Accessibility across transport modes and residential developments in Nairobi

A key goal of urban transportation planning is to provide people with access to a greater number of opportunities for interaction with people and places. Measures of accessibility are gaining attention globally for use in planning, yet few studies measure accessibility in cities in low-income countries, and even fewer incorporate semi-formal bus systems, also called paratransit. Drawing on rich datasets available for Nairobi, Kenya this analysis quantifies place-based accessibility for walking, paratransit, and driving using three different measures: a mobility measure quantifying how many other locations in Nairobi can be reached in 60 min, a contour measure quantifying the number of health facilities that can be reached in 60 min, and a gravity measure quantifying the number of health facilities weighted by a time-decay function. Health facilities are used because they are an essential service that people need physical access to and as a representation of the spatial distribution of activities more broadly. The findings show that place-based accessibility is highest for driving, then paratransit, then walking, and that there are high levels of access to health facilities near the Central Business District (CBD) for all modes. Additionally, paratransit accessibility is comparatively better in the contour and gravity measures, which may mean that paratransit is efficiently providing access based on the spatial distribution of services. The contour measure results are also compared across different residential levels, which are grouped based on neighborhood characteristics and ordered by income. Counterintuitively, the wealthiest areas have very low levels of place-based accessibility for all modes, while poor areas have comparatively better walking access to health facilities. Interestingly, the medium low residential level, characterized in part by tenement apartment buildings, has significantly higher accessibility than other residential types. One way to reduce inequality in access across income groups is to increase spatial accessibility for the modes used by low- and middle-income households, for example with policies that prioritize public transport and non-motorized travel, integrate paratransit with land use development, and provide safe, efficient, and affordable options

Inferring Mobility of Care Travel Behavior From Transit Origin-Destination Data

There are substantial differences in travel behavior by gender on public transit. Studies have concluded that these differences are largely attributable to household responsibilities typically falling disproportionately on women, leading to women being more likely to utilize transit for purposes referred to by the umbrella concept of "mobility of care". In contrast to past studies that have quantified the impact of gender using survey and qualitative data, we propose a novel data-driven workflow utilizing a combination of previously developed origin, destination, and transfer inference (ODX) based on individual transit fare card transactions, name-based gender inference, and geospatial analysis as a framework to identify mobility of care trip making. We apply this framework to data from the Washington Metropolitan Area Transit Authority (WMATA). Analyzing data from millions of journeys conducted in the first quarter of 2019, the results of this study show that our proposed workflow can identify mobility of care travel behavior, detecting times and places of interest where the share of women travelers in an equally-sampled subset (on basis of inferred gender) of transit users is 10% - 15% higher than that of men. The workflow presented in this study provides a blueprint for combining transit origin-destination data, inferred customer demographics, and geospatial analyses enabling public transit agencies to assess, at the fare card level, the gendered impacts of different policy and operational decisions.Comment: Updated reference formatting and discussion point

The evolution of lung cancer and impact of subclonal selection in TRACERx

Lung cancer is the leading cause of cancer-associated mortality worldwide. Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource

The evolution of non-small cell lung cancer metastases in TRACERx

Metastatic disease is responsible for the majority of cancer-related deaths. We report the longitudinal evolutionary analysis of 126 non-small cell lung cancer (NSCLC) tumours from 421 prospectively recruited patients in TRACERx who developed metastatic disease, compared with a control cohort of 144 non-metastatic tumours. In 25% of cases, metastases diverged early, before the last clonal sweep in the primary tumour, and early divergence was enriched for patients who were smokers at the time of initial diagnosis. Simulations suggested that early metastatic divergence more frequently occurred at smaller tumour diameters (less than 8 mm). Single-region primary tumour sampling resulted in 83% of late divergence cases being misclassified as early, highlighting the importance of extensive primary tumour sampling. Polyclonal dissemination, which was associated with extrathoracic disease recurrence, was found in 32% of cases. Primary lymph node disease contributed to metastatic relapse in less than 20% of cases, representing a hallmark of metastatic potential rather than a route to subsequent recurrences/disease progression. Metastasis-seeding subclones exhibited subclonal expansions within primary tumours, probably reflecting positive selection. Our findings highlight the importance of selection in metastatic clone evolution within untreated primary tumours, the distinction between monoclonal versus polyclonal seeding in dictating site of recurrence, the limitations of current radiological screening approaches for early diverging tumours and the need to develop strategies to target metastasis-seeding subclones before relapse

