The liver X receptor (LXR) is considered a therapeutic target for atherosclerosis treatment, but synthetic LXR agonists generally also cause hepatic steatosis and hypertriglyceridemia. Desmosterol,... Show moreThe liver X receptor (LXR) is considered a therapeutic target for atherosclerosis treatment, but synthetic LXR agonists generally also cause hepatic steatosis and hypertriglyceridemia. Desmosterol, a final intermediate in cholesterol biosynthesis, has been identified as a selective LXR ligand that suppresses inflammation without inducing lipogenesis. Δ24-Dehydrocholesterol reductase (DHCR24) converts desmosterol into cholesterol, and we previously showed that the DHCR24 inhibitor SH42 increases desmosterol to activate LXR and attenuate experimental peritonitis and metabolic dysfunction-associated steatotic liver disease. Here, we aimed to evaluate the effect of SH42 on atherosclerosis development in APOE∗3-Leiden.CETP mice and low-density lipoproteins (LDL) receptor knockout mice, models for lipid- and inflammation-driven atherosclerosis, respectively. In both models, SH42 increased desmosterol without affecting plasma lipids. While reducing liver lipids in APOE∗3-Leiden.CETP mice, and regulating populations of circulating monocytes in LDL receptor knockout mice, SH42 did not attenuate atherosclerosis in either model. Show less
Dubbeldeman, E.M.; Crone, M.R.; Jong, J.C.K.D.; Kleij, R.M.J.J. van der 2024
Introduction Behavior change techniques (BCTs) are considered as active components of implementation strate‑ gies, infuencing determinants and, ultimately, implementation performance. In our... Show moreIntroduction Behavior change techniques (BCTs) are considered as active components of implementation strate‑ gies, infuencing determinants and, ultimately, implementation performance. In our previous Delphi study, experts formulated ‘implementation hypotheses’, detailing how specifc combinations of BCTs and strategies (referred to as BCT-strategy combinations) might infuence determinants and guideline implementation within youth care. For example, educational meetings providing instructions on guideline use were hypothesized to enhance practition‑ ers’ knowledge and, consequently, guideline implementation. However, these hypotheses have not been verifed in practice yet. Method We conducted a cross-sectional study involving practitioners and management professionals from youth (health)care organizations. Using questionnaires, we obtained data on the presence of BCT-strategy combinations and their perceived infuence on determinants and implementation performance. Chi-squared tests and regres‑ sion analyses were employed to determine the infuence of specifc BCT-strategy combinations on determinants and implementation performance. Results Our analyses included data from 104 practitioners and 34 management professionals. Most of the manage‑ ment professionals indicated that the BCT-strategy combinations positively infuenced or had the potential to infu‑ ence their implementation performance. At the practitioner level, half of the combinations were perceived to have a positive infuence on determinants and implementation performance. Furthermore, practitioners who reported the absence of BCT-strategy combinations were more skeptical about their potential infuence on determinants and implementation performance. Conclusion Several BCT-strategy combinations were perceived to improve or potentially improve implementation performance of both practitioners and management professionals. In the development and evaluation of imple‑ mentation eforts, we advocate for clearly describing the implementation efort’s objective and using frameworks that detail the BCTs inducing behavior change, the strategy employed, and the processes driving the observed changes. Understanding these interconnected processes is important in designing targeted, evidence-based Show less
