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BACKGROUND: Closed-loop control systems of insulin delivery may improve glycemic outcomes in young children with type 1 diabetes. The efficacy and safety of initiating a closed-loop system virtually are unclear. METHODS: In this 13-week, multicenter trial, we randomly assigned, in a 2:1 ratio, children who were at least 2 years of age but younger than 6 years of age who had type 1 diabetes to receive treatment with a closed-loop system of insulin delivery or standard care that included either an insulin pump or multiple daily injections of insulin plus a continuous glucose monitor. The primary outcome was the percentage of time that the glucose level was in the target range of 70 to 180 mg per deciliter, as measured by continuous glucose monitoring. Secondary outcomes included the percentage of time that the glucose level was above 250 mg per deciliter or below 70 mg per deciliter, the mean glucose level, the glycated hemoglobin level, and safety outcomes. RESULTS: A total of 102 children underwent randomization (68 to the closed-loop group and 34 to the standard-care group); the glycated hemoglobin levels at baseline ranged from 5.2 to 11.5%. Initiation of the closed-loop system was virtual in 55 patients (81%). The mean (±SD) percentage of time that the glucose level was within the target range increased from 56.7±18.0% at baseline to 69.3±11.1% during the 13-week follow-up period in the closed-loop group and from 54.9±14.7% to 55.9±12.6% in the standard-care group (mean adjusted difference, 12.4 percentage points [equivalent to approximately 3 hours per day]; 95% confidence interval, 9.5 to 15.3; P<0.001). We observed similar treatment effects (favoring the closed-loop system) on the percentage of time that the glucose level was above 250 mg per deciliter, on the mean glucose level, and on the glycated hemoglobin level, with no significant between-group difference in the percentage of time that the glucose level was below 70 mg per deciliter. There were two cases of severe hypoglycemia in the closed-loop group and one case in the standard-care group. One case of diabetic ketoacidosis occurred in the closed-loop group. CONCLUSIONS: In this trial involving young children with type 1 diabetes, the glucose level was in the target range for a greater percentage of time with a closed-loop system than with standard care. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases; PEDAP ClinicalTrials.gov number, NCT04796779.).
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Glucemia , Diabetes Mellitus Tipo 1 , Hipoglucemiantes , Sistemas de Infusión de Insulina , Insulina , Niño , Preescolar , Humanos , Glucemia/análisis , Automonitorización de la Glucosa Sanguínea , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Hemoglobina Glucada/análisis , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/uso terapéutico , Insulina/administración & dosificación , Insulina/efectos adversos , Insulina/uso terapéutico , Sistemas de Infusión de Insulina/efectos adversosRESUMEN
Children with type 1 diabetes and their caregivers face numerous challenges navigating the unpredictability of this complex disease. Although the burden of managing diabetes remains significant, new technology has eased some of the load and allowed children with type 1 diabetes to achieve tighter glycaemic management without fear of excess hypoglycaemia. Continuous glucose monitor use alone improves outcomes and is considered standard of care for paediatric type 1 diabetes management. Similarly, automated insulin delivery (AID) systems have proven to be safe and effective for children as young as 2 years of age. AID use improves not only blood glucose levels but also quality of life for children with type 1 diabetes and their caregivers and should be strongly considered for all youth with type 1 diabetes if available and affordable. Here, we review key data on the use of diabetes technology in the paediatric population and discuss management issues unique to children and adolescents.
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OBJECTIVE: To evaluate in a rural Tanzanian birth cohort the association between birth timing in relation to the preharvest lean season and early-life growth and cognitive development. STUDY DESIGN: Children were enrolled within 14 days of birth and followed up for 18 months. Child anthropometry was measured every 3 months. The Malawi Developmental Assessment Test was administered at the end of follow-up. We estimated the association between timing of birth in the context of other early childhood risk factors and both growth and Malawi Developmental Assessment Test scores. RESULTS: Children born in the preharvest months September and October had the lowest cognitive scores at 18 months, compared with birth in July and August (-1.05 change in overall Malawi Developmental Assessment Test development-for-age Z score, 95% CI: -1.23, -0.86). This association was observed for the language (-1.67 change in development-for-age Z score; 95% CI: -1.93, -1.40) and fine motor subcomponent scores (-1.67; 95% CI: -1.96, -1.38) but not for gross motor (-0.07; 95% CI: -0.23, 0.10) or social subcomponents (-0.07; 95% CI: -0.23, 0.10). Children born in September and October were the longest at birth but had the largest declines in growth Z scores during the first 6 months. CONCLUSIONS: There was a strong association between birth at the beginning of the preharvest season and poor growth and cognitive development. If these associations were mediated by the preharvest postnatal environment, targeted maternal and child interventions for children born during high-risk periods may improve these outcomes. TRIAL REGISTRATION: NCT03268902 (https://clinicaltrials.gov/study/NCT03268902).
