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Lung cancer screening with low-dose CT:definition of positive, indeterminate, and negative screen results. A nodule management recommendation from the European Society of Thoracic Imaging
No full textEarly detection of lung cancer through low-dose CT lung cancer screening in a high-risk population has proven to reduce lung cancer-specific mortality. Nodule management plays a pivotal role in early detection and further diagnostic approaches. The European Society of Thoracic Imaging (ESTI) has established a nodule management recommendation to improve the handling of pulmonary nodules detected during screening. For solid nodules, the primary method for assessing the likelihood of malignancy is to monitor nodule growth using volumetry software. For subsolid nodules, the aggressiveness is determined by measuring the solid part. The ESTI-recommendation enhances existing protocols but puts a stronger focus on lesion aggressiveness. The main goals are to minimise the overall number of follow-up examinations while preventing the risk of a major stage shift and reducing the risk of overtreatment.Key PointsQuestion: Assessment of nodule growth and management according to guidelines is essential in lung cancer screening.Findings: Assessment of nodule aggressiveness defines follow-up in lung cancer screening.Clinical relevance: The ESTI nodule management recommendation aims to reduce follow-up examinations while preventing major stage shift and overtreatment.</p
Elevated serum glutathione reflects endoscopic disease activity in inflammatory bowel disease
No full textBackground: Redox imbalance and systemic oxidative stress are implicated in the pathophysiology of inflammatory bowel disease (IBD). Oxidative stress previously demonstrated strong associations with endoscopic disease activity in IBD. In this study, we aimed to prospectively evaluate a panel of redox proteins, including circulating total freethiols (FTs), low-molecular-weight thiols, and thioredoxin-1, as biomarkers for endoscopic disease activity in IBD. Methods: Patients with IBD (n=111) undergoing surveillance endoscopy were enrolled. Blood was collected at endoscopy along with clinical and biochemical assessments. Endoscopic activity was graded using the Mayo endoscopic score for ulcerative colitis (UC)or the Simple Endoscopic Score for Crohn’s disease (SES-CD) (CD). Serum and plasma biomarkers (FTs, glutathione (GSH), ischemia-modified albumin (IMA), homocysteine, cysteine, thioredoxin-1) were analyzed. Logistic regression was used to test associations withdisease activity, adjusting for relevant confounders. Results: Among all biomarkers, only serum GSH significantly associated with active endoscopic disease (adjusted odds ratio (OR) per doubling: 4.19, p=0.04). This was most evident in CD, but not significant in UC. IMA only showed a univariable association (p<0.05). ROC analysis identified GSH as the most accurate oxidative stress marker (AUC=0.71 in CD; 0.65 in UC). All were outperformed by fecal calprotectin (AUC=0.77). However, combining calprotectin with oxidative stress markers substantially improved discrimination (AUC=0.95). Finally, Trx1 and FTs were significantly increased in patients with colonic disease activity (p<0.05).Conclusions: Serum GSH may serve as a systemic biomarker of endoscopic activity in IBD, particularly CD. While less accurate than fecal calprotectin alone, oxidative stress markers 3strongly enhance its diagnostic performance, suggesting complementary value for disease monitoring
Cognitive determinants of late life depression:Who and why? - Understanding the association between cognitive impairment and late life depression
No full textDepression is one of the most common psychiatric disorders among older adults and is often accompanied by reduced cognitive function, which can lead to early admission to a nursing home or even death.In her doctoral research, Astrid Lugtenburg researched the relationship between depression and reduced cognitive function. Not all older adults with depression experience cognitive impairment: a study involving 375 elderly people with depression showed that about half suffer from reduced cognitive ability, some of whom also displayed physical ageing. This group in particular, was found to have the greatest risk of death within six years, compared to their non-depressed peers.It is also notable that use of medications that can negatively affect cognitive function, such as sleeping pills and certain antidepressants (with sedative or anticholinergic effects), occurs in nine out of ten elderly people with depression, although the negative effects of these medications on cognitive function was small in this study. Furthermore, analysis of 83,613 participants from the Lifelines study showed that the negative effects of depression on cognitive function could be explained in part by (future) vascular damage.These results highlight that the way in which depression and reduced cognitive function are linked can differ between individuals. To study this further each patient was also analysed individually. This revealed that factors contributing to cognitive impairment (such as sleep and severity of depression) vary from person to person.It is essential that future research and treatment focus more on the individual to ensure every elderly person receives the most appropriate care, which subsequently hopefully improves their quality of life
