A Patient-Driven Mobile Health Innovation in Cystic Fibrosis Care: Comparative Cross-Case Study.

BACKGROUND: Patient-driven innovation in health care is an emerging phenomenon with benefits for patients with chronic conditions, such as cystic fibrosis (CF). However, previous research has not examined what may facilitate or hinder the implementation of such innovations from the provider perspective. OBJECTIVE: The aim of this study was to explain variations in the adoption of a patient-driven innovation among CF clinics. METHODS: A comparative multiple-case study was conducted on the adoption of a patient-controlled app to support self-management and collaboration with health care professionals (HCPs). Data collection and analysis were guided by the nonadoption, abandonment, spread, scale-up, and sustainability and complexity assessment tool (NASSS-CAT) framework. Data included user activity levels of patients and qualitative interviews with staff at 9 clinics (n=8, 88.9%, in Sweden; n=1, 11.1%, in the United States). We calculated the maximum and mean percentage of active users at each clinic and performed statistical process control (SPC) analysis to explore how the user activity level changed over time. Qualitative data were subjected to content analysis and complexity analysis and used to generate process maps. All data were then triangulated in a cross-case analysis. RESULTS: We found no evidence of nonadoption or clear abandonment of the app. Distinct patterns of innovation adoption were discernable based on the maximum end-user activity for each clinic, which we labeled as low (16%-23%), middle (25%-47%), or high (58%-95%) adoption. SPC charts illustrated that the introduction of new app features and research-related activity had a positive influence on user activity levels. Variation in adoption was associated with providers' perceptions of care process complexity. A higher perceived complexity of the value proposition, adopter system, and organization was associated with lower adoption. In clinics that adopted the innovation early or those that relied on champions, user activity tended to plateau or decline, suggesting a negative impact on sustainability. CONCLUSIONS: For patient-driven innovations to be adopted and sustained in health care, understanding patient-provider interdependency and providers' perspectives on what generates value is essential.

Bioinformatic Analysis of Topoisomerase IIα Reveals Interdomain Interdependencies and Critical C-Terminal Domain Residues.

DNA Topoisomerase IIα (Top2A) is a nuclear enzyme that is a cancer drug target, and there is interest in identifying novel sites on the enzyme to inhibit cancer cells more selectively and to reduce off-target toxicity. The C-terminal domain (CTD) is one potential target, but it is an intrinsically disordered domain, which prevents structural analysis. Therefore, we set out to analyze the sequence of Top2A from 105 species using bioinformatic analysis, including the PSICalc algorithm, Shannon entropy analysis, and other approaches. Our results demonstrate that large (10th-order) interdependent clusters are found including non-proximal positions across the major domains of Top2A. Further, CTD-specific clusters of the third, fourth, and fifth order, including positions that had been previously analyzed via mutation and biochemical assays, were identified. Some of these clusters coincided with positions that, when mutated, either increased or decreased relaxation activity. Finally, sites of low Shannon entropy (i.e., low variation in amino acids at a given site) were identified and mapped as key positions in the CTD. Included in the low-entropy sites are phosphorylation sites and charged positions. Together, these results help to build a clearer picture of the critical positions in the CTD and provide potential sites/regions for further analysis.

Metrics to quantify the degree of co-location of urban water infrastructure.

Co-located infrastructure networks such as road, water, and sewer in theory offer the possibility for integrated multi-infrastructure interventions. However, how closely these networks are aligned in space and time determines the practical extent to which such coordinated interventions can be realized. This study quantifies the spatial alignment of the aforementioned infrastructure networks and demonstrates its application for integrated interventions and potential cost savings. It proposes two metrics, namely 1) shared surface area and, 2) shared trench volume, to quantify the spatial relationship (i.e., degree of co-location) of infrastructures. Furthermore, the study demonstrates how the degree of co-location can be used as a proxy for cost-saving potential of integrated interventions compared to silo-based, single-infrastructure, interventions. Through six case studies conducted in Norwegian municipalities, the research reveals that implementing integrated interventions across road, water, and sewer networks can result in potential average cost savings of 24% in urban areas and 11% in rural areas. Utility-specific savings under different cost-sharing scenarios were also analysed. To identify the yearly potential of integrated multi-infrastructure interventions, future work should add the temporal alignment of rehabilitation of infrastructures (i.e., time of intervention need for the infrastructures).

