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Abstract A hypertensive response to exercise is a precursor leading to hypertension, which is a major risk factor for the development of heart failure and diastolic dysfunction. Herein, we aimed to assess blood pressure (BP) in patients with a hypertensive response to exercise and different degrees of diastolic dysfunction. Between January 2009 and December 2014, 373 patients with a hypertensive response to exercise (HRE) and echocardiographic data assessing diastolic function were enrolled at the University Hospital of Zurich. ANCOVA was used to assess the changes in BP response during exercise testing in individuals with different degrees of diastolic dysfunction. Normalization of systolic BP was blunted in patients with grade II and III diastolic dysfunction after 3 min of recovery in univariable [β (95%) ‐ 9.2 (‐13.8 to ‐ 4.8) p

Abstract Stem cells preferentially use glycolysis instead of oxidative phosphorylation and this metabolic rewiring plays an instructive role in their fate; however, the underlying molecular mechanisms remain largely unexplored. PIWI-interacting RNAs (piRNAs) and PIWI proteins have essential functions in a range of adult stem cells across species. Here, we show that piRNAs and the PIWI protein Aubergine (Aub) are instrumental in activating glycolysis in Drosophila female germline stem cells (GSCs). Higher glycolysis is required for GSC self-renewal and aub loss-of-function induces a metabolic switch in GSCs leading to their differentiation. Aub directly binds glycolytic mRNAs and Enolase mRNA regulation by Aub depends on its 5′UTR. Furthermore, mutations of a piRNA target site in Enolase 5′UTR lead to GSC loss. These data reveal an Aub/piRNA function in translational activation of glycolytic mRNAs in GSCs, and pinpoint a mechanism of regulation of metabolic reprogramming in stem cells based on small RNAs.

Abstract Most RNA-protein condensates are composed of heterogeneous immiscible phases. However, how this multiphase organization contributes to their biological functions remains largely unexplored. Drosophila germ granules, a class of RNA-protein condensates, are the site of mRNA storage and translational activation. Here, using super-resolution microscopy and single-molecule imaging approaches, we show that germ granules have a biphasic organization and that translation occurs in the outer phase and at the surface of the granules. The localization, directionality, and compaction of mRNAs within the granule depend on their translation status, translated mRNAs being enriched in the outer phase with their 5′end oriented towards the surface. Translation is strongly reduced when germ granule biphasic organization is lost. These findings reveal the intimate links between the architecture of RNA-protein condensates and the organization of their different functions, highlighting the functional compartmentalization of these condensates.

Abstract Fusobacterium necrophorum is a Gram-negative anaerobic bacterium responsible for localized infections of the oropharynx that can evolve into bacteremia and/or septic thrombophlebitis of the jugular vein or peritonsillar vein, called Lemierre’s syndrome. To identify microbial genetic determinants associated with the severity of this life-threatening disease, 70 F. necrophorum strains were collected and grouped into two categories according to the clinical presentation: (i) localized infection, (ii) bacteremia with/without Lemierre’s syndrome. Comparative genomic analyses revealed two clades with distinct genetic content, one clade being significantly enriched with isolates from subjects with bacteremia. To identify genetic determinants contributing to F. necrophorum pathogenicity, genomic islands and virulence factor orthogroups (OVFs) were predicted. The presence/absence profiles of OVFs did not group isolates according to their clinical category, but rather according to their phylogeny. However, a variant of lktA, a key virulence factor, with a frameshift deletion that results in two open reading frames, was associated with bacteremia. Moreover, a genome-wide association study identified three orthogroups associated with bacteremic strains: (i) cas8a1, (ii) a sodium/solute symporter, and (iii) a POP1 domain-containing protein. Further studies must be performed to assess the functional impact of lktA mutation and of these orthogroups on the physiopathological mechanisms of F. necrophorum infections.

Although the effects of cigarette smoke (CS) on the development of several intestinal diseases is well documented, the impact of e-cigarette aerosol (e-cig) on digestive health is largely unknown. To compare the effects of e-cig and CS on mouse ileum and colon, animals were chronically exposed for 6 months by nose-only inhalation to e-cig at 18 or 30 W power, or to 3R4F CS. Results showed that e-cig exposure decreased colon cell proliferation. Several other proliferative defects were observed in response to both e-cig and CS exposure, including up- and down-regulation of cyclin D1 protein levels in the ileum and colon, respectively. E-cig and CS exposure reduced myeloperoxidase activity in the ileum. In the colon, both exposures disrupted gene expression of cytokines and T cell transcription factors. For tight junction genes, ZO-1- and occludin-protein expression levels were reduced in the ileum and colon, respectively, by e-cig and CS exposure. The 16S sequencing of microbiota showed specific mild dysbiosis, according to the type of exposure. Overall, e-cig exposure led to altered proliferation, inflammation, and barrier function in both the ileum and colon, and therefore may be a gut hazard on par with conventional CS.

Abstract Background The objective was to assess the agreement between therapeutic proposals derived from basic critical care echocardiography performed by novice operators in ultrasonography after a limited training (residents) and by experts considered as reference. Secondary objectives were to assess the agreement between operators’ answers to simple clinical questions and the concordance between basic two-dimensional measurements. Methods This observational, prospective, single-center study was conducted over a 3-year period in a medical-surgical intensive care unit. Adult patients with acute circulatory and/or respiratory failure requiring a transthoracic echocardiography (TTE) examination were studied. In each patient, a TTE was performed by a resident novice in ultrasonography after a short training program and by an expert, independently but within 1 h and in random order. Each operator addressed standardized simple clinical questions and subsequently proposed a therapeutic strategy based on a predefined algorithm. Results Residents performed an average of 33 TTE studies in 244 patients (156 men; age: 63 years [52–74]; SAPS2: 45 [34–59]; 182 (75%) mechanically ventilated). Agreement between the therapeutic proposals of residents and experienced operators was good-to-excellent. The concordance was excellent for suggesting fluid loading, inotrope or vasopressor support (all Kappa values > 0.80). Inter-observer agreement was only moderate when considering the indication of negative fluid balance (Kappa: 0.65; 95% CI 0.50–0.80), since residents proposed diuretics in 23 patients (9.5%) while their counterparts had the same suggestion in 35 patients (14.4%). Overall agreement of responses to simple clinical questions was also good-to-excellent. Intraclass correlation coefficient exceeded 0.75 for measurement of ventricular and inferior vena cava size. Conclusions A limited training program aiming at acquiring the basic level in critical care echocardiography enables ICU residents novice in ultrasonography to propose therapeutic interventions with a good-to-excellent agreement with experienced operators.

