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PURPOSE: This study was undertaken to collect baseline growth parameters in children with achondroplasia who might enroll in interventional trials of vosoritide, and to establish a historical control. METHODS: In this prospective, observational study, participants (≤17 years) underwent a detailed medical history and physical examination and were followed every 3 months until they finished participating in the study by enrolling in an interventional trial or withdrawing. RESULTS: A total of 363 children were enrolled (28 centers, 8 countries). Mean (SD) follow up was 20.4 (15.0) months. In participants <1 year, mean annualized growth velocity (AGV) was 11.6 cm/year for girls and 14.6 cm/year for boys. By age 1 year, mean AGV decreased to 7.4 cm/year in girls and 7.1 cm/year in boys. By age 10 years, mean AGV decreased to 3.6 cm/year for both sexes. Mean height z-score in participants <1 year was -2.5 for girls and -3.2 for boys and decreased up to the age 5 years (-5.3 for girls; -4.6 for boys). Girls and boys had a disproportionate upper-to-lower body segment ratio. Mean ratio was highest in participants aged <1 year (2.9 for girls; 2.8 for boys) and decreased gradually to approximately 2 in both sexes from 4 years of age onward. CONCLUSION: This study represents one of the largest datasets of prospectively collected medical and longitudinal growth data in children with achondroplasia. It serves as a robust historical control to measure therapeutic interventions against and to further delineate the natural history of this condition.
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Acondroplasia , Niño , Masculino , Femenino , Humanos , Preescolar , Estudios Prospectivos , Acondroplasia/epidemiología , Acondroplasia/genética , Acondroplasia/diagnóstico , EstaturaRESUMEN
People with multiple long-term conditions (MLTC) are a growing population, not only in the United Kingdom but internationally. Health and care systems need to adapt to rise to this challenge. Policymakers need to better understand how medical education and training, and service configuration and delivery should change to meet the needs of people with MLTC and their carers. A series of workshops with people with MLTC and carers across the life-course identified areas of unmet need including the impact of stigma; poorly coordinated care designed around single conditions; inadequate communication and consultations that focus on clinical outcomes rather than patient-oriented goals and imperfectly integrate mental and physical wellbeing. Research which embeds the patient voice at its centre, from inception to implementation, can provide the evidence to drive the change to patient-centred, coordinated care. This should not only improve the lives of people living with MLTC and their carers but also create a health and care system which is more effective and efficient. The challenge of MLTC needs to be bought to the fore and it will require joint effort by policymakers, practitioners, systems leaders, educators, the third sector and those living with MLTC to design a health and care system from the perspective of patients and carers, and provide practitioners with the skills and tools needed to provide the highest quality care.
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BACKGROUND: Achondroplasia is a genetic disorder that inhibits endochondral ossification, resulting in disproportionate short stature and clinically significant medical complications. Vosoritide is a biologic analogue of C-type natriuretic peptide, a potent stimulator of endochondral ossification. METHODS: In a multinational, phase 2, dose-finding study and extension study, we evaluated the safety and side-effect profile of vosoritide in children (5 to 14 years of age) with achondroplasia. A total of 35 children were enrolled in four sequential cohorts to receive vosoritide at a once-daily subcutaneous dose of 2.5 µg per kilogram of body weight (8 patients in cohort 1), 7.5 µg per kilogram (8 patients in cohort 2), 15.0 µg per kilogram (10 patients in cohort 3), or 30.0 µg per kilogram (9 patients in cohort 4). After 6 months, the dose in cohort 1 was increased to 7.5 µg per kilogram and then to 15.0 µg per kilogram, and in cohort 2, the dose was increased to 15.0 µg per kilogram; the patients in cohorts 3 and 4 continued to receive their initial doses. At the time of data cutoff, the 24-month dose-finding study had been completed, and 30 patients had been enrolled in an ongoing long-term extension study; the median duration of follow-up across both studies was 42 months. RESULTS: During the treatment periods in the dose-finding and extension studies, adverse events occurred in 35 of 35 patients (100%), and serious adverse events occurred in 4 of 35 patients (11%). Therapy was discontinued in 6 patients (in 1 because of an adverse event). During the first 6 months of treatment, a dose-dependent increase in the annualized growth velocity was observed with vosoritide up to a dose of 15.0 µg per kilogram, and a sustained increase in the annualized growth velocity was observed at doses of 15.0 and 30.0 µg per kilogram for up to 42 months. CONCLUSIONS: In children with achondroplasia, once-daily subcutaneous administration of vosoritide was associated with a side-effect profile that appeared generally mild. Treatment resulted in a sustained increase in the annualized growth velocity for up to 42 months. (Funded by BioMarin Pharmaceutical; ClinicalTrials.gov numbers, NCT01603095, NCT02055157, and NCT02724228.).
