RESUMEN
BACKGROUND: Among ambulatory people with incomplete spinal cord injury (iSCI), balance deficits are a primary factor limiting participation in walking activities. There is broad recognition that effective interventions are needed to enhance walking balance following iSCI. Interventions that amplify self-generated movements (e.g., error augmentation) can accelerate motor learning by intensifying sensorimotor feedback and facilitating exploration of motor control strategies. These features may be beneficial for retraining walking balance after iSCI. We have developed a cable-driven robot that creates a movement amplification environment during treadmill walking. The robot applies a continuous, laterally-directed, force to the pelvis that is proportional in magnitude to real-time lateral velocity. Our purpose is to investigate the effects of locomotor training in this movement amplification environment on walking balance. We hypothesize that for ambulatory people with iSCI, locomotor training in a movement amplification environment will be more effective for improving walking balance and participation in walking activities than locomotor training in a natural environment (no applied external forces). METHODS: We are conducting a two-arm parallel-assignment intervention. We will enroll 36 ambulatory participants with chronic iSCI. Participants will be randomized into either a control or experimental group. Each group will receive 20 locomotor training sessions. Training will be performed in either a traditional treadmill environment (control) or in a movement amplification environment (experimental). We will assess changes using measures that span the International Classification of Functioning, Disability and Health (ICF) framework including 1) clinical outcome measures of gait, balance, and quality of life, 2) biomechanical assessments of walking balance, and 3) participation in walking activities quantified by number of steps taken per day. DISCUSSION: Training walking balance in people with iSCI by amplifying the individual's own movement during walking is a radical departure from current practice and may result in new strategies for addressing balance impairments. Knowledge gained from this study will expand our understanding of how people with iSCI improve walking balance and how an intervention targeting walking balance affects participation in walking activities. Successful outcomes could motivate development of clinically feasible tools to replicate the movement amplification environment within clinical settings. TRIAL REGISTRATION: NCT04340063.
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Marcha , Traumatismos de la Médula Espinal , Traumatismos de la Médula Espinal/rehabilitación , Traumatismos de la Médula Espinal/fisiopatología , Humanos , Marcha/fisiología , Adulto , Terapia por Ejercicio/métodos , Equilibrio Postural/fisiología , Caminata/fisiología , Masculino , Femenino , Robótica/métodos , Método Simple Ciego , Persona de Mediana Edad , Locomoción/fisiologíaRESUMEN
BACKGROUND: Kawasaki disease (KD) is a febrile illness of young childhood that can result in coronary artery aneurysms and death. Coronavirus disease 2019 (COVID-19) mitigation strategies resulted in a marked decrease in KD cases worldwide, supporting a transmissible respiratory agent as the cause. We previously reported a peptide epitope recognized by monoclonal antibodies (MAbs) derived from clonally expanded peripheral blood plasmablasts from 3 of 11 KD children, suggesting a common disease trigger in a subset of patients with KD. METHODS: We performed amino acid substitution scans to develop modified peptides with improved recognition by KD MAbs. We prepared additional MAbs from KD peripheral blood plasmablasts and assessed MAb characteristics that were associated with binding to the modified peptides. RESULTS: We report a modified peptide epitope that is recognized by 20 MAbs from 11 of 12 KD patients. These MAbs predominantly use heavy chain VH3-74; two-thirds of VH3-74 plasmablasts from these patients recognize the epitope. The MAbs were nonidentical between patients but share a common complementarity-determining region 3 (CDR3) motif. CONCLUSIONS: These results demonstrate a convergent VH3-74 plasmablast response to a specific protein antigen in children with KD, supporting one predominant causative agent in the etiopathogenesis of the illness.
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COVID-19 , Síndrome Mucocutáneo Linfonodular , Humanos , Niño , Epítopos , Formación de Anticuerpos , Anticuerpos Monoclonales , PéptidosRESUMEN
BACKGROUND & AIMS: Cow's milk protein (CMP) is the most common trigger of inflammation in children and adults with eosinophilic esophagitis (EoE). We sought to assess the clinical, endoscopic, and histologic efficacy of dietary elimination of all CMP-containing foods in EoE. METHODS: We performed a prospective observational study in children with EoE treated with the 1-food elimination diet (1FED), excluding all CMP. Children and their caretakers were educated by a registered dietitian regarding dietary elimination of all CMP-containing foods, with substitutions to meet nutritional needs for optimal growth and development, and daily meal planning. Upper endoscopy with biopsies was performed after 8 to 12 weeks of treatment. The primary end point was histologic remission, defined as fewer than 15 eosinophils per high-power field. Secondary end points were symptomatic, endoscopic, and quality-of-life (QOL) improvements. RESULTS: Forty-one children (76% male; ages, 9 ± 4 years; 88% white) underwent 1FED education and post-treatment endoscopy with biopsies. Histologic remission occurred in 21 (51%) children, with a decrease in peak eosinophils per high-power field from a median of 50 (interquartile range, 35-70) to a median of 1 (interquartile range, 0-6; P < .0001). Endoscopic abnormalities improved in 24 (59%) patients, while symptoms improved in 25 (61%). Improved symptoms included chest pain, dysphagia, and pocketing/spitting out food. Parents perceived worse QOL, while children perceived improved QOL with the 1FED. CONCLUSIONS: One-food elimination of CMP-containing foods from the diet induced histologic remission in more than 50% of children with EoE and led to significant improvement in symptoms and endoscopic abnormalities. The ease of implementation and adherence supports the 1FED as first-line dietary treatment.
