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This study proposes an exact model for timetable recovery after disturbances in the context of high-frequency public transport services. The objective of our model is the minimization of the deviation between the actual headway and the respective planned value. The resulting mathematical program for the rescheduling problem is nonlinear and non-smooth; thus, it cannot be solved to optimality. To rectify this, we reformulate the model using slack variables. The reformulated model can be solved to global optimality in real-time with quadratic programming. We apply the model to real data from the red metro line in Washington D.C. in a series of experiments. In our experiments, we investigate how many upstream trips should be rescheduled to respond to a service disturbance. Our findings demonstrate an improvement potential of service regularity of up to 30% if we reschedule the five upstream trips of a disturbed train.

We assessed the prevalence of Lyme neuroborreliosis in children with acute facial nerve palsy in a Lyme-endemic region and patient characteristics associated with this. All children visiting one of three participating hospitals between January 2010 and December 2016 were included in the study. Of 104 children referred to the hospital with facial nerve palsy, 43% had Lyme neuroborreliosis and 57% idiopathic facial palsy. Characteristics significantly associated with Lyme neuroborreliosis were headache (55% versus 18%), meningeal irritation (21% versus 5%), presentation in summer months (69% versus 37%), and a previous tick bite (33% versus 7%).

The most relevant issues related to headway variability in public transport planning, operations and quality of service are reviewed in this paper. We discuss the causes and consequences of headway variability, the alternative metrics that have been proposed to measure it, the preventive and reactive strategies to control headway variability in both research and practice, including the role of drivers and of present and future technology, and how service provision contracts might deal with headway variability through metrics and financial incentives. The most influential elements that explain headway variability along a route are the irregularity at which vehicles are dispatched, the scheduled frequency, the distance travelled or route length, the passenger demand and associated dwell times, and the number of stops. We conclude that there is a large gap between the state-of-the-art and the state-of-practice in terms of identification of headway variability issues, as well as in the development of mitigation and control measures. It is therefore paramount that future research will contribute to closing this gap by addressing organisational, contractual and technological barriers in the implementation of measures aimed at mitigating headway variability in public transport services.

To gain further insight in the immunopathology underlying multifocal motor neuropathy (MMN) by exploring the association between MMN and the human leukocyte antigen (HLA) class II DRB1, DQB1, and DQA loci in depth and by correlating associated haplotypes to detailed clinical and anti-ganglioside antibody data.We performed high-resolution HLA-class II typing for the DRB1, DQB1, and DQA1 loci in 126 well-characterized MMN patients and assessed disease associations with haplotypes. We used a cohort of 1305 random individuals as a reference for haplotype distribution in the Dutch population.The DRB1*15:01-DQB1*06:02 haplotype (OR 1.6 [95% CI 1.1-2.2], p0.05) and the DRB1*12:01-DQB1*03:01 haplotype (OR 2.7 [95% CI 1.2-5.5], p0.05) were more frequent in patients with MMN than in controls. These haplotypes were not associated with disease course, response to treatment or anti-ganglioside antibodies.MMN is associated with the DRB1*15:01-DQB1*06:02 and DRB1*12:01-DQB1*03:01 haplotypes. These HLA molecules or gene variants in their immediate vicinity may promote the specific inflammatory processes underlying MMN.

Many public transport networks worldwide experience high crowding levels. Overcrowding can result in passengers not able to board the first arriving vehicle. We infer how waiting time induced by being denied boarding in crowded public transport systems is valued by passengers, based on observed passenger route choice behaviour. For this purpose, we estimate a revealed preference route choice model based on passenger and vehicle movement data. As denied boarding typically occurs only at specific locations and within strict time bands, whilst its occurrence is notoriously uncertain, we propose additional constraints to generate an appropriate choice set for which observed route choices can be used to estimate denied boarding perceptions. We found that the additional waiting time caused by denied boarding is valued 68% more negatively compared to the initial waiting time. On average, one minute of initial and denied boarding wait time are perceived as 1.62 and 2.72 min on-board an uncrowded vehicle, respectively. Not incorporating this more negative denied boarding wait time valuation can result in an underestimation of the passenger and societal impact of overcrowding in public transport systems. Moreover, it can underestimate the benefits of potential crowding relief measures and as such underestimate the benefit-cost ratio of these measures.

Aim To evaluate the prognostic value of tumor markers in a European cohort of patients with resectable gastric cancer. Methods We performed a post hoc analysis of the CRITICS trial, in which 788 patients received perioperative therapy. Association between survival and pretreatment CEA, CA 19-9, alkaline phosphatase, neutrophils, hemoglobin and lactate dehydrogenase were explored in uni- and multivariable Cox regression analyses. Likelihoods to receive potentially curative surgery were investigated for patients without elevated tumor markers versus one of the tumor markers elevated versus both tumor markers elevated. The association between tumor markers and the presence of circulating tumor DNA (ctDNA) was explored in 50 patients with available ctDNA data. Results In multivariable analysis, in which we corrected for allocated treatment and other baseline characteristics, elevated pretreatment CEA (HR 1.43; 95% CI 1.11–1.85, p p p Conclusion CEA and CA 19-9 were independent prognostic factors for survival in a large cohort of European patients with resectable gastric cancer. No relationship was found between tumor markers and ctDNA. These factors could potentially guide treatment choices and should be included in future trials to determine their definitive position. Trial registration ClinicalTrial.gov identifier: NCT00407186. EudraCT number: 2006-00413032.

The deployment of autonomous buses (AB) is expected to have consequences for service design facilitated by its cost function structure. We study the impacts of AB deployment in line-based public transport (PT) systems. In particular, we examine the transition phase where AB is sequentially deployed, involving the selection of lines for which AB will be introduced. To this end, we develop a modeling framework using a dynamic public transportation assignment and operations simulation model that captures users’ adaptive path choices. An analytical model is used to determine the initial solutions in terms of service frequency and vehicle capacity for the simulation framework. Due to their different cost function structures, the deployment of AB may be accompanied by changes in the service frequency and vehicle capacity settings and consequently also on passenger flow distribution across the network. Both the simultaneous and the sequential deployment of AB on multiple lines are investigated. Deployment solutions are assessed in terms of the both total operator and user cost. The decision variables are vehicle capacity per line, service frequency per line and vehicle technology per line - i.e. either manually driven or fully automated buses. The framework is applied to a case study in Kista, Stockholm. The study shows that AB service have the potential to attract passengers through improved service provision. A sensitivity analysis is carried out concerning the effects of different cost parameters and demand levels on the deployment of AB in fixed line operations.

