Age-Dependent Variations in Kawasaki Disease Incidence in Japan.

Importance: The etiology of Kawasaki disease (KD) remains elusive, with immunologic and epidemiologic data suggesting different triggers in individuals who are genetically susceptible. KD remains the most common cause of acquired heart disease in pediatric patients, and Japan is the country of highest incidence, with an increasing number of cases. Objective: To investigate whether an analysis of the epidemiologic KD record in Japan stratified by age and prefecture (subregion) may yield new clues regarding mechanisms of exposure to etiologic agents associated with KD. Design, Setting, and Participants: This cross-sectional study was conducted using a dataset of patients with KD with detailed information on location and age at onset created through nationwide surveys of hospitals caring for pediatric patients with KD throughout Japan. Pediatric patients hospitalized in Japan for KD from 1970 to 2020 were included. Data were analyzed from January 2022 to January 2024. Exposure: Pediatric patients with KD. Main Outcomes and Measures: The KD dataset was analyzed by patient age (infants [aged <6 months], toddlers [aged 6 to <24 months], children aged 2 years [aged 24 to <36 months], and children and adolescents aged 3 years or older [aged ≥36 months]), with investigations of seasonal cycles, interannual variations, and correlations across regions. Results: Among 422 528 pediatric patients (243 803 males [57.7%] and 178 732 females [42.3%]; median [IQR] age, 23.69 [11.96-42.65] months), infants, toddlers, and patients aged 3 years or older exhibited different rates of increase in KD incidence, seasonality, and degrees of coherence of seasonality across prefectures. Although the mean (SD) incidence of KD among infants remained relatively stable over the past 30 years compared with older patients (1.00 [0.07] in 1987-1992 to 2.05 [0.11] in 2011-2016), the mean (SD) incidence rate for children and adolescents aged 3 years or older increased 5.2-fold, from 1.00 (0.08) in 1987 to 1992 to 5.17 (0.46) in 2014 to 2019. Patients aged 3 years or older saw a reduction in mean (SD) incidence, from peaks of 5.71 (0.01) in October 2014 through June 2015 and July 2018 through March 2019 to 4.69 (0.11) in 2016 to 2017 (17.8% reduction) not seen in younger children. The seasonal cycle varied by age group; for example, mean (SD) incidence peaked in July and August (5.63 [0.07] cases/100 000 individuals) for infants and in December and January (4.67 [0.13] cases/100 000 individuals) for toddlers. Mean (SD) incidence changed dramatically for toddlers beginning in the early 2010s; for example, the normalized mean (SD) incidence among toddlers for October was 0.74 (0.03) in 1992 to 1995 and 1.10 (0.01) in 2016 to 2019. Across Japan, the seasonal cycle of KD incidence of older children and adolescents exhibited mean (SD) correlation coefficients between prefectures as high as 0.78 (0.14) for prefecture 14 among patients aged 3 years or older, while that of infants was much less (highest mean [SD] correlation coefficient, 0.43 [0.23]). Conclusions and Relevance: This study found distinct temporal signatures and changing spatial consistency of KD incidence across age groups, suggesting different age-related mechanisms of exposure. Some results suggested that social factors may modulate exposure to etiologic agents of KD; however, the increase in KD incidence in older children coupled with the correlation across prefectures of KD incidence suggest that the intensity of an environmental exposure that triggers KD in this age group may have increased over time.

Climate change contributions to future atmospheric river flood damages in the western United States.

Atmospheric rivers (ARs) generate most of the economic losses associated with flooding in the western United States and are projected to increase in intensity with climate change. This is of concern as flood damages have been shown to increase exponentially with AR intensity. To assess how AR-related flood damages are likely to respond to climate change, we constructed county-level damage models for the western 11 conterminous states using 40 years of flood insurance data linked to characteristics of ARs at landfall. Damage functions were applied to 14 CMIP5 global climate models under the RCP4.5 "intermediate emissions" and RCP8.5 "high emissions" scenarios, under the assumption that spatial patterns of exposure, vulnerability, and flood protection remain constant at present day levels. The models predict that annual expected AR-related flood damages in the western United States could increase from $1 billion in the historical period to $2.3 billion in the 2090s under the RCP4.5 scenario or to $3.2 billion under the RCP8.5 scenario. County-level projections were developed to identify counties at greatest risk, allowing policymakers to target efforts to increase resilience to climate change.

Epidemiological and Clinical Features of Kawasaki Disease During the COVID-19 Pandemic in the United States.

