Indirect Impact Assessment of Pluvial Flooding in Urban Areas Using a Graph-Based Approach: The Mexico City Case Study

This paper presents the application of a graph-based methodology for the assessment of flood impacts in an urban context. In this methodology, exposed elements are organized as nodes on a graph, which is used to propagate impacts from directly affected nodes to other nodes across graph links. Compared to traditional approaches, the main advantage of the adopted methodology lies in the possibility of identifying and understanding indirect impacts and cascading effects. The application case concerns floods numerically reconstructed in Mexico City in response to rainfall events of increasing return periods. The hazard reconstruction was carried out by using a simplified hydrological/hydraulic model of the urban drainage system, implemented in EPASWMM, the Storm Water Management Model developed by the United States Environmental Protection Agency. The paper shows how the impacts are propagated along different orders of the impact chain for each return period and compares the risk curves between direct and indirect impact. It also highlights the extent to which the reduction in demand of services from consumers and the loss of services from suppliers are respectively contributing to the final indirect impacts. Finally, it illustrates how different impact mitigation measures can be formulated based on systemic information provided by the analysis of graph properties and taking into account indirect impacts

Holocene evolution of halite caves in the Cordillera de la Sal (Central Atacama, Chile) in different climate conditions

Geomorphological studies have been carried out in rapidly evolving salt caves related to small watersheds in the San Pedro de Atacama area, Chile. Radiocarbon ages of bones and wood from cave deposits, combined with the presence of large salt caves, geomorphological and sedimentological observations, and the results of micrometer measurements outside and in some of the caves, suggest a period of speleogenesis in the Cordillera de la Sal during the onset of the Holocene, during which the large halite cave systems developed, followed by an early Holocene hyperarid period.Most smaller caves (i.e. Lechuza del Campanario) most probably formed at the start of the wetter mid-Holocene period (5–4.4 ka), when precipitation was never intense enough to entrain large amounts of sediments, but enough to trigger cave development. A diamicton in Lechuza del Campanario Cave radiocarbon dated at ca. 4.4 ka shows that at least one high intensity rainfall event occurred in this recharge basin during the mid-Holocene wet interval. A wet period with lower intensity rainfall events followed between 4.0 and 2.5 ka, causing the 4.4 kyrs old diamicton in Lechuza del Campanario Cave to be entrenched, and the alluvial fan at the downstream end of Palacio del Sal Cave to be covered with windborne sediments dated by OSL at around 3.6 ka. At ca. 2 ka there was a high-intensity rainfall event documented by the age of a twig stuck in the ceiling of the Palacio del Sal Cave, followed by a period with lower intensity rain events until ca. 1.3 ka, when another intense flood produced a mudflow that deposited a second diamicton in Lechuza del Campanario Cave. From then on clustering of radiocarbon ages forwood and bone recovered fromcaves indicates increased rainfall intensity in the period ca. 0.9–0.5 ka, followed by no registered events until a minor flood at ca. 0.13 ka. The fourcenturies long wetter time interval (0.9–0.5 ka), corresponding to the Medieval Climate Anomaly, has been an archeologically important period in the Atacama Desert (Tiwanaku culture). The observations and a detailed review of paleoclimate literature from this key area have allowed the development of a landscape evolution model related to changing climate conditions during the Late Holocene

Conceptual framework for the definition of preclinical and prodromal frontotemporal dementia

The presymptomatic stages of frontotemporal dementia (FTD) are still poorly defined and encompass a long accrual of progressive biological (preclinical) and then clinical (prodromal) changes, antedating the onset of dementia. The heterogeneity of clinical presentations and the different neuropathological phenotypes have prevented a prior clear description of either preclinical or prodromal FTD. Recent advances in therapeutic approaches, at least in monogenic disease, demand a proper definition of these predementia stages. It has become clear that a consensus lexicon is needed to comprehensively describe the stages that anticipate dementia. The goal of the present work is to review existing literature on the preclinical and prodromal phases of FTD, providing recommendations to address the unmet questions, therefore laying out a strategy for operationalizing and better characterizing these presymptomatic disease stages

The Benson Complex Figure Test detects deficits in visuoconstruction and visual memory in symptomatic familial frontotemporal dementia: A GENFI study