Disruptions in public transport can have major implications for passengers and service providers. Our study objective is to develop a generic approach to predict how often different disruption types occur at different stations of a public transport network, and to predict the impact related to these disruptions as measured in terms of passenger delays. We propose a supervised learning approach to perform these predictions, as this allows for predictions for individual stations for each time period, without the requirement of having sufficient empirical disruption observations available for each location and time period. This approach also enables a fast prediction of disruption impacts for a large number of disruption instances, hence addressing the computational challenges that rise when typical public transport assignment or simulation models would be used for real-world public transport networks. To improve transferability of our study results, we cluster stations based on their contribution to network vulnerability using unsupervised learning. This supports public transport agencies to apply the appropriate type of measure aimed to reduce disruptions or to mitigate disruption impacts for each station type. Applied to the Washington metro network, we predict a yearly passenger delay of 5.9 million hours for the total metro network. Based on the clustering, five different types of station are distinguished. Stations with high train frequencies and high passenger volumes located at central trunk sections of the network show to be most critical, along with start/terminal and transfer stations. Intermediate stations located at branches of a line are least critical.

We present a transit model that, based on automated fare collection and train tracking data, describes pedestrian movements in train stations and vehicle-specific train ridership distributions. Our approach differs from existing models in that we describe on-board passenger dynamics and pedestrian dynamics at stations in a joint framework. We assume that travelers first decide on the train(s) they will take, and then pursue their journey through the network by successively choosing pedestrian paths, waiting positions on platforms, and specific train cars. Travelers explicitly maximize their travel utility. We model how crowding influences their walking speeds, and how it affects travel utility both at stations and on-board. To illustrate the framework, we present a real case study of a major Dutch rail corridor, for which we collect a rich set of passenger, pedestrian and train operation data. We observe a good agreement of model estimates with empirical observations, and discuss the use of the model for various transit-related problems including level-of-service assessment, crowding estimation, transit optimization, and integrated investment appraisal.

Contains fulltext : 225261.pdf (Publisher’s version ) (Closed access) Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer syndrome that is characterised by a high prevalence of diffuse gastric cancer and lobular breast cancer. It is largely caused by inactivating germline mutations in the tumour suppressor gene CDH1, although pathogenic variants in CTNNA1 occur in a minority of families with HDGC. In this Policy Review, we present updated clinical practice guidelines for HDGC from the International Gastric Cancer Linkage Consortium (IGCLC), which recognise the emerging evidence of variability in gastric cancer risk between families with HDGC, the growing capability of endoscopic and histological surveillance in HDGC, and increased experience of managing long-term sequelae of total gastrectomy in young patients. To redress the balance between the accessibility, cost, and acceptance of genetic testing and the increased identification of pathogenic variant carriers, the HDGC genetic testing criteria have been relaxed, mainly through less restrictive age limits. Prophylactic total gastrectomy remains the recommended option for gastric cancer risk management in pathogenic CDH1 variant carriers. However, there is increasing confidence from the IGCLC that endoscopic surveillance in expert centres can be safely offered to patients who wish to postpone surgery, or to those whose risk of developing gastric cancer is not well defined.

ObjectiveTo assess the clinical course of multifocal motor neuropathy (MMN) in a large cohort of patients and to identify predictive factors of a progressive disease course.MethodsBetween May 2015 and February 2016, we collected clinical data from 100 patients with MMN, of whom 60 had participated in a nationwide cross-sectional cohort study in 2007. We documented clinical characteristics using standardized questionnaires and performed a standardized neurologic examination. We used multiple linear regression analysis to identify factors that correlated with worse outcome.ResultsWe found that age at diagnosis (45.2 vs 48.6 years, p < 0.02) was significantly increased between 2007 and 2015–2016, whereas diagnostic delay decreased by 15 months. Seven out of 10 outcome measures deteriorated over time (all p < 0.01). Patients who had a lower Medical Research Council (MRC) sumscore and absence of 1 or more reflexes at the baseline visit showed a greater functional loss at follow-up (p = 0.007 and p = 0.016).ConclusionsOur study shows that MMN is a progressive disease. Although 87% of patients received maintenance treatment, muscle strength, reflexes, vibration sense, and the Self-Evaluation Scale score significantly deteriorated over time. Lower MRC sumscore and absence of reflexes predicted a more progressive disease course.Classification of evidenceThis study provides Class II evidence that lower MRC sumscore and the absence of reflexes predict a more progressive disease course in patients with MMN.

Due to the multi-level nature of public transport networks, disruption impacts may spill-over beyond the primary effects occurring at the disrupted network level. During a public transport disruption, it is therefore important to quantify and control the disruption impacts for the total public transport network, instead of delimiting the analysis of their impacts to the public transport network level where this particular disruption occurs. We propose a modelling framework to quantify disruption impact propagation from the train network to the urban tram or bus network. This framework combines an optimisation-based train rescheduling model and a simulation-based dynamic public transport assignment model in an iterative procedure. The iterative process allows devising train schedules that take into account their impact on passenger flow re-distribution and related delays. Our study results in a framework which can improve public transport contingency plans on a strategic and tactical level in response to short- to medium-lasting public transport disruptions, by incorporating how the passenger impact of a train network disruption propagates to the urban network level. Furthermore, this framework allows for a more complete quantification of disruption costs, including their spilled-over impacts, retrospectively. We illustrate the successful implementation of our framework to a multi-level case study network in the Netherlands. © 2021 Tongji University and Tongji University Press open access

While transferring between public transport services has a negative impact on the level-of-service, it is an inevitable feature of public transport networks. Transfer coordination can help reduce passenger transfer waiting times and improve service connectivity. In this paper, we systematically review the literature on transfer coordination design in public transport systems. First, four solution approaches for solving the transfer coordination design problem (TCDP) are identified and reviewed in detail, namely heuristic rule-based, analytical modelling, mathematical programming, and simulation. We then identify and review three extensions of the TCDP, i.e., considering first or last train transfer optimization, integrating vehicle scheduling, and incorporating passenger demand assignment. Finally, following the synthesis of the literature, some promising future research directions are outlined. This paper provides comprehensive insights on how to better design coordinated transfers to provide a seamless travel experience and improve the service connectivity of public transport networks.

We propose a method to evaluate public transport network vulnerability. We study the evolution of the passenger Volume Over Capacity (VOC) ratio throughout the network to measure the spatial and temporal extent of the impacts caused by an unplanned service segment disruption. The VOC ratio provides an indication of the on-board travel comfort, an important level-of-service indicator, as well as reflects the residual capacity for absorbing additional demand. Because of the dynamic nature of public transport systems, disturbances propagate through the network in both time and space. Our modelling approach is able to capture transit system dynamics and quantify the extent to which the network exhibits spillover effects. We apply the method to the case of the rapid public transport system of Stockholm Sweden We demonstrate how the changes in network saturation and the corresponding recovery time can be quantified.