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Acondroplasia/tratamiento farmacológico , Crecimiento/efectos de los fármacos , Péptido Natriurético Tipo-C/análogos & derivados , Osteogénesis/efectos de los fármacos , Acondroplasia/fisiopatología , Adolescente , Biomarcadores/análisis , Estatura/efectos de los fármacos , Niño , Preescolar , Colágeno/sangre , GMP Cíclico/orina , Relación Dosis-Respuesta a Droga , Femenino , Gráficos de Crecimiento , Humanos , Inyecciones Subcutáneas , Masculino , Péptido Natriurético Tipo-C/administración & dosificación , Péptido Natriurético Tipo-C/efectos adversos , Péptido Natriurético Tipo-C/uso terapéuticoRESUMEN
In autumn 2016, the UK Department of Health (now Department of Health and Social Care) convened 2 meetings to discuss how to address research evidence gaps in order to minimize the impact of infant group B streptococcus (GBS) disease in the United Kingdom. At that meeting, a number of research priorities were highlighted, including improving the screening for GBS colonization in pregnant women, offering intrapartum antibiotic prophylaxis and point-of-care testing, and understanding the effect of widespread intrapartum antibiotic use on long-term infant health. Further discussions involved investigating the feasibility of a large prospective study of pregnant women and their infants in order to understand the role of antibodies in the protection against GBS disease in infancy following maternal exposure to GBS colonization. Here, we summarize the research uncertainties identified at that meeting.
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Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Complicaciones Infecciosas del Embarazo , Infecciones Estreptocócicas , Streptococcus agalactiae , Antibacterianos/administración & dosificación , Antibacterianos/uso terapéutico , Profilaxis Antibiótica , Portador Sano/diagnóstico , Portador Sano/tratamiento farmacológico , Femenino , Humanos , Recién Nacido , Embarazo , Complicaciones Infecciosas del Embarazo/diagnóstico , Complicaciones Infecciosas del Embarazo/tratamiento farmacológico , Complicaciones Infecciosas del Embarazo/prevención & control , Infecciones Estreptocócicas/diagnóstico , Infecciones Estreptocócicas/tratamiento farmacológico , Infecciones Estreptocócicas/prevención & control , Reino UnidoRESUMEN
The preparation of a family of composite particles comprising gold nanoparticles (AuNP) assembled at a polystyrene (PS) surface is reported. Tunable loading is demonstrated for AuNP sizes (4.5-26 nm). The robust composites are stable to multiple centrifugation and dispersion cycles and to conditions of high ionic strength, physiological buffer and cell culture media. These properties provide potential for a variety of applications from cellular studies to catalysis.
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Oro/química , Nanopartículas del Metal/química , Poliestirenos/química , Microscopía Electrónica de Transmisión , Tamaño de la Partícula , Propiedades de SuperficieRESUMEN
INTRODUCTION: 3-Methyl CoA carboxylase (3-MCC) deficiency is an inborn error of metabolism in the catabolism of the amino acid leucine. Original reports suggested this disorder was associated with significant neurological and biochemical effects. However newborn screening has identified a higher than expected incidence of this disorder with apparent normal outcome in most cases. METHOD: A retrospective analysis of thirty-five cases of 3-MCC deficiency identified by newborn screening and diagnosed by enzyme or molecular analysis. RESULTS: There was a strong inverse correlation between initial C5OH level and residual enzyme activity. A few reports of hypoglycemia, ketosis, poor feeding/failure to thrive or fasting intolerance were reported, but there was no clear relationship between symptoms and residual enzyme activity. Developmental outcome included several children with mental retardation (including one with Down syndrome and one with schizencephaly) and two with Autism Spectrum disorders but there was no apparent relationship to residual enzyme activity. Free carnitine deficiency was relatively common. DISCUSSION: Although residual enzyme activity was clearly related to metabolite elevation, there was no apparent relationship with other measures of outcome. The number of reports of neurologic abnormalities or metabolic symptoms (poor feeding, hypoglycemia, fasting intolerance, etc.) is concerning, but the significance is unclear in this retrospective sample.
