4-producing Tfh-like cells originate from Bcl6+ precursors in the LNs and have gut-homing capacity. Hence, B cells program the efferent lymph Th cell response within a limited window of time after antigenic challenge.

Carbon pricing has now been implemented as a key policy instrument for climate change mitigation in many countries globally. However, existing systems differ significantly in design with regard to stringency, coverage and the use of the revenues collected through the system. In this literature study, we synthesise existing knowledge of how key factors affect the adoption, implementation, and design of carbon pricing systems. We find that the characteristics of actual political systems, the degree and nature of business influence and public opposition, as well as international influences, have impacted implementation. Obstacles to implementation have been overcome by adapting the design of the systems to meet different societal interests. Preferential treatment and tax exemptions are thus common, which makes the incentives for emission mitigation less coherent across sectors. The results are of practical relevance for policy makers when designing and implementing carbon policies and indicate that carbon pricing needs to be part of a policy package in order to secure both rapid mitigation and a long-term decarbonisation. Further research is needed on the nature of obstacles to carbon pricing policies in various contexts and on how to combine carbon pricing with other types of policies.

Background: We aimed to study bone mineral density (BMD) and skeletal strength in the growing population of adults with moderate or complex congenital heart disease (CHD). Methods: Peripheral quantitative computed tomography (pQCT) was performed on the radius and tibia in 49 adults with moderate or complex CHD, and in 49 age and sex matched controls (n ​= ​23 [47%] female, mean age 36 ​± ​15.5 years.) Strength in the radius and tibia were presented, respectively, in terms of Strength-Strain Index (SSI). Results: Patients had similar total BMD as controls in both the radius (807 ​± ​82 vs. 792 ​± ​75 ​mg/cm3, p ​= ​0.3) and tibia (663 ​± ​86 vs. 689 ​± ​67 ​mg/cm3, p ​= ​0.1). In the radius, patients had a lower xSSI than controls (154 ​± ​46 vs. 175 ​± ​54 ​mm3, p ​= ​0.04) but a similar ySSI (178 ​± ​58 vs. 195 ​± ​55 ​mm3, p ​= ​0.1). In the tibia, patients had a lower xSSI (1492 ​± ​399 vs. 1780 ​± ​372 ​mm3, p ​

Background: On a group level, patients with repaired tetralogy of Fallot have impaired exercise capacity. Since exercise capacity is related to prognosis, and more patients survive into higher age, it is important to know the expected exercise capacity at different ages. Furthermore, factors associated with exercise capacity and the relation between exercise capacity and mortality need further evaluation. Methods: The national register of congenital heart disease was searched for exercise tests in adults with repaired tetralogy of Fallot. The results from exercise tests were compared with national reference data. Results: 314 patients were identified (median age 33.2 [IQR 24.8–44.7], 40.8% women). The mean percent of predicted workload was 74.8 (±19.6) % without change across ages. In multivariable analysis, NYHA class I (odds ratio [OR]4.2, 95% confidence interval [CI]1.7–10.0) and higher physical activity level (>3 ​h/week) (OR 3.6, 95%CI 1.8–7.3) were positively associated with higher exercise capacity, while ongoing cardiovascular therapy (OR 0.4, 95%CI 0.2–0.7) and male sex (OR 0.3, 95%CI 0.2–0.6) were negatively associated with higher exercise capacity. Both exercise capacity (HR 0.96, 95%CI 0.93–0.98) and heart rate reserve (HR 0.96, 95%CI 0.94–0.98) were associated with mortality. Conclusions: In patients with repaired tetralogy of Fallot the exercise capacity was approximately 75% of expected, regardless of age. Patients with better NYHA class and high physical activity level had a higher exercise capacity. Low exercise capacity and low heart rate reserve were associated with higher mortality. Therefore, evaluating exercise capacity as part of follow up is of importance.

Background: Patients with adult congenital heart disease (ACHD) have many risk factors for chronic pain such as prior cardiac interventions and adult comorbidities. However, the prevalence of chronic pain has not been well described in this population. We sought to determine the prevalence of pain in a large international cohort of patients with ACHD. Methods: Data from the APPROACH-IS dataset was utilized for this study which includes 4028 patients with ACHD from 15 different countries. The prevalence of pain was assessed under the health status patient reported outcome domain utilizing the EuroQol-5D 3 level version tool. Multivariable logistic regression was used to assess differences across countries in pain, taking into account country-level random effects for clustering across observations within each country. Results: A total of 3832 patients with ACHD met the study criteria, median age 32 years [IQR 25, 42], 52.6% females. The prevalence of at least moderate pain was reported by 28.9% (95% CO 27.5 ​= ​30.3%) of participants. Pain was associated with country of origin, age, gender, background, education and marital status as well as several clinical variables including disease complexity, cardiac device presence, history of heart failure, psychiatric conditions and presence of other medical conditions. Those with pain had lower levels of perceived health and a lower quality of life score. Conclusion: Pain in patients with ACHD is common, impacting nearly one-third of patients. Given the far reaching implications of pain in patients with ACHD, further study of pain characteristics and treatment management appear warranted.