Gastric cancer (GC) patients at high risk of developing peritoneal metastasis (PM) as a single site of metastasis after curative treatment may be candidates for adjuvant prophylactic strategies. Here we investigated risk factors for metachronous isolated PM in patients who were treated in the CRITICS trial (NCT00407186). Univariable and multivariable analyses on both metachronous isolated PM and ‘other events’, i.e., (concurrent) distant metastasis, locoregional recurrence or death, were performed using a competing risk model and summarized by cumulative incidences. Isolated PM occurred in 64 of the 606 (11%) included patients. Diffuse or mixed histological subtype, ypT4 tumor stage and LNhigh (ypN3 lymph node stage or a lymph node ratio &gt, 20%) were independent risk factors for isolated PM in both univariable and multivariable analyses. Likewise, LNhigh was an independent risk factor for ‘other events’. Patients with tumors who were positive for all three independent risk factors had the highest two-year cumulative incidence of 43% for isolated PM development. In conclusion, diffuse or mixed histological subtype, ypT4 and LNhigh were identified as independent risk factors for isolated PM in patients treated with preoperative chemotherapy followed by surgical resection. The combination of these factors may identify a subgroup that may benefit from PM-preventing treatment strategies.

Objective To gain insight in the expression profile of long non-coding RNAs (lncRNAs) in OA subchondral bone. Methods RNA sequencing data of macroscopically preserved and lesioned OA subchondral bone of patients that underwent joint replacement surgery due to OA (N = 22 pairs; 5 hips, 17 knees, Research osteoArthrits Articular Tissue (RAAK study) was run through an in-house pipeline to detect expression of lncRNAs. Differential expression analysis between preserved and lesioned bone was performed. Spearman correlations were calculated between differentially expressed lncRNAs and differentially expressed mRNAs identified previously in the same samples. Primary osteogenic cells were transfected with locked nucleic acid (LNA) GapmeRs targeting AC005165.1 lncRNA, to functionally investigate its potential mRNA targets. Results In total, 2816 lncRNAs were well-expressed in subchondral bone and we identified 233 lncRNAs exclusively expressed in knee and 307 lncRNAs exclusively in hip. Differential expression analysis, using all samples (N = 22 pairs; 5 hips, 17 knees), resulted in 21 differentially expressed lncRNAs [false discovery rate (FDR) < 0.05, fold change (FC) range 1.19–7.39], including long intergenic non-protein coding RNA (LINC) 1411 (LINC01411, FC = 7.39, FDR = 2.20 × 10−8), AC005165.1 (FC = 0.44, FDR = 2.37 × 10−6) and empty spiracles homeobox 2 opposite strand RNA (EMX2OS, FC = 0.41, FDR = 7.64 × 10−3). Among the differentially expressed lncRNAs, five were also differentially expressed in articular cartilage, including AC005165.1, showing similar direction of effect. Downregulation of AC005165.1 in primary osteogenic cells resulted in consistent downregulation of highly correlated frizzled related protein (FRZB). Conclusion The current study identified a novel lncRNA, AC005165.1, being dysregulated in OA articular cartilage and subchondral bone. Downregulation of AC005165.1 caused a decreased expression of OA risk gene FRZB, an important member of the wnt pathway, suggesting that AC005165.1 could be an attractive potential therapeutic target with effects in articular cartilage and subchondral bone.

Public transport networks constitute critical infrastructure in urban systems. Public transport networks are characterised by their hierarchical structure, yet methods to quantify their underlying hierarchy are lacking. We propose a metric for quantifying the hierarchy in public transport networks which incorporates topological as well as passenger flow information. Our proposed metric consists of three components which jointly define the relative hierarchical position of nodes across the network while the distribution of hierarchy defines the hierarchy of the network itself. We apply the metric to the case studies of Amsterdam and Rotterdam to demonstrate its usefulness in comparing different network states both within and across networks. Using this metric, we identify different patterns in network structures for network states and different spatial distributions of hierarchy between networks. Furthermore, by dividing the network into functional levels, we identify a multilayer hierarchical structure that describes the functionality of the network. The potential application of this metric relates to the assessment of network development scenarios, evaluating bottlenecks and analysing the network vulnerability. Furthermore, the metric is potentially suitable for assessing different network structures such as aviation or maritime networks.

Classifying public transport service attributes based on their influence on overall traveler satisfaction can assist stakeholders and practitioners in introducing cost-efficient measures. To date most studies employed methods that were based on the assumption that the impact of service attributes on traveler satisfaction is entirely linear and symmetric. This study examines whether service attributes have a non-linear and asymmetric influence on the overall travel experience by employing the Three-factor theory (basic, performance and exciting factors). The analysis is conducted for different traveler segments depending on their level of captivity, travel frequency by public transport and travel mode used, and is based on a relatively large sample size collected for Stockholm County. Moreover, the estimated models control for important socio-demographic and travel characteristics that have been insofar overlooked. Results are presented in the form of a series of multi-level cubes that represent different essentiality of traveler needs which provide a useful methodological framework to further design quality service improvements that can be applied to various geographical contexts. Our findings highlight that a “one size fits all” approach is not adequate for identifying the needs of distinct traveler segments and of travelers using different travel modes. Furthermore, two-thirds of the attributes are consistently classified into the same factor category which entails important policy implications. This research deepens and expands the very limited knowledge of the application of the three-factor theory in the transport field.

Service reliability has an important impact on the satisfaction stated by public transport users with the service they receive. The main source of unreliability is found in headway variance, which also affects waiting times and distributes passengers unevenly across vehicles. However, it is still unclear how headway irregularity, with its impact in waiting, crowdedness and reliability, affect travellers’ service satisfaction. Different stated preference studies have identified non-linear impacts produced by overcrowding. However, none of these studies is directly related to users’ satisfaction evaluation. In this study, we investigate the existence of this non-linearity in users’ satisfaction caused by both the crowding level and the number of denied boardings through a post-service satisfaction survey of bus and metro users. An Ordered Logit Model was estimated, accounting for sample heteroscedasticity and preference heterogeneity. Overall, there is a significant and negative perception of the bus mode, keeping all other attributes equal. For users under 35 years old, comfort experienced almost always plays an important role in service satisfaction, while for those over 35 years old women are significantly more sensitive to this attribute. Most important, crowding has a negative and non-linear impact on how passengers evaluate their travel satisfaction. Using a Likert-type scale, this curve is convex. This relationship between crowding and satisfaction might bias service planning and delivery if performance indicators associated to service are not properly weighted by the number of passengers served. Improving level of service indicators in this direction might provide public transport agencies a clearer and more accurate perception of the actual users’ experience.

