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Cancers evade T-cell immunity by several mechanisms such as secretion of anti-inflammatory cytokines, down regulation of antigen presentation machinery, upregulation of immune checkpoint molecules, and exclusion of T cells from tumor tissues. The distribution and function of immune checkpoint molecules on tumor cells and tumor-infiltrating leukocytes is well established, but less is known about their impact on intratumoral endothelial cells. Here, we demonstrated that V-domain Ig suppressor of T-cell activation (VISTA), a PD-L1 homolog, was highly expressed on endothelial cells in synovial sarcoma, subsets of different carcinomas, and immune-privileged tissues. We created an ex vivo model of the human vasculature and demonstrated that expression of VISTA on endothelial cells selectively prevented T-cell transmigration over endothelial layers under physiologic flow conditions, whereas it does not affect migration of other immune cell types. Furthermore, endothelial VISTA correlated with reduced infiltration of T cells and poor prognosis in metastatic synovial sarcoma. In endothelial cells, we detected VISTA on the plasma membrane and in recycling endosomes, and its expression was upregulated by cancer cell-secreted factors in a VEGF-A-dependent manner. Our study reveals that endothelial VISTA is upregulated by cancer-secreted factors and that it regulates T-cell accessibility to cancer and healthy tissues. This newly identified mechanism should be considered when using immunotherapeutic approaches aimed at unleashing T cell-mediated cancer immunity., (©2023 American Association for Cancer Research.)

This paper presents a new coupled urban change and hazard consequence model that considers population growth, a changing built environment, natural hazard mitigation planning, and future acute hazards. Urban change is simulated as an agent-based land market with six agent types and six land use types. Agents compete for parcels with successful bids leading to changes in both urban land use-affecting where agents are located-and structural properties of buildings-affecting the building's ability to resist damage to natural hazards. IN-CORE, an open-source community resilience model, is used to compute damages to the built environment. The coupled model operates under constraints imposed by planning policies defined at the start of a simulation. The model is applied to Seaside, Oregon, a coastal community in the North American Pacific Northwest subject to seismic-tsunami hazards emanating from the Cascadia Subduction Zone. Ten planning scenarios are considered including caps on the number of vacation homes, relocating community assets, limiting new development, and mandatory seismic retrofits. By applying this coupled model to the testbed community, we show that: (a) placing a cap on the number of vacation homes results in more visitors in damaged buildings, (b) that mandatory seismic retrofits do not reduce the number of people in damaged buildings when considering population growth, (c) polices diverge beyond year 10 in the model, indicating that many policies take time to realize their implications, and (d) the most effective policies were those that incorporated elements of both urban planning and enforced building codes., (© 2022 The Authors.)

Physics-based fragilities for damage, loss, and resilience analysis are needed to model a community to earthquakes, hurricane winds, tornados, or floods. Currently, most building flood fragilities such as those available in assessment tools such as HAZUS-MH do not account for the hydrodynamic forces caused by surge and waves, only the depth of a flood. In this paper, a methodology to evaluate forces on all building components including windows, doors, walls, and floor systems for elevated coastal buildings under a combination of hurricane surge and waves is proposed. The model was validated by comparing vertical and horizontal forces from existing laboratory test results of a one-tenth-scale elevated structure under wave loading. A full-scale wood-frame residential building was then modeled as an example to illustrate the method and is intended to be representative of an elevated coastal structure in a typical coastal region of the United States. The hurricane was modeled as a combination of two intensity parameters, namely significant wave height and surge level at the building location and is better able to represent the loading condition and thus damage to the structure than static flood alone. Fragility surfaces for four damage states for the building as a whole were generated as a damage combination of all damageable building components. Finally, a comparison of the loss estimated using the fragility surfaces versus the current loss model in HAZUS-MH is provided to illustrate the effect on loss estimates when including wave height in predicting damage for near-coast buildings under hurricane wave and surge. By calibrating the physics-based fragilities with empirical data, the surface fragilities developed in this paper are ready to use in HAZUS-MH or other loss and resilience-focused analysis at the community level for coastal communities subjected to both waves and storm surge during hurricanes.

