Improving out-domain PLDA speaker verification using unsupervised inter-dataset variability compensation approach

Experimental studies have found that when the state-of-the-art probabilistic linear discriminant analysis (PLDA) speaker verification systems are trained using out-domain data, it significantly affects speaker verification performance due to the mismatch between development data and evaluation data. To overcome this problem we propose a novel unsupervised inter dataset variability (IDV) compensation approach to compensate the dataset mismatch. IDV-compensated PLDA system achieves over 10% relative improvement in EER values over out-domain PLDA system by effectively compensating the mismatch between in-domain and out-domain data.

Process quality indicators targeting cognitive impairment to support quality of care for older people with cognitive impairment in emergency departments

Objectives The objective of this study was to develop process quality indicators (PQIs) to support the improvement of care services for older people with cognitive impairment in emergency departments (ED). Methods A structured research approach was taken for the development of PQIs for the care of older people with cognitive impairment in EDs, including combining available evidence with expert opinion (phase 1), a field study (phase 2), and formal voting (phase 3). A systematic review of the literature identified ED processes targeting the specific care needs of older people with cognitive impairment. Existing relevant PQIs were also included. By integrating the scientific evidence and clinical expertise, new PQIs were drafted and, along with the existing PQIs, extensively discussed by an advisory panel. These indicators were field tested in eight hospitals using a cohort of older persons aged 70 years and older. After analysis of the field study data (indicator prevalence, variability across sites), in a second meeting, the advisory panel further defined the PQIs. The advisory panel formally voted for selection of those PQIs that were most appropriate for care evaluation. Results In addition to seven previously published PQIs relevant to the care of older persons, 15 new indicators were created. These 22 PQIs were then field tested. PQIs designed specifically for the older ED population with cognitive impairment were only scored for patients with identified cognitive impairment. Following formal voting, a total of 11 PQIs were included in the set. These PQIs targeted cognitive screening, delirium screening, delirium risk assessment, evaluation of acute change in mental status, delirium etiology, proxy notification, collateral history, involvement of a nominated support person, pain assessment, postdischarge follow-up, and ED length of stay. Conclusions This article presents a set of PQIs for the evaluation of the care for older people with cognitive impairment in EDs. The variation in indicator triggering across different ED sites suggests that there are opportunities for quality improvement in care for this vulnerable group. Applied PQIs will identify an emergency services' implementation of care strategies for cognitively impaired older ED patients. Awareness of the PQI triggers at an ED level enables implementation of targeted interventions to improve any suboptimal processes of care. Further validation and utility of the indicators in a wider population is now indicated.

Mapping the regional influence of genetics on brain structure variability - A Tensor-Based Morphometry study

Genetic and environmental factors influence brain structure and function profoundly. The search for heritable anatomical features and their influencing genes would be accelerated with detailed 3D maps showing the degree to which brain morphometry is genetically determined. As part of an MRI study that will scan 1150 twins, we applied Tensor-Based Morphometry to compute morphometric differences in 23 pairs of identical twins and 23 pairs of same-sex fraternal twins (mean age: 23.8 ± 1.8 SD years). All 92 twins' 3D brain MRI scans were nonlinearly registered to a common space using a Riemannian fluid-based warping approach to compute volumetric differences across subjects. A multi-template method was used to improve volume quantification. Vector fields driving each subject's anatomy onto the common template were analyzed to create maps of local volumetric excesses and deficits relative to the standard template. Using a new structural equation modeling method, we computed the voxelwise proportion of variance in volumes attributable to additive (A) or dominant (D) genetic factors versus shared environmental (C) or unique environmental factors (E). The method was also applied to various anatomical regions of interest (ROIs). As hypothesized, the overall volumes of the brain, basal ganglia, thalamus, and each lobe were under strong genetic control; local white matter volumes were mostly controlled by common environment. After adjusting for individual differences in overall brain scale, genetic influences were still relatively high in the corpus callosum and in early-maturing brain regions such as the occipital lobes, while environmental influences were greater in frontal brain regions that have a more protracted maturational time-course.

