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More than half of all patients with cancer receive radiation therapy, but resistance is commonly observed. Currently, it is unknown whether resistance to radiation therapy is acquired or inherently present. Here, we employed organoids derived from rectal cancer and single-cell whole-genome sequencing to investigate the long-term evolution of subclones in response to radiation. Comparing single-cell whole-genome karyotypes between in-vitro-unirradiated and -irradiated organoids revealed three patterns of subclonal evolution: (1) subclonal persistence, (2) subclonal extinction, and (3) subclonal expansion. Organoids in which subclonal shifts occurred (i.e., expansion or extinction) became more resistant to radiation. Although radioresistant subclones did not share recurrent copy-number alterations that could explain their radioresistance, resistance was associated with reduced chromosomal instability, an association that was also observed in 529 human cancer cell lines. These data suggest that resistance to radiation is inherently present and associated with reduced chromosomal instability.

Global scheduling reduces the average response times as it can use the available computing cores more efficiently for scheduling ready tasks. However, this flexibility poses challenges in accurately quantifying interference scenarios, often resulting in either conservative response-time analyses or scalability issues. In this paper, we present a new response-time analysis for preemptive periodic tasks (or job sets) subject to release jitter under global job-level fixed-priority (JLFP) scheduling. Our analysis relies on the notion of schedule-abstraction graph (SAG), a reachability-based response-time analysis known for its potential accuracy and efficiency. Up to this point, SAG was limited to non-preemptive tasks due to the complexity of handling preemption when the number of preemptions and the moments they occur are not known beforehand. In this paper, we introduce the concept of time partitions and demonstrate how it facilitates the extension of SAG for preemptive tasks. Moreover, our paper provides the first response-time analysis for the global EDF(k) policy - a JLFP scheduling policy introduced in 2003 to address the Dhall’s effect. Our experiments show that our analysis is significantly more accurate compared to the state-of-the-art analyses. For example, we identify 12 times more schedulable task sets than existing tests for the global EDF policy (e.g., for systems with 6 to 16 tasks, 70% utilization, and 4 cores) with an average runtime of 30 minutes. We show that EDF(k) outperforms global RM and EDF by scheduling on average 24.9% more task sets (e.g., for systems with 2 to 10 cores and 70% utilization). Moreover, for the first time, we show that global JLFP scheduling policies (particularly, global EDF(k)) are able to schedule task sets that are not schedulable using well-known partitioning heuristics.

Importance: Neoadjuvant short-course radiotherapy was routinely applied for nonlocally advanced rectal cancer (cT1-3N0-1M0 with >1 mm distance to the mesorectal fascia) in the Netherlands following the Dutch total mesorectal excision trial. This policy has shifted toward selective application after guideline revision in 2014. Objective: To determine the association of decreased use of neoadjuvant radiotherapy with cancer-related outcomes and overall survival at a national level. Design, Setting, and Participants: This multicenter, population-based, nationwide cross-sectional cohort study analyzed Dutch patients with rectal cancer who were treated in 2011 with a 4-year follow-up. A similar study was performed in 2021, analyzing all patients that were surgically treated in 2016. From these cohorts, all patients with cT1-3N0-1M0 rectal cancer and radiologically unthreatened mesorectal fascia were included in the current study. The data of the 2011 cohort were collected between May and October 2015, and the data of the 2016 cohort were collected between October 2020 and November 2021. The data were analyzed between May and October 2022. Main Outcomes and Measures: The main outcomes were 4-year local recurrence and overall survival rates. Results: Among the 2011 and 2016 cohorts, 1199 (mean [SD] age, 68 [11] years; 430 women [36%]) of 2095 patients (57.2%) and 1576 (mean [SD] age, 68 [10] years; 547 women [35%]) of 3057 patients (51.6%) had cT1-3N0-1M0 rectal cancer and were included, with proportions of neoadjuvant radiotherapy of 87% (2011) and 37% (2016). Four-year local recurrence rates were 5.8% and 5.5%, respectively (P =.99). Compared with the 2011 cohort, 4-year overall survival was significantly higher in the 2016 cohort (79.6% vs 86.4%; P <.001), with lower non-cancer-related mortality (13.8% vs 6.3%; P <.001). Conclusions and Relevance: The results of this cross-sectional study suggest that an absolute 50% reduction in radiotherapy use for nonlocally

China wants to become a science, technology, and manufacturing superpower by upgrading and modernizing its industrial base and concentrating the nation’s innovation resources around strategic priorities. However, in this policy brief, Jeroen Groenewegen-Lau, head of the Science, Technology and Innovation program at MERICS, argues that it is difficult for the state to integrate innovation resources because of the gap separating universities and research organizations from industry, which impedes the translation of scientific output into technological prowess. By contrast, Beijing has been much more successful at directing industrial development. As a result, he says, achieving a modernized industrial base is now the dominant framework for Chinese policymakers as they pursue technological self-reliance.