A large-scale physical model was created in Oregon State University's Large Wave Flume to collect an extensive dataset measuring wave-induced horizontal and vertical forces on an idealized coastal structure. Water depth was held constant while wave conditions included regular, irregular, and transient (tsunami-like) waves with different significant wave heights and peak periods for each test. The elevation of the base of the test specimen with respect to the stillwater depth (air gap) was also varied from at-grade to 0.28 m above the stillwater level to better understand the effects of raising or lowering a nearshore structure on increasing or decreasing the horizontal and vertical wave forces. Results indicate that while both horizontal and vertical forces tend to increase with increasing significant wave height, the maximum and top 0.4% of forces increased disproportionally to other characteristic values such as the mean or top 10%. As expected, the horizontal force increased as the test specimen was more deeply submerged and decreased as the structure was elevated to larger air gaps above the stillwater level. However, this trend was not true for the vertical force, which was maximized when the elevation of the base of the structure was equal to the elevation of the stillwater depth. Small wave heights were characterized by low horizontal to vertical force ratios, highlighting the importance of considering vertical wave forces in addition to horizontal wave forces in the design of coastal structures. The findings and data presented here may be used by city planners, engineers, and numerical modelers, for future analyses, informed coastal design, and numerical benchmarking to work toward enabling more resilient nearcoast structures.

The movements of organisms and the resultant flows of ecosystem services are strongly shaped by landscape connectivity. Studies of urban ecosystems have relied on two-dimensional (2D) measures of greenspace structure to calculate connectivity. It is now possible to explore three-dimensional (3D) connectivity in urban vegetation using waveform lidar technology that measures the full 3D structure of the canopy. Making use of this technology, here we evaluate urban greenspace 3D connectivity, taking into account the full vertical stratification of the vegetation. Using three towns in southern England, UK, all with varying greenspace structures, we describe and compare the structural and functional connectivity using both traditional 2D greenspace models and waveform lidar-generated vegetation strata (namely, grass, shrubs and trees). Measures of connectivity derived from 3D greenspace are lower than those derived from 2D models, as the latter assumes that all vertical vegetation strata are connected, which is rarely true. Fragmented landscapes that have more complex 3D vegetation showed greater functional connectivity and we found highest 2D to 3D functional connectivity biases for short dispersal capacities of organisms (6 m to 16 m). These findings are particularly pertinent in urban systems where the distribution of greenspace is critical for delivery of ecosystem services.

Exposure to nature provides a wide range of health benefits. A significant proportion of these are delivered close to home, because this offers an immediate and easily accessible opportunity for people to experience nature. However, there is limited information to guide recommendations on its management and appropriate use. We apply a nature dose-response framework to quantify the simultaneous association between exposure to nearby nature and multiple health benefits. We surveyed ca. 1000 respondents in Southern England, UK, to determine relationships between (a) nature dose type, that is the frequency and duration (time spent in private green space) and intensity (quantity of neighbourhood vegetation cover) of nature exposure and (b) health outcomes, including mental, physical and social health, physical behaviour and nature orientation. We then modelled dose-response relationships between dose type and self-reported depression. We demonstrate positive relationships between nature dose and mental and social health, increased physical activity and nature orientation. Dose-response analysis showed that lower levels of depression were associated with minimum thresholds of weekly nature dose. Nearby nature is associated with quantifiable health benefits, with potential for lowering the human and financial costs of ill health. Dose-response analysis has the potential to guide minimum and optimum recommendations on the management and use of nearby nature for preventative healthcare.

With an ever-increasing urban population, promoting public health and well-being in towns and cities is a major challenge. Previous research has suggested that participating in allotment gardening delivers a wide range of health benefits. However, evidence from quantitative analyses is still scarce. Here, we quantify the effects, if any, of participating in allotment gardening on physical, psychological and social health. A questionnaire survey of 332 people was performed in Tokyo, Japan. We compared five self-reported health outcomes between allotment gardeners and non-gardener controls: perceived general health, subjective health complaints, body mass index (BMI), mental health and social cohesion. Accounting for socio-demographic and lifestyle variables, regression models revealed that allotment gardeners, compared to non-gardeners, reported better perceived general health, subjective health complaints, mental health and social cohesion. BMI did not differ between gardeners and non-gardeners. Neither frequency nor duration of gardening significantly influenced reported health outcomes. Our results highlight that regular gardening on allotment sites is associated with improved physical, psychological and social health. With the recent escalation in the prevalence of chronic diseases, and associated healthcare costs, this study has a major implication for policy, as it suggests that urban allotments have great potential for preventative healthcare., Competing Interests: The authors declare no conflict of interest.