Objective This qualitative study describes factors affecting continued follow-up as perceived and experienced by young adults with CHD.Participants Using a mixed purposive sampling technique, 16 young adults with CHD were included. Three participants had discontinued follow-up care and 13 had continued follow-up care after transfer.Setting Participants were recruited from all seven university hospitals in Sweden, which is considered a low-prevalence setting in terms of discontinuation.Design Individual interviews were performed and subjected to qualitative content analysis.Results The analysis resulted in three main categories, illuminating factors affecting continued follow-up: (1) motivation for follow-up care; (2) participation in care and sense of connectedness with healthcare provider (HCP) and (3) care accessibility. The choice of continuing follow-up or not was multifactorial. Knowledge of your CHD and the importance of continuing follow-up care was a central factor, as well as experiencing CHD-related symptoms and having ongoing or planned medical treatment or interventions. Sensing a clear purpose with follow-up care was facilitating, as was feeling well treated and cared for by HCPs. Practical aspects, such as travel distance was also stressed, as well as active invitations and reminders for visits.Conclusion Factors on both patient, hospital and healthcare system level were raised by participants, stressing the importance of holistic approaches when developing preventive strategies for discontinuation. There is a need for improved skills and competencies among HCPs, as well as a person-centred approach to follow-up care. In addition, specific healthcare needs and remaining transitional needs after transfer to adult care require careful consideration to prevent discontinuation.

Background: Peripheral muscle factors are presumed to be contributors to the reduced exercise capacity in congenital heart disease (CHD), but the underlying mechanisms are poorly understood. The aim was to investigate if muscle oxygenation, at rest and during exercise, and the resting blood flow in the calf muscle is impaired in adults with complex CHD in comparison to controls. Method: Seventy-four adults with complex CHD (35.6 ± 14.3 years, females n = 22 [30%], males n = 52 [70%]) and seventy-four age and sex matched subjects were recruited. Muscle oxygenation was successfully determined using near-infrared spectroscopy on the medial portion of m. gastrocnemius in 63 patients and 67 controls. Measurements were made at rest, during venous occlusion to estimate blood flow (indicated by slope increase of total haemoglobin, HbT), and post arterial occlusion. Additionally, measurements were made at the onset of isotonic unilateral heel-lifts to exhaustion and during recovery post exercise. Results: Adults with CHD had a slower desaturation rate at exercise onset (−7.7 ± 4.3%StO2x3.5sec−1 vs. −11.7 ± 5.8%StO2x3.5sec−1, p

Background: Physical activity is important to maintain and promote health. This is of particular interest in patients with congenital heart disease (CHD) where acquired heart disease should be prevented. The World Health Organization (WHO) recommends a minimum of 2.5 h/week of physical activity exceeding 3 metabolic equivalents (METS) to achieve positive health effects. It is unknown whether physical activity levels (PAL) in adult CHD patients differ by country of origin. Methods: 3896 adults with CHD recruited from 15 countries over 5 continents completed self-reported instruments, including the Health Behaviour Scale (HBS-CHD), within the APPROACH-IS project. For each patient, we calculated whether WHO recommendations were achieved or not. Associated factors were investigated using Generalized Linear Mixed Models. Results: On average, 31% reached the WHO recommendations but with a great variation between geographical areas (India: 10%–Norway: 53%). Predictors for physical activity level in line with the WHO recommendations, with country of residence as random effect, were male sex (OR 1.78, 95%CI 1.52–2.08), NYHA-class I (OR 3.10, 95%CI 1.71–5.62) and less complex disease (OR 1.46, 95%CI 1.16–1.83). In contrast, older age (OR 0.97, 95%CI 0.96–0.98), lower educational level (OR 0.41, 95%CI 0.26–0.64) and being unemployed (OR 0.57, 95%CI 0.42–0.77) were negatively associated with reaching WHO recommendations. Conclusions: A significant proportion of patients with CHD did not reach the WHO physical activity recommendations. There was a large variation in physical activity level by country of origin. Based on identified predictors, vulnerable patients may be identified and offered specific behavioral interventions. Keywords: Adult congenital heart disease, Physical activity level, Patient-reported outcome, Health-behaviour scale, Physical activity recommendation, Metabolic equivalent

