An orally available Cav2.2 calcium channel inhibitor for the treatment of neuropathic pain.

BACKGROUND AND PURPOSE: Neuropathic pain affects up to 10% of the global population and is caused by an injury or a disease affecting the somatosensory, peripheral, or central nervous system. NP is characterized by chronic, severe and opioid-resistant properties. Therefore, its clinical management remains very challenging. The N-type voltage-gated calcium channel, Cav2.2, is a validated target for therapeutic intervention in chronic and neuropathic pain. The conotoxin ziconotide (Prialt®) is an FDA-approved drug that blocks Cav2.2 channel but needs to be administered intrathecally. Thus, although being principally efficient, the required application route is very much in disfavour. EXPERIMENTAL APPROACH AND KEY RESULTS: Here, we describe an orally available drug candidate, RD2, which competes with ziconotide binding to Cav2.2 at nanomolar concentrations and inhibits Cav2.2 almost completely reversible. Other voltage-gated calcium channel subtypes, like Cav1.2 and Cav3.2, were affected by RD2 only at concentrations higher than 10 µM. Data from sciatic inflammatory neuritis rat model demonstrated the in vivo proof of concept, as low-dose RD2 (5 mg·kg-1) administered orally alleviated neuropathic pain compared with vehicle controls. High-dose RD2 (50 mg·kg-1) was necessary to reduce pain sensation in acute thermal response assessed by the tail flick test. CONCLUSIONS AND IMPLICATIONS: Taken together, these results demonstrate that RD2 has antiallodynic properties. RD2 is orally available, which is the most convenient application form for patients and caregivers. The surprising and novel result from standard receptor screens opens the room for further optimization into new promising drug candidates, which address an unmet medical need.

A Case Series of Late Vascular Lesions of Traumatic Etiology: Endovascular and Surgical Approaches.

There is a broad spectrum of pathology in traumatic vascular injury. Arteriovenous fistula (AVF) is an abnormal communication between the high-flow arterial system and the low-flow venous network, directly connecting the afferent artery and nearby draining veins without the regular intervention of the capillary bed. Most of these fistulas occur due to incidental or iatrogenic injury. A retrospective review of procedures performed by an endovascular surgeon in a tertiary center identified 15 cases of vascular injuries that encompassed all these different clinical scenarios, including post-traumatic, iatrogenic, or spontaneous origin. The information collected, including patient age, sex, previous symptoms, and treatment, was gathered from medical records. In addition, information on procedural technique, endovascular devices used, and specific intraprocedural details were collected from procedure notes and angiographic images. A broad spectrum of injuries can present as late trauma complications (over three months); endovascular treatment is a safe and effective approach for intracranial and extracranial injuries. Endovascular treatment can be a sole option or adjuvant to other hybrid therapies and has emerged as essential for treating these lesions as a first option. We have described standard techniques to treat different vascular pathologies, sometimes with limited resources.

CLC Anion/Proton Exchangers Regulate Secretory Vesicle Filling and Granule Exocytosis in Chromaffin Cells.

ClC-3, ClC-4, and ClC-5 are electrogenic chloride/proton exchangers that can be found in endosomal compartments of mammalian cells. Although the association with genetic diseases and the severe phenotype of knock-out animals illustrate their physiological importance, the cellular functions of these proteins have remained insufficiently understood. We here study the role of two Clcn3 splice variants, ClC-3b and ClC-3c, in granular exocytosis and catecholamine accumulation of adrenal chromaffin cells using a combination of high-resolution capacitance measurements, amperometry, protein expression/gene knock out/down, rescue experiments, and confocal microscopy. We demonstrate that ClC-3c resides in immature as well as in mature secretory granules, where it regulates catecholamine accumulation and contributes to the establishment of the readily releasable pool of secretory vesicles. The lysosomal splice variant ClC-3b contributes to vesicle priming only with low efficiency and leaves the vesicular catecholamine content unaltered. The related Cl-/H+ antiporter ClC-5 undergoes age-dependent downregulation in wild-type conditions. Its upregulation in Clcn3-/- cells partially rescues the exocytotic mutant defect. Our study demonstrates how different CLC transporters with similar transport functions, but distinct localizations can contribute to vesicle functions in the regulated secretory pathway of granule secretion in chromaffin cells.SIGNIFICANCE STATEMENT Cl-/H+ exchangers are expressed along the endosomal/lysosomal system of mammalian cells; however, their exact subcellular functions have remained insufficiently understood. We used chromaffin cells, a system extensively used to understand presynaptic mechanisms of synaptic transmission, to define the role of CLC exchangers in neurosecretion. Disruption of ClC-3 impairs catecholamine accumulation and secretory vesicle priming. There are multiple ClC-3 splice variants, and only expression of one, ClC-3c, in double Cl-/H+ exchanger-deficient cells fully rescues the WT phenotype. Another splice variant, ClC-3b, is present in lysosomes and is not necessary for catecholamine secretion. The distinct functions of ClC-3c and ClC-3b illustrate the impact of expressing multiple CLC transporters with similar transport functions and separate localizations in different endosomal compartments.