Whether travelling, playing games, or debugging code, any situation where an agent desires change can be framed as a problem. Despite this ubiquity, there is no unifying framework describing how people reason backwards when solving problems. We introduce AND/OR trees, which chain together subgoals and actions to attain them, as a way to represent this process. To investigate whether actions from AND/OR trees were predictive of human behavior, we conducted a study in which participants solved deterministic, long-horizon puzzles. AND/OR trees were able to explain most of the actions the participants took. Next, we modeled search through these trees using a psychologically plausible, single-parameter search algorithm. We fit this model to the data of individual participants and found that it captures trends in summary statistics of human play. Our results show the promise of AND/OR trees as a representation for backward reasoning in problem solving.

Herpes simplex virus type 1 (HSV-1) is a neurotropic alphaherpesvirus that establishes a lifelong infection in sensory neurons of infected individuals, accompanied with intermittent reactivation of latent virus causing (a)symptomatic virus shedding. Whereas acyclovir (ACV) is a safe and highly effective antiviral to treat HSV-1 infections, long-term usage can lead to emergence of ACV resistant (ACVR) HSV-1 and subsequently ACV refractory disease. Here, we isolated an HSV-1 strain from a patient with reactivated herpetic eye disease that did not respond to ACV treatment. The isolate carried a novel non-synonymous F289S mutation in the viral UL23 gene encoding the thymidine kinase (TK) protein. Because ACV needs conversion by viral TK and subsequently cellular kinases to inhibit HSV-1 replication, the UL23 gene is commonly mutated in ACVR HSV-1 strains. The potential role of the F289S mutation causing ACVR was investigated using CRISPR/Cas9-mediated HSV-1 genome editing. Reverting the F289S mutation in the original clinical isolate to the wild-type sequence S289F resulted in an ACV-sensitive (ACVS) phenotype, and introduction of the F289S substitution in an ACVS HSV-1 reference strain led to an ACVR phenotype. In summary, we identified a new HSV-1 TK mutation in the eye of a patient with ACV refractory herpetic eye disease, which was identified as the causative ACVR mutation with the aid of CRISPR/Cas9-mediated genome engineering technology. Direct editing of clinical HSV-1 isolates by CRISPR/Cas9 is a powerful strategy to assess whether single residue substitutions are causative to a clinical ACVR phenotype.

Atherosclerosis is the predominant underlying etiopathology of coronary artery disease. Changes in plaque phenotype from stable to high risk may spur future major adverse cardiac events (MACE). Different pharmacological therapies have been implemented to mitigate this risk. Over the last two decades, intravascular imaging modalities have emerged in clinical studies to clarify how these therapies may affect the composition and burden of coronary plaques. Lipid-lowering agents, such as statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 inhibitors, were shown not only to reduce low-density lipoprotein levels and MACE but also to directly affect features of coronary plaque vulnerability. Studies have demonstrated that lipid-lowering therapy reduces the percentage of atheroma volume and number of macrophages and increases fibrous cap thickness. Future studies should answer the question of whether pharmacological plaque stabilization may be sufficient to mitigate the risk of MACE for selected groups of patients with atherosclerotic coronary disease.

This chapter discusses the fundamental trade-off between competence and loyalty in the authoritarian security apparatus. Research suggests that the survival of autocracies and dictatorships hinges on loyal security officers. However, the management of regime security also requires skills and competence, which officers may use to oust the very regime they pledged to protect. The chapter highlights the importance of command experience as a key ingredient to successful officer careers. It then explains how autocrats use command posts to generate loyalty among competent officers. Employing original data on an entire officer corps, it illustrates the dual logic of officer selection and placement at work in Argentina’s last dictatorship. The regime assigned skilled officers to field positions and co-opted those with uncertain loyalties by placing them close to their home regions. The chapter concludes by highlighting avenues for future research.

Osteoarthritis (OA) is a multifactorial degenerative joint disease of which the underlying mechanisms are yet to be fully understood. At the molecular level, multiple factors including altered signaling pathways, epigenetics, metabolic imbalance, extracellular matrix degradation, production of matrix metalloproteinases, and inflammatory cytokines, are known to play a detrimental role in OA. However, these factors do not initiate OA, but are mediators or consequences of the disease, while many other factors causing the etiology of OA are still unknown. Here, it is revealed that microenvironmental osmolarity can induce and reverse osteoarthritis-related behavior of chondrocytes via altered intracellular molecular crowding, which represents a previously unknown mechanism underlying OA pathophysiology. Decreased intracellular crowding is associated with increased sensitivity to proinflammatory triggers and decreased responsiveness to anabolic stimuli. OA-induced lowered intracellular molecular crowding could be renormalized via exposure to higher extracellular osmolarity such as those found in healthy joints, which reverse OA chondrocyte's sensitivity to catabolic stimuli as well as its glycolytic metabolism.

