The impact of pace of life on pedestrian heat stress: A computational modelling approach.

Elevated walking speed is an indicator of increased pace of life in cities, caused by environmental pressures inherent to urban environments, which lead to short- and long-term consequences for health and well-being. In this paper we investigate the effect of walking speed on heat stress. We define the heat-stress-optimal walking speed and estimate its values for a wide range of air temperatures with the use of computational modelling of metabolic heat production and thermal regulation. The heat-stress-optimal walking speed shows three distinct phases in relation to air temperature, determined by different modes of interaction between the environment and physiology. Simulation results suggest that different temperature regimes require walking speed adaptation to preserve heat balance. Empirical data collected for Singapore reveals elevated average walking speed, which is not responsive to slight changes in microclimate (4-5 °C). The proposed computational model predicts the amount of additional heat produced by an individual due to the high pace of life. We conclude that there are direct implications of the high pace of life in cities on the immediate heat stress of people, and we show how a lower walking speed significantly reduces self-overheating and improves thermal comfort.

The present and future burden of previously treated advanced non-small cell lung cancer (NSCLC) by histology and line of therapy in France, Germany, Italy, and Spain: model-based predictions.

BACKGROUND: The burden of advanced non-small cell lung cancer (NSCLC) is not well understood, and the number of patients likely to receive treatment in Europe has not been quantified. The aim of this study was to forecast the annual number of patients with squamous and non-squamous advanced NSCLC likely to receive second and third lines of therapy (LOT) from 2016 to 2020 in France, Germany, Italy, and Spain. METHODS: A patient count model (PCM) was developed in Microsoft Excel to estimate the number of patients with refractory advanced NSCLC eligible to receive systemic treatment. Using historical population-based cancer registry data, segmented linear regression ("Joinpoint") was used to forecast age- and sex-stratified lung cancer incidence rates in each country through 2020. Yearly incident case count totals by country were apportioned according to NSCLC histology and stage at diagnosis. Country-specific treatment rates came from a recent medical chart review study, and early- to advanced-stage disease progression rates were estimated over a 10-year interval. A probabilistic sensitivity analysis (PSA) was performed to estimate variability in the patient counts. RESULTS: The combined number of squamous and non-squamous advanced NSCLC patients estimated to receive second and third LOT, respectively, in 2016 were France = 11,600 and 3500; Germany = 15,100 and 4900; Italy = 13,500 and 2500; Spain = 9400 and 2100. The forecasted numbers of patients receiving second and third LOT, respectively, in 2020 were France = 13,900 and 4200; Germany = 16,200 and 5200; Italy = 15,100 and 2600; Spain = 11,000 and 2500. CONCLUSIONS: Driven by growth in the incidence of NSCLC among women, the model forecasts an overall increase in the number of patients with advanced-stage squamous and non-squamous NSCLC likely to receive systemic treatment in the year 2020. The results highlight the significant burden of refractory advanced NSCLC and the need for more robust surveillance data to accurately quantify the burden of disease.

The influence of memory on indoor environment exploration: A numerical study.

Understanding human behavior in the context of exploration and navigation is an important but challenging problem. Such understanding can help in the design of safe structures and spaces that implicitly aid humans during evacuation or other emergency situations. In particular, the role that memory plays in this process is something that is crucial to understand. In this paper, we develop a novel serious game-based experimental approach to understanding the non-randomness and the impact of memory on the human exploration process. We show that a simple memory model, with a depth of between 6 and 8 steps, is sufficient to approximate a 'human-like' level of exploration efficiency. We also demonstrate the advantages that a game-based experimental methodology brings to these kinds of experiments in the amount of data that can be collected as compared to traditional experiments. We feel that these findings have important implications for 'safety-by-design' in complex infrastructural structures.

microRNA-101 is a potent inhibitor of autophagy.

Autophagy is an evolutionarily conserved mechanism of cellular self-digestion in which proteins and organelles are degraded through delivery to lysosomes. Defects in this process are implicated in numerous human diseases including cancer. To further elucidate regulatory mechanisms of autophagy, we performed a functional screen in search of microRNAs (miRNAs), which regulate the autophagic flux in breast cancer cells. In this study, we identified the tumour suppressive miRNA, miR-101, as a potent inhibitor of basal, etoposide- and rapamycin-induced autophagy. Through transcriptome profiling, we identified three novel miR-101 targets, STMN1, RAB5A and ATG4D. siRNA-mediated depletion of these genes phenocopied the effect of miR-101 overexpression, demonstrating their importance in autophagy regulation. Importantly, overexpression of STMN1 could partially rescue cells from miR-101-mediated inhibition of autophagy, indicating a functional importance for this target. Finally, we show that miR-101-mediated inhibition of autophagy can sensitize breast cancer cells to 4-hydroxytamoxifen (4-OHT)-mediated cell death. Collectively, these data establish a novel link between two highly important and rapidly growing research fields and present a new role for miR-101 as a key regulator of autophagy.

