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Ketones, such as beta-hydroxybutyrate (BHB), are important metabolites that can be used to monitor for conditions such as diabetic ketoacidosis (DKA) and ketosis. Compared to conventional approaches that rely on samples of urine or blood evaluated using laboratory techniques, processes for monitoring of ketones in sweat using on-body sensors offer significant advantages. Here, we report a class of soft, skin-interfaced microfluidic devices that can quantify the concentrations of BHB in sweat based on simple and low-cost colorimetric schemes. These devices combine microfluidic structures and enzymatic colorimetric BHB assays for selective and accurate analysis. Human trials demonstrate the broad applicability of this technology in practical scenarios, and they also establish quantitative correlations between the concentration of BHB in sweat and in blood. The results represent a convenient means for managing DKA and aspects of personal nutrition/wellness.
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The objective of this study was to assess the feasibility and effectiveness of a novel WeChat applet-based personalized dietary intervention aimed at promoting healthier dietary intakes. A two-arm parallel, randomized, controlled trial was conducted in a real-world scenario and involved a total of 153 participants (the intervention group, n = 76; the control group, n = 77), lasting for 4 months in Shanghai, China. The intervention group had access to visualized nutrition evaluations through the applet during workday lunch time, while the control group received no interventions. A total of 3413 lunch dietary intake records were captured through the applet. Linear mixed models were utilized to assess the intervention effects over time. At baseline, the participants' lunchtime dietary intakes were characterized by insufficient consumption of plant foods (86.9% of the participants) and excessive intake of animal foods (79.7% of the participants). Following the commencement of the intervention, the intervention group showed a significant decrease in the animal/plant food ratio (ß = -0.03/week, p = 0.024) and the consumption of livestock and poultry meat (ß = -1.80 g/week, p = 0.035), as well as a borderline significant increase in the consumption of vegetables and fruits (ß = 3.22 g/week, p = 0.055) and plant foods (ß = 3.26 g/week, p = 0.057) over time at lunch compared to the control group. The applet-based personalized dietary intervention was feasible and effective in improving dietary intakes and, consequently, possibly may manage body weight issues in real-world scenarios.
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Frutas , Verduras , Animales , Humanos , China , Programas Informáticos , Ingestión de Alimentos , DietaRESUMEN
Aim: To assess the associations between genome-wide DNA methylation (DNAm) and glucose metabolism among a Chinese population, in particular the multisite correlation. Materials & methods: Epigenome-wide associations with fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) were analyzed among 100 Shanghai monozygotic (MZ) twin pairs using the Infinium HumanMethylationEPIC v2.0 BeadChip. We conducted a Pearson's correlation test, hierarchical cluster and pairwise analysis to examine the differential methylation patterns from clusters. Results: Cg01358804 (TXNIP) was identified as the most significant site associated with FPG and HbA1c. Two clusters with hypermethylated and hypomethylated patterns were observed for both FPG and HbA1c. Conclusion: Differential methylation patterns from clusters may provide new clues for epigenetic changes and biological mechanisms in glucose metabolism.
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Metilación de ADN , Epigénesis Genética , Humanos , Hemoglobina Glucada , Islas de CpG , China , Glucosa , Gemelos Monocigóticos/genéticaRESUMEN
BACKGROUND: Nutrition service needs are huge in China. Previous studies indicated that personalized nutrition (PN) interventions were effective. The aim of the present study is to identify the effectiveness and feasibility of a novel PN approach supported by artificial intelligence (AI). METHODS: This study is a two-arm parallel, randomized, controlled trial in real world scenario. The participants will be enrolled among who consume lunch at a staff canteen. In Phase I, a total of 170 eligible participants will be assigned to either intervention or control group on 1:1 ratio. The intervention group will be instructed to use the smartphone applet to record their lunches and reach the real-time AI-based information of dish nutrition evaluation and PN evaluation after meal consumption for 3 months. The control group will receive no nutrition information but be asked to record their lunches though the applet. Dietary pattern, body weight or blood pressure optimizing is expected after the intervention. In phase II, the applet will be free to all the diners (about 800) at the study canteen for another one year. Who use the applet at least 2 days per week will be regarded as the intervention group while the others will be the control group. Body metabolism normalization is expected after this period. Generalized linear mixed models will be used to identify the dietary, anthropometric and metabolic changes. DISCUSSION: This novel approach will provide real-time AI-based dish nutrition evaluation and PN evaluation after meal consumption in order to assist users with nutrition information to make wise food choice. This study is designed under a real-life scenario which facilitates translating the trial intervention into real-world practice. TRIAL REGISTRATION: This trial has been registered with the Chinese Clinical Trial Registry (ChiCTR2100051771; date registered: 03/10/2021).