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Esofagitis Eosinofílica , Animales , Bovinos , Femenino , Humanos , Masculino , Alérgenos , Dieta , Endoscopía Gastrointestinal , Esofagitis Eosinofílica/patología , Calidad de VidaRESUMEN
BACKGROUND: Disparities in access to anti-SARS-CoV-2 monoclonal antibodies have not been well characterized. OBJECTIVE: We sought to explore the impact of race/ethnicity as a social construct on monoclonal antibody delivery. DESIGN/PATIENTS: Following implementation of a centralized infusion program at a large academic healthcare system, we reviewed a random sample of high-risk ambulatory adult patients with COVID-19 referred for monoclonal antibody therapy. MAIN MEASURES: We examined the relationship between treatment delivery, race/ethnicity, and other demographics using descriptive statistics, binary logistic regression, and spatial analysis. KEY RESULTS: There was no significant difference in racial composition between patients who did (n = 25) and patients who did not (n = 378) decline treatment (p = 0.638). Of patients who did not decline treatment, 64.8% identified as White, 14.8% as Hispanic/Latinx, and 11.1% as Black. Only 44.6% of Hispanic/Latinx and 31.0% of Black patients received treatment compared to 64.1% of White patients (OR 0.45, 95% CI 0.25-0.81, p = 0.008, and OR 0.25, 95% CI 0.12-0.50, p < 0.001, respectively). In multivariable analysis including age, race, insurance status, non-English primary language, county Social Vulnerability Index, illness severity, and total number of comorbidities, associations between receiving treatment and Hispanic/Latinx or Black race were no longer statistically significant (AOR 1.32, 95% CI 0.69-2.53, p = 0.400, and AOR 1.34, 95% CI 0.64-2.80, p = 0.439, respectively). However, patients who were uninsured or whose primary language was not English were less likely to receive treatment (AOR 0.16, 95% CI 0.03-0.88, p = 0.035, and AOR 0.37, 95% CI 0.15-0.90, p = 0.028, respectively). Spatial analysis suggested decreased monoclonal antibody delivery to Cook County patients residing in socially vulnerable communities. CONCLUSIONS: High-risk ambulatory patients with COVID-19 who identified as Hispanic/Latinx or Black were less likely to receive monoclonal antibody therapy in univariate analysis, a finding not explained by patient refusal. Multivariable and spatial analyses suggested insurance status, language, and social vulnerability contributed to racial disparities.
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COVID-19 , Disparidades en Atención de Salud , Adulto , Humanos , Anticuerpos Monoclonales , Negro o Afroamericano , COVID-19/epidemiología , COVID-19/etnología , COVID-19/terapia , Estudios Retrospectivos , Blanco , Hispánicos o LatinosRESUMEN
BACKGROUND: Esophageal histology is critical for diagnosis and surveillance of disease activity in eosinophilic esophagitis (EoE). A validated noninvasive biomarker has not been identified. We aimed to determine the utility of blood and urine eosinophil-associated proteins to diagnose EoE and predict esophageal eosinophilia. METHODS: Blood and urine were collected from children undergoing endoscopy with biopsy. Absolute eosinophil count (AEC), plasma eosinophil-derived neurotoxin (EDN), eosinophil cationic protein (ECP), major basic protein-1 (MBP-1), galectin-10 (CLC/GAL-10), Eotaxin-2 and Eotaxin-3, and urine osteopontin (OPN) and matrix metalloproteinase-9 (MMP-9) were determined. Differences were assessed between EoE and control, and with treatment response. The capacity to predict EoE diagnosis and esophageal eosinophil counts was assessed. RESULTS: Of 183 specimens were collected from 56 EoE patients and 15 non-EoE controls with symptoms of esophageal dysfunction; 33 EoE patients had paired pre- and post-treatment specimens. Plasma (CLC/GAL-10, ECP, EDN, Eotaxin-3, MBP-1) and urine (OPN) biomarkers were increased in EoE compared to control. A panel comprising CLC/GAL-10, Eotaxin-3, ECP, EDN, MBP-1, and AEC was superior to AEC alone in distinguishing EoE from control. AEC, CLC/GAL-10, ECP, and MBP-1 were significantly decreased in patients with esophageal eosinophil counts <15/hpf in response to treatment. AEC, CLC/GAL-10, ECP, EDN, OPN, and MBP-1 each predicted esophageal eosinophil counts utilizing mixed models controlled for age, gender, treatment, and atopy; AEC combined with MBP-1 best predicted the counts. CONCLUSIONS: We identified novel panels of eosinophil-associated proteins that along with AEC are superior to AEC alone in distinguishing EoE from controls and predicting esophageal eosinophil counts.