This paper is devoted to the mathematical analysis of the contact capabilities of the fluid-structure interaction (FSI) model with seepage reported in [Comput. Methods Appl. Mech., 392:114637, 2022]. In the case of a rigid disk moving over a fixed horizontal plane, we show that this model encompasses contact and hence removes the non collision paradox of traditional FSI models which rely on Dirichlet or Dirichlet/Navier boundary conditions. Numerical evidence on the theoretical results is also provided.

Background Neurological inherited disorders are rare in domestic animals. Cerebellar cortical degeneration remains amongst the most common of these disorders. The condition is defined as the premature loss of fully differentiated cerebellar components due to genetic or metabolic defects. It has been studied in dogs and cats, and various genetic defects and diagnostic tests (including magnetic resonance imaging (MRI)) have been refined in these species. Cases in cats remain rare and mostly individual, and few diagnostic criteria, other than post-mortem exam, have been evaluated in reports with multiple cases. Here, we report three feline cases of cerebellar cortical degeneration with detailed clinical, diagnostic imaging and post-mortem findings. Case presentation The three cases were directly (siblings, case #1 and #2) or indirectly related (same farm, case #3) and showed early-onset of the disease, with clinical signs including cerebellar ataxia and tremors. Brain MRI was highly suggestive of cerebellar cortical degeneration on all three cases. The relative cerebrospinal fluid (CSF) space, relative cerebellum size, brainstem: cerebellum area ratio, and cerebellum: total brain area ratio, were measured and compared to a control group of cats and reference cut-offs for dogs in the literature. For the relative cerebellum size and cerebellum: total brain area ratio, all affected cases had a lower value than the control group. For the relative CSF space and brainstem: cerebellum area ratio, the more affected cases (#2 and #3) had higher values than the control group, while the least affected case (#3) had values within the ranges of the control group, but a progression was visible over time. Post-mortem examination confirmed the diagnosis of cerebellar cortical degeneration, with marked to complete loss of Purkinje cells and associated granular layer depletion and proliferation of Bergmann glia. One case also had Wallerian-like degeneration in the spinal cord, suggestive of spinocerebellar degeneration. Conclusion Our report further supports a potential genetic component for the disease in cats. For the MRI examination, the relative cerebellum size and cerebellum: total brain area ratio seem promising, but further studies are needed to establish specific feline cut-offs. Post-mortem evaluation of the cerebellum remains the gold standard for the final diagnosis.

Abstract Background In the initial phase of the SARS-CoV-2 pandemic, masking has been widely accepted in healthcare institutions to mitigate the risk of healthcare-associated infection. Evidence, however, is still scant and the role of masks in preventing healthcare-associated SARS-CoV-2 acquisition remains unclear.We investigated the association of variation in institutional mask policies with healthcare-associated SARS-CoV-2 infections in acute care hospitals in Switzerland during the BA.4/5 2022 wave. Methods SARS-CoV-2 infections in hospitalized patients between June 1 and September 5, 2022, were obtained from the “Hospital-based surveillance of COVID-19 in Switzerland”-database and classified as healthcare- or community-associated based on time of disease onset. Institutions provided information regarding institutional masking policies for healthcare workers and other prevention policies. The percentage of healthcare-associated SARS-CoV-2 infections was calculated per institution and per type of mask policy. The association of healthcare-associated SARS-CoV-2 infections with mask policies was tested using a negative binominal mixed-effect model. Results We included 2’980 SARS-CoV-2 infections from 13 institutions, 444 (15%) were classified as healthcare-associated. Between June 20 and June 30, 2022, six (46%) institutions switched to a more stringent mask policy. The percentage of healthcare-associated infections subsequently declined in institutions with policy switch but not in the others. In particular, the switch from situative masking (standard precautions) to general masking of HCW in contact with patients was followed by a strong reduction of healthcare-associated infections (rate ratio 0.39, 95% CI 0.30–0.49). In contrast, when compared across hospitals, the percentage of health-care associated infections was not related to mask policies. Conclusions Our findings suggest switching to a more stringent mask policy may be beneficial during increases of healthcare-associated SARS-CoV-2 infections at an institutional level.

Abstract Tissue injury causes activation of mesenchymal lineage cells into wound-repairing myofibroblasts (MFs), whose uncontrolled activity ultimately leads to fibrosis. Although this process is triggered by deep metabolic and transcriptional reprogramming, functional links between these two key events are not yet understood. Here, we report that the metabolic sensor post-translational modification O-linked β-D-N-acetylglucosaminylation (O-GlcNAcylation) is increased and required for myofibroblastic activation. Inhibition of protein O-GlcNAcylation impairs archetypal myofibloblast cellular activities including extracellular matrix gene expression and collagen secretion/deposition as defined in vitro and using ex vivo and in vivo murine liver injury models. Mechanistically, a multi-omics approach combining proteomic, epigenomic, and transcriptomic data mining revealed that O-GlcNAcylation controls the MF transcriptional program by targeting the transcription factors Basonuclin 2 (BNC2) and TEA domain transcription factor 4 (TEAD4) together with the Yes-associated protein 1 (YAP1) co-activator. Indeed, inhibition of protein O-GlcNAcylation impedes their stability leading to decreased functionality of the BNC2/TEAD4/YAP1 complex towards promoting activation of the MF transcriptional regulatory landscape. We found that this involves O-GlcNAcylation of BNC2 at Thr455 and Ser490 and of TEAD4 at Ser69 and Ser99. Altogether, this study unravels protein O-GlcNAcylation as a key determinant of myofibroblastic activation and identifies its inhibition as an avenue to intervene with fibrogenic processes.

Background Immunogenic cell death (ICD) and ferroptosis have recently emerged as key factors in the anticancer immune response. Among the treatments able to induce ICD and the associated release of danger signals is photodynamic therapy (PDT). Ferroptosis for its part results from lipid peroxidation and is induced by CD8+ T cells to kill nearby cancer cells on IFN-γ production. We aimed to combine the two concepts, that is, to evaluate whether the strong pro-oxidant effects of PDT may promote ferroptosis and antigen release and to develop a procedure for in situ PDT to prepare the soil for highly endocytotic immature dendritic cell (iDC) adoptive transfer. This approach was implemented for managing peritoneal carcinomatosis, a lesion often associated with poor outcomes.Methods We used three-dimensional (3D) heterotypic spheroids made of cancer cells, exposed them to a white light-activated OR141 photosensitizer (PS), and subsequently complexified them by adding iDC and naive lymphocytes. We next used a model of mouse peritoneal carcinomatosis and administered PDT using laparoscopy to locally induce photoactivation using the endoscope light. The immune response following adoptive transfer of iDC was tracked both in vivo and ex vivo using isolated immune cells from in situ vaccinated mice.Results Cancer cells undergoing PDT-induced cell death significantly increased ICD markers and the infiltration of iDCs in spheroids, relying on ferroptosis. These actions induced the sequential activation of CD8+ and CD4+ T cells as revealed by a significant spheroid 3D structure deterioration and, remarkably, were not recapitulated by conventional ferroptosis inducer RSL3. Using LED light from an endoscope for in situ photoactivation of PS enabled us to apply the vaccination modality in mice with peritoneal tumors. Consecutive intraperitoneal injection of iDCs resulted in delayed tumor growth, increased survival rates, and prevented tumor relapse on rechallenge. CD8+ T cell response was supported by depletion experiments, nodal detection of early activated T cells, and ex vivo T cell-induced cytotoxicity toward spheroids.Conclusions The combination of in situ PDT locally delivered by an endoscope light and iDC administration induces a durable memory immune response against peritoneal carcinomatosis thereby opening new perspectives for the treatment of a life-threatening condition.