A two-step strategy combining assisted benchmark testing (entry controls) and External Quality Assessments (EQAs) with blinded simulated clinical specimens to enhance and maintain the quality of nucleic acid amplification testing was developed. This strategy was successfully applied to 71 diagnostic laboratories in The Netherlands when upscaling the national diagnostic capacity during the SARS-CoV-2 pandemic. The availability of benchmark testing in combination with advice for improvement substantially enhanced the quality of the laboratory testing procedures for SARS-CoV-2 detection. The three subsequent EQA rounds demonstrated high quality testing with regard to specificity (99.6% correctly identified) and sensitivity (93.3% correctly identified). Even with the implementation of novel assays, changing workflows using diverse equipment and a high degree of assay heterogeneity, the overall high quality was maintained using this two-step strategy. We show that in contrast to the limited value of Cq value for absolute proxies of viral load, these Cq values can, in combination with metadata on strategies and techniques, provide valuable information for laboratories to improve their procedures. In conclusion, our two-step strategy (preparation phase followed by a series of EQAs) is a rapid and flexible system capable of scaling, improving, and maintaining high quality diagnostics even in a rapidly evolving (e.g. pandemic) situation.

BACKGROUND AND OBJECTIVES: Cerebral small vessel disease (cSVD) is a major cause of stroke and dementia, but little is known about disease mechanisms at the level of the small vessels. 7T-MRI allows assessing small vessel function in vivo in different vessel populations. We hypothesized that multiple aspects of small vessel function are altered in patients with cSVD and that these abnormalities relate to disease burden.METHODS: Patients and controls participated in a prospective observational cohort study, the ZOOM@SVDs study. Small vessel function measures on 7T-MRI included perforating artery blood flow velocity and pulsatility index in the basal ganglia and centrum semiovale, vascular reactivity to visual stimulation in the occipital cortex, and reactivity to hypercapnia in the gray and white matter. Lesion load on 3T-MRI and cognitive function were used to assess disease burden.RESULTS: Forty-six patients with sporadic cSVD (mean age ± SD 65 ± 9 years) and 22 matched controls (64 ± 7 years) participated in the ZOOM@SVDs study. Compared with controls, patients had increased pulsatility index (mean difference 0.09, p = 0.01) but similar blood flow velocity in basal ganglia perforating arteries and similar flow velocity and pulsatility index in centrum semiovale perforating arteries. The duration of the vascular response to brief visual stimulation in the occipital cortex was shorter in patients than in controls (mean difference -0.63 seconds, p = 0.02), whereas reactivity to hypercapnia was not significantly affected in the gray and total white matter. Among patients, reactivity to hypercapnia was lower in white matter hyperintensities compared with normal-appearing white matter (blood-oxygen-level dependent mean difference 0.35%, p = 0.001). Blood flow velocity and pulsatility index in basal ganglia perforating arteries and reactivity to brief visual stimulation correlated with disease burden.DISCUSSION: We observed abnormalities in severa

BACKGROUND: In treatment of colon cancer, strict waiting-time targets are enforced, leaving professionals no room to lengthen treatment intervals when advisable, for instance to optimise a patient's health status by means of prehabilitation. Good quality studies supporting these targets are lacking. With this study we aim to establish whether a prolonged treatment interval is associated with a clinically relevant deterioration in overall and cancer free survival. METHODS: This retrospective multicenter non-inferiority study includes all consecutive patients who underwent elective oncological resection of a biopsy-proven primary non-metastatic colon carcinoma between 2010 and 2016 in six hospitals in the Southern Netherlands. Treatment interval was defined as time between diagnosis and surgical treatment. Cut-off points for treatment interval were =35 days and =49 days. FINDINGS: 3376 patients were included. Cancer recurred in 505 patients (15.0%) For cancer free survival, a treatment interval >35 days and >49 days was non-inferior to a treatment interval =35 days. Results for overall survival were inconclusive, but no association was found. CONCLUSION: For cancer free survival, a prolonged treatment interval, even over 49 days, is non-inferior to the currently set waiting-time target of =35 days. Therefore, the waiting-time targets set as fundamental objective in current treatment guidelines should become directional instead of strict targets.