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Esofagitis Eosinofílica , Biomarcadores , Niño , Neurotoxina Derivada del Eosinófilo/metabolismo , Esofagitis Eosinofílica/metabolismo , Eosinófilos/metabolismo , Humanos , Estudios Longitudinales , Estudios ProspectivosRESUMEN
OBJECTIVE: To investigate an intensive asynchronous computer-based treatment delivered remotely with clinician oversight to people with aphasia. DESIGN: Single-blind, randomized placebo-controlled trial. SETTING: Free-standing urban rehabilitation hospital. PARTICIPANTS: Adults with aphasia (at least six months post-onset). INTERVENTIONS: Experimental treatment was Web ORLA® (Oral Reading for Language in Aphasia) which provides repeated choral and independent reading aloud of sentences with a virtual therapist. Placebo was a commercially available computer game. Participants were instructed to practice 90 minutes/day, six days/week for six weeks. MAIN MEASURES: Change in Language Quotient of the Western Aphasia Battery-Revised from pre-treatment to post-treatment and pre-treatment to six weeks following the end of treatment. RESULTS: 32 participants (19 Web ORLA®, 13 Control) completed the intervention and post-treatment assessment; 27 participants (16 Web ORLA®, 11 Control) completed the follow-up assessment six weeks after treatment had ended. Web ORLA® treatment resulted in significant improvements in language performance from pre-treatment to immediately post-treatment (X = 2.96; SD = 4.32; P < 0.01; ES = 0.68) and from pre-treatment to six weeks following the end of treatment (X = 4.53; SD = 3.16; P < 0.001; ES = 1.43). There was no significant difference in the gain from pre-treatment to post-treatment for the Web ORLA® versus Control groups. However, the Web ORLA® group showed significantly greater gains at the six-week follow-up than the control group (X = 2.70; SD = 1.01; P = 0.013; ES = 1.92). CONCLUSION: Results provide evidence for improved language outcomes following intensive, web-based delivery of ORLA® to individuals with chronic aphasia. Findings underscore the value of combining clinician oversight with the flexibility of asynchronous practice.
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Afasia/rehabilitación , Terapia del Lenguaje/métodos , Logopedia/métodos , Telerrehabilitación , Terapia Asistida por Computador , Afasia/etiología , Humanos , Internet , Masculino , Persona de Mediana Edad , Proyectos Piloto , Método Simple Ciego , Accidente Cerebrovascular/complicacionesRESUMEN
BACKGROUND: Kawasaki disease (KD) is the leading cause of childhood acquired heart disease in developed nations and can result in coronary artery aneurysms and death. Clinical and epidemiologic features implicate an infectious cause but specific antigenic targets of the disease are unknown. Peripheral blood plasmablasts are normally highly clonally diverse but the antibodies they encode are approximately 70% antigen-specific 1-2 weeks after infection. METHODS: We isolated single peripheral blood plasmablasts from children with KD 1-3 weeks after onset and prepared 60 monoclonal antibodies (mAbs). We used the mAbs to identify their target antigens and assessed serologic response among KD patients and controls to specific antigen. RESULTS: Thirty-two mAbs from 9 of 11 patients recognize antigen within intracytoplasmic inclusion bodies in ciliated bronchial epithelial cells of fatal cases. Five of these mAbs, from 3 patients with coronary aneurysms, recognize a specific peptide, which blocks binding to inclusion bodies. Sera from 5/8 KD patients dayâ ≥â 8 after illness onset, compared with 0/17 infant controls (Pâ <â .01), recognized the KD peptide antigen. CONCLUSIONS: These results identify a protein epitope targeted by the antibody response to KD and provide a means to elucidate the pathogenesis of this important worldwide pediatric problem.