This paper presents a framework for a probabilistic hazard assessment for the multi-hazard seismic and tsunami phenomena (PSTHA). For this work, we consider a full-rupture event along the Cascadia Subduction Zone and apply the methodology to the study area of Seaside, Oregon, along the US Pacific Northwest coast. In this work, we show that the annual exceedance probabilities ( A E P ) of the tsunami intensity measures ( I M ) are qualitatively dissimilar to the IMs of the seismic ground motion in the study area. Specifically, the spatial gradients for the tsunami IM are much stronger across the length scale of the city owing to the physical differences of energy dissipation of the two mechanisms. Example results of probabilistic seismic hazard analysis (PSHA) and probabilistic tsunami hazard analysis (PTHA) are shown for three observation points in the study area of Seaside. For the seismic hazard, the joint mean annual rate of exceedance shows similar trends for the three observation points, even though there is a large scatter between P G A and S a ( T 1 = 0.3 s ) . For the tsunami hazard, the joint A E P of h max and ( M F ) max shows a high correlation between the two I M s in the study area. The joint A E P at each of the three observation points follows a particular Froude number ( F r ) due to the local site-specific conditions locally rather than the distributions of fault slips. The joint probability distribution of h max and ( M F ) max throughout the study region falls between 0.1 ≤ F r < 1.0 (i.e., the flow is subcritical) regardless of return interval (500-, 1,000-, and 2,500-yr). However, the peak of the joint probability distribution with respect to h max and ( M F ) max varies with the return interval, and the largest values of h max and ( M F ) max were observed with the highest return intervals (2,500 yr) as would be expected. The results of the PSTHA can be the basis for a probabilistic multi-hazard damage assessment and help to understand the uncertainties of the multi-hazard assessments.

Private gardens provide vital opportunities for people to interact with nature. The most popular form of interaction is through garden bird feeding. Understanding how landscape features and seasons determine patterns of movement of feeder-using songbirds is key to maximising the well-being benefits they provide. To determine these patterns we established three networks of automated data loggers along a gradient of greenspace fragmentation. Over a 12-month period we tracked 452 tagged blue tits Cyantistes caeruleus and great tits Parus major moving between feeder pairs 9,848 times, to address two questions: (i) Do urban features within different forms, and season, influence structural (presence-absence of connections between feeders by birds) and functional (frequency of these connections) connectivity? (ii) Are there general patterns of structural and functional connectivity across forms? Vegetation cover increased connectivity in all three networks, whereas the presence of road gaps negatively affected functional but not structural connectivity. Across networks structural connectivity was lowest in the summer when birds maintain breeding territories, however patterns of functional connectivity appeared to vary with habitat fragmentation. Using empirical data this study shows how key urban features and season influence movement of feeder-using songbirds, and we provide evidence that this is related to greenspace fragmentation.

At a time of unprecedented biodiversity loss, researchers are increasingly recognizing the broad range of benefits provided to humankind by nature. However, as people live more urbanized lifestyles there is a progressive disengagement with the natural world that diminishes these benefits and discourages positive environmental behaviour. The provision of food for garden birds is an increasing global phenomenon, and provides a readily accessible way for people to counter this trend. Yet despite its popularity, quite why people feed birds remains poorly understood. We explore three loosely defined motivations behind bird feeding: that it provides psychological benefits, is due to a concern about bird welfare, and/or is due to a more general orientation towards nature. We quantitatively surveyed households from urban towns in southern England to explore attitudes and actions towards garden bird feeding. Each household scored three Likert statements relating to each of the three motivations. We found that people who fed birds regularly felt more relaxed and connected to nature when they watched garden birds, and perceived that bird feeding is beneficial for bird welfare while investing time in minimising associated risks. Finally, feeding birds may be an expression of a wider orientation towards nature. Overall, we found that the feelings of being relaxed and connected to nature were the strongest drivers. As urban expansion continues both to threaten species conservation and to change peoples' relationship with the natural world, feeding birds may provide an important tool for engaging people with nature to the benefit of both people and conservation.

