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1.
Nature ; 594(7862): 271-276, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33910229

RESUMEN

Vascular malformations are thought to be monogenic disorders that result in dysregulated growth of blood vessels. In the brain, cerebral cavernous malformations (CCMs) arise owing to inactivation of the endothelial CCM protein complex, which is required to dampen the activity of the kinase MEKK31-4. Environmental factors can explain differences in the natural history of CCMs between individuals5, but why single CCMs often exhibit sudden, rapid growth, culminating in strokes or seizures, is unknown. Here we show that growth of CCMs requires increased signalling through the phosphatidylinositol-3-kinase (PI3K)-mTOR pathway as well as loss of function of the CCM complex. We identify somatic gain-of-function mutations in PIK3CA and loss-of-function mutations in the CCM complex in the same cells in a majority of human CCMs. Using mouse models, we show that growth of CCMs requires both PI3K gain of function and CCM loss of function in endothelial cells, and that both CCM loss of function and increased expression of the transcription factor KLF4 (a downstream effector of MEKK3) augment mTOR signalling in endothelial cells. Consistent with these findings, the mTORC1 inhibitor rapamycin effectively blocks the formation of CCMs in mouse models. We establish a three-hit mechanism analogous to cancer, in which aggressive vascular malformations arise through the loss of vascular 'suppressor genes' that constrain vessel growth and gain of a vascular 'oncogene' that stimulates excess vessel growth. These findings suggest that aggressive CCMs could be treated using clinically approved mTORC1 inhibitors.


Asunto(s)
Fosfatidilinositol 3-Quinasa Clase I/genética , Hemangioma Cavernoso del Sistema Nervioso Central/genética , Hemangioma Cavernoso del Sistema Nervioso Central/patología , Mutación , Neoplasias/genética , Animales , Animales Recién Nacidos , Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Modelos Animales de Enfermedad , Células Endoteliales/metabolismo , Células Endoteliales/patología , Mutación con Ganancia de Función , Hemangioma Cavernoso del Sistema Nervioso Central/irrigación sanguínea , Hemangioma Cavernoso del Sistema Nervioso Central/metabolismo , Humanos , Factor 4 Similar a Kruppel , Factores de Transcripción de Tipo Kruppel/metabolismo , Mutación con Pérdida de Función , MAP Quinasa Quinasa Quinasa 3/metabolismo , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina/antagonistas & inhibidores , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Ratones , Neoplasias/irrigación sanguínea , Neoplasias/patología , Sirolimus/farmacología , Serina-Treonina Quinasas TOR/metabolismo
2.
Stroke ; 55(1): 31-39, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-38134265

RESUMEN

BACKGROUND: Quantitative susceptibility mapping (QSM) and dynamic contrast-enhanced quantitative perfusion (DCEQP) magnetic resonance imaging sequences assessing iron deposition and vascular permeability were previously correlated with new hemorrhage in cerebral cavernous malformations. We assessed their prospective changes in a multisite trial-readiness project. METHODS: Patients with cavernous malformation and symptomatic hemorrhage (SH) in the prior year, without prior or planned lesion resection or irradiation were enrolled. Mean QSM and DCEQP of the SH lesion were acquired at baseline and at 1- and 2-year follow-ups. Sensitivity and specificity of biomarker changes were analyzed in relation to predefined criteria for recurrent SH or asymptomatic change. Sample size calculations for hypothesized therapeutic effects were conducted. RESULTS: We logged 143 QSM and 130 DCEQP paired annual assessments. Annual QSM change was greater in cases with SH than in cases without SH (P=0.019). Annual QSM increase by ≥6% occurred in 7 of 7 cases (100%) with recurrent SH and in 7 of 10 cases (70%) with asymptomatic change during the same epoch and 3.82× more frequently than clinical events. DCEQP change had lower sensitivity for SH and asymptomatic change than QSM change and greater variance. A trial with the smallest sample size would detect a 30% difference in QSM annual change during 2 years of follow-up in 34 or 42 subjects (1 and 2 tailed, respectively); power, 0.8, α=0.05. CONCLUSIONS: Assessment of QSM change is feasible and sensitive to recurrent bleeding in cavernous malformations. Evaluation of an intervention on QSM percent change may be used as a time-averaged difference between 2 arms using a repeated measures analysis. DCEQP change is associated with lesser sensitivity and higher variability than QSM. These results are the basis of an application for certification by the US Food and Drug Administration of QSM as a biomarker of drug effect on bleeding in cavernous malformations. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03652181.