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Anticuerpos Monoclonales/genética , Anticuerpos Monoclonales/inmunología , Formación de Anticuerpos/genética , Células Sanguíneas/inmunología , Epítopos/inmunología , Síndrome Mucocutáneo Linfonodular/genética , Síndrome Mucocutáneo Linfonodular/inmunología , Femenino , Humanos , Lactante , Masculino , Síndrome Mucocutáneo Linfonodular/epidemiología , Estados Unidos/epidemiologíaRESUMEN
Background: Cardiovascular comorbidities are risk factors for human immunodeficiency virus (HIV)-associated cognitive impairment. Given differences in cardiometabolic risk profiles between women and men with HIV, we investigated whether associations between cardiometabolic risk factors and prevalent cognitive impairment differ by sex. Methods: Separate logistic regression models were constructed for women and men at entry into a prospective study of older persons with HIV (PWH) to assess the association of cardiometabolic and other risk factors with cognitive impairment. Results: Of 988 participants, 20% were women. Women had higher total cholesterol (194 vs 186 mg/dL; P = .027), hemoglobin A1c (5.9% vs 5.7%; P = .003), and body mass index (30.8 vs 27.4 kg/m2; P < .001) compared with men, and were less physically active (43% vs 55%; P = .005). In a multivariable model, physical activity was associated with lower odds of cognitive impairment in women (odds ratio, 0.35 [95% confidence interval, .15-.80]; P = .013) but not men. Conclusions: Physical activity may have a greater positive impact on cognitive health in women than in men with HIV. This finding should be confirmed in studies examining the longitudinal association between physical activity and incident cognitive impairment in PWH and the effect of interventions that increase physical activity on cognitive impairment in women with HIV.
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Disfunción Cognitiva/epidemiología , Ejercicio Físico , Infecciones por VIH/complicaciones , Adulto , Índice de Masa Corporal , Enfermedades Cardiovasculares/epidemiología , Colesterol/sangre , Comorbilidad , Estudios Transversales , Femenino , Hemoglobina Glucada , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Oportunidad Relativa , Prevalencia , Estudios Prospectivos , Factores de Riesgo , Caracteres Sexuales , Factores SexualesRESUMEN
BACKGROUND: Individuals with incomplete spinal cord injury (iSCI) exhibit considerable lateral center of mass (COM) movement variability during gait transitions from a stabilizing to unassisted environment, while non-impaired individuals do not. To understand how iSCI influences gait adaption, we examined persons with and without iSCI performing repeated locomotor transitions. We hypothesized that, with practice, individuals with iSCI would prioritize COM control performance during the transition as exhibited by a reduction in kinematic variability. In, contrast, we hypothesized that non-impaired individuals would prioritize control effort by decreasing muscular activity. METHODS: Thirteen participants with iSCI and 12 non-impaired participants performed five treadmill-walking trials. During some trials, a cable-robot applied stabilizing lateral forces to the pelvis proportional in magnitude and opposite in direction to real-time lateral COM velocity. Each trial consisted of 300 continuous steps with or without a transition. During the first and last trials, no forces were applied and no transitions occurred (Null trials). During trials 2-4 (transition trials), the first 200 steps occurred in the stabilizing force field, forces were then abruptly removed, and 100 more unassisted steps were performed. We analyzed COM and step width variability, and hip abductor muscle activity during transitions (force removal until gait returned to steady state). RESULTS: Participants with iSCI displayed large COM movement variability during the first transition but reduced variability with practice. During the first transition, lateral COM speed, lateral COM excursion, and step width were all more variable than during the first Null trial (p < 0.05). By the third transition, no metric was different from Null trials (p > 0.05). In contrast, non-impaired participants' movement variability during the first transition was not different from Null trials (p > 0.05). With practice, movement variability increased: lateral COM excursion was more variable during Transitions 2 and 3 versus the first Null trial (p < 0.05). Non-impaired participants decreased hip abductor activity from Transition 1 to 3 (p < 0.05). CONCLUSIONS: Individuals with iSCI demonstrated rapid motor savings. By the third transition, individuals with iSCI reduced locomotor variability to baseline levels. In contrast, non-impaired participants prioritized control effort over control performance. With practice transitioning, non-impaired participants increased locomotor variability and decreased muscular effort.
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Marcha/fisiología , Equilibrio Postural/fisiología , Traumatismos de la Médula Espinal/fisiopatología , Traumatismos de la Médula Espinal/rehabilitación , Adulto , Fenómenos Biomecánicos/fisiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Movimiento , Músculo Esquelético/fisiologíaRESUMEN
BACKGROUND: Several large epidemiologic studies and clinical trials have included echocardiography, but images were stored in analog format and these studies predated tissue Doppler imaging (TDI) and speckle tracking echocardiography (STE). We hypothesized that digitization of analog echocardiograms, with subsequent quantification of cardiac mechanics using STE, is feasible, reproducible, accurate, and produces clinically valid results. METHODS: In the NHLBI HyperGEN study (N = 2234), archived analog echocardiograms were digitized and subsequently analyzed using STE to obtain tissue velocities/strain. Echocardiograms were assigned quality scores and inter-/intra-observer agreement was calculated. Accuracy was evaluated in: (1) a separate second study (N = 50) comparing prospective digital strain versus post hoc analog-to-digital strain, and (2) in a third study (N = 95) comparing prospectively obtained TDI e' velocities with post hoc STE e' velocities. Finally, we replicated previously known associations between tissue velocities/strain, conventional echocardiographic measurements, and clinical data. RESULTS: Of the 2234 HyperGEN echocardiograms, 2150 (96.2%) underwent successful digitization and STE analysis. Inter/intra-observer agreement was high for all STE parameters, especially longitudinal strain (LS). In accuracy studies, LS performed best when comparing post hoc STE to prospective digital STE for strain analysis. STE-derived e' velocities correlated with, but systematically underestimated, TDI e' velocity. Several known associations between clinical variables and cardiac mechanics were replicated in HyperGEN. We also found a novel independent inverse association between fasting glucose and LS (adjusted ß = -2.4 [95% CI -3.6, -1.2]% per 1-SD increase in fasting glucose; P < 0.001). CONCLUSIONS: Archeological echocardiography, the digitization and speckle tracking analysis of archival echocardiograms, is feasible and generates indices of cardiac mechanics similar to contemporary studies.
