Foetal development and infancy are life stages that are characterised by rapid growth, development and maturation of organs and systems. Variation in the quality or quantity of nutrients consumed by ...mothers during pregnancy, or infants during the first year of life, can exert permanent and powerful effects upon developing tissues. These effects are termed ‘programming’ and represent an important risk factor for noncommunicable diseases of adulthood, including the metabolic syndrome and coronary heart disease. This narrative review provides an overview of the evidence‐base showing that indicators of nutritional deficit in pregnancy are associated with a greater risk of type‐2 diabetes and cardiovascular mortality. There is also a limited evidence‐base that suggests some relationship between breastfeeding and the timing and type of foods used in weaning, and disease in later life. Many of the associations reported between indicators of early growth and adult disease appear to interact with specific genotypes. This supports the idea that programming is one of several cumulative influences upon health and disease acting across the lifespan. Experimental studies have provided important clues to the mechanisms that link nutritional challenges in early life to disease in adulthood. It is suggested that nutritional programming is a product of the altered expression of genes that regulate the cell cycle, resulting in effective remodelling of tissue structure and functionality. The observation that traits programmed by nutritional exposures in foetal life can be transmitted to further generations adds weight the argument that heritable epigenetic modifications play a critical role in nutritional programming.
We analyzed the long-term outcome of 1011 patients treated in five successive clinical trials (Total Therapy Studies 11, 12, 13A, 13B, and 14) between 1984 and 1999. The event-free survival improved ...significantly (P=0.003) from the first two trials conducted in the 1980s to the three more recent trials conducted in the 1990s. Approximately 75% of patients treated in the 1980s and 80% in the 1990s were cured. Early intensive triple intrathecal therapy, together with more effective systemic therapy, including consolidation and reinduction treatment (Studies 13A and 13B) as well as dexamethasone (Study 13B), resulted in a very low rate of isolated central nervous system (CNS) relapse rate (<2%), despite the reduced use of cranial irradiation. Factors consistently associated with treatment outcome were age, leukocyte count, immunophenotype, DNA index, and minimal residual disease level after remission induction treatment. Owing to concerns about therapy-related secondary myeloid leukemia and brain tumors, in our current trials we reserve the use of etoposide for patients with refractory or relapsed leukemia undergoing hematopoietic stem cell transplantation, and cranial irradiation for those with CNS relapse. The next main challenge is to further increase cure rates while improving quality of life for all patients.
While many studies have demonstrated positive associations between childhood obesity and adult metabolic risk, important questions remain as to the nature of the relationship. In particular, it is ...unclear whether the associations reflect the tracking of body mass index (BMI) from childhood to adulthood or an independent level of risk. This systematic review aimed to investigate the relationship between childhood obesity and a range of metabolic risk factors during adult life.
To perform an unbiased systematic review to investigate the association between childhood BMI and risk of developing components of metabolic disease in adulthood, and whether the associations observed are independent of adult BMI.
Electronic databases were searched from inception until July 2010 for studies investigating the association between childhood BMI and adult metabolic risk. Two investigators independently reviewed studies for eligibility according to the inclusion/exclusion criteria, extracted the data and assessed study quality using the Newcastle-Ottawa Scale.
The search process identified 11 articles that fulfilled the inclusion and exclusion criteria. Although several identified weak positive associations between childhood BMI and adult total cholesterol, low-density lipo protein-cholesterol, triglyceride and insulin concentrations, these associations were ameliorated or inversed when adjusted for adult BMI or body fatness. Of the four papers that considered metabolic syndrome as an end point, none showed evidence of an independent association with childhood obesity.
Little evidence was found to support the view that childhood obesity is an independent risk factor for adult blood lipid status, insulin levels, metabolic syndrome or type 2 diabetes. The majority of studies failed to adjust for adult BMI and therefore the associations observed may reflect the tracking of BMI across the lifespan. Interestingly, where adult BMI was adjusted for, the data showed a weak negative association between childhood BMI and metabolic variables, with those at the lower end of the BMI range in childhood, but obese during adulthood at particular risk.
