Purpose Examining epigenetic patterns is a crucial step in identifying molecular changes of disease pathophysiology, with DNA methylation as the most accessible epigenetic measure. Diet is... Show morePurpose Examining epigenetic patterns is a crucial step in identifying molecular changes of disease pathophysiology, with DNA methylation as the most accessible epigenetic measure. Diet is suggested to affect metabolism and health via epigenetic modifications. Thus, our aim was to explore the association between food consumption and DNA methylation. Methods Epigenome-wide association studies were conducted in three cohorts: KORA FF4, TwinsUK, and Leiden Longevity Study, and 37 dietary exposures were evaluated. Food group definition was harmonized across the three cohorts. DNA methylation was measured using Infinium MethylationEPIC BeadChip in KORA and Infinium HumanMethylation450 BeadChip in the Leiden study and the TwinsUK study. Overall, data from 2293 middle-aged men and women were included. A fixed-effects meta-analysis pooled study-specific estimates. The significance threshold was set at 0.05 for false-discovery rate-adjusted p values per food group. Results We identified significant associations between the methylation level of CpG sites and the consumption of onions and garlic (2), nuts and seeds (18), milk (1), cream (11), plant oils (4), butter (13), and alcoholic beverages (27). The signals targeted genes of metabolic health relevance, for example, GLI1, RPTOR, and DIO1, among others. Conclusion This EWAS is unique with its focus on food groups that are part of a Western diet. Significant findings were mostly related to food groups with a high-fat content. Show less
Background The optimal management of ipsilateral extracranial internal carotid artery (ICA) stenosis during endovascular treatment (EVT) is unclear. We compared the outcomes of two different... Show moreBackground The optimal management of ipsilateral extracranial internal carotid artery (ICA) stenosis during endovascular treatment (EVT) is unclear. We compared the outcomes of two different strategies: EVT with vs without carotid artery stenting (CAS).Methods In this observational study, we included patients who had an acute ischaemic stroke undergoing EVT and a concomitant ipsilateral extracranial ICA stenosis of ≥50% or occlusion of presumed atherosclerotic origin, from the Dutch Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) Registry (2014–2017). The primary endpoint was a good functional outcome at 90 days, defined as a modified Rankin Scale score ≤2. Secondary endpoints were successful intracranial reperfusion, new clot in a different vascular territory, symptomatic intracranial haemorrhage, recurrent ischaemic stroke and any serious adverse event.Results Of the 433 included patients, 169 (39%) underwent EVT with CAS. In 123/168 (73%) patients, CAS was performed before intracranial thrombectomy. In 42/224 (19%) patients who underwent EVT without CAS, a deferred carotid endarterectomy or CAS was performed. EVT with and without CAS were associated with similar proportions of good functional outcome (47% vs 42%, respectively; adjusted OR (aOR), 0.90; 95% CI, 0.50 to 1.62). There were no major differences between the groups in any of the secondary endpoints, except for the increased odds of a new clot in a different vascular territory in the EVT with CAS group (aOR, 2.96; 95% CI, 1.07 to 8.21).Conclusions Functional outcomes were comparable after EVT with and without CAS. CAS during EVT might be a feasible option to treat the extracranial ICA stenosis but randomised studies are warranted to prove non-inferiority or superiority. Show less
Skilled vision is more-than-visual because the enskilment of vision happens in intersensorial contexts and because it pertains to the broader formation of aesthetic and ethical sensibilities.... Show moreSkilled vision is more-than-visual because the enskilment of vision happens in intersensorial contexts and because it pertains to the broader formation of aesthetic and ethical sensibilities. Sensory and social apprenticeship coexist in practice. I dwell on the intersensoriality of learning to see in an analytical way and on the sociality and morality of skilled visions, using ethnographic examples from my fieldwork with food gardeners in the Netherlands and from other scholars who use a skilled-visions approach, notably Judith Willkomm on skilled listening in bioacoustic field research in Germany, Tom Martin on craft learning as perceptual transformation in maritime carpentry in the United States, and Jonathan Hankins on the apprenticeship of traditional upholstery in the United Kingdom. Each example shows how the realignment of visual perception in one's learning environment (with other senses, with technical apparatuses, and with human and nonhuman others) mediate the acquisition of perspicuity, namely the perceptual and aesthetic realization of each detail in their proper function and as appropriate to their context. Show less