Asunto(s)
Hemangioma Cavernoso del Sistema Nervioso Central , Hemorragia , Humanos , Estudios Prospectivos , Hemorragia/etiología , Hemorragia/complicaciones , Hemangioma Cavernoso del Sistema Nervioso Central/complicaciones , Hemangioma Cavernoso del Sistema Nervioso Central/diagnóstico por imagen , Hemangioma Cavernoso del Sistema Nervioso Central/patología , Biomarcadores , Imagen por Resonancia Magnética/métodos , Hemorragia Cerebral/diagnóstico por imagen , Hemorragia Cerebral/complicaciones
3.
Haemophilia ; 30(4): 988-997, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38698539

RESUMEN

INTRODUCTION: Plasminogen deficiency is an ultra rare disease whose patients may develop ligneous lesions if untreated. Prophylactic replacement therapy with plasma derived plasminogen, Ryplazim, is efficient in treating lesions and could benefit from pharmacokinetic (PK) tailoring. AIM: The objectives of this study are to develop, evaluate and integrate into the WAPPS-Hemo platform a Population PK model supporting prophylactic replacement therapy for Plasminogen deficient patients. METHODS: Population PK modelling and evaluations followed the same protocol performed for factor VIII and IX concentrates. Limited sampling analysis used dosing and sampling scenarios in accordance with recommended treatment for Ryplazim. RESULTS: The population PK model, derived from 16 participants included in previous clinical studies, was a 2-compartment model whose variability was best described by fat-free mass. Evaluations showed that the model described well the data and Bayesian forecasting in limited sampling environment led to acceptable precision for PK parameters relevant to plasminogen treatment. CONCLUSION: The model was integrated into the WAPPS-Hemo webservice to help individualize prophylactic treatment in plasminogen deficient patients. Prospective PK data to be collected through the WAPPS-Hemo database will be used to better understand plasminogen PK and improve patient care.


Asunto(s)
Plasminógeno , Humanos , Plasminógeno/deficiencia , Plasminógeno/uso terapéutico
4.
Nature ; 545(7654): 305-310, 2017 05 18.
Artículo en Inglés | MEDLINE | ID: mdl-28489816

RESUMEN

Cerebral cavernous malformations (CCMs) are a cause of stroke and seizure for which no effective medical therapies yet exist. CCMs arise from the loss of an adaptor complex that negatively regulates MEKK3-KLF2/4 signalling in brain endothelial cells, but upstream activators of this disease pathway have yet to be identified. Here we identify endothelial Toll-like receptor 4 (TLR4) and the gut microbiome as critical stimulants of CCM formation. Activation of TLR4 by Gram-negative bacteria or lipopolysaccharide accelerates CCM formation, and genetic or pharmacologic blockade of TLR4 signalling prevents CCM formation in mice. Polymorphisms that increase expression of the TLR4 gene or the gene encoding its co-receptor CD14 are associated with higher CCM lesion burden in humans. Germ-free mice are protected from CCM formation, and a single course of antibiotics permanently alters CCM susceptibility in mice. These studies identify unexpected roles for the microbiome and innate immune signalling in the pathogenesis of a cerebrovascular disease, as well as strategies for its treatment.


Asunto(s)
Microbioma Gastrointestinal/inmunología , Hemangioma Cavernoso del Sistema Nervioso Central/inmunología , Hemangioma Cavernoso del Sistema Nervioso Central/patología , Inmunidad Innata , Receptor Toll-Like 4/inmunología , Animales , Antibacterianos/administración & dosificación , Antibacterianos/farmacología , Susceptibilidad a Enfermedades , Células Endoteliales/metabolismo , Femenino , Vida Libre de Gérmenes , Bacterias Gramnegativas/inmunología , Hemangioma Cavernoso del Sistema Nervioso Central/microbiología , Humanos , Inyecciones Intravenosas , Receptores de Lipopolisacáridos/genética , Receptores de Lipopolisacáridos/metabolismo , Lipopolisacáridos/administración & dosificación , Lipopolisacáridos/inmunología , Masculino , Ratones , Transducción de Señal , Receptor Toll-Like 4/antagonistas & inhibidores , Receptor Toll-Like 4/deficiencia , Receptor Toll-Like 4/genética
5.
J Magn Reson Imaging ; 55(5): 1440-1449, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-34558140