The patent ductus arteriosus is a very common condition in preterm infants, and a hemodynamically significant patent ductus arteriosus increases morbidity and mortality in these vulnerable patients. However, despite numerous randomized controlled trials, there is no consensus regarding management. Medical therapy is typically offered as first-line treatment, although it yields limited success and carries the potential for severe adverse events. In recent years, there has been rapid development in transcatheter patent ductus arteriosus closure primary with the use of the Amplatzer Piccolo Occluder, and this has gained widespread acceptance as a safe and effective alternative to surgical ligation in extremely low-birth-weight infants weighing over 700 g. This article aims to provide an appraisal of the patient selection process, a step-by-step procedural guide, and a comprehensive review of the outcomes associated with this approach.

Abstract YAP and TAZ, the Hippo pathway terminal transcriptional activators, are frequently upregulated in cancers. In tumor cells, they have been mainly associated with increased tumorigenesis controlling different aspects from cell cycle regulation, stemness, or resistance to chemotherapies. In fewer cases, they have also been shown to oppose cancer progression, including by promoting cell death through the action of the p73/YAP transcriptional complex, in particular after chemotherapeutic drug exposure. Using HCT116 cells, we show here that oxaliplatin treatment led to core Hippo pathway down-regulation and nuclear accumulation of TAZ. We further show that TAZ was required for the increased sensitivity of HCT116 cells to oxaliplatin, an effect that appeared independent of p73, but which required the nuclear relocalization of TAZ. Accordingly, Verteporfin and CA3, two drugs affecting the activity of YAP and TAZ, showed antagonistic effects with oxaliplatin in co-treatments. Importantly, using several colorectal cell lines, we show that the sensitizing action of TAZ to oxaliplatin is dependent on the p53 status of the cells. Our results support thus an early action of TAZ to sensitize cells to oxaliplatin, consistent with a model in which nuclear TAZ in the context of DNA damage and p53 activity pushes cells towards apoptosis.

Abstract Background Estetrol (E4) is a natural estrogen produced by the fetal liver during pregnancy. Due to its favorable safety profile, E4 was recently approved as estrogenic component of a new combined oral contraceptive. E4 is a selective ligand of estrogen receptor (ER)α and ERβ, but its binding to the G Protein-Coupled Estrogen Receptor (GPER) has not been described to date. Therefore, we aimed to explore E4 action in GPER-positive Triple-Negative Breast Cancer (TNBC) cells. Methods The potential interaction between E4 and GPER was investigated by molecular modeling and binding assays. The whole transcriptomic modulation triggered by E4 in TNBC cells via GPER was explored through high-throughput RNA sequencing analyses. Gene and protein expression evaluations as well as migration and invasion assays allowed us to explore the involvement of the GPER-mediated induction of the plasminogen activator inhibitor type 2 (SERPINB2) in the biological responses triggered by E4 in TNBC cells. Furthermore, bioinformatics analysis was aimed at recognizing the biological significance of SERPINB2 in ER-negative breast cancer patients. Results After the molecular characterization of the E4 binding capacity to GPER, RNA-seq analysis revealed that the plasminogen activator inhibitor type 2 (SERPINB2) is one of the most up-regulated genes by E4 in a GPER-dependent manner. Worthy, we demonstrated that the GPER-mediated increase of SERPINB2 is engaged in the anti-migratory and anti-invasive effects elicited by E4 in TNBC cells. In accordance with these findings, a correlation between SERPINB2 levels and a good clinical outcome was found in ER-negative breast cancer patients. Conclusions Overall, our results provide new insights into the mechanisms through which E4 can halt migratory and invasive features of TNBC cells.

Abstract In recent decades, detailed country-level estimates of income and wealth have become widely available and inform us about the evolution of inequality between and within countries. But a substantial portion of these available datasets lack sub-national geographical information, precluding the exploration of the spatial distribution and evolution of inequalities within countries. We present here a new dataset of disposable income for Europe at the subnational level. It has been compiled from existing income data (gross income, gross earnings, equivalised income, etc.) published by national statistical institutes at different geographical levels. We used linear regressions and numerical operations to estimate disposable income from other available socio-economic statistics (e.g. household size, tax rates). We developed a harmonization and adjustment procedures to ensure of the consistency of statistical units, income indicators, costs of living and inflation. The dataset covers 42 European countries distributed over more than 120,000 geographical entities on the 1995 to 2021 period (most of the data being available for the 2010–2020 decade). This new dataset opens avenues for investigating the links between income inequality and other socio-economic or ecological processes.