Importance: Public health measures implemented during the COVID-19 pandemic had widespread effects on population behaviors, transmission of infectious diseases, and exposures to environmental pollutants. This provided an opportunity to study how these factors potentially influenced the incidence of Kawasaki disease (KD), a self-limited pediatric vasculitis of unknown etiology. Objectives: To examine the change in KD incidence across the United States and evaluate whether public health measures affected the prevalence of KD. Design, Setting, and Participants: This multicenter cohort study included consecutive, unselected patients with KD who were diagnosed between January 1, 2018, and December 31, 2020 (multicenter cohort with 28 pediatric centers), and a detailed analysis of patients with KD who were diagnosed between January 1, 2002, and November 15, 2021 (Rady Children's Hospital San Diego [RCHSD]). Main Outcomes and Measures: For the multicenter cohort, the date of fever onset for each patient with KD was collected. For RCHSD, detailed demographic and clinical data as well as publicly available, anonymized mobile phone data and median household income by census block group were collected. The study hypothesis was that public health measures undertaken during the pandemic would reduce exposure to the airborne trigger(s) of KD and that communities with high shelter-in-place compliance would experience the greatest decrease in KD incidence. Results: A total of 2461 KD cases were included in the multicenter study (2018: 894; 2019: 905; 2020: 646), and 1461 cases (median [IQR] age, 2.8 years [1.4-4.9 years]; 900 [61.6%] males; 220 [15.1%] Asian, 512 [35.0%] Hispanic, and 338 [23.1%] White children) from RCHSD between 2002 and 2021 were also included. The 28.2% decline in KD cases nationally during 2020 (646 cases) compared with 2018 (894 cases) and 2019 (905 cases) was uneven across the United States. For RCHSD, there was a disproportionate decline in KD cases in 2020 to 2021 compared with the mean (SD) number of cases in earlier years for children aged 1 to 5 years (22 vs 44.9 [9.9]; P = .02), male children (21 vs 47.6 [10.0]; P = .01), and Asian children (4 vs 11.8 [4.4]; P = .046). Mobility data did not suggest that shelter-in-place measures were associated with the number of KD cases. Clinical features including strawberry tongue, enlarged cervical lymph node, and subacute periungual desquamation were decreased during 2020 compared with the baseline period (strawberry tongue: 39% vs 63%; P = .04; enlarged lymph node: 21% vs 32%; P = .09; periungual desquamation: 47% vs 58%; P = .16). School closures, masking mandates, decreased ambient pollution, and decreased circulation of respiratory viruses all overlapped to different extents with the period of decreased KD cases. KD in San Diego rebounded in the spring of 2021, coincident with lifting of mask mandates. Conclusions and Relevance: In this study of epidemiological and clinical features of KD during the COVID-19 pandemic in the United States, KD cases fell and remained low during the period of masking and school closure. Mobility data indicated that differential intensity of sheltering in place was not associated with KD incidence. These findings suggest that social behavior is associated with exposure to the agent(s) that trigger KD and are consistent with a respiratory portal of entry for the agent(s).

Temporal clustering of Kawasaki disease cases around the world.

In a single-site study (San Diego, CA, USA), we previously showed that Kawasaki Disease (KD) cases cluster temporally in bursts of approximately 7 days. These clusters occurred more often than would be expected at random even after accounting for long-term trends and seasonality. This finding raised the question of whether other locations around the world experience similar temporal clusters of KD that might offer clues to disease etiology. Here we combine data from San Diego and nine additional sites around the world with hospitals that care for large numbers of KD patients, as well as two multi-hospital catchment regions. We found that across these sites, KD cases clustered at short time scales and there were anomalously long quiet periods with no cases. Both of these phenomena occurred more often than would be expected given local trends and seasonality. Additionally, we found unusually frequent temporal overlaps of KD clusters and quiet periods between pairs of sites. These findings suggest that regional and planetary range environmental influences create periods of higher or lower exposure to KD triggers that may offer clues to the etiology of KD.

Ignitions explain more than temperature or precipitation in driving Santa Ana wind fires.

Autumn and winter Santa Ana wind (SAW)-driven wildfires play a substantial role in area burned and societal losses in southern California. Temperature during the event and antecedent precipitation in the week or month prior play a minor role in determining area burned. Burning is dependent on wind intensity and number of human-ignited fires. Over 75% of all SAW events generate no fires; rather, fires during a SAW event are dependent on a fire being ignited. Models explained 40 to 50% of area burned, with number of ignitions being the strongest variable. One hundred percent of SAW fires were human caused, and in the past decade, powerline failures have been the dominant cause. Future fire losses can be reduced by greater emphasis on maintenance of utility lines and attention to planning urban growth in ways that reduce the potential for powerline ignitions.