RESUMEN

BACKGROUND: Cerebral cavernous angioma (CA) is a capillary vasculopathy affecting more than a million Americans with a small fraction of cases demonstrating lesional bleed or growth with major clinical sequelae. Perfusion and permeability are fundamental features of CA pathophysiology, but their role as prognostic biomarkers is unclear. PURPOSE: To investigate whether perfusion or permeability lesional descriptors derived from dynamic contrast-enhanced quantitative perfusion (DCEQP) magnetic resonance imaging (MRI) can predict subsequent lesional bleed/growth in the year following imaging. STUDY TYPE: Single-site case-controlled study. SUBJECTS: Two hundred and five consecutively enrolled patients (63.4% female). FIELD STRENGTH/SEQUENCE: Three-Tesla/T1 -mapping with contrast-enhanced dynamic two-dimensional (2D) spoiled gradient recalled acquisition (SPGR) sequences. ASSESSMENT: Prognostic associations with bleed/growth (present or absent) in the following year were assessed in 745 CA lesions evaluated by DCEQP in the 205 patients in relation to lesional descriptors calculated from permeability and perfusion maps. A subgroup of 30 cases also underwent peripheral blood collection at the time of DCEQP scans and assays of plasma levels of soluble CD14, IL-1ß, VEGF, and soluble ROBO4 proteins, whose weighted combination had been previously reported in association with future CA bleeding. STATISTICAL TESTS: Mann-Whitney U-test for univariate analyses. Logistic regression models minimizing the Bayesian information criterion (BIC), testing sensitivity and specificity (receiver operating characteristic curves) of weighted combinations of parameters. RESULTS: The best prognostic biomarker for lesional bleed or growth included brainstem lesion location, mean lesional permeability, and low-value perfusion cluster mean (BIC = 201.5, sensitivity = 77%, specificity = 72%, P < 0.05). Adding a previously published prognostic plasma protein biomarker improved the performance of the imaging model (sensitivity = 100%, specificity = 88%, P < 0.05). DATA CONCLUSION: A combination of MRI-based descriptors reflecting higher lesional permeability and lower perfusion cluster may potentially predict future bleed/growth in CAs. The sensitivity and specificity of the prognostic imaging biomarker can be enhanced when combined with brainstem lesion location and a plasma protein biomarker of CA hemorrhage. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 5.


Asunto(s)
Hemangioma Cavernoso , Imagen por Resonancia Magnética , Teorema de Bayes , Biomarcadores , Medios de Contraste , Femenino , Hemangioma Cavernoso/complicaciones , Hemorragia/complicaciones , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Perfusión , Permeabilidad
6.
Stroke ; 52(12): 3829-3838, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34525838

RESUMEN

BACKGROUND AND PURPOSE: Brain cavernous angiomas with symptomatic hemorrhage (CASH) have a high risk of neurological disability from recurrent bleeding. Systematic assessment of baseline features and multisite validation of novel magnetic resonance imaging biomarkers are needed to optimize clinical trial design aimed at novel pharmacotherapies in CASH. METHODS: This prospective, multicenter, observational cohort study included adults with unresected, adjudicated brain CASH within the prior year. Six US sites screened and enrolled patients starting August 2018. Baseline demographics, clinical and imaging features, functional status (modified Rankin Scale and National Institutes of Health Stroke Scale), and patient quality of life outcomes (Patient-Reported Outcomes Measurement Information System-29 and EuroQol-5D) were summarized using descriptive statistics. Patient-Reported Outcomes Measurement Information System-29 scores were standardized against a reference population (mean 50, SD 10), and one-sample t test was performed for each domain. A subgroup underwent harmonized magnetic resonance imaging assessment of lesional iron content with quantitative susceptibility mapping and vascular permeability with dynamic contrast-enhanced quantitative perfusion. RESULTS: As of May 2020, 849 patients were screened and 110 CASH cases enrolled (13% prevalence of trial eligible cases). The average age at consent was 46±16 years, 53% were female, 41% were familial, and 43% were brainstem lesions. At enrollment, ≥90% of the cohort had independent functional outcome (modified Rankin Scale score ≤2 and National Institutes of Health Stroke Scale score <5). However, perceived health problems affecting quality of life were reported in >30% of patients (EuroQol-5D). Patients had significantly worse Patient-Reported Outcomes Measurement Information System-29 scores for anxiety (P=0.007), but better depression (P=0.002) and social satisfaction scores (P=0.012) compared with the general reference population. Mean baseline quantitative susceptibility mapping and permeability of CASH lesion were 0.45±0.17 ppm and 0.39±0.31 mL/100 g per minute, respectively, which were similar to historical CASH cases and consistent across sites. CONCLUSIONS: These baseline features will aid investigators in patient stratification and determining the most appropriate outcome measures for clinical trials of emerging pharmacotherapies in CASH.


