As summarized in the World Health Organization's latest Global Status Report on Alcohol, the pleasure of alcohol is indicated by the fact that, worldwide, just over two-fifths of the population aged ...15+ years drink alcohol; 2 ....
A key goal of precision medicine is predicting the best drug therapy for a specific patient from genomic information. In oncology, cancers that appear similar pathologically can vary greatly in how ...they respond to the same drug. Fortunately, data from high-throughput screening programs often reveal important relationships between genomic variability of cancer cells and their response to drugs. Nevertheless, many current computational methods to predict compound activity against cancer cells require large quantities of genomic, epigenomic, and additional cellular data to develop and to apply. Here we integrate recent screening data and machine learning to train classification models that predict the activity/inactivity of compounds against cancer cells based on the mutational status of only 145 oncogenes and a set of compound structural descriptors. Using IC50 values of 1 μM as activity cutoffs, our predictive models have sensitivities of 87%, specificities of 87%, and yield an area under the receiver operating characteristic curve equal to 0.94. We also develop regression models to predict log(IC50) values of compounds for cancer cells; the models achieve a Pearson correlation coefficient of 0.86 for cross-validation and up to 0.65-0.73 against blind test sets. Predictive performance remains strong when as few as 50 oncogenes are included. Finally, even when 40% of experimental IC50 values are missing from screening data, they can be imputed with sufficient reliability that classification accuracy is not diminished. The presented models are fast to generate and may serve as easily implemented screening tools for personalized oncology medicine, drug repurposing, and drug discovery.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The World Health Organization has called on economic operators to "substitute, whenever possible, higher-alcohol products with no-alcohol and lower-alcohol products in their overall product ...portfolios, with the goal of decreasing the overall levels of alcohol consumption in populations and consumer groups, while avoiding the circumvention of existing regulations for alcoholic beverages and the targeting of new consumer groups with alcohol marketing, advertising and promotional activities" (see ....
Summary Considerable research has investigated the consequences of being born very preterm (VP; <32 weeks of gestation), especially in relation to cognitive functioning. While numerous cognitive and ...neuropsychological outcome studies have been published, it is important to consider methodological issues when reviewing this research, as the generalizability of the studies varies greatly. This article describes the nature of cognitive difficulties confronting VP children, both in terms of the frequency and severity of deficits. The breadth of cognitive difficulties reported in this population implies a generalized cognitive impairment; however, the presence of selective or primary cognitive deficits is discussed. It is concluded that whereas mortality and neonatal morbidity rates have decreased significantly in VP infants in recent decades, these children continue to be at significant risk for cognitive impairments and need to be closely monitored throughout childhood.
Objective: Early detection of children with developmental delay is crucial for determining which children require close surveillance and intervention services. For many decades, the Bayley Scales has ...been the most widely used objective measure of early developmental delay, both in clinical and research settings. Significant structural changes were incorporated in the most recent edition, the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III). This article reviews the psychometric properties of the Bayley-III and investigates criticisms raised on the Bayley-III, namely that it overestimates developmental status and is a poor predictor of later functioning. Method: This critical review examines the literature on the Bayley-III, which was released in 2006. Results: The Cognitive, Language, and Motor composites of the Bayley-III overestimate development, resulting in an under-identification of children with developmental delay. A range of strategies have been proposed for dealing with the inflated scores on the Bayley-III, none of which are ideal. Evidence to date suggests that the Bayley-III is a poor predictor of later cognitive and motor impairments. Conclusions: The Bayley-III needs new norms, or alternatively, it may be time for a new edition of the Bayley Scales.
Glutamine is a major dietary amino acid that is both a fuel and nitrogen donor for healing tissues damaged by chemotherapy and radiation. Evidence supports the benefit of oral (enteral) glutamine to ...reduce symptoms and improve and/or maintain quality of life of cancer patients. Benefits include not only better nutrition, but also decreased mucosal damage (mucositis, stomatitis, pharyngitis, esophagitis, and enteritis). Glutamine supplementation in a high protein diet (10 grams/day) + disaccharides, such as sucrose and/or trehalose, is a combination that increases glutamine uptake by mucosal cells. This increased topical effect can reduce painful mucosal symptoms and ulceration associated with chemotherapy and radiation in the head and neck region, esophagus, stomach and small intestine. Topical and oral glutamine seem to be the preferred routes for this amino acid to promote mucosal healing during and after cancer treatment.