Is it possible to evaluate upper and lower cervical interdependency on supine magnetic resonance imaging?

Background and purpose:

There is a significant correlation between the upper and lower cervical alignments associated with a compensatory mechanism to maintain horizontal gaze. Evaluating this correlation before cervical fusion operations is essential, particularly in the upper cervical region, to prevent the occurrence of postoperative malalignment. This study was designed to investigate whether evaluating the interdependency between the upper and lower cervical alignments on neutral supine magnetic resonance imaging (MRI) or supine MRI with neck extension is possible. 

This study included 36 male and 30 female volunteers without symptoms aged between 16 and 60 years. Cervical radiographic images and supine cervical spinal MRI scans were obtained twice on the neutral supine position and on the supine position with pillows placed at 5 cm high under the shoulder. Cervical lordosis (CL) (C2–7 Cobb angle), C0–2 Cobb angle, C2–7 sagittal vertical axis (C2–7SVA), T1 slope (T1S), and T1 slope minus CL (T1S-CL (C2S)) were measured from the imaging sets from each patient, including X-ray images and two MRI scans, and the main values were obtained. The mean values of the measurements from the radiographic images were compared with those obtained from MRI scans using Student’s t-test. The agreement between the parameters (C0–2 Cobb angle, CL Cobb angle, and T1S-CL) obtained from the radiographic images and MRI scans was evaluated using Pearson correlation analysis.

Pearson correlation analysis revealed significant correlations between the C0–2 and C2–7 Cobb angles in standing X-ray and neutral MRI values (r = −0.425 and -0.397, respectively). In plain radiography and MR studies, the T1 slope was correlated with the C2–7 angle (r = 0.4824, 0.734, and 0.702, respectively). The C2 slope values were also significantly correlated with the C0–2 Cobb angle in standing X-ray and neutral MRI images (r = 0.5595 and 0.5719, respectively). There were significant correlations between the C2 slope and C2–7 Cobb angles in all modalities (r = −0.5645, −0.7917, and −0.8526).

Negative correlations between the upper and lower cervical alignments are also present in supine MRI studies, consequently in the supine position, with statistical significance. The C2 slope is an important cervical spine parameter that is significantly correlated with both the C0–2 and CL Cobb angles. The C2 slope can be used to evaluate the interdependency of the upper and lower cervical alignments.

Reciprocal allostery arising from a bienzyme assembly controls aromatic amino acid biosynthesis in Prevotella nigrescens.

Modular protein assembly has been widely reported as a mechanism for constructing allosteric machinery. Recently, a distinctive allosteric system has been identified in a bienzyme assembly comprising a 3-deoxy-d-arabino heptulosonate-7-phosphate synthase (DAH7PS) and chorismate mutase (CM). These enzymes catalyze the first and branch point reactions of aromatic amino acid biosynthesis in the bacterium Prevotella nigrescens (PniDAH7PS), respectively. The interactions between these two distinct catalytic domains support functional interreliance within this bifunctional enzyme. The binding of prephenate, the product of CM-catalyzed reaction, to the CM domain is associated with a striking rearrangement of overall protein conformation that alters the interdomain interactions and allosterically inhibits the DAH7PS activity. Here, we have further investigated the complex allosteric communication demonstrated by this bifunctional enzyme. We observed allosteric activation of CM activity in the presence of all DAH7PS substrates. Using small-angle X-ray scattering (SAXS) experiments, we show that changes in overall protein conformations and dynamics are associated with the presence of different DAH7PS substrates and the allosteric inhibitor prephenate. Furthermore, we have identified an extended interhelix loop located in CM domain, loopC320-F333, as a crucial segment for the interdomain structural and catalytic communications. Our results suggest that the dual-function enzyme PniDAH7PS contains a reciprocal allosteric system between the two enzymatic moieties as a result of this bidirectional interdomain communication. This arrangement allows for a complex feedback and feedforward system for control of pathway flux by connecting the initiation and branch point of aromatic amino acid biosynthesis.

