RESUMO
BACKGROUND: The effect of calorie restriction (CR) on cognitive function is not well understood, and the impact of the dietary patterns consumed during CR has not been investigated. OBJECTIVES: We analyzed the combined association of CR and dietary quality with spatial working memory (SWM) in healthy adults without obesity. METHODS: The Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) trial was a 2-y, multisite clinical trial. This trial was registered at clinicaltrials.gov as NCT00427193. Participants were randomized to a 25% reduction in EI (n = 143) or an ad libitum Control (n = 76). The Dietary Inflammatory Index (DII) and the Healthy Eating Index (HEI) captured dietary quality, with a lower DII and higher HEI score indicating a healthier diet. The Cambridge Neuropsychological Test Automated Battery battery was used to assess SWM. Longitudinal associations between each dietary pattern index and SWM for CR and Control were assessed by multivariable negative binomial models that included baseline, 12-mo, and 24-mo visits. RESULTS: Participants were aged 38.1 ± 7.2 y with a BMI of 25.1 ± 1.7 kg/m2. A total of 70% of the participants were female. Baseline mean DII and HEI scores were -0.15 (range: -3.77, 4.21) and 59.1 (24.1, 91.0) and did not differ between groups. Improvements in DII and HEI were significantly different between CR and Control over 2 y (both P-interaction = 0.001). In longitudinal analyses, there was no association of either index with SWM. Furthermore, though within-group improvements in SWM were observed at 12 mo, there was no statistically significant difference between CR (SWM errors: 9.0; 95% CI: 1.9, 41.6) and Control (11.7; 95% CI: 2.6, 53.5; P > 0.99), holding DII constant. Comparable results were observed at 24 mo and for the HEI. CONCLUSIONS: Dietary quality during CR was not associated with measures of SWM over 2 y in healthy adults without obesity. These results suggest that, in healthy populations, dietary patterns and CR may have a limited impact on working memory. Further research is required to understand the concurrent effect of these nutritional strategies.
Assuntos
Restrição Calórica , Memória de Curto Prazo , Adulto , Humanos , Feminino , Masculino , Ingestão de Energia , Dieta , ObesidadeRESUMO
Rapid significant weight fluctuations can indicate severe health conditions such as edema due to congestive heart failure or severe dehydration that could require prompt intervention. Daily body weighing does not accurately represent the patient's body weight fluctuations occurring within a day. The patient's lack of compliance with tracking their weight measurements is also a predominant issue. Using shoe insole sensors embedded into footwear could achieve accurate real-time monitoring systems for estimating continuous body weight changes. Here, the machine learning models' predictive capabilities for continuous real-time weight estimation using the insole data are presented. The lack of availability of public datasets to feed these models is also addressed by introducing two novel datasets. The proposed framework is designed to adapt to the patient, considering several unique factors such as shoe type, posture, foot shape, and gait pattern. The proposed framework estimates the mean absolute percentage error of 0.61% and 0.74% and the MAE of 1.009 lbs. and 1.154 lbs. for the less controlled and more controlled experimental settings, respectively. This will help researchers utilize machine learning techniques for more accurate real-time continuous weight estimation using sensor data and enable more reliable aging-in-place monitoring and telehealth.
Assuntos
Sistemas Computacionais , Sapatos , Humanos , Desidratação , Aprendizado de Máquina , Peso CorporalRESUMO
In the Men's Lifestyle Validation Study (2011-2013), we examined the validity and relative validity of a physical activity questionnaire (PAQ), a Web-based 24-hour recall (Activities Completed Over Time in 24 Hours (ACT24)), and an accelerometer by multiple comparison methods. Over the course of 1 year, 609 men completed 2 PAQs, two 7-day accelerometer measurements, at least 1 doubly labeled water (DLW) physical activity level (PAL) measurement (n = 100 with repeat measurements), and 4 ACT24s; they also measured their resting pulse rate. A subset (n = 197) underwent dual-energy x-ray absorptiometry (n = 99 with repeated measurements). The method of triads was used to estimate correlations with true activity using DLW PAL, accelerometry, and the PAQ or ACT24 as alternative comparison measures. Estimated correlations of the PAQ with true activity were 0.60 (95% confidence interval (95% CI): 0.52, 0.68) for total activity, 0.69 (95% CI: 0.61, 0.79) for moderate-to-vigorous physical activity (MVPA), and 0.76 (95% CI: 0.62, 0.93) for vigorous activity. Corresponding correlations for total activity were 0.53 (95% CI: 0.45, 0.63) for the average of 4 ACT24s and 0.68 (95% CI: 0.61, 0.75) for accelerometry. Total activity and MVPA measured by PAQ, ACT24, and accelerometry were all significantly correlated with body fat percentage and resting pulse rate, which are physiological indicators of physical activity. Using a combination of comparison methods, we found the PAQ and accelerometry to have moderate validity for assessing physical activity, especially MVPA, in epidemiologic studies.
