KU Leuven

Building on previous research indicating the robust biological effects of coumarins, we focused on exploring imino-coumarin 2-benzazole conjugates. Compounds were tested for antiproliferative activity in vitro, with the most active ones further examined to determine the mechanism of biological action. Five derivatives exhibited significant antiproliferative activity against all tested cancer cells (IC50 ranging from 0.04 to 8.5 μM), falling within the low micromolar/submicromolar range of inhibitory concentrations. Three compounds had remarkable antiproliferative effects against Capan-1 (IC50 0.04–0.05 μM) and DND-41 (IC50 0.06–0.07 μM). Promising compounds were further investigated, confirming their mechanism of action through tubulin polymerization inhibition. Computational docking and molecular dynamics simulations confirmed the high affinity of potent derivatives for the tubulin colchicine site and justified the suitability of the employed skeleton by identifying crucial protein–ligand interactions promoting binding. This insight highlights a strategy for further potency improvements through substituents that can donate hydrogen bonds or bear a positive charge, allowing such ligands to more optimally adapt to the identified anionic binding site environment.

Longitudinal data is frequently encountered in medical research, where participants are followed throughout time. Additional structure and hence complexity occurs when there is pairing between the participants (e.g., matched case-control studies) or within the participants (e.g., analysis of participants' both eyes). Various modelling approaches, identified through a systematic review, are discussed, including (un)paired t-tests, multivariate analysis of variance (MANOVA), difference scores, linear mixed models (LMM), and new or more recent statistical methods. Next, highlighting the importance of selecting appropriate models based on the data's characteristics, the methods are applied on both a real-life case study in ophthalmology and a simulated case-control study. Key findings include the superiority of the conditional linear mixed model and multilevel models in handling paired longitudinal data in terms of precision. Moreover, the article underscores the impact of accounting for intra-pair correlations and missing data mechanisms. Focus will be on discussing the advantages and disadvantages of the approaches, rather than on the mathematical or computational details.

Background [⁶⁸Ga]PentixaFor detects C-X-C chemokine receptor type 4 (CXCR4) overexpression in various malignancies, such as multiple myeloma and non-Hodgkin lymphomas, as well as in endocrine and inflammatory disorders. This study aimed to develop an Al¹⁸F-labeled radiotracer derived from LY2510924 for CXCR4-targeted imaging, leveraging the physical and logistical advantages of fluorine-18. Methods We designed a CXCR4-specific radioprobe, [¹⁸F]AlF-NOTA-SC, based on LY2510924 by incorporating a triglutamate linker and NOTA chelator to enable Al¹⁸F-labeling. The in vitro CXCR4 affinity was assessed using cell-based binding assays. Subsequently, in vivo pharmacokinetics and tumor uptake of [¹⁸F]AlF-NOTA-SC were assessed in naïve mice and mice with xenografts derived from U87.CD4/U87.CD4.CXCR4 and MM.1 S cells. Finally, biodistribution was determined in a non-human primate using PET-MR. Results Compared to Ga-PentixaFor, AlF-NOTA-SC demonstrated similar in vitro affinity for human CXCR4. [¹⁸F]AlF-NOTA-SC was produced with a decay-corrected radiochemical yield of 21.0 ± 7.1% and an apparent molar activity of 16.4 ± 3.6 GBq/µmol. In [¹⁸F]AlF-NOTA-SC binding assays on U87.CD4.CXCR4 cells, the total bound fraction was 7.1 ± 0.5% (58% blocking by AMD3100). In naïve mice, the radiotracer did not accumulate in any organs; however, it showed a significant CXCR4-specific uptake in xenografted tumors (SUVmeanU87.CD4 = 0.04 ± 0.00 (n = 3); SUVmeanU87.CD4.CXCR4 = 3.04 ± 0.65 (n = 3); SUVmeanMM.1 S = 1.95 ± 0.11 (n = 3)). In a non-human primate, [¹⁸F]AlF-NOTA-SC accumulated in CXCR4 expressing organs, such as the spleen and bone marrow. Conclusion [¹⁸F]AlF-NOTA-SC exhibited CXCR4-specific uptake in vitro and in vivo, with fast and persistent tumor accumulation, making it a strong candidate for clinical translation as an ¹⁸F-alternative to [⁶⁸Ga]PentixaFor. Graphical abstract

Pathological tremors can often be debilitating to activities of daily living and significantly affect the quality of life. Such tremulous movements are commonly observed in wrist flexion-extension (FE). To suppress this tremor we present a wearable robot (WR) with a customized mechanical metamaterial (MM) as the physical human-robot interface (pHRI). The MM is optimized to conform to the user’s wrist posture and follow the hand’s Cartesian trajectory. This is done to minimize the shear between the pHRI and the user’s skin and consequently improve wearability. This WR is then used to effect a viscous tremor suppression using the velocity of the user’s wrist FE. We present a model for the interaction between the WR and the user with which we develop the viscous damping approach for tremor. This is then evaluated in simulation and using a dedicated test bed. This tremor suppression approach demonstrates an attenuation of 20–30 dB at various tremulous frequencies resulting in significantly lower tremor amplitudes due to the viscous damping.