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Inteligencia Artificial , Estado Nutricional , Humanos , Programas Informáticos , Evaluación Nutricional , Peso Corporal , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
The recent global pandemic was a spillover from the SARS-CoV-2 virus. Viral entry involves the receptor binding domain (RBD) of the viral spike protein interacting with the protease domain (PD) of the cellular receptor, ACE2. We hereby present a comprehensive mutational landscape of the effects of ACE2-PD point mutations on RBD-ACE2 binding using a saturation mutagenesis approach based on microarray-based oligo synthesis and a single-cell screening assay. We observed that changes in glycosylation sites and directly interacting sites of ACE2-PD significantly influenced ACE2-RBD binding. We further engineered an ACE2 decoy receptor with critical point mutations, D30I, L79W, T92N, N322V, and K475F, named C4-1. C4-1 shows a 200-fold increase in neutralization for the SARS-CoV-2 D614G pseudotyped virus compared to wild-type soluble ACE2 and a sevenfold increase in binding affinity to wild-type spike compared to the C-terminal Ig-Fc fused wild-type soluble ACE2. Moreover, C4-1 efficiently neutralized prevalent variants, especially the omicron variant (EC50=16 ng/mL), and rescued monoclonal antibodies, vaccine, and convalescent sera neutralization from viral immune-escaping. We hope to next investigate translating the therapeutic potential of C4-1 for the treatment of SARS-CoV-2.
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COVID-19 , SARS-CoV-2 , Enzima Convertidora de Angiotensina 2/genética , COVID-19/terapia , Humanos , Inmunización Pasiva , Mutagénesis , Unión Proteica , SARS-CoV-2/genética , Glicoproteína de la Espiga del Coronavirus/química , Sueroterapia para COVID-19RESUMEN
Oocyte maturation disorder and decreased quality are the main causes of infertility in women, and granulosa cells (GCs) provide the only microenvironment for oocyte maturation through autocrine and paracrine signaling by steroid hormones and growth factors. However, chronic inflammation and oxidative stress caused by ovarian hypoxia are the largest contributors to ovarian aging and GC dysfunction. Therefore, the amelioration of chronic inflammation and oxidative stress is expected to be a pivotal method to improve GC function and oocyte quality. In this study, we detected the protective effect of chitosan oligosaccharides (COS), on hydrogen peroxide- (H2O2-) stimulated oxidative damage in a human ovarian granulosa cell line (KGN). COS significantly increased cell viability, mitochondrial function, and the cellular glutathione (GSH) content and reduced apoptosis, reactive oxygen species (ROS) content, and the levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), 4-hydroxynonenal (4-HNE), hypoxia-inducible factor-1α (HIF-1α), and vascular endothelial-derived growth factor (VEGF) in H2O2-stimulated KGN cells. COS treatment significantly increased levels of the TGF-ß1 and IL-10 proteins and decreased levels of the IL-6 protein. Compared with H2O2-stimulated KGN cells, COS significantly increased the levels of E2 and P4 and decreased SA-ß-gal protein expression. Furthermore, COS caused significant inactivation of the HIF-1α-VEGF pathway in H2O2-stimulated KGN cells. Moreover, inhibition of this pathway enhanced the inhibitory effects of COS on H2O2-stimulated oxidative injury and apoptosis in GCs. Thus, COS protected GCs from H2O2-stimulated oxidative damage and apoptosis by inactivating the HIF-1α-VEGF signaling pathway. In the future, COS might represent a therapeutic approach for ameliorating disrupted follicle development.
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Quitosano , Peróxido de Hidrógeno , Quitosano/farmacología , Femenino , Glutatión/metabolismo , Células de la Granulosa/metabolismo , Humanos , Peróxido de Hidrógeno/farmacología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Inflamación/metabolismo , Oligosacáridos/metabolismo , Oligosacáridos/farmacología , Transducción de Señal , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Sugar-sweetened beverage (SSB) consumption among children and adolescents is steadily increasing in China, while the main taste of Chinese food is salty. The present study aimed to determine the relationships between SSB and total fluid consumption and dietary sodium and salt intake among children and adolescents in China. The data were obtained from a cross-sectional investigation in 2015. A total of 3958 participants were included. A 24-h dietary record for three consecutive days was collected to determine the SSB intake and food consumption across school days and rest days. After adjusting for age, sex, yearly household income, maternal education, intentional physical exercise, and instances of eating out in the last week, the dietary sodium intake was positively associated with the SSB consumption (p < 0.05), but salt was not. After stratifying by sex, grades, and puberty status, the associations between dietary sodium intake and SSB consumption were significant in girls, in grades 1-5 and before puberty (p < 0.05). Dietary sodium intake was positively associated with SSB consumption in Chinese children and adolescents, particularly in young children. A reduction of the sodium intake might help reduce SSB consumption among children and adolescents.
