Efficacy and safety of mogamulizumab by patient baseline blood tumour burden: a post hoc analysis of the MAVORIC trial.

BACKGROUND: Mogamulizumab was compared with vorinostat in the phase 3 MAVORIC trial (NCT01728805) in 372 patients with relapsed/refractory mycosis fungoides (MF) or Sézary syndrome (SS) who had failed ≥1 prior systemic therapy. Mogamulizumab significantly prolonged progression-free survival (PFS), with a superior objective response rate (ORR) vs. vorinostat. OBJECTIVES: This post hoc analysis was performed to evaluate the effect of baseline blood tumour burden on patient response to mogamulizumab. METHODS: PFS, ORR, time to next treatment (TTNT), skin response (modified Severity-Weighted Assessment Tool [mSWAT]) and safety were assessed in patients stratified by blood classification (B0 [n = 126], B1 [n = 62], or B2 [n = 184], indicating increasing blood involvement). RESULTS: Investigator-assessed PFS was longer for mogamulizumab versus vorinostat across all blood classes, significantly so for B1 and B2 patients. ORR was higher with mogamulizumab than with vorinostat in all blood classification groups and more markedly so with escalating B class (B0: 15.6% vs. 6.5%, P = 0.0549; B1: 25.8% vs. 6.5%, P = 0.2758; B2: 37.4% vs. 3.2%, P < 0.0001). TTNT was significantly longer for patients treated with mogamulizumab versus vorinostat with B1 (12.63 vs. 3.07 months; HR 0.32 [95% CI 0.16-0.67]; P = 0.0018) and B2 (13.07 vs. 3.53 months; HR 0.30 [95% CI 0.21-0.43]; P < 0.0001) blood involvement. In the mogamulizumab arm, 81 patients (43.5%) had ≥50% change in the mSWAT vs. 41 patients (22.0%) with vorinostat; mSWAT improvements with mogamulizumab occurred most often in B1 and B2 patients. Rapid, sustained reductions were seen in CD4+ CD26- cell counts and CD4:CD8 ratios in mogamulizumab patients for all B classes. Treatment-emergent adverse events were less frequent overall with mogamulizumab and similar in frequency regardless of B class. CONCLUSIONS: This post hoc analysis indicates greater clinical benefit with mogamulizumab vs. vorinostat in patients with MF and SS classified as having B1 and B2 blood involvement.

Dermatology consultation service at a large metropolitan hospital system serving minority populations.

BACKGROUND: Dermatology consultations in the inpatient hospital setting can improve diagnostic accuracy and management. OBJECTIVE: Characterize dermatologic diagnostic and treatment trends in the hospital setting and identify variables that may affect patient care. METHODS: Retrospective chart review from 1 January 2012 to 31 December 2017 at Jackson Memorial Hospital (JMH) (Miami, Florida, USA), an academic non-profit tertiary care centre affiliated with University of Miami Miller School of Medicine, was performed. Patients who received dermatology consultations in the emergency department (ED) or inpatient settings were included. Patient demographics, admission information, provisional diagnosis and management plans by primary teams, final diagnosis, management plans and testing recommendations by the dermatology consults team, and follow-up information were collected. Analysis using Microsoft Excel of how time to consultation, admission length, inpatient versus ED setting and primary team affected diagnostic accuracy was also performed. RESULTS: The 1004 consultations for 812 patients (n = 812) were reviewed (359 women, 453 men). Most patients were Hispanic (n = 359; 44.2%) or African American (n = 273; 33.6%). Mean admission length was 20.6 days (range 0-439; median 6). The most common consulting service was internal medicine (n = 452). In 387 cases (47.6%), primary teams did not give a provisional diagnosis. The most common provisional diagnoses were bacterial infection (n = 93), viral infection (n = 49) and drug reaction (n = 44). The most common diagnoses by dermatology were viral infection (n = 93), bacterial infection (n = 90) and drug reaction (n = 80). Dermatology consultation changed the provisional diagnosis in 55.7% of cases, more often in cases where consultation took place ≥2 days after admission (P < 0.05). Primary teams followed dermatology treatment recommendations in 85.2% of cases. CONCLUSION: Dermatology consultation improves diagnostic accuracy in skin disorders in the hospital setting and serves as a valuable resource for inpatient care. A notable aspect of data from this study is the unique patient population, predominantly comprised of underrepresented racial and ethnic minorities including Hispanics and African Americans.