Assuntos
Acelerometria , Exercício Físico , Estudos Epidemiológicos , Exercício Físico/fisiologia , Humanos , Estilo de Vida , Masculino , Reprodutibilidade dos Testes , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Personalizing approaches to prevention and treatment of obesity will be a crucial aspect of precision health initiatives. However, in considering individual susceptibility to obesity, much remains to be learned about how to support healthy weight management in different population subgroups, environments and geographical locations. SUBJECTS/METHODS: The International Weight Control Registry (IWCR) has been launched to facilitate a deeper and broader understanding of the spectrum of factors contributing to success and challenges in weight loss and weight loss maintenance in individuals and across population groups. The IWCR registry aims to recruit, enroll and follow a diverse cohort of adults with varying rates of success in weight management. Data collection methods include questionnaires of demographic variables, weight history, and behavioral, cultural, economic, psychological, and environmental domains. A subset of participants will provide objective measures of physical activity, weight, and body composition along with detailed reports of dietary intake. Lastly, participants will be able to provide qualitative information in an unstructured format on additional topics they feel are relevant, and environmental data will be obtained from public sources based on participant zip code. CONCLUSIONS: The IWCR will be a resource for researchers to inform improvements in interventions for weight loss and weight loss maintenance in different countries, and to examine environmental and policy-level factors that affect weight management in different population groups. This large scale, multi-level approach aims to inform efforts to reduce the prevalence of obesity worldwide and its associated comorbidities and economic impacts. TRIAL REGISTRATION: NCT04907396 (clinicaltrials.gov) sponsor SB Roberts; Tufts University IRB #13075.
Assuntos
Obesidade , Redução de Peso , Adulto , Exercício Físico , Nível de Saúde , Humanos , Obesidade/epidemiologia , Obesidade/prevenção & controle , Sistema de RegistrosRESUMO
Lifestyle interventions for weight loss combine support for changing diet and physical activity with weight management education and are considered the first line treatment for obesity. A variety of diet-focused interventions including time-restricted eating are also increasingly being promoted for weight management. This chapter reviews different types of interventions for weight management, their underlying health behavior change models, and effectiveness to date in randomized trials. The results justify increasing efforts to improve program effectiveness generally, and to personalize interventions to support long-term adherence. The high prevalence of obesity worldwide, combined with the known increase in risk of non-communicable diseases with duration of excess weight, provides a compelling justification for routine delivery of effective weight management interventions in the community and in clinical care.