Background: Physical activity reduces the risk of acquired cardiovascular disease, which is of great importance in patients with congenital heart disease (CHD). There are diverging data whether physical activity level (PAL) differs between patients with CHD and controls. Furthermore, it is unknown if PAL can be reliably assessed in patients with CHD using self-reported instruments. Methods: Seventy-five patients with CHD (mean age 37.5 ± 15.5 years, women n = 29 [38.7%]) and 42 age and sex matched controls completed the International Physical Activity Questionnaire (IPAQ) and carried the activity monitor Actiheart over 4 days. Time spent at ≥3 METS ≥21.4 min/day, i.e. reaching the WHO recommendation for PAL to promote health, was used as the outcome measure. Data on PAL obtained from IPAQ were compared with Actiheart. Results: The proportion of individuals reaching target PAL according to IPAQ was similar in patients with CHD and controls (70.7%vs.76.2%, p = 0.52) as well as between patients with simple and complex lesions. There was an overall difference between IPAQ and Actiheart in detecting recommended PAL (72.6%vs.51.3%, p

Aims High-sensitivity troponin T (hs-TnT) and high-sensitivity C reactive protein (hs-CRP) may convey prognostic information in patients with aortic stenosis (AS). This study evaluated if hs-TnT and hs-CRP associate with myocardial mass, and risk of future surgery for AS.Methods In total, 336 patients (48% women) with surgery for AS with previous participation in large population surveys were identified. Preoperatively, myocardial mass and the presence of coronary artery disease (CAD) were assessed. Two matched referents were allocated for each case, and hs-TnT and hs-CRP were determined in stored plasma from the baseline survey. Conditional logistic regression analysis was used to estimate the risk (OR (95% CI)) related to one (natural logarithm) SD increase in hs-TnT and hs-CRP. Kaplan-Mayer and Cox regression analyses were used to evaluate time to surgery.Results Median age (IQR) was 59.8 (10.3) years at survey, and median time between survey and surgery was 10.9 (9.3) years. Hs-TnT was independently associated with surgery for AS (1.24 (1.06–1.44)) irrespective of CAD, whereas Hs-CRP was not (1.05 (0.90–1.22)). Elevated hs-TnT levels at survey associated with shorter time to surgery (p

Background: Physical activity improves health, exercise tolerance and quality of life in adults with congenital heart disease (CHD), and exercise training is in most patients a high-benefit low risk intervention. However, factors that influence the confidence to perform exercise training, i.e. exercise self-efficacy (ESE), in CHD patients are virtually unknown. We aimed to identify factors related to low ESE in adults with CHD, and potential strategies for being physically active. Methods: Seventy-nine adults with CHD; 38 with simple lesions (16 women) and 41 with complex lesions (17 women) with mean age 36.7 ± 14.6 years and 42 matched controls were recruited. All participants completed questionnaires on ESE and quality of life, carried an activity monitor (Actiheart) during four consecutive days and performed muscle endurance tests. Results: ESE in patients was categorised into low, based on the lowest quartile within controls, (≤29 points, n = 34) and high (>29 points, n = 45). Patients with low ESE were older (42.9 ± 15.1 vs. 32.0 ± 12.4 years, p = 0.001), had more complex lesions (65% vs. 42%, p = 0.05) more often had New York Heart Association functional class III (24% vs. 4%, p = 0.01) and performed fewer shoulder flexions (32.5 ± 15.5 vs. 47.7 ± 25.0, p = 0.001) compared with those with high ESE. In a logistic multivariate model age (OR; 1.06, 95% CI 1.02–1.10), and number of shoulder flexions (OR; 0.96, 95% CI 0.93–0.99) were associated with ESE. Conclusion: In this study we show that many adults with CHD have low ESE. Age is an important predictor of low ESE and should, therefore, be considered in counselling patients with CHD. In addition, muscle endurance training may improve ESE, and thus enhance the potential for being physically active in this population. Keywords: Exercise self-efficacy, Adult congenital heart disease, Quality of life, Muscle function, Physical activity