Summary Background VEGF and VEGF receptor 2 (VEGFR-2)-mediated signalling and angiogenesis can contribute to the pathogenesis and progression of gastric cancer. We aimed to assess whether the addition of ramucirumab, a VEGFR-2 antagonist monoclonal antibody, to first-line chemotherapy improves outcomes in patients with metastatic gastric or gastro-oesophageal junction adenocarcinoma. Methods For this double-blind, randomised, placebo-controlled, phase 3 trial done at 126 centres in 20 countries, we recruited patients aged 18 years or older with metastatic, HER2-negative gastric or gastro-oesophageal junction adenocarcinoma, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate organ function. Eligible patients were randomly assigned (1:1) with an interactive web response system to receive cisplatin (80 mg/m2, on the first day) plus capecitabine (1000 mg/m2, twice daily for 14 days), every 21 days, and either ramucirumab (8 mg/kg) or placebo on days 1 and 8, every 21 days. 5-Fluorouracil (800 mg/m2 intravenous infusion on days 1–5) was permitted in patients unable to take capecitabine. The primary endpoint was investigator-assessed progression-free survival, analysed by intention to treat in the first 508 patients. We did a sensitivity analysis of the primary endpoint, including a central review of CT scans. Overall survival was a key secondary endpoint. This study is registered with ClinicalTrials.gov, number NCT02314117. Findings Between Jan 28, 2015, and Sept 16, 2016, 645 patients were randomly assigned to receive ramucirumab plus fluoropyrimidine and cisplatin (n=326) or placebo plus fluoropyrimidine and cisplatin (n=319). Investigator-assessed progression-free survival was significantly longer in the ramucirumab group than the placebo group (hazard ratio [HR] 0·753, 95% CI 0·607–0·935, p=0·0106; median progression-free survival 5·7 months [5·5–6·5] vs 5·4 months [4·5–5·7]). A sensitivity analysis based on central independent review of the radiological images did not corroborate the investigator-assessed difference in progression-free survival (HR 0·961, 95% CI 0·768–1·203, p=0·74). There was no difference in overall survival between groups (0·962, 0·801–1·156, p=0·6757; median overall survival 11·2 months [9·9–11·9] in the ramucirumab group vs 10·7 months [9·5–11·9] in the placebo group). The most common grade 3–4 adverse events were neutropenia (85 [26%] of 323 patients in the ramucirumab group vs 85 [27%] of 315 in the placebo group), anaemia (39 [12%] vs 44 [14%]), and hypertension (32 [10%] vs 5 [2%]). The incidence of any-grade serious adverse events was 160 (50%) of 323 patients in the ramucirumab group and 149 (47%) of 315 patients in the placebo group. The most common serious adverse events were vomiting (14 [4%] in the ramucirumab group vs 21 [7%] in the placebo group) and diarrhoea (11 [3%] vs 19 [6%]). There were seven deaths in each group, either during study treatment or within 30 days of discontinuing study treatment, which were the result of treatment-related adverse events. In the ramucirumab group, these adverse events were acute kidney injury, cardiac arrest, gastric haemorrhage, peritonitis, pneumothorax, septic shock, and sudden death (n=1 of each). In the placebo group, these adverse events were cerebrovascular accident (n=1), multiple organ dysfunction syndrome (n=2), pulmonary embolism (n=2), sepsis (n=1), and small intestine perforation (n=1). Interpretation Although the primary analysis for progression-free survival was statistically significant, this outcome was not confirmed in a sensitivity analysis of progression-free survival by central independent review, and did not improve overall survival. Therefore, the addition of ramucirumab to cisplatin plus fluoropyrimidine chemotherapy is not recommended as first-line treatment for this patient population. Funding Eli Lilly and Company.

Active modes (i.e. walking and cycling) have received significant attention by governments worldwide, due to the benefits related to the use of these modes. Consequently, governments are aiming for a modal shift from motorised to active modes. Attitudes are generally considered to play an important role in travel behaviour. Understanding the relationship between the attitude towards modes and the daily mobility pattern, can support policies that aim at increasing the active mode share. This paper investigates the daily mobility patterns of individuals using a latent class cluster analysis. The relationship between these classes and attitudes towards modes is investigated. Data of the Netherlands Mobility Panel (MPN) of the year 2016 is used, in combination with a companion survey focussing on active modes. This study identifies five classes of mobility patterns: (1) car and bicycle users, (2) exclusive car users, (3) car, walk, and bicycle users, (4) public transport + users, and (5) exclusive bicycle users. Eight factors of attitudes towards modes are identified: five mode related attitudes, two public transport related attitudes, and one related to the prestige of using modes. The results show that the majority of the users exhibits a multimodal daily mobility pattern. Generally, individuals are more positive toward used modes, compared to unused modes. Furthermore, a high level of travel mode consonance is found. When this is not the case (dissonance), often active modes or sustainable modes are preferred. Consequently, when the goal is achieving a higher active mode share, some individuals need to be targeted to change their mobility portfolio (exclusive car users and car and bicycle users), whereas others should be encouraged to increase the use of active modes at the cost of car use (public transport + users and car, walk, and bicycle users).

Carriers of the genetic DPYD*2A variant, resulting in dihydropyrimidine dehydrogenase deficiency, are at significantly increased risk of developing severe fluoropyrimidine-associated toxicity. Upfront DPYD*2A genotype-based dose reductions improve patient safety, but uncertainty exists whether this has a negative impact on treatment effectiveness. Therefore, our study investigated effectiveness and safety of DPYD*2A genotype-guided dosing. A cohort of 40 prospectively identified heterozygous DPYD*2A carriers, treated with a ~50% reduced fluoropyrimidine dose, was identified. For effectiveness analysis, a matched pair-analysis was performed in which for each DPYD*2A carrier a matched DPYD*2A wild-type patient was identified. Overall survival and progression-free survival were compared between the matched groups. The frequency of severe (grade ≥ 3) treatment-related toxicity was compared to 1] a cohort of 1606 wild-type patients treated with full dose and 2] a cohort of historical controls derived from literature, i.e. 86 DPYD*2A variant carriers who received a full fluoropyrimidine dose. For 37 out of 40 DPYD*2A carriers, a matched control could be identified. Compared to matched controls, reduced doses did not negatively affect overall survival (median 27 months versus 24 months, p = 0.47) nor progression-free survival (median 14 months versus 10 months, p = 0.54). Risk of severe fluoropyrimidine-related toxicity in DPYD*2A carriers treated with reduced dose was 18%, comparable to wild-type patients (23%, p = 0.57) and significantly lower than the risk of 77% in DPYD*2A carriers treated with full dose (p < 0.001). Our study is the first to show that DPYD*2A genotype-guided dosing appears to have no negative effect on effectiveness of fluoropyrimidine-based chemotherapy, while resulting in significantly improved patient safety.

Minimizing passenger transfer times through public transport (PT) transfer synchronization is important during tactical planning and real-time control. However, there are computational challenges for solving this Timetable Synchronization Problem (TSP) for large, real-world urban PT networks. Hence, in this study we propose a data-driven, passenger-oriented methodology as a preparatory selection stage to reduce problem dimensionality by (1) determining the significant transfer hubs in the network, and (2) identifying subsets of lines within these hubs that need to be prioritized for transfer synchronization. In the first phase of our methodology we determine the spatial boundaries of transfer locations, using a clustering technique based on the passenger transfer flow matrix inferred from smartcard data. After that, a subset of hubs to be prioritized for synchronization is selected. In the second phase, we characterize the transfer patterns within the hubs based on a topological representation. Based on these topological graphs, the line bundles that need to be prioritized within the hubs are further identified using a modularity-based community detection technique. We apply our methodology to a real-world case study, i.e. the PT network of The Hague, the Netherlands. For this case study, our approach allows for prioritizing 70% of all transfers within identified transfer locations while only requiring 0.9% of these transfer locations, thus reducing the complexity of solving the TSP substantially at a relatively low cost. Our method supports public transport operators during timetable design and real-time control in determining where and which lines to prioritize when devising measures for improving transfer experience and synchronization.

