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Maria Luz Cuadrado - One of the best experts on this subject based on the ideXlab platform.

  • The clinical, histologic, and genotypic spectrum of SEPN1 -related myopathy
    Neurology, 2020
    Co-Authors: Rocio Villar-quiles, Maja Von Der Hagen, Corinne Métay, Victoria Gonzalez, Sandra Donkervoort, Enrico Bertini, Claudia Castiglioni, Denys Chaigne, Jaume Colomer, Maria Luz Cuadrado
    Abstract:

    Objective: To clarify the prevalence, long-term natural history, and severity determinants of SEPN1-related myopathy (SEPN1-RM), we analyzed a large international case series. Methods: Retrospective clinical, histologic, and genetic analysis of 132 pediatric and adult patients (2-58 years) followed up for several decades. Results: The clinical phenotype was marked by severe axial muscle weakness, spinal rigidity, and scoliosis (86.1%, from 8.9 ± 4 years), with relatively preserved limb strength and previously unreported ophthalmoparesis in severe cases. All patients developed respiratory failure (from 10.1±6 years), 81.7% requiring ventilation while ambulant. Histopathologically, 79 muscle biopsies showed large variability, partly determined by site of biopsy and Age. Multi-minicores were the most common lesion (59.5%), often associated with mild dystrophic features and occasionally with eosinophilic inclusions. Identification of 65 SEPN1 mutations, including 32 novel ones and the first pathogenic copy number variation, unveiled exon 1 as the main mutational hotspot and revealed the first genotype-phenotype correlations, bi-allelic null mutations being significantly associated with disease severity (p = 0.017). SEPN1-RM was more severe and progressive than previously thought, leading to loss of ambulation in 10% of cases, systematic functional decline from the end of the third decade, and reduced lifespan even in mild cases. The main prognosis determinants were scoliosis/respiratory manAgement, SEPN1 mutations, and body mass abnormalities, which correlated with disease severity. We propose a set of severity criteria, provide quantitative data for outcome identification, and establish a need for Age Stratification. Conclusion: Our results inform clinical practice, improving diagnosis and manAgement, and represent a major breakthrough for clinical trial readiness in this not so rare disease.

  • the clinical histologic and genotypic spectrum of sepn1 related myopathy a case series
    Neurology, 2020
    Co-Authors: Rocio Nur Villarquiles, Maja Von Der Hagen, Corinne Métay, Victoria Gonzalez, Sandra Donkervoort, Enrico Bertini, Claudia Castiglioni, Denys Chaigne, Jaume Colomer, Maria Luz Cuadrado
    Abstract:

    Objective To clarify the prevalence, long-term natural history, and severity determinants of SEPN1-related myopathy (SEPN1-RM), we analyzed a large international case series. Methods Retrospective clinical, histologic, and genetic analysis of 132 pediatric and adult patients (2–58 years) followed up for several decades. Results The clinical phenotype was marked by severe axial muscle weakness, spinal rigidity, and scoliosis (86.1%, from 8.9 ± 4 years), with relatively preserved limb strength and previously unreported ophthalmoparesis in severe cases. All patients developed respiratory failure (from 10.1±6 years), 81.7% requiring ventilation while ambulant. Histopathologically, 79 muscle biopsies showed large variability, partly determined by site of biopsy and Age. Multi-minicores were the most common lesion (59.5%), often associated with mild dystrophic features and occasionally with eosinophilic inclusions. Identification of 65 SEPN1 mutations, including 32 novel ones and the first pathogenic copy number variation, unveiled exon 1 as the main mutational hotspot and revealed the first genotype–phenotype correlations, bi-allelic null mutations being significantly associated with disease severity (p = 0.017). SEPN1-RM was more severe and progressive than previously thought, leading to loss of ambulation in 10% of cases, systematic functional decline from the end of the third decade, and reduced lifespan even in mild cases. The main prognosis determinants were scoliosis/respiratory manAgement, SEPN1 mutations, and body mass abnormalities, which correlated with disease severity. We propose a set of severity criteria, provide quantitative data for outcome identification, and establish a need for Age Stratification. Conclusion Our results inform clinical practice, improving diagnosis and manAgement, and represent a major breakthrough for clinical trial readiness in this not so rare disease.

Lu Shen - One of the best experts on this subject based on the ideXlab platform.

