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PubMed2000

The distribution of inhaled particles in aerosol measurements of pulmonary airspace size.

When the deposition of aerosol boluses is used to estimate mean pulmonary airspace size, an implicit assumption is made that the inhaled particles are distributed uniformly among normal and diseased lung regions. This assumption was examined in a series of dogs in which emphysema was experimentally induced by exposure to papain. After the experimental disease had developed for several weeks, boluses of fluorescent particles were inhaled, using a breathing pattern similar to that used for aerosol measurements of airspace size. The lungs were then excised and 18-20 tissue blocks were obtained from each lung. A section from each tissue block was analyzed to determine the mean liner intercept (Lm), which was considered as an index of lung injury. In the same sections, the density of particles was determined by counting particles in a number of microscopic fields and dividing the particle count by the number of fields sampled. Correlation analysis generally revealed a negative correlation of particle density with Lm, indicating fewer particles being delivered to diseased regions. One lung, however, showed a positive correlation between particle density and Lm. Correction for the fractional deposition of aerosol in the lung regions weakened but did not reverse the relationship between particle density and Lm. A model calculation of the effect of the observed nonuniform distribution of aerosol on the determination of airspace size found a negligible effect of uneven ventilation on mean airspace size determination in this experimental preparation.

Administration, Inhalation↗

PubMed2005

Use of the next generation pharmaceutical impactor for particle size distribution measurements of live viral aerosol vaccines.

Aerosol administration of live measles vaccine virus has proven to be extremely efficacious in field trials using an industrial compressor coupled to a disposable nebulizer (IPI). To develop a new system for administration, it is necessary to characterize the operating characteristics of the old system. There are no standardized techniques for measuring particle size of live biological agents. This study evaluated the Next Generation Pharmaceutical Impactor's (NGI) ability to particle size wet aerosols in an effort to measure the particle size distribution of live measles vaccine from the IPI nebulizer. As a control albuterol was aerosolized using a Pari LC Star, since the soluble albuterol is evenly distributed throughout the droplets and laser diffraction measurements should agree with those from the NGI, as long as the NGI is cooled to prevent heat transfer to the aerosol. Albuterol was also used as a control for the IPI using quantitative ultraviolet spectrophotometry. There was close agreement in MMD (mean +/- 95% CI) for the LC Star, measured by laser diffraction (3.24 +/- 0.06 microm) and the NGI (2.93 +/- 0.22 microm) and the IPI (4.26 +/- 0.17 and 4.26 +/- 0.24 microm, respectively). For the measles vaccine assayed for plaque forming units, there were significant differences between the NGI MMD (6.14 +/- 0.39 microm) compared to laser diffraction (4.95 +/- 0.16 microm) indicating that the vaccine is not evenly distributed among the droplets of various sizes. This is likely clumping of the virus due to gelatin in the formulation. These data indicate that the NGI is capable of particle sizing live biological agents.

Administration, Inhalation↗

PubMed2006

A closed-loop control "playback" smoking machine for generating mainstream smoke aerosols.

A first generation smoking machine capable of reading and replicating detailed puffing behavior from recorded smoking topography data is presented. Unlike standard smoking machines, which model human puffing behavior as a steady periodic waveform with a fixed puff frequency, volume, and duration, this novel machine generates a mainstream smoke aerosol by automatically "playing-back" puff topography recordings. Because combustion chemistry is highly non-linear, representing real smoking behavior with a smoothed periodic waveform may result in a tobacco smoke aerosol with a significantly different chemical composition and physical properties than that generated by a smoker. The machine presented here utilizes a rapid closed-loop control algorithm coded in Labview to generate smoke aerosols for toxicological assessment and inhalation studies. To illustrate its use, dry particulate matter and carbon monoxide yields generated using the playback and equivalent periodic puffing regimens are compared for a single smoking session by a 26-year-old male narghile water-pipe smoker. It was found that the periodic puffing regimen yielded 20% less carbon monoxide (CO) than the played-back smoking session, indicating that steady periodic smoking regimens, which are widely used in tobacco smoke research, may not produce realistic smoke aerosols.

Aerosols↗

PubMed2006

Dry powder aerosol delivery systems: current and future research directions.

