Delayed or impaired language development is a common developmental concern, yet there is little agreement about the criteria used to identify and classify language impairments in children. Children's ...language difficulties are at the interface between education, medicine and the allied professions, who may all adopt different approaches to conceptualising them. Our goal in this study was to use an online Delphi technique to see whether it was possible to achieve consensus among professionals on appropriate criteria for identifying children who might benefit from specialist services. We recruited a panel of 59 experts representing ten disciplines (including education, psychology, speech-language therapy/pathology, paediatrics and child psychiatry) from English-speaking countries (Australia, Canada, Ireland, New Zealand, United Kingdom and USA). The starting point for round 1 was a set of 46 statements based on articles and commentaries in a special issue of a journal focusing on this topic. Panel members rated each statement for both relevance and validity on a seven-point scale, and added free text comments. These responses were synthesised by the first two authors, who then removed, combined or modified items with a view to improving consensus. The resulting set of statements was returned to the panel for a second evaluation (round 2). Consensus (percentage reporting 'agree' or 'strongly agree') was at least 80 percent for 24 of 27 round 2 statements, though many respondents qualified their response with written comments. These were again synthesised by the first two authors. The resulting consensus statement is reported here, with additional summary of relevant evidence, and a concluding commentary on residual disagreements and gaps in the evidence base.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background:
Substantial progress has been made toward unraveling the genetic architecture of multiple sclerosis (MS) within populations of European ancestry, but few genetic studies have focused on ...Hispanic and African American populations within the United States.
Objective:
We sought to test the relevance of common European MS risk variants outside of the major histocompatibility complex (n = 200) within these populations.
Methods:
Genotype data were available on 2652 Hispanics (1298 with MS, 1354 controls) and 2435 African Americans (1298 with MS, 1137 controls). We conducted single variant, pathway, and cumulative genetic risk score analyses.
Results:
We found less replication than statistical power suggested, particularly among African Americans. This could be due to limited correlation between the tested and causal variants within the sample or alternatively could indicate allelic and locus heterogeneity. Differences were observed between pathways enriched among the replicating versus all 200 variants. Although these differences should be examined in larger samples, a potential role exists for gene–environment or gene–gene interactions which alter phenotype differentially across racial and ethnic groups. Cumulative genetic risk scores were associated with MS within each study sample but showed limited diagnostic capability.
Conclusion:
These findings provide a framework for fine-mapping efforts in multi-ethnic populations of MS.
Biomarkers for Smoking Cessation Bough, K J; Lerman, C; Rose, J E ...
Clinical pharmacology and therapeutics,
June 2013, Letnik:
93, Številka:
6
Journal Article
Recenzirano
Odprti dostop
One way to enhance therapeutic development is through the identification and development of evaluative tools such as biomarkers. This review focuses on putative diagnostic, pharmacodynamic, and ...predictive biomarkers for smoking cessation. These types of biomarkers may be used to more accurately diagnose a disease, personalize treatment, identify novel targets for drug discovery, and enhance the efficiency of drug development. Promising biomarkers are presented across a range of approaches including metabolism, genetics, and neuroimaging. A preclinical viewpoint is also offered, as are analytical considerations and a regulatory perspective summarizing a pathway toward biomarker qualification.
Clinical Pharmacology & Therapeutics (2013); 93 6, 526–538. doi:10.1038/clpt.2013.57
An efficient testing strategy called the “focused interaction testing framework” (FITF) was developed to identify susceptibility genes involved in epistatic interactions for case-control studies of ...candidate genes. In the FITF approach, likelihood-ratio tests are performed in stages that increase in the order of interaction considered. Joint tests of main effects and interactions are performed conditional on significant lower-order effects. A reduction in the number of tests performed is achieved by prescreening gene combinations with a goodness-of-fit χ
2 statistic that depends on association among candidate genes in the pooled case-control group. Multiple testing is accounted for by controlling false-discovery rates. Simulation analysis demonstrated that the FITF approach is more powerful than marginal tests of candidate genes. FITF also outperformed multifactor dimensionality reduction when interactions involved additive, dominant, or recessive genes. In an application to asthma case-control data from the Children’s Health Study, FITF identified a significant multilocus effect between the nicotinamide adenine dinucleotide (phosphate) reduced:quinone oxidoreductase gene (
NQO1), myeloperoxidase gene (
MPO), and catalase gene (
CAT) (unadjusted
P
=.00026), three genes that are involved in the oxidative stress pathway. In an independent data set consisting primarily of African American and Asian American children, these three genes also showed a significant association with asthma status (
P
=.0008).
Abstract
Polygenic risk scores (PRSs) of common genetic variants have shown promise in prostate cancer risk stratification, but their validity across populations has yet to be confirmed. We evaluated ...a multiethnic PRS model based on 269 germline genetic risk variants (261 were available for analysis) using an independent population of 13 628 US men. The PRS was strongly associated with prostate cancer but not with any other disease. Comparing men in the top PRS decile with those at average risk (40%-60%), the odds ratio of prostate cancer was 3.89 (95% confidence interval = 3.24 to 4.68) for men of European ancestry and 3.81 (95% confidence interval = 1.48 to 10.19) for men of African ancestry. By age 85 years, the cumulative incidence of prostate cancer for European American men was 7.1% in the bottom decile and 54.1% in the top decile. This suggests that the PRS can be used to identify a substantial proportion of men at high risk for prostate cancer.