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BACKGROUND: Children with asthma are at risk for low lung function extending into adulthood, but understanding of clinical predictors is incomplete. OBJECTIVE: We sought to determine phenotypic factors associated with FEV1 throughout childhood in the Severe Asthma Research Program 3 pediatric cohort. METHODS: Lung function was measured at baseline and annually. Multivariate linear mixed-effects models were constructed to assess the effect of baseline and time-varying predictors of prebronchodilator FEV1 at each assessment for up to 6 years. All models were adjusted for age, predicted FEV1 by Global Lung Function Initiative reference equations, race, sex, and height. Secondary outcomes included postbronchodilator FEV1 and prebronchodilator FEV1/forced vital capacity. RESULTS: A total of 862 spirometry assessments were performed for 188 participants. Factors associated with FEV1 include baseline Feno (B, -49 mL/log2 PPB; 95% CI, -92 to -6), response to a characterizing dose of triamcinolone acetonide (B, -8.4 mL/1% change FEV1 posttriamcinolone; 95% CI, -12.3 to -4.5), and maximal bronchodilator reversibility (B, -27 mL/1% change postbronchodilator FEV1; 95% CI, -37 to -16). Annually assessed time-varying factors of age, obesity, and exacerbation frequency predicted FEV1 over time. Notably, there was a significant age and sex interaction. Among girls, there was no exacerbation effect. For boys, however, moderate (1-2) exacerbation frequency in the previous 12 months was associated with -20 mL (95% CI, -39 to -2) FEV1 at each successive year. High exacerbation frequency (≥3) 12 to 24 months before assessment was associated with -34 mL (95% CI, -61 to -7) FEV1 at each successive year. CONCLUSIONS: In children with severe and nonsevere asthma, several clinically relevant factors predict FEV1 over time. Boys with recurrent exacerbations are at high risk of lower FEV1 through childhood.
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Asma , Masculino , Femenino , Niño , Humanos , Adulto , Volumen Espiratorio Forzado , Asma/tratamiento farmacológico , Broncodilatadores/uso terapéutico , Broncodilatadores/farmacología , Pruebas de Función Respiratoria , Espirometría , PulmónRESUMEN
The role of the social, physical, and organisational environments in shaping how patients and their caregivers perform work remains largely unexplored in human factors/ergonomics literature. This study recruited 19 dyads consisting of a parent and their child with type 1 diabetes to be interviewed individually and analysed using a macroergonomic framework. Our findings aligned with the macroergonomic factors as presented in previous models, while highlighting the need to expand upon certain components to gain a more comprehensive representation of the patient work system as relevant to dyadic management. Examples of design efforts that should follow from these findings include expanding existing data sharing options to include information from the external environment and capitalising on the capabilities of artificial intelligence as a decision support system. Future research should focus on longitudinally assessing patient work systems throughout transition periods in addition to more explicitly exploring the roles of social network members.
Work performed by patients and their caregivers is shaped by the social, physical, and organisational contexts they are embedded within. This paper explored how adolescents with type 1 diabetes managed their health alongside their parents in the context of these macroergonomic factors. These findings have implications for research and design.
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BACKGROUND: A closed-loop system of insulin delivery (also called an artificial pancreas) may improve glycemic outcomes in children with type 1 diabetes. METHODS: In a 16-week, multicenter, randomized, open-label, parallel-group trial, we assigned, in a 3:1 ratio, children 6 to 13 years of age who had type 1 diabetes to receive treatment with the use of either a closed-loop system of insulin delivery (closed-loop group) or a sensor-augmented insulin pump (control group). The primary outcome was the percentage of time that the glucose level was in the target range of 70 to 180 mg per deciliter, as measured by continuous glucose monitoring. RESULTS: A total of 101 children underwent randomization (78 to the closed-loop group and 23 to the control group); the glycated hemoglobin levels at baseline ranged from 5.7 to 10.1%. The mean (±SD) percentage of time that the glucose level was in the target range of 70 to 180 mg per deciliter increased from 53±17% at baseline to 67±10% (the mean over 16 weeks of treatment) in the closed-loop group and from 51±16% to 55±13% in the control group (mean adjusted difference, 11 percentage points [equivalent to 2.6 hours per day]; 95% confidence interval, 7 to 14; P<0.001). In both groups, the median percentage of time that the glucose level was below 70 mg per deciliter was low (1.6% in the closed-loop group and 1.8% in the control group). In the closed-loop group, the median percentage of time that the system was in the closed-loop mode was 93% (interquartile range, 91 to 95). No episodes of diabetic ketoacidosis or severe hypoglycemia occurred in either group. CONCLUSIONS: In this 16-week trial involving children with type 1 diabetes, the glucose level was in the target range for a greater percentage of time with the use of a closed-loop system than with the use of a sensor-augmented insulin pump. (Funded by Tandem Diabetes Care and the National Institute of Diabetes and Digestive and Kidney Diseases; ClinicalTrials.gov number, NCT03844789.).