Surgical management of a penetrating drill bit injury to the skull base.

BACKGROUND: Low-energy penetrating brain injuries are rarely encountered in neurosurgical practice. Immediate surgical management remains the primary treatment strategy to control potential bleeding and prevents infectious complications. CASE DESCRIPTION: A 28-year-old man presented with an orbital injury with left-sided chemosis, amaurosis, and ophthalmoplegia following an assault. Cranial CT revealed an industrial drill bit causing a penetrating injury to the skull base. The tip of the object reached the petrous apex. CT angiography showed no signs of cerebrovascular damage. The drill bit was visualized through a frontotemporal craniotomy. It was then carefully removed under direct microscopic vision. Postoperative ceftriaxone was administered. The patient was discharged in good condition on postoperative day 6. His vision impairment remained. CONCLUSION: Timely access to neuroimaging diagnostics and microneurosurgical facilities allows for good outcomes in the surgical treatment of low-velocity penetrating brain injuries.

CaV ß controls the endocytic turnover of CaV 1.2 L-type calcium channel.

Membrane depolarization activates the multisubunit CaV 1.2 L-type calcium channel initiating various excitation coupling responses. Intracellular trafficking into and out of the plasma membrane regulates the channel's surface expression and stability, and thus, the strength of CaV 1.2-mediated Ca2+ signals. The mechanisms regulating the residency time of the channel at the cell membrane are unclear. Here, we coexpressed the channel core complex CaV 1.2α1 pore-forming and auxiliary CaV ß subunits and analyzed their trafficking dynamics from single-particle-tracking trajectories. Speed histograms obtained for each subunit were best fitted to a sum of diffusive and directed motion terms. The same mean speed for the highest-mobility state underlying directed motion was found for all subunits. The frequency of this component increased by covalent linkage of CaV ß to CaV 1.2α1 suggesting that high-speed transport occurs in association with CaV ß. Selective tracking of CaV 1.2α1 along the postendocytic pathway failed to show the highly mobile state, implying CaV ß-independent retrograde transport. Retrograde speeds of CaV 1.2α1 are compatible with myosin VI-mediated backward transport. Moreover, residency time at the cell surface was significantly prolonged when CaV 1.2α1 was covalently linked to CaV ß. Thus, CaV ß promotes fast transport speed along anterograde trafficking and acts as a molecular switch controlling the endocytic turnover of L-type calcium channels.

Manejo bimodal de aneurismas asociados a malformaciones arteriovenosas cerebrales. Reporte de caso y breve revisión de la literatura.

La patogénesis de los aneurismas intracraneales asociados a malformaciones arteriovenosas cerebrales no es bien entendida y es aún objeto de discusión. Las decisiones sobre cuándo y cómo tratar los aneurismas intracraneales de estas características siempre han sido un reto terapéutico tanto para neurocirujanos vasculares como para terapistas endovasculares neurológicos. Reportamos el caso de una paciente de 51 años con aneurismas múltiples asociados a una malformación arteriovenosa, así como su manejo neuroquirúrgico, con un análisis comparativo con lo publicado en la literatura médica y científica en los últimos 10 años.The pathogenesis of intracranial aneurysms associated with arteriovenous malformations is not well understood and is still under discussion; the decisions about when and how to treat intracranial aneurysms of these characteristics have always been a therapeutic challenge for both, vascular neurosurgeons and endovascular neurological therapists. We report the case of a 51-year-old patient with multiple aneurysms associated with arteriovenous malformation, as well as her neurosurgical management, with a comparative analysis what has been published in the medical and scientific literature in the last 10 years.

The avocado genome informs deep angiosperm phylogeny, highlights introgressive hybridization, and reveals pathogen-influenced gene space adaptation.