D'Onofrio, B.; Helm-van Mil, A. van der; Huizinga, T.W.J.; Mulligen, E. van 2022
Introduction: Drug-free remission (DFR) and its maintenance have been defined as the most desirable outcome for rheumatoid arthritis (RA) patients. DFR is linked to resolution of arthritis-related... Show moreIntroduction: Drug-free remission (DFR) and its maintenance have been defined as the most desirable outcome for rheumatoid arthritis (RA) patients. DFR is linked to resolution of arthritis-related symptoms and restoration of normal functioning. However, there is currently no consensus if an optimal strategy, upon the initiation of treatment to the proper drugs withdrawal, is enough to induce it, or whether it is a predetermined condition related to patients' intrinsic characteristics. Areas covered: This review focuses on two key concepts around DFR. First, we analyze patients' intrinsic factors that may increase the chance of DFR, regardless of therapeutic choices. Second, we discuss on the evidence that it can be induced thanks to adequate, extrinsic disease management. Finally, we provide a glimpse into consequences of drugs discontinuation .Expert opinion: The early initiation of DMARD and the subsequent strict monitoring and drug adjustments are of primary importance to allow patients to achieve DFR, irrespective of initial treatment strategy. Once remission is obtained and maintained, it is possible to gradually taper and discontinue drugs with no dramatic consequences on the disease course. Among those who stop medication, ACPA-negative patients more often maintain the remission. Thus, DFR might depend on a combination of intrinsic and extrinsic factors. Show less
Purpose: Machine Learning (ML) algorithms represent an interesting alternative to maximum a posteriori Bayesian estimators (MAP-BE) for tacrolimus AUC estimation, but it is not known if training an... Show morePurpose: Machine Learning (ML) algorithms represent an interesting alternative to maximum a posteriori Bayesian estimators (MAP-BE) for tacrolimus AUC estimation, but it is not known if training an ML model using a lower number of full pharmacokinetic (PK) profiles (="true" reference AUC) provides better performances than using a larger dataset of less accurate AUC estimates. The objectives of this study were: to develop and benchmark ML algorithms trained using full PK profiles to estimate MeltDose (R)-tacrolimus individual AUCs using 2 or 3 blood concentrations; and to compare their performance to MAP-BE. Methods: Data from liver (n = 113) and kidney (n = 97) transplant recipients involved in MeltDose-tacrolimus PK studies were used for the training and evaluation of ML algorithms. "True" AUC0-24 h was calculated for each patient using the trapezoidal rule on the full PK profile. ML algorithms were trained to estimate tacrolimus true AUC using 2 or 3 blood concentrations. Performances were evaluated in 2 external sets of 16 (renal) and 48 (liver) transplant patients. Results: Best estimation performances were obtained with the MARS algorithm and the following limited sampling strategies (LSS): predose (0), 8, and 12 h post-dose (rMPE = -1.28%, rRMSE = 7.57%), or 0 and 12 h (rMPE = -1.9%, rRMSE = 10.06%). In the external dataset, the performances of the final ML algorithms based on two samples in kidney (rMPE = -3.1%, rRMSE = 11.1%) or liver transplant recipients (rMPE = -3.4%, rRMSE = 9.86%) were as good as or better than those of MAP-BEs based on three time points. Conclusion: The MARS ML models developed using "true" MeltDose (R)-tacrolimus AUCs yielded accurate individual estimations using only two blood concentrations. Show less
Treatment with targeted therapy and immune checkpoint inhibitors has significantly improved survival of patients with advanced melanoma. Unfortunately, a large proportion of patients are either... Show moreTreatment with targeted therapy and immune checkpoint inhibitors has significantly improved survival of patients with advanced melanoma. Unfortunately, a large proportion of patients are either primary non-responders or will eventually develop secondary resistance. In 2017, Nosrati and colleagues published a prediction scale in the British Journal of Cancer, which included five clinical parameters that were associated with lower response to anti-PD-1 treatment; female sex (1 point), age <65 years (1 point), history of ipilimumab (anti-CTLA-4) treatment (2 points), elevated lactate dehydrogenase (LDH) (1 point), and the presence of liver metastasis (2 points) [1]. This study used a derivation cohort of 228 patients treated in California, and a validation cohort of 87 patients treated in Switzerland. The primary outcome measure was best tumour response to treatment evaluated using computed tomography at 12 and 16 weeks after the first administration of anti-PD-1 monotherapy, and every 12 weeks thereafter. The aim of this correspondence is to validate the prediction scale, published by Nosrati and colleagues. Show less