Aim: The aim of this study was to evaluate the relationship between coronary artery calcification (CAC) assessed by multi-detector computed tomography (MDCT) and myocardial perfusion assessed by cardiac magnetic resonance imaging (CMR) in a group of symptomatic patients. Method: Retrospective analysis of 120 patients (age 65.1 ± 8.9 years, 88 males) who presented with atypical chest pain to Bethanien Hospital, Frankfurt, Germany, between 2007 and 2010 and who underwent CAC scoring using MDCT, CMR, and conventional coronary angiography. Patients were divided into those with high-grade (HG) stenosis (n = 67, age 65.1 ± 9.4 years) and those with no-HG stenosis (n = 53, age 65.1 ± 8.6 years). Results: There were more males with HG stenosis (82.1% vs. 62.3%, p = 0.015), in whom the percentage and number of abnormal perfusion segments were higher at rest (37.3% vs. 17%, p = 0.014) but not different with stress (p = 0.83) from those with no-HG stenosis. Thirty-four patients had myocardial perfusion abnormalities at rest and 26 patients developed perfusion defects with stress. Stress-induced myocardial perfusion defects were 22.4% sensitive and 79.2% specific for detecting HG stenosis. The CAC score was lower in patients with no-HG stenosis compared to those with HG stenosis (p

This study examines the geopolitical role of 14 metals and metalloids needed for renewable energy technologies. The analysis focuses on three factors with potential geopolitical importance: the geographic concentration of resources, potential revenues of resources rich countries and the size of total global markets.The geographic concentration of most of the fourteen studied metals and metalloids will be higher than for oil. The only exceptions are tellurium, copper and silicon. The economic revenues as fraction of total economic throughput will be rather low for most of the countries studied. This will reduce the risk for a resource curse to emerge. The exceptions are the Democratic republic of Congo, Chile, Cuba, Madagascar and Zambia. The total economic value of the studied metals and metalloids will also be much smaller than the current oil market. Keywords: Critical material, Geopolitics, Resource curse, Renewable energy, Energy transition

Background Due to improved care, the numbers of patients with tetralogy of Fallot (ToF) are increasing. However, long-term morbidity and need for reinterventions are concerns and also address issues of quality of life (QoL).Methods Patients with ToF and valid EuroQol-5 dimensions questionnaire (EQ-5D) were identified in the national Swedish register on congenital heart disease. EQ-5Dindex was calculated and dichotomised into best possible health-related QoL (EQ-5Dindex=1) or differed from 1.Results 288 patients met the criteria and were analysed. Univariate logistic regression showed a positive association between New York Heart Association (NYHA) class I (OR 8.32, 95% CI 3.80 to 18.21), physical activity >3 h/week (OR 3.34, 95% CI 1.67 to 6.66) and a better right ventricular function (OR 2.56, 95% CI 1.09 to 6.02). A negative association between symptoms (OR 0.23, 95% CI 0.13 to 0.42), cardiovascular medication (OR 0.31, 95% CI 0.18 to 0.53), age (OR 0.97, 95% CI 0.96 to 0.99) and EQ-5Dindex was observed. In multivariate logistic regression, NYHA I (OR 7.28, 95% CI 3.29 to 16.12) and physical activity >3 h/week (OR 2.27, 95% CI 1.07 to 4.84) remained associated with best possible health-related QoL. Replacing NYHA with symptoms in the model yielded similar results.Conclusion In this registry study, self-reported physical activity, staff-reported NYHA class and absence of symptoms were strongly associated with best possible health-related QoL measured by EQ-5D. Physical activity level is a potential target for intervention to improve QoL in this population but randomised trials are needed to test such a hypothesis.

Background: High-intensity training (HIT) with extremely short intervals (designated here as supramaximal HIT) is a time-efficient training method for health and performance. However, a protocol for regulation and control of intensity is missing, impeding implementation in various groups, such as older individuals.Methods: This study presents the development and characteristics of a novel training protocol with regulated and controlled supramaximal intervals adapted for older people. Using both quantitative and qualitative analyses, we explored the feasibility of the program, performed in a group training setting, with physically active older individuals (aged 65–75, n = 7; five women). The developed supramaximal HIT program consisted of 10 × 6 s cycle sprint intervals with ∼1 min of active recovery with the following key characteristics: (1) an individual target power output was reached and maintained during all intervals and regulated and expressed as the percentage of the estimated maximum mean power output for the duration of the interval (i.e., 6 s); (2) pedaling cadence was standardized for all participants, while resistance was individualized; and (3) the protocol enabled controlled and systematic adjustments of training intensity following standardized escalation criteria.Aim: Our aim was to test the feasibility of a novel training regimen with regulated and controlled supramaximal HIT, adapted for older people. The feasibility criteria for the program were to support participants in reaching a supramaximal intensity (i.e., power output > 100% of estimated VO2 max), avoid inducing a negative affective response, and have participants perceive it as feasible and acceptable.Results: All feasibility criteria were met. The standardized escalation procedure provided safe escalation of training load up to a supramaximal intensity (around three times the power output at estimated VO2 max). The participants never reported negative affective responses, and they perceived the program as fun and feasible.Conclusion: This novel program offers a usable methodology for further studies on supramaximal HIT among older individuals with different levels of physical capacity. Future research should explore the effects of the program in various populations of older people and their experiences and long-term adherence compared with other forms of training.