ObjectiveUS can detect subclinical joint-inflammation in patients with clinically suspect arthralgia (CSA), which is valuable as predictor for RA development. In most research protocols both hands... Show moreObjectiveUS can detect subclinical joint-inflammation in patients with clinically suspect arthralgia (CSA), which is valuable as predictor for RA development. In most research protocols both hands and forefeet are scanned, but it is unclear if US of the forefeet has additional value for predicting RA, especially since synovial hypertrophy in MTP-joints of healthy individuals is also common. To explore the possibility to omit scanning of the forefeet we determined if US of the forefeet is of additional predictive value for RA-development in CSA patients.MethodsCSA patients of two independent cohorts underwent US of the hands and forefeet. We analysed the association between RA-development and US-positivity for the full US-protocol, the full US-protocol with correction for gray scale (GS)-findings in the forefeet of healthy and the protocol without forefeet.ResultsIn total, 298 CSA patients were studied. In patients with a positive US, subclinical joint-inflammation was mostly present in the hands (90–86%). Only 10–14% of patients had subclinical joint-inflammation solely in the forefeet. US-positivity was associated with inflammatory arthritis development in both cohorts, with HRs 2.6 (95% CI 0.9–7.5) and 3.1 (95% CI 1.5–6.4) for the full protocol, 3.1 (95% CI 1.3–7.7) and 2.7 (95% CI 1.3–5.4) for the full US-protocol with correction, and 3.1 (95% CI 1.4–6.9) and 2.8 (95% CI 1.4–5.6) without the forefeet. AUROCs were equal across both cohorts.ConclusionThe forefeet can be omitted when US is used for the prediction of RA-development in CSA patients. This is due to the finding that subclinical joint-inflammation in the forefeet without concomitant inflammation in the hands is infrequent. Show less
Unsaturated fatty acids (UFA) are crucial for T-cell effector functions, as they can affect the growth, differentiation, survival, and function of T cells. Nonetheless, the mechanisms by which UFA... Show moreUnsaturated fatty acids (UFA) are crucial for T-cell effector functions, as they can affect the growth, differentiation, survival, and function of T cells. Nonetheless, the mechanisms by which UFA affects T-cell behavior are ill-defined. Therefore, we analyzed the processing of oleic acid, a prominent UFA abundantly present in blood, adipocytes, and the fat pads surrounding lymph nodes, in CD4+ T cells. We found that exogenous oleic acid increases proliferation and enhances the calcium flux response upon CD3/CD28 activation. By using a variety of techniques, we found that the incorporation of oleic acid into membrane lipids, rather than regulation of cellular metabolism or TCR expression, is essential for its effects on CD4+ T cells. These results provide novel insights into the mechanism through which exogenous oleic acid enhances CD4+ T-cell function. Show less
The famous ''light-switch'' ruthenium complex [Ru(bpy)2(dppz)](PF6)2 (1) has been long known for its DNA binding properties in vitro. However, the biological utility of this compound has been... Show moreThe famous ''light-switch'' ruthenium complex [Ru(bpy)2(dppz)](PF6)2 (1) has been long known for its DNA binding properties in vitro. However, the biological utility of this compound has been hampered by its poor cellular uptake in living cells. Here we report a bioimaging application of 1 as cell viability probe in both 2D cells monolayer and 3D multi-cellular tumor spheroids of various human cancer cell lines (U87, HepG2, A549). When compared to propidium iodide, a routinely used cell viability probe, 1 was found to enhance the staining of dead cells in particular in tumor spheroids. 1 has high photostability, longer Stokes shift, and displays lower cytotoxicity compared to propidium iodide, which is a known carcinogenic. Finally, 1 was also found to displace the classical DNA binding dye Hoechst in dead cells, which makes it a promising dye for time-dependent imaging of dead cells in cell cultures, including multi-cellular tumor spheroids. Show less
Gestel, L.C. van; Adriaanse, M.A.; Kanis, S.L.; Mensink-Bout, S.M.; Schoones, J.W.; Numans, M.E.; ... ; Brink, G. van den 2024