Enhanced coverage by integrating site interdependencies in capacitated EMS location models.

In order to allocate limited resources in emergency medical services (EMS) networks, mathematical models are used to select sites and their capacities. Many existing standard models are based on simplifying assumptions, including site independency and a similar system-wide busyness of ambulances. In practice, when a site is busy, a call is forwarded to another site. Thus, the busyness of each site depends not only on the rate of calls in the surrounding area, but also on interactions with other facilities. If the demand varies across the urban area, assuming an average system-wide server busy fraction may lead to an overestimation of the actual coverage. We show that site interdependencies can be integrated into the well-known Maximum Expected Covering Location Problem (MEXCLP) by introducing an upper bound for the busyness of each site. We apply our new mathematical formulation to the case of a local EMS provider. To evaluate the solution quality, we use a discrete event simulation based on anonymized real-world call data. Results of our simulation-optimization approach indicate that the coverage can be improved in most cases by taking site interdependencies into account, leading to an improved ambulance allocation and a faster emergency care.

What COVID-19 tells us about the self: The deep intersubjective and cultural layers of our brain.

The COVID-19 crisis is affecting our sense of self and touches upon our existential fears. This extends to the self-other relationship, as there is both being infected and infecting the other. What does this pandemic crisis tell us about our self and relatedness, its cultural differences, and how these are rooted in the brain's relation to the world? First, we discuss the psychological and neuronal features of self and self-other relation and how they are rooted in a deeper layer of the brain's neural activity complementing its cognitive surface layer. Second, we demonstrate cultural differences of Eastern and Western concepts of the self (i.e., independency and interdependency) and how these reflect the manifestation of the brain's neuro-social and neuro-ecological alignment. Finally, we highlight the intersubjective and cultural nature of the self and its surface in the COVID-19 crisis. Discussing various lines of empirical data showing the brain's intimate alignment to both social and ecological environmental contexts, our results support the assumption of the brain's deep layer features by laying bare a continuum of different degrees of neuro-social and neuro-ecological alignment. This entails a two-stage model of self with neuro-social-ecological and psychological levels that extends the previously suggested basis model of self-specificity. We conclude that the current pandemic shows the importance of the deeper intersubjective and cultural layers of both the self and brain; their neglect can be life-threatening for the self and others and, paradoxically, might reduce, rather than enlarge, the self's sense of freedom and independence.

Genomic Tackling of Human Satellite DNA: Breaking Barriers through Time.

(Peri)centromeric repetitive sequences and, more specifically, satellite DNA (satDNA) sequences, constitute a major human genomic component. SatDNA sequences can vary on a large number of features, including nucleotide composition, complexity, and abundance. Several satDNA families have been identified and characterized in the human genome through time, albeit at different speeds. Human satDNA families present a high degree of sub-variability, leading to the definition of various subfamilies with different organization and clustered localization. Evolution of satDNA analysis has enabled the progressive characterization of satDNA features. Despite recent advances in the sequencing of centromeric arrays, comprehensive genomic studies to assess their variability are still required to provide accurate and proportional representation of satDNA (peri)centromeric/acrocentric short arm sequences. Approaches combining multiple techniques have been successfully applied and seem to be the path to follow for generating integrated knowledge in the promising field of human satDNA biology.

In or Out? New Insights on Exon Recognition through Splice-Site Interdependency.