Development of dry powder aerosol delivery system involves powder production, formulation, dispersion, delivery, and deposition of the powder aerosol in the airways. Insufficiency of conventional powder production by crystallization and milling has led to development of alternative techniques. Over the last decade, performance of powder formulations has been improved significantly through the use of engineered drug particles and excipient systems which are (i) of low aerodynamic diameters (being porous or of low particle density), and/or (ii) less cohesive and adhesive (via corrugated surfaces, low bulk density, reduced surface energy and particle interaction, hydrophobic additives, and fine carrier particles). Early insights into particle forces and surface energy that help explain the improvement have been provided by analytical techniques such as the atomic force microscopy (AFM) and inverse gas chromatography (IGC). Relative humidity is critical to the performance of dry powder inhaler (DPI) products via capillary force and electrostatic interaction. Electrostatic charge of different particle size fractions of an aerosol can now be measured using a modified electrical low-pressure impactor (ELPI). Compared with powders, much less work has been done on the inhaler devices at the fundamental level. Most recently, computational fluid dynamics has been applied to understand how the inhaler design (such as mouthpiece, grid structure, air inlet) affects powder dispersion. The USP throat is known to under-represent the oropharyngeal deposition of DPI aerosols. Studies using magnetic resonance imaging (MRI) model casts have been undertaken to explain the inter- and intra- subject variation in oropharyngeal deposition. Most of the lung deposition studies performed on commercial products did not allow a thorough understanding of the determinants affecting in vivo lung deposition. A more systematic approach would be necessary to build a useful database on the dependence of lung deposition on the breathing parameters, inhaler design, and powder formulation properties.

Administration, Inhalation↗

PubMed2006

Characterization of regional and local deposition of inhaled aerosol drugs in the respiratory system by computational fluid and particle dynamics methods.

The present work describes the local deposition patterns of therapeutic aerosols in the oropharyngeal airways, healthy and diseased bronchi and alveoli using computational fluid and particle dynamics techniques. A user-enhanced computational fluid dynamics commercial finite- volume software package was used to compute airflow fields, deposition efficiencies, and deposition patterns of therapeutic aerosols along the airways. Adequate numerical meshes, generated in different airway sections, enabled us to more precisely define trajectories and local deposition patterns of inhaled particles than before. Deposition patterns show a high degree of heterogeneity of deposition along the airways, being more uniform for nanoparticles compared to micro-particles in the whole respiratory system at all inspiratory flow rates. Extrathoracic and tracheobronchial deposition fractions of nanoparticles decrease with increasing flow rates. However, vice versa happens to the micron-size particles, that is, the deposition fraction is higher at high flow rates. Both airway constrictions and the presence of tumors significantly increased the deposition efficiencies compared to the deposition efficiencies in healthy airways by a factor ranging from 1.2 to 4.4. In alveoli, the deposition patterns are strongly influenced by particle size and direction of gravity. This study demonstrated that numerical modeling can be a powerful tool in the aerosol drug delivery optimization. Present results may be integrated in future aerosol drug therapy protocols.

Administration, Inhalation↗

PubMed2006

Analytical technique to recover the third dimension in planar imaging of inhaled aerosols: (1) impact on spatial quantification.

An analytical algorithm is described for converting planar scintigraphic images of aerosol distributions in the lungs to an equivalent three-dimensional (3D) representation. The recovery of volumetric information should benefit regional quantification. The technique has been validated using simulated planar images of eleven known aerosol distributions in ten realistic lungs. Global and regional 3D parameters, such as the total activity deposition (A), the penetration index (PI) and the relative penetration index (rPI), were quantified on the planar images and on their 3D representation. Random and systematic errors of the estimation were measured. Finally, the performance of planar imaging was compared with that of single-photon emission computed tomography (SPECT). SPECT images were simulated for the same aerosol distributions in the same subjects and quantified for A, PI, and rPI. The systematic errors in A, PI and rPI obtained from planar imaging were 8.9%, 64.8%, and 54.1%, respectively, using the two-dimensional (2D) analysis; they improved significantly to 4.4%, 19.0%, and 25.5% with the 3D analysis (p < 0.01). The corresponding values for SPECT were 5.2%, 9.8%, and 15.7%, significantly better for PI and rPI (p < 0.01). The random errors of A were similar for all techniques being about 5%; those of PI and rPI measurements were significantly higher for planar imaging (<or=14%) than SPECT (<or=8%). In conclusion, 3D spatial parameters can be derived from planar imaging that are significantly more accurate in characterizing different aerosol depositions than their 2D counterpart. However, the errors remain significantly higher than with SPECT.

Administration, Inhalation↗

PubMed2003

Estimating aerosol surface area from number and mass concentration measurements.