Assuntos
Obesidade , Redução de Peso , Exercício Físico , Humanos , Estilo de Vida , Obesidade/epidemiologia , Obesidade/terapiaRESUMO
In low- and middle-income countries (LMIC), growth impairment is common; however, the trajectory of growth over the course of the first month has not been well characterised. To describe newborn growth trajectory and predictors of growth impairment, we assessed growth frequently over the first 30 days among infants born ≥2000 g in Guinea-Bissau, Nepal, Pakistan and Uganda. In this cohort of 741 infants, the mean birth weight was 3036 ± 424 g. For 721 (98%) infants, weight loss occurred for a median of 2 days (interquartile range, 1-4) following birth until weight nadir was reached 5.9 ± 4.3% below birth weight. At 30 days of age, the mean weight was 3934 ± 592 g. The prevalence of being underweight at 30 days ranged from 5% in Uganda to 31% in Pakistan. Of those underweight at 30 days of age, 56 (59%) had not been low birth weight (LBW), and 48 (50%) had reached weight nadir subsequent to 4 days of age. Male sex (relative risk [RR] 2.73 [1.58, 3.57]), LBW (RR 6.41 [4.67, 8.81]), maternal primiparity (1.74 [1.20, 2.51]) and reaching weight nadir subsequent to 4 days of age (RR 5.03 [3.46, 7.31]) were highly predictive of being underweight at 30 days of age. In this LMIC cohort, country of birth, male sex, LBW and maternal primiparity increased the risk of impaired growth, as did the modifiable factor of delayed initiation of growth. Interventions tailored to infants with modifiable risk factors could reduce the burden of growth impairment in LMIC.
Assuntos
Magreza , Peso ao Nascer , Feminino , Guiné-Bissau/epidemiologia , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Nepal/epidemiologia , Paquistão/epidemiologia , Magreza/epidemiologia , Uganda/epidemiologiaRESUMO
It is estimated that more than 170 million people are infected with hepatitis C virus (HCV) worldwide. Clinical trials have demonstrated that, for the first time in human history, the potential exists to eradicate a chronic viral disease using combination therapies that contain only direct-acting antiviral agents. HCV non-structural protein 5A (NS5A) is a multifunctional protein required for several stages of the virus replication cycle. NS5A replication complex inhibitors, exemplified by daclatasvir (DCV; also known as BMS-790052 and Daklinza), belong to the most potent class of direct-acting anti-HCV agents described so far, with in vitro activity in the picomolar (pM) to low nanomolar (nM) range. The potency observed in vitro has translated into clinical efficacy, with HCV RNA declining by ~3-4 log10 in infected patients after administration of single oral doses of DCV. Understanding the exceptional potency of DCV was a key objective of this study. Here we show that although DCV and an NS5A inhibitor analogue (Syn-395) are inactive against certain NS5A resistance variants, combinations of the pair enhance DCV potency by >1,000-fold, restoring activity to the pM range. This synergistic effect was validated in vivo using an HCV-infected chimaeric mouse model. The cooperative interaction of a pair of compounds suggests that NS5A protein molecules communicate with each other: one inhibitor binds to resistant NS5A, causing a conformational change that is transmitted to adjacent NS5As, resensitizing resistant NS5A so that the second inhibitor can act to restore inhibition. This unprecedented synergistic anti-HCV activity also enhances the resistance barrier of DCV, providing additional options for HCV combination therapy and new insight into the role of NS5A in the HCV replication cycle.
Assuntos
Antivirais/farmacologia , Compostos de Bifenilo/farmacologia , Farmacorresistência Viral/efeitos dos fármacos , Hepacivirus/efeitos dos fármacos , Hepacivirus/genética , Imidazóis/farmacologia , Proteínas não Estruturais Virais/metabolismo , Regulação Alostérica/efeitos dos fármacos , Animais , Carbamatos , Linhagem Celular , Sinergismo Farmacológico , Quimioterapia Combinada , Hepacivirus/metabolismo , Hepatite C/virologia , Hepatócitos/transplante , Humanos , Camundongos , Modelos Moleculares , Conformação Proteica/efeitos dos fármacos , Multimerização Proteica/efeitos dos fármacos , Estrutura Quaternária de Proteína/efeitos dos fármacos , Pirrolidinas , Reprodutibilidade dos Testes , Valina/análogos & derivados , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/genética , Replicação Viral/efeitos dos fármacosRESUMO
