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Using the biomarker hypermethylated DNA (hmDNA) for cancer detection requires a pretreatment to isolate or concentrate hmDNA from nonmethylated DNA. Affinity chromatography using a methyl binding domain-2 (MBD2) protein can be used, but the relatively low enrichment selectivity of MBD2 limits its clinical applicability. Here, we developed a superselective, multivalent, MBD2-coated platform to improve the selectivity of hmDNA enrichment. The multivalent platform employs control over the MBD2 surface receptor density, which is shown to strongly affect the binding of DNA with varying degrees of methylation, improving both the selectivity and the affinity of DNAs with higher numbers of methylation sites. Histidine-10-tagged MBD2 was immobilized on gold surfaces with receptor density control by tuning the amount of nickel nitrilotriacetic acid (NiNTA)-functionalized thiols in a thiol-based self-assembled monolayer. The required MBD2 surface receptor densities for DNA surface binding decreases for DNA with higher degrees of methylation. Both higher degrees of superselectivity and surface coverages were observed upon DNA binding at increasing methylation levels. Adopting the findings of this study into hmDNA enrichment of clinical samples has the potential to become more selective and sensitive than current MBD2-based methods and, therefore, to improve cancer diagnostics.

Funder: Dutch Research Council (NWO), Colloidal molecules are designed to mimic their molecular analogues through their anisotropic shape and interactions. However, current experimental realizations are missing the structural flexibility present in real molecules thereby restricting their use as model systems. We overcome this limitation by assembling reconfigurable colloidal molecules from silica particles functionalized with mobile DNA linkers in high yields. We achieve this by steering the self-assembly pathway toward the formation of finite-sized clusters by employing high number ratios of particles functionalized with complementary DNA strands. The size ratio of the two species of particles provides control over the overall cluster size, i.e., the number of bound particles N, as well as the degree of reconfigurability. The bond flexibility provided by the mobile linkers allows the successful assembly of colloidal clusters with the geometrically expected maximum number of bound particles and shape. We quantitatively examine the self-assembly dynamics of these flexible colloidal molecules by a combination of experiments, agent-based simulations, and an analytical model. Our "flexible colloidal molecules" are exciting building blocks for investigating and exploiting the self-assembly of complex hierarchical structures, photonic crystals, and colloidal metamaterials.

This study aimed to investigate the potential progressiveness of mandibular asymmetry and to study factors that influence chin point deviation in patients with unilateral craniofacial microsomia (CFM). Paediatric patients with unilateral CFM with available radiologic imaging and medical photographs were included. Chin point deviation was measured on clinical photographs. A Jonckheere-Terpstra test and linear mixed model for repeated measurements assessed the relation of chin point deviation on natural growth, Pruzansky−Kaban score, and soft tissue score. A total of 110 patients were included. The linear mixed model showed no statistically significant changes of chin point deviation during growth (effect estimate −0.006°, 95% CI –0.04° to −0.03°, p = 0.74). A statistical significant relation between both the Pruzansky-Kaban and soft tissue score on chin point deviation was found (effect estimate −5.10°, 95% CI –6.45° to −3.75°, p ≤ 0.001 and effect estimate −3.42°, CI –5.86° to −0.98°, p ≤ 0.001, respectively). Within the limitations of the study it seems that craniofacial microsomia may be a non-progressive disorder, because chin point deviation did not change over time.

Background: Revascularisation of a chronic total coronary occlusion (CTO) impacts on the coronary physiology of the remote myocardial territory. Aims: This study aimed to evaluate the intrinsic effect of CTO percutaneous coronary intervention (PCI) on changes in absolute perfusion in remote myocardium. Methods: A total of 164 patients who underwent serial [ 15O]H 2O positron emission tomography (PET) perfusion imaging at baseline and three months after successful single-vessel CTO PCI were included to evaluate changes in hyperaemic myocardial blood flow (hMBF) and coronary flow reserve (CFR) in the remote myocardium supplied by both non-target coronary arteries. Results: Perfusion indices in CTO and remote myocardium showed a positive correlation before (resting MBF: r=0.84, hMBF: r =0.75, and CFR: r =0.77, p–1·g –1 and from 2.48±0.76 to 2.74±0.85, respectively, p

Logistics planning is a complex optimization problem involving multiple decision makers. Automated scheduling systems offer support to human planners; however state-of-the-art approaches often employ a centralized control paradigm. While these approaches have shown great value, their application is hindered in dynamic settings with no central authority. Motivated by real-world scenarios, we present a decentralized approach to collaborative multi-agent scheduling by casting the problem as a Distributed Constraint Optimization Problem (DCOP). Our model-based heuristic approach uses message passing with a novel pruning technique to allow agents to cooperate on mutual agreement, leading to a near-optimal solution while offering low computational costs and flexibility in case of disruptions. Performance is evaluated in three real-world field trials with a logistics carrier and compared against a centralized model-free Deep Q-Network (DQN)-based Reinforcement Learning (RL) approach, a Mixed-Integer Linear Programming (MILP)-based solver, and both human and heuristic baselines. The results demonstrate that it is feasible to have virtual agents make autonomous decisions using our DCOP method, leading to an efficient distributed solution. To facilitate further research in Self-Organizing Logistics (SOL), we provide a novel real-life dataset.