Generation of structured light by multilevel orbital angular momentum holograms.

Structured light has been created by a myriad of near-and far-field techniques and has found both classical and quantum applications. In the case of orbital angular momentum (OAM), continuous spiral phase patterns in dynamic or geometric phase are often employed with the phase patterns existing across the entire transverse plane. Here, we exploit the uncertain relationship between OAM and angle in order to create structured OAM fields by using multilevel OAM holograms. We show theoretically and experimentally that only a multilevel angular phase contour in the near-field is needed to create structured OAM light in the far-field, exploiting the reciprocal nature of angular momentum and angle. We use this approach to demonstrate exotic 3D structured light control to show the Poynting vector's evolution in such fields and to highlight the physics underlying this phenomenon.

Optogenetic silencing of a corticotropin-releasing factor pathway from the central amygdala to the bed nucleus of the stria terminalis disrupts sustained fear.

The lateral central nucleus of the amygdala (CeAL) and the dorsolateral bed nucleus of the stria terminalis (BNSTDL) coordinate the expression of shorter- and longer-lasting fears, respectively. Less is known about how these structures communicate with each other during fear acquisition. One pathway, from the CeAL to the BNSTDL, is thought to communicate via corticotropin-releasing factor (CRF), but studies have yet to examine its function in fear learning and memory. Thus, we developed an adeno-associated viral-based strategy to selectively target CRF neurons with the optogenetic silencer archaerhodopsin tp009 (CRF-ArchT) to examine the role of CeAL CRF neurons and projections to the BNSTDL during the acquisition of contextual fear. Expression of our CRF-ArchT vector injected into the amygdala was restricted to CeAL CRF neurons. Furthermore, CRF axonal projections from the CeAL clustered around BNSTDL CRF cells. Optogenetic silencing of CeAL CRF neurons during contextual fear acquisition disrupted retention test freezing 24 h later, but only at later time points (>6 min) during testing. Silencing CeAL CRF projections in the BNSTDL during contextual fear acquisition produced a similar effect. Baseline contextual freezing, the rate of fear acquisition, freezing in an alternate context after conditioning and responsivity to foot shock were unaffected by optogenetic silencing. Our results highlight how CeAL CRF neurons and projections to the BNSTDL consolidate longer-lasting components of a fear memory. Our findings have implications for understanding how discrete amygdalar CRF pathways modulate longer-lasting fear in anxiety- and trauma-related disorders.

A review of the evidence and cost of therapies for cutaneous lupus erythematosus.

Cutaneous lupus erythematosus (CLE)-a common presentation of lupus erythematosus-may exist independently or as a part of the systemic manifestations of systemic lupus erythematosus. The effects of living with and treating a chronic condition such as CLE can be debilitating to a patient's health and finances. The management of patients with CLE is made particularly challenging by poor compliance, limited therapeutic options, scarcity of evidence supporting their use, and significant differences in costs of medications. Effective management of CLE should center on prevention, individualized treatment regimens, and a mutual understanding of the challenges that patients with CLE face. This article seeks to provide an overview of the efficacy, safety, and cost of therapeutic options for CLE.

Validation of 'ItchApp©' in Poland and in the USA: multicentre validation study of an electronical diary for the assessment of pruritus.

BACKGROUND: Although chronic pruritus affects a large part of the population, its reliable assessment remains difficult. Electronical diaries (eDiaries) are often used in multicentre clinical trials. The ItchApp© for Android was developed to assess itch intensity and course and was validated for the German language in 2017. OBJECTIVE: To validate ItchApp© for the use in the Polish and US English languages. METHODS: Fifty-three subjects in Poland and thirty subjects in the USA with chronic pruritus completed the paper-based and app-based questionnaires. These questionnaires contained items for measuring the itch intensity, including a numerical rating scale (NRS) and verbal rating scale (VRS), and for detecting the change of pruritus since the beginning of treatment. RESULTS: The ItchApp© showed a high level of test-retest reliability [Intraclass correlation, Kappa and Kendall-Tau B coefficients: 0.915-1.000 (Poland) and 0.863-1.000 (USA)]. The convergent validity showed strong correlation between the itch intensity scales on the ItchApp© (Items II-IV = VRS mean, NRS mean and NRS worst) and the paper-based itch intensity scales (mean and worst: VRS, NRS, VAS) [Spearman-Rho and Pearson correlation coefficients: 0.710-0.987 (Poland) and 0.646-0.954 (USA)]. The ItchApp© items moderately correlated with the ItchyQol scores [Spearman-Rho and Pearson correlation coefficients: 0.303-0.554 (Poland) and 0.275-0.447 (USA)]. After completing the ItchApp© questionnaire, a feasibility questionnaire was completed and showed that subjects feel the app is well suited for assessing pruritus. CONCLUSION: We provide evidence for the ItchApp© as a validated eDiary for the assessment of pruritus in Polish and US English languages, enabling its use in multicentre international clinical trials.