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Pueblo Asiatico , Ingestión de Alimentos , Cloruro de Sodio Dietético/efectos adversos , Bebidas Azucaradas/efectos adversos , Adolescente , Niño , Preescolar , China , Femenino , Humanos , Lactante , Modelos Lineales , MasculinoRESUMEN
We set up a series of school-based interventions on the basis of an ecological model targeting sugar-sweetened beverage (SSB) reduction in Chinese elementary and middle schools and evaluated the effects. A total of 1046 students from Chinese elementary and middle schools were randomly recruited in an intervention group, as were 1156 counterparts in a control group. The interventions were conducted in the intervention schools for one year. The participants were orally instructed to answer all the questionnaires by themselves at baseline and after intervention. The difference in difference statistical approach was used to identify the effects exclusively attributable to the interventions. There were differences in grade composition and no difference in sex distribution between the intervention and control groups. After adjusting for age, sex, and group differences at baseline, a significant reduction in SSB intake was found in the intervention group post intervention, with a decrease of 35.0 mL/day (p = 0.034). Additionally, the frequency of SSB consumption decreased by 0.2 times/day (p = 0.071). The students in the elementary schools with interventions significantly reduced their SSB intake by 61.6 mL/day (p = 0.002) and their frequency of SSB consumption by 0.3 times/day (p = 0.017) after the intervention. The boys in the intervention group had an intervention effect of a 50.2 mL/day reduction in their SSB intake (p = 0.036). School-based interventions were effective in reducing SSB consumption, especially among younger ones. The boys were more responsive to the interventions than the girls. (ChiCTR, ChiCTR1900020781.).
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Dieta/métodos , Evaluación de Programas y Proyectos de Salud/métodos , Servicios de Salud Escolar , Bebidas Azucaradas/estadística & datos numéricos , Adolescente , Niño , China , Dieta/estadística & datos numéricos , Femenino , Humanos , Masculino , Factores Sexuales , Encuestas y CuestionariosRESUMEN
OBJECTIVE: To evaluate the effect of brodalumab on psoriasis signs and symptoms assessed by the Psoriasis Symptom Inventory (PSI) in patients with psoriatic arthritis (PsA). METHODS: This prespecified analysis of a phase II study (NCT01516957) evaluated patients with active PsA and psoriasis-affected body surface area ≥ 3%, randomized to brodalumab (140 or 280 mg) or placebo every 2 weeks (Q2W) for 12 weeks with loading dose at Week 1. At Week 12, patients entering an open-label extension received brodalumab 280 mg Q2W. The PSI measures 8 psoriasis signs and symptoms: itch, redness, scaling, burning, stinging, cracking, flaking, and pain. PSI response is defined as total PSI ≤ 8 (range 0-32), each item ≤ 1 (range 0-4). PSI scores were assessed at weeks 12 and 24. RESULTS: There were 107 eligible patients. At Week 12, mean improvement in PSI scores was 7.8, 11.2, and 1.5 in brodalumab 140 mg, 280 mg, and placebo groups, respectively; by Week 24, improvement was 10.2, 12.4, and 11.7. At Week 12, 75.0%, 81.8%, and 16.7% of patients receiving brodalumab 140 mg, 280 mg, and placebo, respectively, achieved PSI response; improvement was sustained through Week 24, when 83.9% of prior placebo recipients achieved response. At Week 12, 25.0%, 36.4%, and 2.8% of patients receiving brodalumab 140 mg, 280 mg, and placebo, respectively, achieved PSI 0. Percentages improved through Week 24: 40.0% brodalumab 140 mg, 42.9% brodalumab 280 mg, and 48.4% placebo. CONCLUSION: Significantly more brodalumab-treated patients with PsA achieved patient-reported improvements in psoriasis signs and symptoms than did those receiving placebo. Improvements were comparable between brodalumab groups.