The avocado, Persea americana, is a fruit crop of immense importance to Mexican agriculture with an increasing demand worldwide. Avocado lies in the anciently diverged magnoliid clade of angiosperms, which has a controversial phylogenetic position relative to eudicots and monocots. We sequenced the nuclear genomes of the Mexican avocado race, P. americana var. drymifolia, and the most commercially popular hybrid cultivar, Hass, and anchored the latter to chromosomes using a genetic map. Resequencing of Guatemalan and West Indian varieties revealed that ∼39% of the Hass genome represents Guatemalan source regions introgressed into a Mexican race background. Some introgressed blocks are extremely large, consistent with the recent origin of the cultivar. The avocado lineage experienced 2 lineage-specific polyploidy events during its evolutionary history. Although gene-tree/species-tree phylogenomic results are inconclusive, syntenic ortholog distances to other species place avocado as sister to the enormous monocot and eudicot lineages combined. Duplicate genes descending from polyploidy augmented the transcription factor diversity of avocado, while tandem duplicates enhanced the secondary metabolism of the species. Phenylpropanoid biosynthesis, known to be elicited by Colletotrichum (anthracnose) pathogen infection in avocado, is one enriched function among tandems. Furthermore, transcriptome data show that tandem duplicates are significantly up- and down-regulated in response to anthracnose infection, whereas polyploid duplicates are not, supporting the general view that collections of tandem duplicates contribute evolutionarily recent "tuning knobs" in the genome adaptive landscapes of given species.

A Tripartite Interaction Among the Calcium Channel α1- and ß-Subunits and F-Actin Increases the Readily Releasable Pool of Vesicles and Its Recovery After Depletion.

Neurotransmitter release is initiated by the influx of Ca2+ via voltage-gated calcium channels. The accessory ß-subunit (CaVß) of these channels shapes synaptic transmission by associating with the pore-forming subunit (CaVα1) and up-regulating presynaptic calcium currents. Besides CaVα1, CaVß interacts with several partners including actin filaments (F-actin). These filaments are known to associate with synaptic vesicles (SVs) at the presynaptic terminals and support their translocation within different pools, but the role of CaVß/F-actin association on synaptic transmission has not yet been explored. We here study how CaVß4, the major calcium channel ß isoform in mamalian brain, modifies synaptic transmission in concert with F-actin in cultured hippocampal neurons. We analyzed the effect of exogenous CaVß4 before and after pharmacological disruption of the actin cytoskeleton and dissected calcium channel-dependent and -independent functions by comparing the effects of the wild-type subunit with the one bearing a double mutation that impairs binding to CaVα1. We found that exogenously expressed wild-type CaVß4 enhances spontaneous and depolarization-evoked excitatory postsynaptic currents (EPSCs) without altering synaptogenesis. CaVß4 increases the size of the readily releasable pool (RRP) of SVs at resting conditions and accelerates their recovery after depletion. The enhanced neurotransmitter release induced by CaVß4 is abolished upon disruption of the actin cytoskeleton. The CaVα1 association-deficient CaVß4 mutant associates with actin filaments, but neither alters postsynaptic responses nor the time course of the RRP recovery. Furthermore, this mutant protein preserves the ability to increase the RRP size. These results indicate that the interplay between CaVß4 and F-actin also support the recruitment of SVs to the RRP in a CaVα1-independent manner. Our studies show an emerging role of CaVß in determining SV maturation toward the priming state and its replenishment after release. We envision that this subunit plays a role in coupling exocytosis to endocytosis during the vesicle cycle.

Thermal Optimization of a Dual Pressure Goswami Cycle for Low Grade Thermal Sources.

This paper presents a theoretical investigation of a new configuration of the combined power and cooling cycle known as the Goswami cycle. The new configuration consists of two turbines operating at two different working pressures with a low-heat source temperature, below 150 °C. A comprehensive analysis was conducted to determine the effect of key operation parameters such as ammonia mass fraction at the absorber outlet and boiler-rectifier, on the power output, cooling capacity, effective first efficiency, and effective exergy efficiency, while the performance of the dual-pressure configuration was compared with the original single pressure cycle. In addition, a Pareto optimization with a genetic algorithm was conducted to obtain the best power and cooling output combinations to maximize effective first law efficiency. Results showed that the new dual-pressure configuration generated more power than the single pressure cycle, by producing up to 327.8 kW, while the single pressure cycle produced up to 110.8 kW at a 150 °C boiler temperature. However, the results also showed that it reduced the cooling output as there was less mass flow rate in the refrigeration unit. Optimization results showed that optimum effective first law efficiency ranged between 9.1% and 13.7%. The maximum effective first law efficiency at the lowest net power (32 kW) and cooling (0.38 kW) outputs was also shown. On the other hand, it presented 13.6% effective first law efficiency when the net power output was 100 kW and the cooling capacity was 0.38 kW.