  • multiple visual rating scales based on structural mri and a novel prediction model combining visual rating scales and Age Stratification in the diagnosis of alzheimer s disease in the chinese population
    Frontiers in Neurology, 2019
    Co-Authors: Zhenhua Yuan, Chuzheng Pan, Tingting Xiao, Menghui Liu, Weiwei Zhang, Bin Jiao, Xinxiang Yan, Beisha Tang, Lu Shen
    Abstract:

    Objective: To explore the value of multiple visual rating scales based on structural MRI in the diagnosis of Alzheimer’s disease (AD) in the Chinese population. Materials and Methods: One hundred patients with AD and 100 Age- and gender- matched cognitively normal controls were enrolled in this study. All the participants underwent neuropsychological tests and a structural MRI scan of the brain, among them, 42 AD cases and 47 cognitively normal controls also underwent 3D-T1 weighted sequence used for the analysis of voxel-based morphometry (VBM). The AD cases were divided into mild and moderate–severe groups according to the mini-mental state examination. Each participant was evaluated by two trained radiologists who were blind to the clinical information, according to the six visual rating scales, including for medial temporal lobe atrophy (MTA), posterior atrophy (PA), anterior temporal (AT), orbitofrontal (OF) cortex, anterior cingulate (AC), and fronto-insula (FI). Finally, we estimated the relationship between the visual rating scales and the volume of corresponding brain regions, using correlation analysis, and evaluated the specificity and sensitivity of every single scale and combination of multiple scales in the diagnosis of AD, using a receiver operating characteristic (ROC) curve and establishing a logistic regression model. Results: The optimal cutoff of all six visual rating scales for distinguishing AD cases from normal controls was 1.5. Using automated classification based on all six rating scales, the accuracy for distinguishing AD cases from healthy controls ranged from 0.68-0.80 (for mild AD) and 0.77-0.90 (for moderate–severe AD), respectively. A diagnostic prediction model with a combination of MTA and OF results was made as follows: Score = BMTA(score) + BOF(score) –1.58 (Age <65 years); Score = BMTA(score) + BOF(score) –4.09 (Age ≥65 years). The model was superior to any single visual rating scale in the diagnosis of mild AD (P <0.05). Conclusion: Each of the six visual rating scales could be applied to the diagnosis of moderate-severe AD alone in the Chinese population. A prediction model of the combined usAge of MTA, OF, and Age Stratification for the early diagnosis of AD was preliminarily established.

Zhenhua Yuan - One of the best experts on this subject based on the ideXlab platform.

  • multiple visual rating scales based on structural mri and a novel prediction model combining visual rating scales and Age Stratification in the diagnosis of alzheimer s disease in the chinese population
    Frontiers in Neurology, 2019
    Co-Authors: Zhenhua Yuan, Chuzheng Pan, Tingting Xiao, Menghui Liu, Weiwei Zhang, Bin Jiao, Xinxiang Yan, Beisha Tang, Lu Shen
    Abstract:

    Objective: To explore the value of multiple visual rating scales based on structural MRI in the diagnosis of Alzheimer’s disease (AD) in the Chinese population. Materials and Methods: One hundred patients with AD and 100 Age- and gender- matched cognitively normal controls were enrolled in this study. All the participants underwent neuropsychological tests and a structural MRI scan of the brain, among them, 42 AD cases and 47 cognitively normal controls also underwent 3D-T1 weighted sequence used for the analysis of voxel-based morphometry (VBM). The AD cases were divided into mild and moderate–severe groups according to the mini-mental state examination. Each participant was evaluated by two trained radiologists who were blind to the clinical information, according to the six visual rating scales, including for medial temporal lobe atrophy (MTA), posterior atrophy (PA), anterior temporal (AT), orbitofrontal (OF) cortex, anterior cingulate (AC), and fronto-insula (FI). Finally, we estimated the relationship between the visual rating scales and the volume of corresponding brain regions, using correlation analysis, and evaluated the specificity and sensitivity of every single scale and combination of multiple scales in the diagnosis of AD, using a receiver operating characteristic (ROC) curve and establishing a logistic regression model. Results: The optimal cutoff of all six visual rating scales for distinguishing AD cases from normal controls was 1.5. Using automated classification based on all six rating scales, the accuracy for distinguishing AD cases from healthy controls ranged from 0.68-0.80 (for mild AD) and 0.77-0.90 (for moderate–severe AD), respectively. A diagnostic prediction model with a combination of MTA and OF results was made as follows: Score = BMTA(score) + BOF(score) –1.58 (Age <65 years); Score = BMTA(score) + BOF(score) –4.09 (Age ≥65 years). The model was superior to any single visual rating scale in the diagnosis of mild AD (P <0.05). Conclusion: Each of the six visual rating scales could be applied to the diagnosis of moderate-severe AD alone in the Chinese population. A prediction model of the combined usAge of MTA, OF, and Age Stratification for the early diagnosis of AD was preliminarily established.