The importance of species richness in maintaining ecosystem function in the field remains unclear. Recent studies however have suggested that in some systems functionality is maintained by a few abundant species. Here we determine this relationship by quantifying the species responsible for a key ecosystem role, carcass removal by scavengers. We find that, unlike those within largely unaltered environments, the scavenger community within our highly altered system is dominated by a single species, the Carrion crow, despite the presence of a number of other scavenging species. Furthermore, we find no relationship between abundance of crows and carcass removal. However, the overall activity of crows predicts carcass biomass removal rate in an asymptotic manner, suggesting that a relatively low level of abundance and scavenging activity is required to maintain this component of ecosystem function.

Interacting with nature is widely recognised as providing many health and well-being benefits. As people live increasingly urbanised lifestyles, the provision of food for garden birds may create a vital link for connecting people to nature and enabling them to access these benefits. However, it is not clear which factors determine the pleasure that people receive from watching birds at their feeders. These may be dependent on the species that are present, the abundance of individuals and the species richness of birds around the feeders. We quantitatively surveyed urban households from towns in southern England to determine the factors that influence the likeability of 14 common garden bird species, and to assess whether people prefer to see a greater abundance of individuals or increased species richness at their feeders. There was substantial variation in likeability across species, with songbirds being preferred over non-songbirds. Species likeability increased for people who fed birds regularly and who could name the species. We found a strong correlation between the number of species that a person could correctly identify and how connected to nature they felt when they watched garden birds. Species richness was preferred over a greater number of individuals of the same species. Although we do not show causation this study suggests that it is possible to increase the well-being benefits that people gain from watching birds at their feeders. This could be done first through a human to bird approach by encouraging regular interactions between people and their garden birds, such as through learning the species names and providing food. Second, it could be achieved through a bird to human approach by increasing garden songbird diversity because the pleasure that a person receives from watching an individual bird at a feeder is dependent not only on its species but also on the diversity of birds at the feeder.

Both mass (as a measure of body reserves) during breeding and adult survival should reflect variation in food availability. Those species that are adapted to less seasonally variable foraging niches and so where competition dominates during breeding, will tend to have a higher mass increase via an interrupted foraging response, because their foraging demands increase and so become more unpredictable. They will then produce few offspring per breeding attempt, but trade this off with higher adult survival. In contrast, those species that occupy a more seasonal niche will not gain mass because foraging remains predictable, as resources become superabundant during breeding. They can also produce more offspring per breeding attempt, but with a trade-off with reduced adult survival. We tested whether the then predicted positive correlation between levels of mass gained during seasonal breeding and adult survival was present across 40 species of tropical bird measured over a 10-year period in a West African savannah. We showed that species with a greater seasonal mass increase had higher adult survival, controlling for annual mass variation (i.e. annual variation in absolute food availability) and variation in the timing of peak mass (i.e. annual predictability of food availability), clutch size, body size, migratory status and phylogeny. Our results support the hypothesis that the degree of seasonal mass variation in birds is probably an indication of life history adaptation: across tropical bird species it may therefore be possible to use mass gain during breeding as an index of adult survival.

Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified >300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLA-viral peptide interaction as the major factor modulating durable control of HIV infection.