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Anticuerpos Monoclonales/uso terapéutico , Artritis Psoriásica/tratamiento farmacológico , Psoriasis/tratamiento farmacológico , Adulto , Anciano , Anticuerpos Monoclonales Humanizados , Artritis Psoriásica/diagnóstico , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Psoriasis/diagnóstico , Índice de Severidad de la Enfermedad , Evaluación de Síntomas , Resultado del TratamientoRESUMEN
BACKGROUND: High bronchodilator reversibility in adult asthma is associated with distinct clinical characteristics. This analysis compares lung function, biomarker profiles, and disease control in patients with high reversibility (HR) and low reversibility (LR) asthma. METHODS: A retrospective analysis was performed with data from two completed clinical trials of similar design. Patients were divided into HR and LR subgroups based on their response to bronchodilators (HR = ΔFEV1 postbronchodilator ≥ 20%). Blood eosinophil count, serum IgE level, and fraction of exhaled nitric oxide concentration, biomarkers commonly used to stratify patients into T-helper (Th)-2-high vs Th2-low phenotypes, were measured in patients with not well controlled (1.5 ≤ Asthma Control Questionnaire [ACQ] ≤ 2.143) and very poorly controlled (ACQ > 2.143) disease. RESULTS: The majority of patients in the HR and LR subgroups displayed Th2-low biomarker profiles and very poor disease control. HR was more frequently associated with Th2-high biomarker profiles (40.1% vs 29.4%, P = .006), lower lung function (FEV1, 63.5 ± 7.7% predicted vs 67.9 ± 8.4% predicted; P < .001), and atopy (93.7% vs 86.5%, P = .005). CONCLUSIONS: HR is a physiologic indicator of reduced lung function and is more often associated with elevations in Th2 biomarkers than LR in moderate to severe asthma. However, the majority of patients with HR and LR asthma in this analysis had a Th2-low biomarker profile. Moreover, a Th2-high biomarker profile was not associated with worse disease control.
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Asma , Broncodilatadores/farmacología , Eosinófilos/inmunología , Glucocorticoides/farmacología , Inmunoglobulina E/sangre , Óxido Nítrico/análisis , Sistema Respiratorio , Células Th2/inmunología , Adulto , Asma/sangre , Asma/diagnóstico , Asma/tratamiento farmacológico , Asma/fisiopatología , Biomarcadores/análisis , Biomarcadores/sangre , Pruebas Respiratorias/métodos , Monitoreo de Drogas/métodos , Femenino , Humanos , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Prostaglandina D2/antagonistas & inhibidores , Pruebas de Función Respiratoria/métodos , Sistema Respiratorio/efectos de los fármacos , Sistema Respiratorio/inmunología , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Estadística como Asunto , Resultado del TratamientoRESUMEN
BACKGROUND: Controversy exists in understanding the effects of age at onset and comorbidities in predicting rheumatoid arthritis (RA) response to biologic therapy. OBJECTIVE: The objective of this study was to investigate the influence of age at onset and number of comorbidities on Health Assessment Questionnaire-Disability Index (HAQ-DI) and Clinical Disease Activity Index (CDAI) responses in active RA patients after 6 months of treatment with etanercept. METHODS: One thousand eight hundred ninety-nine RA patients were assessed after 6 months of etanercept therapy. Patients met the following inclusion criteria: initiated etanercept, continued therapy for at least 6 months, and were not in CDAI low disease activity (LDA) at baseline (CDAI ≤10.0). Changes in HAQ-DI and CDAI scores over 6 months were analyzed across age of onset quintiles. Multivariate regression models evaluated the independent association between both age at onset and number of comorbidities with change in HAQ-DI/CDAI scores or achieving LDA, while accounting for other covariates. RESULTS: Significant improvements in HAQ-DI and CDAI scores were observed in all age-onset groups, although HAQ-DI improvements were less in older-onset patients. Results of multiple linear regression demonstrated that younger age at onset, higher baseline HAQ-DI/CDAI score, rheumatoid factor positivity, shorter disease duration, and fewer comorbidities at baseline were independently associated with improvement in both HAQ-DI and CDAI scores. Similarly, achieving CDAI LDA after 6 or more months of etanercept was associated with younger age at onset, higher baseline CDAI, shorter disease duration, and fewer comorbidities. CONCLUSIONS: These patients with older-onset RA and more comorbidities clinically improved with etanercept, but had lower odds of achieving CDAI LDA. Age of onset and number of comorbidities may be important in determining RA tumor necrosis factor inhibitor response.