A number of toxicology studies have been published indicating that health effects associated with low-solubility inhaled particles may be more appropriately associated with particulate surface area than mass. While exposure data from the workplace is needed to further investigate the relevance of such an association, the means of measuring exposure to aerosol surface area are not readily available. A possible interim solution is to estimate surface area from measurements of particle number and mass concentration using readily available direct-reading instruments. By assuming a lognormal aerosol size distribution with a specific geometric standard deviation, number and mass concentration measurements may be used to estimate the surface area concentration associated with the distribution. Simulations have shown that surface area estimates made on unimodal lognormal aerosols will frequently lie within 100% of the actual value. Simulations using bimodal distributions indicate estimates of surface area vary from the actual value by less than an order of magnitude. Calculations based on experimental unimodal and bimodal data confirm these findings, with estimated surface area rarely being a factor of 4 greater than the actual value, and frequently being much closer than this. These findings indicate that estimating aerosol surface area exposure using readily available number and mass concentration direct-reading instruments may be suitable for providing initial data on the magnitude of surface area exposures with minimal additional effort. This would allow the accumulation of valuable exposure-response data prior to the development and implementation of more sophisticated instrumentation to more accurately estimate surface area exposure.

Aerosols↗

PubMed2004

Determinants of exposure to metalworking fluid aerosol in small machine shops.

The purpose of this study was to evaluate personal exposure to metalworking fluid (MWF) aerosols in very small machine shops (1-8 machinists per shop) and to investigate workplace factors associated with exposures. A total of 20 willing machine shops in Vancouver, Canada (from 46 eligible shops, 43%) and 88 machinists participated (participation rate for machinists 92%). Most machinists wore two personal sampling trains (an open-faced 37 mm cassette and a PM10 impactor) on each of two full work shifts. Observational data were collected regarding potential determinants of exposure at 15 min intervals throughout each shift. A total of 322 personal samples were taken over 54 days. Mean aerosol exposure was 0.32 mg/m3 (range 0.06-2.19) for the 37 mm cassette samples and 0.27 mg/m3 (range 0.026-3.67) for PM10. Exposures from the two sampler types were highly correlated (R = 0.86). The mean shop-specific ratio comparing exposure from the 37 mm cassette with that from the PM10 sampler was 1.43 and varied significantly across shops, ranging from 0.97 to 2.19. Machine, task and shop characteristics associated with significantly increased aerosol exposure included the proportion of time spent grinding, operating an enclosed computer controlled machine, the presence of welding in the shop for both sampler types and the number of machines using MWF for PM10 samples only. Factors associated with reduced aerosol exposure included machining aluminum, milling, the height (and shape) of the shop roof (for both sample types) and the presence of mechanical shop ventilation (for the 37 mm cassette samples).

Aerosols↗

PubMed1990

Separation and quantitation of monovalent anionic and cationic species in mainstream cigarette smoke aerosols by high-performance ion chromatography.

A simple method has been developed to separate and quantitate monovalent ionic species in mainstream cigarette smoke aerosols based on ion chromatography (IC) with conductivity detection. The method entails collecting the smoke aerosol particulate phase by electrostatic precipitation, dissolving the smoke condensate in methanol (MeOH), and separating the ionic species on either a cation- or anion-exchange column. The method has been applied to the analysis of smoke aerosols from two cigarettes, 1R4F Kentucky Reference cigarettes and a new cigarette that heats but does not burn tobacco. The predominant cations in smoke aerosols from 1R4F Kentucky Reference and the new cigarettes are sodium (Na+), ammonium (NH4+), and potassium (K+) ions; the predominant anions are acetate (AcO-) and formate (HCOO-). Trace amounts of chloride (Cl-), nitrite (NO2-), and nitrate (NO3-) ions are also present.

1-Propanol↗

PubMed1996

Aerosolization of imipenem/cilastatin prevents pseudomonas-induced acute lung injury.

Aerosolization of imipenem/cilastatin was compared with continuous intravenous infusions of the antibiotic for pharmacokinetic/pharmacodynamic analysis. The concentrations of imipenim/cilastatin in bronchoalveolar lavage fluids (BAL) obtained from rats exposed to the aerosolized antibiotic were significantly greater than the concentrations in BAL in the rats that had received intravenous infusions of imipenem/cilastatin. The two methods of antibiotic delivery were compared for their effects on bacterial-induced lung injury in rats that had Pseudomonas aeruginosa instilled into their airspaces. The aerosolization of antibiotic was associated with significantly decreased bacterial-induced lung injury. The high concentrations of antibiotic in the airspaces secondary to aerosolization appears to kill bacteria more quickly and preserve lung epithelial and endothelial integrity better than systemic delivery of the same antibiotic.

Administration, Inhalation↗

PubMed1995

Effects of aerosolized pentamidine on glucose homeostasis and insulin secretion in HIV-positive patients: a controlled study.