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Ligasas de Carbono-Carbono/deficiencia , Tamizaje Neonatal/métodos , Trastornos Innatos del Ciclo de la Urea/diagnóstico , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Trastornos Innatos del Ciclo de la Urea/enzimologíaRESUMEN
Loneliness is a psychological experience related to social isolation and perceived lack of companionship, and may be relevant to health risk. The revised UCLA loneliness scale was completed by 240 working men and women aged 47-59 years, and related to affective state and neuroendocrine, cardiovascular, and inflammatory responses. Loneliness scores were not associated with gender, age or socioeconomic position, but were lower in married than single or divorced participants, and were positively related to social isolation, low emotional support, ratings of depression, hopelessness and low self-esteem, and to reported sleep problems. Diastolic blood pressure reactions to acute mental stress were positively correlated with loneliness in women but not men, independently of age, socioeconomic status, smoking, body mass and marital status (p = 0.014). Lonely individuals also displayed significantly greater fibrinogen (p = 0.038) and natural killer cell responses (p = 0.042) to stress, independently of covariates. The cortisol response over the first 30 min following waking was positively associated with loneliness after adjusting for waking cortisol value, sex, socioeconomic status, smoking, time of waking, and body mass (p = 0.046). We conclude that loneliness is a psychological experience with potentially adverse effects on biological stress processes that may be relevant to health.
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Sistema Cardiovascular/fisiopatología , Inflamación/fisiopatología , Soledad/psicología , Sistemas Neurosecretores/fisiopatología , Estrés Psicológico/fisiopatología , Adulto , Presión Sanguínea , Depresión , Emociones , Femenino , Fibrinógeno/análisis , Humanos , Hidrocortisona/sangre , Células Asesinas Naturales/fisiología , Masculino , Estado Civil , Persona de Mediana Edad , Estudios Prospectivos , Autoimagen , Caracteres Sexuales , Trastornos del Sueño-Vigilia , Aislamiento Social , Factores SocioeconómicosRESUMEN
Low socioeconomic status (SES) is associated with increased risk of coronary heart disease and immune-related disorders. We hypothesised that SES would be inversely associated with the acute phase reactant C-reactive protein (CRP) and with circulating lymphocyte levels, and that lymphocyte responses to acute psychological stress would also vary with SES. CRP was obtained from 226, and lymphocyte counts from 127 healthy volunteers from the Whitehall II cohort, and SES was defined primarily by grade of employment. CRP concentration was greater in lower compared with higher SES participants (1.18+/-0.75 vs. 0.75+/-0.8 mg/l,p=.002) independently of sex, age, body mass, waist/hip ratio, smoking, alcohol, and season of the year. Similar differences were evident when SES was defined by income and educational attainment. Higher SES was also associated with lower total lymphocyte (p=.023), T-lymphocyte (p=.024) and natural killer (NK) cell counts (p=.006). Total, T- and B-lymphocyte, and NK cell counts increased with stress, but immune stress reactivity did not vary with SES. Post-stress recovery was delayed in women compared with men. The results suggest that moderate inflammation and immune activation may be processes through which lower SES increases disease risk.
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Proteína C-Reactiva/análisis , Linfocitos/inmunología , Clase Social , Estrés Psicológico/inmunología , Adulto , Índice de Masa Corporal , Estudios de Cohortes , Femenino , Humanos , Inflamación/epidemiología , Inflamación/inmunología , Masculino , Persona de Mediana Edad , Psiconeuroinmunología , Factores Sexuales , Estadística como Asunto , Estrés Psicológico/sangre , Estrés Psicológico/epidemiologíaRESUMEN
We assessed the changes in cardiac index and total peripheral resistance underlying blood pressure reactions and recovery from acute mental stress, in relation to socioeconomic status. A sample of 200 men and women aged 47-59 years was divided on the basis of occupation into higher, intermediate, and lower socioeconomic status groups. Blood pressure was monitored using the Portapres, and hemodynamic measures were derived by Modelflow processing of the arterial pressure waveform. Blood pressure increases during two stressful behavioral tasks were sustained by increases in cardiac index and total peripheral resistance. During the 45-min posttask recovery period, cardiac index fell below baseline levels, whereas peripheral resistance remained elevated. Peripheral resistance changes during recovery varied with socioeconomic status and blood pressure stress reactivity, with particularly high levels in reactive low status participants. Results are consistent with the hypothesis that disturbances of stress-related autonomic processes are relevant to the social gradient in cardiovascular disease risk.
