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Dysregulation of the renin-angiotensin-aldosterone-system (RAAS) in sepsis is a complex and early phenomenon with a likely significant contribution to organ failure and patient outcomes. A better understanding of the pathophysiology and intricacies of the RAAS in septic shock has led to the use of exogenous angiotensin II as a new therapeutic agent. In this review, we report a multinational and multi-disciplinary expert panel discussion on the role and implications of RAAS modulation in sepsis and the use of exogenous angiotensin II. The panel proposed guidance regarding patient selection and treatment options with exogenous angiotensin II which should trigger further research.

Aim: To evaluate the contribution of a multiplex PCR for respiratory viruses on antibiotic and antiviral prescription, ancillary test prescription, admission and length of stay of patients. Methods: Two hundred ninety-one adult and pediatric patients visiting the emergency department during the 2015–2016 influenza epidemic were prospectively included and immediately tested 24/7 using the FilmArray Respiratory Panel. The results were communicated to the practitioner in charge as soon as they became available. Clinical and biological data were gathered and analyzed. Findings: Results from the FilmArray Respiratory Panel do not appear to impact admission or antibiotic prescription, with the exception of a lower admission rate for children who tested positive for influenza B. Parameters that account for the clinical decisions evaluated are CRP level, white blood cell count, suspected or proven bacterial infection and, for adult patients only, signs of respiratory distress. Length of stay is also not significantly different between patients with a positive and a negative result. A rapid influenza test result permits a more appropriate prescription of oseltamivir. Keywords: FilmArray Respiratory Panel, Patient management, Respiratory viruses, Influenza, Antibiotic, Antiviral, Length of stay

Abstract A rapid data-driven method for determining regional deposition of inhaled medication aerosols in human airways is presented, which is patient specific. Inhalation patterns, device characteristics, and aerodynamic particle size distribution of medications are considered. The method is developed using dimensional analysis and Buckingham Pi theorem, and provides total, regional, and lobar distributions of aerosol deposition. 34 dimensionless quantities are selected, of which 22 encode features of the airway trees and segmented lobes, 14 pertain to the device and the drug formulation, and 13 the inhalation profile of the subject. The dimensionless correlations are obtained using a large database of computational fluid dynamics results on patient specific airways. The intraclass correlation coefficient between the current method and its training dataset is 0.92. The difference between the predicted average lobar deposition in the six asthma patients and the in-vivo data is 1.3%. The model has the potential to offer insights into the effectiveness of personalized drug delivery in clinical settings and can aid in drug development cycles.

The well-preserved Llandovery (lower Silurian) succession of Anticosti Island (Quebec, eastern Canada) contains an expanded Aeronian–Telychian boundary interval when compared to other coeval basins. This boundary interval on Anticosti Island also includes two of the most important Llandovery biogeochemical events, the late Aeronian and Valgu events. These two events were previously documented in the Jupiter and Chicotte formations through the study of conodont, graptolite, and brachiopod biostratigraphy and δ13C chemostratigraphy. Despite these multiple investigations, the exact position of the Aeronian–Telychian stage boundary on Anticosti Island has not been firmly established. Here we locally define and globally correlate chitinozoan biozones to refine the position of this stage boundary. The Ancyrochitina ramosaspina biozone, recognized in the Ferrum Member of the Jupiter Formation, correlates with the global Conochitina alargada biozone and indicates an Aeronian age. The Eisenackitina dolioliformis biozone suggests mostly a Telychian age for the Pavillon Member of the Jupiter Formation and the Chicotte Formation. Three new species are defined, namely Conochitina asselinae sp. nov., Spinachitina glooscapi sp. nov., and Ancyrochitina wilsonae sp. nov. (registration date: 4 December 2024, publication LSID: urn:lsid:zoobank.org:pub:11184506-F273-4D7A-BC28-A1BB4BC8FCD8, asselinae LSID: D282DA9D-6A9C-4B9E-AA6C-9ADC4473E95B, glooscapi LSID: 5801DC12-4EA1-439F-B7C8-FAF7C1B9D2C7, wilsonae LSID: 549EEF2F-7F19-4E6D-9F8E-384594B2FE65). Our new chitinozoan data, combined with previous studies, allow a comparison with the well-studied Baltic succession, confirming that limited unconformities mark the Aeronian–Telychian boundary interval on Anticosti Island, in contrast to the less complete coeval location. Our refined age model for the Aeronian to Telychian succession of Anticosti Island provides a solid baseline to study further Llandovery biochemical events in the aftermath of the Late Ordovician mass extinction.