BACKGROUND: Quick-service restaurants (QSRs) serve one-third of US children on any given day, yet no methods can directly measure energy (kcal) consumed in QSRs. Weighed plate waste is one feasible option, but the accuracy is unknown. OBJECTIVE: The objective of this study was to determine the accuracy of weighed plate waste for measuring children's energy consumption in QSRs. METHODS: Children's plate waste (entrées and sides) was collected for a larger study assessing a community-wide health messaging campaign to inform parents' orders for children in QSRs; a subsample (n = 194) was used for validation. Gross energy left over estimated by weighed plate waste combined with restaurant-stated nutrition information was compared to gross energy determined by bomb calorimetry, the gold-standard energy assessment technique. Analyses were conducted at the meal level (all food items, combined) and stratified by the number of items per meal (1, 2, or 3). Pearson correlations and paired t tests analyzed agreement; Bland-Altman statistics examined differences between energy estimations for the total and stratified subsample. RESULTS: Overall, significant agreement was observed between weighed plate waste and bomb calorimetry (r = 0.99, P < 0.001). On average, weighed plate waste underestimated energy content by <2 kcal compared with bomb calorimetry (mean percent difference ± SD of 0.3% ± 10.7%); 94% of estimations fell within the limits of agreement (-23.5 to 26.8 kcal), and 63% and 24% of estimations differed by <10 or <20 net kcal, respectively. Although stratification by item number showed slight variation, mean differences for all strata were <5 kcal (t test P > 0.80), suggesting the accuracy of weighed plate waste for measuring meals of various sizes. CONCLUSIONS: Weighed plate waste is an accurate and valid field technique for measuring children's energy consumption from food in QSRs. Future improvements to capturing beverages, self-serve condiments, and sharing behaviors may improve the overall feasibility and accuracy.
Assuntos
Ingestão de Energia , Refeições , Restaurantes , Criança , Pré-Escolar , Promoção da Saúde , HumanosRESUMO
Food cravings are a desire for specific foods which, if uncontrolled may lead to excess energy intake and weight gain. However, information on the relation between food cravings, dietary intake, and indices of metabolic health is limited. This study used baseline data from females (n = 229; aged 40.9 ± 0.7 years; BMI 34.7 ± 6.4 kg/m2) who were dependents of active duty and retired military personnel, and enrolled in the Healthy Families Healthy Forces weight loss and maintenance study. Measures obtained included food cravings using the Food Craving Questionnaire-Trait (which provides a habitual and stable measure of food cravings), dietary composition and eating patterns from three 24-h dietary recalls and the Stanford 7-day Physical Activity Recall, body composition from anthropometric measures, cardiometabolic risk factors from blood measures, and demographic information from questionnaires. Linear, quantile, or logistic regression models were used to examine the association of total food craving scores on dietary intake, and indices of metabolic health. In individuals reporting plausible energy intake (n = 146; 2210 ± kcals/day) higher food craving scores were associated with a lower diet quality (P < 0.05), higher eating frequency (P = 0.02), longer daily eating interval (P < 0.05), and a lower likelihood of following a time restricted eating pattern (P = 0.02). Food cravings were also positively associated with BMI (P = 0.03) and waist circumference (P = 0.01), but not with measures of cardiometabolic risk (LDL, HDL, total cholesterol:HDL, triglycerides, glucose, glycated hemoglobin, insulin and C-reactive protein concentrations, blood pressure, metabolic syndrome). Our findings of significant associations of food cravings with lower diet quality, poor eating patterns, and unfavorable body composition strongly support efforts of targeting cravings in behavioral programs for weight management.
Assuntos
Fissura , Ingestão de Alimentos , Índice de Massa Corporal , Dieta , Ingestão de Energia , Comportamento Alimentar , Feminino , HumanosRESUMO
Alkoxyanthranilic acid derivatives have been identified to inhibit HCV NS5B polymerase, binding in an allosteric site located at the convergence of the palm and thumb regions. Information from co-crystal structures guided the structural design strategy. Ultimately, two independent structural modifications led to a similar shift in binding mode that when combined led to a synergistic improvement in potency and the identification of inhibitors with sub-micromolar HCV NS5B binding potency.
Assuntos
Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , ortoaminobenzoatos/farmacologia , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/metabolismo , ortoaminobenzoatos/síntese química , ortoaminobenzoatos/químicaRESUMO
The synthesis, structure-activity relationship (SAR) data, and further optimization of the metabolic stability and pharmacokinetic (PK) properties for a previously disclosed class of cyclopropyl-fused indolobenzazepine HCV NS5B polymerase inhibitors are described. These efforts led to the discovery of BMS-961955 as a viable contingency backup to beclabuvir which was recently approved in Japan for the treatment of HCV as part of a three drug, single pill combination marketed as XimencyTM.