Noncanonical splice-site mutations are an important cause of inherited diseases. Based on in vitro and stem-cell-based studies, some splice-site variants show a stronger splice defect than expected based on their predicted effects, suggesting that other sequence motifs influence the outcome. We investigated whether splice defects due to human-inherited-disease-associated variants in noncanonical splice-site sequences in ABCA4, DMD, and TMC1 could be rescued by strengthening the splice site on the other side of the exon. Noncanonical 5'- and 3'-splice-site variants were selected. Rescue variants were introduced based on an increase in predicted splice-site strength, and the effects of these variants were analyzed using in vitro splice assays in HEK293T cells. Exon skipping due to five variants in noncanonical splice sites of exons in ABCA4, DMD, and TMC1 could be partially or completely rescued by increasing the predicted strengths of the other splice site of the same exon. We named this mechanism "splicing interdependency", and it is likely based on exon recognition by splicing machinery. Awareness of this interdependency is of importance in the classification of noncanonical splice-site variants associated with disease and may open new opportunities for treatments.

Households, bubbles and hugging grandparents: Caring and lockdown rules during COVID-19.

Efforts to combat the COVID-19 crisis brought mountains of legislation and guidance to coerce or encourage people to stay at home and reduce the spread of the virus. During peak lockdown in the United Kingdom (UK) regulations defined when people could or could not leave their homes. Meanwhile guidance on social distancing advised people to stay within 'households'. This paper explores the legislation under lockdowns in the UK from March to October 2020 and the implications for women's gendered caring roles. The regulations and guidance assumed that households were separate units and ignored the interdependencies which exist between households and between individuals and wider society. The continuing focus in the lockdown regulations has been on households as autonomous, safe, adequate and secure. This overlooks the interdependency of human life, gendered aspects of caring and the inequalities of housing and living conditions, highlighted by feminist scholarship.

Mechanistic understanding of photorespiration paves the way to a new green revolution.

Photorespiration is frequently considered a wasteful and inefficient process. However, mutant analysis demonstrated that photorespiration is essential for recycling of 2-phosphoglycolate in C3 and C4 land plants, in algae, and even in cyanobacteria operating carboxysome-based carbon (C) concentrating mechanisms. Photorespiration links photosynthetic C assimilation with other metabolic processes, such as nitrogen and sulfur assimilation, as well as C1 metabolism, and it may contribute to balancing the redox poise between chloroplasts, peroxisomes, mitochondria and cytoplasm. The high degree of metabolic interdependencies and the pleiotropic phenotypes of photorespiratory mutants impedes the distinction between core and accessory functions. Newly developed synthetic bypasses of photorespiration, beyond holding potential for significant yield increases in C3 crops, will enable us to differentiate between essential and accessory functions of photorespiration.

CNNH_PSS: protein 8-class secondary structure prediction by convolutional neural network with highway.

BACKGROUND: Protein secondary structure is the three dimensional form of local segments of proteins and its prediction is an important problem in protein tertiary structure prediction. Developing computational approaches for protein secondary structure prediction is becoming increasingly urgent. RESULTS: We present a novel deep learning based model, referred to as CNNH_PSS, by using multi-scale CNN with highway. In CNNH_PSS, any two neighbor convolutional layers have a highway to deliver information from current layer to the output of the next one to keep local contexts. As lower layers extract local context while higher layers extract long-range interdependencies, the highways between neighbor layers allow CNNH_PSS to have ability to extract both local contexts and long-range interdependencies. We evaluate CNNH_PSS on two commonly used datasets: CB6133 and CB513. CNNH_PSS outperforms the multi-scale CNN without highway by at least 0.010 Q8 accuracy and also performs better than CNF, DeepCNF and SSpro8, which cannot extract long-range interdependencies, by at least 0.020 Q8 accuracy, demonstrating that both local contexts and long-range interdependencies are indeed useful for prediction. Furthermore, CNNH_PSS also performs better than GSM and DCRNN which need extra complex model to extract long-range interdependencies. It demonstrates that CNNH_PSS not only cost less computer resource, but also achieves better predicting performance. CONCLUSION: CNNH_PSS have ability to extracts both local contexts and long-range interdependencies by combing multi-scale CNN and highway network. The evaluations on common datasets and comparisons with state-of-the-art methods indicate that CNNH_PSS is an useful and efficient tool for protein secondary structure prediction.