Abstract Supramolecular extracellular matrix (ECM) networks play an essential role in skin architecture and function. Elastin microfibril interface-located proteins (EMILINs) comprise a family of three extracellular glycoproteins that serve as essential structural components of the elastin/fibrillin microfibril network, and exert crucial functions in cellular signaling. Little is known about the structural nature of EMILIN networks in skin. We therefore investigated the spatiotemporal localization of EMILIN-1, -2, -3 in human skin induced by aging, UV-exposure, fibrosis, and connective tissue disorder. Confocal immunofluorescence and immunogold electron microscopy analysis identified all EMILINs as components of elastic fibers and elastin-free oxytalan fibers inserted into the basement membrane (BM). Further, our ultrastructural analysis demonstrates cellular contacts of dermally localized EMILIN-1 positive fibers across the BM with the surface of basal keratinocytes. Analysis of skin biopsies and fibroblast cultures from fibrillin-1 deficient Marfan patients revealed that EMILINs require intact fibrillin-1 as deposition scaffold. In patients with scleroderma and the bleomycin-induced murine fibrosis model EMILIN-2 was upregulated. EMILIN-3 localizes to the tips of candelabra-like oxytalan fibers, and to specialized BMs engulfing hair follicles and sebaceous glands. Our data identify EMILINs as important markers to monitor rearrangements of the dermal ECM architecture induced by aging and pathological conditions.

No higher-order skill will be more important for pupils to develop in the twenty-first century than critical thinking. Schools should integrate it into their curricula, thereby allowing students to acquire new skills in preparation for a dynamic and rapidly changing labour market. Educators, psychologists, and philosophers agree on the importance of critical thinking, but there is a lack of agreement on what the concept entails and on how it should be taught. It is against this background that the present study examines primary-school teachers' perceptions of teaching strategies aimed at stimulating pupils' core critical-thinking skills. Twenty-one teachers working in European Schools in Brussels were questioned by means of semi-structured interviews, and the results showed the importance of group discussion, cooperative learning, brainstorming, and debate to teaching practice aimed at promoting critical thinking. This research contributes to defining a framework in innovative teaching methods for promoting critical thinking.

Teaching practice in remote areas is beneficial for pre-service teachers' professional development. The geographical structure and society in remote areas provide unique experiences. This study focuses on how teaching practice in remote areas opens up opportunities for transformative learning. Forty-one pre-service primary teachers from three universities participated in semi-structured interviews. The interviews were conducted in retrospect after participants had finished their teaching practice. Results show that PSTs encountered nine types of challenges during teaching practice; parents' low awareness of the importance of their children's education, local teachers' low motivation, limited teaching resources at school, pupils' absenteeism, pupils' poor numeracy and literacy skills, the principal's low responsibility, natural hazard factors, pupils' low ability to understand Indonesian, and local conflicts between different communities. Encountering these nine types of challenges fosters PSTs' disorientation, which might lead to transformative learning. In conclusion, remote areas have potential for transformative learning.

The literature strongly emphasises the importance of constructive relationships between parents and their children's caregivers. However, minimal empirical research has investigated relationships between language minority parents and caregivers in childcare. This large-scale study seeks to fill this gap by exploring the quality of the language minority parent-caregiver relationship with a focus on the child's multilingual upbringing. Therefore, three domains that reflect the quality of parent-caregiver relationships were assessed: (1) interpersonal connections, (2) home-childcare continuity, and (3) language and multilingual upbringing advice parents receive from caregivers. The sample consists of 404 language minority parents, recruited from 85 childcare facilities (0-3 years). Results indicate that most parents reported positive relationships with their child's caregiver with respect to interpersonal characteristics (communication and trust). In contrast, parents responded less favorably regarding issues pertaining to their language expectations, including whether multilingual upbringing advice, either solicited or unsolicited, was discussed. While language advice was not frequently given, when it was given, multilingual advice was more prevalent than monolingual advice, and one-parent one-language (OPOL) advice was common. Practical and policy implications are discussed.