Background Hodgkin lymphoma (HL) survivors treated with abdominal radiotherapy and/or alkylating chemotherapy have an increased risk of colorectal cancer (CRC). This study was aimed at evaluating the prevalence of colorectal neoplasia in HL survivors. Methods This multicenter cohort study assessed the diagnostic yield of advanced colorectal neoplasia detected by a first surveillance colonoscopy among HL survivors treated with abdominal radiotherapy and/or procarbazine. Advanced colorectal neoplasia included advanced adenomas (high‐grade dysplasia, ≥25% villous component, or ≥10‐mm diameter), advanced serrated lesions (dysplasia or ≥10‐mm diameter), and CRC. The results were compared with those for a Dutch general population cohort that underwent a primary screening colonoscopy (1426 asymptomatic individuals 50‐75 years old). This study demonstrated the results of a predefined interim analysis. Results A colonoscopy was performed in 101 HL survivors, who were significantly younger (median, 51 years; interquartile range [IQR], 45‐57 years) than the general population controls (median, 60 years; IQR, 55‐65 years; P, Hodgkin lymphoma survivors treated with abdominal radiotherapy and/or procarbazine have a high prevalence of advanced colorectal neoplasia. The implementation of a colonoscopy surveillance program should be considered.

Objective: We examined the association between surgical hospital volume and both overall survival (OS) and disease-free survival (DFS) using data obtained from the international CRITICS (ChemoRadiotherapy after Induction chemotherapy In Cancer of the Stomach) trial. Summary Background Data: In the CRITICS trial, patients with resectable gastric cancer were randomized to receive preoperative chemotherapy followed by adequate gastrectomy and either chemotherapy or chemoradiotherapy. Methods: Patients in the CRITICS trial who underwent a gastrectomy with curative intent in a Dutch hospital were included in the analysis. The annual number of gastric cancer surgeries performed at the participating hospitals was obtained from the Netherlands Cancer Registry; the hospitals were then classified as low-volume (1 – 20 surgeries/year) or high-volume (≥21 surger-surgeries/year) and matched with the CRITICS trial data. Univariate and multivariate analyses were then performed to evaluate the hazard ratio (HR) between hospital volume and both OS and DFS. Results: From 2007 through 2015, 788 patients were included in the CRITICS trial. Among these 788 patients, 494 were eligible for our study; the median follow-up was 5.0 years. Five-year OS was 59.2% and 46.1% in the high-volume and low-volume hospitals, respectively. Multivariate analysis revealed that undergoing surgery in a high-volume hospital was associated with higher OS [HR ¼ 0.69, 95% confidence interval (CI) ¼ 0.50 – 0.94, P ¼ 0.020] and DFS (HR ¼ 0.73, 95% CI: 0.54 – 0.99, P ¼ 0.040). Conclusions: In the CRITICS trial, hospitals with a high annual volume of gastric cancer surgery were associated with higher overall and DFS. These findings emphasize the value of centralizing gastric cancer surgeries in the Western world.

Introduction Polyneuropathy with immunoglobulin M monoclonal gammopathy (IgM-PNP) is associated with the presence of IgM antibodies against nerve constituents such as myelin associated glycoprotein (MAG) and gangliosides. Methods To test whether B-cell-stimulating cytokines are increased in IgM-PNP, we measured serum concentrations of 11 cytokines in 81 patients with IgM-PNP and 113 controls. Results Median interleukin (IL)-6 concentrations were higher in patients with IgM-PNP, and median IL-10 concentrations were higher in the subgroup with anti-MAG IgM antibodies. These serum concentrations were not increased in 110 patients with multifocal motor neuropathy. Discussion Median IL-6 and IL-10 serum concentrations differ between patients with anti-MAG neuropathy and other patients with IgM-PNP compared with healthy and neuropathy controls. These differences may indicate differences in immune-mediated disease mechanisms. Muscle Nerve 59:694-698, 2019.

Urban mobility needs alternative sustainable travel modes to keep our pandemic cities in motion. Ride-pooling, where a single vehicle is shared by more than one traveller, is not only appealing for mobility platforms and their travellers, but also for promoting the sustainability of urban mobility systems. Yet, the potential of ride-pooling rides to serve as a safe and effective alternative given the personal and public health risks considerations associated with the COVID-19 pandemic is hitherto unknown. To answer this, we combine epidemiological and behavioural shareability models to examine spreading among ride-pooling travellers, with an application for Amsterdam. Findings are at first sight devastating, with only few initially infected travellers needed to spread the virus to hundreds of ride-pooling users. Without intervention, ride-pooling system may substantially contribute to virus spreading. Notwithstanding, we identify an effective control measure allowing to halt the spreading before the outbreaks (at 50 instead of 800 infections) without sacrificing the efficiency achieved by pooling. Fixed matches among co-travellers disconnect the otherwise dense contact network, encapsulating the virus in small communities and preventing the outbreaks.

Background: The Intergroup 0116 and the MAGIC trials changed clinical practice for resectable gastric cancer in the Western world. In these trials, overall survival improved with post-operative chemoradiotherapy (CRT) and perioperative chemotherapy (CT). Intention-to-treat analysis in the CRITICS trial of post-operative CT or post-operative CRT did not show a survival difference. The current study reports on the per-protocol (PP) analysis of the CRITICS trial. Patients and methods: The CRITICS trial was a randomized, controlled trial in which 788 patients with stage Ib–Iva resectable gastric or esophagogastric adenocarcinoma were included. Before start of preoperative CT, patients from the Netherlands, Sweden and Denmark were randomly assigned to receive post-operative CT or CRT. For the current analysis, only patients who started their allocated post-operative treatment were included. Since it is uncertain that the two treatment arms are balanced in such PP analysis, adjusted proportional hazards regression analysis and inverse probability weighted analysis were used to minimize the risk of selection bias and to estimate and compare overall and event-free survival. Results: Of the 788 patients, 478 started post-operative treatment according to protocol, 233 (59%) patients in the CT group and 245 (62%) patients in the CRT group. Patient and tumor characteristics between the groups before start of the post-operative treatment were not different. After a median follow-up of 6.7 years since the start of post-operative treatment, the 5-year overall survival was 57.9% (95% confidence interval: 51.4% to 64.3%) in the CT group versus 45.5% (95% confidence interval: 39.2% to 51.8%) in the CRT group (adjusted hazard ratio CRT versus CT: 1.62 (1.24-2.12), P = 0.0004). Inverse probability weighted analysis resulted in similar hazard ratios. Conclusion: After adjustment for all known confounding factors, the PP analysis of patients who started the allocated post-operative treatment in the CRITICS trial showed that the CT group had a significantly better 5-year overall survival than the CRT group (NCT00407186).