The optimal ventilation strategy for patients on extracorporeal membrane oxygenation (ECMO) remains uncertain. This survey reports current mechanical ventilation strategies adopted by ECMO centers worldwide. An international, multicenter, cross-sectional survey was conducted anonymously through an internet-based tool. Participants from North America, Europe, Asia, and Oceania were recruited from the extracorporeal life support organization (ELSO) directory. Responses were received from 48 adult ECMO centers (response rate 10.6%). Half of these had dedicated ventilation protocols for ECMO support. Pressure-controlled ventilation was the preferred initial ventilation mode for both venovenous ECMO (VV-ECMO) (60%) and venoarterial ECMO (VA-ECMO) (34%). In VV-ECMO, the primary goal was lung rest (93%), with rescue therapies commonly employed, especially neuromuscular blockade (93%) and prone positioning (74%). Spontaneous ventilation was typically introduced after signs of pulmonary recovery, with few centers using it as the initial mode (7%). A quarter of centers stopped sedation within 3 days after ECMO initiation. Ventilation strategies during VA-ECMO focused less on lung-protective goals and transitioned to spontaneous ventilation earlier. Ventilation strategies during ECMO support differ considerably. Controlled ventilation is predominantly used initially to provide lung rest, often facilitated by sedation and neuromuscular blockade. Few centers apply "awake ECMO" early during ECMO support, some utilizing partial neuromuscular blockade.

Introduction: The reflective pause, taking a pause during performance to reflect, is an important practice in simulation-based learning. However, for novice learners, it is a highly complex self-regulatory skill that cannot stand alone without guidance. Using educational theories, we propose how to design cognitive and metacognitive aids to guide learners with the reflective pause and investigate its effects on performance in a simulation training environment. Methods: These effects are examined in four aspects of performance: cognitive load, primary performance, secondary performance, and encapsulation. Medical students (N = 72) performed tasks in simulation training for emergency medicine, under 2 conditions: reflection condition (n = 36) where reflection was prompted and guided, and control condition (n = 36) without such reflection. Results: The effects of reflective pauses emerged for 2 aspects of performance: cognitive load decreased and secondary performance improved. However, primary performance and encapsulation did not show significant difference. Conclusions: The results demonstrate that reflective pauses with cognitive and metacognitive aids implemented can enhance some aspects of performance. We suggest that to secure these effects, feedback during reflection and an adaptation period should be provided.

Background: Ruptured intracranial aneurysms resulting in subarachnoid haemorrhage can be treated by open surgical or endovascular treatment. Despite multiple previous studies, uncertainties on the optimal treatment practice still exists. The resulting treatment variation may result in a variable, potentially worse, patient outcome. To better inform future treatment strategies, this study aims to identify the effectiveness of different treatment strategies in patients with ruptured intracranial aneurysms by investigating long-term functional outcome, complications and cost-effectiveness. An explorative analysis of the diagnostic and prognostic value of radiological imaging will also be performed. Methods: This multi-centre observational prospective cohort study will have a follow-up of 10 years. A total of 880 adult patients with a subarachnoid haemorrhage caused by a ruptured intracranial aneurysm will be included. Calculation of sample size (N = 880) was performed to show non-inferiority of clip-reconstruction compared to endovascular treatment on 1 year outcome, assessed by using the ordinal modified Rankin Scale. The primary endpoint is the modified Rankin Scale score and mortality at 1 year after the initial subarachnoid haemorrhage. Patients will receive ‘non-experimental’ regular care during their hospital stay. For this study, health questionnaires and functional outcome will be assessed at baseline, before discharge and at follow-up visits. Discussion: Despite the major healthcare and societal burden, the optimal treatment strategy for patients with subarachnoid haemorrhage caused by ruptured intracranial aneurysms is yet to be determined. Findings of this comparative effectiveness study, in which in-between centre variation in practice and patient outcome are investigated, will provide evidence on the effectiveness of treatment strategies, hopefully contributing to future high value treatment standa

Deep learning models have achieved high performance in medical applications, however, their adoption in clinical practice is hindered due to their black-box nature. Self-explainable models, like prototype-based models, can be especially beneficial as they are interpretable by design. However, if the learnt prototypes are of low quality then the prototype-based models are as good as black-box. Having high quality prototypes is a pre-requisite for a truly interpretable model. In this work, we propose a prototype evaluation framework for coherence (PEF-C) for quantitatively evaluating the quality of the prototypes based on domain knowledge. We show the use of PEF-C in the context of breast cancer prediction using mammography. Existing works on prototype-based models on breast cancer prediction using mammography have focused on improving the classification performance of prototype-based models compared to black-box models and have evaluated prototype quality through anecdotal evidence. We are the first to go beyond anecdotal evidence and evaluate the quality of the mammography prototypes systematically using our PEF-C. Specifically, we apply three state-of-the-art prototype-based models, ProtoPNet, BRAIxProtoPNet++ and PIP-Net on mammography images for breast cancer prediction and evaluate these models w.r.t. i) classification performance, and ii) quality of the prototypes, on three public datasets. Our results show that prototype-based models are competitive with black-box models in terms of classification performance, and achieve a higher score in detecting ROIs. However, the quality of the prototypes are not yet sufficient and can be improved in aspects of relevance, purity and learning a variety of prototypes. We call the XAI community to systematically evaluate the quality of the prototypes to check their true usability in high stake decisions and improve such models further., Comment: Accepted at World Conference on Explainable Artificial Intelligence; 21 pages, 5 figures, 3 tables