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IMPORTANCE:. Ventilator-associated pneumonia (VAP) frequently occurs in patients with cardiac arrest. Diagnosis of VAP after cardiac arrest remains challenging, while the use of current biomarkers such as C-reactive protein (CRP) or procalcitonin (PCT) is debated. OBJECTIVES:. To evaluate biomarkers’ impact in helping VAP diagnosis after cardiac arrest. DESIGN, SETTING, AND PARTICIPANTS:. This is a prospective ancillary study of the randomized, multicenter, double-blind placebo-controlled ANtibiotherapy during Therapeutic HypothermiA to pRevenT Infectious Complications (ANTHARTIC) trial evaluating the impact of antibiotic prophylaxis to prevent VAP in out-of-hospital patients with cardiac arrest secondary to shockable rhythm and treated with therapeutic hypothermia. An adjudication committee blindly evaluated VAP according to predefined clinical, radiologic, and microbiological criteria. All patients with available biomarker(s), sample(s), and consent approval were included. MAIN OUTCOMES AND MEASURES:. The main endpoint was to evaluate the ability of biomarkers to correctly diagnose and predict VAP within 48 hours after sampling. The secondary endpoint was to study the combination of two biomarkers in discriminating VAP. Blood samples were collected at baseline on day 3. Routine and exploratory panel of inflammatory biomarkers measurements were blindly performed. Analyses were adjusted on the randomization group. RESULTS:. Among 161 patients of the ANTHARTIC trial with available biological sample(s), patients with VAP (n = 33) had higher body mass index and Acute Physiology and Chronic Health Evaluation II score, more unwitnessed cardiac arrest, more catecholamines, and experienced more prolonged therapeutic hypothermia duration than patients without VAP (n = 121). In univariate analyses, biomarkers significantly associated with VAP and showing an area under the curve (AUC) greater than 0.70 were CRP (AUC = 0.76), interleukin (IL) 17A and 17C (IL17C) (0.74), macrophage colony-stimulating factor 1 (0.73), PCT (0.72), and vascular endothelial growth factor A (VEGF-A) (0.71). Multivariate analysis combining novel biomarkers revealed several pairs with p value of less than 0.001 and odds ratio greater than 1: VEGF-A + IL12 subunit beta (IL12B), Fms-related tyrosine kinase 3 ligands (Flt3L) + C–C chemokine 20 (CCL20), Flt3L + IL17A, Flt3L + IL6, STAM-binding protein (STAMBP) + CCL20, STAMBP + IL6, CCL20 + 4EBP1, CCL20 + caspase-8 (CASP8), IL6 + 4EBP1, and IL6 + CASP8. Best AUCs were observed for CRP + IL6 (0.79), CRP + CCL20 (0.78), CRP + IL17A, and CRP + IL17C. CONCLUSIONS AND RELEVANCE:. Our exploratory study shows that specific biomarkers, especially CRP combined with IL6, could help to better diagnose or predict early VAP occurrence in cardiac arrest patients.

Colorectal cancer (CRC) remains a significant global health burden, emphasizing the need for innovative treatment strategies. 95% of the CRC population are microsatellite stable (MSS), insensitive to classical immunotherapies such as anti-PD-1; on the other hand, responders can become resistant and relapse. Recently, the use of cancer vaccines enhanced the immune response against tumor cells. In this context, we developed a therapeutic vaccine based on Stimulated Tumor Cells (STC) platform technology. This vaccine is composed of selected tumor cell lines stressed and haptenated in vitro to generate a factory of immunogenic cancer-related antigens validated by a proteomic cross analysis with patient’s biopsies. This technology allows a multi-specific education of the immune system to target tumor cells harboring resistant clones. Here, we report safety and antitumor efficacy of the murine version of the STC vaccine on CT26 BALB/c CRC syngeneic murine models. We showed that one cell line (1CL)-based STC vaccine suppressed tumor growth and extended survival. In addition, three cell lines (3CL)-based STC vaccine significantly improves these parameters by presenting additional tumor-related antigens inducing a multi-specific anti-tumor immune response. Furthermore, proteomic analyses validated that the 3CL-based STC vaccine represents a wider quality range of tumor-related proteins than the 1CL-based STC vaccine covering key categories of tumor antigens related to tumor plasticity and treatment resistance. We also evaluated the efficacy of STC vaccine in an MC38 anti-PD-1 resistant syngeneic murine model. Vaccination with the 3CL-based STC vaccine significantly improved survival and showed a confirmed complete response with an antitumor activity carried by the increase of CD8+ lymphocyte T cells and M1 macrophage infiltration. These results demonstrate the potential of this technology to produce human vaccines for the treatment of patients with CRC.

Rare early-onset lower urinary tract disorders include defects of functional maturation of the bladder. Current treatments do not target the primary pathobiology of these diseases. Some have a monogenic basis, such as urofacial, or Ochoa, syndrome (UFS). Here, the bladder does not empty fully because of incomplete relaxation of its outflow tract, and subsequent urosepsis can cause kidney failure. UFS is associated with biallelic variants of HPSE2, encoding heparanase-2. This protein is detected in pelvic ganglia, autonomic relay stations that innervate the bladder and control voiding. Bladder outflow tracts of Hpse2 mutant mice display impaired neurogenic relaxation. We hypothesized that HPSE2 gene transfer soon after birth would ameliorate this defect and explored an adeno-associated viral (AAV) vector-based approach. AAV9/HPSE2, carrying human HPSE2 driven by CAG, was administered intravenously into neonatal mice. In the third postnatal week, transgene transduction and expression were sought, and ex vivo myography was undertaken to measure bladder function. In mice administered AAV9/HPSE2, the viral genome was detected in pelvic ganglia. Human HPSE2 was expressed and heparanase-2 became detectable in pelvic ganglia of treated mutant mice. On autopsy, wild-type mice had empty bladders, whereas bladders were uniformly distended in mutant mice, a defect ameliorated by AAV9/HPSE2 treatment. Therapeutically, AAV9/HPSE2 significantly ameliorated impaired neurogenic relaxation of Hpse2 mutant bladder outflow tracts. Impaired neurogenic contractility of mutant detrusor smooth muscle was also significantly improved. These results constitute first steps towards curing UFS, a clinically devastating genetic disease featuring a bladder autonomic neuropathy.

The last decade, smoke and smokeless products claiming to be tobacco-free, including herbal cigarettes and herbal shisha, became available on the European market and gained popularity. This study proposes a new digital droplet PCR (ddPCR) method, designed based on a previously developed real-time PCR (qPCR) method being currently used by the U.S. Food and Drug Administration (FDA) to specifically detect the presence of tobacco DNA in targeting a sequence from the Nicotiana tabacum nia-1 gene. To ensure a harmonized and reliable control by enforcement laboratories, both of these qPCR and ddPCR methods were then evaluated and validated for their compliance to an international standard. First, the performance of these PCR-based methods was successfully assessed as specific and sensitive, and in line with minimum performance requirements from international standard. Secondly, the transferability to external laboratory was confirmed for these PCR-based methods. Finally, the applicability of these PCR-based methods was demonstrated using 7 ground tobacco reference materials from the Tobacco Research Center (TRC) Toronto University as well as 6 commercial smokeless and tobacco-free smoke and smokeless products. Based on this study, the previously developed qPCR method was confirmed as complying with international standard, ensuring a efficient and harmonize use by enforcement laboratories for tobacco control on the European market. Moreover, this study proposed to enforcement laboratories the possibility to use a ddPCR method, enabling the simultaneous detection and absolute quantification of tobacco DNA as well as a limited impact of PCR inhibitors.

