Adaptive and Maladaptive Correlates of Repetitive Behavior and Restricted Interests in Persons with Down Syndrome and Developmentally-Matched Typical Children: A Two-Year Longitudinal Sequential Design

We examined the course of repetitive behavior and restricted interests (RBRI) in children with and without Down syndrome (DS) over a two-year time period. Forty-two typically-developing children and 43 persons with DS represented two mental age (MA) levels: `` younger'' 2-4 years; `` older'' 5-11 years. For typically developing younger children some aspects of RBRI increased from Time 1 to Time 2. In older children, these aspects remained stable or decreased over the two-year period. For participants with DS, RBRI remained stable or increased over time. Time 1 RBRI predicted Time 2 adaptive behavior (measured by the Vineland Scales) in typically developing children, whereas for participants with DS, Time 1 RBRI predicted poor adaptive outcome (Child Behavior Checklist) at Time 2. The results add to the body of literature examining the adaptive and maladaptive nature of repetitive behavior.

Sequential Quantitative Trait Locus Mapping in Experimental Crosses

The etiology of complex diseases is heterogeneous. The presence of risk alleles in one or more genetic loci affects the function of a variety of intermediate biological pathways, resulting in the overt expression of disease. Hence, there is an increasing focus on identifying the genetic basis of disease by sytematically studying phenotypic traits pertaining to the underlying biological functions. In this paper we focus on identifying genetic loci linked to quantitative phenotypic traits in experimental crosses. Such genetic mapping methods often use a one stage design by genotyping all the markers of interest on the available subjects. A genome scan based on single locus or multi-locus models is used to identify the putative loci. Since the number of quantitative trait loci (QTLs) is very likely to be small relative to the number of markers genotyped, a one-stage selective genotyping approach is commonly used to reduce the genotyping burden, whereby markers are genotyped solely on individuals with extreme trait values. This approach is powerful in the presence of a single quantitative trait locus (QTL) but may result in substantial loss of information in the presence of multiple QTLs. Here we investigate the efficiency of sequential two stage designs to identify QTLs in experimental populations. Our investigations for backcross and F2 crosses suggest that genotyping all the markers on 60% of the subjects in Stage 1 and genotyping the chromosomes significant at 20% level using additional subjects in Stage 2 and testing using all the subjects provides an efficient approach to identify the QTLs and utilizes only 70% of the genotyping burden relative to a one stage design, regardless of the heritability and genotyping density. Complex traits are a consequence of multiple QTLs conferring main effects as well as epistatic interactions. We propose a two-stage analytic approach where a single-locus genome scan is conducted in Stage 1 to identify promising chromosomes, and interactions are examined using the loci on these chromosomes in Stage 2. We examine settings under which the two-stage analytic approach provides sufficient power to detect the putative QTLs.

Sequential immunosuppressive therapy in progressive IgA nephropathy

BACKGROUNDS: Cyclophosphamide and high-dose steroids have been used as limited induction therapy in progressive IgA nephropathy (IgAN) to reduce the loss of renal function and proteinuria. We evaluated the effect of cyclophosphamide pulses (CyP) and mycophenolic acid (MPA) as sequential therapy on renal function in patients with progressive IgAN. METHODS: Twenty patients with progressive IgAN and advanced renal failure (median GFR 22 ml/min per 1.73 m2) and further disease activity (triangle downGFR -0.8 ml/min per month) after cyclophosphamide (CyP; n = 18) or steroid pulse therapy (n = 2) were treated with mycophenolate mofetil 1 g per day for a median of 27 months. RESULTS: The monthly loss of renal function was significantly reduced in linear regression analysis from -2.4 ml/min before CyP to -0.12 ml/min with CyP/MPA (p = 0.0009). Estimated renal survival time was significantly prolonged by a median of 65 months (p = 0.0014). Proteinuria decreased significantly from 1.7 to 0.4 g/l during MPA treatment (p = 0.015). In Cox regression analysis, only proteinuria >1.0 g/l was an independent risk factor for doubling of creatinine during CyP/MPA treatment (p = 0.03). CONCLUSION: A sequential therapy with CyP/MPA may arrest or slow down the loss of renal function and reduces proteinuria even in patients who passed the so called 'point of no return' with progressive IgAN.

Ending Exploitation: Natural Resource Extraction and 1970s Legislature – Tom Towe & Harrison Fagg “In the Crucible of Change”

Abstract to be posted.