The World Health Organisation recommends exclusive breastfeeding until 6 months of age and continued breastfeeding until 2 years of age or beyond. Appropriate complementary foods should be introduced ...in a timely fashion, beginning when the infant is 6 months old. In developing countries, early or inappropriate complementary feeding may lead to malnutrition and poor growth, but in countries such as the United Kingdom and United States of America, where obesity is a greater public health concern than malnutrition, the relationship to growth is unclear. We conducted a systematic review of the literature that investigated the relationship between the timing of the introduction of complementary feeding and overweight or obesity during childhood. Electronic databases were searched from inception until 30 September 2012 using specified keywords. Following the application of strict inclusion/exclusion criteria, 23 studies were identified and reviewed by two independent reviewers. Data were extracted and aspects of quality were assessed using an adapted Newcastle-Ottawa scale. Twenty-one of the studies considered the relationship between the time at which complementary foods were introduced and childhood body mass index (BMI), of which five found that introducing complementary foods at <3 months (two studies), 4 months (2 studies) or 20 weeks (one study) was associated with a higher BMI in childhood. Seven of the studies considered the association between complementary feeding and body composition but only one study reported an increase in the percentage of body fat among children given complementary foods before 15 weeks of age. We conclude that there is no clear association between the timing of the introduction of complementary foods and childhood overweight or obesity, but some evidence suggests that very early introduction (at or before 4 months), rather than at 4-6 months or >6 months, may increase the risk of childhood overweight.
Enzalutamide is an oral androgen-receptor inhibitor that prolongs survival in men with metastatic castration-resistant prostate cancer in whom the disease has progressed after chemotherapy. New ...treatment options are needed for patients with metastatic prostate cancer who have not received chemotherapy, in whom the disease has progressed despite androgen-deprivation therapy.
In this double-blind, phase 3 study, we randomly assigned 1717 patients to receive either enzalutamide (at a dose of 160 mg) or placebo once daily. The coprimary end points were radiographic progression-free survival and overall survival.
The study was stopped after a planned interim analysis, conducted when 540 deaths had been reported, showed a benefit of the active treatment. The rate of radiographic progression-free survival at 12 months was 65% among patients treated with enzalutamide, as compared with 14% among patients receiving placebo (81% risk reduction; hazard ratio in the enzalutamide group, 0.19; 95% confidence interval CI, 0.15 to 0.23; P<0.001). A total of 626 patients (72%) in the enzalutamide group, as compared with 532 patients (63%) in the placebo group, were alive at the data-cutoff date (29% reduction in the risk of death; hazard ratio, 0.71; 95% CI, 0.60 to 0.84; P<0.001). The benefit of enzalutamide was shown with respect to all secondary end points, including the time until the initiation of cytotoxic chemotherapy (hazard ratio, 0.35), the time until the first skeletal-related event (hazard ratio, 0.72), a complete or partial soft-tissue response (59% vs. 5%), the time until prostate-specific antigen (PSA) progression (hazard ratio, 0.17), and a rate of decline of at least 50% in PSA (78% vs. 3%) (P<0.001 for all comparisons). Fatigue and hypertension were the most common clinically relevant adverse events associated with enzalutamide treatment.
Enzalutamide significantly decreased the risk of radiographic progression and death and delayed the initiation of chemotherapy in men with metastatic prostate cancer. (Funded by Medivation and Astellas Pharma; PREVAIL ClinicalTrials.gov number, NCT01212991.).
The determinants of childhood overweight and obesity are complex, but infant feeding and the early diet are important contributing factors. The complementary feeding period in particular, is a time ...during which children are nutritionally vulnerable, and a time where life-long eating habits may be established. We conducted a systematic review of the literature that investigated the relationship between the types of food consumed by infants during the complementary feeding period and overweight or obesity during childhood. Electronic databases were searched from inception until June 2012 using specified keywords. Following the application of strict inclusion/exclusion criteria, 10 studies were identified and reviewed by two independent reviewers. Data were extracted and aspects of quality were assessed using an adapted Newcastle-Ottawa scale. Studies were categorised into three groups: macronutrient intake, food type/group and adherence to dietary guidelines. Some association was found between high protein intakes at 2-12 months of age and higher body mass index (BMI) or body fatness in childhood, but was not the case in all studies. Higher energy intake during complementary feeding was associated with higher BMI in childhood. Adherence to dietary guidelines during weaning was associated with a higher lean mass, but consuming specific foods or food groups made no difference to children's BMI. We concluded that high intakes of energy and protein, particularly dairy protein, in infancy could be associated with an increase in BMI and body fatness, but further research is needed to establish the nature of the relationship. Adherence to dietary guidelines during weaning is recommended.