Background
Infants born preterm are at increased risk of developing cognitive and motor impairment compared with infants born at term. Early developmental interventions have been provided in the ...clinical setting with the aim of improving overall functional outcomes for these infants. Long‐term benefits of these programmes remain unclear.
Objectives
Primary objective
To compare the effectiveness of early developmental intervention programmes provided post hospital discharge to prevent motor or cognitive impairment in preterm (< 37 weeks) infants versus standard medical follow‐up of preterm infants at infancy (zero to < three years), preschool age (three to < five years), school age (five to < 18 years) and adulthood (≥ 18 years).
Secondary objectives
To perform subgroup analyses to determine the following.
• Effects of gestational age, birth weight and brain injury (periventricular leukomalacia (PVL)/intraventricular haemorrhage (IVH)) on cognitive and motor outcomes when early intervention is compared with standard follow‐up.
∘ Gestational age: < 28 weeks, 28 to < 32 weeks, 32 to < 37 weeks.
∘ Birth weight: < 1000 grams, 1000 to < 1500 grams, 1500 to < 2500 grams.
∘ Brain injury: absence or presence of grade III or grade IV IVH or cystic PVL (or both) or an abnormal ultrasound/magnetic resonance image (MRI) before initiation of the intervention.
• Effects of interventions started during inpatient stay with a post‐discharge component versus standard follow‐up care.
• Effects of interventions focused on the parent‐infant relationship, infant development or both compared with standard follow‐up care.
To perform sensitivity analysis to identify the following.
• Effects on motor and cognitive impairment when early developmental interventions are provided within high‐quality randomised trials with low risk of bias for sequence generation, allocation concealment, blinding of outcome measures and selective reporting bias.
Search methods
The search strategy of the Cochrane Neonatal Review Group was used to identify randomised and quasi‐randomised controlled trials of early developmental interventions provided post hospital discharge. Two review authors independently searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE Advanced, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO and EMBASE (1966 to August 2015).
Selection criteria
Studies included had to be randomised or quasi‐randomised controlled trials of early developmental intervention programmes that began within the first 12 months of life for infants born before 37 weeks' gestational age. Interventions could commence on an inpatient basis but had to include a post‐discharge component for inclusion in this review. Outcome measures were not prespecified, other than that they had to assess cognitive outcomes, motor outcomes or both. Rates of cerebral palsy were documented.
Data collection and analysis
Two independent review authors extracted and entered data. Cognitive and motor outcomes were pooled by four age groups: infancy (zero to < three years), preschool age (three to < five years), school age (five to < 18 years) and adulthood (≥ 18 years). Meta‐analysis using RevMan 5.1 was carried out to determine the effects of early developmental interventions at each age range. Subgroup analyses focused on gestational age, birth weight, brain injury, commencement of the intervention, focus of the intervention and study quality.
Main results
Twenty‐five studies met the inclusion criteria (3615 randomly assigned participants). Only 12 of these studies were randomised controlled trials with appropriate allocation concealment. Variability was evident with regard to focus and intensity of the intervention, participant characteristics and length of follow‐up. Meta‐analysis led to the conclusion that intervention improved cognitive outcomes at infancy (developmental quotient (DQ): standardised mean difference (SMD) 0.32 standard deviations (SDs), 95% confidence interval (CI) 0.16 to 0.47; P value < 0.001; 16 studies; 2372 participants) and at preschool age (intelligence quotient (IQ); SMD 0.43 SDs, 95% CI 0.32 to 0.54; P value < 0.001; eight studies; 1436 participants). However, this effect was not sustained at school age (IQ: SMD 0.18 SDs, 95% CI ‐0.08 to 0.43; P value = 0.17; five studies; 1372 participants). Heterogeneity between studies for cognitive outcomes at infancy and at school age was significant. With regards to motor outcomes, meta‐analysis of 12 studies showed a significant effect in favour of early developmental interventions at infancy only; however, this effect was small (motor scale DQ: SMD 0.10 SDs, 95% CI 0.01 to 0.19; P value = 0.03; 12 studies; 1895 participants). No effect was noted on the rate of cerebral palsy among survivors (risk ratio (RR) 0.82, 95% CI 0.52 to 1.27; seven studies; 985 participants). Little evidence showed a positive effect on motor outcomes in the long term, but only five included studies reported outcomes at preschool age (n = 3) or at school age (n = 2).