Abstract Non-thermal plasma (NTP) has shown promising anti-cancer effects, but there is still limited knowledge about the underlying cell death mechanisms induced by NTP and inherent differences between NTP treatment modalities. This study aimed to investigate four major regulated cell death (RCD) pathways, namely apoptosis, pyroptosis, necroptosis, and ferroptosis, in melanoma cancer cells following NTP treatment, and to provide an overview of molecular mechanistic differences between direct and indirect NTP treatment modalities. To discriminate which cell death pathways were triggered after treatment, specific inhibitors of apoptosis, pyroptosis, necroptosis, and ferroptosis were evaluated. RCD-specific molecular pathways were further investigated to validate the findings with inhibitors. Both direct and indirect NTP treatment increased caspase 3/7 and annexin V expression, indicative of apoptosis, as well as lipid peroxidation, characteristic of ferroptosis. Pyroptosis, on the other hand, was only induced by direct NTP treatment, evidenced by increased caspase 1 activity, whereas necroptosis was stimulated in a cell line-dependent manner. These findings highlight the molecular differences and implications of direct and indirect NTP treatment for cancer therapy. Altogether, activation of multiple cell death pathways offers advantages in minimizing treatment resistance and enhancing therapeutic efficacy, particularly in a combination setting. Understanding the mechanisms underlying NTP-induced RCD will enable the development of strategic combination therapies targeting multiple pathways to achieve cancer lethality.

Abstract Background Acute Disseminated Encephalomyelitis (ADEM) is an acute demyelinating disorder of the central nervous system, characterize by multiple white matter hyperintensities on T2 MRI. Patients usually present with subacute progressive encephalopathy and polyfocal neurological deficits. Possible treatments are corticosteroids, immunoglobulins and plasma exchange. Full clinical recovery is seen in more than half of the cases. Case We describe a case of a 62-year-old patient presenting with thunderclap headache as the first symptom, two weeks after an upper respiratory tract infection. The clinical course was complicated by progressive coma and intracranial hypertension mandating external ventricular drainage and sedation. Initial treatment with methylprednisolone was unsuccessful but clinical resolution and radiological regression was achieved after plasma exchanges and cyclophosphamide. Conclusion To our knowledge, this is the first reported case of ADEM presenting with thunderclap headache. Intracranial hypertension with the need for invasive neuromonitoring and pressure management is also a very rare complication of ADEM. In this report, we describe the findings of the literature review concerning ADEM, thunderclap headache and intracranial hypertension.

Abstract Background Fluid administration is the first line treatment in intensive care unit (ICU) patients with sepsis and septic shock. While fluid boluses administration can be titrated by predicting preload dependency, the amount of other forms of fluids may be more complex to be evaluated. We conducted a retrospective analysis in a tertiary hospital, to assess the ratio between fluids given as boluses and total administered fluid intake during early phases of ICU stay, and to evaluate the impact of fluid strategy on ICU mortality. Data related to fluid administration during the first four days of ICU stay were exported from an electronic health records system (ICCA®, Philips Healthcare). Demographic data, severity score, norepinephrine dose at ICU admission, overall fluid balance and the percentage of different fluid components of the overall volume administered were included in a multivariable logistic regression model, evaluating the association with ICU survival. Results We analyzed 220 patients admitted with septic shock and sepsis-induced hypotension from 1st July 2021 to 31st December 2023. Fluid boluses and maintenance represented 49.3% ± 22.8 of the overall fluid intake, being balanced solution the most represented (40.4% ± 22.0). The fluid volume for drug infusion represented 34.0% ± 2.9 of the total fluid intake, while oral or via nasogastric tube fluid intake represented 18.0% ± 15.7 of the total fluid intake. Fluid volume given as boluses represented 8.6% of the total fluid intake over the four days, with a reduction from 25.1% ± 24.0 on Day 1 to 4.8% ± 8.7 on Day 4. A positive fluid balance [OR 1.167 (1.029–1.341); p = 0.021] was the most important factor associated with ICU mortality. Non-survivors (n = 66; 30%) received a higher amount of overall inputs than survivors only on Day 1 [2493 mL vs. 1855 mL; p = 0.022]. Conclusions This retrospective analysis of fluids given over the early phases of septic shock and sepsis-induced hypotension showed that the overall volume given by boluses ranges from about 25% on Day 1 to about 5% on Day 4 from ICU admission. Our data confirms that a positive fluid balance over the first 4 days of ICU is associated with mortality.

