RESUMEN
Girls with fragile X syndrome (FXS) often manifest significant symptoms of avoidance, anxiety, and arousal, particularly in the context of social interaction. However, little is currently known about the associations among neurobiological, biobehavioral such as eye gaze pattern, and social-cognitive dysfunction in real-world settings. In this study, we sought to characterize brain network properties and eye gaze patterns in girls with FXS during natural social interaction. Participants included 42 girls with FXS and 31 age- and verbal IQ-matched girls (control). Portable functional near-infrared spectroscopy (fNIRS) and an eye gaze tracker were used to investigate brain network alterations and eye gaze patterns associated with social-cognitive dysfunction in girls with FXS during a structured face-to-face conversation. Compared to controls, girls with FXS showed significantly increased inter-regional functional connectivity and greater excitability within the prefrontal cortex (PFC), frontal eye field (FEF) and superior temporal gyrus (STG) during the conversation. Girls with FXS showed significantly less eye contact with their conversational partner and more unregulated eye gaze behavior compared to the control group. We also demonstrated that a machine learning approach based on multimodal data, including brain network properties and eye gaze patterns, was predictive of multiple domains of social-cognitive behaviors in girls with FXS. Our findings expand current knowledge of neural mechanisms and eye gaze behaviors underlying naturalistic social interaction in girls with FXS. These results could be further evaluated and developed as intermediate phenotypic endpoints for treatment trial evaluation in girls with FXS.
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Síndrome del Cromosoma X Frágil , Femenino , Humanos , Fijación Ocular , Interacción Social , Encéfalo , CogniciónRESUMEN
Fragile X syndrome is a genetic condition associated with alterations in brain and subsequent cognitive development. However, due to a milder phenotype relative to males, females with fragile X syndrome are underrepresented in research studies. In the current study, we investigate neuroanatomical differences in young females (age range: 6.03-16.32 years) with fragile X syndrome (N = 46) as compared to age-, sex-, and verbal abilities-matched participants (comparison group; N = 35). Between-group analyses of whole-brain and regional brain volumes were assessed using voxel-based morphometry. Results demonstrate significantly larger total gray and white matter volumes in girls with fragile X syndrome compared to a matched comparison group (Ps < 0.001). In addition, the fragile X group showed significantly larger gray matter volume in a bilateral parieto-occipital cluster and a right parieto-occipital cluster (Ps < 0.001). Conversely, the fragile X group showed significantly smaller gray matter volume in the bilateral gyrus rectus (P < 0.03). Associations between these regional brain volumes and key socio-emotional variables provide insight into gene-brain-behavior relationships underlying the fragile X syndrome phenotype in females. These findings represent the first characterization of a neuroanatomical phenotype in a large sample of girls with fragile X syndrome and expand our knowledge about potential neurodevelopmental mechanisms underlying cognitive-behavioral outcomes in this condition.
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Síndrome del Cromosoma X Frágil , Sustancia Blanca , Encéfalo/diagnóstico por imagen , Femenino , Síndrome del Cromosoma X Frágil/diagnóstico por imagen , Sustancia Gris/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Sustancia Blanca/diagnóstico por imagenRESUMEN
Children with fragile X syndrome (FXS) often avoid eye contact, a behavior that is potentially related to hyperarousal. Prior studies, however, have focused on between-person associations rather than coupling of within-person changes in gaze behaviors and arousal. In addition, there is debate about whether prompts to maintain eye contact are beneficial for individuals with FXS. In a study of young females (ages 6-16), we used eye tracking to assess gaze behavior and pupil dilation during social interactions in a group with FXS (n = 32) and a developmentally similar comparison group (n = 23). Participants engaged in semi-structured conversations with a female examiner during blocks with and without verbal prompts to maintain eye contact. We identified a social-behavioral and psychophysiological profile that is specific to females with FXS; this group exhibited lower mean levels of eye contact, significantly increased mean pupil dilation during conversations that included prompts to maintain eye contact, and showed stronger positive coupling between eye contact and pupil dilation. Our findings strengthen support for the perspective that gaze aversion in FXS reflects negative reinforcement of social avoidance behavior. We also found that behavioral skills training may improve eye contact, but maintaining eye contact appears to be physiologically taxing for females with FXS.