Kevin Bishop - One of the best experts on this subject based on the ideXlab platform.

  • Catchment-scale groundwater Age Stratification reveals groundwater recharge and discharge processes
    2020
    Co-Authors: Tamara Kolbe, Jean Marçais, Jean-raynald De Dreuzy, Thierry Labasque, Kevin Bishop
    Abstract:

    The distribution of groundwater Ages with depth provides information about subsurface structures and flow dynamics. Upslope measured groundwater Age Stratifications are commonly used to estimate groundwater recharge rates, whereas downslope measured Age Stratifications are influenced by recharge conditions, the aquifer structure and interactions between groundwater and surface water. In our study we address the question whether downslope measured groundwater Ages from different locations can provide spatial and temporal information about catchment-scale groundwater dynamics and the relationship between groundwater recharge and discharge. We derived an overall groundwater Age Stratification, representative for the Svartberget subcatchment (0.47 km2) located within the Krycklan study site, by measuring CFCs from 9 different sampling locations with depths of 2 m to 18 m. All sampling locations were downslope and located in basal till which is overlain by ablation till. The CFC-based groundwater Age Stratification reveals an unexpected pattern, with groundwater Ages of already 30 years immediately below the water table. Groundwater Ages increase then with depth. We could reproduce the observed groundwater Age Stratification by using a groundwater flow model and show that the lag of rejuvenation, noticeable in groundwater Ages of 30 years at the water table, derives from return flow of groundwater at a subsurface discharge zone that evolves at the interface between the two soil types (basal and ablation till). Furthermore, we demonstrate by varying the infiltration rate how the extent of the discharge zone and the partitioning of the infiltration amount to the two layers change, i.e. young runoff in the upper layer (ablation till) and old groundwater circulation through the deeper layer (basal till). By providing a simple analytical approximations of the observed groundwater Age Stratification, we show that the extent of the subsurface discharge zone is a powerful indicator of the relation between the recharge and discharge zone, while the vertical gradient of the Age-depth relationship provides information about the overall aquifer recharge.

  • Lagged rejuvenation of groundwater indicates internal flow structures and hydrological connectivity
    Hydrological Processes, 2020
    Co-Authors: Tamara Kolbe, Jean Marçais, Jean-raynald De Dreuzy, Thierry Labasque, Kevin Bishop
    Abstract:

    Large proportions of rain water and snowmelt infiltrate into the subsurface before contributing to stream flow and stream water quality. Subsurface flow dynamics steer the transport and transformation of contaminants, carbon, weathering products and other biogeochemistry. The distribution of groundwater Ages with depth is a key feature of these flow dynamics. Predicting these Ages are a strong test of hypotheses about subsurface structures and time varying processes. CFC‐based groundwater Ages revealed an unexpected groundwater Age Stratification in a 0.47 km2 forested catchment called Svartberget in northern Sweden. An overall groundwater Age Stratification, representative for the Svartberget site, was derived by measuring CFCs from 9 different wells with depths of 2 m to 18 m close to the stream network. Immediately below the water table, CFC‐based groundwater Ages of already 30 years that increased with depth were found. Using complementary groundwater flow models, we could reproduce the observed groundwater Age Stratification and show that the 30 year lag in rejuvenation comes from return flow of groundwater at a subsurface discharge zone that evolves along the interface between two soil types. By comparing the observed groundwater Age Stratification with a simple analytical approximation, we show that the observed lag in rejuvenation can be a powerful indicator of the extent and structure of the subsurface discharge zone, while the vertical gradient of the Age‐depth relationship can still be used as a proxy of the overall aquifer recharge even when sampled in the discharge zone. The single Age Stratification profile measured in the discharge zone, close to the aquifer outlet, can reveal the main structure of the groundwater flow pattern from recharge to discharge. This groundwater flow pattern provides information on the participation of groundwater in the hydrological cycle and indicates the lower boundary of hydrological connectivity.

  • Hydrological disconnection of deep groundwater in Krycklan
    2018
    Co-Authors: Tamara Kolbe, Jean-raynald De Dreuzy, Kevin Bishop
    Abstract:

