Maastricht University
  • Maastricht, Netherlands
Recent publications
Insomnia is prevalent among patients with alcohol use disorder (AUD), potentially undermining treatment and increasing the risk of relapse. Cognitive behavioral therapy for insomnia (CBT-I) is the recommended first-line treatment for insomnia, but its efficacy is not well-characterized in patients across the spectrum of AUD. The aim of this meta-analysis was to quantify the effectiveness of CBT-I in improving insomnia severity and alcohol-related outcomes in adults with heavy alcohol use and/or varying levels of AUD severity and comorbid insomnia. MEDLINE, Cochrane Library, PsycINFO and ClinicalTrials.gov were systematically searched (up to February 2024) to retrieve randomized controlled trials (RCTs). Multilevel meta-analyses were conducted to estimate mean differences over time in insomnia severity, measured using the Insomnia Severity Index (ISI), as well as in alcohol craving and alcohol-related psychosocial problems between CBT-I and control groups. For the number of heavy-drinking/abstinent days, incidence rate ratios were estimated. Risk of bias was assessed using the Risk of Bias 2 (RoB 2) tool. Eight RCTs encompassing 426 adults (68.78 % men) were included. Compared with control conditions, CBT-I resulted in a large reduction of insomnia severity post-treatment [estimated ISI reduction = -5.51, 95% CI (-7.13 to -3.90)], which was maintained at 1-to-3-month [7 studies; estimate = -4.39, 95% CI (-6.08 to -2.70)], and 6-month follow-up [4 studies; estimate = -4.55, 95% CI (-6.77 to -2.33)]. Alcohol-related outcomes were reported less consistently, and no significant differences were found. The included trials were judged to have a low or moderate overall risk of bias for the assessment of all outcomes. CBT-I effectively reduces insomnia severity across the spectrum of AUD, supporting wide implementation in AUD prevention and treatment settings. PROSPERO registration number: CRD42023464612.
Background The effectiveness of the Dutch breast cancer screening programme depends on the quality of the full trajectory, from the first screening to the final treatment of a screen-detected breast cancer. Interhospital variation in breast cancer treatment has been explored by several studies, however, not specifically in a screen-detected breast cancer population. The current study compares the treatment strategies of women with screen-detected breast cancer between hospitals in the South of the Netherlands. Methods A total of 1450 women with screen-detected breast cancer, who participated in the Dutch screening programme between January 2009 and July 2019, were included in this retrospective analysis of a prospectively obtained database. Breast cancer treatment (i.e. preoperative MRI, neoadjuvant systemic therapy and type and outcomes of surgery) was compared between hospitals using multivariate analysis. Results Statistically significant interhospital variation was observed in the use of preoperative MRI (range 20.8–35.8 %, p < 0.001), neoadjuvant systemic therapy (range 4.0–13.3 %, p < 0.001) and breast conserving surgery (range 70.0–87.1 %, p < 0.001). These differences persisted after adjustment for case-mix. In patients with invasive breast cancer treated by breast conserving surgery, the mean volume of the resection specimen ranged from 381 to 541 ml between hospitals (p < 0.001). However, this was not accompanied by significant differences in the percentage of patients with positive resection margins (range 2.9–5.7 %, p = 0.34). Conclusions We observed significant interhospital variation in the management of women with screen-detected breast cancer. Quality assurance in screen-detected breast cancer may reduce these differences, but evolving breast cancer care and more personalised approaches should be accounted for.
Colour plays an important role in the sighted world, not only by guiding and warning, but also by helping to make decisions, form opinions, and influence emotional landscape. While not everyone has direct access to this information, even people without colour vision (i.e., blind, achromatope) understand the meanings of colour terms and can assign sensory and affective properties to colours. To learn which aspects of colour are transmitted non-visually, and thus, are pertinent to those without colour vision, we conducted qualitative interviews with 11 participants (2 congenitally blind, 2 early blind, 4 late blind, 2 late blind with synaesthesia, and 1 achromatope). Our thematic analysis revealed that all participants had detailed knowledge of colours and displayed opinions and attitudes. Colour was important to them as it allowed to take part in the sighted world, navigate the surroundings , and communicate with the sighted peers. While participants with non-congenital colour vision absence could remember and even visualise colours, colour was more abstract to participants with congenital colour vision absence. This was possibly a reason why colour was not very important to their personal lives. Nonetheless, all our participants associated colours with diverse objects, concepts, and emotions, and also had colour preferences, indicating that semantic (conceptual, symbolic, affective) meanings of colour can be transmitted without direct visual experience. Future quantitative and qualitative studies are needed for a systematic understanding of such connotations in the visually impaired population, and their implications to those who can and cannot see colour.
