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OBJECTIVES: To facilitate the development of new therapies for Prader-Willi syndrome (PWS), we sought to develop a reliable and valid assessment of anxiousness and distress, common characteristics that have a significant negative impact on individuals with PWS and their families. METHODS: The PWS Anxiousness and Distress Behaviors Questionnaire (PADQ) was developed with extensive input from clinical experts, as well as caregivers of individuals with PWS, who participated in iterative sets of qualitative interviews. The psychometric properties of the PADQ were subsequently demonstrated in a cross-sectional evaluation using data from the Global PWS Registry provided by > 400 caregivers and confirmed using data from a phase 3 clinical trial of an oxytocin analogue (intranasal carbetocin, LV-101). RESULTS: Qualitative interview participants consistently endorsed the content of the PADQ and were confident they could accurately respond to each item based on their observations of their child's behavior. Analysis of cross-sectional data supported the computation of a total PADQ score, as well as the reliability and validity of the measure. The results of analyses using longitudinal clinical trial data confirmed these properties and provided evidence for the responsiveness of the PADQ, further supporting its appropriateness for the evaluation of new treatments targeting anxiousness and distress in PWS. CONCLUSIONS: The current body of evidence supports the conclusion that the PADQ measures observable behaviors that are meaningful to patients and their families and provides a valid and reliable method to assess beneficial treatment effects for some of the most challenging behaviors associated with PWS.
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Síndrome de Prader-Willi , Niño , Humanos , Síndrome de Prader-Willi/tratamiento farmacológico , Psicometría , Reproducibilidad de los Resultados , Estudios Transversales , Ansiedad , Encuestas y CuestionariosRESUMEN
PURPOSE: To compare the performance of anchor-based methods for estimating thresholds of meaningful within-patient change (i.e., individual change) of clinical outcome assessments in conditions reflecting data characteristics of small- to medium-sized clinical trials. METHODS: Datasets were generated from the joint distributions of the PROMIS PF 20a T-score changes and a seven-point global change anchor measure. The 108 simulation conditions (1000 replications per condition) included combinations of three marginal distributions of T-score changes, three improvement percentages in the anchor measure, four levels of responsiveness correlations, and three sample sizes. Threshold estimation methods included mean change, median change, ROC curve, predictive modeling, half SD, and SEM. Relative bias, precision, accuracy, and measurement significance of the estimates were evaluated based on comparison with true thresholds and IRT-based individual reliable changes of PROMIS scores. Quantile regression models were applied to select and interpret effects of simulation conditions on estimation bias. RESULTS: When PROMIS T-score changes were distributed normally, the predictive modeling method performed best with 50% or more responders identified by the anchor; the mean and median methods were preferred with 30% responders. For skewed distributions, the median method and ROC method gained more advantages. Among the evaluated study conditions, the improvement percentage condition had the most obvious effects on estimation bias. CONCLUSION: To establish accurate and precise thresholds, clinical researchers are recommended to prioritize study designs with at least 50% anchor-defined responders and strongly responsive target endpoints with highly reliable scoring calibration and to select optimal anchor-based methods given the data characteristics.
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Medición de Resultados Informados por el Paciente , Calidad de Vida , Humanos , Calidad de Vida/psicología , Diferencia Mínima Clínicamente ImportanteRESUMEN
BACKGROUND: The Clinician Reported Photonumeric Cellulite Severity Scale (CR-PCSS) and Patient Reported PCSS (PR-PCSS) are newly developed tools for assessing cellulite severity. OBJECTIVE: To report on the reliability, validity, and ability to detect a change in cellulite severity on the buttocks of adult women with the CR-PCSS and PR-PCSS. MATERIALS AND METHODS: Content validity of both scales was established through concept elicitation and cognitive interviews. Test-retest reliability was evaluated, and intra-rater (both scales) and inter-rater (CR-PCSS only) reliability were estimated using intraclass correlation coefficients (ICCs) for agreement and consistency. Ability to detect a change was determined using the Subject-Global Aesthetic Improvement Scale (GAIS) or Investigator-GAIS as anchors. RESULTS: For the CR-PCSS (n = 6) at baseline and Day 2, the mean interrater ICCs were ≥0.70 and mean intrarater ICCs (95% confidence interval [CI]) were ≥0.81 (0.72-0.90) for both buttocks. For the PR-PCSS (n = 99) at baseline and Day 14, the mean test-retest reliability ICCs (95% CI) were ≥0.86 (0.79-0.91) for both buttocks. A clinically meaningful change was 1.0 point on the PR-PCSS and 1.0 on the CR-PCSS. CONCLUSION: The CR-PCSS and PR-PCSS reliably assess cellulite severity of the buttocks and can detect a clinically meaningful change after treatment for cellulite.