Endothelial cell activation leads to neutrophil transmigration as supported by the sequential roles of ICAM-2, JAM-A, and PECAM-1

Leukocyte transmigration is mediated by endothelial cell (EC) junctional molecules, but the associated mechanisms remain unclear. Here we investigate how intercellular adhesion molecule-2 (ICAM-2), junctional adhesion molecule-A (JAM-A), and platelet endothelial cell adhesion molecule (PECAM-1) mediate neutrophil transmigration in a stimulus-dependent manner (eg, as induced by interleukin-1beta [IL-1beta] but not tumor necrosis factor-alpha [TNF-alpha]), and demonstrate their ability to act in sequence. Using a cell-transfer technique, transmigration responses of wild-type and TNF-alpha p55/p75 receptor-deficient leukocytes (TNFR(-/-)) through mouse cremasteric venules were quantified by fluorescence intravital microscopy. Whereas wild-type leukocytes showed a normal transmigration response to TNF-alpha in ICAM-2(-/-), JAM-A(-/-), and PECAM-1(-/-) recipient mice, TNFR(-/-) leukocytes exhibited a reduced transmigration response. Hence, when the ability of TNF-alpha to directly stimulate neutrophils is blocked, TNF-alpha-induced neutrophil transmigration is rendered dependent on ICAM-2, JAM-A, and PECAM-1, suggesting that the stimulus-dependent role of these molecules is governed by the target cell being activated. Furthermore, analysis of the site of arrest of neutrophils in inflamed tissues from ICAM-2(-/-), JAM-A(-/-), and PECAM-1(-/-) mice demonstrated that these molecules act sequentially to mediate transmigration. Collectively, the findings provide novel insights into the mechanisms of action of key molecules implicated in leukocyte transmigration.

The Role of Ambidexterity in Marketing Strategy Implementation: Resolving the Exploration-Exploitation Dilemma

Formulating consistent marketing strategies is a difficult task, but successfully implementing them is even more challenging. This is even more pertinent as marketing strategies quite often incorporate inherent conflicts between major breakthroughs and consolidation. Consequently, marketers need to balance exploratory and exploitative strategies. However, the literature lacks concrete insights for marketing managers as to how exploratory and exploitative strategies can be best combined. This paper addresses this issue by introducing a framework of multiple types of ambidexterity. Based on qualitative research, tools and procedures are identified to overcome marketing dilemmas and support strategy implementation by drawing on ambidextrous designs.

Sequential overchoice in product customization

The present study demonstrates how consumers can suffer from sequential overchoice. Customizing a tailor-made suit from combined-attribute choices (e.g., deciding on color and fabric in combination) leads to less satisfaction, more information overload, and less additional consumption than customizing it from single-attribute choices (e.g., deciding on color, then on fabric).

Corrected kriging update formulae for batch-sequential data assimilation

Recently, a lot of effort has been spent in the efficient computation of kriging predictors when observations are assimilated sequentially. In particular, kriging update formulae enabling significant computational savings were derived. Taking advantage of the previous kriging mean and variance computations helps avoiding a costly matrix inversion when adding one observation to the TeX already available ones. In addition to traditional update formulae taking into account a single new observation, Emery (2009) proposed formulae for the batch-sequential case, i.e. when TeX new observations are simultaneously assimilated. However, the kriging variance and covariance formulae given in Emery (2009) for the batch-sequential case are not correct. In this paper, we fix this issue and establish correct expressions for updated kriging variances and covariances when assimilating observations in parallel. An application in sequential conditional simulation finally shows that coupling update and residual substitution approaches may enable significant speed-ups.

KrigInv: An efficient and user-friendly implementation of batch-sequential inversion strategies based on kriging

Several strategies relying on kriging have recently been proposed for adaptively estimating contour lines and excursion sets of functions under severely limited evaluation budget. The recently released R package KrigInv 3 is presented and offers a sound implementation of various sampling criteria for those kinds of inverse problems. KrigInv is based on the DiceKriging package, and thus benefits from a number of options concerning the underlying kriging models. Six implemented sampling criteria are detailed in a tutorial and illustrated with graphical examples. Different functionalities of KrigInv are gradually explained. Additionally, two recently proposed criteria for batch-sequential inversion are presented, enabling advanced users to distribute function evaluations in parallel on clusters or clouds of machines. Finally, auxiliary problems are discussed. These include the fine tuning of numerical integration and optimization procedures used within the computation and the optimization of the considered criteria.