  • Arnela Saljic
    Arnela Saljic
  • Dobromir Dobrev
    Dobromir Dobrev
  • Jordi Heijman
    Jordi Heijman
The growing burden of cardiac arrhythmias in combination with the suboptimal efficacy and safety of current therapeutic modalities for arrhythmia management highlights the need for developing more efficacious and safer treatment options. Antiarrhythmic drugs (AADs) continue to play a crucial role in the treatment of cardiac arrhythmias. Although there has been a paucity of new AADs, significant progress has been made in the understanding of arrhythmia mechanisms, giving rise to novel potential targets and indications for AAD treatment. Recent results obtained with novel AADs and the discovery of new drug targets are promising, while developments in repurposing and reformulating already approved drugs for novel therapeutic indications, are being explored as potential faster routes to clinical application of new therapeutic approaches. This chapter reviews the most promising novel AAD targets and compounds currently under development.
The relationship between rheumatoid arthritis (RA) and fracture risk was estimated in an international meta-analysis of individual-level data from 29 prospective cohorts. RA was associated with an increased fracture risk in men and women, and these data will be used to update FRAX®. RA is a well-documented risk factor for subsequent fracture that is incorporated into the FRAX algorithm. The aim of this study was to evaluate, in an international meta-analysis, the association between rheumatoid arthritis and subsequent fracture risk and its relation to sex, age, duration of follow-up, and bone mineral density (BMD) with a view to updating FRAX. The resource comprised 1,909,896 men and women, aged 20–116 years, from 29 prospective cohorts in which the prevalence of RA was 3% or less (primary analysis) and an additional 17 cohorts with a prevalence greater than 3% (supplementary analysis). The association between RA and fracture risk (any clinical fracture, osteoporotic fracture, major osteoporotic fracture (MOF), and hip fracture) was examined using an extension of the Poisson regression model in each cohort and each sex, followed by random-effects meta-analyses of the weighted beta coefficients. In the primary analysis, RA was reported in 1.3% of individuals. During 15,683,133 person-years of follow-up, 139,002 fractures occurred, of which 27,518 were hip fractures. RA was associated with an increased risk of any clinical fracture (hazard ratio [HR] 1.49, 95% confidence interval [CI] 1.35–1.65). The HRs were of similar magnitude for osteoporotic fracture and MOF but higher for hip fracture (HR = 2.23; 95% CI 1.85–2.69). For hip fracture, there was a significant interaction with age with higher HRs at younger ages. HRs did not differ between men and women and were independent of exposure to glucocorticoids and femoral neck BMD. Lower HRs were observed in the supplementary analysis cohorts, particularly in those with a high apparent prevalence of RA, possibly from conflation of RA with osteoarthritis. A diagnosis of RA confers an increased risk of fracture that is largely independent of BMD, sex, and corticosteroids. RA should be retained as a risk factor in future iterations of FRAX with updated risk functions to improve fracture risk prediction.