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BACKGROUND: Fragile X syndrome (FXS) is an X chromosome-linked genetic disorder characterized by increased risk for behavioral, social, and neurocognitive deficits. Because males express a more severe phenotype than females, research has focused largely on identifying neural abnormalities in all-male or both-sex populations with FXS. Therefore, very little is known about the neural alterations that contribute to cognitive behavioral symptoms in females with FXS. This cross-sectional study aimed to elucidate the large-scale resting-state brain networks associated with the multidomain cognitive behavioral phenotype in girls with FXS. METHODS: We recruited 38 girls with full-mutation FXS (11.58 ± 3.15 years) and 32 girls without FXS (11.66 ± 2.27 years). Both groups were matched on age, verbal IQ, and multidomain cognitive behavioral symptoms. Resting-state functional magnetic resonance imaging data were collected. RESULTS: Compared with the control group, girls with FXS showed significantly greater resting-state functional connectivity of the default mode network, lower nodal strength at the right middle temporal gyrus, stronger nodal strength at the left caudate, and higher global efficiency of the default mode network. These aberrant brain network characteristics map directly onto the cognitive behavioral symptoms commonly observed in girls with FXS. An exploratory analysis suggested that brain network patterns at a prior time point (time 1) were predictive of the longitudinal development of participants' multidomain cognitive behavioral symptoms. CONCLUSIONS: These findings represent the first examination of large-scale brain network alterations in a large sample of girls with FXS, expanding our knowledge of potential neural mechanisms underlying the development of cognitive behavioral symptoms in girls with FXS.
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Síndrome del Cromosoma X Frágil , Femenino , Humanos , Masculino , Síndrome del Cromosoma X Frágil/complicaciones , Estudios Transversales , Encéfalo , Síntomas Conductuales , Cognición , Imagen por Resonancia MagnéticaRESUMEN
BACKGROUND: Children and adolescents with fragile X syndrome (FXS) manifest significant symptoms of anxiety, particularly in response to face-to-face social interaction. In this study, we used functional near-infrared spectroscopy to reveal a specific pattern of brain activation and habituation in response to face stimuli in young girls with FXS, an important but understudied clinical population. METHODS: Participants were 32 girls with FXS (age: 11.8 ± 2.9 years) and a control group of 28 girls without FXS (age: 10.5 ± 2.3 years) matched for age, general cognitive function, and autism symptoms. Functional near-infrared spectroscopy was used to assess brain activation during a face habituation task including repeated upright/inverted faces and greeble (nonface) objects. RESULTS: Compared with the control group, girls with FXS showed significant hyperactivation in the frontopolar and dorsal lateral prefrontal cortices in response to all face stimuli (upright + inverted). Lack of neural habituation (and significant sensitization) was also observed in the FXS group in the frontopolar cortex in response to upright face stimuli. Finally, aberrant frontopolar sensitization in response to upright faces in girls with FXS was significantly correlated with notable cognitive-behavioral and social-emotional outcomes relevant to this condition, including executive function, autism symptoms, depression, and anxiety. CONCLUSIONS: These findings strongly support a hypothesis of neural hyperactivation and accentuated sensitization during face processing in FXS, a phenomenon that could be developed as a biomarker end point for improving treatment trial evaluation in girls with this condition.
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Reconocimiento Facial , Síndrome del Cromosoma X Frágil , Niño , Femenino , Adolescente , Humanos , Síndrome del Cromosoma X Frágil/psicología , Encéfalo , Corteza Cerebral , BiomarcadoresRESUMEN
Haematopoietic stem cell transplantation (HSCT) is a curative approach for blood cancers, yet its efficacy is undermined by a range of acute and chronic complications. In light of mounting evidence to suggest that these complications are linked to a dysbiotic gut microbiome, we aimed to evaluate the feasibility of faecal microbiota transplantation (FMT) delivered during the acute phase after HSCT. Of note, this trial opted for FMT prepared using the individual's own stool (autologous FMT) to mitigate the risks of disease transmission from a donor stool. Adults (>18 years) with multiple myeloma were recruited from a single centre. The stool was collected prior to starting first line therapy. Patients who progressed to HSCT were offered FMT via 3 × retention enemas before day +5 (HSCT = day 0). The feasibility was determined by the recruitment rate, number and volume of enemas administered, and the retention time. Longitudinally collected stool samples were also collected to explore the influence of auto-FMT using 16S rRNA gene sequencing. n = 4 (2F:2M) participants received auto-FMT in 12 months. Participants received an average of 2.25 (1-3) enemas 43.67 (25-50) mL total, retained for an average of 60.78 (10-145) min. No adverse events (AEs) attributed to the FMT were identified. Although the minimum requirements were met for the volume and retention of auto-FMT, the recruitment was significantly impacted by the logistical challenges of the pretherapy stool collection. This ultimately undermined the feasibility of this trial and suggests that third party (donor) FMT should be prioritised.