Asunto(s)
Neoplasias Encefálicas/complicaciones , Neoplasias Encefálicas/diagnóstico por imagen , Hemorragia Cerebral/etiología , Hemangioma Cavernoso del Sistema Nervioso Central/complicaciones , Hemangioma Cavernoso del Sistema Nervioso Central/diagnóstico por imagen , Adulto , Anciano , Neoplasias Encefálicas/patología , Estudios de Cohortes , Femenino , Hemangioma Cavernoso del Sistema Nervioso Central/patología , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Neuroimagen
7.
Angiogenesis ; 23(4): 651-666, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32710309

RESUMEN

Cerebral cavernous malformations (CCMs) are ectatic capillary-venous malformations that develop in approximately 0.5% of the population. Patients with CCMs may develop headaches, focal neurologic deficits, seizures, and hemorrhages. While symptomatic CCMs, depending upon the anatomic location, can be surgically removed, there is currently no pharmaceutical therapy to treat CCMs. Several mouse models have been developed to better understand CCM pathogenesis and test therapeutics. The most common mouse models induce a large CCM burden that is anatomically restricted to the cerebellum and contributes to lethality in the early days of life. These inducible models thus have a relatively short period for drug administration. We developed an inducible CCM3 mouse model that develops CCMs after weaning and provides a longer period for potential therapeutic intervention. Using this new model, three recently proposed CCM therapies, fasudil, tempol, vitamin D3, and a combination of the three drugs, failed to substantially reduce CCM formation when treatment was administered for 5 weeks, from postnatal day 21 (P21) to P56. We next restricted Ccm3 deletion to the brain vasculature and provided greater time (121 days) for CCMs to develop chronic hemorrhage, recapitulating the human lesions. We also developed the first model of acute CCM hemorrhage by injecting mice harboring CCMs with lipopolysaccharide. These efficient models will enable future drug studies to more precisely target clinically relevant features of CCM disease: CCM formation, chronic hemorrhage, and acute hemorrhage.


Asunto(s)
Hemangioma Cavernoso del Sistema Nervioso Central/patología , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/farmacología , Enfermedad Aguda , Animales , Proteínas Reguladoras de la Apoptosis/deficiencia , Encéfalo/irrigación sanguínea , Encéfalo/patología , Colecalciferol/farmacología , Enfermedad Crónica , Óxidos N-Cíclicos/farmacología , Modelos Animales de Enfermedad , Eliminación de Gen , Hemangioma Cavernoso del Sistema Nervioso Central/complicaciones , Hemorragia/complicaciones , Lipopolisacáridos , Ratones Endogámicos C57BL , Modelos Biológicos , Fenotipo , Marcadores de Spin
8.
J Magn Reson Imaging ; 51(4): 1192-1199, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-31515878

RESUMEN

BACKGROUND: Quantitative susceptibility mapping (QSM) and dynamic contrast-enhanced quantitative permeability (DCEQP) on magnetic resonance (MR) have been shown to correlate with neurovascular disease progression as markers of vascular leakage and hemosiderin deposition. Applying these techniques as monitoring biomarkers in clinical trials will be necessary; however, their validation across multiple MR platforms and institutions has not been rigorously verified. PURPOSE: To validate quantitative measurement of MR biomarkers on multiple instruments at different institutions. STUDY TYPE: Phantom validation between platforms and institutions. PHANTOM MODEL: T1 /susceptibility phantom, two-compartment dynamic flow phantom. FIELD STRENGTH/SEQUENCE: 3T/QSM, T1 mapping, dynamic 2D SPGR. ASSESSMENT: Philips Ingenia, Siemens Prisma, and Siemens Skyra at three different institutions were assessed. A QSM phantom with concentrations of gadolinium, corresponding to magnetic susceptibilities of 0, 0.1, 0.2, 0.4, and 0.8 ppm was assayed. DCEQP was assessed by measuring a MultiHance bolus as the consistency of the width ratio of the curves at the input and outputs over a range of flow ratios between outputs. STATISTICAL TESTS: Each biomarker was assessed by measures of accuracy (Pearson correlation), precision (paired t-test between repeated measurements), and reproducibility (analysis of covariance [ANCOVA] between instruments). RESULTS: QSM accuracy of r2 > 0.997 on all three platforms was measured. Precision (P = 0.66 Achieva, P = 0.76 Prisma, P = 0.69 Skyra) and reproducibility (P = 0.89) were good. T1 mapping of accuracy was r2 > 0.98. No significant difference between width ratio regression slopes at site 2 (P = 0.669) or site 3 (P = 0.305), and no significant difference between width ratio regression slopes between sites was detected by ANCOVA (P = 0.48). DATA CONCLUSION: The phantom performed as expected and determined that MR measures of QSM and DCEQP are accurate and consistent across repeated measurements and between platforms. LEVEL OF EVIDENCE: 1 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2020;51:1192-1199.


