It is challenging to identify and understand the specific mechanisms through which an implementation strategy affects implementation outcomes, as implementation happens in the context of complex, ...multi-level systems. These systems and the mechanisms within each level have their own dynamic environments that change frequently. For instance, sequencing may matter in that a mechanism may only be activated indirectly by a strategy through another mechanism. The dosage or strength of a mechanism may vary over time or across different health care system levels. To elucidate the mechanisms relevant to successful implementation amidst this complexity, systems analysis methods are needed to model and manage complexity.
The fields of systems engineering and systems science offer methods-which we refer to as systems analysis methods-to help explain the interdependent relationships between and within systems, as well as dynamic changes to systems over time. When applied to studying implementation mechanisms, systems analysis methods can help (i) better identify and manage unknown conditions that may or may not activate mechanisms (both expected mechanisms targeted by a strategy and unexpected mechanisms that the methods help detect) and (ii) flexibly guide strategy adaptations to address contextual influences that emerge after the strategy is selected and used.
In this paper, we delineate a structured approach to applying systems analysis methods for examining implementation mechanisms. The approach includes explicit steps for selecting, tailoring, and evaluating an implementation strategy regarding the mechanisms that the strategy is initially hypothesized to activate, as well as additional mechanisms that are identified through the steps. We illustrate the approach using a case example. We then discuss the strengths and limitations of this approach, as well as when these steps might be most appropriate, and suggest work to further the contributions of systems analysis methods to implementation mechanisms research.
Our approach to applying systems analysis methods can encourage more mechanisms research efforts to consider these methods and in turn fuel both (i) rigorous comparisons of these methods to alternative mechanisms research approaches and (ii) an active discourse across the field to better delineate when these methods are appropriate for advancing mechanisms-related knowledge.
Abstract The relative motion between the tooth and alveolar bone is facilitated by the soft-hard tissue interfaces which include periodontal ligament-bone (PDL-bone) and periodontal ligament-cementum ...(PDL-cementum). The soft-hard tissue interfaces are responsible for attachment and are critical to the overall biomechanical efficiency of the bone–tooth complex. In this study, the PDL-bone and PDL-cementum attachment sites in human molars were investigated to identify the structural orientation and integration of the PDL with bone and cementum. These attachment sites were characterized from a combined materials and mechanics perspective and were related to macro-scale function. High resolution complimentary imaging techniques including atomic force microscopy, scanning electron microscopy and micro-scale X-ray computed tomography (Micro XCT™) illustrated two distinct orientations of PDL; circumferential-PDL (cir-PDL) and radial-PDL (rad-PDL). Within the PDL-space, the primary orientation of the ligament was radial (rad-PDL) as is well known. Interestingly, circumferential orientation of PDL continuous with rad-PDL was observed adjacent to alveolar bone and cementum. The integration of the cir-PDL was identified by 1–2 μm diameter PDL-inserts or Sharpey’s fibers in alveolar bone and cementum. Chemically and biochemically the cir-PDL adjacent to bone and cementum was identified by relatively higher carbon and lower calcium including the localization of small leucine rich proteins responsible for maintaining soft-hard tissue cohesion, stiffness and hygroscopic nature of PDL-bone and PDL-cementum attachment sites. The combined structural and chemical properties provided graded stiffness characteristics of PDL-bone (Er range for PDL: 10–50 MPa; bone: 0.2–9.6 GPa) and PDL-cementum (Er range for cementum: 1.1–8.3 GPa), which was related to the macro-scale function of the bone–tooth complex.
The role of the medial temporal lobe in learning and memory has been well established in research on humans and other animals. In humans, clinical and neuroimaging studies typically suggest ...material-specific lateralization in which the left and right temporal lobes are associated with verbal and nonverbal memory, respectively. It is often assumed that the temporal lobes are functionally alike, differing only in terms of the content to be learned. Here we present data that challenge this notion, showing that the type of material used during a memory task can influence fMRI activation patterns beyond the expected left-verbal/right-nonverbal dichotomy. Our results also suggest some degree of functional asymmetry in the medial temporal lobe that is independent of material type, pointing to underlying processing differences between the left and right temporal lobes.