This work investigates the peculiarities of using a liquid blowing agent, namely dimethoxymethane (Methylal) to foam a thermoplastic polyurethane (TPU) in the laboratory practice of batch foaming equipment. We preliminarily measured thermodynamic properties of the polymer/gas system relevant to foaming, namely the vapor-liquid pressures at the TPU foaming temperatures. Three different paths were then explored for foaming. First, we used Methylal under its liquid-vapor equilibrium condition, in which both liquid and vapor are present. Secondly, we used Methylal in the liquid state to experiment with liquid foaming strategies. We have observed specific aspects, details, and issues related to the use of liquid blowing agents and devised strategies to deal with them. Finally, we used Methylal as a co-blowing agent together with CO2. In all cases, we examined the impact of pressure, pressure drop rate, and temperature on foam density and morphology.Overall, liquid foaming has proven to be a viable technique and Methylal an effective blowing agent, especially in cooperation with other gaseous blowing agents, where it significantly improves the expansion ratio of the final product.

Abstract The 5th edition of the Global Ministerial Summit on Patient Safety was held in Montreux, Switzerland, in February 2023, delayed by three years due to the COVID-19 pandemic. The overarching theme of the summit was “Less Harm, Better Care – from Resolution to Implementation”, focusing on the challenges of implementation of infection prevention and control (IPC) strategies as well as antimicrobial stewardship programs (ASP) around the world. IPC strategies and ASP are of increasing importance due to the substantial burden of healthcare-associated infections and antimicrobial resistance threatening patient safety. Here, we summarize countries’ and regional experiences and activities related to the implementation of IPC strategies and ASP shared at the meeting. Full implementation of effective programs remains a major challenge in all settings due to limited support by political and healthcare leaders, and human and financial constraints. In addition, the COVID-19 pandemic challenged already well-established programs. By enforcing sustained implementation by dedicated, cross-disciplinary healthcare personnel with a broad skill set, a reduction in healthcare-associated infections and multidrug-resistant pathogens can be achieved, leading ultimately to improved patient safety.

This study aimed to examine the interrater agreement of Critical-Care Pain Observation Tool-Neuro (CPOT-Neuro) scores as a newly developed tool for pain assessment in patients with critical illness and brain injury between raters using two methods of rating (bedside versus video) during standard care procedures (i.e., non-invasive blood pressure and turning). The bedside raters were research staff, and the two video raters had different backgrounds (health and non-health disciplines). Raters received standardized 45 min training by the principal investigator. Video recordings of 56 patient participants with a brain injury at different levels of consciousness were included. Interrater agreement was supported with an Intraclass Correlation Coefficient (ICC) > 0.65 for all pairs of raters and for each procedure. Interrater agreement was highest during turning in the conscious group, with ICCs ranging from 0.79 to 0.90. The use of video recordings was challenging for the observation of some behaviors (i.e., tearing, face flushing), which were influenced by factors such as lighting and the angle of the camera. Ventilator alarms were also challenging to distinguish from other sources for the video rater from a non-health discipline. Following standardized training, video technology was useful in achieving an acceptable interrater agreement of CPOT-Neuro scores between bedside and video raters for research purposes.

Abstract HIV remission can be achieved in some people, called post-treatment HIV controllers, after antiretroviral treatment discontinuation. Treatment initiation close to the time of infection was suggested to favor post-treatment control, but the circumstances and mechanisms leading to this outcome remain unclear. Here we evaluate the impact of early (week 4) vs. late (week 24 post-infection) treatment initiation in SIVmac251-infected male cynomolgus macaques receiving 2 years of therapy before analytical treatment interruption. We show that early treatment strongly promotes post-treatment control, which is not related to a lower frequency of infected cells at treatment interruption. Rather, early treatment favors the development of long-term memory CD8+ T cells with enhanced proliferative and SIV suppressive capacity that are able to mediate a robust secondary-like response upon viral rebound. Our model allows us to formally demonstrate a link between treatment initiation during primary infection and the promotion of post-treatment control and provides results that may guide the development of new immunotherapies for HIV remission.

Abstract Background Methyl‐aminolevulinate‐based photodynamic therapy (MAL‐PDT) has been successfully used in early‐stage mycosis fungoides (MF) lesions. However, the long‐term outcome of initially responding lesions has not been systematically investigated to date. To address this issue, we hereby report a large series of early‐stage MF lesions treated with MAL‐PDT and followed up for 1 year after initial treatment. Objectives The objective of this study was to retrospectively evaluate short‐ and middle‐term clinical results of MAL‐PDT on early‐stage MF lesions (patches and plaques) and to identify characteristics possibly predictive of effectiveness. Methods Data from all early‐stage MF lesions (plaques and patches) treated with MAL‐PDT between 2010 and 2017 in a tertiary referral centre were retrospectively collected. Primary endpoints were initial clinical response rated as complete response (CR) or partial response (PR), and the rate of relapse of initially responding lesions was further evaluated 1 year after the last PDT session. Secondary endpoints addressed tolerance and the relevancy of predefined parameters possibly predictive of CR achievement. Results A total of 62 lesions from 30 patients with early‐stage MF (21 Ia, nine Ib) were treated and analysed. At the 6‐week evaluation, the overall clinical response rate (RR) was 87.25% (55% CR and 32.25% PR) with a mean of 2.7 PDT sessions per lesion. Twenty‐five percent of initially responding lesions relapsed locally within 1 year. Transient, although significant, pain occurred at least once in 30% of patients. In univariate analysis, the location of lesions on sun‐protected areas was the only parameter statistically related to CR, a result confirmed in multivariate analysis. Conclusions Overall, these data confirm the interest in the use of MAL‐PDT in early‐stage MF even for deep (folliculotropic) lesions with a higher efficiency on sun‐protected areas. Furthermore, this study demonstrates for the first time that the response is often sustained over time. Accordingly, MAL‐PDT should be considered in the management of early‐stage MF, especially in oligolesional forms or in residual lesions refractory to systemic treatment.