Tensor parameters that are amortized or regularized over large tensor powers, often called "asymptotic" tensor parameters, play a central role in several areas including algebraic complexity theory (constructing fast matrix multiplication algorithms), quantum information (entanglement cost and distillable entanglement), and additive combinatorics (bounds on cap sets, sunflower-free sets, etc.). Examples are the asymptotic tensor rank, asymptotic slice rank and asymptotic subrank. Recent works (Costa-Dalai, Blatter-Draisma-Rupniewski, Christandl-Gesmundo-Zuiddam) have investigated notions of discreteness (no accumulation points) or "gaps" in the values of such tensor parameters. We prove a general discreteness theorem for asymptotic tensor parameters of order-three tensors and use this to prove that (1) over any finite field (and in fact any finite set of coefficients in any field), the asymptotic subrank and the asymptotic slice rank have no accumulation points, and (2) over the complex numbers, the asymptotic slice rank has no accumulation points. Central to our approach are two new general lower bounds on the asymptotic subrank of tensors, which measures how much a tensor can be diagonalized. The first lower bound says that the asymptotic subrank of any concise three-tensor is at least the cube-root of the smallest dimension. The second lower bound says that any concise three-tensor that is "narrow enough" (has one dimension much smaller than the other two) has maximal asymptotic subrank. Our proofs rely on new lower bounds on the maximum rank in matrix subspaces that are obtained by slicing a three-tensor in the three different directions. We prove that for any concise tensor, the product of any two such maximum ranks must be large, and as a consequence there are always two distinct directions with large max-rank.

The Editors-in-Chief for Journal of Materials Chemistry A, B and C look back at the 10th anniversary year and the celebratory activities that took place.

Sediments in urban drainage systems (UDS) significantly impact their operation, so effective strategies are required to reduce their negative effects. Monitoring sediment accumulation provides valuable insights into sediment characteristics, sediment transport dynamics, and system performance. However, the effectiveness of monitoring systems is limited due to cost constraints and installation challenges. This study describes the development and application of a new system based on temperature dynamics to measure sediment depths in sewer systems. The methodology involves the analysis of temperature time series under dry weather flow conditions to identify harmonic patterns between wastewater and sediment-bed temperatures. These patterns are increasingly attenuated by increasing sediment depth. This study combines a system called MONitoring Temperatures in SEdiments (MONTSE), which integrates a dual-probe heat-pulse (DPHP) method to characterize sediment thermal properties, and a surrogate model, which includes temperature pattern analysis, to estimate sediment depths. Likewise, laboratory-scale experiments were performed to validate the temperature monitoring system and the surrogate model performance. The maximum absolute errors in measured sediment depths were less than 22 mm, and the uncertainty of the system was estimated at ±7.3 mm. Groundbreaking measurements of thermal properties of UDS sediments were also reported. Reliable information on sediment depths and properties was provided, so the system could significantly optimize sewer system operation and cleaning strategies., Validerad;2024;Nivå 2;2024-04-03 (joosat);Full text: CC BY license;Funder: Xunta de Galicia (Consellería de Cultura, Educación e Universidade, ED481B2021-082)

G-Quadruplex (G4) DNA structures are important regulatory elements in central biological processes. Small molecules that selectively bind and stabilize G4 structures have therapeutic potential, and there are currently >1000 known G4 ligands. Despite this, only two G4 ligands ever made it to clinical trials. In this work, we synthesized several heterocyclic G4 ligands and studied their interactions with G4s (e.g., G4s from the c-MYC, c-KIT, and BCL-2 promoters) using biochemical assays. We further studied the effect of selected compounds on cell viability, the effect on the number of G4s in cells, and their pharmacokinetic properties. This identified potent G4 ligands with suitable properties and further revealed that the dispersion component in arene-arene interactions in combination with electron-deficient electrostatics is central for the ligand to bind with the G4 efficiently. The presented design strategy can be applied in the further development of G4-ligands with suitable properties to explore G4s as therapeutic targets.