Quantifying the burden of informal caregiving for patients with cancer in Europe.

PURPOSE: Informal caregivers for patients with cancer provide critical emotional and instrumental support, but this role can cause substantial burden. This study expands our understanding of cancer-related caregiving burden in Europe. METHODS: Caregivers (n = 1,713) for patients with cancer and non-caregivers (n = 103,868) were identified through the 2010 and 2011 European Union National Health and Wellness Survey, administered via the Internet to adult populations in France, Germany, Italy, Spain, and the United Kingdom. Respondents completed measures of sociodemographics and health behaviors, health-related quality of life (using SF-12v2), work productivity and activity impairment (using WPAI), healthcare resource use (emergency room visits, hospitalizations, and traditional provider visits), and reported diagnosis of stress-related comorbidities (depression, anxiety, insomnia, headache, migraine, and gastrointestinal problems). Two-sided tests of means or proportions compared caregivers against non-caregivers. Multivariable regression models, comparing caregivers for patients with any cancer vs. non-caregivers on all health outcomes, adjusted for covariates (age, sex, college, income, marital status, employment, body mass index, alcohol, smoking, and Charlson comorbidity index). RESULTS: Caregivers for patients with cancer vs. non-caregivers reported significant (P < 0.05) impairment across all health outcomes, even after adjusting for several confounds (e.g., 3.26-point lower mental health status, 0.043-point lower health utilities, 1.46 times as much work impairment, and 1.97 times the odds of anxiety). CONCLUSIONS: Caregivers for patients with cancer experienced significant impairments. These findings reinforce the need for enhancing our understanding of the caregiving experience and developing supportive and personalized multicomponent interventions for caregivers, given their pivotal role in providing support for patients.

Cloning and tissue distribution of novel splice variants of the ovine ghrelin gene.

BACKGROUND: The ghrelin axis is involved in the regulation of metabolism, energy balance, and the immune, cardiovascular and reproductive systems. The manipulation of this axis has potential for improving economically valuable traits in production animals, and polymorphisms in the ghrelin (GHRL) and ghrelin receptor (GHSR) genes have been associated with growth and carcass traits. Here we investigate the structure and expression of the ghrelin gene (GHRL) in sheep, Ovis aries. RESULTS: We identify two ghrelin mRNA isoforms, which we have designated Δex2 preproghrelin and Δex2,3 preproghrelin. Expression of Δex2,3 preproghrelin is likely to be restricted to ruminants, and would encode truncated ghrelin and a novel C-terminal peptide. Both Δex2 preproghrelin and canonical preproghrelin mRNA isoforms were expressed in a range of tissues. Expression of the Δex2,3 preproghrelin isoform, however, was restricted to white blood cells (WBC; where the wild-type preproghrelin isoform is not co-expressed), and gastrointestinal tissues. Expression of Δex2 preproghrelin and Δex2,3 preproghrelin mRNA was elevated in white blood cells in response to parasitic worm (helminth) infection in genetically susceptible sheep, but not in resistant sheep. CONCLUSIONS: The restricted expression of the novel preproghrelin variants and their distinct WBC expression pattern during parasite infection may indicate a novel link between the ghrelin axis and metabolic and immune function in ruminants.

The role of the P2X7 receptor in infectious diseases.

ATP is an extracellular signal for the immune system, particularly during an inflammatory response. It is sensed by the P2X7 receptor, the expression of which is upregulated by pro-inflammatory cytokines. Activation of the P2X7 receptor opens a cation-specific channel that alters the ionic environment of the cell, activating several pathways, including (i) the inflammasome, leading to production of IL-1ß and IL-18; (ii) the stress-activated protein kinase pathway, resulting in apoptosis; (iii) the mitogen-activated protein kinase pathway, leading to generation of reactive oxygen and nitrogen intermediates; and (iv) phospholipase D, stimulating phagosome-lysosome fusion. The P2X7 receptor can initiate host mechanisms to remove pathogens, most particularly those that parasitise macrophages. At the same time, the P2X7 receptor may be subverted by pathogens to modulate host responses. Moreover, recent genetic studies have demonstrated significant associations between susceptibility or resistance to parasites and bacteria, and loss-of-function or gain-of-function polymorphisms in the P2X7 receptor, underscoring its importance in infectious disease.