Asunto(s)
Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Espectroscopía de Resonancia Magnética , Permeabilidad , Fantasmas de Imagen , Reproducibilidad de los Resultados
9.
Stroke ; 50(3): 738-744, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30744543

RESUMEN

Background and Purpose- Previously, murine models Krit1 +/- Msh2 -/- and Ccm2 +/- Trp53 -/- showed a reduction or no effect on cerebral cavernous malformation (CCM) burden and favorable effects on lesional hemorrhage by the robust Rock (Rho-associated protein kinase) inhibitor fasudil and by simvastatin (a weak pleiotropic inhibitor of Rock). Herein, we concurrently investigated treatment of the more aggressive Pdcd10/Ccm3 model with fasudil, simvastatin, and higher dose atorvastatin to determined effectiveness of Rock inhibition. Methods- The murine models, Pdcd10 +/- Trp53 -/- and Pdcd10 +/- Msh2 -/-, were contemporaneously treated from weaning to 5 months of age with fasudil (100 mg/kg per day in drinking water, n=9), simvastatin (40 mg/kg per day in chow, n=11), atorvastatin (80 mg/kg per day in chow, n=10), or with placebo (n=16). We assessed CCM volume in mouse brains by microcomputed tomography. Lesion burden was calculated as lesion volume normalized to total brain volume. We analyzed chronic hemorrhage in CCM lesions by quantitative intensity of Perls staining in brain sections. Results- The Pdcd10 +/- Trp53 -/- /Msh2 -/- models showed a mean CCM lesion burden per mouse reduction from 0.0091 in placebos to 0.0042 ( P=0.027) by fasudil, and to 0.0047 ( P=0.025) by atorvastatin treatment, but was not changed significantly by simvastatin. Hemorrhage intensity per brain was commensurately decreased by Rock inhibition. Conclusions- These results support the exploration of proof of concept effect of high-dose atorvastatin on human CCM disease for potential therapeutic testing.


Asunto(s)
Inhibidores Enzimáticos/uso terapéutico , Hemangioma Cavernoso del Sistema Nervioso Central/tratamiento farmacológico , Hemangioma Cavernoso del Sistema Nervioso Central/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Hemorragias Intracraneales/tratamiento farmacológico , Hemorragias Intracraneales/genética , Quinasas Asociadas a rho/antagonistas & inhibidores , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/uso terapéutico , Animales , Proteínas Reguladoras de la Apoptosis , Atorvastatina/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hemorragias Intracraneales/diagnóstico por imagen , Proteína KRIT1/genética , Ratones , Ratones Noqueados , Simvastatina/uso terapéutico , Microtomografía por Rayos X
10.
J Magn Reson Imaging ; 47(4): 1133-1138, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-28791783

RESUMEN

BACKGROUND: Quantitative Susceptibility Mapping (QSM) MRI allows accurate assessment of iron content in cerebral cavernous malformations (CCM), and a threshold increase by 6% in QSM has been shown to reflect new symptomatic hemorrhage (SH) in previously stable lesions. PURPOSE/HYPOTHESIS: It is unclear how lesional QSM evolves in CCMs after recent SH, and whether this could serve as a monitoring biomarker in clinical trials aimed at preventing rebleeding in these lesions. STUDY TYPE: This is a prospective observational cohort study. POPULATION: 16 CCM patients who experienced a SH within the past year, whose lesion was not resected or irradiated. FIELD STRENGTH/SEQUENCE: The data acquisition was performed using QSM sequence implemented on a 3T MRI system ASSESSMENT: The lesional QSM assessments at baseline and yearly during 22 patient-years of follow-up were performed by a trained research staff including imaging scientists. STATISTICAL TESTS: Biomarker changes were assessed in relation to clinical events. Clinical trial modeling was performed using two-tailed tests of time-averaged difference (assuming within-patient correlation of 0.8, power = 0.9 and alpha = 0.1) to detect 20%, 30% or 50% effects of intervention on clinical and biomarkers event rates during two years of follow-up. RESULTS: The change in mean lesional QSM of index hemorrhagic lesions was +7.93% per patient-year in the whole cohort. There were 5 cases (31%) of recurrent SH or lesional growth, and twice as many instances (62%) with a threshold (6%) increase in QSM. There were no instances of SH hemorrhage or lesional growth without an associated threshold increase in QSM during the same epoch. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 4 J. Magn. Reson. Imaging 2018;47:1133-1138.