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Nalgas/diagnóstico por imagen , Celulitis/diagnóstico , Medición de Resultados Informados por el Paciente , Índice de Severidad de la Enfermedad , Adulto , Anciano , Celulitis/terapia , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Dermatólogos/estadística & datos numéricos , Estética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Variaciones Dependientes del Observador , Fotograbar/estadística & datos numéricos , Investigación Cualitativa , Reproducibilidad de los Resultados , Cirujanos/estadística & datos numéricos , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: The objective of this study was to evaluate the measurement properties of the Migraine Physical Function Impact Diary (MPFID), a novel patient-reported outcome (PRO) measure for assessing the impact of migraine on physical functioning. METHODS: In a prospective, observational study, adults with episodic migraine (EM) or chronic migraine (CM) used an eDiary to complete the MPFID (assessing daily impacts of migraine on physical function) and a headache diary (capturing migraine days, migraine pain intensity, and migraine interference) each day, and other PRO instruments related to migraine. Item-level evaluation, item response theory (IRT), and exploratory factor analysis (EFA) methods were applied to identify domains, select final MPFID items, and develop scoring procedures. Psychometric properties of the final 13-item MPFID were evaluated using confirmatory factor analysis and tests of reliability (Cronbach's α for internal consistency and intra-class correlation [ICC] for test-retest) and validity (convergent and known-groups). RESULTS: The study enrolled 569 adults with chronic or episodic migraine, mean (SD) age 39.9 (12.0) years and 87.2% female. Item-level analyses based on interim data informed selection of a set of 13 items for the MPFID, through evaluation of floor/ceiling effects, item-to-item correlations, factor loadings, and IRT-based fit/misfit statistics. Two domain scores (EA: Impact on Everyday Activities; PI: Physical Impairment) and a global item score for impact on everyday activities were identified. EA and PI domains exhibited high internal consistency (α = 0.97; α = 0.93) and good test-retest reliability among stable subjects (ICCs = 0.74 and 0.77). Convergent validity was demonstrated by moderate correlations (r = ±0.50-0.68; P < .0001) between MPFID domain scores and number of migraine days, headache days, bed days, and other migraine-related PRO instruments. EA and PI scores differentiated between groups who varied by number of migraine days, migraine interference levels, migraine pain intensity, and median split groups of scores based on other PROs instruments (P < .05). CONCLUSIONS: The MPFID has robust psychometric properties (ie, reliability and validity). Findings supported two distinct domains about the impact of migraine on physical functioning: Impact on Everyday Activities and Physical Impairment. Both domain scores showed evidence of excellent reliability and construct validity in assessing the impacts of migraine on physical functioning.
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Actividades Cotidianas/psicología , Ejercicio Físico/psicología , Registros Médicos/normas , Trastornos Migrañosos/diagnóstico , Trastornos Migrañosos/psicología , Medición de Resultados Informados por el Paciente , Adolescente , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Psicometría , Adulto JovenRESUMEN
Data from 1,364 children and families who participated in the National Institute of Child Health and Human Development's Study of Early Child Care and Youth Development were analyzed to track the early correlates and later academic outcomes of planning during middle childhood. Maternal education, through its effect on parenting quality when children were 54 months old, predicts their concurrent performance on sustained attention, inhibition, and short-term verbal memory tests. This performance predicts planning in first grade, which predicts third-grade reading and mathematics attainment, but not the rate of growth in academic skills from first to fifth grades. This path was also found when the same parenting, cognitive, and academic constructs were measured at later time points.