Age and experience dependent changes in Egr-1 expression during the ontogeny of the context preexposure facilitation effect (CPFE).

The context preexposure facilitation effect (CPFE) is a variant of contextual fear conditioning in which acquisition of the contextual representation and association of the retrieved contextual memory with an immediate foot-shock are separated by 24 h. During the CPFE, learning- related expression patterns of the early growth response-1 gene (Egr-1) vary based on training phase and brain sub-region in adult and adolescent rats (Asok, Schreiber, Jablonski, Rosen, & Stanton, 2013; Schreiber, Asok, Jablonski, Rosen, & Stanton, 2014; Chakraborty, Asok, Stanton, & Rosen, 2016). The current experiments extended our previous findings by examining Egr-1 expression in infant (PD17) and juvenile (PD24) rats during the CPFE using preexposure protocols involving single-exposure (SE) or multiple-exposure (ME) to context. Following a 5 min preexposure to the training context (i.e. the SE protocol), Egr-1 expression in the medial prefrontal cortex (mPFC), dorsal hippocampus (dHPC) and lateral nucleus of the amygdala (LA) was differentially increased in PD24 rats relative to PD17 rats. In contrast, increased Egr-1 expression following an immediate foot-shock (2s, 1.5 mA) did not differ between PD17 and PD24 rats, and was not learning-related. Interestingly, increasing the number of exposures to the training chamber on the preexposure day (i.e. ME protocol) altered training-day expression such that a learning-related increase in expression was observed in the mPFC in PD24 but not PD17 rats. Together, these results illustrate a clear maturation of Egr-1 expression that is both age- and experience-dependent. In addition, the data suggest that regional activity and plasticity within the mPFC on the preexposure but not the training day may contribute to the ontogenetic profile of the effect. Further studies are necessary to elucidate the causal role of sub-region-specific neuroplasticity in the ontogeny of the CPFE.

An investigation of the in-plane chemically ordered atomic laminates (Mo2/3Sc1/3)2AlC and (Mo2/3Y1/3)2AlC from first principles.

We have calculated electronic, vibrational, and elastic properties of (Mo2/3Sc1/3)2AlC and (Mo2/3Y1/3)2AlC, two recently discovered nanolaminated materials in the family of so-called i-MAX phases. A comparison is made to the properties of the related hypothetical MAX phases Sc2AlC, Y2AlC, and Mo2AlC. From an analysis of the electronic band structures and projected crystal orbital Hamilton populations (pCOHP), we show that the i-MAX phases have more isotropic band structures than the MAX phases, but that their bonding characteristics are very similar, despite belonging to different space groups. However, the similar bonding notwithstanding, qualitative as well as significant quantitative differences are seen in the phonon density of states (PDOS). We also compare the Voigt-Reuss-Hill (VRH) bulk, shear, and Young's moduli. For (Mo2/3Sc1/3)2AlC, BVRH = 132 GPa, GVRH = 89 GPa, and EVRH = 218 GPa, all of which are higher values than for Sc2AlC, but lower than for Mo2AlC. For (Mo2/3Y1/3)2AlC, BVRH = 117 GPa, GVRH = 85 GPa, and EVRH = 205 GPa, which are higher than for Y2AlC, but lower than for Mo2AlC.

The Z-cad dual fluorescent sensor detects dynamic changes between the epithelial and mesenchymal cellular states.