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Hemodinámica/fisiología , Clase Social , Estrés Psicológico/fisiopatología , Adulto , Presión Sanguínea/fisiología , Gasto Cardíaco/fisiología , Electrocardiografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Caracteres Sexuales , Resistencia Vascular/fisiologíaRESUMEN
Associations between natural killer (NK) cell, proinflammatory cytokine stress responsivity, and cardiac autonomic responses (indexed by heart rate and heart rate variability) were assessed in 211 middle-aged men and women. Blood was drawn at baseline, immediately following color-word interference and mirror tracing tasks for the assessment of NK cell numbers, and 45 min post-stress for assessing plasma interleukin 6 (IL-6) and tumor necrosis factor alpha (TNFalpha) responses. Heart rate variability was measured as the root mean square of successive differences (RMSSD) in R-R intervals. Increases in NK cell counts following stress were positively associated with heart rate responses independently of age, sex, socioeconomic status, smoking, and change in hematocrit. Heart rate 45 min post-stress was positively associated with plasma IL-6 post-stress, and with TNFalpha changes from baseline, independently of covariates. No relationship between immune responses and heart rate variability was observed. We conclude that individual differences in sympathetically-driven cardiac stress responses are associated with NK and proinflammatory cytokine responses to psychological stress.
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Frecuencia Cardíaca/inmunología , Frecuencia Cardíaca/fisiología , Interleucina-6/sangre , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/fisiología , Estrés Psicológico/inmunología , Factor de Necrosis Tumoral alfa/análisis , Adulto , Sistema Nervioso Autónomo/inmunología , Sistema Nervioso Autónomo/fisiología , Femenino , Humanos , Inflamación , Interleucina-6/farmacología , Masculino , Persona de Mediana Edad , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
OBJECTIVES: The influence of low socioeconomic status on cardiovascular disease may be mediated in part by sustained activation of stress-related autonomic and neuroendocrine processes. We hypothesized that low socioeconomic status would be associated with heightened ambulatory blood pressure and cortisol output over the working day. METHODS: One hundred eight men and 94 women from the Whitehall II epidemiological cohort participated. Blood pressure and heart rate were monitored every 20 minutes over a working day and evening, and salivary cortisol was sampled on waking up and at 2-hour intervals. Measures were also taken under resting laboratory conditions. Socioeconomic status was indexed by grade of employment. RESULTS: Resting blood pressure, heart rate, and cortisol did not differ by grade. Ambulatory systolic pressure was greater in the morning in the lower (128.9 +/- 15.7 mm Hg) than the intermediate (122.6 +/- 12.5 mm Hg) and higher grades (123.3 +/- 12.7 mm Hg) after adjustment for age, sex, smoking, and alcohol intake (p =.019). Heart rate was also raised in the morning in the lower grade participants. Differences in morning systolic pressure and heart rate were independent of concurrent physical activity. Cortisol concentration was greater in lower than higher grade men (9.54 +/- 4.1 vs. 7.38 +/- 2.8 nmol/liter, p =.008) but was more elevated in higher than lower grade women (7.84 +/- 2.5 vs. 6.35 +/- 1.9 nmol/liter, p =.014). Differences remained significant after adjustment for age, time of awakening, smoking, and alcohol intake. CONCLUSIONS: Socioeconomic differences in blood pressure and cortisol may reflect stress-related activation of biological pathways that contribute to variations in disease risk.