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Atención/fisiología , Desarrollo Infantil/fisiología , Función Ejecutiva/fisiología , Matemática/estadística & datos numéricos , Responsabilidad Parental/psicología , Solución de Problemas/fisiología , Lectura , Niño , Preescolar , Escolaridad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Relaciones Madre-Hijo , Estados Unidos/epidemiologíaRESUMEN
INTRODUCTION: Vasomotor symptoms (VMS), the characteristic symptoms of menopausal transition, are often the primary reason women seek treatment. Current treatment options for VMS include fezolinetant, a nonhormonal, selective neurokinin 3 receptor antagonist. This study aimed to define a clinically meaningful threshold for reduction of moderate-to-severe VMS in postmenopausal women treated with fezolinetant and then apply it in a responder analysis of the pooled trial data. METHODS: This analysis pooled data from two identical phase 3, double-blind, placebo-controlled studies that randomized women with moderate-to-severe VMS to once-daily fezolinetant 30 mg, 45 mg, or placebo (SKYLIGHT 1 and 2). The frequency of VMS was collected daily using an electronic diary. Patients completed the Patient Global Impression of Change in VMS (PGI-C VMS) instrument, which assessed changes in hot flushes/night sweats at weeks 4 and 12 compared with baseline using a seven-point Likert scale. VMS frequency data were anchored to PGI-C VMS data; the anchor level for meaningful within-patient change in PGI-C VMS was "moderately better." RESULTS: In the pooled population (N = 1022), the mean (standard deviation) estimated thresholds for a meaningful within-patient change in moderate-to-severe VMS frequency were - 5.73 (3.47) at week 4 and - 6.20 (5.18) at week 12. Applying the thresholds for meaningful within-patient change to responder analyses ("missing as non-responder" imputation method) indicated a favorable clinical benefit: greater proportions of responders were observed in the fezolinetant 30-mg and 45-mg groups compared with placebo at week 4 (odds ratio range 2.48-2.91; P < 0.001) and week 12 (odds ratio range 1.908-2.68; P < 0.001). CONCLUSION: PGI-C VMS is sensitive to change and correlates with VMS frequency: a reduction of approximately six VMS episodes per day from baseline to week 12 was meaningful at the individual patient level. Fezolinetant provides a meaningful clinical benefit for women with moderate-to-severe VMS associated with menopause and represents an important nonhormonal treatment option. TRIAL REGISTRATION NUMBER: NCT04003155 and NCT04003142.
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Sofocos , Humanos , Femenino , Sofocos/tratamiento farmacológico , Persona de Mediana Edad , Método Doble Ciego , Posmenopausia , Anciano , Resultado del Tratamiento , Sudoración/efectos de los fármacos , Ensayos Clínicos Fase III como AsuntoRESUMEN
BACKGROUND: Patient-reported outcome (PRO) measures are important to consider when evaluating treatments, yet there are no PRO measures for patients with acromegaly that have been developed in accordance with US Food and Drug Administration guidance. Acromegaly is a rare, chronic condition caused by hypersecretion of growth hormone. Disease activity is monitored by measurement in serum of growth hormone and insulin-like growth factor-I. The objectives of this research were to develop the Acromegaly Symptom Diary (ASD), establish a scoring algorithm, and evaluate the psychometric measurement properties of the ASD. METHODS: Semistructured interviews consisting of concept elicitation and cognitive debriefing components were conducted with 16 adult participants with acromegaly. The concept elicitation component identified symptoms important to individuals with acromegaly. The cognitive debriefing component gathered information about the participants' experience with each proposed item of the ASD, their thought process for answering each question, and their interpretation of the items. The psychometric properties of the draft ASD were then evaluated using data from the ACROBAT Evolve (NCT03792555; n = 13) and ACROBAT Edge (NCT03789656; n = 47) clinical trials. RESULTS: The 16 participants from the interviews described ongoing symptoms, with the most frequently reported being joint pain (n = 13) and fatigue (n = 12), followed by swelling (n = 8), headache (n = 7), and mood swings (n = 6), and were able to interpret and understand the ASD items and had no issues with the 24-hour recall period. From data collected in the clinical studies, the psychometric properties of internal consistency (0.91 - 0.80), test-retest reliability with item-level and total ASD scores (> 0.70), baseline construct validity (r ≥ |0.38|) across scales, and responsiveness to change (r = 0.52-0.56) were supported for the ASD. The proposed preliminary threshold range to characterize a meaningful change from the patients' perspective for the ASD total is a 4- to 6-point change for improvement or worsening out of a total score of 70. CONCLUSION: These findings provide qualitative and quantitative evidence to support the ASD as fit for the purpose of evaluating the symptom experience of patients with acromegaly in clinical trials.