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Conversión Analogo-Digital , Ecocardiografía/métodos , Diagnóstico por Imagen de Elasticidad/métodos , Sistemas de Información Radiológica/organización & administración , Disfunción Ventricular Izquierda/diagnóstico por imagen , Disfunción Ventricular Izquierda/fisiopatología , Minería de Datos/métodos , Humanos , Interpretación de Imagen Asistida por Computador/métodos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Procesamiento de Señales Asistido por ComputadorRESUMEN
BACKGROUND: Albuminuria is a marker of endothelial dysfunction and has been associated with adverse cardiovascular outcomes. The reasons for this association are unclear but may be attributable to the relationship between endothelial dysfunction and intrinsic myocardial dysfunction. METHODS AND RESULTS: In the Hypertension Genetic Epidemiology Network (HyperGEN) Study, a population- and family-based study of hypertension, we examined the relationship between urine albumin-to-creatinine ratio (UACR) and cardiac mechanics (n=1894, all of whom had normal left ventricular ejection fraction and wall motion). We performed speckle-tracking echocardiographic analysis to quantify global longitudinal, circumferential, and radial strain, and early diastolic (e') tissue velocities. We used E/e' ratio as a marker of increased left ventricular filling pressures. We used multivariable-adjusted linear mixed effect models to determine independent associations between UACR and cardiac mechanics. The mean age was 50±14 years, 59% were female, and 46% were black. Comorbidities were increasingly prevalent among higher UACR quartiles. Albuminuria was associated with global longitudinal strain, global circumferential strain, global radial strain, e' velocity, and E/e' ratio on unadjusted analyses. After adjustment for covariates, UACR was independently associated with lower absolute global longitudinal strain (multivariable-adjusted mean global longitudinal strain [95% confidence interval] for UACR Quartile 1 = 15.3 [15.0-15.5]% versus UACR Q4 = 14.6 [14.3-14.9]%, P for trend <0.001) and increased E/e' ratio (Q1 = 25.3 [23.5-27.1] versus Q4 = 29.0 [27.0-31.0], P=0.003). The association between UACR and global longitudinal strain was present even in participants with UACR < 30 mg/g (P<0.001 after multivariable adjustment). CONCLUSIONS: Albuminuria, even at low levels, is associated with adverse cardiac mechanics and higher E/e' ratio.
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Albuminuria/epidemiología , Albuminuria/genética , Hipertensión/epidemiología , Hipertensión/genética , Disfunción Ventricular Izquierda/epidemiología , Disfunción Ventricular Izquierda/genética , Adulto , Presión Sanguínea , Comorbilidad , Ecocardiografía , Femenino , Tasa de Filtración Glomerular , Humanos , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Volumen Sistólico , Disfunción Ventricular Izquierda/diagnóstico por imagen , Presión VentricularRESUMEN
BACKGROUND: Kawasaki Disease (KD) can cause potentially life-threatening coronary arteritis in young children, and has a likely infectious etiology. Transcriptome profiling is a powerful approach to investigate gene expression in diseased tissues. RNA sequencing of KD coronary arteries could elucidate the etiology and the host response, with the potential to improve KD diagnosis and/or treatment. METHODS: Deep RNA sequencing was performed on KD (n = 8) and childhood control (n = 7) coronary artery tissues, revealing 1074 differentially expressed mRNAs. Non-human RNA sequences were subjected to a microbial discovery bioinformatics platform, and microbial sequences were analyzed by Metastats for association with KD. RESULTS: T lymphocyte activation, antigen presentation, immunoglobulin production, and type I interferon response were significantly upregulated in KD arteritis, while the tumor necrosis factor α pathway was not differentially expressed. Transcripts from known infectious agents were not specifically associated with KD coronary arteritis. CONCLUSIONS: The immune transcriptional profile in KD coronary artery tissues has features of an antiviral immune response such as activated cytotoxic T lymphocyte and type I interferon-induced gene upregulation. These results provide new insights into the pathogenesis of KD arteritis that can guide selection of new immunomodulatory therapies for high-risk KD patients, and provide direction for future etiologic studies.