Genomic–transcriptomic evolution in lung cancer and metastasis

Intratumour heterogeneity (ITH) fuels lung cancer evolution, which leads to immune evasion and resistance to therapy. Here, using paired whole-exome and RNA sequencing data, we investigate intratumour transcriptomic diversity in 354 non-small cell lung cancer tumours from 347 out of the first 421 patients prospectively recruited into the TRACERx study. Analyses of 947 tumour regions, representing both primary and metastatic disease, alongside 96 tumour-adjacent normal tissue samples implicate the transcriptome as a major source of phenotypic variation. Gene expression levels and ITH relate to patterns of positive and negative selection during tumour evolution. We observe frequent copy number-independent allele-specific expression that is linked to epigenomic dysfunction. Allele-specific expression can also result in genomic–transcriptomic parallel evolution, which converges on cancer gene disruption. We extract signatures of RNA single-base substitutions and link their aetiology to the activity of the RNA-editing enzymes ADAR and APOBEC3A, thereby revealing otherwise undetected ongoing APOBEC activity in tumours. Characterizing the transcriptomes of primary–metastatic tumour pairs, we combine multiple machine-learning approaches that leverage genomic and transcriptomic variables to link metastasis-seeding potential to the evolutionary context of mutations and increased proliferation within primary tumour regions. These results highlight the interplay between the genome and transcriptome in influencing ITH, lung cancer evolution and metastasis

Antibodies against endogenous retroviruses promote lung cancer immunotherapy

B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS). Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive. Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma. We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response

Sharing riders: How bikesharing impacts bus ridership in New York City

The objective of this research is to quantify the impact that bikesharing systems have on bus ridership. We exploit a natural experiment of the phased implementation of a bikesharing system to different areas of New York City. This allows us to use a difference-in-differences identification strategy. We divide bus routes into control and treatment groups based on if they are located in areas that received bikesharing infrastructure or not. We find a significant decrease in bus ridership on treated routes compared to control routes that coincides with the implementation of the bikesharing system in New York City. The results from our preferred model indicate that every thousand bikesharing docks along a bus route is associated with a 2.42% fall in daily unlinked bus trips on routes in Manhattan and Brooklyn. A second model that also controls for the expansion of bike lanes during this time suggests that the decrease in bus ridership attributable to bikesharing infrastructure alone may be smaller (a 1.69% fall in daily unlinked bus trips). Although the magnitude of the reduction is a small proportion of total bus trips, these findings indicate that either a large proportion of overall bikeshare members are substituting bikesharing for bus trips or that bikesharing may have impacted the travel behavior of non-members, such as private bicyclists. Understanding how bikesharing and public transit systems are interrelated is vital for planning a mutually reinforcing sustainable transport network

Can Mobility of Care be Identified from Transit Fare Card Data? A Case Study in Washington D.C.

Studies in the literature have found significant differences in travel behavior by gender on public transit that are largely attributable to household and care responsibilities falling disproportionately on women. While the majority of studies have relied on survey and qualitative data to assess “mobility of care”, we propose a novel data-driven workflow utilizing transit fare card transactions, name-based gender inference, and geospatial analysis to identify mobility of care trip making. We find that the share of women travelers trip-chaining in the direct vicinity of mobility of care places of interest is 10% - 15% higher than men

Opposing chemokine gradients control human thymocyte migration in situ

The ordered migration of thymocytes from the cortex to the medulla is critical for the appropriate selection of the mature T cell repertoire. Most studies of thymocyte migration rely on mouse models, but we know relatively little about how human thymocytes find their appropriate anatomical niches within the thymus. Moreover, the signals that retain CD4(+)CD8(+) double-positive (DP) thymocytes in the cortex and prevent them from entering the medulla prior to positive selection have not been identified in mice or humans. Here, we examined the intrathymic migration of human thymocytes in both mouse and human thymic stroma and found that human thymocyte subsets localized appropriately to the cortex on mouse thymic stroma and that MHC-dependent interactions between human thymocytes and mouse stroma could maintain the activation and motility of DP cells. We also showed that CXCR4 was required to retain human DP thymocytes in the cortex, whereas CCR7 promoted migration of mature human thymocytes to the medulla. Thus, 2 opposing chemokine gradients control the migration of thymocytes from the cortex to the medulla. These findings point to significant interspecies conservation in thymocyte-stroma interactions and provide the first evidence that chemokines not only attract mature thymocytes to the medulla, but also play an active role in retaining DP thymocytes in the cortex prior to positive selection