Treatment of critical‐sized bone defects remains challenging despite bone's regenerative capacity. Herein, a combination of a biodegradable polymer possessing bone‐bonding properties with bioactive β‐tricalcium phosphate (βTCP) particles coated with osteogenic (Zinc) and angiogenic (copper or cobalt) ions has been proposed. βTCP was coated with zinc and copper (Zn/Cu) or zinc and cobalt (Zn/Co) using 15 mM (low) or 45 mM (high) metallic ion solutions. Composites were obtained by a combination of the βTCP with poly(ethylene oxide terephthalate)/poly(butylene terephthalate) (PEOT/PBT) copolymer in a 50:50 ratio. Composites were additively manufactured into 3D porous scaffolds and their osteogenic and angiogenic properties evaluated using a direct culture with human mesenchymal stromal cells (hMSCs) as well as an indirect coculture with human umbilical vein endothelial cells (HUVECs). We hypothesized that the combination of Zn/Cu or Zn/Co in the form of a coating of the βTCP particles would stimulate both osteogenic and angiogenic properties of PEOT/PBT‐βTCP scaffolds. In addition, we investigated whether the resulting biomaterials influenced the paracrine function of hMSCs. Zn/Cu or Zn/Co were successfully co‐incorporated into the ceramic without changing its chemistry. Scaffolds containing low concentrations of Zn/Co increased the expression of RUNX2, OCN, and OPN, while scaffolds with low concentrations of Zn/Cu enhanced the expression of ALPL. On the protein level, high Zn/Co concentrations elevated ALP and collagen production. Angiogenic properties improved with increased VEGFA expression by hMSCs and branching of tubules formed by HUVECs, particularly with low concentrations of Zn/Co. Scaffolds with high ion concentrations also increased cytokine and chemokine secretion, suggesting enhanced paracrine effects.
Prokaryotes rely on proteinaceous compartments such as encapsulin to isolate harmful reactions. Encapsulin are widely expressed by bacteria, including the Mycobacteriaceae, which include the human pathogens Mycobacterium tuberculosis and Mycobacterium leprae. Structures of fully assembled encapsulin shells have been determined for several species, but encapsulin assembly and cargo encapsulation are still poorly characterised, because of the absence of encapsulin structures in intermediate assembly states. We combine in situ and in vitro structural electron microscopy to show that encapsulins are dynamic assemblies with intermediate states of cargo encapsulation and shell assembly. Using cryo-focused ion beam (FIB) lamella preparation and cryo-electron tomography (CET), we directly visualise encapsulins in Mycobacterium marinum, and observed ribbon-like attachments to the shell, encapsulin shells with and without cargoes, and encapsulin shells in partially assembled states. In vitro cryo-electron microscopy (EM) single-particle analysis of the Mycobacterium tuberculosis encapsulin was used to obtain three structures of the encapsulin shell in intermediate states, as well as a 2.3 Å structure of the fully assembled shell. Based on the analysis of the intermediate encapsulin shell structures, we propose a model of encapsulin self-assembly via the pairwise addition of monomers.
Purpose In 20–30% of the patients, fluoropyrimidines (5-FU) based chemotherapy leads to severe toxicity, which is associated with dihydropyridine dehydrogenase (DPD) deficiency. Therefore, DPYD genotyping became standard practice before treatment with fluoropyrimidines. Nevertheless, only 17% of the patients with severe toxicity have a DPYD variant. Therefore, an urgent need persists to investigate other strategies contributing to prediction and prevention of toxicity. Endogenous DPD substrates are considered as potential biomarkers to predict toxicity, yet contradictional data exist on demonstrating uracil as a reliable biomarker. Thymine as biomarker for toxicity has been investigated less. The aim of this study was to determine the association between the concentrations of uracil, thymine dihydrouracil (DHU) and dihydrothymine (DHT), with the systemic drug exposure of 5-FU and DPD enzyme activity in patients treated with 5-FU. Methods We included 36 patients with gastrointestinal malignancy who received 5-FU infusion. DPYD genotyping was conducted before start of treatment. Blood samples for determining 5-FU, uracil and thymine concentrations during infusion and DPD enzyme activity were taken. Results We found a significant correlation between the 5-FU systematic exposure and baseline thymine concentrations (R² = 0.1468; p = 0.0402). DPD enzyme activity was significantly correlated with baseline thymine concentrations but no correlation was found between DPD enzyme activity and 5-FU systemic drug exposure. Conclusion 5-FU dose individualization based on thymine concentrations could be a promising addition to DPYD genotyping to predict 5-FU-induced toxicity. Larger prospective trials are needed to examine thymine as predictor for toxicity in daily practice. Trial registration Trial NL7539 at ‘Overview of Medical Research in the Netherlands’ (ID NL-OMON21471). Date of registration 19-02-2019.