Multi-site study of additive genetic effects on fractional anisotropy of cerebral white matter: Comparing meta and megaanalytical approaches for data pooling

Combining datasets across independent studies can boost statistical power by increasing the numbers of observations and can achieve more accurate estimates of effect sizes. This is especially important for genetic studies where a large number of observations are required to obtain sufficient power to detect and replicate genetic effects. There is a need to develop and evaluate methods for joint-analytical analyses of rich datasets collected in imaging genetics studies. The ENIGMA-DTI consortium is developing and evaluating approaches for obtaining pooled estimates of heritability through meta-and mega-genetic analytical approaches, to estimate the general additive genetic contributions to the intersubject variance in fractional anisotropy (FA) measured from diffusion tensor imaging (DTI). We used the ENIGMA-DTI data harmonization protocol for uniform processing of DTI data from multiple sites. We evaluated this protocol in five family-based cohorts providing data from a total of 2248 children and adults (ages: 9-85) collected with various imaging protocols. We used the imaging genetics analysis tool, SOLAR-Eclipse, to combine twin and family data from Dutch, Australian and Mexican-American cohorts into one large "mega-family". We showed that heritability estimates may vary from one cohort to another. We used two meta-analytical (the sample-size and standard-error weighted) approaches and a mega-genetic analysis to calculate heritability estimates across-population. We performed leave-one-out analysis of the joint estimates of heritability, removing a different cohort each time to understand the estimate variability. Overall, meta- and mega-genetic analyses of heritability produced robust estimates of heritability.

The ADMIN-ICU survey: A survey on antimicrobial dosing and monitoring in ICUs

Objectives: There is little evidence and few guidelines to inform the most appropriate dosing and monitoring for antimicrobials in the ICU. We aimed to survey current practices around the world. Methods: An online structured questionnaire was developed and sent by e-mail to obtain information on local antimicrobial prescribing practices for glycopeptides, piperacillin/tazobactam, carbapenems, aminoglycosides and colistin. Results: A total of 402 professionals from 328 hospitals in 53 countries responded, of whom 78% were specialists in intensive care medicine (41% intensive care, 30% anaesthesiology, 14% internal medicine) and 12% were pharmacists. Vancomycin was used as a continuous infusion in 31% of units at a median (IQR) daily dose of 25 (25–30) mg/kg. Piperacillin/tazobactam was used as an extended infusion by 22% and as a continuous infusion by 7%. An extended infusion of carbapenem (meropenem or imipenem) was used by 27% and a continuous infusion by 5%. Colistin was used at a daily dose of 7.5 (3.9–9) million IU (MIU)/day, predominantly as a short infusion. The most commonly used aminoglycosides were gentamicin (55%) followed by amikacin (40%), with administration as a single daily dose reported in 94% of the cases. Gentamicin was used at a daily dose of 5 (5–6) mg/day and amikacin at a daily dose of 15 (15–20) mg/day. Therapeutic drug monitoring of vancomycin, piperacillin/tazobactam and meropenem was used by 74%, 1% and 2% of the respondents, respectively. Peak aminoglycoside concentrations were sampled daily by 28% and trough concentrations in all patients by 61% of the respondents. Conclusions: We found wide variability in reported practices for antibiotic dosing and monitoring. Research is required to develop evidence-based guidelines to standardize practices.

To increase or decrease dosage of antimicrobials in septic patients during continuous renal replacement therapy: the eternal doubt

Critical illness, acute renal failure and continuous renal replacement therapy (CRRT) are associated with changes in pharmacokinetics. Initial antibiotic dose should be based on published volume of distribution and generally be at least the standard dose, as volume of distribution is usually unchanged or increased. Subsequent doses should be based on total clearance. Total clearance varies with the CRRT clearance which mainly depends on effluent flow rate, sieving coefficient/saturation coefficient. As antibiotic clearance by healthy kidneys is usually higher than clearance by CRRT, except for colistin, subsequent doses should generally be lower than given to patients without renal dysfunction. In the future therapeutic drug monitoring, together with sophisticated pharmacokinetic models taking into account the pharmacokinetic variability, may enable more appropriate individualized dosing.

Developments of the total entropy utility function for the dual purpose of model discrimination and parameter estimation in Bayesian design

The total entropy utility function is considered for the dual purpose of Bayesian design for model discrimination and parameter estimation. A sequential design setting is proposed where it is shown how to efficiently estimate the total entropy utility for a wide variety of data types. Utility estimation relies on forming particle approximations to a number of intractable integrals which is afforded by the use of the sequential Monte Carlo algorithm for Bayesian inference. A number of motivating examples are considered for demonstrating the performance of total entropy in comparison to utilities for model discrimination and parameter estimation. The results suggest that the total entropy utility selects designs which are efficient under both experimental goals with little compromise in achieving either goal. As such, the total entropy utility is advocated as a general utility for Bayesian design in the presence of model uncertainty.