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Empleo/psicología , Factores Socioeconómicos , Estrés Fisiológico/fisiopatología , Consumo de Bebidas Alcohólicas/epidemiología , Citas y Horarios , Presión Sanguínea , Monitoreo Ambulatorio de la Presión Arterial , Ritmo Circadiano , Estudios de Cohortes , Femenino , Frecuencia Cardíaca , Humanos , Hidrocortisona/sangre , Londres/epidemiología , Masculino , Persona de Mediana Edad , Fumar/epidemiología , Estrés Fisiológico/psicología , Factores de TiempoRESUMEN
OBJECTIVE: An elevation in plasma fibrinogen may be one of the pathways through which low socioeconomic status increases cardiovascular disease risk. This study assessed the influence of socioeconomic status, job control, and social isolation on fibrinogen responses to acute stress. METHODS: The study was conducted with 125 white men and 96 white women aged 47 to 58 years, drawn from the Whitehall II cohort. Socioeconomic status was indexed by grade of employment, with 82 high, 75 intermediate, and 64 low grade participants. Plasma fibrinogen and hematocrit were assessed at baseline, immediately after performance of color-word and mirror tracing tasks, and 45 minutes later. RESULTS: Plasma fibrinogen increased from baseline to stress (from 2.85 +/- 0.57 to 2.92 +/- 0.58 g/liter), remaining elevated 45 minutes after stress (2.89 +/- 0.58 g/liter, p <.001). Fibrinogen concentration was greater in the low than in the high or intermediate employment grade groups, independently of sex, age, body mass index, smoking status, and hematocrit. Fibrinogen responses to acute stress did not differ across employment grades. Women had higher fibrinogen levels than men, but this pattern was abolished in women taking hormone replacement therapy. Men experiencing low job control showed greater fibrinogen responses to acute stress than did those with high job control (p =.003). Fibrinogen levels were greater in socially isolated individuals, but social isolation did not affect responses to acute stress. CONCLUSIONS: Socioeconomic status and acute stress had independent effects on the plasma fibrinogen level. Low job control may influence cardiovascular disease risk in men partly through provoking greater fibrinogen stress responses.
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Fibrinógeno/análisis , Autonomía Profesional , Clase Social , Estrés Psicológico/sangre , Enfermedad Aguda , Estudios de Cohortes , Femenino , Hematócrito , Hemodinámica , Terapia de Reemplazo de Hormonas , Humanos , Renta , Londres , Masculino , Persona de Mediana Edad , Fumar/epidemiología , Aislamiento Social , Factores Socioeconómicos , Estrés Psicológico/psicologíaRESUMEN
Socioeconomic status is a major determinant of coronary heart disease (CHD). Proinflammatory cytokines are implicated in the etiology of CHD, and are also sensitive to emotional stress. We hypothesised that concentration of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1 receptor antagonist (IL-1Ra) would be inversely related to socioeconomic status, and that cytokine responses to stress would be associated with SES. One hundred and twenty-five middle-aged men and 105 women from the Whitehall II epidemiological cohort were tested, and socioeconomic status was indexed by grade of employment, with participants divided into high, intermediate, and low status groups. Plasma concentrations at rest of TNF-alpha, IL-1Ra, and IL-6 (women only) were associated with socioeconomic status, with lower levels in the high status group, but the effect was non-linear. There was no relationship between socioeconomic status and cytokine responses to stress, but sex differences were observed, with men showing greater TNF-alpha, and women greater IL-6 and IL-1Ra increases. The role of inflammatory cytokines in mediating psychosocial influences on CHD is discussed.
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Interleucina-6/sangre , Sialoglicoproteínas/sangre , Estrés Psicológico/sangre , Estrés Psicológico/inmunología , Factor de Necrosis Tumoral alfa/metabolismo , Enfermedad Aguda , Adulto , Empleo , Femenino , Humanos , Proteína Antagonista del Receptor de Interleucina 1 , Masculino , Persona de Mediana Edad , Factores de Riesgo , Distribución por Sexo , Clase Social , Estrés Psicológico/epidemiologíaRESUMEN
BACKGROUND: The Whitehall cohort studies (I and II) of British civil servants have identified sociodemographic, psychosocial, and biological risk factors for coronary heart disease (CHD). To identify mechanisms responsible for susceptibility to CHD, specific biological markers of stress are increasingly being measured. One marker linked to susceptibility to CHD is heat shock protein (Hsp) 60. METHODS AND RESULTS: Blood was taken from 229 civil servants (126 men and 103 women) in the Whitehall II cohort drawn equally from the range of employment grades. Plasma was assayed for levels of Hsp60, tumor necrosis factor alpha (TNFalpha), C-reactive protein, von Willebrand factor, high density lipoprotein (HDL), total cholesterol, and total/HDL ratio. Psychosocial measures included socioeconomic status, psychological distress, and social isolation. The majority of the participants had Hsp60 in their plasma, and approximately 20% had >1000 ng/mL of this protein (a concentration likely to induce biological effects). A positive association between plasma Hsp60 and TNFalpha and a negative association with von Willebrand factor was found. There was also a significant association between elevated Hsp60 levels, low socioeconomic status, and social isolation, together with an association with psychological distress in women. CONCLUSIONS: The majority of participants exhibited Hsp60 in their plasma, and there was evidence of an association between levels of this stress protein and the proinflammatory cytokine, TNFalpha, and with various psychosocial measures.