For some adolescent gamers, playing online games may become problematic, impairing functioning in personal, family, and other life domains. Parental and family factors are known to influence the... Show moreFor some adolescent gamers, playing online games may become problematic, impairing functioning in personal, family, and other life domains. Parental and family factors are known to influence the odds that adolescents may develop problematic gaming (PG), negative parenting and conflictual family dynamics increasing the risk, whereas positive parenting and developmentally supportive family dynamics protecting against PG. This suggests that a treatment for adolescent PG should not only address the gaming behaviors and personal characteristics of the youth, but also the parental and family domains. An established research-supported treatment meeting these requirements is multidimensional family therapy (MDFT), which we adapted for use as adolescent PG treatment. We report here on one adaptation, applying in-session gaming.In-session demonstration of the "problem behavior" is feasible and informative in PG. In the opening stage of therapy, we use in-session gaming to establish an alliance between the therapist and the youth. By inviting them to play games, the therapist demonstrates that they are taken seriously, thus boosting treatment motivation.Later in treatment, gaming is introduced in family sessions, offering useful opportunities to intervene in family members' perspectives and interactional patterns revealed in vivo as the youth plays the game. These sessions can trigger strong emotions and reactions from the parents and youth and give rise to maladaptive transactions between the family members, thus offering ways to facilitate new discussions and experiences of each other. The insights gained from the game demonstration sessions aid the therapeutic process, more so than mere discussion about gaming. Show less
Balcı H.; Özbal, R.; Gerritsen, F.A.; Fidan E. 2022
The Neolithic way of life was first established in Northwest Anatolia before the middle of the 7th millennium BC. The recently excavated sites of Barcın Höyük and Bahçelievler have yielded... Show moreThe Neolithic way of life was first established in Northwest Anatolia before the middle of the 7th millennium BC. The recently excavated sites of Barcın Höyük and Bahçelievler have yielded archaeological evidence for the earliest Neolithic levels in the region and provide new archaeobotanical datasets. To compare different adaptations to the changes brought on by the Neolithization processes, we studied 348 archaeobotanical samples from Phases VIe and VId1 at Barcın and 63 samples from the contemporaneous levels, Phase 6 and Phase 5, at Bahçelievler. The economic plants include hulled and naked six-row barley, einkorn, emmer, bread/hard wheat, small-sized naked wheat, lentil, bitter vetch, pea, chickpea, flax, hazelnut, bramble, and pistacia. Our analyses show small but significant differences between the sites in the selected economic plant ranges, among the cereals, pulses as well as gathered plants. Show less
Battery energy storage systems (BESS) are expected to fulfill a crucial role in the renewable energy systems of the future. Within current regulatory frameworks, assessing the sustainability as... Show moreBattery energy storage systems (BESS) are expected to fulfill a crucial role in the renewable energy systems of the future. Within current regulatory frameworks, assessing the sustainability as well as the social risks for BESS should be considered. In this research we conducted a social life cycle assessment (S-LCA) of two BESS: the vanadium redox flow battery (VRFB) and the lithium-ion battery (LIB). The S-LCA was conducted based on the guidelines set by UNEP/SETAC and using the PSILCA v.3 database. It was found that most social risks related to the life cycle of the batteries are associated with the raw material extraction stage, while sectors related to chemicals also entail considerable risks. Workers are the stakeholder group affected most. These results apply to