Abstract Cytoglobin (CYGB) is a member of the oxygen-binding globin superfamily. In this study we generated stable CYGB overexpressing A375 melanoma cells and performed RNA-sequencing to comprehensively explore the CYGB-dependent transcriptome. Our findings reveal that ectopic expression of CYGB dysregulated multiple cancer-associated genes, including the mTORC1 and AKT/mTOR signaling pathways, which are frequently overactivated in tumors. Moreover, several cancer-associated pathways, such as epithelial-mesenchymal transition (EMT) mediated by CSPG4, were downregulated upon CYGB overexpression. Intriguingly, ectopic expression suggested anti-inflammatory potential of CYGB, as exemplified by downregulation of key inflammasome-associated genes, including NLRP1, CASP1 and CD74, which play pivotal roles in cytokine regulation and inflammasome activation. Consistent with established globin functions, CYGB appears to be involved in redox homeostasis. Furthermore, our study indicates CYGB's association to DNA repair mechanisms and its regulation of NOX4, reinforcing its functional versatility. Additionally, multiple significantly enriched pathways in CYGB overexpressing cells were consistently dysregulated in opposite direction in CYGB depleted cells. Collectively, our RNA-sequencing based investigations illustrate the diverse functions of CYGB in melanoma cells, pointing to its putative roles in cellular protection against oxidative stress, inflammation, and cancer-associated pathways. These findings pave the way for further research into the physiological role of CYGB and its potential as a candidate therapeutic target in melanoma.

Abstract The continuously reinforced concrete pavement (CRCP) system grapples with challenges such as non-uniform transverse crack patterns and the need for substantial reinforcement. Field research on the Belgian CRCP sections along motorway E313 indicates that active cracking induced by partial surface saw-cuts consistently leads to transverse crack patterns. This study introduces an innovative modification to the CRCP: the actively reinforced concrete pavement design (ARCP). The ARCP leverages partial surface saw-cuts to reduce reinforcement needs by replacing continuous-length steel bars with partial-length counterparts. The main objective of the present study is to develop a 3D finite element (FE) model capturing the active cracking behavior of ARCP under realistic external temperature variations. Comparative analysis with CRCP considers early-age crack patterns, crack strain development, and the distribution of maximum steel stress for different steel ratios (0.67%, 0.75%, and 0.85%). FE simulation results align with field data, indicating that ARCP exhibits similar early-age cracking behavior to CRCP but with a significant 24 to 42% reduction in total reinforcement. This innovation presents a promising avenue for addressing CRCP challenges while optimizing material usage in pavement construction.

Abstract The integration of eDNA metabarcoding into monitoring programs provides valuable information about fish community structures. Despite the growing body of evidence supporting the method's effectiveness in distinguishing fine-scale eDNA signals, there is a limited understanding of eDNA distribution in shallow, well-mixed environments, especially related to sampling depth. We analyzed 167 samples collected from the surface and bottom water at 17 locations of the Belgian Part of the North Sea (BPNS), where the deepest sampling point was 31 m, and compared this to beam trawl catch data collected simultaneously at the same locations. eDNA metabarcoding identified an additional 22 species compared to beam trawl catch data. Diversity measures and patterns were very similar between surface and bottom samples and revealed community patterns that were previously described by long-term beam trawl catch data. Surface and bottom samples had 39 fish species in common, while six and eight rare species were uniquely detected, respectively. Our results demonstrate that eDNA metabarcoding effectively identifies spatial community patterns of fishes in the highly dynamic environment of the BPNS regardless of sampling depth. Out of the six most common species tested, eDNA metabarcoding read abundances correlated strongly with catch-based abundance data for one species, but moderately for two others, indicating that inferring fish abundance and biomass via eDNA metabarcoding remains challenging.

Abstract Because renal artery stenosis (RAS) often presents bilateral, we sought to investigate the renal pressure‐flow relationship and its relation to renin release, in the presence of a contralateral significant stenosis. A porcine model of graded unilateral RAS in the presence of a significant contralateral stenosis was created. The severity of the stenosis was expressed as the ratio between distal renal pressure (Pd) and aortic pressure (Pa). Pd and renal flow velocity were continuously measured using a combined pressure‐flow wire (Combowire®). Hemodynamic measurements and blood sampling for renin, angiotensin, and aldosterone were performed in baseline conditions and during progressive balloon inflation in the renal artery leading to stepwise 5% Pd decrements. Resistive index (RI) was computed as (1‐(End Diastolic V/Maximum Peak Systolic V))*100. A decrease of average peak flow velocity (APV) was observed when distal renal perfusion pressure decreased by 25% and was associated with activation of renin secretion. The RI decreased already for minimal changes in Pd/Pa ratio. In an animal model of unilateral graded RAS in the presence of a significant contralateral stenosis, a 25% decrease in perfusion pressure results in a significant decrease in distal renal flow, causing a more pronounced upregulation of renin secretion when compared to a model of graded unilateral RAS without contralateral significant RAS.