Objective: Sensitive cognitive markers are still needed for frontotemporal dementia (FTD). The Benson Complex Figure Test (BCFT) is an interesting candidate test, as it assesses visuospatial, visual memory, and executive abilities, allowing the detection of multiple mechanisms of cognitive impairment. To investigate differences in BCFT Copy, Recall and Recognition in presymptomatic and symptomatic FTD mutation carriers, and to explore its cognitive and neuroimaging correlates.Method: We included cross-sectional data from 332 presymptomatic and 136 symptomatic mutation carriers (GRN, MAPT or C9orf72 mutations), and 290 controls in the GENFI consortium. We examined gene-specific differences between mutation carriers (stratified by CDR (R) NACC-FTLD score) and controls using Quade's / Pearson X2 tests. We investigated associations with neuropsychological test scores and grey matter volume using partial correlations and multiple regression models respectively.Results: No significant differences were found between groups at CDR (R) NACC-FTLD 0-0.5. Symptomatic GRN and C9orf72 mutation carriers had lower Copy scores at CDR (R) NACC-FTLD >= 2. All three groups had lower Recall scores at CDR (R) NACC-FTLD >= 2, with MAPT mutation carriers starting at CDR (R) NACC-FTLD >= 1. All three groups had lower Recognition scores at CDR (R) NACC FTLD >= 2. Performance correlated with tests for visuoconstruction, memory, and executive function. Copy scores correlated with frontal-subcortical grey matter atrophy, while Recall scores correlated with temporal lobe atrophy. Conclusions: In the symptomatic stage, the BCFT identifies differential mechanisms of cognitive impairment depending on the genetic mutation, corroborated by gene-specific cognitive and neuroimaging correlates. Our findings suggest that impaired performance on the BCFT occurs relatively late in the genetic FTD disease process. Therefore its potential as cognitive biomarker for upcoming clinical trials in presymptomatic to early-stage FTD is most likely limited

Characterizing the Clinical Features and Atrophy Patterns of MAPT-Related Frontotemporal Dementia With Disease Progression Modeling.

BACKGROUND AND OBJECTIVE: Mutations in the MAPT gene cause frontotemporal dementia (FTD). Most previous studies investigating the neuroanatomical signature of MAPT mutations have grouped all different mutations together and shown an association with focal atrophy of the temporal lobe. The variability in atrophy patterns between each particular MAPT mutation is less well-characterized. We aimed to investigate whether there were distinct groups of MAPT mutation carriers based on their neuroanatomical signature. METHODS: We applied Subtype and Stage Inference (SuStaIn), an unsupervised machine learning technique that identifies groups of individuals with distinct progression patterns, to characterize patterns of regional atrophy in MAPT-associated FTD within the Genetic FTD Initiative (GENFI) cohort study. RESULTS: Eighty-two MAPT mutation carriers were analyzed, the majority of whom had P301L, IVS10+16, or R406W mutations, along with 48 healthy noncarriers. SuStaIn identified 2 groups of MAPT mutation carriers with distinct atrophy patterns: a temporal subtype, in which atrophy was most prominent in the hippocampus, amygdala, temporal cortex, and insula; and a frontotemporal subtype, in which atrophy was more localized to the lateral temporal lobe and anterior insula, as well as the orbitofrontal and ventromedial prefrontal cortex and anterior cingulate. There was one-to-one mapping between IVS10+16 and R406W mutations and the temporal subtype and near one-to-one mapping between P301L mutations and the frontotemporal subtype. There were differences in clinical symptoms and neuropsychological test scores between subtypes: the temporal subtype was associated with amnestic symptoms, whereas the frontotemporal subtype was associated with executive dysfunction. CONCLUSION: Our results demonstrate that different MAPT mutations give rise to distinct atrophy patterns and clinical phenotype, providing insights into the underlying disease biology and potential utility for patient stratification in therapeutic trials.National Institute for Health Research Cambridge Biomedical Research Centre Medical Research Counci

High Levels of Exosomes Expressing CD63 and Caveolin-1 in Plasma of Melanoma Patients

BACKGROUND: Metastatic melanoma is an untreatable cancer lacking reliable and non-invasive markers of disease progression. Exosomes are small vesicles secreted by normal as well as tumor cells. Human tumor-derived exosomes are involved in malignant progression and we evaluated the presence of exosomes in plasma of melanoma patients as a potential tool for cancer screening and follow-up. METHODOLOGY/PRINCIPAL FINDINGS: We designed an in-house sandwich ELISA (Exotest) to capture and quantify exosomes in plasma based on expression of housekeeping proteins (CD63 and Rab-5b) and a tumor-associated marker (caveolin-1). Western blot and flow cytometry analysis of exosomes were used to confirm the Exotest-based findings. The Exotest allowed sensitive detection and quantification of exosomes purified from human tumor cell culture supernatants and plasma from SCID mice engrafted with human melanoma. Plasma levels of exosomes in melanoma-engrafted SCID mice correlated to tumor size. We evaluated the levels of plasma exosomes expressing CD63 and caveolin-1 in melanoma patients (n = 90) and healthy donors (n = 58). Consistently, plasma exosomes expressing CD63 (504+/-315) or caveolin-1 (619+/-310) were significantly increased in melanoma patients as compared to healthy donors (223+/-125 and 228+/-102, respectively). While the Exotest for CD63+ plasma exosomes had limited sensitivity (43%) the Exotest for detection of caveolin-1+ plasma exosomes showed a higher sensitivity (68%). Moreover, caveolin-1+ plasma exosomes were significantly increased with respect to CD63+ exosomes in the patients group. CONCLUSIONS/SIGNIFICANCE: We describe a new non-invasive assay allowing detection and quantification of human exosomes in plasma of melanoma patients. Our results suggest that the Exotest for detection of plasma exosomes carrying tumor-associated antigens may represent a novel tool for clinical management of cancer patients

Social cognition impairment in genetic frontotemporal dementia within the GENFI cohort.