Multiple climate change-driven tipping points for coastal systems.

As the climate evolves over the next century, the interaction of accelerating sea level rise (SLR) and storms, combined with confining development and infrastructure, will place greater stresses on physical, ecological, and human systems along the ocean-land margin. Many of these valued coastal systems could reach "tipping points," at which hazard exposure substantially increases and threatens the present-day form, function, and viability of communities, infrastructure, and ecosystems. Determining the timing and nature of these tipping points is essential for effective climate adaptation planning. Here we present a multidisciplinary case study from Santa Barbara, California (USA), to identify potential climate change-related tipping points for various coastal systems. This study integrates numerical and statistical models of the climate, ocean water levels, beach and cliff evolution, and two soft sediment ecosystems, sandy beaches and tidal wetlands. We find that tipping points for beaches and wetlands could be reached with just 0.25 m or less of SLR (~ 2050), with > 50% subsequent habitat loss that would degrade overall biodiversity and ecosystem function. In contrast, the largest projected changes in socioeconomic exposure to flooding for five communities in this region are not anticipated until SLR exceeds 0.75 m for daily flooding and 1.5 m for storm-driven flooding (~ 2100 or later). These changes are less acute relative to community totals and do not qualify as tipping points given the adaptive capacity of communities. Nonetheless, the natural and human built systems are interconnected such that the loss of natural system function could negatively impact the quality of life of residents and disrupt the local economy, resulting in indirect socioeconomic impacts long before built infrastructure is directly impacted by flooding.

Hot and cold flavors of southern California's Santa Ana winds: their causes, trends, and links with wildfire.

Santa Ana winds (SAWs) are associated with anomalous temperatures in coastal Southern California (SoCal). As dry air flows over SoCal's coastal ranges on its way from the elevated Great Basin down to sea level, all SAWs warm adiabatically. Many but not all SAWs produce coastal heat events. The strongest regionally averaged SAWs tend to be cold. In fact, some of the hottest and coldest observed temperatures in coastal SoCal are linked to SAWs. We show that hot and cold SAWs are produced by distinct synoptic dynamics. High-amplitude anticyclonic flow around a blocking high pressure aloft anchored at the California coast produces hot SAWs. Cold SAWs result from anticyclonic Rossby wave breaking over the northwestern U.S. Hot SAWs are preceded by warming in the Great Basin and dry conditions across the Southwestern U.S. Precipitation over the Southwest, including SoCal, and snow accumulation in the Great Basin usually precede cold SAWs. Both SAW flavors, but especially the hot SAWs, yield low relative humidity at the coast. Although cold SAWs tend to be associated with the strongest winds, hot SAWs tend to last longer and preferentially favor wildfire growth. Historically, out of large (> 100 acres) SAW-spread wildfires, 90% were associated with hot SAWs, accounting for 95% of burned area. As health impacts of SAW-driven coastal fall, winter and spring heat waves and impacts of smoke from wildfires have been recently identified, our results have implications for designing early warning systems. The long-term warming trend in coastal temperatures associated with SAWs is focused on January-March, when hot and cold SAW frequency and temperature intensity have been increasing and decreasing, respectively, over our 71-year record. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00382-021-05802-z.

Temporal Clusters of Kawasaki Disease Cases Share Distinct Phenotypes That Suggest Response to Diverse Triggers.

OBJECTIVE: To test the hypothesis that cases of Kawasaki disease within a temporal cluster have a similar pattern of host response that is distinct from cases of Kawasaki disease in different observed clusters and randomly constructed clusters. STUDY DESIGN: We designed a case-control study to analyze 47 clusters derived from 1332 patients with Kawasaki disease over a 17-year period (2002-2019) from a single clinical site and compared the cluster characteristics with those of 2 control groups of synthetic Kawasaki disease clusters. We defined a "true" Kawasaki disease cluster as at least 5 patients within a 7-day moving window. The observed and synthetic Kawasaki disease clusters were compared with respect to demographic and clinical characteristics and median values for standard laboratory data using univariate analysis and a multivariate, rotated empirical orthogonal function analysis. RESULTS: In a univariate analysis, the median values for age, coronary artery z-score, white blood cell count, erythrocyte sedimentation rate, C-reactive protein, and age-adjusted hemoglobin for several of the true Kawasaki disease clusters exceeded the 95th percentile for the 2 synthetic clusters. REOF analyses revealed distinct patterns of demographic and clinical measures within clusters. CONCLUSIONS: Cases of Kawasaki disease within a cluster were more similar with respect to demographic and clinical features and levels of inflammation than would be expected by chance. These observations suggest that different triggers and/or different intensities of exposures result in clusters of cases of Kawasaki disease that share a similar response pattern. Analyzing cases within clusters or cases who share demographic and clinical features may lead to new insights into the etiology of Kawasaki disease.