Background The accumulation of myocardial triglycerides and remodeling of the left ventricle are common features in type 2 diabetes mellitus and represent potential risk factors for the development of diastolic and systolic dysfunction. A few studies have investigated the separate effects of diet and exercise training on cardiac function, but none have investigated myocardial changes in response to a combined diet and exercise intervention. This 12‐week randomized study assessed the effects of a Paleolithic diet, with and without additional supervised exercise training, on cardiac fat, structure, and function. Methods and Results Twenty‐two overweight and obese subjects with type 2 diabetes mellitus were randomized to either a Paleolithic diet and standard‐care exercise recommendations (PD) or to a Paleolithic diet plus supervised exercise training 3 hours per week (PD‐EX). This study includes secondary end points related to cardiac structure and function, ie, myocardial triglycerides levels, cardiac morphology, and strain were measured using cardiovascular magnetic resonance, including proton spectroscopy, at baseline and after 12 weeks. Both groups showed major favorable metabolic changes. The PD‐EX group showed significant decreases in myocardial triglycerides levels (−45%, P=0.038) and left ventricle mass to end‐diastolic volume ratio (−13%, P=0.008) while the left ventricle end‐diastolic volume and stroke volume increased significantly (+14%, P=0.004 and +17%, P=0.008, respectively). These variables were unchanged in the PD group. Conclusions Exercise training plus a Paleolithic diet reduced myocardial triglycerides levels and improved left ventricle remodeling in overweight/obese subjects with type 2 diabetes mellitus. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01513798.

Purpose : Aim of the COBRA (Consortium for Brachytherapy Data Analysis) project is to create a multicenter group (consortium) and a web-based system for standardized data collection. Material and methods: GEC-ESTRO (Groupe Européen de Curiethérapie – European Society for Radiotherapy & Oncology) Head and Neck (H&N) Working Group participated in the project and in the implementation of the consortium agreement, the ontology (data-set) and the necessary COBRA software services as well as the peer reviewing of the general anatomic site-specific COBRA protocol. The ontology was defined by a multicenter task-group. Results : Eleven centers from 6 countries signed an agreement and the consortium approved the ontology. We identified 3 tiers for the data set: Registry (epidemiology analysis), Procedures (prediction models and DSS), and Research (radiomics). The COBRA-Storage System (C-SS) is not time-consuming as, thanks to the use of “brokers”, data can be extracted directly from the single center’s storage systems through a connection with “structured query language database” (SQL-DB), Microsoft Access®, FileMaker Pro®, or Microsoft Excel®. The system is also structured to perform automatic archiving directly from the treatment planning system or afterloading machine. The architecture is based on the concept of “on-purpose data projection”. The C-SS architecture is privacy protecting because it will never make visible data that could identify an individual patient. This C-SS can also benefit from the so called “distributed learning” approaches, in which data never leave the collecting institution, while learning algorithms and proposed predictive models are commonly shared. Conclusions : Setting up a consortium is a feasible and practicable tool in the creation of an international and multi-system data sharing system. COBRA C-SS seems to be well accepted by all involved parties, primarily because it does not influence the center’s own data storing technologies, procedures, and habits. Furthermore, the method preserves the privacy of all patients.