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Diabetes Mellitus Tipo 1/tratamiento farmacológico , Hipoglucemiantes/administración & dosificación , Bombas de Infusión Implantables , Sistemas de Infusión de Insulina , Insulina/administración & dosificación , Adolescente , Glucemia/análisis , Niño , Diabetes Mellitus Tipo 1/sangre , Cetoacidosis Diabética/etiología , Femenino , Hemoglobina Glucada/análisis , Humanos , Hipoglucemia/inducido químicamente , Hipoglucemiantes/efectos adversos , Inyecciones Subcutáneas , Insulina/efectos adversos , Sistemas de Infusión de Insulina/efectos adversos , Masculino , Páncreas ArtificialRESUMEN
BACKGROUND: Children in low-resource areas experience nutritional and infection challenges delaying growth and cognitive development. OBJECTIVES: Our goal was to assess for associations of circulating biomarkers related to nutrition and inflammation, with growth and developmental outcomes among children in a birth cohort in a resource-poor area in rural Tanzania. METHODS: We assessed data from 1,120 children participating in the Early Life Interventions for Childhood Growth and Development in Tanzania (ELICIT) study. At age 12 and 18 mo, participants had blood tests performed for hemoglobin, collagen-X, insulin-like growth factor-1 (IGF-1), fibroblast growth factor-21 (FGF21), thyroglobulin, ferritin, soluble transferrin receptor (sTFR), retinol binding protein-4 (RBP4), C-reactive protein (CRP), α1-acid glycoprotein (AGP), and CD14. At 18 mo, participants had anthropometry measured and converted to z-scores for length-for-age (LAZ), weight-for-age (WAZ) and head-circumference-for-age (HCZ) and had the Malawi Developmental Assessment Tool (MDAT) performed to evaluate cognitive development. We performed linear regression assessing biomarkers (predictor variable) on anthropometry and MDAT scores (dependent variables), adjusted for sex, socioeconomic status, and baseline values. RESULTS: There was a high degree of intrafactor correlation between 12 and 18 mo and interfactor correlation between biomarkers. IGF-1 and sTFR were positively and FGF21 and ferritin negatively associated with LAZ at 18 mo, whereas collagen-X and CD14 were additionally associated with recent linear growth. Only markers predominantly related to nutrition were consistently linked with WAZ at 18 mo, while RBP4 and AGP were additionally associated with recent change in WAZ. IGF-1 was positively and thyroglobulin, RBP4, and CD14 negatively linked to MDAT scores. IGF-1 was the only factor linked to both 18-mo LAZ and MDAT. CONCLUSIONS: Individual biomarkers were consistently linked to growth and cognitive outcomes, providing support for relationships between nutrition and inflammation in early child development. Further research is needed to assess overlaps in how biomarker-related processes interact with both growth and learning. REGISTERED AT CLINICALTRIALS.GOV: NCT03268902.
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Factor I del Crecimiento Similar a la Insulina , Tiroglobulina , Niño , Humanos , Lactante , Adolescente , Tanzanía , Biomarcadores , Inflamación , Desarrollo Infantil , Cognición , Ferritinas , Proteínas Plasmáticas de Unión al RetinolRESUMEN
Rationale: The role of obesity-associated insulin resistance (IR) in airflow limitation in asthma is uncertain. Objectives: Using data in the Severe Asthma Research Program 3 (SARP-3), we evaluated relationships between homeostatic measure of IR (HOMA-IR), lung function (cross-sectional and longitudinal analyses), and treatment responses to bronchodilators and corticosteroids. Methods: HOMA-IR values were categorized as without (<3.0), moderate (3.0-5.0), or severe (>5.0). Lung function included FEV1 and FVC measured before and after treatment with inhaled albuterol and intramuscular triamcinolone acetonide and yearly for 5 years. Measurements and Main Results: Among 307 participants in SARP-3, 170 (55%) were obese and 140 (46%) had IR. Compared with patients without IR, those with IR had significantly lower values for FEV1 and FVC, and these lower values were not attributable to obesity effects. Compared with patients without IR, those with IR had lower FEV1 responses to ß-adrenergic agonists and systemic corticosteroids. The annualized decline in FEV1 was significantly greater in patients with moderate IR (-41 ml/year) and severe IR (-32 ml/year,) than in patients without IR (-13 ml/year, P < 0.001 for both comparisons). Conclusions: IR is common in asthma and is associated with lower lung function, accelerated loss of lung function, and suboptimal lung function responses to bronchodilator and corticosteroid treatments. Clinical trials in patients with asthma and IR are needed to determine if improving IR might also improve lung function.