Associations of breeding-bird abundance with climate vary among species and trait-based groups in southern California.

The responses of individuals and populations to climate change vary as functions of physiology, ecology, and plasticity. We investigated whether annual variation in seasonal temperature and precipitation was associated with relative abundances of breeding bird species at local and regional levels in southern California, USA, from 1968-2013. We tested our hypotheses that abundances were correlated positively with precipitation and negatively with temperature in this semiarid to arid region. We also examined whether responses to climate varied among groups of species with similar land-cover associations, nesting locations, and migratory patterns. We investigated relations between seasonal climate variables and the relative abundances of 41 species as estimated by the North American Breeding Bird Survey. Associations with climate variables varied among species. Results of models of species associated with arid scrublands or that nest on the ground strongly supported our hypotheses, whereas those of species associated with coniferous forests or that nest in cavities did not. Associations between climate variables and the abundances of other trait-based groups were diverse. Our results suggest that species in arid areas may be negatively affected by increased temperature and aridity, but species in nearby areas that are cooler and less arid may respond positively to those fluctuations in climate. Relations with climate variables can differ among similar species, and such knowledge may inform projections of future abundance trajectories and geographic ranges.

Atmospheric rivers drive flood damages in the western United States.

Atmospheric rivers (ARs) are extratropical storms that produce extreme precipitation on the west coasts of the world's major landmasses. In the United States, ARs cause significant flooding, yet their economic impacts have not been quantified. Here, using 40 years of data from the National Flood Insurance Program, we show that ARs are the primary drivers of flood damages in the western United States. Using a recently developed AR scale, which varies from category 1 to 5, we find that flood damages increase exponentially with AR intensity and duration: Each increase in category corresponds to a roughly 10-fold increase in damages. Category 4 and 5 ARs cause median damages in the tens and hundreds of millions of dollars, respectively. Rising population, increased development, and climate change are expected to worsen the risk of AR-driven flood damage in future decades.

Precipitation regime change in Western North America: The role of Atmospheric Rivers.

Daily precipitation in California has been projected to become less frequent even as precipitation extremes intensify, leading to uncertainty in the overall response to climate warming. Precipitation extremes are historically associated with Atmospheric Rivers (ARs). Sixteen global climate models are evaluated for realism in modeled historical AR behavior and contribution of the resulting daily precipitation to annual total precipitation over Western North America. The five most realistic models display consistent changes in future AR behavior, constraining the spread of the full ensemble. They, moreover, project increasing year-to-year variability of total annual precipitation, particularly over California, where change in total annual precipitation is not projected with confidence. Focusing on three representative river basins along the West Coast, we show that, while the decrease in precipitation frequency is mostly due to non-AR events, the increase in heavy and extreme precipitation is almost entirely due to ARs. This research demonstrates that examining meteorological causes of precipitation regime change can lead to better and more nuanced understanding of climate projections. It highlights the critical role of future changes in ARs to Western water resources, especially over California.

Author Correction: Clustering and climate associations of Kawasaki Disease in San Diego County suggest environmental triggers.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Clustering and climate associations of Kawasaki Disease in San Diego County suggest environmental triggers.

Kawasaki Disease (KD) is the most common cause of pediatric acquired heart disease, but its etiology remains unknown. We examined 1164 cases of KD treated at a regional children's hospital in San Diego over a period of 15 years and uncovered novel structure to disease incidence. KD cases showed a well-defined seasonal variability, but also clustered temporally at much shorter time scales (days to weeks), and spatiotemporally on time scales of up to 10 days and spatial scales of 10-100 km. Temporal clusters of KD cases were associated with strongly significant regional-scale air temperature anomalies and consistent larger-scale atmospheric circulation patterns. Gene expression analysis further revealed a natural partitioning of KD patients into distinct groups based on their gene expression pattern, and that the different groups were associated with certain clinical characteristics that also exhibit temporal autocorrelation. Our data suggest that one or more environmental triggers exist, and that episodic exposures are modulated at least in part by regional weather conditions. We propose that characterization of the environmental factors that trigger KD in genetically susceptible children should focus on aerosols inhaled by patients who share common disease characteristics.