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The overall survival (OS) has improved significantly in multiple myeloma (MM) over the last decade with the use of proteasome inhibitor and immunomodulatory drug-based combinations, followed by high-dose melphalan and autologous hematopoietic stem cell transplantation (auto-HSCT) and subsequent maintenance therapies in eligible newly diagnosed patients. However, clinical trials using auto-HSCT followed by lenalidomide maintenance have shown an increased risk of second primary malignancies (SPM), including second hematological malignancies (SHM). We evaluated the impact of SPM and SHM on progression-free survival (PFS) and OS in patients with MM after auto-HSCT using CIBMTR registry data. Adult patients with MM who underwent first auto-HSCT in the United States with melphalan conditioning regimen from 2011 to 2018 and received maintenance therapy were included (n = 3948). At a median follow-up of 37 months, 175 (4%) patients developed SPM, including 112 (64%) solid, 36 (20%) myeloid, 24 (14%) SHM, not otherwise specified, and 3 (2%) lymphoid malignancies. Multivariate analysis demonstrated that SPM and SHM were associated with an inferior PFS (hazard ratio [HR] 2.62, P < .001 and HR 5.01, P < .001, respectively) and OS (HR 3.85, P < .001 and HR 8.13, P < .001, respectively). In patients who developed SPM and SHM, MM remained the most frequent primary cause of death (42% vs 30% and 53% vs 18%, respectively). We conclude the development of SPM and SHM leads to a poor survival in patients with MM and is an important survivorship challenge. Given the median survival for MM continues to improve, continued vigilance is needed to assess the risks of SPM and SHM with maintenance therapy post-auto-HSCT.
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Neoplasias Hematológicas , Mieloma Múltiple , Neoplasias Primarias Secundarias , Adulto , Humanos , Estados Unidos , Mieloma Múltiple/tratamiento farmacológico , Melfalán/efectos adversos , Neoplasias Primarias Secundarias/etiología , Neoplasias Primarias Secundarias/tratamiento farmacológico , Trasplante Autólogo , Lenalidomida/uso terapéutico , Neoplasias Hematológicas/tratamiento farmacológicoRESUMEN
We tested whether empathy is impaired and associated with anxiety in girls with fragile X syndrome (FXS). We measured parent-reported empathy and self-reported anxiety in young girls with FXS and in a developmentally-matched comparison group. Girls with FXS received higher parent-reported scores on cognitive and affective empathy but also self-reported more severe anxiety symptoms, particularly separation anxiety and phobia symptoms, than girls in the comparison group. Girls with FXS who received higher cognitive empathy scores, however, appeared buffered against risk for separation anxiety and phobia symptoms. Girls with FXS experience elevated empathy and anxiety relative to their developmentally-matched peers. Higher cognitive empathy in girls with FXS may indicate resilience against specific forms of anxiety that are commonly observed in FXS.
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Trastorno del Espectro Autista , Síndrome del Cromosoma X Frágil , Ansiedad , Trastornos de Ansiedad/psicología , Trastorno del Espectro Autista/complicaciones , Empatía , Femenino , Síndrome del Cromosoma X Frágil/psicología , HumanosRESUMEN
OBJECTIVE: Female patients with fragile X syndrome (FXS), a genetic condition associated with a mutation in the FMR1 gene, are at significantly elevated risk for developing anxiety and depression. This study is designed to better understand these symptoms in school-age girls, particularly as they relate to age, social skills, and functional outcomes. METHODS: We compared 58 girls aged 6 to 16 years with FXS with 46 age-matched, sex-matched, and developmentally matched peers without FXS on measures of anxiety, depression, social skills, adaptive behavior, and quality of life. RESULTS: Girls with FXS 10.5 years and older demonstrated significantly higher levels of depression, withdrawal, and social avoidance than girls younger than 10.5 years with FXS ( p -values < 0.01). Girls in the comparison group did not show any age-related differences on these measures. The older FXS cohort also showed associations between social communication and interaction skills, adaptive behavior, and measures of anxiety and depression ( p -values < 0.05) not seen in the comparison group, regardless of age. CONCLUSION: We found that age seems to play an important role in the development of mood symptoms and that such symptoms are uniquely correlated with social communication and reciprocal social interaction behaviors and adaptive functioning in girls with FXS after puberty. These data suggest a critical window of intervention for girls with FXS in the improvement of social interaction skills and the prevention of social avoidance and symptoms of anxiety and depression, with the ultimate goal of improving quality of life and promoting greater independence.