A key symptom of frontotemporal dementia (FTD) is difficulty interacting socially with others. Social cognition problems in FTD include impaired emotion processing and theory of mind difficulties, and whilst these have been studied extensively in sporadic FTD, few studies have investigated them in familial FTD. Facial Emotion Recognition (FER) and Faux Pas (FP) recognition tests were used to study social cognition within the Genetic Frontotemporal Dementia Initiative (GENFI), a large familial FTD cohort of C9orf72, GRN, and MAPT mutation carriers. 627 participants undertook at least one of the tasks, and were separated into mutation-negative healthy controls, presymptomatic mutation carriers (split into early and late groups) and symptomatic mutation carriers. Groups were compared using a linear regression model with bootstrapping, adjusting for age, sex, education, and for the FP recognition test, language. Neural correlates of social cognition deficits were explored using a voxel-based morphometry (VBM) study. All three of the symptomatic genetic groups were impaired on both tasks with no significant difference between them. However, prior to onset, only the late presymptomatic C9orf72 mutation carriers on the FER test were impaired compared to the control group, with a subanalysis showing differences particularly in fear and sadness. The VBM analysis revealed that impaired social cognition was mainly associated with a left hemisphere predominant network of regions involving particularly the striatum, orbitofrontal cortex and insula, and to a lesser extent the inferomedial temporal lobe and other areas of the frontal lobe. In conclusion, theory of mind and emotion processing abilities are impaired in familial FTD, with early changes occurring prior to symptom onset in C9orf72 presymptomatic mutation carriers. Future work should investigate how performance changes over time, in order to gain a clearer insight into social cognitive impairment over the course of the disease

Prodromal language impairment in genetic frontotemporal dementia within the GENFI cohort

Objective: To identify whether language impairment exists presymptomatically in genetic frontotemporal dementia (FTD), and if so, the key differences between the main genetic mutation groups. Methods: 682 participants from the international multicentre Genetic FTD Initiative (GENFI) study were recruited: 290 asymptomatic and 82 prodromal mutation carriers (with C9orf72, GRN, and MAPT mutations) as well as 310 mutation-negative controls. Language was assessed using items from the Progressive Aphasia Severity Scale, as well as the Boston Naming Test (BNT), modified Camel and Cactus Test (mCCT) and a category fluency task. Participants also underwent a 3 T volumetric T1-weighted MRI from which regional brain volumes within the language network were derived and compared between the groups. Results: 3% of asymptomatic (4% C9orf72, 4% GRN, 2% MAPT) and 48% of prodromal (46% C9orf72, 42% GRN, 64% MAPT) mutation carriers had impairment in at least one language symptom compared with 13% of controls. In prodromal mutation carriers significantly impaired word retrieval was seen in all three genetic groups whilst significantly impaired grammar/syntax and decreased fluency was seen only in C9orf72 and GRN mutation carriers, and impaired articulation only in the C9orf72 group. Prodromal MAPT mutation carriers had significant impairment on the category fluency task and the BNT whilst prodromal C9orf72 mutation carriers were impaired on the category fluency task only. Atrophy in the dominant perisylvian language regions differed between groups, with earlier, more widespread volume loss in C9orf72, and later focal atrophy in the temporal lobe in MAPT mutation carriers. Conclusions: Language deficits exist in the prodromal but not asymptomatic stages of genetic FTD across all three genetic groups. Improved understanding of the language phenotype prior to phenoconversion to fully symptomatic FTD will help develop outcome measures for future presymptomatic trials

Impairment of episodic memory in genetic frontotemporal dementia: A GENFI study.

Introduction: We aimed to assess episodic memory in genetic frontotemporal dementia (FTD) with the Free and Cued Selective Reminding Test (FCSRT). Methods: The FCSRT was administered in 417 presymptomatic and symptomatic mutation carriers (181 chromosome 9 open reading frame 72 [C9orf72], 163 progranulin [GRN], and 73 microtubule-associated protein tau [MAPT]) and 290 controls. Group differences and correlations with other neuropsychological tests were examined. We performed voxel-based morphometry to investigate the underlying neural substrates of the FCSRT. Results: All symptomatic mutation carrier groups and presymptomatic MAPT mutation carriers performed significantly worse on all FCSRT scores compared to controls. In the presymptomatic C9orf72 group, deficits were found on all scores except for the delayed total recall task, while no deficits were found in presymptomatic GRN mutation carriers. Performance on the FCSRT correlated with executive function, particularly in C9orf72 mutation carriers, but also with memory and naming tasks in the MAPT group. FCSRT performance also correlated with gray matter volumes of frontal, temporal, and subcortical regions in C9orf72 and GRN, but mainly temporal areas in MAPT mutation carriers. Discussion: The FCSRT detects presymptomatic deficits in C9orf72- and MAPT-associated FTD and provides important insight into the underlying cause of memory impairment in different forms of FTD