We assessed the feasibility of adjuvant S-1 and oxaliplatin following neoadjuvant chemoradiotherapy (nCRT) and esophagectomy. Patients treated with nCRT (paclitaxel, carboplatin) and esophagectomy received six 21-day cycles with oxaliplatin (130 mg/m2) on day 1 and S-1 (25 mg/m2 twice daily) on days 1–14. The primary endpoint was feasibility, defined as ≥50% completing treatment. We performed exploratory propensity-score matching to compare survival, ERCC1 and Thymidylate Synthase (TS) immunohistochemistry analyses, proteomics biomarker discovery and 5-FU pharmacokinetic analyses. Forty patients were enrolled and 48% completed all adjuvant cycles. Median dose intensity was 98% for S-1 and 62% for oxaliplatin. The main reason for early discontinuation was toxicity (67%). The median recurrence-free and overall survival were 28.3 months and 40.8 months, respectively (median follow-up 29.1 months). Survival was not significantly prolonged compared to a matched cohort (p = 0.09). Patients with ERCC1 negative tumor expression had significantly better survival compared to ERCC1 positivity (p = 0.01). Our protein signature model was predictive of survival [p = 0.04, Area under the curve (AUC) 0.80]. Moreover, 5-FU pharmacokinetics significantly correlated with treatment-related toxicity. To conclude, six cycles adjuvant S-1 and oxaliplatin were not feasible in pretreated esophageal adenocarcinoma. Although the question remains whether additional treatment with chemotherapy should be provided in the adjuvant setting, subgroups such as patients with ERCC1 negativity could potentially benefit from adjuvant SOX based on our exploratory biomarker research.

Identification of molecular predictive markers of response to neoadjuvant chemoradiation could aid clinical decision‐making in patients with localized oesophageal cancer. Therefore, we subjected pretreatment biopsies of 75 adenocarcinoma (OAC) and 16 squamous cell carcinoma (OSCC) patients to targeted next‐generation DNA sequencing, as well as biopsies of 85 OAC and 20 OSCC patients to promoter methylation analysis of eight GI‐specific genes, and subsequently searched for associations with histopathological response and disease‐free (DFS) and overall survival (OS). Thereby, we found that in OAC, CSMD1 deletion (8%) and ETV4 amplification (5%) were associated with a favourable histopathological response, whereas SMURF1 amplification (5%) and SMARCA4 mutation (7%) were associated with an unfavourable histopathological response. KRAS (15%) and GATA4 (7%) amplification were associated with shorter OS. In OSCC, TP63 amplification (25%) and TFPI2 (10%) gene promoter methylation were associated with an unfavourable histopathological response and shorter DFS (TP63) and OS (TFPI2), whereas CDKN2A deletion (38%) was associated with prolonged OS. In conclusion, this study identified candidate genetic biomarkers associated with response to neoadjuvant chemoradiotherapy in patients with localized oesophageal cancer., Using DNA sequencing and methylation panels on pretreatment biopsies, we identified candidate molecular alterations associated with response [tumour regression grade (TRG) or survival] to neoadjuvant chemoradiotherapy in localized oesophageal adenocarcinoma (OAC) and squamous cell carcinoma (OSCC). These findings may assist approaches to further individualize oesophageal cancer treatment.

Delays in transport networks has adverse implications for infrastructure and service managers as well as travellers. While it is widely acknowledged that delays occurring across the transport networks may be related, there are is lack of knowledge on the underlying properties of these relations and means for quantifying them. To this end, we develop a network-wide data-driven delay analysis method. First, we construct a Bayesian network to represent the relations between delays associated with different transport network elements and assess the reliability of critical infrastructure elements. Second, we propose a series of original metrics denominated informativity indicators for quantifying the spatial extent of the delays observed based on the Bayesian network obtained. The proposed approach is applied to the Washington DC metro network. Time-dependent passenger waiting and transferring delays inferred over more than a year from smartcard data are utilized as input to the Bayesian network. Our findings indicate that passenger delays at few selected stations are directly informative of delays occurring at many other stations. We also examine the relation between the proposed informativity metrics and the topological properties of metro stations, concluding that the latter have a limited value in approximating network-wide delay correlations.

The maturing of autonomous driving technology in recent years has led to several pilot projects and the initial integration of autonomous pods and buses into the public transport (PT) system. An emerging field of interest is the design of public transport networks operating autonomous buses and the potential to attract higher levels of travel demand. In this work a multi-objective optimization and multi-agent simulation framework is developed to study potential changes in the network design and frequency settings compared to conventional PT systems when autonomous vehicles (AV) systems are deployed on fixed-route networks. During the optimization process multiple deployment scenarios (network configurations and service frequency) are evaluated and optimized considering the operator cost, user cost and infrastructure preparation costs of the system. User-focused network design and operator-focused network design are studied for a real-world urban area in Sweden. The results provide insights into the network design and level of service implications brought about by the deployment of autonomous bus (AB) when those are integrated in route-based PT systems. We show that the deployment of autonomous buses result with a network design that increases service ridership. In the context of our case study this increase is likely to primarily substitute walking.

This paper develops a method for analysing the elasticity of travel demand to public transport fares. The methodology utilizes public transport smartcard data for collecting disaggregate full population data about passengers’ travel behaviour. The study extends previous work by deriving specific fare elasticities for distinct socioeconomic (e.g., car ownership and income) groups and public transport modes (metro, trains and buses), and by considering the directionality of the fare change. The case study involves a public transport fare policy introduced by the regional administration of Stockholm County in January 2017, where the zonal fare system for single-trip tickets was replaced by a flat-fare policy. The overall fare elasticity of travel funds is found to be −0.46. User sensitivity grows along with the journey distance. Metro users demonstrate the lowest sensitivity, followed by bus and commuter train riders. Low socioeconomic groups, in particular with respect to car ownership, tend to be less sensitive than the high-factor groups. In addition to the direct effect of changed fares, simplification and unification of the fare scheme appears to have substantially contributed to its attractiveness. The flat fare may allow the geographic disparity of public transport travel to be reduced and new users to be attracted from remote areas who are more prone to own cars.