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Asma , Resistencia a la Insulina , Humanos , Estudios Transversales , Broncodilatadores/uso terapéutico , Pulmón , Corticoesteroides/uso terapéutico , Obesidad/complicaciones , Volumen Espiratorio ForzadoRESUMEN
Asthma resistance to glucocorticoid treatment is a major health problem with unclear etiology. Glucocorticoids inhibit adrenal androgen production. However, androgens have potential benefits in asthma. HSD3B1 encodes for 3ß-hydroxysteroid dehydrogenase-1 (3ß-HSD1), which catalyzes peripheral conversion from adrenal dehydroepiandrosterone (DHEA) to potent androgens and has a germline missense-encoding polymorphism. The adrenal restrictive HSD3B1(1245A) allele limits conversion, whereas the adrenal permissive HSD3B1(1245C) allele increases DHEA metabolism to potent androgens. In the Severe Asthma Research Program (SARP) III cohort, we determined the association between DHEA-sulfate and percentage predicted forced expiratory volume in 1 s (FEV1PP). HSD3B1(1245) genotypes were assessed, and association between adrenal restrictive and adrenal permissive alleles and FEV1PP in patients with (GC) and without (noGC) daily oral glucocorticoid treatment was determined (n = 318). Validation was performed in a second cohort (SARP I&II; n = 184). DHEA-sulfate is associated with FEV1PP and is suppressed with GC treatment. GC patients homozygous for the adrenal restrictive genotype have lower FEV1PP compared with noGC patients (54.3% vs. 75.1%; P < 0.001). In patients with the homozygous adrenal permissive genotype, there was no FEV1PP difference in GC vs. noGC patients (73.4% vs. 78.9%; P = 0.39). Results were independently confirmed: FEV1PP for homozygous adrenal restrictive genotype in GC vs. noGC is 49.8 vs. 63.4 (P < 0.001), and for homozygous adrenal permissive genotype, it is 66.7 vs. 67.7 (P = 0.92). The adrenal restrictive HSD3B1(1245) genotype is associated with GC resistance. This effect appears to be driven by GC suppression of 3ß-HSD1 substrate. Our results suggest opportunities for prediction of GC resistance and pharmacologic intervention.
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Asma/tratamiento farmacológico , Asma/enzimología , Glucocorticoides/administración & dosificación , Complejos Multienzimáticos/genética , Progesterona Reductasa/genética , Esteroide Isomerasas/genética , Adulto , Anciano , Alelos , Andrógenos/metabolismo , Asma/genética , Asma/metabolismo , Estudios de Cohortes , Resistencia a Medicamentos , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Complejos Multienzimáticos/metabolismo , Progesterona Reductasa/metabolismo , Esteroide Isomerasas/metabolismo , Adulto JovenRESUMEN
BACKGROUND: In population-based growth surveys in sub-Saharan Africa, boys have higher rates of growth failure than girls. OBJECTIVES: Our goal was to assess for the presence, timing, and potential etiology of sex-based differences in length-for-age z score (LAZ), weight-for-age z score (WAZ), and head circumference-for-age z score (HCZ) in a birth cohort in rural Tanzania. METHODS: We performed a secondary analysis of randomized controlled trial data on 1084 children followed from age <2 wk to 18 mo, assessing anthropometry (measured every 3 mo), illness (hospitalization and monthly maternal report of symptoms), and feeding [monthly maternal report of exclusive breastfeeding (EBF) and complementary solids and liquids (CSLs)]. We used linear regression to assess sex differences in LAZ, WAZ, and HCZ over time. RESULTS: Although male and female infants had similar anthropometry measures at study entry, males exhibited poorer growth through 6 mo (e.g., 3-mo mean LAZ: males -0.94, females -0.74, P < 0.01; 3-mo mean WAZ: males -0.63, females -0.48, P < 0.05), without significant worsening from 6 to 18 mo. Males had lower HCZ only at 9 mo. In evaluating possible etiologies, mediation analysis failed to identify illness or hospitalization as mediators of poorer growth among males, although at age 3 mo, males with recently reported illness exhibited greater decline in WAZ than females with illness (ΔWAZ: males -0.24, females 0.03, heterogeneity test P = 0.01). Differences in EBF and introduction of CSL did not explain the sex-based growth outcomes. CONCLUSIONS: In longitudinal analysis, males exhibited more severe growth failure by 3 mo than girls and did not exhibit catchup growth between 6 and 18 mo. Reported symptoms of illness and early introduction of CSL did not appear to be mediators of these sex-based differences, although likely not all sickness was captured by monthly maternal report. Given the early nature of these deficits, LAZ and WAZ measures at 6 mo may be good outcomes for intervention studies targeting improvements in early childhood growth and thriving.