Genetic structure of the Korean black scraper Thamnaconus modestus inferred from microsatellite marker analysis

The Korean black scraper, Thamnaconus modestus, is one of the most economically important maricultural fish species in Korea. However, the annual catch of this fish has been continuously declining over the past several decades. In this study, the genetic diversity and relationships among four wild populations and two hatchery stocks of Korean black scraper were assessed based on 16 microsatellite (MS) markers. A total of 319 different alleles were detected over all loci with an average of 19.94 alleles per locus. The hatchery stocks [mean number of alleles (N A) = 12, allelic richness (A R) = 12, expected heterozygosity (He) = 0.834] showed a slight reduction (P > 0.05) in genetic variability in comparison with wild populations (mean N A = 13.86, A R = 12.35, He = 0.844), suggesting a sufficient level of genetic variation in the hatchery populations. Similarly low levels of inbreeding and significant Hardy–Weinberg equilibrium deviations were detected in both wild and hatchery populations. The genetic subdivision among all six populations was low but significant (overall F ST = 0.008, P < 0.01). Pairwise F ST, a phylogenetic tree, and multidimensional scaling analysis suggested the existence of three geographically structured populations based on different sea basin origins, although the isolation-by-distance model was rejected. This result was corroborated by an analysis of molecular variance. This genetic differentiation may result from the co-effects of various factors, such as historical dispersal, local environment and ocean currents. These three geographical groups can be considered as independent management units. Our results show that MS markers may be suitable not only for the genetic monitoring of hatchery stocks but also for revealing the population structure of Korean black scraper populations. These results will provide critical information for breeding programs, the management of cultured stocks and the conservation of this species.

Immunochip analysis identifies multiple susceptibility loci for systemic sclerosis

In this study, 1,833 systemic sclerosis (SSc) cases and 3,466 controls were genotyped with the Immunochip array. Classical alleles, amino acid residues, and SNPs across the human leukocyte antigen (HLA) region were imputed and tested. These analyses resulted in a model composed of six polymorphic amino acid positions and seven SNPs that explained the observed significant associations in the region. In addition, a replication step comprising 4,017 SSc cases and 5,935 controls was carried out for several selected non-HLA variants, reaching a total of 5,850 cases and 9,401 controls of European ancestry. Following this strategy, we identified and validated three SSc risk loci, including DNASE1L3 at 3p14, the SCHIP1-IL12A locus at 3q25, and ATG5 at 6q21, as well as a suggested association of the TREH-DDX6 locus at 11q23. The associations of several previously reported SSc risk loci were validated and further refined, and the observed peak of association in PXK was related to DNASE1L3. Our study has increased the number of known genetic associations with SSc, provided further insight into the pleiotropic effects of shared autoimmune risk factors, and highlighted the power of dense mapping for detecting previously overlooked susceptibility loci.

Total transcriptome, proteome, and allergome of Johnson grass pollen, which is important for allergic rhinitis in subtropical regions

Background Genomic data are lacking for many allergen sources. To circumvent this limitation, we implemented a strategy to reveal the repertoire of pollen allergens of a grass with clinical importance in subtropical regions, where an increasing proportion of the world's population resides. Objective We sought to identify and immunologically characterize the allergenic components of the Panicoideae Johnson grass pollen (JGP; Sorghum halepense). Methods The total pollen transcriptome, proteome, and allergome of JGP were documented. Serum IgE reactivities with pollen and purified allergens were assessed in 64 patients with grass pollen allergy from a subtropical region. Results Purified Sor h 1 and Sor h 13 were identified as clinically important allergen components of JGP with serum IgE reactivity in 49 (76%) and 28 (43.8%), respectively, of patients with grass pollen allergy. Within whole JGP, multiple cDNA transcripts and peptide spectra belonging to grass pollen allergen families 1, 2, 4, 7, 11, 12, 13, and 25 were identified. Pollen allergens restricted to subtropical grasses (groups 22-24) were also present within the JGP transcriptome and proteome. Mass spectrometry confirmed the IgE-reactive components of JGP included isoforms of Sor h 1, Sor h 2, Sor h 13, and Sor h 23. Conclusion Our integrated molecular approach revealed qualitative differences between the allergenic components of JGP and temperate grass pollens. Knowledge of these newly identified allergens has the potential to improve specific diagnosis and allergen immunotherapy treatment for patients with grass pollen allergy in subtropical regions and reduce the burden of allergic respiratory disease globally.