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Acromegalia , Adulto , Humanos , Acromegalia/diagnóstico , Reproducibilidad de los Resultados , Encuestas y Cuestionarios , Recuerdo Mental , Hormona del CrecimientoRESUMEN
BACKGROUND: The Respiratory Infection Intensity and Impact Questionnaire (RiiQ™) is a patient-reported outcome measure designed to assess symptoms and impacts of respiratory syncytial virus (RSV) infection. This study evaluated the construct validity, reliability, and responsiveness of the RiiQ™ Respiratory and Systemic Symptoms Scale scores. METHODS: Prospective data were analyzed from a total of 1795 participants, including from non-hospitalized patients with acute respiratory infection (ARI) and no coinfections enrolled in a Phase 2b RSV vaccine study (RSV-positive: n = 60; RSV-negative: n = 1615), and two observational studies of patients hospitalized with RSV (n = 20; n = 100). Descriptive statistics, confirmatory factor analysis (CFA), test-retest intraclass correlation coefficients (ICCs), construct validity correlations (between a clinician-assessed clinical questionnaire and the RiiQ™ symptoms scale), known-groups validity, and responsiveness (correlations of change scores) were evaluated. RESULTS: Mean patient age ranged from 66.5 to 71.5 years and the majority of patients were female. Initial assessments in the vaccine trial (ARI Day 1) were suggestive of less severe illness than in the observational studies with hospitalized patients. CFA loadings (> 0.40) supported summary scores. ICCs exceeding the recommended threshold of 0.70 supported test-retest reliability for Respiratory and Systemic Symptoms, except in the small observational study. At the scale level, correlations were moderate to strong (|r| ≥ 0.3) and positive between the Respiratory Symptoms Scale and the related clinical questionnaire scores, reflecting measurement of similar symptoms in support of convergent validity. Correlations with change in Patient Global Impression of Severity > 0.30 supported responsiveness. CONCLUSIONS: Psychometric tests applied to the RiiQ™ Symptoms scales provide evidence of its reliability, construct validity, discriminating ability, and responsiveness for use in clinical studies to assess the onset and severity of RSV symptoms.
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Infecciones por Virus Sincitial Respiratorio , Infecciones del Sistema Respiratorio , Humanos , Adulto , Masculino , Femenino , Anciano , Infecciones por Virus Sincitial Respiratorio/diagnóstico , Psicometría , Reproducibilidad de los Resultados , Estudios Prospectivos , Infecciones del Sistema Respiratorio/diagnósticoRESUMEN
INTRODUCTION: Individuals with alopecia areata (AA) may experience significant impacts on their health-related quality of life. The novel Alopecia Areata Patient Priority Outcomes (AAPPO) questionnaire has been developed to assess hair loss signs, emotional symptoms, and activity limitations associated with AA. The objective of this study was to evaluate psychometric properties and establish scoring of the AAPPO in adults and adolescents with AA. METHODS: Scoring and measurement properties of the AAPPO were examined using baseline and 2-week follow-up data from a prospective, noninterventional, web-based study of 121 patients with AA (85 adults aged ≥ 18 years, 36 adolescents aged 12-17 years) with Severity of Alopecia Tool (SALT) ≥ 25% scalp hair loss. RESULTS: Exploratory and confirmatory factor analysis supported four single Hair Loss (HL) items, an Emotional Symptoms domain (ES; 4 items), and an Activity Limitations domain (AL; 3 items). Among all patients, the multi-item ES and AL domains had strong internal consistency (α ≥ 0.87); all HL items and domain scores had strong test-retest reliability (weighted kappa or intraclass correlation coefficients ≥ 0.78). All HL item scores demonstrated strong construct validity (r ≥ 0.52) compared with the patient-reported Alopecia Areata Symptom and Impact Scale (AASIS) hair loss subscale score; ES and AL domain scores exhibited strong construct validity (r ≥ 0.66) compared with the SF-36 Mental Component Summary (MCS) score. Using SALT scores, HL mean item scores were better (lower) in the 25-49% SALT subgroup versus those with highest SALT scores (76-100%); however, ES mean domain scores were better in the SALT 76-100% subgroup in the same comparison (p < 0.0001). Using AASIS and MCS score-created subgroups, ES and AL mean domain scores demonstrated hypothesized differences across subgroups (all p values < 0.0001). CONCLUSION: The AAPPO questionnaire is a reliable, valid disease-specific measure of hair loss severity and impact in individuals with AA.