A genetic screen identifies BRCA2 and PALB2 as key regulators of G2 checkpoint maintenance.

To identify key connections between DNA-damage repair and checkpoint pathways, we performed RNA interference screens for regulators of the ionizing radiation-induced G2 checkpoint, and we identified the breast cancer gene BRCA2. The checkpoint was also abrogated following depletion of PALB2, an interaction partner of BRCA2. BRCA2 and PALB2 depletion led to premature checkpoint abrogation and earlier activation of the AURORA A-PLK1 checkpoint-recovery pathway. These results indicate that the breast cancer tumour suppressors and homologous recombination repair proteins BRCA2 and PALB2 are main regulators of G2 checkpoint maintenance following DNA-damage.

P2X7 receptor-mediated killing of an intracellular parasite, Toxoplasma gondii, by human and murine macrophages.

The P2X7R is highly expressed on the macrophage cell surface, and activation of infected cells by extracellular ATP has been shown to kill intracellular bacteria and parasites. Furthermore, single nucleotide polymorphisms that decrease receptor function reduce the ability of human macrophages to kill Mycobacterium tuberculosis and are associated with extrapulmonary tuberculosis. In this study, we show that macrophages from people with the 1513C (rs3751143, NM_002562.4:c.1487A>C) loss-of-function P2X7R single nucleotide polymorphism are less effective in killing intracellular Toxoplasma gondii after exposure to ATP compared with macrophages from people with the 1513A wild-type allele. Supporting a P2X7R-specific effect on T. gondii, macrophages from P2X7R knockout mice (P2X7R-/-) are unable to kill T. gondii as effectively as macrophages from wild-type mice. We show that P2X7R-mediated T. gondii killing occurs in parallel with host cell apoptosis and is independent of NO production.

Behavioural thermal regulation explains pedestrian path choices in hot urban environments.

Due to phenomena such as urban heat islands, outdoor thermal comfort of the cities' residents emerges as a growing concern. A major challenge for mega-cities in changing climate is the design of urban spaces that ensure and promote pedestrian thermal comfort. Understanding pedestrian behavioural adaptation to urban thermal environments is critically important to attain this goal. Current research in pedestrian behaviour lacks controlled experimentation, which limits the quantitative modelling of such complex behaviour. Combining well-controlled experiments with human participants and computational methods inspired by behavioural ecology and decision theory, we examine the effect of sun exposure on route choice in a tropical city. We find that the distance walked in the shade is discounted by a factor of 0.86 compared to the distance walked in the sun, and that shadows cast by buildings have a stronger effect than trees. The discounting effect is mathematically formalised and thus allows quantification of the behaviour that can be used in understanding pedestrian behaviour in changing urban climates. The results highlight the importance of assessment of climate through human responses to it and point the way forward to explore scenarios to mitigate pedestrian heat stress.

Modelling the dynamic relationship between spread of infection and observed crowd movement patterns at large scale events.

Understanding how contact patterns arise from crowd movement is crucial for assessing the spread of infection at mass gathering events. Here we study contact patterns from Wi-Fi mobility data of large sports and entertainment events in the Johan Cruijff ArenA stadium in Amsterdam. We show that crowd movement behaviour at mass gathering events is not homogeneous in time, but naturally consists of alternating periods of movement and rest. As a result, contact duration distributions are heavy-tailed, an observation which is not explained by models assuming that pedestrian contacts are analogous to collisions in the kinetic gas model. We investigate the effect of heavy-tailed contact duration patterns on the spread of infection using various random walk models. We show how different types of intermittent movement behaviour interact with a time-dependent infection probability. Our results point to the existence of a crossover point where increased contact duration presents a higher level of transmission risk than increasing the number of contacts. In addition, we show that different types of intermittent movement behaviour give rise to different mass-action kinetics, but also show that neither one of two mass-action mechanisms uniquely describes events.

Correction: A Screen Identifies the Oncogenic Micro-RNA miR-378a-5p as a Negative Regulator of Oncogene-Induced Senescence.

[This corrects the article DOI: 10.1371/journal.pone.0091034.].

Maximum expected survival rate model for public access defibrillator placement.