Background Return to work has become more valuable today more than ever especially for adult workers who experience post-COVID condition. Objective This scoping review aims to map the extant literature on the role of occupational therapists for people with post COVID condition returning to work. Specifically, we described the roles of occupational therapists, identified the professionals occupational therapists work with in this practice setting, and determined whether the concept of return to work is perceived as an outcome or a process. Method The review followed Arksey and O’Malley's framework and reported the results using PRISMA extension. A systematic database search was performed in June 2024 and was updated in February 2024 to retrieve literature published from 2021 onwards. Results A total of 33 papers from 5106 records were included. The included records were studies from varying designs and largely coming from Western and developed countries. Our results revealed that ooccupational therapists have a wide-ranging role from providing clinical assessments and interventions, facilitating and advocating activities to prepare for work participation, and working within teams to target clinical and return-to-work outcomes. To be effective in their role, occupational therapists work interprofessionally within teams composed of health, social, legal and service professionals. The concept of return to work was largely perceived as an outcome of rehabilitation and recovery, and less likely as a dynamic process that bridges patients from the health system to societal integration. Conclusion Occupational therapists have a crucial role in return-to-work practice especially for people with post COVID condition.

Binaural unmasking is a remarkable phenomenon that it is substantially easier to detect a signal in noise when the interaural parameters of the signal are different from those of the noise – a useful mechanism in so‐called cocktail party scenarios. In this study, we investigated the effect of binaural unmasking on neural tracking of the speech envelope. We measured EEG in 8 participants who listened to speech in noise at a fixed signal‐to‐noise ratio, in two conditions: one where speech and noise had the same interaural phase difference (both speech and noise having an opposite waveform across ears, SπNπ ), and one where the interaural phase difference of the speech was different from that of the noise (only the speech having an opposite waveform across ears, SπN ). We measured a clear benefit of binaural unmasking in behavioural speech understanding scores, accompanied by increased neural tracking of the speech envelope. Moreover, analysing the temporal response functions revealed that binaural unmasking also resulted in decreased peak latencies and increased peak amplitudes. Our results are consistent with previous research using auditory evoked potentials and steady‐state responses to quantify binaural unmasking at cortical levels. Moreover, they confirm that neural tracking of speech is associated with speech understanding, even if the acoustic signal‐to‐noise ratio is kept constant. From a clinical perspective, these results offer the potential for the objective evaluation of binaural speech understanding mechanisms, and the objective detection of pathologies sensitive to binaural processing, such as asymmetric hearing loss, auditory neuropathy and age‐related deficits.

We prove that for any second‐countable, locally compact group , any continuous ‐action on the primitive ideal space of a separable, nuclear ‐algebra such that is induced by an action on . As a direct consequence, we establish that every continuous action on the primitive ideal space of a separable, nuclear ‐algebra is induced by an action on a ‐algebra with the same primitive ideal space. Moreover, we discuss an application to the classification of equivariantly ‐stable actions.

We study a policy introducing diagnosis related payment for inpatient mental health care in Germany with rates decreasing over length of stay. Using data on all hospital cases, we first examine which hospitals voluntarily opt into the new scheme. We show that specialized hospitals that treat more complicated cases and are reimbursed more highly under the new scheme select into it. Second, we study the effect of diagnosis related payment on length of stay. We find that diagnosis related payment is associated with large reductions in length of stay but has no effect on mortality, post‐acute care, or the ambulatory sector. We argue that the reductions in length of stay are driven by the fact that diagnoses related reimbursement is higher for more complex cases and by payment decreasing over length of stay. This novel evidence contributes to a scarce literature on the role of payment systems for inpatient mental health care and provides important insights for policymakers.

Background Behavioral parent training (BPT) is a well‐established intervention for children with attention‐deficit/hyperactivity disorder (ADHD), but most programs are long, which may limit their accessibility. This could be improved by making programs shorter. Here, we studied (1) the feasibility of a new brief BPT program and its procedures, and (2) pre–post changes in daily rated problem behaviors (primary outcome), children's disruptive behaviors, ADHD/ODD characteristics, impairment, and parents' sense of parenting competence (secondary outcomes). Methods We conducted a nonrandomized pilot study including parents of 28 children (4–12 years) with impaired ADHD characteristics. We examined treatment dropout, parent and therapist satisfaction, recruitment rates, study drop‐out, measurement response and completion rates, acceptability of measurements according to parents, and treatment fidelity. Pre–post changes in the treatment group were compared to those in a historical control group using mixed model analysis, except for those outcomes that were not assessed in the control group. Within‐group differences were analyzed for all outcomes. Results Feasibility of the program and study procedures were good. Treatment dropout was 14.2%, parents and therapists were satisfied with the new program. We recruited 1.5 participants per month, study dropout was 10.7%, response/completion rates ranged from 82% to 100%, measurements were acceptable for parents, and treatment fidelity was 96%. We found substantial within‐group changes (d's = .68–.77) and medium‐sized between‐group changes (d's = .46–.48) on daily rated problem behaviors. We observed no changes on most of the secondary outcomes, except for disruptive behaviors and impairment. Conclusion Our newly developed brief BPT program was feasible and we observed improvements in children's daily‐rated problem behaviors. These results suggest that brief BPT might be beneficial for clinical practice if the findings are confirmed in large‐scale randomized controlled trials.