Purpose Hepatocellular carcinoma (HCC) remains a global health concern, marked by increasing incidence rates and poor outcomes. This study seeks to develop a robust predictive model by integrating radiomics and deep learning features with clinical data to predict 2-year survival in HCC patients treated with stereotactic body radiation therapy (SBRT). Methods This study analyzed a cohort of 186 HCC patients who underwent SBRT. Radiomics features were extracted from CT scans, complemented by collection of clinical data. Training and validation of machine learning models were conducted using nested cross-validation techniques. Deep learning models, leveraging various convolutional neural networks (CNNs), were employed to effectively integrate both image and clinical data. Post-hoc explainability techniques were applied to elucidate the contribution of imaging data to predictive outcomes. Results Handcrafted radiomics features demonstrated moderate predictive performance, with area under the receiver operating characteristic curve (AUC) values ranging from 0.59 to 0.72. Deep learning models, harnessing the fusion of image and clinical data, exhibited improved predictive accuracy, with AUC values ranging from 0.71 to 0.81. Notably, the ensemble model, amalgamating handcrafted radiomics and deep learning features with clinical data, demonstrated the most robust predictive capability, achieving an AUC of 0.86 (95% CI: 0.80–0.93). Conclusion The ensemble model represents a significant advancement, providing a comprehensive tool for predicting survival outcomes in HCC patients undergoing SBRT. The inclusion of interpretability methods such as Grad-CAM enhances transparency and understanding of these complex predictive models.
Introduction: Advanced training experiences are required in certain countries for subspecialization. In the United States, a decline in Milestones and in levels of supervision for Entrustable Professional Activities for incoming subspecialty fellows has been described and attributed to changes in context that fellows experience. We aimed to explore this transition to advanced training, and specifically to describe which contextual factors are salient to fellows at the residency to fellowship transition and the supports available for a smooth transition to fellowship. Methods: Using contextual competence as a sensitizing concept, ten semi-structured interviews with first- and second-year pediatric subspecialty fellows from three subspecialties were performed at a large academic medical center in 2023, using thematic analysis informed by elements of constructivist grounded theory. Results: Contextual factors that impacted the transition included changes in systems, necessary knowledge, and roles and responsibilities. At times, participants describe a tension between feeling like novices while simultaneously feeling like they should have more expertise than they had. Supports in navigating this tension, and in navigating the transition more generally, included formal orientations, fellow behaviors and perspective, and input from others. Conclusions: The transition to advanced training is characterized, at times, by experiencing tension between feeling like a novice while feeling like one should have expertise, with fellows’ own behaviors and the support of those around them being essential to fellows’ smooth transition. While fellowship programs offer orientations, systems-level solutions for supporting fellows’ navigation of the transition are underexplored.
Background Interventions targeting dementia prevention typically lack comprehensive exploration of feasibility, acceptability, and long-term translation factors prior to deployment. Our study aimed to explore the acceptability, fidelity and participants’ experiences with Brain Bootcamp, a multi-domain behaviour change intervention targeting reduced dementia risk and increased dementia risk factor awareness for older adults. Methods Conducted in New South Wales, Australia, from January to August 2021, our concurrent single-group mixed-methods feasibility study involved post-intervention surveys and qualitative interviews with community-dwelling older adults. Descriptive statistics were used to assess acceptability of the methods, outcome measures, and fidelity to the program components. Thematic analysis of semi-structured interviews explored participant experiences, preferences, barriers, and recommendations. Results Out of 853 enrolled participants, only 355 completed the program (41.6%). Among these participants, 79.1% agreed that the intervention improved their awareness of dementia risk factors, and 92.4% expressed intent to continue maintaining brain healthy behaviours post- program. Participants typically set 2–4 modifiable risk factor lifestyle goals, which were most often related to physical activity (83.7%). A majority (91.5%) successfully achieved at least one brain health goal. Qualitative analyses (n = 195) identified three overarching themes on the role of education on behaviour modification (i.e., the transformative role of the program in enhancing knowledge about dementia prevention and fostering behavioral modifications), psychological considerations (e.g., intrinsic versus extrinsic motivation on their engagement and perception of the program) and future directions (e.g., sustainability concerns and the need for tailored strategies for specific demographics). Conclusions While Brain Bootcamp had low completion rates, those who completed the program reported high acceptability. Future refinements, incorporating targeted strategies and enhanced participant support and communication, will facilitate pragmatic initiatives. Clinical trial number ACTRN12621000165886.