Assuntos
Antivirais/química , Antivirais/farmacologia , Benzazepinas/química , Benzazepinas/farmacologia , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/farmacocinética , Benzazepinas/farmacocinética , Cães , Haplorrinos , Hepacivirus/enzimologia , Hepacivirus/metabolismo , Hepatite C/virologia , Humanos , RNA Polimerase Dependente de RNA/antagonistas & inibidores , RNA Polimerase Dependente de RNA/metabolismo , Ratos , Proteínas não Estruturais Virais/metabolismoRESUMO
BACKGROUND: Children regularly consume foods from quick-service restaurants (QSR), but little is known about the foods that children order, the calories and nutrients consumed, the accuracy of stated calorie information, or the ability to assess food orders and consumption in QSRs. This study evaluated the feasibility of plate waste collection in QSRs and examined children's orders and consumption of meals from the standard and children's menus. Additional aims were to examine if the meals ordered met healthier standards for children's menu items and determine the accuracy of the QSR-stated energy content of foods. METHODS: Fifteen QSRs, two malls, and 116 eligible parents were approached to participate in the study in 2015. Among the families recruited, children's meal orders and consumption were analyzed using plate waste methodology, and a subsample of foods was analyzed using bomb calorimetry in 2015. RESULTS: Two individual QSRs and one mall food court with two QSRs agreed to participate, and n = 50 participants (parents with children between the ages of 5-10 years) were recruited. Children consumed on average 519 calories, 5.7 g saturated fat, 957 mg sodium, 3.7 g fiber, and 22.7 g sugar. Children ordered and consumed significantly fewer calories and less sodium and sugar with meals ordered exclusively from the children's menu compared with the standard menu. Overall there were no significant differences between the measured and stated energy contents of the QSR foods. CONCLUSIONS: Conducting plate waste research in QSRs is feasible and there is concordance with stated calorie information. Consuming foods exclusively from the children's menu may help limit overconsumption in QSRs.
Assuntos
Ingestão de Alimentos , Fast Foods/análise , Comportamento Alimentar , Resíduos de Alimentos , Restaurantes/estatística & dados numéricos , Criança , Ingestão de Energia , Estudos de Viabilidade , Feminino , Humanos , Masculino , Refeições , Projetos PilotoRESUMO
BACKGROUND: Nutrition clubs (NC) operate in community settings and provide members with nutrition education and meal replacements for weight management. NC are owned and operated by distributors of Herbalife products. There are over 6200 NC in the US, but there has been no independent assessment of the association of these NC with biomarkers of health. METHODS: We conducted a cross-sectional pilot study to compare the health status of 100 NC members to 100 community-matched controls (CC) in the greater Boston area. Each CC was matched to a NC member for community of residence (zip code), age category, gender, BMI category, race/ethnicity, education level (category), and readiness to make health changes. Measures obtained included cardio-metabolic risk factors, body composition, markers of nutritional status, reported health status, dietary intake, physical activity, sleep and depression. RESULTS: Participants were predominantly female (64%) and Hispanic (73%). NC members had significantly lower fasting insulin (P < 0.001) and lower HbA1c (P = 0.008), higher levels of 25 hydroxy-vitamin D (P = 0.001), and vitamin E:cholesterol ratio (P < 0.001), and lower prevalence of metabolic syndrome (P = 0.02) compared to CC. In addition, most of the NC members (99%) were satisfied with Herbalife NC membership for themselves and their families. A higher percentage of NC members (86%) compared to CC (32%) reported being in much better or somewhat better health compared to a year ago (P < 0.001); and they reported significantly better physical health (P = 0.03), and fewer sleep problems (P = 0.03). CONCLUSION: Herbalife NC membership was positively associated with perceived health and measured cardiometabolic benefits. However, causality cannot be inferred from these findings.