Importance: Exposure to traumatic brain injury (TBI) has raised widespread concern over participation in sports, particularly over possible long-term consequences. However, little is known about the outcomes of individuals presenting to hospitals with sports-related TBI. Objective: To compare the characteristics and outcomes of individuals presenting to hospitals with sports-related and non-sports-related TBI. Design, setting, and participants: The CENTER-TBI (Collaborative European NeuroTrauma Effectiveness Research in TBI) observational cohort study was conducted at hospitals in 18 countries. The study enrolled 4509 patients who had TBI and had an indication for computed tomography (CT), of whom 4360 were 16 years or older. Outcomes were assessed at 3 and 6 months, and groups were compared using regression analyses adjusting for clinical and demographic differences. Data were collected between December 9, 2014, and December 17, 2017, and analyzed from August 2022 to March 2023. Exposure: Sports-related and non-sports-related TBI with subgroups selected by severity of injury. Main outcomes and measures: The main outcome was the Glasgow Outcome Scale-Extended (GOSE) at 6 months, with secondary outcomes covering postconcussion symptoms, health-related quality of life, and mental health. Results: A total of 4360 patients were studied, including 256 (6%) with sports-related TBI (mean [SD] age, 38.9 [18.1] years; 161 [63%] male) and 4104 with non-sports-related TBI (mean [SD] age, 51.0 [20.2] years; 2773 [68%] male). Compared with patients with non-sports-related TBI, patients with sports-related TBI were younger, more likely to have tertiary education, more likely to be previously healthy, and less likely to have a major extracranial injury. After adjustment, the groups did not differ in incomplete recovery (GOSE scores <8) at 6 months (odds ratio [OR], 1.27; 95% CI, 0.90-1.78; P = .22 for all patients; OR, 1.20; 95% CI, 0.83-1.73; P = .34 for those with mild TBI; a

Tyrosine kinase inhibitor (TKI) discontinuation in chronic myeloid leukemia (CML) has become part of routine care for patients with a sustained deep molecular response (DMR). Approximately 50% experience a molecular relapse upon TKI cessation. Most of them quickly regain DMR upon TKI resumption. Whether these patients can achieve a second treatment-free remission (TFR) remains unclear. DAstop2 (ClinicalTrials.gov ID: NCT03573596) is a prospective study including patients with a failed first TFR attempt re-treated with any TKI for ≥ one year. Upon entering the study, patients received the TKI dasatinib for additional two years. Patients with sustained DMR for ≥1 year qualified for a second TKI stop. Ninety-four patients were included between Oct 2017-Dec 2021. At the time of data analysis, 62 patients had attempted a 2nd stop. After a median follow-up of 27 months from 2nd stop, TFR rates were 61, 56 and 46% at 6, 12 and 24 months respectively. No progression to advanced stage disease was seen and 87% had re-achieved MR4 within a median of 3 months from TKI re-initiation. In summary, we show that a 2nd TFR attempt after dasatinib treatment is safe, feasible and TFR rates seem in the range of those reported in trials of a first TKI stop.

This study proposes a detailed soot modeling framework for large-eddy simulation (LES) to accurately predict soot formation and particle size distributions (PSD) in turbulent reacting flows. The framework incorporates Flamelet Generated Manifold (FGM) chemistry and a soot model based on the discrete sectional method (DSM) to predict both qualitative and quantitative sooting behavior while keeping the computational cost affordable. Two elementary modeling strategies are considered in the LES formalism for describing soot formation rates. These strategies rely on an a-priori tabulation of soot formation rates and their run-time computation. The LES formalism is applied to the simulations of a well-characterized, non-premixed, turbulent jet flame. A comparative analysis of strategies employed for filtered soot source term treatment is conducted to investigate their impact on the prediction of soot quantities and the evolution of soot PSDs. The LES results for the gas phase and soot phase are compared against the available experimental data. A good prediction of soot evolution is achieved with the two methodologies. The tabulation of soot formation rates leads to a significant reduction in computational cost compared to the model based on their explicit runtime computation. The LES results reveal that the modeling of filtered soot source terms has a significant impact on the quantitative prediction of soot formation. The possible reasons for the observed differences in the soot prediction are discussed. The run-time computation-based model provides a more consistent treatment of the non-linear interactions between the gas and soot phases in soot source terms compared to the tabulated soot chemistry approach. On the other hand, the tabulated soot chemistry model is an interesting and efficient modeling approach for predicting soot formation in turbulent conditions. Overall, both approaches have their strengths and limitations, and the choice of approach may depend on the, The research leading to these results has received funding from the European Union’s Horizon 2020 Programme under the ESTiMatE project, grant agreement No. 821418, and the AHEAD PID2020-118387RB-C33 and SAFLOW TED2021-131618B-C21 projects from the Ministerio de Ciencia e Innovación. DM acknowledges the grant from the Ministerio de Ciencia e Innovación, Ayudas para contratos Ramón y Cajal (RYC) 2021: RYC2021-034654-I. The authors gratefully acknowledge the Partnership for Advanced Computing in Europe (PRACE) grant Soot Aero for computational resources and technical support in the numerical simulations., Peer Reviewed, Postprint (published version)