PTHR1 polymorphisms influence BMD variation through effects on the growing skeleton

We investigated whether polymorphisms in PTHR1 are associated with bone mineral density (BMD), to determine whether the association of this gene with BMD was due to effects on attainment of peak bone mass or effects on subsequent bone loss. The PTHR1 gene, including its 14 exons, their exon-intron boundaries, and 1,500 bp of its promoter region, was screened for polymorphisms by denaturing high-performance liquid chromatography (dHPLC) and sequencing in 36 osteoporotic cases. Eleven single-nucleotide polymorphisms (SNPs), one tetranucleotide repeat, and one tetranucleotide deletion were identified. A cohort of 634 families, including 1,236 men (39%) and 1,926 women (61%) ascertained with probands with low BMD (Z< -2.0) and the Children in Focus subset of the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort (785 unrelated individuals, mean age 118 months), were genotyped for the five most informative SNPs (minor allele frequency >5%) and the tetranucleotide repeat. In our osteoporosis families, association was noted between lumbar spine BMD and alleles of a known functional tetranucleotide repeat (U4) in the PTHR1 promoter region (P = 0.042) and between two and three marker haplotypes of PTHR1 polymorphisms with lumbar spine, femoral neck, and total hip BMD (P = 0.021-0.047). This association was restricted to the youngest tertile of the population (age 16-39 years, P = 0.013-0.048). A similar association was found for the ALSPAC cohort: two marker haplotypes of SNPs A48609T and C52813T were associated with height (P = 0.006) and total body less head BMD (P = 0.02), corrected for age and gender, confirming the family findings. These findings suggest a role for PTHR1 variation in determining peak BMD.

Association of IL23R and ERAP1 genes with ankylosing spondylitis in a Portuguese population

Objective: Association between ankylosing spondylitis (AS) and two genes, ERAP1 and IL23R, has recently been reported in North American and British populations. The population attributable risk fraction for ERAP1 in this study was 25%, and for IL23R, 9%. Confirmation of these findings to ERAP1 in other ethnic groups has not yet been demonstrated. We sought to test the association between single nucleotide polymorphisms (SNPs) in these genes and susceptibility to AS among a Portuguese population. We also investigated the role of these genes in clinical manifestations of AS, including age of symptom onset, the Bath Ankylosing Spondylitis Disease Activity, Metrology and Functional Indices, and the modified Stoke Ankylosing Spondylitis Spinal Score. Methods: The study was conducted on 358 AS cases and 285 ethnically matched Portuguese healthy controls. AS was defined according to the modified New York Criteria. Genotyping of IL23R and ERAP1 allelic variants was carried out with TaqMan allelic discrimination assays. Association analysis was performed using the Cochrane-Armitage and linear regression tests of genotypes as implemented in PLINK for dichotomous and quantitative variables respectively. A meta-analysis for Portuguese and previously published Spanish IL23R data was performed using the StatsDirect® Statistical tools, by fixed and random effects models. Results: A total of 14 nsSNPs markers (8 for IL23R, 5 for ERAPl, 1 for LN-PEP) were analysed. Three markers (2 for IL23R and 1 for ERAP1) showed significant single-locus disease associations, confirming that the association of these genes with AS in the Portuguese population. The strongest associated SNP in IL23R was rs1004819 (OR=1.4, p=0.0049), and in ERAP1 was rs30187 (OR=1.26, p=0.035). The population attributable risk fractions in the Portuguese population for these SNPs are 11% and 9.7% respectively. No association was seen with any SNP in LN-PEP, which flanks ERAP1 and was associated with AS in the British population. No association was seen with clinical manifestations of AS. Conclusions: These results show that IL23R and ERAP1 genes are also associated with susceptibility to AS in the Portuguese population, and that they contribute a significant proportion of the population risk for this disease.