Assuntos
Dieta , Nível de Saúde , Apoio Social , Adolescente , Adulto , Fatores Etários , Biomarcadores , Composição Corporal , Índice de Massa Corporal , Boston , Estudos Transversais , Exercício Físico , Jejum , Feminino , Hemoglobinas Glicadas/análise , Humanos , Insulina/sangue , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Estado Nutricional , Projetos Piloto , Fatores Sexuais , Sono , Fatores Socioeconômicos , Adulto JovemRESUMO
BACKGROUND: Controversy remains over the most effective approaches to prevent childhood malnutrition. OBJECTIVES: We tested the feasibility and effectiveness of delivering ready-to-use supplementary foods (RUSFs) as a second daily meal in preschool children aged 3-5 y in Guinea-Bissau, and compared RUSFs with different levels of dairy protein. METHODS: This study was a 3 mo cluster-randomized controlled pilot trial of 2 RUSFs differing in dairy protein in 533 boys and girls from 9 preschools. Children receiving RUSFs were compared with wait-listed controls, and all students received a daily school lunch. The RUSFs were delivered 5 d/wk for 3 mo and contained 478 kcal and 11.5 g protein per 92-g daily serving. Deliveries included a ready-to-use supplementary food with 15% of protein from dairy sources (RUSF-15%) or one with 33% of protein from dairy sources (RUSF-33%). Intention-to-treat (ITT) and per-protocol analyses (>50 d of RUSF consumption) were conducted. Changes in the weight-for-age z score (WAZ) and height-for-age z score were primary outcomes. Additional outcomes included changes in mid-upper arm circumference (MUAC), hemoglobin, and retinol binding protein. RESULTS: Baseline anthropometry was not different between groups (WAZ, -0.48 ± 1.04) and increased significantly over time (P < 0.01) with no effects of the RUSFs in ITT analyses. However, children consuming RUSFs for >50 d had a significantly greater increase in WAZ relative to the increase in controls (+0.40 and +0.32 for RUSF-15% and RUSF-33%, respectively, compared with +0.24 in controls, P < 0.01 and P < 0.05, respectively). RUSF-33%, but not RUSF-15%, also eliminated a decrease in MUAC observed in controls (-0.01 cm in RUSF-33% compared with -0.34 cm in controls, P < 0.05). The only difference between RUSF-15% and RUSF-33% was a mean decrease in hemoglobin in children receiving RUSF-15% (-0.5 compared with -0.002 g/dL, P = 0.05). CONCLUSIONS: Implementation of 2-meal preschool feeding programs is feasible in low-income countries, and there are measurable benefits relative to 1-meal programs in children attending preschool regularly. In addition, MUAC and hemoglobin measurements indicate that meals with 33% compared with 15% of protein from dairy may help prevent wasting and anemia.
Assuntos
Braço , Laticínios , Desnutrição/epidemiologia , Refeições , Aumento de Peso , Pré-Escolar , Análise por Conglomerados , Gorduras na Dieta , Proteínas Alimentares/administração & dosagem , Ingestão de Energia , Feminino , Guiné-Bissau , Humanos , Masculino , Micronutrientes/administração & dosagem , Micronutrientes/deficiência , Projetos Piloto , PrevalênciaRESUMO
Herein, we describe the synthesis, antiviral structure-activity relationships (SAR), metabolic stability, and pharmacokinetic (PK) properties for a series of cyclopropylindolobenzazepine acylsulfonamide HCV NS5B polymerase inhibitors. Optimization of SAR, metabolic stability and PK led to the identification of compound 19 which was advanced into pre-IND enabling toxicology studies.