Objective: Renal hypothermia, which can be achieved through several techniques, might allow for longer clamping times in complex robot-assisted partial nephrectomy (RAPN). Intra-arterial cooling (IAC) through arteriotomy was previously found safe and feasible. It may offer several advantages such as prolonged clamping times and working in a bloodless field, allowing for more nephron-sparing surgery in challenging lesions. We provide a step-by-step video elaborating on the surgical technique of RAPN with IAC and present the long-term results of our case series. Patients and surgical procedure: Ten patients with complex renal masses (deep endophytic, hilar, multiple ipsilateral and very large lesions), where clamping times over 25 min were expected, were treated with RAPN using IAC between March 2020 and March 2023 in 3 referral centers by 2 surgeons. All surgeries were performed using the Da Vinci Xi robot. Three-dimensional (3D) models were created for pre-operative planning and peri‑operative guidance. Results: Median warm, cold and rewarming ischemia times were 4 (IQR 3-7) min, 60 (IQR 33-75) min and 11 (IQR 7-24) min respectively. One case was converted to radical nephrectomy and one case required postoperative coiling due to pseudo-aneurysm formation (Clavien-Dindo 3b). No other intraoperative or postoperative complications occurred. Median pre- and postoperative (3 month and 6 month) GFR values were 90 (IQR 78-90) ml/min, 87 (IQR 71-90) ml/min and 90 (IQR 67-90) ml/min. At a median follow-up of 24 (IQR 13-44) months, the median GFR was stable at 90 (IQR 82-90) ml/min. Conclusions: We present a step-by-step video description of RAPN using IAC. This technique allows for safe prolonged clamping times in complex renal masses, with maintained kidney function and no long-term complications at a median follow-up of 2 years. This technique could be considered by expert robotic surgeons, expanding indications for robotic nephron-sparing surgery.

Objective Real-life management of patients with hypertension and chronic kidney disease (CKD) among European Society of Hypertension Excellence Centres (ESH-ECs) is unclear : we aimed to investigate it. Methods A survey was conducted in 2023. The questionnaire contained 64 questions asking ESH-ECs representatives to estimate how patients with CKD are managed. Results Overall, 88 ESH-ECS representatives from 27 countries participated. According to the responders, renin-angiotensin system (RAS) blockers, calcium-channel blockers and thiazides were often added when these medications were lacking in CKD patients, but physicians were more prone to initiate RAS blockers (90% [interquartile range: 70–95%]) than MRA (20% [10–30%]), SGLT2i (30% [20–50%]) or (GLP1-RA (10% [5–15%]). Despite treatment optimisation, 30% of responders indicated that hypertension remained uncontrolled (30% (15–40%) vs 18% [10%–25%]) in CKD and CKD patients, respectively). Hyperkalemia was the most frequent barrier to initiate RAS blockers, and dosage reduction was considered in 45% of responders when kalaemia was 5.5–5.9 mmol/L. Conclusions RAS blockers are initiated in most ESH-ECS in CKD patients, but MRA and SGLT2i initiations are less frequent. Hyperkalemia was the main barrier for initiation or adequate dosing of RAS blockade, and RAS blockers’ dosage reduction was the usual management.

ABSTRACT Background Impaired myocardial function and arrhythmia are important manifestations of Marfan syndrome (MFS). Studies assessing myocardial fibrosis in relation to these manifestations are scarce. Methods This cross‐sectional, single‐center study assessed ventricular volumes, ventricular function, and myocardial fibrosis by cardiac magnetic resonance imaging (CMR) in patients with MFS harboring a (likely) pathogenic FBN1 variant. The presence and extent of fibrosis were assessed by late gadolinium enhancement (LGE) and extracellular volume measurement (ECV). Data on 24‐h Holter monitoring and clinical data were extracted from electronic patient records. Results The study included 32 unselected patients with MFS (median age 38 years [range 10–69], 41% women). No focal myocardial fibrosis was detected. Six patients (21%) had diffuse fibrosis (ECV > 29%). No association was found between the presence of diffuse fibrosis and clinically relevant myocardial dysfunction. Five patients (16%) had reduced left ventricular ejection fraction (LVEF 29%. Patients with MAD had increased indexed LV volumes (median end‐diastolic volume, 92 mL/m2 [IQR, 78–100] vs. 78 mL/m2 [IQR, 71–87]; median end‐systolic volume, 31 mL/m2 [IQR, 23–46] vs. 22 mL/m2 [IQR, 21–28]), also after adjusting for the presence of mitral and aortic valve regurgitation. No differences in ECV were seen between patients with and without MAD. Conclusions In this cohort of patients with MFS, focal myocardial fibrosis was not detected using CMR. Although diffuse fibrosis was observed in 21% of patients, no evident connection to clinically relevant myocardial dysfunction was found. Further studies should evaluate the impact of diffuse fibrosis on clinical outcome prediction.