Internationally, many women experience physiological childbirth with positive experiences and good health outcomes for them and their baby. For some, due to health complications and context of childbirth they may experience or be perceived as having had a traumatic birth. Ultimately, whether an individual experiences an event as traumatic or not, is a personal experience. Caring for women who experience their birth as traumatic can be challenging. The risk of exposure to a traumatic birth event(s) as part of maternity care providers (MCPs) work, ranges from 67% to 90%. Thereby to support MCPs to provide quality maternal and newborn care, it is important to explore the impact of work-related events. An anonymised online survey relating to MATernity serious EventS (MATES) was developed utilising validated instruments and hosted on QualtricsXM. Following ethical approval, the questionnaire was disseminated internationally across 33 countries between 1st July and 31st December 2022 via social media and the COST Action DEVOTION (CA18211 www.ca18211.eu) network. In total, 579 MCPs responded with a wide age range and years of experience. Descriptive and inferential statistical analyses were performed, including univariate and multivariate linear regression. Data analyses and management were undertaken using SPSS v.20 and two-sided significance tests were applied (α 0.05). The findings suggest that MCPs are exposed to a large variation of serious events and continue to be intensely affected, up to the present day. Events ranged from stillbirth, neonatal death, maternal death, severe or life-threatening maternal or infant incidents and violence and aggression from women or family member. Institutional support for staff is limited, and when available, seldom used. Family and friends were relied on for support, but this does not appear to be associated with MCPs experiencing less secondary traumatic stress. Subsequently MCPs were absence from work through sickness (22%), changed their professional allocation (19%) and seriously considered leaving (42%). Moreover, many reported low to moderate compassion satisfaction and burnout (65–80%). With international scarcity of MCPs, the impact of these events seem to contribute to this shortage. Effective support for MCPs is required if staff are to be recruited and retained.
The effectiveness of the best-possible-self (BPS) intervention has been well established in Western people but is still under exploration in Eastern samples. A direct comparison of its effectiveness between Western and Eastern people is currently lacking, yet it is essential to comprehend the cultural sensitivity of the BPS. In this study, we compared immediate and short-term effects of the BPS between an Eastern (Chinese) and a Western (Dutch) sample using a three-time online intervention delivered within 1 week. We also investigated its effectiveness in both samples separately as well as the underlying mechanism. Participants (61 Chinese, 48 Dutch) were randomly assigned to the BPS or a control condition. We found that Dutch participants reported more benefits than the Chinese in terms of positive affect (immediate effect) and trait optimism as well as satisfaction with life (short-term effect). Chinese participants reported changes mostly in negative outcomes and only after multiple sessions. Moreover, the within-sample analysis showed that effect sizes were generally larger in the Dutch sample. The results replicate previous findings and add evidence supporting the effectiveness of the BPS in Dutch and Chinese people. This study indicates that BPS may be more effective in the Dutch sample for positive outcomes but can also be effective in the Chinese sample for certain negative outcomes with multiple sessions. Future studies may investigate underlying cultural sensitivity and adapt the BPS to a culture-compatible version based on specific cultural backgrounds.
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Mike Gerards
  • Maastricht Centre for Systems Biology
Ana I. Coelho
  • GROW School for Oncology & Developmental Biology
Willem De Grave
  • Department of Educational Research and Development
Mena Badieh Habib Morgan
  • Department of Data Science and Knowledge Engineering
Ronald Westra
  • Department of Gravitational Waves and Fundamental Physics
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Maastricht, Netherlands
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Rianne Letschert