Background Proton Pump Inhibitors (PPI) are frequently prescribed. Long-term use is associated with side-efects and patients often lack a valid indication. Inappropriate PPI prescribing thus needs... Show moreBackground Proton Pump Inhibitors (PPI) are frequently prescribed. Long-term use is associated with side-efects and patients often lack a valid indication. Inappropriate PPI prescribing thus needs to be addressed. This review aims to scope 1) what determinants are studied as reasons for PPI prescribing, 2) what strategies are used for changing PPI (de)prescribing, and 3) whether important determinants are addressed in these interventions. Methods We searched eight databases for papers on determinants of physician PPI prescribing. Studies were included if they were conducted in a Western country and focused on oral PPIs for an adult population. By follow‑ ing the Behaviour Change Wheel, we extracted information regarding PPI prescribing behavior, behavioral determi‑ nants and intervention strategies. Findings We included 74 papers. Most focused on the determinants knowledge and beliefs about consequences. The latter was consistently related to PPI prescribing. Results for knowledge were mixed. Most interventions used education or enablement (e.g., algorithms, quality check improvements, involvement of pharmacists) as strategies. Enablement consistently improved PPI prescribing, while results for education were mixed. Interpretation There is an overemphasis on refective processes in studies on PPI prescribing. Future research should comprehensively identify behavioral determinants, focusing on refective and impulsive processes, such that interven‑ tions can address the most important determinants. Show less
To test the hypothesis that early-life adversity accelerates the pace of biological aging, we analyzed data from the Dutch Hunger Winter Families Study (DHWFS, N = 951). DHWFS is a natural... Show moreTo test the hypothesis that early-life adversity accelerates the pace of biological aging, we analyzed data from the Dutch Hunger Winter Families Study (DHWFS, N = 951). DHWFS is a natural-experiment birth-cohort study of survivors of in-utero exposure to famine conditions caused by the German occupation of the Western Netherlands in Winter 1944 to 1945, matched controls, and their siblings. We conducted DNA methylation analysis of blood samples collected when the survivors were aged 58 to quantify biological aging using the DunedinPACE, GrimAge, and PhenoAge epigenetic clocks. Famine survivors had faster DunedinPACE, as compared with controls. This effect was strongest among women. Results were similar for GrimAge, although effect-sizes were smaller. We observed no differences in PhenoAge between survivors and controls. Famine effects were not accounted for by blood-cell composition and were similar for individuals exposed early and later in gestation. Findings suggest in-utero undernutrition may accelerate biological aging in later life. Show less
ObjectiveTo evaluate the effectiveness of long-term, personalized, supervised exercise therapy on functional ability compared with usual care in people with axial spondyloarthritis (axSpA) and... Show moreObjectiveTo evaluate the effectiveness of long-term, personalized, supervised exercise therapy on functional ability compared with usual care in people with axial spondyloarthritis (axSpA) and severe functional limitations.MethodsParticipants were randomly 1:1 assigned to the intervention [maximal 64 sessions, with 14 additional optional sessions of supervised active exercise therapy (e.g. aerobic and muscle strengthening) with individualized goal-setting, education and self-management regarding physical activity] or usual care (care determined by clinician(s) and participants themselves). Primary endpoint was the change in the Patient-Specific Complaints activity ranked 1 [PSC1 (0–10)] at 52 weeks. Secondary endpoints were the PSC activities ranked 2 and 3, the Bath Ankylosing Spondylitis Functional Index, 6-min walk test, Patient Reported Outcome Measurement Information System-Physical Function-10 and the Short Form-36 Physical and Mental Component Summary Score (SF-36 PCS and MCS). Statistical comparisons comprised independent student t-tests and linear mixed models, based on intention-to-treat.Results214 participants [49% female, age 52 (S.D. 12) years], were randomized to the intervention (n = 110) or usual care (n = 104) group. In the intervention group 93% started treatment, using on average 40.5 sessions (S.D. 15.1). At 52 weeks, the difference in change in PSC1 between groups favoured the intervention group [mean difference (95% CI); −1.8 (−2.4 to −1.2)]. Additionally, all secondary outcomes, except the SF-36 MSC, showed significantly greater improvements in the intervention group with effect sizes ranging from 0.4 to 0.7.ConclusionLong-term, supervised exercise therapy proved more effective than usual care in improving functional disability and physical quality of life in people with axSpA and severe functional limitations.Trial registrationNetherlands Trial Register NL8238, included in the International Clinical Trial Registry Platform (ICTRP) (https://trialsearch.who.int/Trial2.aspx?TrialID=NL8238). Show less