Aim: This article provides a review of a decade of clinical research studies on clinical features, medical interventions, and surgical interventions for individuals with craniofacial microsomia (CFM). We also provide recommendations for future clinical research. Method: A systematic search of literature was conducted in Embase and PubMed/MEDLINE Ovid. All publications from 2010 to 2020 that included at least 10 individuals with CFM were considered relevant for this study. Results: A total of 91 articles were included. In the past decade, many new studies on CFM have been published providing more insight on the diagnosis and management of patients with CFM. This review encompasses findings on the clinical difficulties patients with CFM encounter, including the craniofacial and extracraniofacial characteristics of patients with CFM and its related clinical consequences on breathing, feeding, speech, and hearing. Conclusions: A considerable number of large multicenter studies have been published in recent years, providing new insights in the clinical consequences of CFM. The phenotypic variety between patients with CFM makes patient-specific treatment tailored to individual needs essential. The research and development of clinical care standards might be challenging because of the heterogeneity of CFM. Future research on clinical and patient-reported outcomes can help identify optimal treatment strategies. Cooperation between craniofacial centers, using uniform registration and outcome measurement tools, could enhance research and future care for these patients. Level of evidence: Level IV.

Aims Coronary flow capacity (CFC) integrates quantitative hyperaemic myocardial blood flow (hMBF) and coronary flow reserve (CFR) to comprehensively assess physiological severity of coronary artery disease (CAD). This study evaluated the effects of revascularization on CFC as assessed by serial [15O]H2O positron emission tomography (PET) perfusion imaging. Methods and results A total of 314 patients with stable CAD underwent [15O]H2O PET imaging at baseline and after myocardial revascularization to assess changes in hMBF, CFR, and CFC in 415 revascularized vessels. Using thresholds for ischaemia and normal perfusion, vessels were stratified in five CFC categories: myocardial steal, severely reduced CFC, moderately reduced CFC, minimally reduced CFC, and normal flow. Additionally, the association between CFC increase and the composite endpoint of death and non-fatal myocardial infarction (MI) was studied. Vessel-specific CFC improved after revascularization (P < 0.01). Furthermore, baseline CFC was an independent predictor of CFC increase (P < 0.01). The largest changes in ΔhMBF (0.90 ± 0.74, 0.93 ± 0.65, 0.79 ± 0.74, 0.48 ± 0.61, and 0.29 ± 0.66 mL/min/g) and ΔCFR (1.01 ± 0.88, 0.99 ± 0.69, 0.87 ± 0.88, 0.66 ± 0.91, and −0.01 ± 1.06) were observed in vessels with lower baseline CFC (P < 0.01 for both). During a median follow-up of 3.5 (95% CI 3.1–3.9) years, an increase in CFC was independently associated with lower rates of death and non-fatal MI (HR 0.43, 95% CI 0.19–0.98, P = 0.04). Conclusion Successful revascularization results in an increase in CFC. Furthermore, baseline CFC was an independent predictor of change in hMBF, CFR, and subsequently CFC. In addition, an increase in CFC was associated with a favourable outcome in terms of death and non-fatal MI.

Background: Craniofacial microsomia (CFM) is characterized by several malformations related to the first and second pharyngeal arch. Patients typically present with facial asymmetry, but extracraniofacial organ systems might be involved, including limb anomalies. The purpose of this study was to analyze the occurrence of upper and lower limb anomalies in CFM patients. Furthermore, the relation between limb anomalies and the OMENS+ (orbital distortion; mandibular hypoplasia; ear anomaly; nerve involvement; soft-tissue deficiency; and associated extracraniofacial anomalies) classification was examined. Methods: A retrospective study was conducted including patients with CFM from craniofacial units in three different countries. Patients were included when clinical and/or radiographic images were available. Demographic, radiographic, and clinical information was obtained. Results: A cohort of 688 patients was available and selected for analysis. In total, 18.2% of the patients were diagnosed with at least one upper and/or lower limb anomaly. Upper and lower limb anomalies were seen in, respectively, 13.4% and 7.8% of patients. Patients with other extracraniofacial anomalies had a significantly higher risk for limb anomalies (OR, 27.98; P = 0.005). Laterality of CFM and a higher OMENS score were not associated with limb anomalies. Conclusions: More than one in six patients with craniofacial microsomia have limb anomalies. Therefore, clinical awareness for these anomalies is warranted. Examination and, if present, follow-up on limb abnormalities in patients with CFM should be implemented in the standard assessment of CFM patients.