With improved contemporary therapy, we reassess long-term outcome in patients completing treatment for childhood acute lymphoblastic leukemia (ALL) to determine when cure can be declared with a high ...degree of confidence. In six successive clinical trials between 1984 and 2007, 1291 (84.5%) patients completed all therapies in continuous complete remission. The post-therapy cumulative risk of relapse or development of a second neoplasm and the event-free survival rate and overall survival were analyzed according to the presenting features and the three treatment periods defined by relative outcome. Over the three treatment periods, there has been progressive increase in the rate of event-free survival (65.2% vs 74.8% vs 85.1% (P<0.001)) and overall survival (76.5% vs 81.1% vs 91.7% (P<0.001)) at 10 years. The most important predictor of outcome after completion of therapy was the type of treatment. In the most recent treatment period, which omitted the use of prophylactic cranial irradiation, the post-treatment cumulative risk of relapse was 6.4%, death in remission 1.5% and development of a second neoplasm 2.3% at 10 years, with all relapses except one occurring within 4 years of therapy. None of the 106 patients with the t(9;22)/BCR-ABL1, t(1;19)/TCF3-PBX1 or t(4;11)/MLL-AFF1 had relapsed after 2 years from completion of therapy. These findings demonstrate that with contemporary effective therapy that excludes cranial irradiation, approximately 6% of children with ALL may relapse after completion of treatment, and those who remain in remission at 4 years post treatment may be considered cured (that is, less than 1% chance of relapse).
Hypersensitivity to asparaginase is common, but the differential diagnosis can be challenging and the diagnostic utility of antibody tests is unclear. We studied allergic reactions and serum ...antibodies to E. coli asparaginase (Elspar) in 410 children treated on St. Jude Total XV protocol for acute lymphoblastic leukemia. Of 169 patients (41.2%) with clinical allergy, 147 (87.0%) were positive for anti-Elspar antibody. Of 241 patients without allergy, 89 (36.9%) had detectable antibody. Allergies (P=0.0002) and antibodies (P=6.6 × 10(-6)) were higher among patients treated on the low-risk arm than among those treated on the standard/high-risk arm. Among those positive for antibody, the antibody titers were higher in those who developed allergy than in those who did not (P<1 × 10(-15)). Antibody measures at week 7 of continuation therapy had a sensitivity of 87-88% and a specificity of 68-69% for predicting or confirming clinical reactions. The level of antibodies was inversely associated with serum asparaginase activity (P=7.0 × 10(-6)). High antibody levels were associated with a lower risk of osteonecrosis (odds ratio=0.83; 95% confidence interval, 0.78-0.89; P=0.007). Antibodies were related to clinical allergy and to low systemic exposure to asparaginase, leading to lower risk of some adverse effects of therapy.
A new open source multi-GPU 2D flood model called TRITON is presented in this work. The model solves the 2D shallow water equations with source terms using a time-explicit first order upwind scheme ...based on an Augmented Roe's solver that incorporates a careful estimation of bed strengths and a local implicit formulation of friction terms. The scheme is demonstrated to be first order accurate, robust and able to solve for flows under various conditions. TRITON is implemented such that the model effectively utilizes heterogeneous architectures, from single to multiple CPUs and GPUs. Different test cases are shown to illustrate the capabilities and performance of the model, showing promising runtimes for large spatial and temporal scales when leveraging the computer power of GPUs. Under this hardware configuration, communication and input/output subroutines may impact the scalability. The code is developed under an open source license and can be freely downloaded in https://code.ornl.gov/hydro/triton.
•TRITON is released as a multi-GPU open source 2D hydrodynamic flood code.•It solves the 2D shallow water equations using a first order time-explicit scheme.•It runs efficiently for realistic configurations using heterogeneous architectures.•The runoff capability is demonstrated to be convenient for flood modeling.•Communication and I/O times may represent a bottleneck for operational purposes.
ETV6-RUNX1 fusion is the most common genetic aberration in childhood acute lymphoblastic leukemia (ALL). To evaluate whether outcomes for this drug-sensitive leukemia are improved by contemporary ...risk-directed therapy, we studied clinical features, response and adverse events of 168 children with newly diagnosed ETV6-RUNX1-positive ALL on St Jude Total Therapy studies XIIIA (N=36), XIIIB (N=38) and XV (N=94). Results were compared with 494 ETV6-RUNX1-negative B-precursor ALL patients. ETV6-RUNX1 was associated with age 1-9 years, pre-treatment classification as low risk and lower levels of minimal residual disease (MRD) on day 19 of therapy (P<0.001). Event-free survival (EFS) or overall survival (OS) did not differ between patients with or without ETV6-RUNX1 in Total XIIIA or XIIIB. By contrast, in Total XV, patients with ETV6-RUNX1 had significantly better EFS (P=0.04; 5-year estimate, 96.8±2.4% versus 88.3±2.5%) and OS (P=0.04; 98.9±1.4% versus 93.7±1.8%) than those without ETV6-RUNX1. Within the ETV6-RUNX1 group, the only significant prognostic factor associated with higher OS was the treatment protocol Total XV (versus XIIIA or XIIIB) (P=0.01). Thus, the MRD-guided treatment schema including intensive asparaginase and high-dose methotrexate in the Total XV study produced significantly better outcomes than previous regimens and demonstrated that nearly all children with ETV6-RUNX1 ALL can be cured.
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