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Antirreumáticos/uso terapéutico , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/tratamiento farmacológico , Evaluación de la Discapacidad , Inmunoglobulina G/uso terapéutico , Receptores del Factor de Necrosis Tumoral/uso terapéutico , Índice de Severidad de la Enfermedad , Encuestas y Cuestionarios , Adulto , Factores de Edad , Edad de Inicio , Anciano , Anciano de 80 o más Años , Antirreumáticos/efectos adversos , Artritis Reumatoide/epidemiología , Estudios de Cohortes , Comorbilidad , Etanercept , Femenino , Estudios de Seguimiento , Humanos , Inmunoglobulina G/efectos adversos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Sistema de Registros , Análisis de Regresión , Medición de Riesgo , Resultado del Tratamiento , Estados UnidosRESUMEN
BACKGROUND: We assessed the efficacy and safety of brodalumab, a human monoclonal antibody against interleukin-17 receptor A (IL17RA), in a phase 2, randomized, double-blind, placebo-controlled study involving patients with psoriatic arthritis. METHODS: We randomly assigned patients with active psoriatic arthritis to receive brodalumab (140 or 280 mg subcutaneously) or placebo on day 1 and at weeks 1, 2, 4, 6, 8, and 10. At week 12, patients who had not discontinued their participation in the study were offered open-label brodalumab (280 mg) every 2 weeks. The primary end point was 20% improvement in American College of Rheumatology response criteria (ACR 20) at week 12. RESULTS: Of the 168 patients who underwent randomization (57 in the brodalumab 140-mg group, 56 in the brodalumab 280-mg group, and 55 in the placebo group), 159 completed the double-blind phase and 134 completed 40 weeks of the open-label extension. At week 12, the brodalumab 140-mg and 280-mg groups had higher rates of ACR 20 than the placebo group (37% [P=0.03] and 39% [P=0.02], respectively, vs. 18%); they also had higher rates of 50% improvement (ACR 50) (14% [P=0.05] and 14% [P=0.05] vs. 4%). Rates of 70% improvement were not significantly higher in the brodalumab groups. Similar degrees of improvement were noted among patients who had received previous biologic therapy and those who had not received such therapy. At week 24, ACR 20 response rates in the brodalumab 140-mg and 280-mg groups were 51% and 64%, respectively, as compared with 44% among patients who switched from placebo to open-label brodalumab; responses were sustained through week 52. At week 12, serious adverse events had occurred in 3% of patients in the brodalumab groups and in 2% of those in the placebo group. CONCLUSIONS: Brodalumab significantly improved response rates among patients with psoriatic arthritis. Larger studies of longer duration are necessary to assess adverse events. (Funded by Amgen; ClinicalTrials.gov number, NCT01516957 .).
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Anticuerpos Monoclonales/uso terapéutico , Antirreumáticos/uso terapéutico , Artritis Psoriásica/tratamiento farmacológico , Receptores de Interleucina-17/antagonistas & inhibidores , Adulto , Anciano , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Antirreumáticos/efectos adversos , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Inyecciones Subcutáneas , Masculino , Persona de Mediana EdadRESUMEN
RATIONALE: IL-17 signaling has been implicated in development and persistence of asthma. Cytokine-targeted strategies blocking IL-17 receptor signaling may be beneficial in asthma treatment. OBJECTIVES: To determine efficacy and safety of brodalumab, a human anti-IL-17 receptor A monoclonal antibody, in subjects with inadequately controlled moderate to severe asthma taking regular inhaled corticosteroids. METHODS: Three hundred two subjects were randomized to brodalumab (140, 210, or 280 mg) or placebo. Primary endpoint was change in Asthma Control Questionnaire (ACQ) score from baseline to Week 12. Secondary endpoints included FEV1, symptom scores, and symptom-free days. Prespecified subgroup analyses were conducted to identify potential responsive subpopulations. Analyses included randomized subjects receiving one or more doses of investigational product using last-observation-carried-forward imputation. MEASUREMENTS AND MAIN RESULTS: Demographics and baseline characteristics were generally balanced among groups (n = 302; n = 226 brodalumab). For the overall study population, no treatment differences were observed. Nine prespecified subgroups were examined without corrections for multiple testing. In only the high-reversibility subgroup (post-bronchodilator FEV1 improvement ≥ 20%; n = 112) was an ACQ change with nominal significance noted; ACQ responses were nominally significant in the 210-mg group (estimated treatment difference, 0.53) but not significant in the higher 280-mg group (estimated treatment difference, 0.38). Adverse events, generally balanced among groups, were most commonly asthma, upper respiratory tract infection, and injection site reaction. CONCLUSIONS: Inhibition of IL-17 receptor A did not produce a treatment effect in subjects with asthma. The results of the high-reversibility subgroup analysis are of uncertain significance, requiring further study of brodalumab in this asthma subpopulation. Clinical trial registered with www.clinicaltrials.gov (NCT01199289).