BACKGROUND: The epithelial to mesenchymal transition (EMT) has been implicated in metastasis and therapy resistance of carcinomas and can endow cancer cells with cancer stem cell (CSC) properties. The ability to detect cancer cells that are undergoing or have completed EMT has typically relied on the expression of cell surface antigens that correlate with an EMT/CSC phenotype. Alternatively these cells may be permanently marked through Cre-mediated recombination or through immunostaining of fixed cells. The EMT process is dynamic, and these existing methods cannot reveal such changes within live cells. The development of fluorescent sensors that mirror the dynamic EMT state by following the expression of bona fide EMT regulators in live cells would provide a valuable new tool for characterizing EMT. In addition, these sensors will allow direct observation of cellular plasticity with respect to the epithelial/mesenchymal state to enable more effective studies of EMT in cancer and development. RESULTS: We generated a lentiviral-based, dual fluorescent reporter system, designated as the Z-cad dual sensor, comprising destabilized green fluorescent protein containing the ZEB1 3' UTR and red fluorescent protein driven by the E-cadherin (CDH1) promoter. Using this sensor, we robustly detected EMT and mesenchymal to epithelial transition (MET) in breast cancer cells by flow cytometry and fluorescence microscopy. Importantly, we observed dynamic changes in cellular populations undergoing MET. Additionally, we used the Z-cad sensor to identify and isolate minor subpopulations of cells displaying mesenchymal properties within a population comprising predominately epithelial-like cells. The Z-cad dual sensor identified cells with CSC-like properties more effectively than either the ZEB1 3' UTR or E-cadherin sensor alone. CONCLUSIONS: The Z-cad dual sensor effectively reports the activities of two factors critical in determining the epithelial/mesenchymal state of carcinoma cells. The ability of this stably integrating dual sensor system to detect dynamic fluctuations between these two states through live cell imaging offers a significant improvement over existing methods and helps facilitate the study of EMT/MET plasticity in response to different stimuli and in cancer pathogenesis. Finally, the versatile Z-cad sensor can be adapted to a variety of in vitro or in vivo systems to elucidate whether EMT/MET contributes to normal and disease phenotypes.

Phase stability of the nanolaminates V2Ga2C and (Mo1-xVx)2Ga2C from first-principles calculations.

We here use first-principles calculations to investigate the phase stability of the hypothetical laminated material V2Ga2C and the related alloy (Mo1-xVx)2Ga2C, the latter for a potential parent material for synthesis of (Mo1-xVx)2C, a new two-dimensional material in the family of so called MXenes. We predict that V2Ga2C is thermodynamically stable with respect to all identified competing phases in the ternary V-Ga-C phase diagram. We further calculate the stability of ordered and disordered configurations of Mo and V in (Mo1-xVx)2Ga2C and predict that ordered (Mo1-xVx)2Ga2C for x≤ 0.25 is stable, with an order-disorder transition temperature of ∼1000 K. Furthermore, (Mo1-xVx)2Ga2C for x = 0.5 and x≥ 0.75 is suggested to be stable, but only for disordered Mo-V configurations, and only at elevated temperatures. We have also investigated the electronic and elastic properties of V2Ga2C; the calculated bulk, shear, and Young's modulus are 141, 94, and 230 GPa, respectively.

Cognitive training in Parkinson's disease reduces cognitive decline in the long term.

BACKGROUND AND PURPOSE: Patients with Parkinson's disease (PD) are at high risk for cognitive dysfunction. Non-pharmacological interventions have attracted increasing interest for enhancing PD patients' cognitive functions. METHODS: One-year follow-up data (T2 ) of a randomized controlled trial evaluating two 6-week cognitive trainings - a structured (NEUROvitalis, NV) and an unstructured (mentally fit, MF) program - compared with a waiting list control group (CG) in non-demented PD patients (Hoehn and Yahr I-III) are presented. Forty-seven PD patients were examined at T2 . Effects on overall cognitive functions (Mini-Mental State Examination and DemTect) were compared between all groups with repeated measurement analyses of variance. A combined score of the percentage change value from baseline (T0 ) to T2 was calculated to identify patients who retained or improved their cognitive state (responders). The risk of developing mild cognitive impairment (MCI) was analyzed. RESULTS: Significant time × treatment effects on overall cognitive functions were found for both training groups, each compared separately to the CG (DemTect, P < 0.05). Nine patients (56.3%) of the NV group, seven (41.2%) of the MF group and three (21.4%) of the CG were responders. Comparing NV to CG the odds ratio was 4.7 [95% confidence interval (0.8; 33.3)], and comparing MF to CG it was 2.6 [95% confidence interval (0.4; 17.4)]. MCI risk for patients without prior MCI was 40.0% in CG, 18.2% in MF and 18.2% in NV. The odds ratio was 3 comparing NV to CG, MF to CG. DISCUSSION: This study gives evidence that cognitive training may be effective to prevent cognitive decline and onset of MCI in PD patients.