Precipitation in a warming world: Assessing projected hydro-climate changes in California and other Mediterranean climate regions.

In most Mediterranean climate (MedClim) regions around the world, global climate models (GCMs) consistently project drier futures. In California, however, projections of changes in annual precipitation are inconsistent. Analysis of daily precipitation in 30 GCMs reveals patterns in projected hydrometeorology over each of the five MedClm regions globally and helps disentangle their causes. MedClim regions, except California, are expected to dry via decreased frequency of winter precipitation. Frequencies of extreme precipitation, however, are projected to increase over the two MedClim regions of the Northern Hemisphere where projected warming is strongest. The increase in heavy and extreme precipitation is particularly robust over California, where it is only partially offset by projected decreases in low-medium intensity precipitation. Over the Mediterranean Basin, however, losses from decreasing frequency of low-medium-intensity precipitation are projected to dominate gains from intensifying projected extreme precipitation. MedClim regions are projected to become more sub-tropical, i.e. made dryer via pole-ward expanding subtropical subsidence. California's more nuanced hydrological future reflects a precarious balance between the expanding subtropical high from the south and the south-eastward extending Aleutian low from the north-west. These dynamical mechanisms and thermodynamic moistening of the warming atmosphere result in increased horizontal water vapor transport, bolstering extreme precipitation events.

A spatially comprehensive, hydrometeorological data set for Mexico, the U.S., and Southern Canada 1950-2013.

A data set of observed daily precipitation, maximum and minimum temperature, gridded to a 1/16° (~6 km) resolution, is described that spans the entire country of Mexico, the conterminous U.S. (CONUS), and regions of Canada south of 53° N for the period 1950-2013. The dataset improves previous products in spatial extent, orographic precipitation adjustment over Mexico and parts of Canada, and reduction of transboundary discontinuities. The impacts of adjusting gridded precipitation for orographic effects are quantified by scaling precipitation to an elevation-aware 1981-2010 precipitation climatology in Mexico and Canada. Differences are evaluated in terms of total precipitation as well as by hydrologic quantities simulated with a land surface model. Overall, orographic correction impacts total precipitation by up to 50% in mountainous regions outside CONUS. Hydrologic fluxes show sensitivities of similar magnitude, with discharge more sensitive than evapotranspiration and soil moisture. Because of the consistent gridding methodology, the current product reduces transboundary discontinuities as compared with a commonly used reanalysis product, making it suitable for estimating large-scale hydrometeorologic phenomena.

Remote Hydrology. Ongoing drought-induced uplift in the western United States.

The western United States has been experiencing severe drought since 2013. The solid earth response to the accompanying loss of surface and near-surface water mass should be a broad region of uplift. We use seasonally adjusted time series from continuously operating global positioning system stations to measure this uplift, which we invert to estimate mass loss. The median uplift is 5 millimeters (mm), with values up to 15 mm in California's mountains. The associated pattern of mass loss, ranging up to 50 centimeters (cm) of water equivalent, is consistent with observed decreases in precipitation and streamflow. We estimate the total deficit to be ~240 gigatons, equivalent to a 10-cm layer of water over the entire region, or the annual mass loss from the Greenland Ice Sheet.

Tropospheric winds from northeastern China carry the etiologic agent of Kawasaki disease from its source to Japan.

Evidence indicates that the densely cultivated region of northeastern China acts as a source for the wind-borne agent of Kawasaki disease (KD). KD is an acute, coronary artery vasculitis of young children, and still a medical mystery after more than 40 y. We used residence times from simulations with the flexible particle dispersion model to pinpoint the source region for KD. Simulations were generated from locations spanning Japan from days with either high or low KD incidence. The postepidemic interval (1987-2010) and the extreme epidemics (1979, 1982, and 1986) pointed to the same source region. Results suggest a very short incubation period (<24 h) from exposure, thus making an infectious agent unlikely. Sampling campaigns over Japan during the KD season detected major differences in the microbiota of the tropospheric aerosols compared with ground aerosols, with the unexpected finding of the Candida species as the dominant fungus from aloft samples (54% of all fungal strains). These results, consistent with the Candida animal model for KD, provide support for the concept and feasibility of a windborne pathogen. A fungal toxin could be pursued as a possible etiologic agent of KD, consistent with an agricultural source, a short incubation time and synchronized outbreaks. Our study suggests that the causative agent of KD is a preformed toxin or environmental agent rather than an organism requiring replication. We propose a new paradigm whereby an idiosyncratic immune response, influenced by host genetics triggered by an environmental exposure carried on winds, results in the clinical syndrome known as acute KD.