Background High-risk human papillomavirus (hrHPV) types represent the aetiological agents in a major proportion of anal squamous cell carcinomas (ASCC). Several studies have suggested a prognostic relevance of HPV-related markers, particularly hrHPV DNA and p16INK4a (p16) protein expression, in patients with ASCC. However, broader evaluation of these prognostic marker candidates has been hampered by small cohort sizes and heterogeneous survival data among the individual studies. We conducted an individual patient data (IPD) meta-analysis to determine the prognostic value of hrHPV DNA and p16 in patients with ASCC while controlling for major clinical and tumour covariates. Patients and methods A systematic literature search was conducted to identify all published studies analysing p16 alone or in combination with hrHPV DNA and reporting survival data in patients with ASCC. Clinical and tumour-related IPD were requested from authors of potentially eligible studies. Survival analyses were performed with a proportional hazard Cox model stratified by study and adjusted for relevant covariates. The study-specific hazard ratios (HRs) for the exposures were pooled using a random-effects model. Kaplan-Meier curves from different studies were pooled per exposure group and weighted by the study's total sample size. Results Seven studies providing IPD from 693 patients with ASCC could be included in the meta-analysis. Seventy-six percent of patients were p16+/hrHPV DNA+, whereas 11% were negative for both markers. A discordant marker status was observed in 13% of cases. Patients with p16+/hrHPV DNA+ ASCC showed significantly superior overall survival (OS) compared with patients with p16-/hrHPV DNA- tumours (pooled adjusted HR = 0.26 [95% confidence interval {CI}, 0.14–0.50]) with pooled three-year OS rates of 86% (95% CI, 82–90%) versus 39% (95% CI, 24–54%). Patients with discordant p16 and hrHPV DNA status showed intermediate three-year OS rates (75% [95% CI, 56–86%] for p16+/hrHPV DNA- and 55% [95% CI, 35–71%] for p16-/hrHPV DNA+ ASCC). Conclusion This first IPD meta-analysis controlling for confounding variables shows that patients with p16+/hrHPV DNA+ ASCC have a significantly better survival than patients with p16-/hrHPV DNA- tumours.

The development of public transport networks in polycentric regions involves making complex trade-offs between extending network coverage, densifying local connections, offering improved connections between urban centers and increasing capacity on existing links. Moreover, different modalities might be suitable for each of these development decisions depending on their speed, capacity and cost function structure. The objective of this study is to identify the influence of polycentric configurations and their respective travel demand distributions on the emerging topology of the corresponding multi-modal public transport network using an iterative growth model. Since polycentricity comes in many forms, our experimental design considers four polycentric configurations inspired by the cases of London, Tokyo, the Flemish Diamond and the Rhine-Ruhr area. The results are analysed in terms of both the properties of the obtained network structure as well as the evolutionary path and the sensitivity of both to key model settings and design variables. We find that more uneven population distributions result with the construction of fewer links and consequently the less connected and shorter the network becomes. The network evolutionary path is marked by distinctive intra- and inter- agglomeration expansion, densification and bulking phases. While the costs associated with each investment are the same regardless of the moment at which the investment is made, the benefits are not. This path dependency means that the evolutionary path is characterized by the need to attain a critical mass to justify further developments.

Bus bunching is a well-known problem in public transport networks. It is characterized by a self-amplifying relationship between uneven distribution of rising passenger loads and deteriorating service regularity. The focus of this study is to analyse whether this negative feedback loop can be addressed by providing real-time crowding information (RTCI) on next vehicle departures at stops. We integrate a departure choice model based on stated-preference analysis of passengers’ willingness to wait with RTCI. A proof-of-concept application to a toy-network model shows that this prevents further progression of bunching effects in certain demand conditions. The RTCI usage reveals substantial benefits - in terms of relative reductions in on-board (over)crowding, headway deviations, as well as mitigated denial-of-boarding risk - in moderately saturated network. These gains may diminish though as high overcrowding eventually emerges in PT network. Nevertheless, our findings indicate that RTCI has the potential to improve travel experience and service utilisation efficiency, even without resorting to supply-side control strategies.

In this literature review, we systematically review studies on public transit control with a specific focus on at-stop measures. In our synthesis of the relevant literature, we consider three perspectives: (1) the mathematical models of the proposed methodologies; (2) their complexity; (3) their applicability in real-time operations and their advantages and disadvantages considering their practical implications. The reviewed control methods include holding, dynamic dispatching, and stop-skipping. Control methods, that have attracted more attention in recent years due to the advancements in automation and data availability, aim at alleviating the negative effects of service variability because of external disruptions. Following the synthesis of the literature, we propose a research agenda pertaining to the combination of control measures, passenger-oriented decision making, coordinated network control, deployment of electric buses and disturbance management.

Although waiting times are inherently uncertain in public transport networks, previous research has primarily studied route choice behaviour under risk. Since understanding such behaviour is important to correctly model network flows and gain better understanding of traveller satisfaction, we propose a method to assess travellers’ route choice behaviour under natural ambiguity. Specifically, we devise a realistic route choice situation whereby travellers’ attitudes and perceptions towards waiting time uncertainty as well as the effects of situational contexts thereon can be quantified in terms of a certainty equivalent. The choice situation is contextualised in a stated preferences experiment to analyse the premium travellers in the Dutch railways are willing to pay for certainty in waiting time. Results indicate a significantly improved model fit and predictive value when accounting for waiting time uncertainty with travellers, on average, willing to trade-off more than 7 minutes of in-vehicle time to have certainty in their waiting time. Minor non-linear effects of elapsed waiting time and anticipated delays on the value of certainty are also found and heterogeneity analysis indicates that younger travellers tend to seek more certainty. The proposed method provides snapshots of travellers’ behaviour under uncertainties in a real-world public transport system and can as such be used to improve transportation models, provide more tailored travel advice, and be used to test the efficacy of different policies.

Holding has been extensively used as control strategy to regulate public transport operations, especially to maintain even headways and prevent buses of the same line to bunch up. Applying holding to multiple lines requires however to deal with the transition between corridor and branching segments. In this study, we introduce a holding criterion for network configurations with lines that operate jointly along a common corridor and then diverge to individual branches serving different urban areas. The proposed holding decision rule accounts for all different passenger groups in the overlapping segment and considers the transition to individual line operation. The holding rule is evaluated using simulation for different demand levels and compositions and is compared with state-of-the-art control schemes for a real-world network. Results show that the proposed multi-line control yields performance improvements along the shared transit corridor as well as at the line level. The performance of the control scheme is affected by the demand composition and we provide indications regarding the conditions under which multi-line control is advisable.

The COVID-19 pandemic crisis has greatly impacted public transport ridership and service provision across the world. As many countries start to navigate their return to normality, new public transport planning requirements are devised. These measures imply a major reduction in service capacity compared to the pre-COVID-19 era. At the time of writing, there is a severe lack of knowledge regarding the potential impact of the pandemic on public transport operations and models that can support the service planning given these new challenges. In this literature review, we systematically review and synthesise the literature on the impacts of COVID on public transport to identify the need to adjust planning measures, and, on the other hand, the existing methods for public transport planning at the strategic, tactical and operational level. We identify intervention measures that can support public transport service providers in planning their services in the post-shutdown phase and their respective modelling development requirements. This can support the transition from the initial ad-hoc planning practices to a more evidence-based decision making.

Liquid biopsies are providing new opportunities for detection of residual disease in cell-free DNA (cfDNA) after surgery but may be confounded through identification of alterations arising from clonal hematopoiesis. Here, we identify circulating tumor-derived DNA (ctDNA) alterations through ultrasensitive targeted sequencing analyses of matched cfDNA and white blood cells from the same patient. We apply this approach to analyze samples from patients in the CRITICS trial, a phase III randomized controlled study of perioperative treatment in patients with operable gastric cancer. After filtering alterations from matched white blood cells, the presence of ctDNA predicts recurrence when analyzed within nine weeks after preoperative treatment and after surgery in patients eligible for multimodal treatment. These analyses provide a facile method for distinguishing ctDNA from other cfDNA alterations and highlight the utility of ctDNA as a predictive biomarker of patient outcome to perioperative cancer therapy and surgical resection in patients with gastric cancer., Identifying patients that will respond to a particular therapy remains a key challenge in precision oncology. Here, in gastric cancer, the authors show that circulating tumour DNA can predict recurrence, provided that the signal from white blood cells is filtered out.