BACKGROUND: Many studies reported associations between long-term exposure to environmental factors and mortality; however, little is known on the combined effects of these factors and health. We aimed to evaluate the association between external exposome and all-cause mortality in large administrative and traditional adult cohorts in Europe.METHODS: Data from six administrative cohorts (Catalonia, Greece, Rome, Sweden, Switzerland and the Netherlands, totaling 27,913,545 subjects) and three traditional adult cohorts (CEANS-Sweden, EPIC-NL-the Netherlands, KORA-Germany, totaling 57,653 participants) were included. Multiple exposures were assigned at the residential addresses, and were divided into three a priori defined domains: (1) air pollution [fine particulate matter (PM 2.5), nitrogen dioxide (NO₂), black carbon (BC) and warm-season Ozone (warm-O 3)]; (2) land/built environment (Normalized Difference Vegetation Index-NDVI, impervious surfaces, and distance to water); (3) air temperature (cold- and warm-season mean and standard deviation). Each domain was synthesized through Principal Component Analysis (PCA), with the aim of explaining at least 80% of its variability. Cox proportional-hazards regression models were applied and the total risk of the external exposome was estimated through the Cumulative Risk Index (CRI). The estimates were adjusted for individual- and area-level covariates. RESULTS: More than 205 million person-years at risk and more than 3.2 million deaths were analyzed. In single-component models, IQR increases of the first principal component of the air pollution domain were associated with higher mortality [HRs ranging from 1.011 (95% CI: 1.005-1.018) for the Rome cohort to 1.076 (1.071-1.081) for the Swedish cohort]. In contrast, lower levels of the first principal component of the land/built environment domain, pointing to reduced vegetation and higher percentage of impervious surfaces, were associated with higher risks. Fi

Wastewater-based epidemiological surveillance at municipal wastewater treatment plants has proven to play an important role in COVID-19 surveillance. Considering international passenger hubs contribute extensively to global transmission of viruses, wastewater surveillance at this type of location may be of added value as well. The aim of this study is to explore the potential of long-term wastewater surveillance at a large passenger hub as an additional tool for public health surveillance during different stages of a pandemic. Here, we present an analysis of SARS-CoV-2 viral loads in airport wastewater by reverse-transcription quantitative polymerase chain reaction (RT-qPCR) from the beginning of the COVID-19 pandemic in Feb 2020, and an analysis of SARS-CoV-2 variants by whole-genome next-generation sequencing from Sep 2020, both until Sep 2022, in the Netherlands. Results are contextualized using (inter)national measures and data sources such as passenger numbers, clinical surveillance data and national wastewater surveillance data. Our findings show that wastewater surveillance was possible throughout the study period, irrespective of measures, as viral loads were detected and quantified in 98.6 % (273/277) of samples. Emergence of SARS-CoV-2 variants, identified in 91.0 % (161/177) of sequenced samples, coincided with increases in viral loads. Furthermore, trends in viral load and variant detection in airport wastewater closely followed, and in some cases preceded, trends in national daily average viral load in wastewater and variants detected in clinical surveillance. Wastewater-based epidemiology at a large international airport is a valuable addition to classical COVID-19 surveillance and the developed expertise can be applied in pandemic preparedness plans for other (emerging) pathogens in the future.

This systematic literature review aimed to investigate the extent to which transport-related interventions induced a reduction in car use. Both qualitative synthesis and meta-analysis were employed. The synthesis included 31 original studies, while the meta-analysis included 21. Of the qualitatively synthesised studies, 74 % demonstrated that interventions were effective in reducing car use. The pooled estimates of the effects showed a significant reduction in car usage with a mean effect size of Hedges’ g = -0.117 (p = 0.024). The effect strongly varies across the studies due to considerable heterogeneity (I2 = .98, with a 95 % prediction interval from −0.589 to 0.355). At the moderator level, no significant differences were identified in the mean effect sizes for any subgroups, and the key factors could not be distinguished. The current body of evidence highlights that transport-related interventions can significantly influence car usage reduction, while literature suggests that this may benefit environment and society.