Asunto(s)
Neoplasias Encefálicas/diagnóstico por imagen , Hemorragia Cerebral/diagnóstico por imagen , Hemangioma Cavernoso del Sistema Nervioso Central/diagnóstico por imagen , Procesamiento de Imagen Asistido por Computador/métodos , Imagen por Resonancia Magnética/métodos , Biomarcadores , Encéfalo/diagnóstico por imagen , Neoplasias Encefálicas/complicaciones , Hemorragia Cerebral/complicaciones , Estudios de Cohortes , Femenino , Hemangioma Cavernoso del Sistema Nervioso Central/complicaciones , Humanos , Interpretación de Imagen Asistida por Computador , Masculino , Estudios Prospectivos , Reproducibilidad de los Resultados
11.
Pers Soc Psychol Rev ; 22(3): 260-284, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29130838

RESUMEN

Traditionally, ritual has been studied from broad sociocultural perspectives, with little consideration of the psychological processes at play. Recently, however, psychologists have begun turning their attention to the study of ritual, uncovering the causal mechanisms driving this universal aspect of human behavior. With growing interest in the psychology of ritual, this article provides an organizing framework to understand recent empirical work from social psychology, cognitive science, anthropology, behavioral economics, and neuroscience. Our framework focuses on three primary regulatory functions of rituals: regulation of (a) emotions, (b) performance goal states, and (c) social connection. We examine the possible mechanisms underlying each function by considering the bottom-up processes that emerge from the physical features of rituals and top-down processes that emerge from the psychological meaning of rituals. Our framework, by appreciating the value of psychological theory, generates novel predictions and enriches our understanding of ritual and human behavior more broadly.


Asunto(s)
Conducta Ceremonial , Cultura , Emociones , Objetivos , Conducta Social , Cognición , Humanos , Teoría Psicológica , Autocontrol
13.
Psychol Sci ; 28(6): 733-750, 2017 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-28447877

RESUMEN

Long-established rituals in preexisting cultural groups have been linked to the cultural evolution of group cooperation. We tested the prediction that novel rituals-arbitrary hand and body gestures enacted in a stereotypical and repeated fashion-can inculcate intergroup bias in newly formed groups. In four experiments, participants practiced novel rituals at home for 1 week (Experiments 1, 2, and 4) or once in the lab (Experiment 3) and were divided into minimal in-groups and out-groups. Our results offer mixed support for the hypothesis that novel rituals promote intergroup bias. Specifically, we found a modest effect for daily repeated rituals but a null effect for rituals enacted only once. These results suggest that novel rituals can inculcate bias, but only when certain features are present: Rituals must be sufficiently elaborate and repeated to lead to bias. Taken together, our results offer modest support that novel rituals can promote intergroup bias.


Asunto(s)
Conducta Ceremonial , Procesos de Grupo , Confianza/psicología , Adolescente , Adulto , Economía del Comportamiento , Femenino , Juegos Experimentales , Humanos , Masculino , Neurofisiología , Adulto Joven
14.
J Med Libr Assoc ; 104(1): 42-6, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26807051

RESUMEN

OBJECTIVE: The research attempted to develop search filters for biomedical literature databases that improve retrieval of studies of clinical relevance for the nursing and rehabilitation professions. METHODS: Diagnostic testing framework compared machine-culled and practitioner-nominated search terms with a hand-tagged clinical literature database. RESULTS: We were unable to: (1) develop filters for nursing, likely because of the overlapping and expanding scope of practice for nurses in comparison with medical professionals, or (2) develop filters for rehabilitation, because of its broad scope and the profession's multifaceted understanding of "health and ability." CONCLUSIONS: We found limitations on search filter development for these health professions: nursing and rehabilitation.


Asunto(s)
Bases de Datos Bibliográficas/normas , Almacenamiento y Recuperación de la Información/normas , Bibliotecas Médicas/normas , Informe de Investigación/normas , Motor de Búsqueda/normas , Terminología como Asunto , Investigación Biomédica/organización & administración , Sensibilidad y Especificidad
15.
Behav Brain Sci ; 39: e14, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26948731

RESUMEN

The target article develops an account of religious prosociality that is driven by increases in self-control. We suggest this account is incomplete. Although religion might increase prosociality to the in-group, it decreases it to the much larger out-group. Rituals, for example, lead to out-group derogation. We also challenge the link between religion and improved self-control, offering evidence that religion hinders self-control.