The highly pathogenic avian influenza virus (HPAIV) H5N1, first isolated in 1996 in China, spread rapidly across Eurasia and caused major epizootics in wild and domesticated birds, as well as spillover infections in humans characterised by high mortality. Avian influenza viruses are therefore candidate viruses for a human pandemic. Surprisingly, HPAIV was not isolated in North America until 2014. With the help of intensive biological sampling and viral genome sequencing, the intrusion of HPAIV into North America could be retraced to two separate events. First, migratory birds carried HPAIV from East Siberia via Beringia and dispersed the virus along the Pacific flyway. After reassortment with genes of local low pathogenic avian influenza viruses, HPAIV H5 caused 2015 a major epizootic on poultry farms in the US Mid‐West. After costly containment, HPAIV dropped below the detection limit. In 2021, Eurasian HPAIV H5 viruses arrived a second time in North America, carried by migratory birds to Canada via the Atlantic flyway, using Iceland as a stop. The H5 virus then spread with water birds along the East Coast of the United States and dispersed across the United States. In contrast to the 2015 poultry outbreak, spillover infections into diverse species of mammals were now observed. The events culminated in the 2024 HPAIV H5 epizootic in dairy cows affecting 300 dairy herds in 14 US states. The cattle epizootic was spread mainly by milking machinery and animal transport. On affected farms infected cats developed fatal neurological diseases. Retail milk across the United States frequently contains viral RNA, but so far only a few milk farm workers have developed mild symptoms. The tracing of HPAIV with viral genome sequencing complicated the taxonomical naming of influenza viruses raising fundamental problems in how to mirror biological complexity in written plain language, rendering communication with the lay public difficult.

Threat modeling involves systematically assessing the likelihood and potential impact of diverse security threat scenarios. Existing threat modeling approaches and tools act at the level of a software architecture or design (e.g., a data flow diagram), at the level of abstract system elements. These approaches, however, do not allow more in-depth analysis that takes into account concrete instances and configurations of these elements. This lack of expressiveness—as threats that require articulation at the level of instances cannot be expressed nor managed properly—hinders systematic risk calculation—as risks cannot be expressed and estimated in terms of instance-level properties. In this paper, we present a novel threat modeling approach that supports modeling complex systems at two distinct levels: (i) the design model defines the classes and entity types in the system, and (ii) the instance model specifies concrete instances and their properties. This innovation allows systematically calculating broader risk estimates at the design level, yet also performing more refined analysis in terms of more precise risk values at the instance level. Moreover, the ability to assess instance-level risks serves as an enabler for run-time continuous threat and risk (re-)assessment, and risk-adaptive security in general. We evaluate this approach in a prototype and through simulation of the dynamics of a realistic IoT-based system, a smart traffic application that involves vehicles and other infrastructural elements such as smart traffic lights. In these efforts, we demonstrate the practical feasibility of the approach, and we quantify the performance cost of maintaining a threat model at run-time, taking into account the time to perform risk assessment.

Purpose Anidulafungin is recommended as a first-line treatment for invasive Candida infections in critically ill patients. Pharmacokinetic (PK) variability is large in critically ill patients, potentially compromising pharmacokinetic-pharmacodynamic (PKPD) target attainment under standard dosing. We aimed to assess anidulafungin exposure, PKPD target attainment, and population (pop)PK in critically ill patients. Methods Adult ICU patients receiving standard anidulafungin dosing [200 mg on day 1, then 100 mg daily] were included (NCT04045366). We performed rich blood sampling on an early (day 2 ± 1) and/or late (day 5 ± 1) treatment day. Using total anidulafungin plasma concentrations, we developed a popPK model (NONMEM7.5) and conducted Monte Carlo simulations (n = 1,000 per virtual patient) to evaluate the impact of patient factors on PKPD target attainment (AUC24h target 83.5 mg×h/L). Results Twenty patients contributed 188 anidulafungin concentrations. PKPD target attainment was 45% and 65% on early and late sampling days, respectively. A two-compartment popPK model with first-order elimination described the data. Anidulafungin clearance increased with bodyweight and central volume of distribution increased as serum albumin decreased. Both bodyweight and serum albumin had a clinically relevant impact on PKPD target attainment at day 1 (area under the ROC curve; AUROC 0.82 and 0.62, respectively), and bodyweight on PKPD target attainment at day 14 (AUROC 0.94). Standard anidulafungin dosing regimen fails to achieve adequate target attainment throughout the treatment period. Conclusion Standard anidulafungin dosing is insufficient for achieving adequate exposure in critically ill patients. An interactive simulation tool is provided to aid dose-finding research and explore different dosing strategies and targets.