Technical Developments in Endothelial Cell Research:Zooming in on Microvascular Heterogeneity in the Kidney
No full textBlood vessels play an essential role in health and disease. Endothelial cells (ECs) residing in the microvasculature of tissues exhibit organ-specific molecular profiles that are influenced by their local microenvironment. Investigating these profiles requires methods to isolate ECs from the organs without compromising their molecular status. This can be achieved by Laser microdissection (LMD), enabling the study of ECs in human and animal tissues. This thesis research aimed to develop methods for analysing ECs in vivo in both healthy and diseased conditions, with a particular focus on the distinct microvascular compartments of the kidney. Protocols combining LMD with RT-qPCR were optimized to ensure a linear correlation between dissected tissue area and quantification of microRNAs. Extending this workflow to integrate LMD with next-generation sequencing (NGS) allowed us to capture the complete transcriptome of ECs within the renal cortical microvasculature of healthy mice. Furthermore, we applied the LMD/NGS workflow to kidney biopsies of patients suffering from lupus nephritis (LN), identifying distinct gene expression profiles in glomeruli associated with disease activity. Finally, we established an inducible EC-specific gene knockout model to investigate the function of EC-related molecules in adult mouse blood vessels. Gene knockout efficiency varied across organs and (micro)vessel types, altering EC responses to inflammation related molecules especially in microvascular regions with high knockout efficiency. This research demonstrated the importance of isolating ECs from tissues by LMD to uncover the molecular basis of microvascular EC behaviour in organs and provides directions for future research in molecular pathology and drug development
Functional Diversification of Yeast Amino Acid Transporters:Integrating Evolutionary, Biochemical and Structural Approaches
No full textUnderstanding how new protein functions emerge over evolutionary time is a central question in biology. This thesis addresses it using membrane transporters as a model system, focusing on the Yeast Amino Acid Transporter (YAT) family in Saccharomyces cerevisiae. These proteins mediate the amino acid uptake across the plasma membrane and represent a diverse group regarding substrate specificity and regulation; yet their functional range, structure and evolutionary flexibility remain incompletely understood.By integrating evolutionary and biochemical approaches, I show that YATs are more functionally plastic than previously recognized. Using growth-based assays and directed evolution, I demonstrate that several transporters display unexpected substrate promiscuity and that single point mutations can significantly broaden substrate specificity without abolishing original functions. These changes occur not only in the substrate-binding core but also in distal regions, highlighting the importance of long-range structural effects.I further characterize the lysine transporter Lyp1, revealing that it can transport multiple additional amino acids across a wide affinity range, from micromolar to millimolar. This suggests that weak, latent interactions with non-canonical substrates may provide a starting point for evolving new functions.Given the strong link between structure and function, this thesis also addresses challenges in structural characterization. I present strategies for improving cryo-EM analysis of small transporters like Lyp1 and evaluate safer alternatives to uranyl acetate for negative-stain electron microscopy, identifying effective lanthanide-based stains.Overall, this work provides a holistic view of how genetic variation, protein structure, and biochemical activity interact to shape the evolution and diversification of membrane transporters
The information value of energy labels:Evidence from the Dutch residential housing market
No full textThis paper examines the information value of energy labels using administrative data on all transactions in the Dutch residential housing market from 2000 to 2017. Specifically, we assess whether energy labels provide additional information beyond what buyers can directly observe, and whether this information is capitalized into transaction prices. We compare the information value of two different labeling systems; one is complex and voluntary, and the other is simple and mandatory. Using a combination of hedonic pricing models and a sharp Regression Discontinuity Design, we find robust evidence that voluntary labels had limited information value from 2008 to 2014. The information value of the mandatory labels adopted since 2015 is less clear. Notably, better-labeled houses already attracted significant price premiums before they obtained energy labels, which implies that at least part of the price premium cannot be attributed to mandatory labels.</p
Symptom Burden and Patient-Reported Outcomes in Kidney Transplant Recipients:Results From the TransplantLines Biobank and Cohort Studies