Asunto(s)
Conducta Ceremonial , Autocontrol , Humanos , Religión
16.
Cochrane Database Syst Rev ; (11): CD000011, 2014 Nov 20.
Artículo en Inglés | MEDLINE | ID: mdl-25412402

RESUMEN

BACKGROUND: People who are prescribed self administered medications typically take only about half their prescribed doses. Efforts to assist patients with adherence to medications might improve the benefits of prescribed medications. OBJECTIVES: The primary objective of this review is to assess the effects of interventions intended to enhance patient adherence to prescribed medications for medical conditions, on both medication adherence and clinical outcomes. SEARCH METHODS: We updated searches of The Cochrane Library, including CENTRAL (via http://onlinelibrary.wiley.com/cochranelibrary/search/), MEDLINE, EMBASE, PsycINFO (all via Ovid), CINAHL (via EBSCO), and Sociological Abstracts (via ProQuest) on 11 January 2013 with no language restriction. We also reviewed bibliographies in articles on patient adherence, and contacted authors of relevant original and review articles. SELECTION CRITERIA: We included unconfounded RCTs of interventions to improve adherence with prescribed medications, measuring both medication adherence and clinical outcome, with at least 80% follow-up of each group studied and, for long-term treatments, at least six months follow-up for studies with positive findings at earlier time points. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted all data and a third author resolved disagreements. The studies differed widely according to medical condition, patient population, intervention, measures of adherence, and clinical outcomes. Pooling results according to one of these characteristics still leaves highly heterogeneous groups, and we could not justify meta-analysis. Instead, we conducted a qualitative analysis with a focus on the RCTs with the lowest risk of bias for study design and the primary clinical outcome. MAIN RESULTS: The present update included 109 new RCTs published since the previous update in January 2007, bringing the total number of RCTs to 182; we found five RCTs from the previous update to be ineligible and excluded them. Studies were heterogeneous for patients, medical problems, treatment regimens, adherence interventions, and adherence and clinical outcome measurements, and most had high risk of bias. The main changes in comparison with the previous update include that we now: 1) report a lack of convincing evidence also specifically among the studies with the lowest risk of bias; 2) do not try to classify studies according to intervention type any more, due to the large heterogeneity; 3) make our database available for collaboration on sub-analyses, in acknowledgement of the need to make collective advancement in this difficult field of research. Of all 182 RCTs, 17 had the lowest risk of bias for study design features and their primary clinical outcome, 11 from the present update and six from the previous update. The RCTs at lowest risk of bias generally involved complex interventions with multiple components, trying to overcome barriers to adherence by means of tailored ongoing support from allied health professionals such as pharmacists, who often delivered intense education, counseling (including motivational interviewing or cognitive behavioral therapy by professionals) or daily treatment support (or both), and sometimes additional support from family or peers. Only five of these RCTs reported improvements in both adherence and clinical outcomes, and no common intervention characteristics were apparent. Even the most effective interventions did not lead to large improvements in adherence or clinical outcomes. AUTHORS' CONCLUSIONS: Across the body of evidence, effects were inconsistent from study to study, and only a minority of lowest risk of bias RCTs improved both adherence and clinical outcomes. Current methods of improving medication adherence for chronic health problems are mostly complex and not very effective, so that the full benefits of treatment cannot be realized. The research in this field needs advances, including improved design of feasible long-term interventions, objective adherence measures, and sufficient study power to detect improvements in patient-important clinical outcomes. By making our comprehensive database available for sharing we hope to contribute to achieving these advances.


Asunto(s)
Quimioterapia , Cumplimiento de la Medicación , Humanos , Educación del Paciente como Asunto , Sesgo de Publicación , Ensayos Clínicos Controlados Aleatorios como Asunto , Autoadministración
18.
medRxiv ; 2023 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-37333396