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OBJECTIVE: To characterize the impact of TX-001HR on the relationship between vasomotor symptom (VMS) improvement and quality of life and sleep. METHODS: REPLENISH (NCT01942668) was a phase 3, randomized, double-blind, placebo-controlled, multicenter trial, which evaluated four daily doses of 17ß-estradiol and progesterone (E2/P4) combined in a single, oral, softgel capsule in postmenopausal women (40-65 years) with a uterus and moderate to severe VMS (≥7/day or ≥50/week). In post hoc analyses, growth models were used to examine relationships between linear changes in VMS frequency and severity over 12 weeks and changes from baseline in the Menopause-Specific Quality of Life (MENQOL; total score and VMS domain) and the Medical Outcomes Study-Sleep (total score, sleep problems indices I and II) questionnaire outcomes at 12 weeks with treatment compared with placebo. RESULTS: Outcomes with all four E2/P4 doses were combined (nâ=â591) and compared with placebo (nâ=â135). In all 5 growth models, the effects of TX-001HR on MENQOL total score and vasomotor domain were significantly associated with changes in VMS frequency and severity observed over 12 weeks (all, Pâ<â0.001). Treatment-mediated effects on MENQOL via VMS frequency and severity models were significant. Similar results were found with Medical Outcomes Study-Sleep total score and sleep problems indices. CONCLUSIONS: TX-001HR improvements in quality of life and sleep outcomes are associated with and may be mediated through improvements in VMS frequency and severity.
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Estradiol/administración & dosificación , Estradiol/uso terapéutico , Terapia de Reemplazo de Estrógeno/métodos , Sofocos/tratamiento farmacológico , Posmenopausia , Progesterona/administración & dosificación , Progesterona/uso terapéutico , Calidad de Vida , Sueño/efectos de los fármacos , Administración Oral , Adulto , Anciano , Método Doble Ciego , Hiperplasia Endometrial , Femenino , Humanos , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Encuestas y Cuestionarios , Resultado del Tratamiento , Útero/fisiologíaRESUMEN
Introduction: It is challenging to identify health state utilities associated with psoriasis because generic preference-based measures may not capture the impact of dermatological symptoms. The Psoriasis Area Severity Index (PASI) is one of the most commonly used psoriasis rating scales in clinical trials. The purpose of this study was to develop a utility scoring algorithm for the PASI. Methods: Forty health states were developed based on PASI scores of 40 clinical trial patients. Health states were valued in time trade-off interviews with UK general population participants. Regression models were conducted to crosswalk from PASI scores to utilities (e.g. OLS linear, random effects, mean, robust, spline, quadratic). Results: A total of 245 participants completed utility interviews (51.4% female; mean age = 45.3 years). Models predicting utility based on the four PASI location scores (head, upper limbs, trunk, lower limbs) had better fit/accuracy (e.g. R2, mean absolute error [MAE]) than models using the PASI total score. Head/upper limb scores were more strongly associated with utility than trunk/lower limb. The recommended model is the OLS linear model based on the four PASI location scores (R2 = 0.13; MAE = 0.03). An alternative is recommended for situations when it is necessary to estimate utility based on the PASI total score. Conclusions: The derived scoring algorithm may be used to estimate utilities based on PASI scores of any treatment group with psoriasis. Because the PASI is commonly used in psoriasis clinical trials, this scoring algorithm greatly expands options for quantifying treatment outcomes in cost-effectiveness analyses of psoriasis therapies. Results indicate that psoriasis of the head/upper limbs could be more important than trunk/lower limbs, suggesting reconsideration of the standard PASI scoring approach.
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Psoriasis/psicología , Calidad de Vida , Índice de Severidad de la Enfermedad , Encuestas y Cuestionarios/normas , Adulto , Anciano , Algoritmos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prioridad del Paciente , Adulto JovenRESUMEN
OBJECTIVE: Pantothenate kinase-associated neurodegeneration (PKAN) is an autosomal-recessive, neurodegenerative disorder with a mixed-motor phenotype caused by a defective PanK2 enzyme, for which there are few adequate treatment options. Clinimetrically sound measures of patient-reported outcomes are necessary to facilitate therapeutic development for this debilitating disease. This study's objective was to develop such a scale and assess its clinimetric properties. METHODS: A conceptually driven, iterative, content development process incorporating input from experts, caregivers, and patients was used. Scale items were initially adapted from the Unified Parkinson's Disease Rating Scale (UPDRS) Part II resulting in the 12-item Pantothenate Kinase-Associated Neurodegeneration Activities of Daily Living (PKAN-ADL). The PKAN-ADL scale was administered to caregivers (n = 37) and patients (n = 2) twice over 2 weeks, along with selected Quality of Life in Neurological Disorders (Neuro-QoL) measures, selected attributes of the Health Utilities Index (HUI)-2/3, and the Stroke Aphasia Depression Questionnaire (SADQ-10) to assess construct validity. RESULTS: Internal consistency was 0.93, with excellent test-retest reliability (intraclass correlation coefficient = 0.99). Of the 12 items, 25% (n = 3) showed a ceiling effect >30% (range, 31-54) and 42% (n = 5) showed a floor effect >30% (range, 31-46), reflecting disease heterogeneity. Convergent validity was shown with Neuro-QoL measures (rs > 0.90) and HUI-2/3 attributes (rs ≥ 0.48); divergent validity was demonstrated with the SADQ-10 (r = 0.11). Participants reported a high level of comprehension (98%), and average item relevance ratings (0-10 scale) ranged from 7.0 to 9.9. CONCLUSION: The PKAN-ADL scale demonstrated acceptable content validity, with evidence of construct validity and excellent reliability. Overall results support the use of the PKAN-ADL scale in clinical trials.