Without taking additional measures, flooding is becoming more likely and intense in a changing climate, which causes large economic damage. Households and firms are directly impacted by physical flood damage, but further ripple effects on society occur through business disruptions. By using post-disaster survey data from the 2021 flood event in the Netherlands, this study adds to the literature on business interruption duration and losses after flooding. The current empirical literature on flood impacts on firms is often unable to distinguish separate effects for flooded and non-flooded firms and does not incorporate flood severity and the influence of risk reduction measures. Here, we use multivariate regression models to determine depth-duration functions that describe the relationship between flood hazard characteristics and business interruption duration. This relationship can be used to calibrate flood damage models that capture indirect firm impacts. The prediction of business interruption after flooding allows for differentiation in business interruption between firms within a flooded area, reducing the reliance of these macroeconomic models on restrictive assumptions. Our results indicate that a day of business interruption duration costs a firm on average 0.5 % of their annual revenue; an effect that is stronger for firms with a weaker connection to their region. Flood damage mitigation (FDM) measures taken at the building level do not significantly affect business interruption duration, although further research on this is required. Finally, quick damage compensation is found to reduce business interruption duration and thus revenue losses, calling for higher insurance uptake and rapid and streamlined post-disaster insurance and government compensation.

CONTEXT Complex rice systems (CRS) are polycultures in which rice is grown together with one or more plant or animal species using combined methods of practices from indigenous knowledge and modern science in augmenting ecological processes to foster ecosystem services in rice agroecosystems. However, their implementation faces challenges due to farmers' knowledge gaps, high capital outlay and labour shortages. OBJECTIVE This study aims to link types of rice farming and farmer perceptions to facilitate recommendations to scale up CRS. METHODS We constructed a farm typology based on a survey of 111 farm households and aggregated cognitive maps (ACMs) based on fuzzy cognitive maps developed in focus group discussions in Malang and Lamongan, East Java Province, Indonesia. RESULTS AND CONCLUSIONS The farm typology classified farm households into three types: (a) small farms with high inputs of agrochemicals (SH, n = 29) which were all identified in Malang; (b) medium-size farms with high input intensity of agrochemicals (MH, n = 43), distributed across Malang and Lamongan; and (c) medium-size farms with low inputs of agrochemicals (ML, n = 39), all detected in Lamongan. ACMs revealed the differences in farmer group's perceptions on farm input-output relations, agroecosystems processes and CRS component interactions. SH and MH farmers prioritised economic benefits over ecosystem services and crop-livestock components. SH farmers were locked into high-input and high-output systems, while MH farmers failed to obtain high output despite high input use. Intervention schemes could be developed such as thorough training on economics for SH farmers and efficient use and on-farm production of fertilisers for MH farmers. Meanwhile, with the majority of ML farmers having adopted CRS, their priorities were more evenly distributed across all components, implying their more holistic understanding of the interacted components. However, technical assistance on agronomic, post-harvest m

Structural equation modeling (``SEM'' for short) is a widely applicable statistical analysis framework that is popular among psychological scientists (and related disciplines). Valid use of this technique requires researchers to clearly distinguish the type of research they are interested in. Scientific research can roughly be divided into descriptive, predictive, and causal research, and each type of research has different implications for the analysis strategy. One of the problems, however, is that this distinction is often implicit in psychological research. Therefore, it can be unclear whether research results actually answer the research question. In Chapters 2 through 5, I collaborate with applied researchers on both descriptive and predictive research projects, and I describe extensions of one specific popular longitudinal SEM model. Moreover, many alternative analytical techniques have been in disciplines such as epidemiology and biostatistics for causal research. These methods are still largely unknown among psychological researchers. In Chapters 6 and 7, I therefore compare popular SEM models with analytical techniques from biostatistics for longitudinal and observational causal research: which method performs better and under what conditions? Furthermore, I introduce psychological researchers to these alternative causal methods, and discuss if they can be applied in the context of psychological research.

In European painting, a transition took place where artists started to consciously introduce blurred or soft contours in their works. There may have been several reasons for this. One suggestion in art historical literature is that this may have been done to create a stronger sense of volume in the depicted figures or objects. Here we describe four experiments in which we tried to test whether soft or blurred contours do indeed enhance a sense volume or depth. In the first three experiments, we found that, for both paintings and abstract shapes, three dimensionality was actually decreased instead of increased for blurred (and line) contours, in comparison with sharp contours. In the last experiment, we controlled for the position of the blur (on the lit or dark side) and found that blur on the lit side evoked a stronger impression of three dimensionality. Overall, the experiments robustly show that an art historical conjecture that a blurred contour increases three dimensionality is not granted. Because the blurred contours can be found in many established art works such as from Leonardo and Vermeer, there must be other rationales behind this use than the creation of a stronger sense of volume or depth.