supply chains located in both China and Germany, but risks were lower for similar supply chains in Germany. An LIB with a nickel manganese cobalt oxide cathode is associated with considerably larger risks compared to a LIB with lithium manganese oxide cathode. For a VRFB life cycle with an increased vanadium price, the social risks were higher than those of the VRFB supply chain with a regular vanadium price. Our paper shows that S-LCA through the PSILCA database can provide interesting insights into the potential social risks associated with a certain product's life cycle. Generalizations of the results are not recommended, and one should be careful with assessments for technologies that have not yet matured due to the cost sensitivity of the methodology. Show less
Low-molecular-weight hydrogels are attractive scaffolds for drug delivery applications because of their modular and facile preparation starting from inexpensive molecular components. The molecular... Show moreLow-molecular-weight hydrogels are attractive scaffolds for drug delivery applications because of their modular and facile preparation starting from inexpensive molecular components. The molecular design of the hydrogelator results in a commitment to a particular release strategy, where either noncovalent or covalent bonding of the drug molecule dictates its rate and mechanism. Herein, we demonstrate an alternative approach using a reaction-coupled gelator to tune drug release in a facile and user-defined manner by altering the reaction pathway of the low-molecular-weight gelator (LMWG) and drug components through an acylhydrazone-bond-forming reaction. We show that an off-the-shelf drug with a reactive handle, doxorubicin, can be covalently bound to the gelator through its ketone moiety when the addition of the aldehyde component is delayed from 0 to 24 h, or noncovalently bound with its addition at 0 h. We also examine the use of an L-histidine methyl ester catalyst to prepare the drugloaded hydrogels under physiological conditions. Fitting of the drug release profiles with the Korsmeyer-Peppas model corroborates a switch in the mode of release consistent with the reaction pathway taken: increased covalent ligation drives a transition from a Fickian to a semi-Fickian mode in the second stage of release with a decreased rate. Sustained release of doxorubicin from the reaction-coupled hydrogel is further confirmed in an MTT toxicity assay with MCF-7 breast cancer cells. We demonstrate the modularity and ease of the reaction-coupled approach to prepare drug-loaded self-assembled hydrogels in situ with tunable mechanics and drug release profiles that may find eventual applications in macroscale drug delivery. Show less
Pluskota, M.; Oosten R.M.R.; Tegelaar, S. van; Windt, M. van der 2022
This article builds on recent calls in urban and gender history for a better understanding of the interaction between gender and the urban environment. Its focus is on male and female offending... Show moreThis article builds on recent calls in urban and gender history for a better understanding of the interaction between gender and the urban environment. Its focus is on male and female offending behaviours and their relation to the urban space, specifically the spaces shared by women and men: the home, the street outside of their house, and the main thoroughfares. The article aims to shed light on common practices and understandings between men and women, while highlighting potential differences. The analysis is based on the mapping of offending behaviours recorded by Leiden police court and Amsterdam correctional court in the second half of the nineteenth century. In part, the article confirms what other historians have already shown: women were on average accused of committing an offence closer to their home than men, but they were also very much present in the streets around their house. But the data presented also shows that women and men were more or less mobile according to the time of day, that they shared a common understanding of what their neighbourhood represented, and that work was an important reason why women would commute outside of their neighbourhood. Overall, the article confirms the value of a nuanced view of gender and the use of the urban space. Show less
Cardol, C.K.; Middendorp, H. van; Dusseldorp, E.M.L.; Boog, P.J.M. van der; Navis, G.; Hilbrands, L.B.; ... ; Dijk, S. van 2022