Chitinases of Bacillus thuringiensis: Phylogeny, Modular Structure, and Applied Potentials.

The most important bioinsecticide used worldwide is Bacillus thuringiensis and its hallmark is a rich variety of insecticidal Cry protein, many of which have been genetically engineered for expression in transgenic crops. Over the past 20 years, the discovery of other insecticidal proteins and metabolites synthesized by B. thuringiensis, including chitinases, antimicrobial peptides, vegetative insecticidal proteins (VIP), and siderophores, has expanded the applied value of this bacterium for use as an antibacterial, fungicidal, and nematicidal resource. These properties allow us to view B. thuringiensis not only as an entity for the production of a particular metabolite, but also as a multifaceted microbial factory. In particular, chitinases of B. thuringiensis are secreted enzymes that hydrolyze chitin, an abundant molecule in the biosphere, second only to cellulose. The observation that chitinases increase the insecticidal activity of Cry proteins has stimulated further study of these enzymes produced by B. thuringiensis. Here, we provide a review of a subset of our knowledge of B. thuringiensis chitinases as it relates to their phylogenetic relationships, regulation of expression, biotechnological potential for controlling entomopathogens, fungi, and nematodes, and their use in generating chitin-derived oligosaccharides (ChOGs) that possess antibacterial activities against a number of clinically significant bacterial pathogens. Recent advances in the structural organization of these enzymes are also discussed, as are our perspective for future studies.

Latin American Consensus for Pediatric Cardiopulmonary Resuscitation 2017: Latin American Pediatric Critical Care Society Pediatric Cardiopulmonary Resuscitation Committee.

OBJECTIVES: To develop a Latin American Consensus about Pediatric Cardiopulmonary Resuscitation. To clarify, reinforce, and adapt some specific recommendations for pediatric patients and to stimulate the implementation of these recommendations in clinical practice. DESIGN: Expert consensus recommendations with Delphi methodology. SETTING: Latin American countries. SUBJECTS: Experts in pediatric cardiopulmonary resuscitation from 19 Latin American countries. INTERVENTIONS: Delphi methodology for expert consensus. MEASUREMENTS AND MAIN RESULTS: The goal was to reach consensus with all the participating experts for every recommendation. An agreement of at least 80% of the participating experts had to exist in order to deliver a recommendation. Two Delphi voting rounds were sent out electronically. The experts were asked to score between 1 and 9 their level of agreement for each recommendation. The score was then classified into three groups: strong agreement (score 7-9), moderate agreement (score 4-6), and disagreement (score 1-3). Nineteen experts from 19 countries participated in both voting rounds and in the whole process of drafting the recommendations. Sixteen recommendations about organization of cardiopulmonary resuscitation, prevention, basic resuscitation, advanced resuscitation, and postresuscitation measures were approved. Ten of them had a consensus of 100%. Four of them were agreed by all the participants except one (94.7% consensus). One recommendation was agreed by all except two experts (89.4%), and finally, one was agreed by all except three experts (84.2%). All the recommendations reached a level of agreement. CONCLUSIONS: This consensus adapts 16 international recommendations to Latin America in order to improve the practice of cardiopulmonary resuscitation in children. Studies should be conducted to analyze the effectiveness of the implementation of these recommendations.

Transport-Limited Adsorption of Plasma Proteins on Bimodal Amphiphilic Polymer Co-Networks: Real-Time Studies by Spectroscopic Ellipsometry.