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Arteritis/etiología , Enfermedad de la Arteria Coronaria/etiología , Síndrome Mucocutáneo Linfonodular/complicaciones , Transcriptoma , Presentación de Antígeno/inmunología , Arteritis/diagnóstico , Biomarcadores , Estudios de Casos y Controles , Análisis por Conglomerados , Biología Computacional/métodos , Enfermedad de la Arteria Coronaria/diagnóstico , Citocinas/metabolismo , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Factores Reguladores del Interferón/genética , Interferón Tipo I/metabolismo , Metabolismo de los Lípidos/genética , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Macrófagos/inmunología , Macrófagos/metabolismo , Masculino , Síndrome Mucocutáneo Linfonodular/diagnóstico , Síndrome Mucocutáneo Linfonodular/terapia , Neutrófilos/inmunología , Neutrófilos/metabolismo , Receptores de Reconocimiento de Patrones/genética , Transducción de Señal , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismoRESUMEN
We used electronic health record data from 162 patients enrolled in the NUgene Project (2002-2013) to determine demographic factors associated with long-term (from 1 to up to 9.5 (mean = 5.6) years) weight loss following Roux-en-Y gastric bypass surgery. Ninety-nine (61.1%) patients self-reported white, and 63 (38.9%) self-reported black, mixed, or missing race. The average percent weight loss was -33.4% (standard deviation, 9.3) at 1 year after surgery and -30.7% (standard deviation, 12.5) at the last follow-up point. We used linear mixed and semiparametric trajectory models to test the association of surgical and demographic factors (height, surgery age, surgery weight, surgery body mass index, marital status, sex, educational level, site, International Classification of Diseases code, Current Procedural Terminology code, Hispanic ethnicity, and self-reported race) with long-term percent weight loss and pattern of weight loss. We found that black, mixed, and missing races (combined) in comparison with white race were associated with a decreased percent weight loss of -4.31% (95% confidence interval: -7.30, -1.32) and were less likely to have higher and sustained percent weight loss (P = 0.04). We also found that less obese patients were less likely to have higher and sustained percent weight loss (P = 0.01). These findings may be helpful to patients in setting expectations after weight loss surgery.
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Derivación Gástrica/estadística & datos numéricos , Modelos Lineales , Obesidad Mórbida/cirugía , Pérdida de Peso/etnología , Análisis de Varianza , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Autoinforme , Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Diastolic wall strain (DWS), defined using posterior wall thickness (PWT) measurements from standard echocardiographic images (DWS = [PWT(systole)-PWT(diastole)]/PWT(systole)), has been proposed as a marker of left ventricular (LV) diastolic stiffness. However, the equation for DWS is closely related to systolic radial strain, and whether DWS is associated with abnormal cardiac mechanics (reduced systolic strains and diastolic tissue velocities) is unknown. We sought to determine the relationship between DWS and systolic and diastolic cardiac mechanics. METHODS: We calculated DWS and performed speckle-tracking analysis in a large population- and family-based study (Hypertension Genetic Epidemiology Network [HyperGEN]; N=1907 after excluding patients with ejection fraction [EF] <50% or posterior wall motion abnormalities). We measured global longitudinal, circumferential, and radial strain (GLS, GCS, and GRS, respectively) and early diastolic (e') tissue velocities, and we determined the independent association of DWS with cardiac mechanics using linear mixed effects models to account for relatedness among study participants. We also prospectively performed receiver-operating characteristic (ROC) analysis of DWS for the detection of abnormal cardiac mechanics in a separate, prospective validation study (N=35). RESULTS: In HyperGEN (age 51 ± 14 years, 59% female, 45% African-American, 57% hypertensive), mean DWS was 0.38 ± 0.05. DWS decreased with increasing comorbidity burden (ß-coefficient -0.013 [95% CI -0.015, -0.011]; P<0.0001). DWS was independently associated with GLS, GCS, GRS, and e' velocity (adjusted P<0.05) but not LV chamber compliance (EDV20, P=0.97). On prospective speckle-tracking analysis, DWS correlated well with GLS, GCS, and GRS (R=0.61, 0.57, and 0.73, respectively; P<0.001 for all comparisons). C-statistics for DWS as a diagnostic test for abnormal GLS, GCS, and GRS were: 0.78, 0.79, and 0.84, respectively. CONCLUSIONS: DWS, a simple parameter than can be calculated from routine 2D echocardiography, is closely associated with systolic strain parameters and early diastolic (e') tissue velocities but not LV chamber compliance.