Quantification of stability in an agility drill using linear and nonlinear measures of variability

This study implemented linear and nonlinear methods of measuring variability to determine differences in stability of two groups of skilled (n = 10) and unskilled (n = 10) participants performing 3m forward/backward shuttle agility drill. We also determined whether stability measures differed between the forward and backward segments of the drill. Finally, we sought to investigate whether local dynamic stability, measured using largest finite-time Lyapunov exponents, changed from distal to proximal lower extremity segments. Three-dimensional coordinates of five lower extremity markers data were recorded. Results revealed that the Lyapunov exponents were lower (P < 0.05) for skilled participants at all joint markers indicative of higher levels of local dynamic stability. Additionally, stability of motion did not differ between forward and backward segments of the drill (P > 0.05), signifying that almost the same control strategy was used in forward and backward directions by all participants, regardless of skill level. Furthermore, local dynamic stability increased from distal to proximal joints (P < 0.05) indicating that stability of proximal segments are prioritized by the neuromuscular control system. Finally, skilled participants displayed greater foot placement standard deviation values (P < 0.05), indicative of adaptation to task constraints. The results of this study provide new methods for sport scientists, coaches to characterize stability in agility drill performance.

Increasing functional variability in the preparatory phase of the takeoff improves elite springboard diving performance

PURPOSE: Previous research demonstrating that specific performance outcome goals can be achieved in different ways is functionally significant for springboard divers whose performance environment can vary extensively. This body of work raises questions about the traditional approach of balking (terminating the takeoff) by elite divers aiming to perform only identical, invariant movement patterns during practice. METHOD: A 12-week training program (2 times per day; 6.5 hr per day) was implemented with 4 elite female springboard divers to encourage them to adapt movement patterns under variable takeoff conditions and complete intended dives, rather than balk. RESULTS: Intraindividual analyses revealed small increases in variability in the board-work component of each diver's pretraining and posttraining program reverse-dive takeoffs. No topological differences were observed between movement patterns of dives completed pretraining and posttraining. Differences were noted in the amount of movement variability under different training conditions (evidenced by higher normalized root mean square error indexes posttraining). An increase in the number of completed dives (from 78.91%-86.84% to 95.59%-99.29%) and a decrease in the frequency of balked takeoffs (from 13.16%-19.41% to 0.63%-4.41%) showed that the elite athletes were able to adapt their behaviors during the training program. These findings coincided with greater consistency in the divers' performance during practice as scored by qualified judges. CONCLUSION: Results suggested that on completion of training, athletes were capable of successfully adapting their movement patterns under more varied takeoff conditions to achieve greater consistency and stability of performance outcomes.

Population of computational rabbit-specific ventricular action potential models for investigating sources of variability in cellular repolarisation

Variability is observed at all levels of cardiac electrophysiology. Yet, the underlying causes and importance of this variability are generally unknown, and difficult to investigate with current experimental techniques. The aim of the present study was to generate populations of computational ventricular action potential models that reproduce experimentally observed intercellular variability of repolarisation (represented by action potential duration) and to identify its potential causes. A systematic exploration of the effects of simultaneously varying the magnitude of six transmembrane current conductances (transient outward, rapid and slow delayed rectifier K(+), inward rectifying K(+), L-type Ca(2+), and Na(+)/K(+) pump currents) in two rabbit-specific ventricular action potential models (Shannon et al. and Mahajan et al.) at multiple cycle lengths (400, 600, 1,000 ms) was performed. This was accomplished with distributed computing software specialised for multi-dimensional parameter sweeps and grid execution. An initial population of 15,625 parameter sets was generated for both models at each cycle length. Action potential durations of these populations were compared to experimentally derived ranges for rabbit ventricular myocytes. 1,352 parameter sets for the Shannon model and 779 parameter sets for the Mahajan model yielded action potential duration within the experimental range, demonstrating that a wide array of ionic conductance values can be used to simulate a physiological rabbit ventricular action potential. Furthermore, by using clutter-based dimension reordering, a technique that allows visualisation of multi-dimensional spaces in two dimensions, the interaction of current conductances and their relative importance to the ventricular action potential at different cycle lengths were revealed. Overall, this work represents an important step towards a better understanding of the role that variability in current conductances may play in experimentally observed intercellular variability of rabbit ventricular action potential repolarisation.