The key role of dry days in changing regional climate and precipitation regimes.

Future changes in the number of dry days per year can either reinforce or counteract projected increases in daily precipitation intensity as the climate warms. We analyze climate model projected changes in the number of dry days using 28 coupled global climate models from the Coupled Model Intercomparison Project, version 5 (CMIP5). We find that the Mediterranean Sea region, parts of Central and South America, and western Indonesia could experience up to 30 more dry days per year by the end of this century. We illustrate how changes in the number of dry days and the precipitation intensity on precipitating days combine to produce changes in annual precipitation, and show that over much of the subtropics the change in number of dry days dominates the annual changes in precipitation and accounts for a large part of the change in interannual precipitation variability.

Seasonality of Kawasaki disease: a global perspective.

BACKGROUND: Understanding global seasonal patterns of Kawasaki disease (KD) may provide insight into the etiology of this vasculitis that is now the most common cause of acquired heart disease in children in developed countries worldwide. METHODS: Data from 1970-2012 from 25 countries distributed over the globe were analyzed for seasonality. The number of KD cases from each location was normalized to minimize the influence of greater numbers from certain locations. The presence of seasonal variation of KD at the individual locations was evaluated using three different tests: time series modeling, spectral analysis, and a Monte Carlo technique. RESULTS: A defined seasonal structure emerged demonstrating broad coherence in fluctuations in KD cases across the Northern Hemisphere extra-tropical latitudes. In the extra-tropical latitudes of the Northern Hemisphere, KD case numbers were highest in January through March and approximately 40% higher than in the months of lowest case numbers from August through October. Datasets were much sparser in the tropics and the Southern Hemisphere extra-tropics and statistical significance of the seasonality tests was weak, but suggested a maximum in May through June, with approximately 30% higher number of cases than in the least active months of February, March and October. The seasonal pattern in the Northern Hemisphere extra-tropics was consistent across the first and second halves of the sample period. CONCLUSION: Using the first global KD time series, analysis of sites located in the Northern Hemisphere extra-tropics revealed statistically significant and consistent seasonal fluctuations in KD case numbers with high numbers in winter and low numbers in late summer and fall. Neither the tropics nor the Southern Hemisphere extra-tropics registered a statistically significant aggregate seasonal cycle. These data suggest a seasonal exposure to a KD agent that operates over large geographic regions and is concentrated during winter months in the Northern Hemisphere extra-tropics.

Projected evolution of California's San Francisco Bay-Delta-river system in a century of climate change.

BACKGROUND: Accumulating evidence shows that the planet is warming as a response to human emissions of greenhouse gases. Strategies of adaptation to climate change will require quantitative projections of how altered regional patterns of temperature, precipitation and sea level could cascade to provoke local impacts such as modified water supplies, increasing risks of coastal flooding, and growing challenges to sustainability of native species. METHODOLOGY/PRINCIPAL FINDINGS: We linked a series of models to investigate responses of California's San Francisco Estuary-Watershed (SFEW) system to two contrasting scenarios of climate change. Model outputs for scenarios of fast and moderate warming are presented as 2010-2099 projections of nine indicators of changing climate, hydrology and habitat quality. Trends of these indicators measure rates of: increasing air and water temperatures, salinity and sea level; decreasing precipitation, runoff, snowmelt contribution to runoff, and suspended sediment concentrations; and increasing frequency of extreme environmental conditions such as water temperatures and sea level beyond the ranges of historical observations. CONCLUSIONS/SIGNIFICANCE: Most of these environmental indicators change substantially over the 21(st) century, and many would present challenges to natural and managed systems. Adaptations to these changes will require flexible planning to cope with growing risks to humans and the challenges of meeting demands for fresh water and sustaining native biota. Programs of ecosystem rehabilitation and biodiversity conservation in coastal landscapes will be most likely to meet their objectives if they are designed from considerations that include: (1) an integrated perspective that river-estuary systems are influenced by effects of climate change operating on both watersheds and oceans; (2) varying sensitivity among environmental indicators to the uncertainty of future climates; (3) inevitability of biological community changes as responses to cumulative effects of climate change and other drivers of habitat transformations; and (4) anticipation and adaptation to the growing probability of ecosystem regime shifts.