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Lactancia Materna , Caracteres Sexuales , Antropometría , Niño , Desarrollo Infantil , Preescolar , Femenino , Crecimiento y Desarrollo , Humanos , Lactante , Masculino , TanzaníaRESUMEN
Rationale: Androgens are potentially beneficial in asthma, but AR (androgen receptor) has not been studied in human airways.Objectives: To measure whether AR and its ligands are associated with human asthma outcomes.Methods: We compared the effects of AR expression on lung function, symptom scores, and fractional exhaled nitric oxide (FeNO) in adults enrolled in SARP (Severe Asthma Research Program). The impact of sex and of androgens on asthma outcomes was also evaluated in the SARP with validation studies in the Cleveland Clinic Health System and the NHANES (U.S. National Health and Nutrition Examination Survey).Measurements and Main Results: In SARP (n = 128), AR gene expression from bronchoscopic epithelial brushings was positively associated with both FEV1/FVC ratio (R2 = 0.135, P = 0.0002) and the total Asthma Quality of Life Questionnaire score (R2 = 0.056, P = 0.016) and was negatively associated with FeNO (R2 = 0.178, P = 9.8 × 10-6) and NOS2 (nitric oxide synthase gene) expression (R2 = 0.281, P = 1.2 × 10-10). In SARP (n = 1,659), the Cleveland Clinic Health System (n = 32,527), and the NHANES (n = 2,629), women had more asthma exacerbations and emergency department visits than men. The levels of the AR ligand precursor dehydroepiandrosterone sulfate correlated positively with the FEV1 in both women and men.Conclusions: Higher bronchial AR expression and higher androgen levels are associated with better lung function, fewer symptoms, and a lower FeNO in human asthma. The role of androgens should be considered in asthma management.
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Asma/genética , Sulfato de Deshidroepiandrosterona/sangre , ARN Mensajero/metabolismo , Receptores Androgénicos/genética , Mucosa Respiratoria/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Asma/sangre , Asma/fisiopatología , Pruebas Respiratorias , Broncoscopía , Femenino , Volumen Espiratorio Forzado , Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/genética , Calidad de Vida , Factores Sexuales , Capacidad Vital , Adulto JovenRESUMEN
Rationale: It is unclear why select patients with moderate-to-severe asthma continue to lose lung function despite therapy. We hypothesized that participants with the smallest responses to parenteral corticosteroids have the greatest risk of undergoing a severe decline in lung function.Objectives: To evaluate corticosteroid-response phenotypes as longitudinal predictors of lung decline.Methods: Adults within the NHLBI SARP III (Severe Asthma Research Program III) who had undergone a course of intramuscular triamcinolone at baseline and at ≥2 annual follow-up visits were evaluated. Longitudinal slopes were calculated for each participant's post-bronchodilator FEV1% predicted. Categories of participant FEV1 slope were defined: severe decline, >2% loss/yr; mild decline, >0.5-2.0% loss/yr; no change, 0.5% loss/yr to <1% gain/yr; and improvement, ≥1% gain/yr. Regression models were used to develop predictors of severe decline.Measurements and Main Results: Of 396 participants, 78 had severe decline, 91 had mild decline, 114 had no change, and 113 showed improvement. The triamcinolone-induced difference in the post-bronchodilator FEV1% predicted (derived by baseline subtraction) was related to the 4-year change in lung function or slope category in univariable models (P < 0.001). For each 5% decrement in the triamcinolone-induced difference the FEV1% predicted, there was a 50% increase in the odds of being in the severe decline group (odds ratio, 1.5; 95% confidence interval, 1.3-1.8), when adjusted for baseline FEV1, exacerbation history, blood eosinophils and body mass index.Conclusions: Failure to improve the post-bronchodilator FEV1 after a challenge with parenteral corticosteroids is an evoked biomarker for patients at risk for a severe decline in lung function.
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Corticoesteroides/administración & dosificación , Corticoesteroides/uso terapéutico , Asma/tratamiento farmacológico , Asma/fisiopatología , Broncodilatadores/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Humanos , Infusiones Parenterales , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Pruebas de Función Respiratoria , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
BACKGROUND: Stunting among children in low-resource settings is associated with enteric pathogen carriage and micronutrient deficiencies. Our goal was to test whether administration of scheduled antimicrobials and daily nicotinamide improved linear growth in a region with a high prevalence of stunting and enteric pathogen carriage. METHODS AND FINDINGS: We performed a randomized, 2 × 2 factorial, double-blind, placebo-controlled trial in the area around Haydom, Tanzania. Mother-child dyads were enrolled by age 14 days and followed with monthly home visits and every 3-month anthropometry assessments through 18 months. Those randomized to the antimicrobial arm received 2 medications (versus corresponding placebos): azithromycin (single dose of 20 mg/kg) at months 6, 9, 12, and 15 and nitazoxanide (3-day course of 100 mg twice daily) at months 12 and 15. Those randomized to nicotinamide arm received daily nicotinamide to the mother (250 mg pills months 0 to 6) and to the child (100 mg sachets months 6 to 18). Primary outcome was length-for-age z-score (LAZ) at 18 months in the modified intention-to-treat group. Between September 5, 2017 and August 31, 2018, 1,188 children were randomized, of whom 1,084 (n = 277 placebo/placebo, 273 antimicrobial/placebo, 274 placebo/nicotinamide, and 260 antimicrobial/nicotinamide) were included in the modified intention-to-treat analysis. The study was suspended for a 3-month period by the Tanzanian National Institute for Medical Research (NIMR) because of concerns related to the timing of laboratory testing and the total number of serious adverse events (SAEs); this resulted in some participants receiving their final study assessment late. There was a high prevalence of stunting overall (533/1,084, 49.2%). Mean 18-month LAZ did not differ between groups for either intervention (mean LAZ with 95% confidence interval [CI]: antimicrobial: -2.05 CI -2.13, -1.96, placebo: -2.05 CI -2.14, -1.97; mean difference: 0.01 CI -0.13, 0.11, p = 0.91; nicotinamide: -2.06 CI -2.13, -1.95, placebo: -2.04 CI -2.14, -1.98, mean difference 0.03 CI -0.15, 0.09, p = 0.66). There was no difference in LAZ for either intervention after adjusting for possible confounders (baseline LAZ, age in days at 18-month measurement, ward, hospital birth, birth month, years of maternal education, socioeconomic status (SES) quartile category, sex, whether the mother was a member of the Datoga tribe, and mother's height). Adverse events (AEs) and SAEs were overall similar between treatment groups for both the nicotinamide and antimicrobial interventions. Key limitations include the absence of laboratory measures of pathogen carriage and nicotinamide metabolism to provide context for the negative findings. CONCLUSIONS: In this study, we observed that neither scheduled administration of azithromycin and nitazoxanide nor daily provision of nicotinamide was associated with improved growth in this resource-poor setting with a high force of enteric infections. Further research remains critical to identify interventions toward improved early childhood growth in challenging conditions. TRIAL REGISTRATION: ClinicalTrials.gov NCT03268902.