The association between patient's and partner's fatigue in couples coping with colorectal cancer: a longitudinal study.

BACKGROUND: Couples coping with colorectal cancer were monitored during the first year after diagnosis to evaluate the following: (i) levels of patients' and partners' fatigue-hereby comparing their scores to each other and a normative population, (ii) association between patients' and partners' fatigue, (iii) the course of partners' fatigue, and (iv) biopsychosocial predictors of the partners' fatigue, including the patients' level of fatigue. METHOD: Couples (n = 171) preoperatively completed questions regarding age and sex as well as questionnaires assessing neuroticism and trait anxiety. Questionnaires assessing fatigue, anxiety, and depressive symptoms were measured preoperative (time-0) and 3 (time-1), 6 (time-2), and 12 months (time-3) postoperative. Patients' clinical characteristics were retrieved from the Eindhoven Cancer Registry. Descriptive statistics, correlations, and linear mixed effect models were used. RESULTS: Compared with a normative population, partners' fatigue was similar (p > .05), while patients' fatigue was higher at Time-2 and Time-3 (p values <.001). At each time point, correlations between patients' and partners' fatigue were small (r < .30). Partner's course of fatigue was as follows: 18.2 at time-0, 19.0 at time-1, 19.4 at time-2, and 19.2 at time-3 (p = 0.64). Scoring higher on neuroticism (ß = .12) and trait anxiety (ß = .23), and more depressive symptoms (ß = .30) significantly contributed to higher partners' fatigue. CONCLUSION: Trait anxiety, neuroticism, and depressive symptoms predicted higher levels of partners' fatigue, while demographic factors, patients' fatigue, and clinical factors did not. Health professionals are advised to be alert for partners with a vulnerable personality and depressive symptoms. If needed, they can for instance refer to a psychologist for treatment.

The role of organisational interdependencies and asset orchestration in business integration: A case study of M.com.

Business integration is an important determinant of business value and firm performance which enables a firm to respond to pressing competitive forces. Given its significant role, business integration in general has been an enduring research topic over the years. However, due to its complex nature, the ways to achieve this important organisational capability in firms are still not clearly understood. Hence, the present study is an attempt to 'open this black box' and examine the relevant issues through a case study of M.com, one of the largest e-commerce firms in China. The findings of this case study emphasise that the ability to coordinate organisational interdependencies and asset orchestration according to the needs of business processes is challenging but necessary in order to achieve business integration in e-commerce firms. It is found that asset orchestration in a firm is contingent on the organisational interdependencies such that different interdependence types demand different coordination methods at the very least. It also shows the significant role of IT in asset orchestration and the coordination of organisational interdependencies during business integration. With these capabilities, firms can experience growth and improve the quality of conformance to customer needs.

Sugar transporters spatially organize microbiota colonization along the longitudinal root axis of Arabidopsis.

Plant roots are functionally heterogeneous in cellular architecture, transcriptome profile, metabolic state, and microbial immunity. We hypothesized that axial differentiation may also impact spatial colonization by root microbiota along the root axis. We developed two growth systems, ArtSoil and CD-Rhizotron, to grow and then dissect Arabidopsis thaliana roots into three segments. We demonstrate that distinct endospheric and rhizosphere bacterial communities colonize the segments, supporting the hypothesis of microbiota differentiation along the axis. Root metabolite profiling of each segment reveals differential metabolite enrichment and specificity. Bioinformatic analyses and GUS histochemistry indicate microbe-induced accumulation of SWEET2, 4, and 12 sugar uniporters. Profiling of root segments from sweet mutants shows altered spatial metabolic profiles and reorganization of endospheric root microbiota. This work reveals the interdependency between root metabolites and microbial colonization and the contribution of SWEETs to spatial diversity and stability of microbial ecosystem.

