Health-related quality of life of Canadian children and youth prenatally exposed to alcohol

BACKGROUND: In Canada, the incidence of Fetal Alcohol Spectrum Disorder (FASD) has been estimated to be 1 in 100 live births. Caused by prenatal exposure to alcohol, FASD is the leading cause of neuro-developmental disabilities among Canadian children, and youth. Objective: To measure the health-related quality of life (HRQL) of Canadian children and youth diagnosed with FASD. METHODS: A prospective cross-sectional study design was used. One-hundred and twenty-six (126) children and youth diagnosed with FASD, aged 8 to 21 years, living in urban and rural communities throughout Canada participated in the study. Participants completed the Health Utilities Index Mark 3 (HUI3). HUI3 measures eight health attributes: vision, hearing, speech, ambulation, dexterity, emotion, cognition, and pain. Utilities were used to measure a single cardinal value between 0 and 1.0 (0 = all-worst health state; 1 = perfect health) to reflect the global HRQL for that child. Mean HRQL scores and range of scores of children and youth with FASD were calculated. A one-sample t-test was used to compare mean HRQL scores of children and youth with FASD to those from the Canadian population. RESULTS: Mean HRQL score of children and youth with FASD was 0.47 (95% CI: 0.42 to 0.52) as compared to a mean score of 0.93 (95% CI: 0.92 to 0.94) in those from the general Canadian population (p < 0.001). Children demonstrated moderate to severe dysfunction on the single-attributes of cognition and emotion. CONCLUSION: Children and youth with FASD have significantly lower HRQL than children and youth from the general Canadian population. This finding has significant implications for practice, policy development, and research

From Next-Generation Sequencing Alignments to Accurate Comparison and Validation of Single-Nucleotide Variants: The Pibase Software

Scientists working with single-nucleotide variants (SNVs), inferred by next-generation sequencing software, often need further information regarding true variants, artifacts and sequence coverage gaps. In clinical diagnostics, e.g. SNVs must usually be validated by visual inspection or several independent SNV-callers. We here demonstrate that 0.5–60% of relevant SNVs might not be detected due to coverage gaps, or might be misidentified. Even low error rates can overwhelm the true biological signal, especially in clinical diagnostics, in research comparing healthy with affected cells, in archaeogenetic dating or in forensics. For these reasons, we have developed a package called pibase, which is applicable to diploid and haploid genome, exome or targeted enrichment data. pibase extracts details on nucleotides from alignment files at user-specified coordinates and identifies reproducible genotypes, if present. In test cases pibase identifies genotypes at 99.98% specificity, 10-fold better than other tools. pibase also provides pair-wise comparisons between healthy and affected cells using nucleotide signals (10-fold more accurately than a genotype-based approach, as we show in our case study of monozygotic twins). This comparison tool also solves the problem of detecting allelic imbalance within heterozygous SNVs in copy number variation loci, or in heterogeneous tumor sequences

Survival probability of mutually killing Brownian motions and the O'Connell process

Recently O'Connell introduced an interacting diffusive particle system in order to study a directed polymer model in 1+1 dimensions. The infinitesimal generator of the process is a harmonic transform of the quantum Toda-lattice Hamiltonian by the Whittaker function. As a physical interpretation of this construction, we show that the O'Connell process without drift is realized as a system of mutually killing Brownian motions conditioned that all particles survive forever. When the characteristic length of interaction killing other particles goes to zero, the process is reduced to the noncolliding Brownian motion (the Dyson model).Comment: v2: AMS-LaTeX, 20 pages, 2 figures, minor corrections made for publication in J. Stat. Phy

Nucleocytoplasmic transport: a thermodynamic mechanism

The nuclear pore supports molecular communication between cytoplasm and nucleus in eukaryotic cells. Selective transport of proteins is mediated by soluble receptors, whose regulation by the small GTPase Ran leads to cargo accumulation in, or depletion from the nucleus, i.e., nuclear import or nuclear export. We consider the operation of this transport system by a combined analytical and experimental approach. Provocative predictions of a simple model were tested using cell-free nuclei reconstituted in Xenopus egg extract, a system well suited to quantitative studies. We found that accumulation capacity is limited, so that introduction of one import cargo leads to egress of another. Clearly, the pore per se does not determine transport directionality. Moreover, different cargo reach a similar ratio of nuclear to cytoplasmic concentration in steady-state. The model shows that this ratio should in fact be independent of the receptor-cargo affinity, though kinetics may be strongly influenced. Numerical conservation of the system components highlights a conflict between the observations and the popular concept of transport cycles. We suggest that chemical partitioning provides a framework to understand the capacity to generate concentration gradients by equilibration of the receptor-cargo intermediary.Comment: in press at HFSP Journal, vol 3 16 text pages, 1 table, 4 figures, plus Supplementary Material include

Metabolic activity in dormant conidia ofAspergillus nigerand developmental changes during conidial outgrowth