P-selectin, found in storage granules of platelets and endothelial cells, can be rapidly expressed upon stimulation. Mice lacking this membrane receptor exhibit a severe impairment of leukocyte ...rolling. We observed that, in addition to leukocytes, platelets were rolling in mesenteric venules of wild-type mice. To investigate the role of P-selectin in this process, resting or activated platelets from wild-type or P-selectin-deficient mice were fluorescently labeled and transfused into recipients of either genotype. Platelet-endothelial interactions were monitored by intravital microscopy. We observed rolling of either wild-type or P-selectin-deficient resting platelets on wild-type endothelium. Endothelial stimulation with the calcium ionophore A23187 increased the number of platelets rolling 4-fold. Activated P-selectin-deficient platelets behaved similarly, whereas activated wild-type platelets bound to leukocytes and were seen rolling together. Platelets of either genotype, resting or activated, interacted minimally with mutant endothelium even after A23187 treatment. The velocity of platelet rolling was 6- to 9-fold greater than that of leukocytes. Our results demonstrate that (i) platelets roll on endothelium in vivo, (ii) this interaction requires endothelial but not platelet P-selectin, and (iii) platelet rolling appears to be independent of platelet activation, indicating constitutive expression of a P-selectin ligand(s) on platelets. We have therefore observed an interesting parallel between platelets and leukocytes in that both of these blood cell types roll on stimulated vessel wall and that this process is dependent on the expression of endothelial P-selectin.
Constructing mixtures of tagged or bar-coded DNAs for sequencing is an important requirement for the efficient use of next-generation sequencers in applications where limited sequence data are ...required per sample. There are many applications in which next-generation sequencing can be used effectively to sequence large mixed samples; an example is the characterization of microbial communities where less-than or equal to1,000 sequences per samples are adequate to address research questions. Thus, it is possible to examine hundreds to thousands of samples per run on massively parallel next-generation sequencers. However, the cost savings for efficient utilization of sequence capacity is realized only if the production and management costs associated with construction of multiplex pools are also scalable. One critical step in multiplex pool construction is the normalization process, whereby equimolar amounts of each amplicon are mixed. Here we compare three approaches (spectroscopy, size-restricted spectroscopy, and quantitative binding) for normalization of large, multiplex amplicon pools for performance and efficiency. We found that the quantitative binding approach was superior and represents an efficient scalable process for construction of very large, multiplex pools with hundreds and perhaps thousands of individual amplicons included. We demonstrate the increased sequence diversity identified with higher throughput. Massively parallel sequencing can dramatically accelerate microbial ecology studies by allowing appropriate replication of sequence acquisition to account for temporal and spatial variations. Further, population studies to examine genetic variation, which require even lower levels of sequencing, should be possible where thousands of individual bar-coded amplicons are examined in parallel.
The latest version of the Soil and Water Assessment Tool (SWAT+) features several improvements compared with previous versions of the model, for example, the definition of landscape units that allow ...for a better representation of spatio‐temporal dynamics. To evaluate the new model capabilities in lowland catchments characterized by near‐surface groundwater tables and extensive tile drainage, we assess the performance of two SWAT+ model setups in comparison to a setup based on a previous SWAT model version (SWAT3S with a modified three groundwater storage model) in the Kielstau catchment in Northern Germany. The Kielstau catchment has an area of about 50 km2, is dominated by agricultural land use, and has been thoroughly monitored since 2005. In both SWAT+ setups, the catchment is divided into upland areas and floodplains, but in the first SWAT+ model setup, runoff from the hydrologic response units is summed up at landscape unit level and added directly to the stream. In the second SWAT+ model setup, runoff is routed across the landscape before it reaches the streams. Model results are compared with regard to (i) model performance for stream flow at the outlet of the catchment and (ii) aggregated as well as temporally and spatially distributed water balance components. All three model setups show a very good performance at the catchment outlet. In comparison to a previous version of the SWAT model that produced more groundwater flow, the SWAT+ model produced more tile drainage flow and surface runoff. Results from the new SWAT+ model confirm that the representation of routing processes from uplands to floodplains in the model further improved the representation of hydrological processes. Particularly, the stronger spatial heterogeneity that can be related to characteristics of the landscape, is very promising for a better understanding and model representation of hydrological fluxes in lowland areas. The outcomes of this study are expected to further prove the applicability of SWAT+ and provide useful information for future model development.