Aim: This paper investigates the conditions for inclusive design of regenerative medicine interventions from a bioethical perspective, taking regenerative valve implants as a showcase. Methods: A... Show moreAim: This paper investigates the conditions for inclusive design of regenerative medicine interventions from a bioethical perspective, taking regenerative valve implants as a showcase. Methods: A value hierarchy is construed to translate the value of justice into norms and design requirements for inclusive design of regenerative valve implants. Results: Three norms are proposed and translated into design requirements: regenerative valve implants should be designed to promote equal opportunity to good health for all potential users; equal respect for all potential users should be shown; and the implants should be designed to be accessible to everyone in need. Conclusion: The norms and design requirements help to design regenerative valve implants that are appropriate, respectful and available for everyone in need. Show less
ObjectiveRecently, a genome-wide association study identified an association between RA-associated interstitial lung disease (ILD) and RPA3-UMAD1 rs12702634 in the Japanese population, especially... Show moreObjectiveRecently, a genome-wide association study identified an association between RA-associated interstitial lung disease (ILD) and RPA3-UMAD1 rs12702634 in the Japanese population, especially for patients with a usual interstitial pneumonia (UIP) pattern. We aimed to replicate this association in a European population and test for interaction with MUC5B rs35705950.MethodsIn this genetic case–control association study, patients with RA and ILD and controls with RA and no ILD were included from France, the USA and the Netherlands. Only cases and controls from European genetic ancestries determined by principal components analysis were included in the analyses. RA was defined by the 1987 ACR or 2010 ACR/EULAR criteria and ILD by chest high-resolution CT scan, except in the control dataset from the Netherlands, where the absence of ILD was determined by chart review. Patients were genotyped for RPA3-UMAD1 rs12702634 and MUC5B rs35705950. Associations were tested using logistic regression adjusted for sex, age at RA onset, age at ILD onset or at certified absence of ILD, tobacco smoking status and country of origin.ResultsAmong the 883 patients included, 322 were RA-ILD cases (36.5%). MUC5B rs35705950 was strongly associated with RA-ILD in all datasets {combined adjusted odds ratio [OR] 2.9 [95% CI 2.1, 3.9], P = 1.1 × 10−11. No association between RPA3-UMAD1 rs12702634 and RA-ILD was observed [combined OR 1.2 (95% CI 0.8, 1.6), P = 0.31. No interaction was found between RPA3-UMAD1 rs12702634 and MUC5B rs35705950 (P = 0.70).ConclusionOur findings did not support a contribution of RPA3-UMAD1 rs12702634 to the overall RA-ILD susceptibility in the European population. Show less
Grewal, S.; Theijse, R.T.; Dunlop, G.; Deurzen, D.F.P. van; Bekerom, M.P.J. van den; Klautz, R.J.M.; ... ; Grewal, N. 2024
Background: Professional athletes navigate a multitude of unique challenges associated to sport-specific factors (e.g., training, travel and competition) and non-sport factors (e.g., performance... Show moreBackground: Professional athletes navigate a multitude of unique challenges associated to sport-specific factors (e.g., training, travel and competition) and non-sport factors (e.g., performance pressure, stress and anxiety) that can interfere with healthy sleep behaviors. Sleep plays a key role in proper biopsychosocial development as well as short- and long-term biological, physical, psychological, and cognitive health. As poor sleep quality is known to impair proper brain function, this study aimed to investigate the effect of sleep quality on a professional athlete's ability to train, recover, and perform, as well as their overall emotional and physical well-being. Methods: A cohort study was performed in 40 professional male cricket athletes from the Dutch national cricket team (mean age 26.5 ± 5.1 