Rationale & Objective: In kidney transplant recipients (KTRs), a belatacept-based immunosuppressive regimen is associated with beneficial effects on cardiovascular (CV) risk factors compared... Show moreRationale & Objective: In kidney transplant recipients (KTRs), a belatacept-based immunosuppressive regimen is associated with beneficial effects on cardiovascular (CV) risk factors compared with calcineurin inhibitor (CNI)-based regimens. Our objective was to compare the calculated CV risk between belatacept and CNI (predominantly tacrolimus) treatments using a validated model developed for KTRs.Study Design: Prospective, randomized, open-label, parallel-group, investigator-initiated, international multicenter trial.Setting & Participants: KTRs aged 18-80 years with a stable graft function (estimated glomerular filtration rate > 20 mL/min/1.73 m2), 3-60 months after transplantation, treated with tacrolimus or cyclosporine A, were eligible for inclusion.Intervention: Continuation with a CNI-based regimen or switch to belatacept for 12 months.Outcomes: Comparison of the change in the esti-mated 7-year risk of major adverse CV events and all-cause mortality, changes in traditional markers of CV health, as well as measures of arterial stiffness.Results: Among the 105 KTRs randomized, we found no differences between the treatment groups in the predicted risk for major adverse CV events or mortality. Diastolic blood pres-sure, measured both centrally by using a SphygmoCor device and peripherally, was lower after the belatacept treatment than after the CNI treatment. The mean changes in traditional cardiovascular (CV) risk factors, including kidney transplant function, were otherwise similar in both the treatment groups. The belatacept group had 4 acute rejection episodes; 2 were severe rejections, of which 1 led to graft loss.Limitations: The heterogeneous baseline esti-mated glomerular filtration rate and time from transplantation to trial enrollment in the partici-pants. A limited study duration of 1 year.Conclusions: We found no effects on the calculated CV risk by switching to the belata-cept treatment. Participants in the belatacept group had not only lower central and peripheral diastolic blood pressure but also a higher rejection rate.Funding: The trial has received a financial grant from Bristol-Myers Squibb.Trial Registration: EudraCT no. 2013-001178-20. Show less
Bulk, S. van den; Spoelman, W.A.; Dijkman, P.R.M. van; Numans, M.E.; Bonten, T.N.; Leiden Univ Med Ctr LUMC 2022
Background: The prevalence of coronary artery disease is increasing due to the aging population and increasing prevalence of cardiovascular risk factors. Non-acute chest pain often is the first... Show moreBackground: The prevalence of coronary artery disease is increasing due to the aging population and increasing prevalence of cardiovascular risk factors. Non-acute chest pain often is the first symptom of stable coronary artery disease. To optimise care for patients with non-acute chest pain and make efficient use of available resources, we need to know more about the current incidence, referral rate and management of these patients. Methods: We used routinely collected health data from the STIZON data warehouse in the Netherlands between 2010 and 2016. Patients > 18 years, with no history of cardiovascular disease, seen by the general practitioner (GP) for non-acute chest pain with a suspected cardiac origin were included. Outcomes were (i) incidence of new non-acute chest pain in primary care, (ii) referral rates to the cardiologist, (iii) correspondence from the cardiologist to the GP, (iv) registration by GPs of received correspondence and; (v) pharmacological guideline adherence after newly diagnosed stable angina pectoris. Results: In total 9029 patients were included during the study period, resulting in an incidence of new non-acute chest pain of 1.01/1000 patient-years. 2166 (24%) patients were referred to the cardiologist. In 857/2114 (41%) referred patients, correspondence from the cardiologist was not available in the GP's electronic medical record. In 753/1257 (60%) patients with available correspondence, the GP did not code the conclusion in the electronic medical record. Despite guideline recommendations, 37/255 (15%) patients with angina pectoris were not prescribed antiplatelet therapy nor anticoagulation, 69/255 (27%) no statin and 67/255 (26%) no beta-blocker. Conclusion: After referral, both communication from cardiologists and registration of the final diagnosis by GPs were suboptimal. Both cardiologists and GPs should make adequate communication and registration a priority, as it improves health outcomes. Secondary pharmacological prevention in patients with angina pectoris was below guideline standards. So, proactive attention needs to be given to optimise secondary prevention in this high-risk group in primary care. Show less
Berkel, S.R. van; Groeneveld, M.G.; Pol, L.D. van der; Linting, M.; Mesman, J. 2022