This paper presents a numerical investigation of the ignition and combustion process of a primary reference fuel in a partially premixed light-duty internal combustion (PPC) engine. Partially pre-mixed combustion is achieved by employing a multiple injection strategy with three short injection events of fuel pulses. The timing of the first two fuel pulses, 48 and 22 crank angle degrees before top dead center, are chosen with the purpose to stratify the fuel and air charge, whereas the third injection, at five crank angle degrees before top dead center, serves as an actuator of the main heat release. In addition to this baseline injection, three alternative injection strategies are studied, including a split-fuel two-injection strategy and modified triple-injection strategies. Large eddy simulations are employed utilizing a skeletal chemical kinetic mechanism for primary reference fuel capable of capturing the low-temperature ignition and the high temperature combustion. The large eddy simulation (LES) results are compared with experiments in an optical accessible engine. The results indicate that the first ignition sites are in the bowl region where the temperature is relatively higher, and the reaction fronts thereafter propagate in the swirl direction and towards the centerline of the cylinder. The charge from the first two injections initially undergoes low-temperature reactions and thereafter high-temperature reservoirs are formed in the bowl region. The main heat-release is initiated in the engine when the fuel from the third injection reaches the high-temperature reservoirs. Finally, the remaining fuel in the lean mixtures from the first two injections is oxidized. By variation of the injection strategy, two trends are identified: (1) by removing the second injection a higher intake temperature is required to enable the ignition of the charge, and (2) by retarding second injection, a longer ignition delay is identified. Both can be explained by the stratification of fuel and air mixture, and the resulting reactivity in various equivalence ratio and temperature ranges. The LES results reveal the details of the charge stratification and the subsequent heat release process. The present results indicate a rather high sensitivity of partially premixed combustion process to the injection strategies.

Systemic immunization with soluble flagellin (sFliC) from Salmonella Typhimurium induces mucosal responses, offering potential as an adjuvant platform for vaccines. Moreover, this engagement of mucosal immunity is necessary for optimal systemic immunity, demonstrating an interaction between these two semi-autonomous immune systems. Although TLR5 and CD103+CD11b+ cDC2 contribute to this process, the relationship between these is unclear in the early activation of CD4+ T cells and the development of antigen-specific B cell responses. In this work, we use TLR5-deficient mice and CD11c-cre.Irf4fl/fl mice (which have reduced numbers of cDC2, particularly intestinal CD103+CD11b+ cDCs), to address these points by studying the responses concurrently in the spleen and the mesenteric lymph nodes (MLN). We show that CD103+CD11b+ cDC2 respond rapidly and accumulate in the MLN after immunization with sFliC in a TLR5-dependent manner. Furthermore, we identify that whilst CD103+CD11b+ cDC2 are essential for the induction of primary T and B cell responses in the mucosa, they do not play such a central role for the induction of these responses in the spleen. Additionally, we show the involvement of CD103+CD11b+ cDC2 in the induction of Th2-associated responses. CD11c-cre.Irf4fl/fl mice showed a reduced primary FliC-specific Th2-associated IgG1 responses, but enhanced Th1-associated IgG2c responses. These data expand our current understanding of the mucosal immune responses promoted by sFliC and highlights the potential of this adjuvant for vaccine usage by taking advantage of the functionality of mucosal CD103+CD11b+ cDC2.

From an evolutionary point of view a pathogen might benefit from regulating the inflammatory response, both in order to facilitate establishment of colonization and to avoid life-threatening host manifestations, such as septic shock. In agreement with this notion Streptococcus pyogenes exploits type I IFN-signaling to limit detrimental inflammation in infected mice, but the host-pathogen interactions and mechanisms responsible for induction of the type I IFN response have remained unknown. Here we used a macrophage infection model and report that S. pyogenes induces anti-inflammatory IL-10 in an M protein-dependent manner, a function that was mapped to the B- and C-repeat regions of the M5 protein. Intriguingly, IL-10 was produced downstream of type I IFN-signaling, and production of type I IFN occurred via M protein-dependent activation of the STING signaling pathway. Activation of STING was independent of the cytosolic double stranded DNA sensor cGAS, and infection did not induce detectable release into the cytosol of either mitochondrial, nuclear or bacterial DNA-indicating DNA-independent activation of the STING pathway in S. pyogenes infected macrophages. These findings provide mechanistic insight concerning how S. pyogenes induces the type I IFN response and identify a previously unrecognized macrophage-modulating role for the streptococcal M protein that may contribute to curb the inflammatory response to infection.