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Ansiedad , Depresión , Síndrome del Cromosoma X Frágil , Habilidades Sociales , Femenino , Humanos , Ansiedad/epidemiología , Depresión/epidemiología , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil , Síndrome del Cromosoma X Frágil/epidemiología , Calidad de Vida , Niño , AdolescenteRESUMEN
BACKGROUND: Despite the recommendation for an early invasive strategy in the treatment of patients who present with non-ST-segment elevation (NSTE) acute coronary syndromes (ACS), referral for cardiac catheterization is suboptimal; the reasons why some patients are not referred remain unclear. METHODS: Patients were recruited into the prospective, observational Canadian ACS Registry II between October 1, 2002, and December 31, 2003; 2136 patients with NSTE ACS identified through the registry were divided into tertiles according to the Thrombolysis in Myocardial Infarction risk score and the rates of catheterization compared. In addition, the most responsible physicians were asked to indicate the main reason they did not refer their patients for catheterization. RESULTS: The rate of referral for catheterization was 64.7%. Patients who underwent catheterization had lower in-hospital (0.8% vs 3.7%; P < .001) and 1-year mortality rates (4.0% vs 10.9%; P < .001) compared with those who did not. Higher-risk patients were referred at a similar rate as low-risk patients (62.5% vs 66.9%; P = .25). Among the reasons provided by the most responsible physician as to why patients were not referred for catheterization, 68.4% of patients were thought to be "not at high enough risk"; however, 59.1% of these patients were found to be at intermediate to high risk according to their baseline Thrombolysis in Myocardial Infarction risk score. CONCLUSIONS: Cardiac catheterization is not used optimally in patients who present with NSTE ACS. Despite better in-hospital and 1-year outcomes in those patients who are referred for catheterization, many higher-risk patients are not being referred because of the perception that they are not at high enough risk. A significant opportunity remains to improve on accurate risk stratification and adherence to an early invasive strategy for higher-risk patients.
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Síndrome Coronario Agudo/diagnóstico , Síndrome Coronario Agudo/terapia , Cateterismo Cardíaco , Síndrome Coronario Agudo/mortalidad , Anciano , Electrocardiografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Derivación y Consulta , Sistema de Registros , Medición de Riesgo , Factores de Riesgo , Resultado del TratamientoRESUMEN
Fragile X syndrome (FXS) is a genetic condition known to increase the risk of cognitive impairment and socio-emotional challenges in affected males and females. To date, the vast majority of research on FXS has predominantly targeted males, who usually exhibit greater cognitive impairment compared to females. Due to their typically milder phenotype, females may have more potential to attain a higher level of independence and quality of life than their male counterparts. However, the constellation of cognitive, behavioral, and, particularly, socio-emotional challenges present in many females with FXS often preclude them from achieving their full potential. It is, therefore, critical that more research specifically focuses on females with FXS to elucidate the role of genetic, environmental, and socio-emotional factors on outcome in this often-overlooked population.
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The prothrombotic risk in multiple myeloma (MM) could be potentially assessed by thrombin generation (TG) assays. TG was performed using Calibrated Automated Thrombography with 5 and 1 pM tissue factor. We compared baseline TG among 24 MM patients, 19 MGUS, and 50 healthy controls, and assessed change in TG in MM patients during the initial treatment period at 1, 2, and 3 months. MM subjects demonstrated increased FVIII and VWF:Ag levels pretreatment, and a prothrombotic TG phenotype with increased velocity index, reduced lag time and time-to-peak, and increased resistance to thrombomodulin inhibition. There were no significant changes in TG with treatment for the majority of parameters, however, MM subjects exhibited persistent elevation of velocity index throughout treatment. Two subjects developed thrombosis during the study period despite thromboprophylaxis. This study provides information on the optimal conditions for examining TG as a predictor of thrombotic risk in MM patients.