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Antiinfecciosos/farmacología , Desarrollo Infantil/efectos de los fármacos , Niacinamida/farmacología , Adulto , Antiinfecciosos/administración & dosificación , Azitromicina/administración & dosificación , Azitromicina/farmacología , Método Doble Ciego , Esquema de Medicación , Femenino , Trastornos del Crecimiento/prevención & control , Humanos , Lactante , Recién Nacido , Parasitosis Intestinales/prevención & control , Niacinamida/administración & dosificación , Nitrocompuestos/administración & dosificación , Nitrocompuestos/farmacología , Embarazo , Tanzanía , Tiazoles/administración & dosificación , Tiazoles/farmacologíaRESUMEN
BACKGROUND: Metabolic syndrome (MetS) is a risk factor for the development of cardiovascular disease and type 2 diabetes. Although the development of MetS is attributed to known lifestyle factors, perceived discrimination may also contribute to MetS development and severity. PURPOSE: We examined the associations of perceived discrimination with MetS severity among African American adults at baseline and 8-year follow-up. METHODS: Three thousand eight hundred and seventy participants (mean age 53.8 ± 13.0; 63.1% female) without diabetes and no missing MetS severity scores at baseline were included. Each self-reported measure of discrimination at baseline (everyday, lifetime, and burden of lifetime) was classified into tertiles (low, medium, high). After adjustment for demographics and MetS risk factors, associations of discrimination were examined with a sex- and race/ethnicity-specific MetS severity Z-score. We employed a mixed model approach that allowed for the assessment of an overall association between reported discrimination at baseline and MetS severity, and for the possible change over time. RESULTS: Sex and age differences were observed in experiences with discrimination, such that men reported higher levels of all aspects of discrimination relative to women. Everyday discrimination decreased with age, whereas lifetime discrimination increased with age (p < .05). Independent of lifestyle and demographic factors, everyday and lifetime discrimination were significantly associated with MetS severity (p = .003 and p = .017, respectively) and the associations remained constant over the 8 years (i.e., no interaction with time). CONCLUSIONS: Our results suggest that, in a large community-based sample of African Americans, discrimination is a salient psychosocial risk factor for severity of MetS.
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Negro o Afroamericano/psicología , Síndrome Metabólico/psicología , Racismo/psicología , Adulto , Negro o Afroamericano/estadística & datos numéricos , Anciano , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Racismo/estadística & datos numéricos , Factores de Riesgo , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: Data on the use of Control-IQ, the latest FDA-approved automated insulin delivery (AID) system for people with T1D 6 years of age or older is still scarce, particularly regarding nonglycemic outcomes. Children with T1D and their parents are at higher risk for sleep disturbances. This study assesses sleep, psycho-behavioral and glycemic outcomes of AID compared to sensor-augmented pump therapy (SAP) therapy in young children with T1D and their parents. METHODS: Thirteen parents and their young children (ages 7-10) on insulin pump therapy were enrolled. Children completed an initial 4-week study with SAP using their own pump and a study CGM followed by a 4-week phase of AID. Sleep outcomes for parents and children were evaluated through actigraphy watches. Several questionnaires were administered at baseline and at the end of each study phase. CGM data were used to assess glycemic outcomes. RESULTS: Actigraphy data did not show any significant change from SAP to AID, except a reduction of number of parental awakenings during the night (p = 0.036). Parents reported statistically significant improvements in Pittsburgh Sleep Quality Index total score (p = 0.009), Hypoglycemia Fear Survey total score (p = 0.011), diabetes-related distress (p = 0.032), and depression (p = 0.023). While on AID, time in range (70-180 mg/dL) significantly increased compared to SAP (p < 0.001), accompanied by a reduction in hyperglycemia (p = 0.001). CONCLUSIONS: These results suggest that use of AID has a positive impact on glycemic outcomes in young children as well as sleep and diabetes-specific quality of life outcomes in their parents.