Fluoropyrimidines are widely used in the treatment of several types of solid tumors. Although most often well tolerated, severe toxicity is encountered in similar to 20-30% of the patients. Individualized dosing for these patients can reduce the incidence of severe fluoropyrimidine-related toxicity. However, no consensus has been achieved on which dosing strategy is preferred. The most established strategy for individualized dosing of fluoropyrimidines is upfront genotyping of the DPYD gene. Prospective research has shown that DPYD-guided dose-individualization significantly reduces the incidence of severe toxicity and can be easily applied in routine daily practice. Furthermore, the measurement of the dihydropyrimidine dehydrogenase (DPD) enzyme activity has shown to accurately detect patients with a DPD deficiency. Yet, because this assay is time-consuming and expensive, it is not widely implemented in routine clinical care. Other methods include the measurement of pretreatment endogenous serum uracil concentrations, the uracil/dihydrouracil-ratio, and the 5-fluorouracil (5-FU) degradation rate. These methods have shown mixed results. Next to these methods to detect DPD deficiency, pharmacokinetically guided follow-up of 5-FU could potentially be used as an addition to dosing strategies to further improve the safety of fluoropyrimidines. Furthermore, baseline characteristics, such as sex, age, body composition, and renal function have shown to have a relationship with the development of severe toxicity. Therefore, these baseline characteristics should be considered as a dose-individualization strategy. We present an overview of the current dose-individualization strategies and provide perspectives for a future multiparametric approach.

Background: The blood metabolome incorporates cues from the environment and the host’s genetic background, potentially offering a holistic view of an individual’s health status. Methods: We have compiled a vast resource of proton nuclear magnetic resonance metabolomics and phenotypic data encompassing over 25 000 samples derived from 26 community and hospital-based cohorts. Results: Using this resource, we constructed a metabolomics-based age predictor (metaboAge) to calculate an individual’s biological age. Exploration in independent cohorts demonstrates that being judged older by one’s metabolome, as compared with one’s chronological age, confers an increased risk on future cardiovascular disease, mortality, and functionality in older individuals. A web-based tool for calculating metaboAge ( metaboage.researchlumc.nl ) allows easy incorporation in other epidemiological studies. Access to data can be requested at bbmri.nl/samples-images-data . Conclusions: In summary, we present a vast resource of metabolomics data and illustrate its merit by constructing a metabolomics-based score for biological age that captures aspects of current and future cardiometabolic health.

Hierarchy is regarded as a natural phenomenon of public transport networks (PTN). The imbalanced distribution of passenger flow result in a hierarchical structure of PTN and it is also related to the development of technology and the introduction of new modes. However, there is still a lack of knowledge on how to identify the hierarchical structure of the multi-layer PTN. This study proposes a three-step passenger transfer flow based methodology for separating and ranking the PTN: (1) using passenger journey data to derive transfer flow matrix; (2) applying network representation with Louvain method of community detection to separate the PTN layers; (3) performing ranking method, separating inner-transfer and inter-transfer flow. To demonstrate our method, we use one-month smart card data of The Hague, the Netherlands provided by the PTN operator HTM. Our results show that our method is able to, regardless of the geographic location and the mode of transportation, identify the hierarchy of PTN based on the passenger transfer flow pattern. Temporal attributes are also discussed to illustrate how hierarchy is time-dependent, e.g. with respect to the day of the week and the time of the day. Our method supports public transport (PT) operators during design and optimization of PTN and in determining which sets of higher-level service to prioritize during different time periods.

Background The occurrence of a venous thromboembolism (VTE) is common in patients with cancer. Gastric cancer has been associated with one of the highest risks for VTE. Chemotherapy, especially cisplatin has been associated with a high VTE risk. In this study, risk factors for VTE occurrence and their potential impact on subsequent therapeutic interventions were investigated in patients who underwent preoperative chemotherapy, in the CRITICS gastric cancer trial. Patients and methods Patients with resectable gastric cancer were preoperatively treated with three cycles of 3‐weekly epirubicin, cisplatin or oxaliplatin, and capecitabine (ECC/EOC). VTE was defined as any thrombus in the venous system, excluding superficial and/or device related VTEs. Potential risk factors were analyzed in a multivariable regression model with age, gender, Body Mass Index (BMI), tumor localization, Lauren classification, type of chemotherapy (ECC/EOC), (cardiovascular) comorbidity, and previous VTE as independent risk factors. The impact of VTE on completion rate of preoperative chemotherapy, surgical resection rate, postoperative complications, and start of postoperative therapy were investigated. Results Of 781 patients, 78 (10%) of 781 patients developed a VTE during preoperative chemotherapy. On multivariable analysis, BMI ≥ 30 kg/m2 and previous VTE were associated with VTE occurrence (reference BMI, High BMI and previous VTE were independent risk factors for VTE occurrence during preoperative chemotherapy in patients with resectable gastric cancer. Comparable proportions of patients proceeded to surgery and started postoperative therapy, suggesting that VTE occurrence during preoperative treatment did not affect receipt of further treatment.

In the past year, EUV lithography scanner systems have entered High-Volume Manufacturing for state-of-the-art Integrated Circuits (IC), with critical dimensions down to 10 nm. This technology uses 13.5 nm EUV radiation, which is shaped and transmitted through a near-vacuum H2 background gas. This gas is excited into a low-density H2 plasma by the energetic EUV and DUV radiation from the Laser-Produced Plasma (LPP) in the EUV Source. In the vicinity of the walls and mirrors within the scanner system, this creates an environment rather similar to that near the surfaces of objects in space, especially when considered in combination with trace species such as N2, O2, H2O and hydrocarbons. This paper will discuss how insights on electrostatics and charging from astrophysics have been used to build understanding of particulate and molecular contamination, and how these were translated into prevention and control schemes to achieve near-zero contamination levels on critical imaging surfaces, compatible with the stringent manufacturing requirements for 10 nm lithography.

Public transport is one of the most disrupted sectors of the COVID-19 pandemic with reported ridership drops up to 90% in majorly affected countries. As many government authorities strive to partially resume activities, public transport operators are in an urgent need for models that can evaluate the impact of different social distancing policies on operational and passenger-related costs. In this study, we introduce a mixed-integer quadratic programming model for the redesign of public transport services considering the operational, passenger, and revenue loss-related costs by evaluating the effects of different social distancing policies. Our model is applied at the metro network of Washington DC and provides optimal redistribution of vehicles across lines for different social distancing scenarios. This model can be used as a decision support tool by other policymakers and public transport operators that are in need of evaluating the costs related to the implementation of different social distancing policies.