Chromosome substitution strains (CSSs) have been proposed as a simple and powerful way to identify quantitative trait loci (QTLs) affecting developmental, physiological, and behavioral processes. ...Here, we report the construction of a complete CSS panel for a vertebrate species. The CSS panel consists of 22 mouse strains, each of which carries a single chromosome substituted from a donor strain (A/J) onto a common host background (C57BL/6J). A survey of 53 traits revealed evidence for 150 QTLs affecting serum levels of sterols and amino acids, diet-induced obesity, and anxiety. These results demonstrate that CSSs greatly facilitate the detection and identification of genes that control the wide diversity of naturally occurring phenotypic variation in the A/J and C57BL/6J inbred strains.
We investigated the association between urinary tract infections (UTIs) and transitional cell carcinoma of the bladder in a population-based case-control study in Los Angeles covering 1586 cases and ...age-, gender-, and race-matched neighbourhood controls. A history of bladder infection was associated with a reduced risk of bladder cancer among women (odds ratio (OR), 0.66; 95% confidence interval (CI), 0.46-0.96). No effect was found in men, perhaps due to power limitations. A greater reduction in bladder cancer risk was observed among women with multiple infections (OR, 0.37; 95% CI, 0.18-0.78). Exclusion of subjects with a history of diabetes, kidney or bladder stones did not change the inverse association. A history of kidney infections was not associated with bladder cancer risk, but there was a weak association between a history of other UTIs and slightly increased risk among men. Our results suggest that a history of bladder infection is associated with a reduced risk of bladder cancer among women. Cytotoxicity from antibiotics commonly used to treat bladder infections is proposed as one possible explanation.
Child blood pressure (BP) is predictive of future cardiovascular risk. Prenatal exposure to metals has been associated with higher BP in childhood, but most studies have evaluated elements ...individually and measured BP at a single time point. We investigated impacts of prenatal metal mixture exposures on longitudinal changes in BP during childhood and elevated BP at 11 years of age.
The current study included 176 mother-child pairs from the Rhea Study in Heraklion, Greece and focused on eight elements (antimony, arsenic, cadmium, cobalt, lead, magnesium, molybdenum, selenium) measured in maternal urine samples collected during pregnancy (median gestational age at collection: 12 weeks). BP was measured at approximately 4, 6, and 11 years of age. Covariate-adjusted Bayesian Varying Coefficient Kernel Machine Regression and Bayesian Kernel Machine Regression (BKMR) were used to evaluate metal mixture impacts on baseline and longitudinal changes in BP (from ages 4 to 11) and the development of elevated BP at age 11, respectively. BKMR results were compared using static versus percentile-based cutoffs to define elevated BP.
Molybdenum and lead were the mixture components most consistently associated with BP. J-shaped relationships were observed between molybdenum and both systolic and diastolic BP at age 4. Similar associations were identified for both molybdenum and lead in relation to elevated BP at age 11. For molybdenum concentrations above the inflection points (~ 40-80 μg/L), positive associations with BP at age 4 were stronger at high levels of lead. Lead was positively associated with BP measures at age 4, but only at high levels of molybdenum. Potential interactions between molybdenum and lead were also identified for BP at age 11, but were sensitive to the cutoffs used to define elevated BP.
Prenatal exposure to high levels of molybdenum and lead, particularly in combination, may contribute to higher BP at age 4. These early effects appear to persist throughout childhood, contributing to elevated BP in adolescence. Future studies are needed to identify the major sources of molybdenum and lead in this population.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Higher ambient temperature and air pollution may contribute to increased risk of behaviors harmful to oneself or to others; however, quantitative evidence is limited. We examined the relationship of ...deaths due to suicide and homicide with temperature and air pollution in California—a state prone to high levels of both exposures.
California death certificates from 2014 to 2019 were used to identify deaths due to suicide and homicide. Residential data for decedents were used to assign exposure to daily temperature (maximumTmax, minimumTmin) and daily average air pollution concentrations (particulate matter <10 μmPM10 and < 2.5 μmPM2.5, nitrogen dioxideNO2, ozoneO3). Tmin served as a surrogate for nighttime temperature. A time-stratified case-crossover study design using conditional logistic regression was used to assess the effects of daily exposure to temperature and air pollutants on suicide and homicide mortality, adjusting for relative humidity. Effect modification by sex and age was assessed.
We observed 24,387 deaths due to suicide and 10,767 deaths due to homicide. We found a monotonic temperature association for both outcomes. A 5 °C increase in Tmax at lag-2 and Tmin at lag-0 was associated with 3.1 % (95 % confidence interval CI: 1.1 %–5.2 %) and 3.8 % (95%CI: 0.9 %–6.8 %) increased odds of death due to suicide, respectively. The increased odds of homicide mortality per 5 °C increase in Tmax at lag-0 and Tmin at lag-1 were 4.9 % (95%CI: 1.6 %–8.1 %) and 6.2 % (95%CI: 1.6 %–11.0 %), respectively. No air pollutant associations were statistically significant. Temperature associations were robust after adjustment for PM2.5. Some temperature effects were larger among women for suicide and men for homicide mortality, and among those over age 65 years for both outcomes.
Risk of suicide and homicide mortality increases with increasing daily ambient temperatures. Findings have public health relevance given anticipated increases in temperatures due to global climate change.
Display omitted
•Increased ambient temperature was associated with increased odds of suicide deaths.•Increased ambient temperature was associated with increased odds of homicide deaths.•The temperature-mortality associations were larger among older individuals.•No associations with suicide or homicide deaths were observed for air pollutants.
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