AIM: Mathematical optimization of automated external defibrillator (AED) placement has demonstrated potential to improve survival of out-of-hospital cardiac arrest (OHCA). Existing models mostly aim to improve accessibility based on coverage radius and do not account for detailed impact of delayed defibrillation on survival. We aimed to predict OHCA survival based on time to defibrillation and developed an AED placement model to directly maximize the expected survival rate. METHODS: We stratified OHCAs occurring in Singapore (2010-2017) based on time to defibrillation and developed a regression model to predict the Utstein survival rate. We then developed a novel AED placement model, the maximum expected survival rate (MESR) model. We compared the performance of MESR with a maximum coverage model developed for Canada that was shown to be generalizable to other settings (Denmark). The survival gain of MESR was assessed through 10-fold cross-validation for placement of 20 to 1000 new AEDs in Singapore. Statistical analysis was performed using χ2 and McNemar's tests. RESULTS: During the study period, 15,345 OHCAs occurred. The power-law approximation with R2 of 91.33% performed best among investigated models. It predicted a survival of 54.9% with defibrillation within the first two minutes after collapse that was reduced by more than 60% without defibrillation within the first 4 minutes. MESR outperformed the maximum coverage model with P-value < 0.05 (<0.0001 in 22 of 30 experiments). CONCLUSION: We developed a novel AED placement model based on the impact of time to defibrillation on OHCA outcomes. Mathematical optimization can improve OHCA survival.

A review of mathematical modeling of addiction regarding both (neuro-) psychological processes and the social contagion perspectives.

Addiction is a complex biopsychosocial phenomenon, impacted by biological predispositions, psychological processes, and the social environment. Using mathematical and computational models that allow for surrogative reasoning may be a promising avenue for gaining a deeper understanding of this complex behavior. This paper reviews and classifies a selection of formal models of addiction focusing on the intra- and inter-individual dynamics, i.e., (neuro) psychological models and social models. We find that these modeling approaches to addiction are too disjoint and argue that in order to unravel the complexities of biopsychosocial processes of addiction, models should integrate intra- and inter-individual factors.

The non-linear impact of data handling on network diffusion models.

Many computational models rely on real-world data, and the steps required in moving from data collection, to data preparation, to model calibration, and input are becoming increasingly complex. Errors in data can lead to errors in model output that might invalidate conclusions in extreme cases. While the challenge of errors in data collection have been analyzed in the literature, here we highlight the importance of data handling in the modeling and simulation process, and how particular data handling errors can lead to errors in model output. We develop a framework for assessing the impact of potential data errors for models of spreading processes on networks, a broad class of models that capture many important real-world phenomena (e.g., epidemics, rumor spread, etc.). We focus on the susceptible-infected-removed (SIR) and Threshold models and examine how systematic errors in data handling impact the predicted spread of a virus (or information). Our results demonstrate that data handling errors can have significant impact on model conclusions especially in critical regions of a system.

Impact of schizophrenia and schizophrenia treatment-related adverse events on quality of life: direct utility elicitation.

OBJECTIVE: To examine the impact of schizophrenia, its treatment and treatment-related adverse events related to antipsychotics, on quality of life from the perspective of schizophrenia patients and laypersons. METHODS: Health state descriptions for stable schizophrenia, extra pyramidal symptoms (EPS), hyperprolactinemia, diabetes, weight gain and relapse were developed based on a review of the literature and expert opinion. The quality of life impact of each health state was elicited using a time trade-off instrument administered by interview to 49 stable schizophrenia patients and 75 laypersons. Regression techniques were employed to examine the importance of subject characteristics on health-related utility scores. RESULTS: Patients and laypersons completed the interview in similar times. Stable schizophrenia had the highest mean utility (0.87 and 0.92 for laypersons and patients respectively), while relapse (0.48 and 0.60) had the lowest mean utility. Of the treatment-related adverse events, EPS had the lowest mean utility (0.57 and 0.72, respectively). Age, gender and PANSS score did not influence the utility results independently of health state. On average, patient utilities are 0.077 points higher than utilities derived from laypersons, although the ranking was similar between the two groups. CONCLUSION: Events associated with schizophrenia and treatment of schizophrenia can bring about a significant detriment in patient quality of life, with relapse having the largest negative impact. Results indicate that patients with stable schizophrenia are less willing to trade years of life to avoid schizophrenia-related symptoms compared to laypersons. Both sets of respondents showed equal ability to complete the questionnaire.