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BACKGROUND: Pantothenate kinase-associated neurodegeneration (PKAN) is an autosomal recessive neurodegenerative disorder with brain iron accumulation (NBIA). OBJECTIVES: To assess PKAN diagnostic pathway, history, and burden across the spectrum of PKAN severity from patient and/or caregiver perspectives. METHODS: Caregivers of patients (n = 37) and patients themselves (n = 2) were interviewed in a validation study of the PKAN-Activities of Daily Living (ADL) scale. The current study used quartiles of the PKAN-ADL total score to divide patients by severity of impairment (Lowest, Second Lowest, Third Lowest, Highest). Diagnostic and treatment history, healthcare utilization, disease burden, and caregiver experience were compared between groups. RESULTS: The analyses included data from 39 patients. Mean age at PKAN symptom onset (P = 0.0007), initial MRI (P = 0.0150), and genetic testing (P = 0.0016) generally decreased across the PKAN severity spectrum. The mean duration of illness did not differ among PKAN severity groups (range, 9.7-15.2 years; P = 0.3029). First MRI led to diagnosis in 56.4% of patients (range, 30.0-90.0%). A mean (SD) of 13.0 (13.1) medical and 55.2 (78.5) therapy visits (eg, physical, speech) occurred in the past year. More patients in the higher PKAN severity groups experienced multiple current functional losses and/or earlier onset of problems (P-values < 0.0500). Over half (56.8%) of caregivers experienced a change in employment because of caregiving. The percentage of patients requiring full-time caregiving increased across the PKAN severity spectrum (range, 11.1-100%; P = 0.0021). CONCLUSIONS: PKAN diagnosis was often delayed, most probably due to low awareness. Considerable burden of functional impairment and high healthcare utilization were found across the PKAN severity spectrum.
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Neurodegeneración Asociada a Pantotenato Quinasa/genética , Actividades Cotidianas , Adolescente , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Niño , Femenino , Pruebas Genéticas , Humanos , Imagen por Resonancia Magnética , Masculino , Neurodegeneración Asociada a Pantotenato Quinasa/diagnóstico por imagen , Clase Social , Encuestas y CuestionariosRESUMEN
The snail Biomphalaria glabrata kills the blood fluke Schistosoma mansoni by a mechanism involving production of hydrogen peroxide, the enzymatic product of cytosolic Cu/Zn superoxide dismutase (SOD1). This enzyme exhibits higher activity in blood cells (hemocytes) from a predominantly resistant strain of B. glabrata than in hemocytes from a susceptible strain. Additionally, B. glabrata SOD1 polymorphisms have been associated with susceptibility/resistance to the parasite. To address the hypothesis that SOD1 transcription levels differ in accordance with variation at the SOD1 locus, quantitative PCR was performed using hemocyte-derived cDNA prepared from SOD1-genotyped snails. Here we report that individuals possessing the allele previously associated with resistance to S. mansoni express significantly higher levels of hemocyte SOD1 transcripts than individuals lacking this allele. A causal relationship between SOD1 expression and susceptibility/resistance to S. mansoni is supported by the correlation of transcript quantity with data (from a previous study) on the probability of infection.