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Módulo de Elasticidad , Ventrículos Cardíacos/diagnóstico por imagen , Ventrículos Cardíacos/fisiopatología , Hipertensión/diagnóstico por imagen , Hipertensión/fisiopatología , Disfunción Ventricular Izquierda/diagnóstico por imagen , Disfunción Ventricular Izquierda/fisiopatología , Biomarcadores , Diástole , Ecocardiografía/estadística & datos numéricos , Diagnóstico por Imagen de Elasticidad/estadística & datos numéricos , Femenino , Humanos , Hipertensión/epidemiología , Interpretación de Imagen Asistida por Computador/métodos , Masculino , Persona de Mediana Edad , Prevalencia , Reproducibilidad de los Resultados , Factores de Riesgo , Sensibilidad y Especificidad , Estrés Mecánico , Estados Unidos/epidemiología , Disfunción Ventricular Izquierda/epidemiologíaRESUMEN
Background: Kawasaki disease (KD) is an acute febrile illness of childhood that can lead to coronary artery aneurysms (CAAs) and myocardial infarction. Intravenous immunoglobulin reduces the prevalence of CAA when given to patients with KD within 10 days of fever onset. Children with KD may undergo evaluation for other diagnoses before treatment, particularly those with incomplete KD criteria. If KD outcomes are improved with early treatment, a delay in treatment while evaluating for other causes might place these patients at risk. Methods: We performed a retrospective cohort study of children treated for KD within the first 10 days of illness at our KD center from 2014 to 2021 to determine the prevalence of CAA by day of treatment. Results: A total of 290 patients met the study criteria. No statistically significant difference was found in the odds of developing a maximum z score ≥2.5 for each day of delayed treatment within 10 days of fever onset (adjusted odds ratio, 0.87; 95% CI, .72-1.05; P = .13). Subgroup analyses by age, sex, and year of treatment did not reveal a significant association between treatment day and maximum z score ≥2.5, although the number of patients <6 months of age was small. Conclusions: Our study supports current recommendations. We found similar odds of developing adverse coronary outcomes regardless of treatment day within 10 days from fever onset.
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BACKGROUND: Understanding why some triple-negative breast cancer (TNBC) patients respond poorly to existing therapies while others respond well remains a challenge. This study aims to understand the potential underlying mechanisms distinguishing early-stage TNBC tumors that respond to clinical intervention from non-responders, as well as to identify clinically viable therapeutic strategies, specifically for TNBC patients who may not benefit from existing therapies. METHODS: We conducted retrospective bioinformatics analysis of historical gene expression datasets to identify a group of genes whose expression levels in early-stage tumors predict poor clinical outcomes in TNBC. In vitro small-molecule screening, genetic manipulation, and drug treatment in syngeneic mouse models of TNBC were utilized to investigate potential therapeutic strategies and elucidate mechanisms of drug action. RESULTS: Our bioinformatics analysis reveals a robust association between increased expression of immunosuppressive cytokine S100A8/A9 in early-stage tumors and subsequent disease progression in TNBC. A targeted small-molecule screen identifies PIM kinase inhibitors as capable of decreasing S100A8/A9 expression in multiple cell types, including TNBC and immunosuppressive myeloid cells. Combining PIM inhibition and immune checkpoint blockade induces significant antitumor responses, especially in otherwise resistant S100A8/A9-high PD-1/PD-L1-positive tumors. Notably, serum S100A8/A9 levels mirror those of tumor S100A8/A9 in a syngeneic mouse model of TNBC. CONCLUSIONS: Our data propose S100A8/A9 as a potential predictive and pharmacodynamic biomarker in clinical trials evaluating combination therapy targeting PIM and immune checkpoints in TNBC. This work encourages the development of S100A8/A9-based liquid biopsy tests for treatment guidance.
Breast cancer is a complex disease, and not all patients respond well to existing treatments. In this study, we sought to understand why some patients with a specific type of breast cancer called triple-negative breast cancer respond poorly to current therapies. We also aimed to identify new treatments for these patients. We analyzed genetic data from breast cancer patients and identified a factor called S100A8/A9, which is linked to poor outcomes in early-stage cancer. We tested drugs that can reduce the levels of this factor in tumors and found promising results, especially when combined with another treatment called immunotherapy. Our findings suggest that S100A8/A9 could help predict how patients will respond to treatments, potentially leading to better therapies in the future.
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Trials of digital mental health interventions (DMHIs) often exclude individuals with suicide-related thoughts and behaviors precluding an understanding of whether DMHIs for affective disorders are safe for, and perform similarly within, this high-risk group. We explore the safety and performance of a DMHI for depression in participants with and without suicidal ideation (SI) at baseline. Three hundred and one participants were included in this secondary data analysis from a trial of an 8-week DMHI comprising 14 smartphone apps. We found that SI decreased across the study among participants with baseline SI and that baseline SI status did not attenuate depression treatment effects. Through a case study of the IntelliCare platform, we find that DMHIs for general affective disorders can be safe.