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Anticuerpos Monoclonales/uso terapéutico , Asma/tratamiento farmacológico , Bronquios/efectos de los fármacos , Receptores de Interleucina-17/efectos de los fármacos , Adolescente , Adulto , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Método Doble Ciego , Femenino , Humanos , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Receptores de Interleucina-17/antagonistas & inhibidores , Receptores de Interleucina-17/fisiología , Adulto JovenRESUMEN
OBJECTIVE: To determine whether disease activity and disability independently correlate with serious infection event (SIE) risk in a large rheumatoid arthritis (RA) cohort. METHODS: The associations between SIE and Clinical Disease Activity Index (CDAI) and Health Assessment Questionnaire-Disability Index (HAQ-DI) in the Rheumatoid Arthritis Disease-Modifying Antirheumatic Drug Intervention and Utilization Study (RADIUS 1) cohort were evaluated using the Andersen-Gill model (a proportional HR model allowing > 1 event per patient). RESULTS: Of 4084 patients with 347 SIE, 271 patients experienced ≥ 1 SIE. A 5-unit CDAI increase and 0.4-unit HAQ-DI increase corresponded to an increase in SIE risk with and without covariate adjustments. A 5-unit CDAI increase corresponded with a 7.7% increased SIE risk (adjusted HR 1.077, 95% CI 1.044-1.112, p < 0.0001) and a 0.4-unit HAQ-DI increase with a 30.1% increased risk (adjusted HR 1.301, 95% CI 1.225-1.381, p < 0.0001). Categorical analysis showed that more severe RA activity (even after controlling for disability) and disability were associated with an increased SIE risk. CONCLUSION: Increased RA disease activity and disability were each associated with a significantly increased SIE risk in the RADIUS 1 cohort, which could not be completely accounted for by disability.
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Artritis Reumatoide/diagnóstico , Evaluación de la Discapacidad , Infecciones/epidemiología , Índice de Severidad de la Enfermedad , Adulto , Anciano , Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de Riesgo , Encuestas y CuestionariosRESUMEN
In the important human pathogen Staphylococcus aureus the cytoplasmic ClpP protease is essential for mounting cellular stress responses and for virulence. To directly identify substrates of the ClpP protease, we expressed in vivo a proteolytic inactive form of ClpP (ClpP(trap)) that will retain but not degrade substrates translocated into its proteolytic chamber. Substrates captured inside the proteolytic barrel were co-purified along with the His-tagged ClpP complex and identified by mass spectrometry. In total, approximately 70 proteins were trapped in both of the two S. aureus strains NCTC8325-4 and Newman. About one-third of the trapped proteins are previously shown to be unstable or to be substrates of ClpP in other bacteria, supporting the validity of the ClpP-TRAP. This group of proteins encompassed the transcriptional regulators CtsR and Spx, the ClpC adaptor proteins McsB and MecA, and the cell division protein FtsZ. Newly identified ClpP substrates include the global transcriptional regulators PerR and HrcA, proteins involved in DNA damage repair (RecA, UvrA, UvrB), and proteins essential for protein synthesis (RpoB and Tuf). Our study hence underscores the central role of Clp-proteolysis in a number of pathways that contribute to the success of S. aureus as a human pathogen.