The early stages of development of Aspergillus niger conidia during outgrowth were explored by combining genome-wide gene expression analysis (RNAseq), proteomics, Warburg manometry and uptake studies. Resting conidia suspended in water were demonstrated for the first time to be metabolically active as low levels of oxygen uptake and the generation of carbon dioxide were detected, suggesting that low-level respiratory metabolism occurs in conidia for maintenance. Upon triggering of spore germination, generation of CO2 increased dramatically. For a short period, which coincided with mobilisation of the intracellular polyol, trehalose, there was no increase in uptake of O2 indicating that trehalose was metabolised by fermentation. Data from genome-wide mRNA profiling showed the presence of transcripts associated with fermentative and respiratory metabolism in resting conidia. Following triggering of conidial outgrowth, there was a clear switch to respiration after 25 min, confirmed by cyanide inhibition. No effect of SHAM, salicylhydroxamic acid, on respiration suggests electron flow via cytochrome c oxidase. Glucose entry into spores was not detectable before 1 h after triggering germination. The impact of sorbic acid on germination was examined and we showed that it inhibits glucose uptake. O2 uptake was also inhibited, delaying the onset of respiration and extending the period of fermentation. In conclusion, we show that conidia suspended in water are not completely dormant and that conidial outgrowth involves fermentative metabolism that precedes respiration

Genomics and drug profiling of fatal TCF3-HLF-positive acute lymphoblastic leukemia identifies recurrent mutation patterns and therapeutic options.

TCF3-HLF-positive acute lymphoblastic leukemia (ALL) is currently incurable. Using an integrated approach, we uncovered distinct mutation, gene expression and drug response profiles in TCF3-HLF-positive and treatment-responsive TCF3-PBX1-positive ALL. We identified recurrent intragenic deletions of PAX5 or VPREB1 in constellation with the fusion of TCF3 and HLF. Moreover somatic mutations in the non-translocated allele of TCF3 and a reduction of PAX5 gene dosage in TCF3-HLF ALL suggest cooperation within a restricted genetic context. The enrichment for stem cell and myeloid features in the TCF3-HLF signature may reflect reprogramming by TCF3-HLF of a lymphoid-committed cell of origin toward a hybrid, drug-resistant hematopoietic state. Drug response profiling of matched patient-derived xenografts revealed a distinct profile for TCF3-HLF ALL with resistance to conventional chemotherapeutics but sensitivity to glucocorticoids, anthracyclines and agents in clinical development. Striking on-target sensitivity was achieved with the BCL2-specific inhibitor venetoclax (ABT-199). This integrated approach thus provides alternative treatment options for this deadly disease

Alcohol Use during Pregnancy: Considerations for Australian Policy

Although there is an extensive recorded history of concerns related to alcohol exposed pregnancies and possible outcomes of fetal alcohol spectrum disorder in recent scientific literature, Australia has only recently begun to accurately or systematically diagnose and record these conditions, or to provide comprehensive, coordinated, policy-guided funding, prevention, and treatment. This article discusses some considerations that can guide policy development within the Australian context including the social context and determinates of alcohol consumption during pregnancy and the need to consider the issue as one that goes beyond the decision making of individual women. The article also identifies the contribution of research to guide evidence-based policy development, including emerging evidence of epigenetics, and systematic reviews for prevention. Other policy considerations include costs, and the possibility of the prevention paradox applying to this field, with its associated impact on costs and focus of prevention

Are psychosocial interventions effective in reducing alcohol consumption during pregnancy and motherhood?:A systematic review and meta‐analysis

Background and Aims Alcohol use by pregnant and parenting women can have serious and long-lasting consequences for both the mother and offspring. We reviewed the evidence for psychosocial interventions to reduce maternal drinking. Design Literature searches of PsycINFO, PubMed and Scopus identified randomised controlled trials of interventions with an aim of reduced drinking or abstinence in mothers or pregnant women. Setting Interventions were delivered in healthcare settings and homes. Participants Pregnant women and mothers with dependent children. Interventions Psychosocial interventions were compared with usual care or no intervention. Measurements The revised Cochrane risk-of-bias tool for randomised trials was used for quality assessments. Narrative synthesis summarised the findings of the studies with a subset of trials eligible for random-effects meta-analysis. General and alcohol-specific behaviour change techniques (BCTs) were identified to investigate potential mechanism of change. Results Twenty-four studies were included (20 pregnancy, four motherhood). Because of quality of reporting, data from only six pregnancy and four motherhood studies could be pooled. A significant treatment effect was revealed by the meta-analyses of pregnancy studies regarding abstinence (OR = 2.31, 95% CI = 1.61, 3.32; P < 0.001) and motherhood studies regarding a reduction in drinking (standardised mean difference [SMD] = −0.20, 95% CI = −0.38, −0.02; P = 0.03). Narrative synthesis of the remaining trials yielded inconsistent results regarding intervention effectiveness. A wide range of BCTs were used, present in both effective and ineffective interventions. The most commonly used general and alcohol-specific BCTs included information about consequences, social support, goal setting and action planning. Conclusions In pregnant women identified as consuming alcohol, psychosocial interventions appear to increase abstinence rates compared with usual care or no intervention. Similarly, such interventions appear to lead to a reduction in alcohol consumption in mothers with dependent children. It is unclear that behaviour change techniques are contributing to these effects. Conclusions from randomised controlled trials are only meaningful if the behavioural outcome, population, setting, intervention and comparator are clearly reported. An important barrier when it comes to identifying effective behaviour change techniques is a widespread failure to provide enough information in study reports