    Water residence times are useful descriptors of hydrological connectivity. Hydrological connectivity and disconnection within or between compartments of a catchment has been demonstrated to determine temporal and spatial variations in runoff processes as well as the export of weathering products or other solutes. In Krycklan, a 67 km2 forested catchment with long-term monitoring in northern Sweden, water stable isotopes and modeling revealed an active flow zone in the upper 1-2 m getting temporally connected/disconnected to the stream. Residence times (mean residence time = 12 y) and water storAge vary between seasons that are well-marked like in other northern catchments. Hydraulic conductivity decreases quickly with depth creating this active flow zone and disconnecting the deeper groundwater under certain climatic conditions. The deep groundwater has been found to contribute to streamflow and to affect stream water chemistry without having further information about timescales of deep groundwater flow or any measure for the extend of the hydrological connectivity between these two groundwater compartments. We compile findings of previous studies regarding water residence times and water storAge of the upper active flow zone while providing new data about the deeper groundwater. We measured chlorofluorocarbons (CFCs) at several locations distributed within the Krycklan catchment. All samples were taken in glacial till and sampling depths varied between 2 and 18 m. We found relatively old CFC based groundwater Ages of 28 years at just 2 m depth increasing up to 55 years at 18 m depth. Groundwater Age Stratification follows a logarithmic increase with depth showing a remarkable shift of 28 years. This shift of CFC based groundwater Ages represents a hydrological disconnection of the deeper groundwater to the upper active flow zone. The analysis of groundwater Age Stratification provides the basis for further investigations of relative contributions of the two zones to the overall water storAge. The observed hydrological disconnection might be also relevant in other forested catchments with low groundwater recharge rates or other northern catchments with similar climatic conditions.

Ion De Andrade - One of the best experts on this subject based on the ideXlab platform.

  • covid 19 pandemics modeling with modified determinist seir social distancing and Age Stratification the effect of vertical confinement and release in brazil
    PLOS ONE, 2020
    Co-Authors: W Lyra, Josedias Do Nascimento, Jaber Belkhiria, Leandro De Almeida, Pedro Paulo M Chrispim, Ion De Andrade
    Abstract:

    The ongoing COVID-19 epidemics poses a particular challenge to low and middle income countries, making some of them consider the strategy of "vertical confinement". In this strategy, contact is reduced only to specific groups (e.g. Age groups) that are at increased risk of severe disease following SARS-CoV-2 infection. We aim to assess the feasibility of this scenario as an exit strategy for the current lockdown in terms of its ability to keep the number of cases under the health care system capacity. We developed a modified SEIR model, including confinement, asymptomatic transmission, quarantine and hospitalization. The population is subdivided into 9 Age groups, resulting in a system of 72 coupled nonlinear differential equations. The rate of transmission is dynamic and derived from the observed delayed fatality rate; the parameters of the epidemics are derived with a Markov chain Monte Carlo algorithm. We used Brazil as an example of middle income country, but the results are easily generalizable to other countries considering a similar strategy. We find that starting from 60% horizontal confinement, an exit strategy on May 1st of confinement of individuals older than 60 years old and full release of the younger population results in 400 000 hospitalizations, 50 000 ICU cases, and 120 000 deaths in the 50-60 years old Age group alone. Sensitivity analysis shows the 95% confidence interval brackets a order of magnitude in cases or three weeks in time. The health care system avoids collapse if the 50-60 years old are also confined, but our model assumes an idealized lockdown where the confined are perfectly insulated from contamination, so our numbers are a conservative lower bound. Our results discourAge confinement by Age as an exit strategy.

  • covid 19 pandemics modeling with seir caqh social distancing and Age Stratification the effect of vertical confinement and release in brazil
    medRxiv, 2020
    Co-Authors: W Lyra, Josedias Do Nascimento, Jaber Belkhiria, Leandro De Almeida, Pedro Paulo M Chrispim, Ion De Andrade
    Abstract:

    The ongoing COVID-19 epidemics poses a particular challenge to low and middle income countries, making some of them consider the strategy of vertical confinement. In this strategy, contact is reduced only to specific groups (like Age groups) that are at increased risk of severe disease following SARS-CoV-2 infection. We aim to assess the feasibility of this scenario as an exit strategy for the current lockdown in terms of its ability to keep the number of cases under the health care system capacity. We developed a modified SEIR model, including confinement, asymptomatic transmission, quarantine and hospitalization. The population is subdivided into 9 Age groups, resulting in a system of 72 coupled nonlinear differential equations. The rate of transmission is dynamic and derived from the observed delayed fatality rate; the parameters of the epidemics are derived with a Markov chain Monte Carlo algorithm. We used Brazil as an example of middle income country, but the results are easily generalizable to other countries considering a similar strategy. We find that starting from 60% horizontal confinement, an exit strategy on May 1st of confinement of individuals older than 60 years old and full release of the younger population results in 400 000 hospitalizations, 50 000 ICU cases, and 120 000 deaths in the 50-60 years old Age group alone. The health care system avoids collapse if the 50-60 years old are also confined, but our model assumes an idealized lockdown where the confined are perfectly insulated from contamination, so our numbers are a conservative lower bound. Our results discourAge confinement by Age as an exit strategy.