Authors' conclusions
Early intervention programmes for preterm infants have a positive influence on cognitive and motor outcomes during infancy, with cognitive benefits persisting into preschool age. A great deal of heterogeneity between studies was due to the variety of early developmental intervention programmes tested and to gestational ages of included preterm infants; thus, comparisons of intervention programmes were limited. Further research is needed to determine which early developmental interventions are most effective in improving cognitive and motor outcomes, and to discern the longer‐term effects of these programmes.
Objectives To determine the associations of breast milk intake after birth with neurological outcomes at term equivalent and 7 years of age in very preterm infants Study design We studied 180 infants ...born at <30 weeks' gestation or <1250 grams birth weight enrolled in the Victorian Infant Brain Studies cohort from 2001-2003. We calculated the number of days on which infants received >50% of enteral intake as breast milk from 0-28 days of life. Outcomes included brain volumes measured by magnetic resonance imaging at term equivalent and 7 years of age, and cognitive (IQ, reading, mathematics, attention, working memory, language, visual perception) and motor testing at 7 years of age. We adjusted for age, sex, social risk, and neonatal illness in linear regression. Results A greater number of days on which infants received >50% breast milk was associated with greater deep nuclear gray matter volume at term equivalent age (0.15 cc/d; 95% CI, 0.05-0.25); and with better performance at age 7 years of age on IQ (0.5 points/d; 95% CI, 0.2-0.8), mathematics (0.5; 95% CI, 0.1-0.9), working memory (0.5; 95% CI, 0.1-0.9), and motor function (0.1; 95% CI, 0.0-0.2) tests. No differences in regional brain volumes at 7 years of age in relation to breast milk intake were observed. Conclusion Predominant breast milk feeding in the first 28 days of life was associated with a greater deep nuclear gray matter volume at term equivalent age and better IQ, academic achievement, working memory, and motor function at 7 years of age in very preterm infants.
RNA aptamers are oligonucleotides that bind with high specificity and affinity to target ligands. In the absence of bound ligand, secondary structures of RNA aptamers are generally stable, but ...single-stranded and loop regions, including ligand binding sites, lack defined structures and exist as ensembles of conformations. For example, the well-characterized theophylline-binding aptamer forms a highly stable binding site when bound to theophylline, but the binding site is unstable and disordered when theophylline is absent. Experimental methods have not revealed at atomic resolution the conformations that the theophylline aptamer explores in its unbound state. Consequently, in the present study we applied 21 microseconds of molecular dynamics simulations to structurally characterize the ensemble of conformations that the aptamer adopts in the absence of theophylline. Moreover, we apply Markov state modeling to predict the kinetics of transitions between unbound conformational states. Our simulation results agree with experimental observations that the theophylline binding site is found in many distinct binding-incompetent states and show that these states lack a binding pocket that can accommodate theophylline. The binding-incompetent states interconvert with binding-competent states through structural rearrangement of the binding site on the nanosecond to microsecond timescale. Moreover, we have simulated the complete theophylline binding pathway. Our binding simulations supplement prior experimental observations of slow theophylline binding kinetics by showing that the binding site must undergo a large conformational rearrangement after the aptamer and theophylline form an initial complex, most notably, a major rearrangement of the C27 base from a buried to solvent-exposed orientation. Theophylline appears to bind by a combination of conformational selection and induced fit mechanisms. Finally, our modeling indicates that when Mg2+ ions are present the population of binding-competent aptamer states increases more than twofold. This population change, rather than direct interactions between Mg2+ and theophylline, accounts for altered theophylline binding kinetics.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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