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Aplicaciones Móviles , Ideación Suicida , Humanos , Salud MentalRESUMEN
Background: There is evidence that ambulatory people with incomplete spinal cord injury (iSCI) have an impaired ability to control lateral motion of their whole-body center of mass (COM) during walking. This impairment is believed to contribute to functional deficits in gait and balance, however that relationship is unclear. Thus, this cross-sectional study examines the relationship between the ability to control lateral COM motion during walking and functional measures of gait and balance in people with iSCI. Methods: We assessed the ability to control lateral COM motion during walking and conducted clinical gait and balance outcome measures on 20 ambulatory adults with chronic iSCI (C1-T10 injury, American Spinal Injury Association Impairment Scale C or D). To assess their ability to control lateral COM motion, participants performed three treadmill walking trials. During each trial, real-time lateral COM position and a target lane were projected on the treadmill. Participants were instructed to keep their lateral COM position within the lane. If successful, an automated control algorithm progressively reduced the lane width, making the task more challenging. If unsuccessful, the lane width increased. The adaptive lane width was designed to challenge each participant's maximum capacity to control lateral COM motion during walking. To quantify control of lateral COM motion, we calculated lateral COM excursion during each gait cycle and then identified the minimum lateral COM excursion occurring during five consecutive gait cycles. Our clinical outcome measures were Berg Balance Scale (BBS), Timed Up and Go test (TUG), 10-Meter Walk Test (10MWT) and Functional Gait Assessment (FGA). We used a Spearman correlation analysis (ρ) to examine the relationship between minimum lateral COM excursion and clinical measures. Results: Minimum lateral COM excursion had significant moderate correlations with BBS (ρ = -0.54, p = 0.014), TUG (ρ = 0.59, p = 0.007), FGA (ρ = -0.59, p = 0.007), 10MWT-preferred (ρ = -0.59, p = 0.006) and 10MWT-fast (ρ = -0.68, p = 0.001). Conclusion: Control of lateral COM motion during walking is associated with a wide range of clinical gait and balance measures in people with iSCI. This finding suggests the ability to control lateral COM motion during walking could be a contributing factor to gait and balance in people with iSCI.
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It remains elusive why some triple-negative breast cancer (TNBC) patients respond poorly to existing therapies while others respond well. Our retrospective analysis of historical gene expression datasets reveals that increased expression of immunosuppressive cytokine S100A8/A9 in early-stage tumors is robustly associated with subsequent disease progression in TNBC. Although it has recently gained recognition as a potential anticancer target, S100A8/A9 has not been integrated into clinical study designs evaluating molecularly targeted therapies. Our small molecule screen has identified PIM kinase inhibitors as capable of decreasing S100A8/A9 expression in multiple cell types, including TNBC and immunosuppressive myeloid cells. Furthermore, combining PIM inhibition and immune checkpoint blockade induces significant antitumor responses, especially in otherwise resistant S100A8/A9-high PD-1/PD-L1-positive tumors. Importantly, serum S100A8/A9 levels mirror those of tumor S100A8/A9 in a syngeneic mouse model of TNBC. Thus, our data suggest that S100A8/A9 could be a predictive and pharmacodynamic biomarker in clinical trials evaluating combination therapy targeting PIM and immune checkpoints in TNBC and encourage the development of S100A8/A9-based liquid biopsy tests.
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Background: Invasive cervical cancer (ICC) is a serious public health burden in Nigeria, where human immunodeficiency virus (HIV) remains highly prevalent. Previous research suggested that epigenetic age acceleration (EAA) could play a role in detection of HIV-associated ICC. However, little research has been conducted on this topic in Africa where the population is most severely affected by HIV-associated ICC. Here, we investigated the association between ICC and EAA using cervical tissues of ICC-diagnosed Nigerian women living with HIV. Methods: We included 116 cervical tissue samples from three groups of Nigerian women in this study: (1) HIV+/ICC+ (n = 39); (2) HIV+/ICC- (n = 53); and (3) HIV-/ICC + (n = 24). We utilized four DNA methylation-based EAA estimators; IEAA, EEAA, GrimAA, and PhenoAA. We compared EAA measurements across the 3 HIV/ICC groups using multiple linear regression models. We also compared EAA between 26 tumor tissues and their surrounding normal tissues using paired t-tests. We additionally performed a receiver operating characteristics (ROC) curve analysis to illustrate the area under the curve (AUC) of EAA in ICC. Results: We found the most striking associations between HIV/ICC status and PhenoAge acceleration (PhenoAA). Among HIV-positive women, PhenoAA was on average 13.4 years higher in women with ICC compared to cancer-free women (P = 0.005). PhenoAA was 20.7 and 7.1 years higher in tumor tissues compared to surrounding normal tissues among HIV-positive women (P = 0.009) and HIV-negative women (P = 0.284), respectively. We did not find substantial differences in PhenoAA between HIV-positive and HIV-negative women with ICC. Conclusion: PhenoAA is associated with ICC in HIV-infected women in our study. Our findings suggest that PhenoAA may serve as a potential biomarker for further risk stratification of HIV-associated ICC in Nigeria and similar resource-constrained settings.