No full textRationale & Objective: A multitude of symptoms may contribute to low health-related quality of life (HRQoL) in kidney transplant recipients (KTR). We aimed to identify the most occurring and distressing symptoms, to explore potential determinants of symptom burden, and to examine associations with patient-reported outcomes in KTR. Study Design: A cross-sectional retrospective patient-reported outcome measures study. Setting & Participants: Stable KTR ≥1 year after transplantation participating in the TransplantLines Biobank and Cohort Studies. Predictors: Clinical variables, including sex, age, and time after transplantation. Outcomes: Symptom occurrence/distress/burden, medication adherence, symptoms of depression/anxiety, societal participation, and HRQoL. Analytical Approach: Symptoms were evaluated using ridit analyses. A burden score was calculated to explore determinants of symptom burden and its associations with other patient-reported outcomes. Results: We included 936 KTR (38.8% female; mean ± SD age, 55.6 ± 13.0 years) at a median [IQR] of 2.0 [1.0-9.0] years after transplantation. Based on ridit scores, most occurring symptoms were tiredness [0.724], bruises [0.718], and lack of energy [0.688]; most distressful symptoms were menstrual problems [0.679], impotence [0.654], and joint pain [0.611]. Worse nutritional status (P < 0.001), being female (P < 0.001), cyclosporine use (P = 0.005), and proton pomp inhibitor use (P < 0.001) were associated with higher symptom burden. Higher symptom burden was associated with medication nonadherence, symptoms of depression and anxiety, lower societal participation, and lower physical and mental HRQoL (st.β = –0.53, 95% CI –0.59 to –0.47, P <0.001 and st.β=-0.53, 95% CI –0.60 to –0.46, P < 0.001, respectively). Limitations: No causality can be established because of the cross-sectional design. Conclusions: The most occurring symptoms were tiredness, bruises, and lack of energy, and the most distressing symptoms were menstrual problems, impotence, and joint pain. The strongest determinants of symptom burden were female sex, malnutrition, cyclosporine use, and proton pump inhibitor use. The associations of symptom burden with patient-related outcomes underline the importance of addressing symptom status after transplant. Plain-language Summary: Symptom burden of immunosuppressive medication may cause lower health-related quality of life (HRQoL) in kidney transplant recipients (KTR). Therefore, we aimed to assess (1) symptom occurrence and distress, (2) determinants of symptom burden, and (3) associations of symptom burden with HRQoL and other patient-reported outcomes. In 936 KTR, the most occurring symptoms were tiredness, bruises, and lack of energy, and the most distressing symptoms were menstrual problems, impotence, and joint pain. Being female, having malnutrition, using cyclosporine, and using proton pump inhibitors were determinants of high symptom burden. Furthermore, a higher symptom burden was associated with more medication nonadherence, more symptoms of anxiety/depression, lower societal participation, and lower physical and mental HRQoL. These findings may help improve patient-centered health care.</p
FGF1 ameliorates hepatic steatosis through acute activation of the unfolded protein response and VLDL production
No full textBackground & Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a serious chronic liver disease with limited therapeutic options. Fibroblast growth factor (FGF) analogs show promising therapeutic benefits for MASLD, yet the underlying mechanisms remain incompletely understood. Here, we studied the mechanism underlying the anti-steatotic properties of FGF1, the prototype member of the FGF family. Methods: The effect of FGF1 was studied in human and rodent hepatocytes and in obese mouse models exhibiting acute or chronic endoplasmic reticulum (ER) stress characteristic of MASLD. Metabolic analysis and proteomics were applied to evaluate liver physiology, ER stress and signaling. Results: We show that FGF1 reduces hepatic triglyceride (TG) levels in obese mice (51%, p <0.01, n = 8) via acute stimulation of very-low-density lipoprotein (VLDL, 3.9-fold, p <0.01, n = 8) secretion in an ER stress-dependent manner. This anti-steatotic effect was independent of adipose FGF receptor 1, which is required for the glucose-lowering effect of FGF1. Mechanistically, activation of the unfolded protein response (UPR), resulting in stabilization of apolipoprotein B (ApoB, 1.8-fold, p <0.01, n = 8), the main structural protein component of atherogenic lipoprotein particles, was identified as the key mechanism by which FGF1 drives VLDL secretion. Post-translational control of ApoB by FGF1 was potentiated by pre-existing ER stress. FGF1 stimulated major regulators of protein synthesis, and during ER stress, all three branches of the UPR were activated. In ER stress-primed lean mice, FGF1 adopted novel TG secretion activity (2.2-fold, p <0.05, n = 6). Conversely, alleviation of ER stress in obese mice suppressed FGF1-stimulated VLDL-TG production (49%, n = 11, p <0.05). Conclusion: These results define ER stress-dependent modulation of VLDL secretion as a mechanism underlying the anti-steatotic activity of FGF1. Targeting the FGF-UPR pathway may thus have therapeutic