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Biomphalaria/enzimología , Biomphalaria/parasitología , Regulación Enzimológica de la Expresión Génica , Variación Genética/genética , Schistosoma mansoni/fisiología , Esquistosomiasis mansoni/enzimología , Superóxido Dismutasa/metabolismo , Alelos , Animales , Biomphalaria/genética , Susceptibilidad a Enfermedades , Genotipo , ARN Mensajero/genética , Esquistosomiasis mansoni/genética , Esquistosomiasis mansoni/parasitología , Esquistosomiasis mansoni/patología , Superóxido Dismutasa/genética , Superóxido Dismutasa-1RESUMEN
Variation in susceptibility of the snail Biomphalaria glabrata to infection by the parasite Schistosoma mansoni is, at least in part, genetically determined. Functional studies have demonstrated that hemocyte-mediated killing of the parasite involves hydrogen peroxide, the enzymatic product of superoxide dismutase (SOD). The present study identifies alleles of the gene coding for cytosolic copper/zinc SOD (SOD1). The resistance/susceptibility phenotypes and SOD1 genotypes were determined for 354 snails of the predominantly resistant 13-16-R1 strain of B. glabrata. Resistance to the parasite was found to be significantly associated with one allele of the SOD1 gene. Conversely, a separate SOD1 allele was significantly associated with susceptibility.
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Biomphalaria/enzimología , Biomphalaria/inmunología , Citosol/enzimología , Schistosoma mansoni/patogenicidad , Superóxido Dismutasa/genética , Alelos , Animales , Biomphalaria/parasitología , Cobre/metabolismo , Inmunidad Innata , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Análisis de Secuencia de ADN , Superóxido Dismutasa/metabolismo , Zinc/metabolismoRESUMEN
BACKGROUND: The SELECT study demonstrated superior effects of daclizumab high-yield process (DAC HYP) to placebo in key endpoints in patients with relapsing and remitting multiple sclerosis (RRMS). OBJECTIVE: To assess the impact of DAC HYP and disease activity on health-related quality of life (HRQoL) using data from this study. METHODS: HRQoL was assessed at baseline, 12, 24, and 52 weeks using the Multiple Sclerosis Impact Scale (MSIS-29), the 12-items Short Form Health Survey, and the EuroQoL-5 Dimensions. An analysis of covariance model was used to compare treatment difference in change from baseline. Mixed-effects models were used to assess the impact of disability progression, relapse, treatment, and interaction between treatment and these events on HRQoL outcome. RESULTS: DAC HYP 150mg resulted in significant positive impacts on HRQoL compared to placebo. It was also found to significantly reduce the adverse impact of relapse on the MSIS-29 physical scale (-12.45; p=0.0006). Relapse and disability progression were significantly associated with impaired HRQoL. CONCLUSION: DAC HYP 150mg improved HRQoL in patients with RRMS compared to placebo. The treatment benefit can be partially attributed to reduction in disease activity and attenuation of the adverse impact of relapse on HRQoL.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Factores Inmunológicos/uso terapéutico , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Adulto , Análisis de Varianza , Daclizumab , Evaluación de la Discapacidad , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Esclerosis Múltiple Recurrente-Remitente/psicología , Calidad de Vida/psicología , Autoinforme , Factores de Tiempo , Resultado del TratamientoRESUMEN
The production of reactive oxygen species by hemocytes from the gastropod Biomphalaria glabrata has been linked to their ability to kill the trematode parasite Schistosoma mansoni. For 2 laboratory strains of the snail, 1 resistant (13-16-R1) and 1 susceptible (MO) to the PR1 strain of S. mansoni, we compared hemocyte production of extracellular hydrogen peroxide when stimulated with the protein kinase C agonist phorbol myristate acetate (PMA). The time course of the PMA-induced response is similar in both strains with respect to onset, peak production, and termination of the respiratory burst. However, the magnitude of the response differs between strains, in that hemocytes from resistant snails generate significantly more hydrogen peroxide. These findings suggest that the capacity to produce hydrogen peroxide could be critical in determining susceptibility or resistance to S. mansoni.