Increasing animal protein, especially from beef, is necessary to satisfy the requirements of the growing global population. However, this is becoming increasingly challenging due to stakeholders prioritizing sustainable systems with low environmental impacts. To answer these challenges, the use of feed additives such as yeast probiotics seems to be an effective route for improvements in feed efficiency and growth performance. The current study was performed to quantify the environmental impacts of the production and use of a yeast probiotic (Actisaf® Sc 47) through an LCA method in four trials performed during the fattening period: France (French trial), Spain (Spanish trial), and Italy (Italian trials A and B). During each trial, two groups of animals with the same characteristics were compared during the fattening period: the control group without Actisaf® Sc 47 supplementation used as a baseline, and the experimental group with Actisaf® Sc 47 supplementation. The calves started the trial at the ages of 224, 92, and 186 days during the French, Spanish, and Italian trials A and B, respectively. Of the sixteen impact category indicators, nine were analyzed. In Italian trials A and B, the Spanish trial, and the French trial, the use of Actisaf® Sc 47 reduced CC by 4.8, 3.8, 6.6, and 5.4%; FE by 4.8, 3.9, 8.2, and 6.3%; ME by 4.9, 4.0, 6, and 6.4%; and TE by 5.3, 4.1, and 6.2%, respectively. Moreover, during the same trials, Actisaf® Sc 47 reduced AC by 6.0, 4.1, 6.3, and 7.1%; LU by 4.7, 3.9, 5.8, and 6.1%; WU by 4.5, 3.4, 5.2, and 5.9%; RU (fossils) by 4.8, 3.7, 7.3, and 4.8%; and PM by 5.2, 4.1, 6.3, and 7.1%, respectively. The use of Actisaf® Sc 47 has beneficial effects on the environment. Regarding Actisaf® Sc 47 production, the results showed that the production of 1 kg of Actisaf® Sc 47 emitted 2.1 kg of CO2 eq, 60% of which came from the fermentation process and 39% from drying. The results demonstrate the interest in using Actisaf® Sc during the fattening period for its multiple positive outcomes: improving performance and efficiency, while reducing the global carbon footprint.

Hypovitaminosis C, or scurvy, is thought to be an uncommon condition. Although prevalent in the 19th century, its ease of absorption and availability in a general diet has greatly reduced its incidence. Vitamin C is necessary for a number of physiological processes and deficiency can result in a number of complications including bleeding/bruising, anaemia and gingival hyperplasia. This case report demonstrates a case of hypovitaminosis C presenting to a tertiary hospital related to poor dietary intake in a patient with behavioural medical conditions. Treatment consisted of oral supplementation of vitamin C with almost immediate resolution of presenting symptoms. [ABSTRACT FROM AUTHOR]

In endemic areas, the genetic diversity among co-circulating dengue virus (DENV) strains is considerable and new, highly divergent strains are identified on a regular basis. It is thus critical to ensure that molecular diagnostic tools effectively detect virus genomes even in case of important genetic variation. Here, we tested both the pan-DENV detection capacity and the limit of detection of two real-time RT-PCR assays: (i) the commercial RealStar Altona 3.0 system and (ii) a laboratory developed test (LDT) combining two RT-PCR systems in a single reaction tube (DenAllDUO). We used a panel of DENV strains representative of the genetic diversity within DENV species, combined with three in vitro transcribed RNAs as surrogates for unavailable strains corresponding to recently discovered strains with substantial genetic divergence: DENV serotype 1 (DENV-1) Brun2014, DENV-2 QML22 and DENV-4 DKE121. Both systems (i) targeted the genome 3′ untranslated region, (ii) displayed a broad detection spectrum, encompassing most of DENV species diversity, and (iii) detected the three aforementioned divergent strains. DenAllDUO detected all the strains tested, whereas the RealStar system failed to detect strains from DENV-4 genotype III. Altogether, our findings support the value of these two RT-PCR systems as part of the Dengue diagnostic arsenal.

Combined oral contraceptives, comprising of both an oestrogen and a progestin component, are released in aquatic environments and potentially pose a risk to aquatic wildlife by their capacity to disrupt physiological mechanisms.In this study, the endocrine disruptive potential of two mixtures, 17α-ethinylestradiol (EE2), a synthetic oestrogen, or estetrol (E4), a natural oestrogen, with the progestin drospirenone (DRSP) have been characterised in three generations of zebrafish, according to an adapted Medaka Extended One Generation Reproduction Test. Zebrafish (Danio rerio) were exposed to a range of concentrations of EE2/DRSP and E4/DRSP (∼1×, ∼3×, ∼10× and ∼30× predicted environmental concentration, PEC). Survival, growth, hatching success, fecundity, fertilisation success, vitellogenin (VTG), gonad histopathology, sex differentiation, and transcriptional analysis of genes related to gonadal sex steroid hormones synthesis were assessed.In the F0 generation, exposure to EE2/DRSP at ∼10 and ∼30× PEC decreased fecundity and increased male VTG concentrations. The highest concentration of EE2/DRSP also affected VTG concentrations in female zebrafish and the expression of genes implicated in steroid hormones synthesis. In the F1 generation, sex determination was impaired in fish exposed to EE2/DRSP at concentrations as low as ∼3× PEC. Decreased fecundity and fertility, and abnormal gonadal histopathology were also observed. No effects were observed in the F2 generation. In contrast, E4/DRSP induced only minor histopathological changes and an increase in the proportion of males, at the highest concentration tested (∼30× PEC) in the F1 generation and had no effect on hatching success of F2 generation.Overall, this study suggests that the combination E4/DRSP has a more favourable environmental profile than EE2/DRSP.

Summary: It is only partially understood how constitutive allelic methylation at imprinting control regions (ICRs) interacts with other regulation levels to drive timely parental allele-specific expression along large imprinted domains. The Peg13-Kcnk9 domain is an imprinted domain with important brain functions. To gain insights into its regulation during neural commitment, we performed an integrative analysis of its allele-specific epigenetic, transcriptomic, and cis-spatial organization using a mouse stem cell-based corticogenesis model that recapitulates the control of imprinted gene expression during neurodevelopment. We found that, despite an allelic higher-order chromatin structure associated with the paternally CTCF-bound Peg13 ICR, enhancer-Kcnk9 promoter contacts occurred on both alleles, although they were productive only on the maternal allele. This observation challenges the canonical model in which CTCF binding isolates the enhancer and its target gene on either side and suggests a more nuanced role for allelic CTCF binding at some ICRs.

Cet article présente une synthèse des textes cantonaux (Fribourg, Neuchâtel, Jura, Tessin, Valais) et intercantonal (IRDP) du numéro 8 de la Revue LEeE, en les mettant en relation avec les propositions conceptuelles du texte introductif de Lucie Mottier Lopez dans ce même numéro. Les démarches de co-élaboration de documents à visée instituante s’inscrivent dans des mouvements plus larges de transformation des cultures évaluatives. Elles impliquent des professionnel∙les de l’éducation à différents niveaux de la sphère éducative. Les processus collaboratifs varient d’un canton à l’autre, mais tous cherchent à associer les enseignant∙es à la démarche. Des défis sont rencontrés, tel que la terminologie à négocier, et des défis sont anticipés, telle que la résistance au changement de la part du terrain. En guise de conclusion, l’article examine les notions d’objet-frontière et de boundary spanners contribuant à bâtir des ponts de dialogue et de cohérence entre les mondes concernés, en faveur d’une transformation des cultures évaluatives vers des évaluations positives pour l’avenir.