Assuntos
Antivirais/química , Hepacivirus/enzimologia , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Sulfonamidas/química , Administração Oral , Animais , Antivirais/síntese química , Antivirais/farmacocinética , Benzazepinas/química , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Macaca fascicularis , Microssomos Hepáticos/metabolismo , RNA Polimerase Dependente de RNA/metabolismo , Ratos , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/farmacocinéticaRESUMO
HCV infection is an urgent global health problem that has triggered a drive to discover therapies that specifically target the virus. BMS-791325 is a novel direct antiviral agent specifically targeting HCV NS5B, an RNA-dependent RNA polymerase. Robust viral clearance of HCV was observed in infected patients treated with BMS-791325 in combination with other anti-HCV agents in Phase 2 clinical studies. Biochemical and biophysical studies revealed that BMS-791325 is a time-dependent, non-competitive inhibitor of the polymerase. Binding studies with NS5B genetic variants (WT, L30S, and P495L) exposed a two-step, slow binding mechanism, but details of the binding mechanism differed for each of the polymerase variants. For the clinically relevant resistance variant (P495L), the rate of initial complex formation and dissociation is similar to WT, but the kinetics of the second step is significantly faster, showing that this variant impacts the final tight complex. The resulting shortened residence time translates into the observed decrease in inhibitor potency. The L30S variant has a significantly different profile. The rate of initial complex formation and dissociation is 7-10 times faster for the L30S variant compared with WT; however, the forward and reverse rates to form the final complex are not significantly different. The impact of the L30S variant on the inhibition profile and binding kinetics of BMS-791325 provides experimental evidence for the dynamic interaction of fingers and thumb domains in an environment that supports the formation of active replication complexes and the initiation of RNA synthesis.
Assuntos
Antivirais/química , Benzazepinas/química , Hepacivirus/enzimologia , Indóis/química , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Proteínas não Estruturais Virais/antagonistas & inibidores , Substituição de Aminoácidos , Antivirais/farmacologia , Benzazepinas/uso terapêutico , Hepatite C/tratamento farmacológico , Hepatite C/enzimologia , Humanos , Indóis/uso terapêutico , Mutação de Sentido Incorreto , Ligação Proteica , RNA Viral/biossíntese , RNA Polimerase Dependente de RNA/química , RNA Polimerase Dependente de RNA/metabolismo , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/metabolismoRESUMO
Daclatasvir (DCV) is a first-in-class hepatitis C virus (HCV) nonstructural 5A replication complex inhibitor (NS5A RCI) that is clinically effective in interferon-free combinations with direct-acting antivirals (DAAs) targeting alternate HCV proteins. Recently, we reported NS5A RCI combinations that enhance HCV inhibitory potential in vitro, defining a new class of HCV inhibitors termed NS5A synergists (J. Sun, D. R. O'Boyle II, R. A. Fridell, D. R. Langley, C. Wang, S. Roberts, P. Nower, B. M. Johnson F. Moulin, M. J. Nophsker, Y. Wang, M. Liu, K. Rigat, Y. Tu, P. Hewawasam, J. Kadow, N. A. Meanwell, M. Cockett, J. A. Lemm, M. Kramer, M. Belema, and M. Gao, Nature 527:245-248, 2015, doi:10.1038/nature15711). To extend the characterization of NS5A synergists, we tested new combinations of DCV and NS5A synergists against genotype (gt) 1 to 6 replicons and gt 1a, 2a, and 3a viruses. The kinetics of inhibition in HCV-infected cells treated with DCV, an NS5A synergist (NS5A-Syn), or a combination of DCV and NS5A-Syn were distinctive. Similar to activity observed clinically, DCV caused a multilog drop in HCV, followed by rebound due to the emergence of resistance. DCV-NS5A-Syn combinations were highly efficient at clearing cells of viruses, in line with the trend seen in replicon studies. The retreatment of resistant viruses that emerged using DCV monotherapy with DCV-NS5A-Syn resulted in a multilog drop and rebound in HCV similar to the initial decline and rebound observed with DCV alone on wild-type (WT) virus. A triple combination of DCV, NS5A-Syn, and a DAA targeting the NS3 or NS5B protein cleared the cells of viruses that are highly resistant to DCV. Our data support the observation that the cooperative interaction of DCV and NS5A-Syn potentiates both the genotype coverage and resistance barrier of DCV, offering an additional DAA option for combination therapy and tools for explorations of NS5A function.