years). The athletes were monitored across a 22 weeks in-season training period. Sleep quality and overall emotional and physical well-being were assessed using daily sleep diaries and questionnaires which scored the readiness to train, stress levels, fatigue, muscle soreness and flu symptoms respectively. Quality of sleep and subsequent association with the consecutive elements of the well-being questionnaire were assessed through statistical using the student t-test and clinical differences with the methodology of Osoba and colleagues: 20% “very much change”. Results: The results demonstrated that the professional athletes assessed their sleep quality as average with a mean score of 3.4 out of 5. Lower perceived quality of sleep (<75th percentile) was correlated with a decreased readiness to train (mean score 3.2 [IQR: 3.0–4.0] vs. 3.5 [IQR: 3.0–5.0]; P < 0.001) and increased extent of muscle soreness (2.7 [IQR: 2.0–3.0] vs. 2.3 [IQR: 2–3]; P < 0.001), stress level (mean score 2.3 [IQR: 2.0–3.0] vs. 1.9 [IQR: 1.0–2.0]; P < 0.001) and perceived fatigue (mean score 2.9 [IQR: 2.0–3.0] vs. 2.3 [IQR: 2.0–3.0]; P < 0.001). Likewise, in patients with lower perceived quality of sleep, the proportion of players presenting with flu symptoms increased over 4-fold (4.1% vs. 17%; P < 0.001). Show less
Acem, I.; Steyerberg, E.W.; Spreafico, M.; Grünhagen, D.J.; Callegaro, D.; Spinner, R.J.; ... ; Martin, E. 2024
While cyberspace as a globally interconnected network offers economic, social and informational potential, at the same time this space also produces a wide variety of risks, for which no easy... Show moreWhile cyberspace as a globally interconnected network offers economic, social and informational potential, at the same time this space also produces a wide variety of risks, for which no easy solutions exist. For the international community, for nation states, for organizations and even for individuals, uncertainty is a common thread for interaction, communication and the general use of (systems connected to) cyberspace. This research shows that there are five different common reactions to dealing with this uncertainty in cyberspace: (1) using risk management to control uncertainty; (2) recovering from uncertainty through resilience; (3) influencing uncertainty with laws and regulation; suspending uncertainty by engaging in trust; and (5) ignoring uncertainty through inaction. Some of these approaches are used more often than others. For instance, risk management is currently the dominant way of responding to uncertainty in cyberspace, with resilience gaining prominence. Other strategies, such as relying on trust or inaction, are less common. Oftentimes, using a mixture of strategies may be helpful, because some strategies may strengthen one another, for instance when a combination of risk management and resilience approaches is used. Each strategy has particular use for specific contexts, but since we lack an overview of which strategies are being used, we also cannot establish under which conditions which strategy is most beneficial. Solving this lack of knowledge can help us be more effective in dealing with uncertainties of a wide variety in cyberspace. Show less
Creutzig, F.; Simoes, S. G.; Leipold, S.; Berrill, P.; Azevedo, I.; Edelenbosch, O.; ... ; Wilson, C. 2024
As fossil fuels are phased out in favour of renewable energy, electric cars and other low-carbon technologies, the future clean energy system is likely to require less overall mining than the... Show moreAs fossil fuels are phased out in favour of renewable energy, electric cars and other low-carbon technologies, the future clean energy system is likely to require less overall mining than the current fossil-fuelled system. However, material extraction and waste flows, new infrastructure development, land-use change, and the provision of new types of goods and services associated with decarbonization will produce social and environmental pressures at localized to regional scales. Demand-side solutions can achieve the important outcome of reducing both the scale of the climate challenge and material resource requirements. Interdisciplinary systems modelling and analysis are needed to identify opportunities and trade-offs for demand-led mitigation strategies that explicitly consider planetary boundaries associated with Earth’s material resources. Show less