Traditional hydrogels are commonly limited by poor mechanical properties and low oxygen permeability. Bimodal amphiphilic co-networks (ß-APCNs) are a new class of materials that can overcome these limitations by combining hydrophilic and hydrophobic polymer chains within a network of co-continuous morphology. Applications that can benefit from these improved properties include therapeutic contact lenses, enzymatic catalysis supports, and immunoisolation membranes. The continuous hydrophobic phase could potentially increase the adsorption of plasma proteins in blood-contacting medical applications and compromise in vivo material performance, so it is critical to understand the surface characteristics of ß-APCNs and adsorption of plasma proteins on ß-APCNs. From real-time spectroscopic visible (Vis) ellipsometry measurements, plasma protein adsorption on ß-APCNs is shown to be transport-limited. The adsorption of proteins on the ß-APCNs is a multistep process with adsorption to the hydrophilic surface initially, followed by diffusion into the material to the internal hydrophilic/hydrophobic interfaces. Increasing the cross-linking of the PDMS phase reduced the protein intake by limiting the transport of large proteins. Moreover, the internalization of the proteins is confirmed by the difference between the surface-adsorbed protein layer determined from XPS and bulk thickness change from Vis ellipsometry, which can differ up to 20-fold. Desorption kinetics depend on the adsorption history with rapid desorption for slow adsorption rates (i.e., slow-diffusing proteins within the network), whereas proteins with fast adsorption kinetics do not readily desorb. This behavior can be directly related to the ability of the protein to spread or reorient, which affects the binding energy required to bind to the internal hydrophobic interfaces.

Zero-Order Antibiotic Release from Multilayer Contact Lenses: Nonuniform Drug and Diffusivity Distributions Produce Constant-Rate Drug Delivery.

A novel approach to zero-order constant-rate drug delivery from contact lenses is presented. Quasi-Case II non-Fickian transport is achieved by nonuniform drug and diffusivity distributions within three-layer bimodal amphiphilic conetworks (ß-APCNs). The center layer is a highly oxygen permeable ß-APCN matrix, which contains the drug and exhibits a high drug diffusivity. The outer ß-APCN layers contain no-drug and are loaded with vitamin E, which slows diffusion. In contrast to single-layer neat-polymer and vitamin E-loaded films that display first-order "burst" kinetics, it is demonstrated experimentally and by modeling that the combined effect of nonuniform distribution of drug loading and diffusion constants within the three-layer lens maintains low local drug concentration at the lens-fluid interface and yields zero-order drug delivery. The release rates of topical antibiotics provide constant-rate therapeutic-level delivery with appropriate oxygen permeability for at least 30 h, at which time ≈25% of the drug was released.

Real-Time Monitoring of Chemical and Topological Rearrangements in Solidifying Amphiphilic Polymer Co-Networks: Understanding Surface Demixing.

Amphiphilic polymer co-networks provide a unique route to integrating contrasting attributes of otherwise immiscible components within a bicontinuous percolating morphology and are anticipated to be valuable for applications such as biocatalysis, sensing of metabolites, and dual dialysis membranes. These co-networks are in essence chemically forced blends and have been shown to selectively phase-separate at surfaces during film formation. Here, we demonstrate that surface demixing at the air-film interface in solidifying polymer co-networks is not a unidirectional process; instead, a combination of kinetic and thermodynamic interactions leads to dynamic molecular rearrangement during solidification. Time-resolved gravimetry, low contact angles, and negative out-of-plane birefringence provided strong experimental evidence of the transitory trapping of thermodynamically unfavorable hydrophilic moieties at the air-film interface due to fast asymmetric solvent depletion. We also find that slow-drying hydrophobic elements progressively substitute hydrophilic domains at the surface as the surface energy is minimized. These findings are broadly applicable to common-solvent bicontinuous systems and open the door for process-controlled performance improvements in diverse applications. Similar observations could potentially be coupled with controlled polymerization rates to maximize the intermingling of bicontinuous phases at surfaces, thus generating true three-dimensional, bicontinuous, and undisturbed percolation pathways throughout the material.

Characterization of the hrpZ gene from Pseudomonas syringae pv. maculicola M2.

Pseudomonas syringae pv. maculicola is a natural pathogen of members of the Brassicaceae plant family. Using a transposon-based mutagenesis strategy in Pseudomonas syringaepv. maculicola M2 (PsmM2), we conducted a genetic screen to identify mutants that were capable of growing in M9 medium supplemented with a crude extract from the leaves of Arabidopsis thaliana. A mutant containing a transposon insertion in the hrpZ gene (PsmMut8) was unable to infect adult plants from Arabidopsis thaliana or Brassica oleracea, suggesting a loss of pathogenicity. The promotorless cat reporter present in the gene trap was expressed if PsmMut8 was grown in minimal medium (M9) supplemented with the leaf extract but not if grown in normal rich medium (KB). We conducted phylogenetic analysis using hrpAZB genes, showing the classical 5-clade distribution, and nucleotide diversity analysis, showing the putative position for selective pressure in this operon. Our results indicate that the hrpAZB operon from Pseudomonas syringaepv. maculicola M2 is necessary for its pathogenicity and that its diversity would be under host-mediated diversifying selection.