Assuntos
Antivirais/farmacologia , Compostos de Bifenilo/farmacologia , Hepacivirus/efeitos dos fármacos , Imidazóis/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Replicação Viral/efeitos dos fármacos , Carbamatos , Linhagem Celular , Sinergismo Farmacológico , Quimioterapia Combinada , Humanos , Simulação de Acoplamento Molecular , Pirrolidinas , Replicon/efeitos dos fármacos , Replicon/genética , Valina/análogos & derivadosRESUMO
BACKGROUND: Despite improved survival, childhood cancer survivors experience significantly elevated risk of premature mortality and serious morbidity due to chronic health conditions. Poor diet quality can exacerbate chronic health conditions in the survivors but their nutritional intake has not been adequately studied. PROCEDURE: We assessed the Healthy Eating Index 2010 (HEI-2010) in 22 survivors of pediatric acute lymphoblastic leukemia and lymphoma (median age = 11.7 years) and compared survivors' dietary intake to the 2010 Dietary Guidelines for Americans. Dietary data were collected using repeated 24 hr dietary recalls over a 1-year period, which were averaged to estimate habitual intake. RESULTS: The mean HEI-2010 in childhood cancer survivors was 52.7, about 50 percent of the maximum score. Long-term survivors (time from diagnosis ≥10 years) had a significantly lower HEI-2010 than recent survivors (time from diagnosis <5 years) (ß = -11.5, 95% CI: -22.1, -0.9, P = 0.047). For individual food groups and nutrients, survivors had a particularly poor adherence to green vegetables and beans, total vegetables, and whole fruits. None of the survivors met the guidelines for dietary fiber and potassium intake. Only 4%, 19%, 24%, and 29% met the guidelines for vitamin D, sodium, calcium, and saturated fat intake. The average intake in relative to the recommended intake was 32% for vitamin D, 50% for potassium, 63% for fiber, and 85% for calcium, but was 115% for saturated fat and 143% for sodium. CONCLUSIONS: Childhood cancer survivors, in particular long-term survivors, have a poor adherence to the US dietary guidelines.
Assuntos
Dieta , Comportamento Alimentar , Política Nutricional , Cooperação do Paciente , Adolescente , Adulto , Índice de Massa Corporal , Criança , Pré-Escolar , Fibras na Dieta , Ingestão de Energia , Feminino , Frutas , Humanos , Masculino , Avaliação Nutricional , Estado Nutricional , Sobreviventes , Verduras , Adulto JovemRESUMO
Cancer diagnosis and treatment may influence dietary intake. The validity of using self-reported methods to quantify dietary intake has not been evaluated in childhood cancer survivors. We validated total energy intake (EI) reported from Food Frequency Questionnaire (FFQ) and repeated 24-hour diet recalls (24HRs) against total energy expenditure (TEE) measured using the doubly labeled water method in 16 childhood cancer survivors. Dietary underreporting, assessed by (EI-TEE)/TEEâ×â100%, was 22% for FFQ and 1% for repeated 24HRs. FFQ significantly underestimates dietary intake and should not be used to assess the absolute intake of foods and nutrients in childhood cancer survivors.
Assuntos
Fenômenos Fisiológicos da Nutrição do Adolescente , Fenômenos Fisiológicos da Nutrição Infantil , Dieta , Neoplasias/terapia , Sobreviventes , Adolescente , Adulto , Antineoplásicos/uso terapêutico , Boston , Criança , Pré-Escolar , Dieta/efeitos adversos , Ingestão de Energia , Metabolismo Energético , Hospitais Pediátricos , Humanos , Quimioterapia de Manutenção , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Avaliação Nutricional , Projetos Piloto , Indução de Remissão , Autorrelato , Adulto JovemRESUMO
Childhood cancer survivors are at an increased risk of obesity but causes for this elevated risk are uncertain. We evaluated total energy expenditure in childhood cancer survivors using the doubly labeled water method in a cross-sectional study of 17 survivors of pediatric leukemia or lymphoma (median age, 11.5 y). Mean total energy expenditure was 2073 kcal/d, which was nearly 500 kcal/d lower than estimated energy requirements with recommended levels of physical activity. This energy gap is likely to contribute to the risk of obesity in this population and future trials are needed to assess implications and potential treatment strategies.