Ce texte introduit le numéro 8 de La Revue LEeE qui donne à voir le produit des échanges du réseau IEAN-CH : International Educational Assessment Network pour la Suisse romande et le Tessin. Ce réseau a été constitué à la suite de la création du réseau IEAN en 2018 en Écosse visant à réunir des « petites nations et états » autour de l'évaluation en éducation. Chaque canton participant est représenté par au moins une personne travaillant dans le monde académique et une autre dans le contexte politico-administratif. Des chercheur∙ses des centres de recherche suisses en éducation ont également été sollicité∙es. Ce numéro expose les travaux du réseau autour de la production de documents de référence liés à la volonté d'insuffler des cultures d'évaluation toujours plus favorables à l'apprentissage des élèves.

Objective: To determine if a lumbar musculature deficiency (paravertebral – PVM – and psoas – PM – muscles) is associated with a higher prevalence of vertebral fractures in osteoporotic patients. Methods: To constitute the fracture group, data were collected retrospectively from patients with one or more recent osteoporotic vertebral fractures between T10 and L5 such as non-injected computerized tomography (CT), dual-energy X-ray absorptiometry (DXA). A control group was made by matching the patients on age, bone mineral density measured by DXA and gender. We analyzed PM and PVM atrophy based on cross-sectional area (CSA) adjusted to the body area as well as fatty infiltration on a 3-level scale and the average muscle density in Hounsfield units (HU). Results: One hundred seventeen patients were included in each group. The fracture group had a lower PVM CSA than the control group (2197.92 ± 460.19 versus 2335.20 ± 394.42 mm2.m−2, respectively p = 0.015), but there was no significant difference in the PM (746.92 ± 197.89 versus 731.74 ± 215.53 mm2.m−2, respectively p = 0.575). The fracture group had a higher grade of fatty infiltration than the control group (PM: 1.3 ± 0.46 versus 1.07 ± 0.25, p < 0.001; PVM: 1.93 ± 0.5 versus 1.74 ± 0.5, p = 0.003) and a lower average muscle density (PM: 26.99 ± 12.83 versus 33.91 ± 8.12 HU, p < 0.001; PVM: 3.42 ± 21.06 versus 12.94 ± 18.88 HU, p < 0.001). Conclusion: This study shows an association between a lack of axial musculature and the occurrence of osteoporotic vertebral fractures. Preventive strengthening exercises could be proposed to osteoporotic patients.

Passive volcanic degassing results in the emission of toxic gases such as H2S at quasi-steady rates over long periods of time that pose a significant hazard to human health even in low gas concentrations. Currently, La Soufrière de Guadeloupe has one of the highest gas emission rates in the Lesser Antilles arc, with gas emitted mainly from low-temperature fumaroles. In this study, gas dispersion from the volcano between 2016–2021 was modelled using a numerical code that takes into account wind and atmospheric data, topography and gas flux measurements. We ran c.100 individual simulations of the most frequently observed wind and gas flux conditions using a Monte-Carlo scheme. Our results, validated using air-quality measurements and citizen-science surveys, show that the most exposed zones are the hamlet of Matouba and the upper St. Claude. These areas have 20% and 5% probability, respectively, of exceeding H2S guidelines for long-term gas exposure (70 ppb).

Abstract Background Healthcare-associated infections in long-term care are associated with substantial morbidity and mortality. While infection prevention and control (IPC) guidelines are well-defined in the acute care setting, evidence of effectiveness for long-term care facilities (LTCF) is missing. We therefore performed a systematic literature review to examine the effect of IPC measures in the long-term care setting. Methods We systematically searched PubMed and Cochrane libraries for articles evaluating the effect of IPC measures in the LTCF setting since 2017, as earlier reviews on this topic covered the timeframe up to this date. Cross-referenced studies from identified articles and from mentioned earlier reviews were also evaluated. We included randomized-controlled trials, quasi-experimental, observational studies, and outbreak reports. The included studies were analyzed regarding study design, type of intervention, description of intervention, outcomes and quality. We distinguished between non-outbreak and outbreak settings. Results We included 74 studies, 34 (46%) in the non-outbreak setting and 40 (54%) in the outbreak setting. The most commonly studied interventions in the non-outbreak setting included the effect of hand hygiene (N = 10), oral hygiene (N = 6), antimicrobial stewardship (N = 4), vaccination of residents (N = 3), education (N = 2) as well as IPC bundles (N = 7). All but one study assessing hand hygiene interventions reported a reduction of infection rates. Further successful interventions were oral hygiene (N = 6) and vaccination of residents (N = 3). In outbreak settings, studies mostly focused on the effects of IPC bundles (N = 24) or mass testing (N = 11). In most of the studies evaluating an IPC bundle, containment of the outbreak was reported. Overall, only four articles (5.4%) were rated as high quality. Conclusion In the non-outbreak setting in LTCF, especially hand hygiene and oral hygiene have a beneficial effect on infection rates. In contrast, IPC bundles, as well as mass testing seem to be promising in an outbreak setting.

Abstract Aims The prognostic value of ‘high dose’ loop diuretics in advanced heart failure outpatients is unclear. We aimed to assess the prognosis associated with loop diuretic dose in ambulatory patients awaiting heart transplantation (HT). Methods and results All ambulatory patients (n = 700, median age 55 years and 70% men) registered on the French national HT waiting list between 1 January 2013 and 31 December 2019 were included. Patients were divided into ‘low dose’, ‘intermediate dose’, and ‘high dose’ loop diuretics corresponding to furosemide equivalent doses of ≤40, 40–250, and >250 mg, respectively. The primary outcome was a combined criterion of waitlist death and urgent HT. N‐terminal pro‐B‐type natriuretic peptide, creatinine levels, pulmonary capillary wedge pressure, and pulmonary pressures gradually increased with higher diuretic dose. At 12 months, the risk of waitlist death/urgent HT was 7.4%, 19.2%, and 25.6% (P = 0.001) for ‘low dose’, ‘intermediate dose’, and ‘high dose’ patients, respectively. When adjusting for confounders, including natriuretic peptides, hepatic, and renal function, the ‘high dose’ group was associated with increased waitlist mortality or urgent HT [adjusted hazard ratio (HR) 2.23, 1.33 to 3.73; P = 0.002] and a six‐fold higher risk of waitlist death (adjusted HR 6.18, 2.16 to 17.72; P 0.05). Conclusions A ‘high dose’ of loop diuretics is strongly associated with residual congestion and is a predictor of outcome in patients awaiting HT despite adjustment for classical cardiorenal risk factors. This routine variable may be helpful for risk stratification of pre‐HT patients.