Objectives: E-mail communication between patients and their providers has diffused slowly in clinical practice. To address concerns about the use of this technology, we performed a randomized controlled trial of a triage-based e-mail system in primary care. DESIGN AND PATIENTS/PARTICIPANTS: Physicians in 2 university-affiliated primary care centers were randomized to a triage-based e-mail system promoted to their patients. E-mails from patients of intervention physicians were routed to a central account and parsed to the appropriate staff for response. Control group physicians and their patients did not have access to the system. We collected information on patient e-mail use, phone calls, and visit distribution by physician over the 10 months and performed physician and patient surveys to examine attitudes about communication., Results: E-mail volume was greater for intervention versus control physicians (46 weekly e-mails per 100 scheduled visits vs 9 in the control group at the study midpoint; P <.01) but there were no between-group differences in phone volume (67 weekly phone calls per 100 scheduled visits vs 55 in the control group; P =.45) or rates of patient no-shows (5% in both groups; P =.77). Intervention physicians reported more favorable attitudes toward electronic communication than did control physicians but there were no differences in attitudes toward patient or staff communication in general. There were few between-group differences in patient attitudes toward electronic communication or communication in general., Conclusions: E-mail generated through a triage-based system did not appear to substitute for phone communication or to reduce visit no-shows in a primary care setting. Physicians' attitudes toward electronic communication were improved, but physicians' and patients' attitudes toward general communication did not change. Growth of e-mail communication in primary care settings may not improve the efficiency of clinical care.

Objective: To determine e-mail utilization patterns and attitudes toward e-mail use among primary care physicians and their ambulatory outpatient clinic patients., Study Design: Cross-sectional baseline survey., Participants and Methods: Participants included 476 consecutive outpatient clinic patients, 126 general medical and family practice physicians, and 16 clinical and office staff from 2 large primary care centers within an academic teaching system. They completed a survey about e-mail usage patterns and their attitudes toward using e-mail for patient-provider communication., Results: More than half of patients (52.1%) were self-defined e-mail users, yet only 10.5% of those users had ever used e-mail to communicate with their doctors. Seventy percent of all patients said they would be willing to use e-mail to communicate with their doctors. Overall, patients were concerned about logistics, such as whether the message would get to the right person and how long it would take to get a response. Physicians and staff were more optimistic than patients about the potential for e-mail to improve the doctor-patient relationship. Patient e-mail users, patient e-mail nonusers, physicians, and staff reported low levels of concern about the security and privacy of e-mail., Conclusions: Patient-provider e-mail may diffuse slowly into the primary care clinical practice setting because of patient concerns about efficiency and effectiveness and whether e-mail use will improve their relationship with providers. Managed care organizations that plan to build e-mail and Web-based patient portals will need to promote these technologies in a way that educates both patient and providers about their appropriate use.

This study investigated the effects on femoral vascular resistance, blood glucose and lactate levels, and plasma catecholamine concentrations of fetal treatment with an adenosine receptor antagonist during acute hypoxemia in fetal sheep during late gestation. Under anesthesia, seven fetal sheep were instrumented between 117 and 118 days gestation (term is approximately 145 days) with vascular and amniotic catheters and an ultrasonic probe around a femoral artery. Six days after surgery, all fetuses were randomly subjected to a 3-h experiment consisting of 1 h of normoxia, 1 h of hypoxemia, and 1 h of recovery. This was done during either intravenous infusion of vehicle or the adenosine receptor antagonist [8-(p-sulfophenyl)-theophylline; 8-SPT] dissolved in vehicle. During vehicle infusion, all fetuses responded to hypoxemia with bradycardia, an increase in arterial blood pressure, and femoral vasoconstriction. Increases in blood glucose and lactate concentrations and in plasma epinephrine and norepinephrine concentrations also occurred in all fetuses during hypoxemia. Fetal treatment with 8-SPT markedly attenuated the bradycardic, hypertensive, vasoconstrictor, glycemic, and adrenergic responses to hypoxemia, but it did not affect the increase in blood lactate concentrations during hypoxemia. These data show that adenosine is involved in the mechanisms mediating fetal cardiovascular, metabolic, and adrenergic responses to hypoxemia in fetal sheep. Fetal treatment with 8-SPT mimics the effects of carotid sinus nerve section on fetal cardiovascular function during hypoxemia, suggesting a role for adenosine in mediating fetal cardiovascular chemoreflexes.

Candida species are increasingly assuming a pathogenic role in patients throughout the spectrum of in competence. This case history documents a unique presentation of candidiasis with marked similarity to the zygomycoses in patients with diabetic ketoacidosis and explores the pathogenetic basis for both.