BackgroundAortic stenosis (AS) has different clinical phenotypes, including AS with or without concomitant coronary artery disease (CAD). It is unknown whether these phenotypes share the same risk factors. In particular, lipoprotein(a) [Lp(a)] and apolipoproteins (Apo) are associated with AS, but it is unknown whether these associations differ among phenotypes. In this prospective analysis we examined the impact of Lp(a) and Apo in subgroups of patients with AS. Methods and ResultsWe identified 336 patients (mean age at survey 56.7 years, 48% female) who underwent surgery for AS after a median 10.9 years (interquartile range 9.3 years), participants in 1 of 3 large population surveys. For each patient, 2 matched referents were allocated. Lp(a) and Apo were analyzed in the baseline samples. Uni‐ and multivariable logistic regression analyses were used to estimate risks related to a 1 (ln) standard deviation increase in Lp(a) and the ratio of Apo B to Apo A1 (Apo B/A1 ratio). High levels of Lp(a) predicted surgery for AS in 203 patients with concomitant CAD (odds ratio [95% confidence intervals]) (1.29 [1.07‐1.55]), but not in 132 patients without CAD (1.04 [0.83‐1.29]) in the fully adjusted model. Similarly, a high Apo B/A1 ratio predicted surgery in patients with concomitant CAD (1.43 [1.16‐1.76]) but not in those without CAD (0.87 [0.69‐1.10]). ConclusionsHigh levels of Lp(a) and a high Apo B/A1 ratio were associated with surgery for AS in patients with concomitant CAD but not in those with isolated AS. This finding may lead to a new avenue of research for targeted risk factor interventions in this population.

BackgroundRisk factors for developing heart valve and ascending aortic disease are based mainly on retrospective data. To elucidate these factors in a prospective manner, we have performed a nested case–referent study using data from large, population‐based surveys. Methods and ResultsA total of 777 patients operated for heart valve disease or disease of the ascending aorta had previously participated in population‐based health surveys in Northern Sweden. Median time (interquartile range) from survey to surgery was 10.5 (9.0) years. Primary indications for surgery were aortic stenosis (41%), aortic regurgitation (12%), mitral regurgitation (23%), and dilatation/dissection of the ascending aorta (17%). For each case, referents were allocated, matched for age, sex, and geographical area. In multivariable models, surgery for aortic stenosis was predicted by hypertension, high cholesterol levels, diabetes mellitus, and active smoking. Surgery for aortic regurgitation was associated with a low cholesterol level, whereas a high cholesterol level predicted surgery for mitral regurgitation. Hypertension, blood pressure, and previous smoking predicted surgery for disease of the ascending aorta whereas diabetes mellitus was associated with reduced risk. After exclusion of cases with coronary atherosclerosis, only the inverse associations between cholesterol and aortic regurgitation and between diabetes mellitus and disease of the ascending aorta remained. ConclusionsThis is the first truly prospective study of traditional cardiovascular risk factors and their association with valvular heart disease and disease of the ascending aorta. We confirm the strong association between traditional risk factors and aortic stenosis, but only in patients with concomitant coronary artery disease. In isolated valvular heart disease, the impact of traditional risk factors is varying.

Purpose: To evaluate the long time outcome with regard to local tumour control and side effects of a pulsed dose rate (PDR) monobrachytherapy of primary or recurrent cancer of the lip. Material and methods: Between 1995 and 2007 we treated 43 patients with primary or recurrent clinical T1-T3N0 lip cancers. There were 22 T1 patients (51%), 16 T2 (37%) and 5 T3 cases (12%). A median dose of 60 (55-66) Gy was given, depending on the tumour volume. The PDR treatment was delivered with 0.83 Gy/pulse every second hour for 5.5-6.5 days. The patients were followed for a median of 55 (1-158) months. Results: The 2-, 5- and 10-year rates of actuarial local control were 97.6%, 94.5% and 94.5%, overall survival 88.0%, 58.9% and 39.1%, disease free survival 92.7%, 86.4% and 86.4% respectively. The regional control rate was 93%. One patient (2%) developed distant metastases. A dosimetrical analysis showed a mean treated volume of 14.9 (3.0-56.2) cm3. Long-term side effects were mild and the cosmetic outcome excellent, except for 1 case (2%) of soft tissue necrosis and 1 case (2%) of osteoradionecrosis. Conclusions: Local outcome is excellent and similar to other published studies of continuous low dose rate (cLDR) brachytherapy.