Abstract The mitigation scenarios database of the Intergovernmental Panel on Climate Change’s Sixth Assessment Report is an important resource for informing policymaking on energy transitions. However, there is a large variety of models, scenario designs, and resulting outputs. Here we analyse the scenarios consistent with limiting warming to 2 °C or below regarding the speed, trajectory, and feasibility of different fossil fuel reduction pathways. In scenarios limiting warming to 1.5 °C with no or limited overshoot, global coal, oil, and natural gas supply (intended for all uses) decline on average by 95%, 62%, and 42%, respectively, from 2020 to 2050, but the long-term role of gas is highly variable. Higher-gas pathways are enabled by higher carbon capture and storage (CCS) and carbon dioxide removal (CDR), but are likely associated with inadequate model representation of regional CO2 storage capacity and technology adoption, diffusion, and path-dependencies. If CDR is constrained by limits derived from expert consensus, the respective modelled coal, oil, and gas reductions become 99%, 70%, and 84%. Our findings suggest the need to adopt unambiguous near- and long-term reduction benchmarks in coal, oil, and gas production and use alongside other climate mitigation targets.

Today, one of the major challenges of dairy farmers is to reduce their environmental footprint to establish more effective, efficient, and sustainable production systems. Feed additives such as yeast probiotics could potentially allow them to achieve these objectives through the improvement of milk production, feed efficiency, and ration valorization, hence mitigating the environmental impacts of milk production. In this study, the life cycle assessment (LCA) principle was performed to estimate the environmental impact of the production and supplementation of a commercial yeast probiotic (Actisaf Sc 47) in three trials performed in three different countries that are representative for around 50% of the milk production in Europe: France (French trial), United Kingdom (UK trial), and Germany (German trial). For each trial, two groups of animals were compared: control, without Actisaf Sc 47 supplementation, used as baseline; and experimental, with Actisaf Sc 47 supplementation at 5 or 10 g/cow/day. Different impact categories were analyzed for each group to calculate the impact of producing 1 kg of fat- and protein-corrected milk. An initial analysis was done only during the period of Actisaf Sc 47 supplementation and showed than the supplementation with Actisaf Sc 47 reduced, on average by 5%, the carbon footprint during the three trials. A second analysis was done via the extrapolation of all the data of each trial to an annual farm level, including the lactation period (305 days), dry period (60 days), and the period with and without Actisaf Sc 47 supplementation. Reported at a farm annual scale, the average reduction allowed by Actisaf Sc 47 supplementation was 2.9, 2.05, 2.47, 1.67, 2.28, 2.18, 2.14, and 2.28% of the carbon footprint, land use, water use, resource use, acidification, freshwater eutrophication, marine eutrophication, and terrestrial eutrophication, respectively. On average, the production of 1 kg of fat- and protein-corrected milk by using Actisaf Sc 47 was shown to improve environmental impacts compared to control. Regarding Actisaf Sc 47 production, the LCA showed that the production of 1 kg of Actisaf Sc 47 emitted 2.1 kg CO2 eq with a negligible contribution to total the carbon footprint of milk ranging from 0.005 to 0.016%. The use of Actisaf Sc 47 in dairy cows could then result in different positive outcomes: improving performance and efficiency while reducing the global carbon footprint.

Abstract In earlier survey research, we observed a severe impact of the first peak of the COVID-19 pandemic on the subjective wellbeing, sleep and activity of adults aged 65 years or older in Flanders, Belgium. The impact on subjective cognitive functioning, however, was limited. Since then, periods of lockdown and periods with less strict regulations alternated, but social distancing remained, especially for older adults. To study the longer-term impact of the pandemic on wellbeing and subjective cognitive functioning, we re-assessed the older adults from the first measurement moment (May–June 2020) in a second (June–July 2020) and third (December 2020) wave of the survey (n = 371, M = 72 years old, range 65–97 years old). Results indicated that wellbeing fluctuated with the severity of the pandemic. Results for self-reported cognitive functioning were mixed. While participants indicated a slightly better general subjective cognitive functioning at the end of the study, experienced problems with most cognitive subdomains significantly increased over time. The presence of depressive and anxiety symptoms were related to the longer-term impact of the pandemic on wellbeing and subjective cognitive functioning. Our study shows the long-lasting impact of the pandemic on the wellbeing and subjective cognitive functioning of older adults, without full recovery from the first wave.

Background: Left atrial (LA) function contributes to the augmentation of cardiac output during exercise. However, LA response to exercise in patients with atrial fibrillation (AF) is unknown. We explored the LA mechanical response to exercise and the association between LA dysfunction and exercise intolerance. Methods: We recruited consecutive patients with symptomatic AF and preserved left ventricular ejection fraction (LVEF). Participants underwent exercise echocardiography and cardiopulmonary exercise testing (CPET). Two-dimensional and speckle-tracking echocardiography were performed to assess LA function at rest and during exercise. Participants were grouped according to presenting rhythm (AF vs sinus rhythm). The relationship between LA function and cardiorespiratory fitness in patients maintaining SR was assessed using linear regression. Results: Of 177 consecutive symptomatic AF patients awaiting AF ablation, 105 met inclusion criteria; 31 (29.5 %) presented in AF whilst 74 (70.5 %) presented in SR. Patients in SR augmented LA function from rest to exercise, increasing LA emptying fraction (LAEF) and LA reservoir strain. In contrast, patients in AF demonstrated reduced LAEF and reservoir strain at rest, with failure to augment either parameter during exercise. This was associated with reduced VO2Peak compared to those in SR (18.4 ± 5.6 vs 22.5 ± 7.7 ml/kg/min, p = 0.003). In patients maintaining SR, LAEF and reservoir strain at rest and during exercise were associated with VO2Peak, independent of LV function. Conclusion: The maintenance of SR in patients with AF is associated with greater LA reservoir function at rest and greater augmentation with exercise compared to patients in AF. In patients in SR, reduced LA function is associated with reduced exercise tolerance, independent of LV function.

BackgroundExposure to ionizing radiation has been linked to cardiovascular diseases. However, the impact of moderate doses of radiation on abdominal aortic aneurysm (AAA) remains unknown.MethodsAngiotensin II-infused Apoe-/- mice were irradiated (acute, 1 Gray) either 3 days before (Day-3) or 1 day after (Day+1) pomp implantation. Isolated primary aortic vascular smooth muscle cells (VSMCs) were irradiated (acute 1 Gray) for mechanistic studies and functional testing in vitro.ResultsDay-3 and Day+1 irradiation resulted in a significant reduction in aorta dilation (Control: 1.39+/-0.12; Day-3: 1.12+/-0.11; Day+1: 1.15+/-0.08 mm, PConclusionModerate doses of ionizing radiation mitigate AAA either through VSCM phenotype or inflammation modulation, depending on the time of irradiation.