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Proteínas Bacterianas/genética , Reparación del ADN/genética , ADN Bacteriano , Endopeptidasa Clp/genética , Regulación Bacteriana de la Expresión Génica , Proteoma/genética , Staphylococcus aureus/genética , Proteínas de la Membrana Bacteriana Externa/genética , Proteínas de la Membrana Bacteriana Externa/metabolismo , Proteínas Bacterianas/metabolismo , Proteínas del Citoesqueleto/genética , Proteínas del Citoesqueleto/metabolismo , Farmacorresistencia Bacteriana/genética , Endopeptidasa Clp/metabolismo , Respuesta al Choque Térmico/genética , Proteínas de Unión a las Penicilinas , Factor Tu de Elongación Peptídica/genética , Factor Tu de Elongación Peptídica/metabolismo , Unión Proteica , Proteínas Quinasas/genética , Proteínas Quinasas/metabolismo , Proteolisis , Proteoma/metabolismo , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Staphylococcus aureus/metabolismoRESUMEN
OBJECTIVE: To evaluate persistence with anti-tumor necrosis factor (TNF) therapy and predictors of discontinuation in patients with rheumatoid arthritis (RA). METHODS: This retrospective analysis used data from RADIUS 1, a 5-year observational registry of patients with RA, to determine time to first- and second-course discontinuation of etanercept, infliximab, and adalimumab. First-course therapy was defined as first exposure to anti-TNF therapy, and second-course therapy was defined as exposure to anti-TNF therapy after the first discontinuation. Kaplan-Meier survival analysis was used to assess persistence, log-rank tests were used to compare therapies, and Cox proportional hazards models were used to assess potential predictors of treatment discontinuation. RESULTS: This analysis included 2418 patients. Mean persistence rates were similar among treatments [first-course: etanercept, 51%; infliximab, 48%; adalimumab, 48% (followup was 54 weeks for etanercept and infliximab and 42 weeks for adalimumab); second-course: 56%, 50%, 46%, respectively (followup was 36 weeks for etanercept and infliximab and 30 weeks for adalimumab)]. Discontinuations of first-course therapy due to ineffectiveness were similar among treatments (etanercept, 19%; infliximab, 19%; adalimumab, 20%) and discontinuations due to adverse events were significantly (p = 0.0006) lower for etanercept than for infliximab (etanercept, 14%; infliximab, 22%; adalimumab, 17%). Predictors from univariable analysis of first- or second-course therapy discontinuation included increased comorbidities (etanercept), female sex (infliximab), Clinical Disease Activity Index > 22 (infliximab), and a Stanford Health Assessment Questionnaire score > 0.5 (adalimumab). CONCLUSION: In this population, first- and second-course persistence was similar among anti-TNF therapies. First-course discontinuation due to adverse events was lower with etanercept compared with infliximab.
Asunto(s)
Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Cumplimiento de la Medicación/estadística & datos numéricos , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adalimumab , Adulto , Anciano , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Etanercept , Femenino , Humanos , Inmunoglobulina G/uso terapéutico , Infliximab , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Receptores del Factor de Necrosis Tumoral/uso terapéutico , Sistema de Registros , Estudios Retrospectivos , Factores de Tiempo , Resultado del Tratamiento , Estados Unidos , Privación de TratamientoRESUMEN
OBJECTIVE: to report the rates of serious adverse events (SAE), serious infectious events (SIE), and events of medical interest (EMI) in patients receiving etanercept; to identify the risk factors for SAE, SIE, and EMI; and to report time to switching from etanercept therapy, reasons for switching, and time to restarting treatment with etanercept in patients with rheumatoid arthritis (RA) in US clinical practice. METHODS: adults ≥ 18 years of age who fulfilled the 1987 American Rheumatism Association criteria for RA were eligible for enrollment in 2 prospective, 5-year, multicenter, observational registries. RADIUS 1 (Rheumatoid Arthritis DMARD Intervention and Utilization Study) enrolled patients with RA who required a change in treatment [either an addition or a switch of a biologic or nonbiologic disease-modifying antirheumatic drug (DMARD)]. In RADIUS 2, patients with RA were required to start etanercept therapy at entry. Patients were seen at a frequency determined by their rheumatologist. RADIUS 1 and RADIUS 2 were registered under the US National Institutes of Health ClinicalTrials.gov identifiers NCT00116714 and NCT00116727, respectively. RESULTS: in these patients, SAE, SIE, and EMI occurred at rates comparable to those seen in clinical trials. No unexpected safety signals were observed. Rates for SAE, SIE, and EMI in etanercept-treated patients were comparable to rates observed in patients receiving methotrexate monotherapy and did not increase with greater exposure to etanercept therapy. CONCLUSION: the RADIUS registries provide a better understanding of the safety of etanercept in patients with RA in the US practice setting.