RESUMEN

Background: Quantitative susceptibility mapping (QSM) and dynamic contrast enhanced quantitative perfusion (DCEQP) MRI sequences assessing iron deposition and vascular permeability were previously correlated with new hemorrhage in cavernous angiomas. We assessed their prospective changes in cavernous angiomas with symptomatic hemorrhage (CASH) in a multisite trial readiness project ( clinicaltrials.gov NCT03652181 ). Methods: Patients with CASH in the prior year, without prior or planned lesion resection or irradiation were enrolled. Mean QSM and DCEQP of CASH lesion were acquired at baseline, and at 1- and 2-year follow-ups. Sensitivity and specificity of biomarker changes were analyzed in relation to predefined lesional symptomatic hemorrhage (SH) or asymptomatic change (AC). Sample size calculations for hypothesized therapeutic effects were conducted. Results: We logged 143 QSM and 130 DCEQP paired annual assessments. Annual QSM change was greater in cases with SH than in cases without SH (p= 0.019). Annual QSM increase by ≥ 6% occurred in 7 of 7 cases (100%) with recurrent SH and in 7 of 10 cases (70%) with AC during the same epoch, and 3.82 times more frequently than clinical events. DCEQP change had lower sensitivity for SH and AC than QSM change, and greater variance. A trial with smallest sample size would detect a 30% difference in QSM annual change in 34 or 42 subjects (one and two-tailed, respectively), power 0.8, alpha 0.05. Conclusions: Assessment of QSM change is feasible and sensitive to recurrent bleeding in CASH. Evaluation of an intervention on QSM percent change may be used as a time-averaged difference between 2 arms using a repeated measures analysis. DCEQP change is associated with lesser sensitivity and higher variability than QSM. These results are the basis of an application for certification by the U.S. F.D.A. of QSM as a biomarker of drug effect in CASH.

19.
J Pers Soc Psychol ; 123(1): 123-153, 2022 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-33492153

RESUMEN

From Catholics performing the sign of the cross since the 4th century to Americans reciting the Pledge of Allegiance since the 1890s, group rituals (i.e., predefined sequences of symbolic actions) have strikingly consistent features over time. Seven studies (N = 4,213) document the sacrosanct nature of rituals: Because group rituals symbolize sacred group values, even minor alterations to them provoke moral outrage and punishment. In Pilot Studies A and B, fraternity members who failed to complete initiation activities that were more ritualistic elicited relatively greater moral outrage and hazing from their fraternity brothers. Study 1 uses secular holiday rituals to explore the dimensions of ritual alteration-both physical and psychological-that elicit moral outrage. Study 2 suggests that altering a ritual elicits outrage even beyond the extent to which the ritual alteration is seen as violating descriptive and injunctive norms. In Study 3, group members who viewed male circumcision as more ritualistic (i.e., Jewish vs. Muslim participants) expressed greater moral outrage in response to a proposal to alter circumcision to make it safer. Study 4 uses the Pledge of Allegiance ritual to explore how the intentions of the person altering the ritual influence observers' moral outrage and punishment. Finally, in Study 5, even minor alterations elicited comparable levels of moral outrage to major alterations of the Jewish Passover ritual. Across both religious and secular rituals, the more ingroup members believed that rituals symbolize sacred group values, the more they protected their rituals-by punishing those who violated them. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Asunto(s)
Conducta Ceremonial , Castigo , Humanos , Intención , Masculino , Principios Morales
20.
JMIR Hum Factors ; 9(1): e30797, 2022 03 02.
Artículo en Inglés | MEDLINE | ID: mdl-35234648

RESUMEN

BACKGROUND: The Patient-Reported Outcomes, Burdens, and Experiences (PROBE) questionnaire is a tool for assessing the quality of life and disease burden in people living with hemophilia. OBJECTIVE: The objectives of our study were (1) to assess the needs of relevant stakeholders involved in the use of PROBE, (2) to develop the software infrastructure needed to meet these needs, and (3) to test the usability of the final product. METHODS: We conducted a series of semistructured interviews of relevant stakeholders, including PROBE investigators, people with hemophilia, and representatives of the sponsor. Based on these, we developed an online survey and a mobile app for iOS and Android. A user group evaluated the final product using the System Usability Scale (SUS) and an open feedback framework. RESULTS: The online survey was updated, and the myPROBE app for mobile devices and a new application programming interface were developed. The app was tested and modified according to user feedback over multiple cycles. The final version of the app was released in July 2019. Seventeen users aged 23 to 67 years evaluated the final version of the app using the SUS. The median (first, third quartile) SUS score for the app was 85 (68, 88) out of 100. The newly introduced functionalities were as follows: (1) capability to longitudinally track repeated fillings of the questionnaire at different time points by the same participant (as opposed to anonymous completion); (2) linking of the questionnaire with hemophilia registries, starting with the Canadian Bleeding Disorders Registry as a proof of concept; (3) removing or adding questions as needed; and (4) sending notifications to the users (eg, reminders). A new secure database was built for securely storing personal information separately from the questionnaire data. The PROBE online survey is currently available in 96 countries and 34 languages. CONCLUSIONS: The online survey was updated successfully, and the myPROBE app was developed, with a SUS score of 85 (out of 100). The app has been released in 81 countries and 34 languages. This will facilitate data collection for research and advocacy purposes, and the use of this tool in everyday clinical practice.

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