Purpose: To evaluate long time outcome with regard to local tumour control, side effects and quality of life of combined pulsed dose rate (PDR) boost and hyperfractionated accelerated external beam radiotherapy (EBRT) for primary base of tongue (BOT) cancers. Material and methods: Between 1994 and 2007, the number of 83 patients were treated with primary T1-T4 BOT cancers. Seven patients (8%) were T1-2N0 (AJCC stage I-II) and 76 (92%) patients were T1-2N+ or T3-4N0-2 (AJCC stage III-IV). The mean estimated primary tumour volume was 15.4 (1-75) cm3. EBRT was given with 1.7 Gy bid to 40.8 Gy to primary tumour and bilateral neck lymph nodes in 2.5 weeks. PDR boost of 35 Gy and a neck dissection in clinical node positive case was performed 2-3 weeks later. The patients were followed for a median of 54 (2-168) months. Results: The 2-, 5- and 10-years rates of actuarial local control were 91%, 89% and 85%, overall survival 85%, 65% and 44%, disease free survival 86%, 80% and 76%, respectively. The regional control rate was 95%. Six patients (7%) developed distant metastases. A dosimetric analysis showed a mean of 100% isodose volume of 58.2 (16.7-134) cm3. In a review of late complications 11 cases of minor (13%) and 5 of major soft tissue necroses (6%), as well as 6 cases of osteoradionecroses (7%) were found. The patients median subjective SOMA/LENT scoring at last follow up was as follow: grade 0 for pain and trismus, grade 1 for dysphagia and taste alteration, and grade 2 for xerostomia. Global visual- analogue-scale (VAS) scoring of quality of life was 8. Conclusion: Local and regional tumour control rate was excellent in this treatment protocol. The data shows the PDR boost as at least as effective as published continuous low dose rate (CLDR) results.

The innate immune system relies to a great deal on the interaction of pattern recognition receptors with pathogen- or damage-associated molecular pattern molecules. Extracellular histones belong to the latter group and their release has been described to contribute to the induction of systemic inflammatory reactions. However, little is known about their functions in the early immune response to an invading pathogen. Here we show that extracellular histones specifically target monocytes in human blood and this evokes the mobilization of the chemotactic chemokines CXCL9 and CXCL10 from these cells. The chemokine induction involves the toll-like receptor 4/myeloid differentiation factor 2 complex on monocytes, and is under the control of interferon-γ. Consequently, subcutaneous challenge with extracellular histones results in elevated levels of CXCL10 in a murine air pouch model and an influx of leukocytes to the site of injection in a TLR4 dependent manner. When analyzing tissue biopsies from patients with necrotizing fasciitis caused by Streptococcus pyogenes, extracellular histone H4 and CXCL10 are immunostained in necrotic, but not healthy tissue. Collectively, these results show for the first time that extracellular histones have an important function as chemoattractants as their local release triggers the recruitment of immune cells to the site of infection.

Introduction. The hypertrophic cardiomyopathy (HCM) disease process is not only limited to cardiomyocyte abnormalities but also engages the extracellular matrix. Hyaluronan (HA) and its receptor CD44 are involved in cellular growth and tissue proliferation but have so far been less studied in myocardial hypertrophy. In HCM, collagens are abundant but their histological distribution and relation to hyaluronan have not been described. Material and Methods. Myocardial specimens from 5 patients with symptomatic left ventricular tract obstruction undergoing myectomy due to HCM were processed for histochemistry and immunohistochemistry. Results. HA staining was more intense in HCM patients. The histological distribution of HA was the same in patients and controls, that is, interstitial staining including the space between cardiomyocytes, in fibrous septa, and in the adventitia of intramyocardial blood vessels. CD44 was not detected in the myocardium of patients or controls. Collagen I showed the same general localisation as HA but detailed distribution differed. Conclusions. This is the first study that describes the distribution of hyaluronan in human HCM. HA staining is more intense in HCM patients but without coexpression of its receptor CD44, at least not in the chronic phase of HCM. HA and collagen I have the same localisation.

BACKGROUND: During myocardial infarction reduced blood flow in the heart muscle results in cell death. These dying/dead cells have been reported to bind several plasma proteins such as IgM and C-reactive protein (CRP). In the present study we investigated whether fluid-phase complement inhibitor C4b-binding protein (C4BP) would also bind to the infarcted heart tissue. METHODS AND FINDINGS: Initial studies using immunohistochemistry on tissue arrays for several cardiovascular disorders indicated that C4BP can be found in heart tissue in several cardiac diseases but that it is most abundantly found in acute myocardial infarction (AMI). This condition was studied in more detail by analyzing the time window and extent of C4BP positivity. The binding of C4BP correlates to the same locations as C3b, a marker known to correlate to the patterns of IgM and CRP staining. Based on criteria that describe the time after infarction we were able to pinpoint that C4BP binding is a relatively early marker of tissue damage in myocardial infarction with a peak of binding between 12 hours and 5 days subsequent to AMI, the phase in which infiltration of neutrophilic granulocytes in the heart is the most extensive. CONCLUSIONS: C4BP, an important fluid-phase inhibitor of the classical and lectin pathway of complement activation binds to jeopardized cardiomyocytes early after AMI and co-localizes to other well known markers such as C3b.