Characterization of the hrpZ gene from Pseudomonas syringae pv. maculicolaM2

Pseudomonas syringae pv. maculicola is a natural pathogen of members of the Brassicaceae plant family. Using a transposon-based mutagenesis strategy in Pseudomonas syringaepv. maculicola M2 (PsmM2), we conducted a genetic screen to identify mutants that were capable of growing in M9 medium supplemented with a crude extract from the leaves of Arabidopsis thaliana. A mutant containing a transposon insertion in the hrpZ gene (PsmMut8) was unable to infect adult plants from Arabidopsis thaliana or Brassica oleracea, suggesting a loss of pathogenicity. The promotorless cat reporter present in the gene trap was expressed if PsmMut8 was grown in minimal medium (M9) supplemented with the leaf extract but not if grown in normal rich medium (KB). We conducted phylogenetic analysis using hrpAZB genes, showing the classical 5-clade distribution, and nucleotide diversity analysis, showing the putative position for selective pressure in this operon. Our results indicate that the hrpAZB operon from Pseudomonas syringaepv. maculicola M2 is necessary for its pathogenicity and that its diversity would be under host-mediated diversifying selection.

Characterization of the hrpZ gene from Pseudomonas syringae pv. maculicolaM2

Pseudomonas syringae pv. maculicola is a natural pathogen of members of the Brassicaceae plant family. Using a transposon-based mutagenesis strategy in Pseudomonas syringaepv. maculicola M2 (PsmM2), we conducted a genetic screen to identify mutants that were capable of growing in M9 medium supplemented with a crude extract from the leaves of Arabidopsis thaliana. A mutant containing a transposon insertion in the hrpZ gene (PsmMut8) was unable to infect adult plants from Arabidopsis thaliana or Brassica oleracea, suggesting a loss of pathogenicity. The promotorless cat reporter present in the gene trap was expressed if PsmMut8 was grown in minimal medium (M9) supplemented with the leaf extract but not if grown in normal rich medium (KB). We conducted phylogenetic analysis using hrpAZB genes, showing the classical 5-clade distribution, and nucleotide diversity analysis, showing the putative position for selective pressure in this operon. Our results indicate that the hrpAZB operon from Pseudomonas syringaepv. maculicola M2 is necessary for its pathogenicity and that its diversity would be under host-mediated diversifying selection.

How best practices are copied, transferred, or translated between health care facilities: A conceptual framework.

INTRODUCTION: In spite of significant investment in quality programs and activities, there is a persistent struggle to achieve quality outcomes and performance improvements within the constraints and support of sociopolitical parsimonies. Equally, such constraints have intensified the need to better understand the best practice methods for achieving quality improvements in health care organizations over time.This study proposes a conceptual framework to assist with strategies for the copying, transferring, and/or translation of best practice between different health care facilities. PURPOSE: Applying a deductive logic, the conceptual framework was developed by blending selected theoretical lenses drawn from the knowledge management and organizational learning literatures. FINDINGS: The proposed framework highlighted that (a) major constraints need to be addressed to turn best practices into everyday practices and (b) double-loop learning is an adequate learning mode to copy and to transfer best practices and deuteron learning mode is a more suitable learning mode for translating best practice. We also found that, in complex organizations, copying, transferring, and translating new knowledge is more difficult than in smaller, less complex organizations. We also posit that knowledge translation cannot happen without transfer and copy, and transfer cannot happen without copy of best practices. Hence, an integration of all three learning processes is required for knowledge translation (copy best practice-transfer knowledge about best practice-translation of best practice into new context). In addition, the higher the level of complexity of the organization, the more best practice is tacit oriented and, in this case, the higher the level of K&L capabilities are required to successfully copy, transfer, and/or translate best practices between organizations. PRACTICE IMPLICATIONS: The approach provides a framework for assessing organizational context and capabilities to guide copy/transfer/translation of best practices. A roadmap is provided to assist managers and practitioners to select appropriate learning modes for building success and positive systemic change.