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Diabetes Mellitus Tipo 1/psicología , Hipoglucemiantes/administración & dosificación , Sistemas de Infusión de Insulina , Insulina/administración & dosificación , Padres/psicología , Calidad del Sueño , Adulto , Automonitorización de la Glucosa Sanguínea , Niño , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Calidad de Vida , Encuestas y CuestionariosRESUMEN
BACKGROUND AND AIM: Non-alcoholic steatohepatitis (NASH), which can lead to liver failure, requires liver biopsies to follow and is difficult to treat. Our goal was to assess metabolic syndrome (MetS) severity as a predictor of treatment success and a marker of response. METHODS: We assessed data from the Pioglitazone, Vitamin E, or Placebo for NASH Study, in which individuals with biopsy-confirmed NASH were randomized to receive pioglitazone, vitamin E, or placebo for 96 weeks. We assessed associations of a sex-specific and race/ethnicity-specific MetS severity Z-score (MetS-Z) at baseline and 48 weeks with biopsy-determined endpoint of NASH resolution at 96 weeks. RESULTS: Baseline MetS-Z was inversely associated with odds of NASH resolution (odds ratio [OR] per 1 SD of MetS-Z: 0.47, 95% confidence interval [CI] 0.28, 0.79). Decrease in MetS-Z during initial 48-week intervention was greatest for pioglitazone treatment (effect size: -0.31, 95% CI -0.15, -0.48) and for vitamin E tended toward being greater for those with versus without NASH resolution (-0.18 vs -0.05). Overall, 48-week change in MetS-Z was associated with NASH resolution (OR per 1-SD change: 0.53, 95% CI 0.33, 0.85), although this was attenuated in models that included transaminases, which remained linked to treatment success (OR by change-in-aspartate aminotransferase Z-score: 0.38, 95% CI 0.19, 0.76). CONCLUSIONS: Individuals with more severe metabolic derangement at baseline were less likely to exhibit NASH resolution, suggesting that individuals may have a threshold of MetS severity beyond which successful treatment is unlikely. As an integrated marker of metabolic abnormalities, MetS-Z was correlated with successful treatment, although transaminases were a more consistent marker of NASH resolution.
Asunto(s)
Síndrome Metabólico/diagnóstico , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Pioglitazona/uso terapéutico , Vitamina E/uso terapéutico , Adulto , Aspartato Aminotransferasas/metabolismo , Biomarcadores/metabolismo , Femenino , Humanos , Masculino , Síndrome Metabólico/complicaciones , Síndrome Metabólico/tratamiento farmacológico , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Enfermedad del Hígado Graso no Alcohólico/etiología , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVE: Executive functions such as working memory and cognitive flexibility are key to lifelong learning. Our hypothesis was that children born low birthweight (LBW), defined as weight < 2,500 g, would have lower cognitive outcomes than those born normal weight, and children with poor executive functioning would be at risk for poor academic outcomes. STUDY DESIGN: We evaluated data from 12,656 children followed prospectively in the Early Childhood Longitudinal Study, Kindergarten Class 2010-2011, assessing outcomes from kindergarten, first grade, and second grade. Multivariable linear and logistic regressions were run evaluating the relationship between birthweight and cognitive outcomes, and the odds of infants with poor executive functioning having poor academic outcomes. RESULTS: Compared with children with normal birthweight, those born LBW had lower mean z-scores for academic and directly assessed executive functions from kindergarten through second grade. LBW children were at an increased risk of scoring in the bottom 20% of children at all time points: second-grade reading odds ratio (OR) = 1.60 (95% confidence interval [CI:] 1.23-2.09), math OR = 1.49 (95% CI: 1.21-1.84), science OR = 1.41 (95% CI: 1.11-1.81), cognitive flexibility OR = 1.61 (95% CI: 1.27-2.02), and working memory OR = 1.40 (95% CI: 1.10-1.77). CONCLUSION: LBW infants remain at risk of poor cognitive outcomes in second grade. Early difficulties with executive functioning can increase the risk of a child's academic performance years later.