Angiotensin-II type 2 receptor-mediated renoprotection is independent of receptor Mas in obese Zucker rats fed high-sodium diet.

The consumption of a high-sodium diet (HSD) is injurious and known to elevate blood pressure (BP), especially in obesity. Acute infusion studies depict a functional interdependency between angiotensin-II type 2 receptor (AT2R) and receptor Mas (MasR). Hence, we hypothesize that the subacute blockade of MasR should reverse AT2R-mediated renoprotection in obese Zucker rats (OZRs). Male OZRs were fed an HSD (for 14 days) and treated with the AT2R agonist C21 (100 ng/min) without or with a MasR antagonist A779 (1,000 ng/min). The indices of oxidative stress, proteinuria, kidney injury, and BP were measured before and after, along with the terminal measurements of an array of inflammatory and kidney injury markers. The HSD significantly decreased the estimated glomerular filtration rate and urinary osmolality and increased thirst, diuresis, natriuresis, kaliuresis, plasma creatinine, urinary excretion of H2O2, proteinuria, renal expression and urinary excretion of kidney injury markers (NGAL and KIM-1), and BP indexes. The HSD feeding showed early changes in the renal expression of CRP, ICAM-1, and galectin-1. The C21 treatment prevented these pathological changes. The MasR antagonist A779 attenuated C21-mediated effects on the urinary excretion and renal expression of NGAL and oxidative stress in the absence of inflammation and BP changes. Overall, we conclude that the subacute functional interactions between AT2R and MasR are weak or transient and that the beneficial effects of AT2R activation are independent of the MasR blockade in the kidney of male obese rats fed an HSD.

Left atrial diastasis strain slope is a marker of hemodynamic recovery in post-ST elevation myocardial infarction: the Laser Atherectomy for STemi, Pci Analysis with Scintigraphy Study (LAST-PASS).

Background: Left atrial (LA) mechanics are strongly linked with left ventricular (LV) filling. The LA diastasis strain slope (LADSS), which spans between the passive and active LA emptying phases, may be a key indicator of the LA-LV interplay during diastole. Aim: This study aimed to investigate the LA-LV interdependencies in post-ST elevation myocardial infarction (STEMI), with particular focus on the LADSS. Materials and methods: Patients with post-anterior STEMI who received primary percutaneous coronary intervention underwent contrast cardiac magnetic resonance imaging (MRI) during acute (5-9 days post-STEMI) and chronic (at 6 months) phases. The LADSS was categorized into three groups: Groups 1, 2, and 3 representing positive, flat, and negative slopes, respectively. Cross-sectional correlates of LADSS Group 2 or 3 compared to Group 1 were identified, adjusting for demographics, LA indices, and with or without LV indices. The associations of acute phase LADSS with the recovery of LV ejection fraction (LVEF) and scar amount were investigated. Results: Sixty-six acute phase (86.4% male, 63.1 ± 11.8 years) and 59 chronic phase cardiac MRI images were investigated. The distribution across LADSS Groups 1, 2, and 3 in the acute phase was 24.2%, 28.9%, and 47.0%, respectively, whereas in the chronic phase, it was 33.9%, 22.0%, and 44.1%, respectively. LADSS Group 3 demonstrated a higher heart rate than Group 1 in the acute phase (61.9 ± 8.7 vs. 73.5 ± 11.9 bpm, p < 0.01); lower LVEF (48.7 ± 8.6 vs. 41.8 ± 9.9%, p = 0.041) and weaker LA passive strain rate (SR) (-1.1 ± 0.4 vs. -0.7 [-1.2 to -0.6] s-1, p = 0.037) in the chronic phase. Chronic phase Group 3 exhibited weaker LA passive SR [relative risk ratio (RRR) = 8.8, p = 0.012] than Group 1 after adjusting for demographics and LA indices; lower LVEF (RRR = 0.85, p < 0.01), higher heart rate (RRR = 1.1, p = 0.070), and less likelihood of being male (RRR = 0.08, p = 0.058) after full adjustment. Acute phase LADSS Groups 2 and 3 predicted poor recovery of LVEF when adjusted for demographics and LA indices; LADSS Group 2 remained a predictor in the fully adjusted model (ß = -5.8, p = 0.013). Conclusion: The LADSS serves both as a marker of current LV hemodynamics and its recovery in post-anterior STEMI. The LADSS is an important index of LA-LV interdependency during diastole. Clinical Trial Registration: https://clinicaltrials.gov/, identifier NCT03950310.