potential for treating MASLD. Impact and implications: Fibroblast growth factors show therapeutic potential in both preclinical models and clinical trials for treating metabolic dysfunction-associated steatotic liver disease, a highly prevalent condition with limited treatment options. Identifying the mechanisms underlying their anti-steatotic effects may accelerate clinical development. Our finding that triglyceride secretion is the major driver of the anti-steatotic action of FGF1, together with the involvement of an adaptive unfolded protein response, provides deeper insight into the therapeutic potential of this pathway. These results also highlight possible implications for liver physiology and for the circulating lipoprotein profile, with relevance for both efficacy and safety considerations.</p
Boundary Spanners in Action:Enhancing Public-Private Collaboration in Public Infrastructure Projects
No full textBoundary spanners are individuals who have the potential to identify collaborative synergies and proactively determine ways to utilise the opportunity. This research focuses on boundary spanning in the context of infrastructure projects undertaken by public managers in the Netherlands. It identifies the added value created by boundary spanners in integrated infrastructural projects in creating sustainable infrastructure. This supports a shift from siloed efforts to a more integrated, system-oriented approach, better suited to addressing broader societal challenges. This research investigates the activities, roles, and enabling conditions that make boundary spanners effective, thereby contributing to the project performance of public infrastructure projects. The understanding gained from this study can help demonstrate the importance of the activities undertaken by the boundary spanners in institutions, instigate policy changes based on data-driven recommendations and tap into their potential for future projects. The findings indicate that each phase of the project requires a varying level of involvement of stakeholders and different boundary spanning activities to maintain the synergetic momentum between the public and private partners. By bridging divides between public and private partners, boundary spanners unlock the potential of infrastructure projects and deliver enduring value
Emotional Needs in the Face of Climate Change and Barriers for Pro-Environmental Behaviour in Dutch Young Adults:A Qualitative Exploration
No full textRapid climate change and its anticipated impacts trigger significant worry and distress among vulnerable groups, including young adults. Little is known about how Dutch young adults experience and cope with climate change within their specific social and environmental context. This study examines Dutch young people’s emotional responses to climate change, their perceived emotional and psychological needs arising from these experiences, and the barriers they encounter in engaging in pro-environmental behaviour, with the aim of informing public health strategies to better support and empower this vulnerable group. Data were drawn from a large online survey among a representative sample of 1006 Dutch young adults (16–35 years; 51% women). The questionnaire included fixed-answer sections assessing emotional responses to climate change, as well as two open-ended questions exploring participants’ perceptions of their emotional and psychological needs related to climate change and the barriers they perceive to pro-environmental behaviour. Descriptive statistics were used for the fixed-response items, and thematic analysis was applied to the open-ended responses. Many Dutch young adults reported worry and sadness about climate change and its impacts, with approximately one third experiencing feelings of powerlessness. A large percentage of respondents attributed responsibility to large companies, and nearly half indicated that they still had hope for the future. One third (31%) felt that nothing could make them feel better about climate change, and another third (36%) reported to experience no climate-related emotions. Key emotional needs included more action at personal, community, and governmental levels, and more motivating positive news. Almost half (46%) of young adults said they already lived sustainably, while perceived barriers to pro-environmental behaviour were mainly financial (21%), knowledge-related (8%), and time-related (7%). This exploratory study highlights key practical and emotional barriers to pro-environmental behaviour reported by Dutch young adults 16–35, who expressed diverse emotional needs while coping with climate change. The findings underscore the need for a multi-level public health response to climate-related emotions, that simultaneously addresses emotional needs, structural barriers, and opportunities for meaningful engagement. Lowering barriers to pro-environmental behaviour and fostering supportive environments that enable sustainable action among young adults may enhance wellbeing and strengthen their sense of agency. Public health supports this by reducing barriers to pro-environmental behaviour in young adults, through targeted support, clear information, and enabling social and structural conditions that promote wellbeing and sustained engagement