The model performance of all three model setups was very good, but the SWAT+ model setup with runoff routing between landscape units performed best. Moreover, the SWAT+ model applications predicted a greater spatial heterogeneity of the water balance components. The representation of hydrological fluxes particularly with regard to groundwater flow, surface runoff, and tile drainage flow differed considerably between the SWAT and SWAT+ model setups.
The complex genomic composition of allopolyploid plants leads to morphologically diverse species. The traditional taxonomical treatment of the medium-sized, hexaploid shrub willows distributed in the ...Alps is difficult based on their variable morphological characters. In this study, RAD sequencing data, infrared-spectroscopy, and morphometric data are used to analyze the phylogenetic relationships of the hexaploid species of the sections
and
in a phylogenetic framework of 45 Eurasian
species. Both sections comprise local endemics as well as widespread species. Based on the molecular data, the described morphological species appeared as monophyletic lineages (except for
s.str. and
, which are intermingled). Both sections
and
are polyphyletic. Infrared-spectroscopy mostly confirmed the differentiation of hexaploid alpine species. The morphometric data confirmed the molecular results and supported the inclusion of
into
s.l., whereas the alpine endemic
is distinct and closely related to species of the section
. The genomic structure and co-ancestry analyses of the hexaploid species revealed a geographical pattern for widespread
, separating the Scandinavian from the alpine populations. The newly described
is tetraploid and is grouped within
. Our data reveal that both sections
and
need to be redefined.
Mediation analysis can be used to evaluate the effect of an exposure on an outcome acting through an intermediate variable or mediator. For studies with small sample sizes, permutation testing may be ...useful in evaluating the indirect effect (i.e., the effect of exposure on the outcome through the mediator) while maintaining the appropriate type I error rate. For mediation analysis in studies with small sample sizes, existing permutation testing methods permute the residuals under the full or alternative model, but have not been evaluated under situations where covariates are included. In this article, we consider and evaluate two additional permutation approaches for testing the indirect effect in mediation analysis based on permutating the residuals under the reduced or null model which allows for the inclusion of covariates.
Simulation studies were used to empirically evaluate the behavior of these two additional approaches: (1) the permutation test of the Indirect Effect under Reduced Models (IERM) and (2) the Permutation Supremum test under Reduced Models (PSRM). The performance of these methods was compared to the standard permutation approach for mediation analysis, the permutation test of the Indirect Effect under Full Models (IEFM). We evaluated the type 1 error rates and power of these methods in the presence of covariates since mediation analysis assumes no unmeasured confounders of the exposure-mediator-outcome relationships.
The proposed PSRM approach maintained type I error rates below nominal levels under all conditions, while the proposed IERM approach exhibited grossly inflated type I rates in many conditions and the standard IEFM exhibited inflated type I error rates under a small number of conditions. Power did not differ substantially between the proposed PSRM approach and the standard IEFM approach.
The proposed PSRM approach is recommended over the existing IEFM approach for mediation analysis in studies with small sample sizes.
The adhesive mechanisms allowing hematopoietic progenitor cells (HPC) homing to the bone marrow (BM) after BM transplantation are poorly understood. We investigated the role of endothelial selectins ...and vascular cell adhesion molecule-1 (VCAM-1) in this process. Lethally irradiated recipient mice deficient in both P-and E-selectins (P/E-/-), reconstituted with minimal numbers (≤ 5 × 104) of wild-type BM cells, poorly survived the procedure compared with wild-type recipients. Excess mortality in P/E-/- mice, after a lethal dose of irradiation, was likely caused by a defect of HPC homing. Indeed, we observed that the recruitment of HPC to the BM was reduced in P/E-/- animals, either splenectomized or spleen-intact. Homing into the BM of P/E-/- recipient mice was further compromised when a function-blocking VCAM-1 antibody was administered. Circulating HPC, 14 hr after transplantation, were greatly increased in P/E-/- mice treated with anti-VCAM-1 compared with P/E-/- mice treated with just IgG or wild-type mice treated with either anti-VCAM-1 or IgG. Our results indicate that endothelial selectins play an important role in HPC homing to the BM. Optimal recruitment of HPC after lethal doses of irradiation requires the combined action of both selectins and VCAM-1 expressed on endothelium of the BM.
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