A Conceptual Model for Professional Identity in Nursing: An Interdependent Perspective.

The purpose of this initiative was to define the development, verification, and evolution of the conceptual model for Professional Identity in Nursing. This action research design occurred over two phases, utilizing observations, a modified Norris process for model development, and focus groups. Analysis consisted of conventional content analysis and the Fawcett method for conceptual model analysis and evaluation. The model was modified, and results are presented based on the model's philosophical underpinnings, content, socialness, and evolution. The model resonates with nurses both in the United States and internationally. The interdependency shown in the model encourages collaboration, accountability, and sustainability within the profession and society.

Moving vision zero programs forward: What pedestrian-focused countermeasure combinations work best and where? A dynamic copula-based time-series approach.

Vision Zero stands out as one of the most promising systemic safety action plans. A crucial step to ensure the successful implementation of Vision Zero is to continuously assess the efficiency of the implemented treatments. Traditionally, this is achieved using before-and-after analyses or cross-sectional studies. However, the applicability of these approaches can be limited in assessing Vision Zero initiatives, which usually involve installing multiple treatments at a location, leading to a significant interdependency between treatments. This study proposes a dynamic R-vine copula-based time series model to evaluate the efficiency of treatments implemented as a part of Vision Zero. The proposed approach enables the accurate assessment of the treatments, understanding of their long-term impacts, and identifying the most effective combination of treatments at a location. The study also investigated the association between location characteristics and the performance of treatments. The proposed framework was applied to the City of Toronto at the macro-level (neighbourhood level) and focused on pedestrian-related treatments. Collision data and the implemented countermeasures were obtained from Toronto's Vision Zero Mapping Tool. The results show that the combination of speed limit reduction, leading pedestrian intervals (LPI), and community safety zones was the most frequent combination in terms of efficiency. Enforcement and speed limit reduction were the most effective combination in neighbourhoods with high school density, while LPI was effective in neighbourhoods with high densities of subway stations, and office density, especially when integrated with speed limit reduction and community zones. Driver feedback signs were effective in neighbourhoods with a high density of intersections, but only when combined with automated enforcement, community safety zones, and speed limit reduction. The results of the study would assist decision-makers in selecting the most effective treatment in a neighbourhood based on the neighbourhood characteristics and the countermeasures that are already installed.

Feed-forward loops between metastatic cancer cells and their microenvironment-the stage of escalation.

Breast cancer is the most frequent cancer among women, and metastases in distant organs are the leading cause of the cancer-related deaths. While survival of early-stage breast cancer patients has increased dramatically, the 5-year survival rate of metastatic patients has barely improved in the last 20 years. Metastases can arise up to decades after primary tumor resection, hinting at microenvironmental factors influencing the sudden outgrowth of disseminated tumor cells (DTCs). This review summarizes how the environment of the most common metastatic sites (lung, liver, bone, brain) is influenced by the primary tumor and by the varying dormancy of DTCs, with a special focus on how established metastases persist and grow in distant organs due to feed-forward loops (FFLs). We discuss in detail the importance of FFL of cancer cells with their microenvironment including the secretome, interaction with specialized tissue-specific cells, nutrients/metabolites, and that novel therapies should target not only the cancer cells but also the tumor microenvironment, which are thick as thieves.