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Mieloma Múltiple/sangre , Trombina/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores , Coagulación Sanguínea/efectos de los fármacos , Factores de Coagulación Sanguínea , Pruebas de Coagulación Sanguínea , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Gammopatía Monoclonal de Relevancia Indeterminada/sangre , Gammopatía Monoclonal de Relevancia Indeterminada/diagnóstico , Gammopatía Monoclonal de Relevancia Indeterminada/tratamiento farmacológico , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/tratamiento farmacológico , Factores de Tiempo , Tromboembolia Venosa/sangre , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/etiología , Adulto JovenRESUMEN
BACKGROUND: Acute coronary syndrome (ACS) patients in the highest risk categories are least likely to receive evidence-based treatments (EBTs). We sought to determine why physicians do not prescribe EBTs for patients with non-ST-segment-elevation ACSs and the factors determining use of these treatments after 1 year. METHODS AND RESULTS: One thousand nine hundred fifty-six non-ST-segment-elevation ACS patients were enrolled in the prospective, multicenter Canadian ACS registry II between October 2002 and December 2003. Each patient's physician gave reasons why guideline-indicated medication(s) was not prescribed during hospitalization. Medication use and reason(s) for discontinuation after 1 year were obtained by telephone interview of the patients. The commonest reason for not prescribing EBTs was "not high-enough risk" or "no evidence/guidelines to support use." However, Global Registry of Acute Coronary Events scores of patients not treated for this reason were often similar to or higher than those of patients prescribed such treatment. After 1 year, 77% of patients not on optimal ACS treatment at discharge remained without optimal treatment, and overall antiplatelet, ß-blocker, and angiotensin-converting enzyme inhibitor use declined. Approximately one third of patients not taking EBTs had stopped their medication without instruction from their doctor. CONCLUSIONS: Nonprovision of EBTs may be due to subjective underestimation of patient risk and hence, likely treatment benefit. Oversights in care delivery were also apparent. Objective risk stratification, combined with efforts to ensure provision and adherence to EBTs, should be encouraged.
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Síndrome Coronario Agudo/epidemiología , Técnicas de Apoyo para la Decisión , Adhesión a Directriz , Cumplimiento de la Medicación , Prescripciones/estadística & datos numéricos , Síndrome Coronario Agudo/tratamiento farmacológico , Síndrome Coronario Agudo/fisiopatología , Antagonistas Adrenérgicos beta/uso terapéutico , Anciano , Medicina Basada en la Evidencia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Alta del Paciente , Pacientes , Médicos , Inhibidores de Agregación Plaquetaria/uso terapéutico , Guías de Práctica Clínica como Asunto , Estudios Prospectivos , Medición de Riesgo , Prevención Secundaria/tendenciasRESUMEN
Venous thromboembolism (VTE) affects 1-2 per 1000 people in the general population each year. Clinical diagnosis of deep venous thrombosis (DVT) is unreliable, and must be confirmed by compression ultrasonography or venography. A low clinical pretest probability of DVT and negative D-dimer result reliably exclude the diagnosis, with no need for diagnostic imaging. Initial treatment of DVT is with low-molecular-weight heparin or unfractionated heparin for at least 5 days, followed by warfarin (target INR, 2.0-3.0) for at least 3 months. A vena cava filter is indicated in patients who are ineligible for anticoagulant therapy or who experience embolism despite therapeutic anticoagulation. Thrombolysis or surgical embolectomy may be used as a limb-saving measure in patients with extensive proximal DVT and circulatory compromise that threatens the viability of the leg. Decisions regarding the optimal duration of anticoagulation to prevent recurrent VTE should be individualised and balance the risk of recurrence if warfarin is stopped against the risk of major bleeding and inconvenience of continuing treatment. The risk of recurrence is highest in people with recurrent unprovoked DVT or chronic predisposing factors (eg, cancer) who require indefinite anticoagulant treatment.
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Tromboembolia/diagnóstico , Tromboembolia/terapia , Trombosis de la Vena/diagnóstico , Trombosis de la Vena/terapia , Algoritmos , Anticoagulantes/uso terapéutico , Contraindicaciones , Heparina de Bajo-Peso-Molecular/uso terapéutico , Humanos , Factores de RiesgoRESUMEN
Pulmonary embolism (PE) affects 0.5-1 per 1000 people in the general population each year, and is one of the most common preventable causes of death among hospitalised patients. The clinical diagnosis of PE is unreliable and must be confirmed objectively with ventilation perfusion scanning or computed tomography pulmonary angiography. The diagnosis of PE can be reliably excluded, without the need for diagnostic imaging, if the clinical pretest probability for PE is low and the D-dimer assay result is negative. The initial treatment of PE is low-molecular-weight heparin or unfractionated heparin for at least 5 days, followed by warfarin (target international normalised ratio [INR], 2.0-3.0) for at least 3-6 months. Patients with a high clinical pretest probability of PE should commence treatment immediately while awaiting the results of the diagnostic work-up. Thrombolysis is indicated for patients with objectively confirmed PE who are haemodynamically unstable. Percutaneous transcatheter or surgical embolectomy may be life-saving in patients ineligible for, or unresponsive to, thrombolytic therapy. Unresolved issues in the management of venous thromboembolism include the roles of thrombophilia testing, thrombolysis for the treatment of stable PE patients who present with right ventricular dysfunction, and new anticoagulants; and the duration of anticoagulation for first unprovoked venous thromboembolism.