Phenotypic convergence is more frequent and stronger in herbivorous freshwater fishes.

Constraints on phenotypic evolution can lead to patterns of convergent evolution, by limiting the 'pool' of potential phenotypes in the face of endogenous (functional, developmental) or exogenous (competition, predation) selective pressures. Evaluation of convergence depends on integrating ecological and morphological data within a robust, comparative phylogenetic context. The staggering diversity of teleost fishes offers a multitude of lineages adapted for similar ecological roles, and therefore, offers numerous replicated evolutionary experiments for exploring phenotypic convergence. However, our understanding of fish feeding systems has been primarily shaped by marine species, with the monolithic exception of freshwater cichlids. Here we use piranhas and pacus (Serrasalmidae) to explore the evolution of different feeding ecologies and their morphological proxies in Neotropical freshwater environments. Specifically, we explore whether convergence is more widespread among plant-eating fishes, arising from strong constraints on phenotypic evolution in herbivores. Using osteological micro-computed tomographic imaging (µCT), we describe the major axes of morphological variation in pacus and piranhas, regarding their diet and feeding behaviors. Next, we evaluated whether herbivorous niches are less labile than other dietary guilds and whether herbivorous species' phenotypes evolve at a slower evolutionary rate than other taxa. We then assess how convergent herbivorous taxa are, using three different suites of morphological characters (dental, jaw, and abdominal morphometrics). Ecologically, herbivory is not a dead end, exhibiting similar observed transition rates as those between carnivores and omnivores. However, we documented widespread convergence in herbivores and that herbivores have slower rates of phenotypic evolution than carnivores. Most instances of convergence are found in herbivorous taxa, specifically in frugivores and folivores. Moreover, instances of 'complete' convergence, indicated by positive convergence metrics observed in more than one morphometric dataset, were only found in herbivores. Herbivores do appear to evolve under constrained circumstances, but this has not limited their ecological lability.

Determining the surface-to-bulk progression in the normal-state electronic structure of Sr(2)RuO(4) by angle-resolved photoemission and density functional theory.

We revisit the normal-state electronic structure of Sr(2)RuO(4) by angle-resolved photoemission spectroscopy with improved data quality, as well as ab initio band structure calculations in the local-density approximation with the inclusion of spin-orbit coupling. We find that the current model of a single surface layer (√2×√2)R45° reconstruction does not explain all detected features. The observed depth-dependent signal degradation, together with the close quantitative agreement with the slab calculations based on the surface crystal structure as determined by low-energy electron diffraction, reveal that-at a minimum-the subsurface layer also undergoes a similar although weaker reconstruction. This model accounts for all features-a key step in understanding the electronic structure-and indicates a surface-to-bulk progression of the electronic states driven by structural instabilities. Finally, we find no evidence for other phases stemming from either topological bulk properties or, alternatively, the interplay between spin-orbit coupling and the broken symmetry of the surface.

Magnetic self-organized atomic laminate from first principles and thin film synthesis.

The first experimental realization of a magnetic M(n+1)AX(n) (MAX) phase, (Cr(0.75)Mn(0.25))(2)GeC, is presented, synthesized as a heteroepitaxial single crystal thin film, exhibiting excellent structural quality. This self-organized atomic laminate is based on the well-known Cr(2)GeC, with Mn, a new element in MAX phase research, substituting Cr. The compound was predicted using first-principles calculations, from which a variety of magnetic behavior is envisaged, depending on the Mn concentration and Cr/Mn atomic configuration within the sublattice. The analyzed thin films display a magnetic signal at room temperature.

The efficacy and safety of ezetimibe/simvastatin combination compared with intensified lipid-lowering treatment strategies in diabetic subjects with and without metabolic syndrome.