Background: Patients with prior coronary artery bypass grafting (CABG) frequently require repeat percutaneous revascularization due to advanced age, progressive coronary artery disease and bypass graft failure. Percutaneous coronary intervention (PCI) of either the bypass graft or the native coronary artery may be performed. Randomized trials comparing native vessel PCI with bypass graft PCI are lacking and long-term outcomes have not been reported. Methods: PROCTOR (NCT03805048) is a prospective, multicenter, randomized controlled trial, that will include 584 patients presenting with saphenous vein graft (SVG) failure and a clinical indication for revascularization, as determined by the local Heart Team. The trial is designed to compare the clinical and angiographic outcomes in patients randomly allocated in a 1:1 fashion to either a strategy of native vessel PCI or SVG PCI. The primary study endpoint is a 3-year composite of major adverse cardiac events (MACE: all-cause mortality, non-fatal target coronary territory myocardial infarction [MI], or clinically driven target coronary territory revascularization). At 3-years, after evaluation of the primary endpoint, follow-up invasive coronary angiography will be performed. Secondary endpoints comprise individual components of MACE at 1, 3 and 5 years follow-up, PCI-related MI, MI >48 hours after index PCI, target vessel failure, target lesion revascularization, renal failure requiring renal-replacement therapy, angiographic outcomes at 3-years and quality of life (delta Seattle Angina Questionnaire, Canadian Cardiovascular Society Grading Scale and Rose Dyspnea Scale). Conclusion: PROCTOR is the first randomized trial comparing an invasive strategy of native coronary artery PCI with SVG PCI in post-CABG patients presenting with SVG failure.

The preselection of hypermethylated DNA (hmDNA) from liquid biopsy samples is key to enable early-stage cancer diagnostics. Due to limited selectivity of the existing preselection approaches, however, wide integration in the clinic is currently prohibited. Here, it is argued that an affinity method on a surface, such as used in affinity chromatography, can be significantly improved by employing the principles of multivalency and superselectivity. In the here proposed method, a methyl binding domain (MBD) protein immobilized at a surface is used as a receptor for (hyper)methylated DNA. By the organization of multiple MBDs on a surface, a multivalent binding platform is achieved. The MBD surface receptor density on that platform is key to increase the enrichment selectivity of hmDNA as a single MBD protein binds both methylated and non-methylated DNA with a small difference in affinity. When the receptor density is varied, multivalent analyte binding typically responds in a non-linear fashion, which phenomenon is called superselectivity. By careful tuning of the MBD density, it is envisaged that the selectivity for methylated over non-methylated DNA can be optimized. Strong applicability is foreseen in a medical setting by implementing such an enrichment step in an analytical process or a lab-on-a-chip device.

A European guideline on craniofacial microsomia was developed within the European Reference Network for rare and/or complex craniofacial anomalies and ear, nose, and throat disorders and published in 2020. The guideline provides an overview of optimal care provisions for patients with craniofacial microsomia and recommendations for the improvement of care. This document seeks to provide a tailored overview of this guideline for patients and their families.

Aims To compare cardiac magnetic resonance (CMR) measurement of T1 reactivity (DT1) with [ 15O]H 2O positron emission tomography (PET) measurements of quantitative myocardial perfusion. ................................................................................................................................................................................................... Methods Forty-three patients with suspected obstructed coronary artery disease underwent [ 15O]H 2O PET and CMR at and results 1.5-T, including rest and adenosine stress T1 mapping (ShMOLLI) and late gadolinium enhancement to rule out presence of scar tissue. DT1 was determined for the three main vascular territories and compared with [ 15O]H 2O PET-derived regional stress myocardial blood flow (MBF) and myocardial flow reserve (MFR). DT1 showed a significant but poor correlation with stress MBF (R 2 = 0.04, P = 0.03) and MFR (R 2 = 0.07, P = 0.004). Vascular territories with impaired stress MBF (i.e. 15O]H 2O PET measurements of absolute myocardial perfusion. Stress T1 and DT1 are lower in vascular territories with reduced stress MBF but have poor accuracy for detecting impaired myocardial perfusion.

Purpose of Review This review will outline the current evidence on the anatomical, functional, and physiological tools that may be applied in the evaluation of patients with late recurrent angina after coronary artery bypass grafting (CABG). Furthermore, we discuss management strategies and propose an algorithm to guide decision-making for this complex patient population. Recent Findings Patients with prior CABG often present with late recurrent angina as a result of bypass graft failure and progression of native coronary artery disease (CAD). These patients are generally older, have a higher prevalence of comorbidities, and more complex atherosclerotic lesion morphology compared to CABG-naïve patients. In addition, guideline recommendations are based on studies in which post-CABG patients have been largely excluded. Summary Several invasive and non-invasive diagnostic tools are currently available to assess graft patency, the hemodynamic significance of native CAD progression, left ventricular function, and myocardial viability. Such tools, in particular the latest generation coronary computed tomography angiography, are part of a systematic diagnostic work-up to guide optimal repeat revascularization strategy in patients presenting with late recurrent angina after CABG.