Asunto(s)
Biomphalaria/metabolismo , Hemocitos/metabolismo , Peróxido de Hidrógeno/metabolismo , Estallido Respiratorio/fisiología , Schistosoma mansoni/inmunología , Animales , Biomphalaria/inmunología , Biomphalaria/parasitología , Susceptibilidad a Enfermedades , Hemocitos/inmunología , Inmunidad Innata , Proteína Quinasa C/metabolismo , Estallido Respiratorio/inmunología , Acetato de Tetradecanoilforbol/farmacologíaRESUMEN
BACKGROUND: Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (EVG/COBI/FTC/TDF; Stribild(®)) is a guideline-recommended regimen for HIV treatment-naïve patients and a switch option for virologically suppressed patients. OBJECTIVE: The purpose of this analysis was to understand how HIV patients' symptoms change after switching to Stribild(®) versus continuing a regimen consisting of a non-nucleoside reverse transcriptase inhibitor (NNRTI) with emtricitabine and tenofovir disoproxil fumarate. METHODS: A secondary analysis was conducted of the STRATEGY-NNRTI study (GS-US-236-0121), a randomized, open-label, phase IIIb trial of HIV-infected adults who were taking an NNRTI plus FTC/TDF and were randomly assigned (2:1) either to Stribild(®) ('switch') or to continue on their existing regimen ('no-switch'). Logistic regressions and longitudinal modeling were conducted to evaluate the relationship of treatment with bothersome symptoms. These models adjusted for age, sex, race, number of bothersome symptoms at baseline, Veterans Aging Cohort Study Risk (VACS) Index score, years since HIV diagnosis, and first antiretroviral therapy use, NNRTI type, serious mental illness, and baseline depression and health-related quality of life (HRQL) scores. RESULTS: At baseline, the prevalence of nightmares, vivid dreams, weird/intense dreams, muscle aches/joint pain, and fevers/chills/sweats was greater in the switch group. The prevalence of nightmare, vivid dreams, weird/intense dreams, dizzy/lightheadedness, fatigue/loss of energy, and pain/numbness/tingling in hands/feet deceased in the switch group at week 4, and these benefits were maintained over time. Nervous/anxious, drowsiness, trouble remembering, off balance, and body changes decreased in the switch group at week 4 but were not maintained over time. Difficulty sleeping, diarrhea/loose bowels, and bloating did not differ in prevalence at week 4 or 48, but longitudinal models suggested differences between groups over time. HRQL did not differ between groups and was unchanged over time. CONCLUSIONS: In this study sample, a switch to co-formulated EVG/COBI/FTC/TDF was associated with significant persistent improvements in six patient-reported HIV symptoms.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Cobicistat/uso terapéutico , Emtricitabina/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Quinolonas/uso terapéutico , Tenofovir/uso terapéutico , Adulto , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/efectos adversos , Cobicistat/administración & dosificación , Cobicistat/efectos adversos , Combinación de Medicamentos , Emtricitabina/administración & dosificación , Emtricitabina/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Evaluación del Resultado de la Atención al Paciente , Calidad de Vida , Quinolonas/administración & dosificación , Quinolonas/efectos adversos , Tenofovir/administración & dosificación , Tenofovir/efectos adversosRESUMEN
BACKGROUND: Coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (EVG/COBI/FTC/TDF; Stribild(®)) is a recommended integrase inhibitor-based regimen in treatment guidelines from the US Department of Health and Human Services and the British HIV Association. The purpose of this analysis was to determine the change in patient-reported symptoms over time among HIV-infected adults who switch to Stribild(®) versus those continuing on a protease inhibitor (PI) with FTC/TDF. METHODS: A secondary analysis was conducted on the STRATEGY-PI study (GS-US-236-0115, ClinicalTrials.gov NCT01475838), a randomized, open-label, phase 3b trial of HIV-infected adults taking a PI with FTC/TDF who were randomly assigned (2:1) either to Stribild(®) (switch) or continuation of their existing regimen (no-switch). Logistic regressions and longitudinal modeling were conducted to evaluate the relationship of treatment with bothersome symptoms. RESULTS: At week 4 as compared with baseline, the switch group experienced a statistically significantly lower prevalence in five symptoms (diarrhea/loose bowels, bloating/pain/gas in stomach, pain/numbness/tingling in hands/feet, nervous/anxious, and trouble remembering). The lower prevalence of diarrhea/loose bowels, bloating/pain/gas in stomach, and pain/numbness/tingling in hands/feet observed at week 4 was maintained over time. While there were no significant differences between groups in the prevalence of sad/down/depressed and problems with sex at week 4 or week 48, longitudinal models indicated the switch group had a statistically significantly decreased prevalence in both symptoms from week 4 to week 48. As compared with the no-switch group, higher levels of satisfaction with treatment were experienced by patients in the switch group at the first follow-up visit and at week 24. CONCLUSIONS: In this study sample, a switch from a ritonavir-boosted PI, FTC, and TDF regimen to coformulated EVG/COBI/FTC/TDF was associated with more treatment satisfaction and a reduction in the prevalence of patient-reported diarrhea/loose bowel symptoms, which was maintained over the 48-week study period.