Asunto(s)
Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Inmunoglobulina G/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Receptores del Factor de Necrosis Tumoral/uso terapéutico , Sistema de Registros , Antirreumáticos/efectos adversos , Etanercept , Femenino , Humanos , Inmunoglobulina G/efectos adversos , Masculino , Estudios Multicéntricos como Asunto , Estudios Prospectivos , Factores de Riesgo , Resultado del TratamientoRESUMEN
BACKGROUND: Direct correlation of assessments of a validated composite measure such as the Asthma Control Questionnaire (ACQ) and risk of exacerbation has not been previously demonstrated in a randomized controlled trial. OBJECTIVE: To evaluate the ability of the ACQ score over time to predict risk of a future asthma exacerbation. METHODS: This analysis included data from a 12-week placebo-controlled trial (N = 292) of AMG 317, an IL-4 receptor α antagonist, in patients with moderate to severe atopic asthma. At baseline, patients had an ACQ score ≥1.5. Exacerbations were defined as requirement for systemic corticosteroids. A Cox proportional hazards model was used, with ACQ score as the time-dependent covariate. The analysis was repeated for individual components of the ACQ. RESULTS: Each 1-point increase in ACQ was associated with a 50% increased risk of exacerbation (hazard ratio, 1.50; 95% CI, 1.03-2.20) for the following 2-week period. Evaluation of individual ACQ components also demonstrated a similar trend, though each to a lesser degree than the full composite ACQ. CONCLUSION: Although based on a retrospective analysis, with small number of exacerbations, these findings support the utility of the composite ACQ score measurement to predict risk of future exacerbation in clinical trials and clinical practice. The composite ACQ score measurement was found to be a better predictor of future risk than individual ACQ components.
Asunto(s)
Asma/diagnóstico , Encuestas y Cuestionarios , Adulto , Antiasmáticos/uso terapéutico , Asma/tratamiento farmacológico , Método Doble Ciego , Femenino , Humanos , Masculino , Estudios Multicéntricos como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios RetrospectivosRESUMEN
BACKGROUND: Pruritus is a common symptom of psoriasis. In many clinical trials of psoriasis treatments, severity of pruritus is a patient-reported outcome. OBJECTIVE: We sought to evaluate a patient-reported pruritus self-assessment tool using data from clinical trials of a tumor necrosis factor blocker. METHODS: The validity of the patient-reported 6-point pruritus assessment tool (0 = none to 5 = severe) was determined using data from a phase III trial of etanercept, a tumor necrosis factor blocker. The performance of the pruritus assessment tool was then evaluated using data from two large etanercept trials. RESULTS: The pruritus assessment tool was validated and deemed to have good test-retest reliability (kappa coefficient = 0.71; 95% confidence interval = 0.62-0.80) and responsiveness (standardized response mean = 1.28; effect size = 1.63, responsiveness statistic = 1.54). Improvements in pruritus scores correlated with improvements in Psoriasis Area and Severity Index after 8 weeks of etanercept therapy in two phase III trials. LIMITATIONS: The pruritus assessment is validated only for patients with moderate to severe plaque psoriasis, and may not be applicable to other patient populations. CONCLUSIONS: The pruritus assessment tool is a valid measurement of pruritus intensity in patients with moderate to severe plaque psoriasis and can discriminate between patients on and off treatment.
Asunto(s)
Inmunoglobulina G/uso terapéutico , Inmunosupresores/uso terapéutico , Prurito/etiología , Psoriasis/tratamiento farmacológico , Calidad de Vida , Receptores del Factor de Necrosis Tumoral/uso terapéutico , Autoevaluación (Psicología) , Adulto , Ensayos Clínicos Fase III como Asunto , Intervalos de Confianza , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Etanercept , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Prurito/fisiopatología , Psoriasis/complicaciones , Psoriasis/diagnóstico , Ensayos Clínicos Controlados Aleatorios como Asunto , Reproducibilidad de los Resultados , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
OBJECTIVE: This study evaluated the statistical distribution of time to treatment response in patients with rheumatic diseases. STUDY DESIGN AND SETTING: The study used a secondary data analysis design. Data from the trial of etanercept and methotrexate with radiographic patient outcomes were used to model the response times for etanercept (ETN), methotrexate (MTX), and combined ETN+MTX in patients with rheumatoid arthritis. The German etanercept registry was used to evaluate the response time distributions in patients with juvenile idiopathic arthritis. RESULTS: For MTX, the lognormal distribution was considered to be the best model for the outcome American College of Rheumatology (ACR20), lognormal, generalized gamma, and log-logistic distributions for ACR50, and lognormal and generalized gamma for ACR70. For ETN, the lognormal model was best for ACR20, the generalized gamma for ACR50, and both lognormal and generalized gamma distributions for ACR70. For combined treatment, the best model was the log-logistic distribution for ACR20, generalized gamma for ACR50, and both lognormal and generalized gamma distributions for ACR70. For the German etanercept registry, the lognormal distribution was the best model for all three outcomes of pediatric ACR30, ACR50, and ACR70 without interval censoring. CONCLUSION: Study designs might be more efficient if the response distributions are taken into consideration during planning.