AIMS: The objective was to assess the consistency of effect of switching to ezetimibe/simvastatin 10/20 mg versus doubling the baseline statin dose (to simvastatin 40 mg or atorvastatin 20 mg) or switching to rosuvastatin 10 mg across subgroups of subjects with (n = 617) and without (n = 191) metabolic syndrome (MetS). METHODS: This was a post hoc analysis of a randomized, double-blind, 6-week study of adults 18-79 years with cardiovascular disease and diabetes mellitus with low-density lipoprotein cholesterol (LDL-C) ≥70 and ≤160 mg/dl. The percent change in LDL-C and other lipids was estimated within each subgroup separately. Safety and tolerability were assessed. RESULTS: In subjects with MetS, percent changes in LDL-C and other lipids were greater with ezetimibe/simvastatin versus doubling baseline statin or numerically greater versus switching to rosuvastatin, except high-density lipoprotein cholesterol and apolipoprotein (Apo) AI (mean percent changes in LDL-C were: -22.49% ezetimibe/simvastatin, -9.64% doubled baseline statin and -19.20% rosuvastatin). In subjects without MetS, percent changes in LDL-C, total cholesterol and Apo B were greater with ezetimibe/simvastatin versus doubling baseline statin or numerically greater versus switching to rosuvastatin (mean percent changes in LDL-C were: -25.14% ezetimibe/simvastatin, -4.75% doubled baseline statin and -19.75% rosuvastatin). Safety profiles were generally similar. CONCLUSION: These results showed that switching to ezetimibe/simvastatin 10/20 mg was more effective at reducing LDL-C, total cholesterol and Apo B versus doubling the baseline statin dose to simvastatin 40 mg or atorvastatin 20 mg or switching to rosuvastatin 10 mg regardless of MetS status. These results were generally similar to those of the full cohort.

Parental responsiveness moderates the association between early-life stress and reduced telomere length.

Early-life stress, such as maltreatment, institutionalization, and exposure to violence, is associated with accelerated telomere shortening. Telomere shortening may thus represent a biomarker of early adversity. Previous studies have suggested that responsive parenting may protect children from the negative biological and behavioral consequences of early adversity. This study examined the role of parental responsiveness in buffering children from telomere shortening following experiences of early-life stress. We found that high-risk children had significantly shorter telomeres than low-risk children, controlling for household income, birth weight, gender, and minority status. Further, parental responsiveness moderated the association between risk and telomere length, with more responsive parenting associated with longer telomeres only among high-risk children. These findings suggest that responsive parenting may have protective benefits on telomere shortening for young children exposed to early-life stress. Therefore, this study has important implications for early parenting interventions.

P190A RhoGAP is required for mammary gland development.

P190A and p190B Rho GTPase activating proteins (GAPs) are essential genes that have distinct, but overlapping roles in the developing nervous system. Previous studies from our laboratory demonstrated that p190B is required for mammary gland morphogenesis, and we hypothesized that p190A might have a distinct role in the developing mammary gland. To test this hypothesis, we examined mammary gland development in p190A-deficient mice. P190A expression was detected by in situ hybridization in the developing E14.5day embryonic mammary bud and within the ducts, terminal end buds (TEBs), and surrounding stroma of the developing virgin mammary gland. In contrast to previous results with p190B, examination of p190A heterozygous mammary glands demonstrated that p190A deficiency disrupted TEB morphology, but did not significantly delay ductal outgrowth indicating haploinsufficiency for TEB development. To examine the effects of homozygous deletion of p190A, embryonic mammary buds were rescued by transplantation into the cleared fat pads of SCID/Beige mice. Complete loss of p190A function inhibited ductal outgrowth in comparison to wildtype transplants (51% vs. 94% fat pad filled). In addition, the transplantation take rate of p190A deficient whole gland transplants from E18.5 embryos was significantly reduced compared to wildtype transplants (31% vs. 90%, respectively). These results suggest that p190A function in both the epithelium and stroma is required for mammary gland development. Immunostaining for p63 demonstrated that the myoepithelial cell layer is disrupted in the p190A deficient glands, which may result from the defective cell adhesion between the cap and body cell layers detected in the TEBs. The number of estrogen- and progesterone receptor-positive cells, as well as the expression levels of these receptors was increased in p190A deficient outgrowths. These data suggest that p190A is required in both the epithelial and stromal compartments for ductal outgrowth and that it may play a role in mammary epithelial cell differentiation.