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Éxito Académico , Desarrollo Infantil/fisiología , Cognición/fisiología , Función Ejecutiva/fisiología , Recién Nacido de Bajo Peso , Niño , Humanos , Lactante , Recién Nacido , Estudios Longitudinales , Masculino , Memoria a Corto Plazo/fisiología , Estudios Prospectivos , Factores de RiesgoRESUMEN
BACKGROUND: Morbidity and mortality associated with childhood asthma are driven disproportionately by children with severe asthma. However, it is not known from longitudinal studies whether children outgrow severe asthma. OBJECTIVE: We sought to study prospectively whether well-characterized children with severe asthma outgrow their asthma during adolescence. METHODS: Children with asthma were assessed at baseline with detailed questionnaires, allergy tests, and lung function tests and were reassessed annually for 3 years. The population was enriched for children with severe asthma, as assessed by the American Thoracic Society/European Respiratory Society guidelines, and subject classification was reassessed annually. RESULTS: At baseline, 111 (59%) children had severe asthma. Year to year, there was a decrease in the proportion meeting the criteria for severe asthma. After 3 years, only 30% of subjects met the criteria for severe asthma (P < .001 compared with enrollment). Subjects experienced improvements in most indices of severity, including symptom scores, exacerbations, and controller medication requirements, but not lung function. Surprisingly, boys and girls were equally likely to has resolved asthma (33% vs 29%). The odds ratio in favor of resolution of severe asthma was 2.75 (95% CI, 1.02-7.43) for those with a peripheral eosinophil count of greater than 436 cells/µL. CONCLUSIONS: In longitudinal analysis of this well-characterized cohort, half of the children with severe asthma no longer had severe asthma after 3 years; there was a stepwise decrease in the proportion meeting severe asthma criteria. Surprisingly, asthma severity decreased equally in male and female subjects. Peripheral eosinophilia predicted resolution. These data will be important for planning clinical trials in this population.
Asunto(s)
Asma , Índice de Severidad de la Enfermedad , Adolescente , Asma/sangre , Asma/tratamiento farmacológico , Asma/patología , Niño , Eosinófilos , Femenino , Humanos , Recuento de Leucocitos , Estudios Longitudinales , Masculino , Estudios ProspectivosRESUMEN
BACKGROUND AND PURPOSE: Ischemic stroke is associated with the metabolic syndrome (MetS) as diagnosed using dichotomous criteria; however, these criteria exhibit racial/ethnic discrepancies. Our goal was to assess whether ischemic stroke risk extended over the spectrum of worsening MetS severity using a sex- and race/ethnicity-specific MetS-severity Z score. METHODS: We used Cox-proportional hazards models to assess the relationship between baseline MetS-Z score and incident ischemic stroke among participants of the Atherosclerosis Risk in Communities study and Jackson Heart Study who were free from diabetes, coronary heart disease or stroke at baseline, evaluating 13 141 white and black individuals with mean follow-up of 18.6 years. RESULTS: We found that risk of ischemic stroke increased consistently with MetS severity, with a hazard ratio of 1.75 (95% CI, 1.35-2.27) for those >75th percentile compared to those <25th percentile. This risk was highest for white females (hazard ratio, 2.63 [CI, 1.70-4.07]) though without significant interaction by sex and race. Relationships between stroke and all the individual components of MetS were only noted for white females, though again without sex-race interactions. Hazard ratio's for systolic blood pressure and stroke were significant among all sex/racial subgroups. CONCLUSIONS: Ischemic stroke risk increased over the spectrum of MetS severity in the absence of baseline diabetes mellitus, further implicating potential etiologic risks from processes underlying MetS. Individuals with elevated MetS severity should be counselled toward lifestyle modification to lower ischemic stroke risk.
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Isquemia Encefálica/epidemiología , Síndrome Metabólico/epidemiología , Índice de Severidad de la Enfermedad , Accidente Cerebrovascular/epidemiología , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/fisiopatología , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Masculino , Síndrome Metabólico/diagnóstico , Síndrome Metabólico/fisiopatología , Persona de Mediana Edad , Factores de Riesgo , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/fisiopatologíaRESUMEN
The incidence of type 1 diabetes (T1D) is increasing annually, in addition to other childhood-onset autoimmune diseases. This review is inspired by recent strides in research defining the pathophysiology of autoimmunity in celiac disease, a disease that has significant genetic overlap with T1D. Population genetic studies have demonstrated an increased proportion of newly diagnosed young children with T1D also have a higher genetic risk of celiac disease, suggesting that shared environmental risk factors are driving the incidence of both diseases. The small intestine barrier forms a tightly regulated interface of the immune system with the outside world and largely controls the mucosal immune response to non-self-antigens, dictating the balance between tolerance and immune response. Zonulin is the only known physiological modulator of the intercellular tight junctions, important in antigen trafficking, and therefore, is a key player in regulation of the mucosal immune response. While usually tightly controlled, when the zonulin pathway is dysregulated by changes in microbiome composition and function, antigen trafficking control is lost, leading to loss of mucosal tolerance in genetically susceptible individuals. The tenant of this hypothesis is that loss of tolerance would not occur if the zonulin-dependent intestinal barrier function is restored, thereby preventing the influence of environmental triggers in individuals genetically susceptible to autoimmunity. This review outlines the current research and a structured hypothesis on how a dysregulated small intestinal epithelial barrier, a "leaky gut," may be important in the pathogenesis of autoimmunity in certain individuals at risk of both T1D and celiac disease.