OBJECTIVE: Intravenous pentamidine induces hypo- and hyperglycaemia (dose-dependent toxicity on islet beta cells), pancreatitis and nephrotoxicity. Conversely, aerosolized pentamidine (AP) is usually devoid of systemic side-effects: few reports of hypo- or hyperglycaemia have been published. Our study aimed to assess the influence on glucose homeostasis and insulin secretion of long-term exposure to AP used for prophylaxis of Pneumocystis carinii pneumonia in HIV-positive patients, and to compare the impact on insulin secretion of AP, whether administered for the first time or after prolonged monthly exposure. DESIGN: Retrospective cross-sectional controlled study (main objective) and non-randomized prospective controlled study. PATIENTS: We compared glucose homeostasis and C peptide response to 1 mg intravenous glucagon in patients who had previously inhaled > or = 10 prophylactic aerosols (group 1, n = 21) and in HIV-positive controls (groups 2 and 3, n = 28) who had received none. Both groups were comparable for age and body-mass index, but CD4 T-lymphocyte counts and Karnofsky scores were both significantly higher in the control group. RESULTS: Fasting (T0) blood glucose, fructosamine and response to the first glucagon test were similar in both groups, but postprandial glucose, glycated haemoglobin and fasting C peptide were significantly higher (P < 0.05) in the pentamidine group. A second glucagon test was performed on the same day, 3 h (T3) after AP inhalation in 35 patients (in 21 after > or = 10 aerosols, group 1; in 14 after the first, group 2) and in 14 HIV-positive controls (group 3). The only significant difference between the three groups in C peptide response to this second test was a lower peak T3/peak T0 ratio in group 1. Plasma amylase and creatinine were not altered by the aerosol. CONCLUSION: Long-term prophylactic exposure to AP had minor but significant effects on glucose homeostasis and insulin secretion but did not modify pancreatic and renal function. The detrimental effects induced by long-term exposure to AP found in our study are probably not clinically relevant, but a more prolonged exposure to AP might conceivably induce more severe alterations.

AIDS-Related Opportunistic Infections↗

PubMed1984

Effects of aerosolized lidocaine on circulatory responses to laryngoscopy and tracheal intubation.

Topical anesthesia of oropharynx with lidocaine aerosol (6 ml of 4% for 5 min) prevented hypertension and tachycardia during laryngoscopy and tracheal intubation. In the control group (saline aerosol), systolic and mean BP as well as heart rate (HR) significantly increased during laryngoscopy and intubation. These changes were still present after 5 min. No patient in the aerosolized lidocaine group developed any premature ventricular contraction (PVC), but 4 of 10 patients in the control group had 2 to 3 PVCs during laryngoscopy and intubation. The pressor response and tachycardia observed during laryngoscopy and tracheal intubation were, thus, successfully prevented by lidocaine aerosolization. This simple technique for oropharyngeal anesthesia before laryngoscopy intubation may be considered, particularly in patients with intracranial pathology and/or decreased myocardial reserve.

Adult↗

PubMed1997

Delivery of metered dose inhaler aerosols to paralyzed and nonparalyzed rabbits.

OBJECTIVE: To assess whether paralysis alters pulmonary deposition of albuterol delivered by metered dose inhaler and spacer to small animals. DESIGN: A parallel group study of intubated and ventilated rabbits. INTERVENTIONS: Animals in group 1 (n = 7) were paralyzed with intravenous pancuronium, and ventilated at a rate of 30 breaths/ min. The animals in group 2 (n = 6) were ventilated at a rate of 10 breaths/min under light anesthesia without paralysis. In this latter group, spontaneous respiration continued at a rate of 40 to 50 breaths/min. Both groups were maintained at PaCO2 of 35 to 40 torr (4.7 to 5.3 kPa), and other ventilatory settings were identical. MEASUREMENTS AND MAIN RESULTS: Technetium-99m labeled albuterol aerosol was delivered by metered dose inhaler via a spacer device to both groups. Pulmonary deposition of the aerosol, determined by measuring the radioactivity in the lung tissues at autopsy, was expressed as percent of the total radioactivity dispensed by the metered dose inhaler. Group 2 showed significantly greater lung deposition than group 1 (0.510 +/- 0.076 [SEM]% vs. 0.226 +/- 0.054%, p = .0094). Deposition in the airway, the endotracheal tube, and the ventilator circuit did not differ significantly. CONCLUSION: Metered dose inhaler delivery of aerosolized medications to ventilated rabbits is significantly enhanced if respiration is not controlled. This observation might have implications for the delivery of therapeutic aerosols to newborns and young infants receiving slow, intermittent, mandatory ventilation.

Aerosols↗

PubMed1998

Aerosolized antibiotics in mechanically ventilated patients: delivery and response.

OBJECTIVES: To determine whether aerosolized antibiotics can be delivered efficiently to the lower respiratory tract in mechanically ventilated patients and to define possible clinical responses to these agents. DESIGN: Prospective serial study with cases as their own control. SETTING: A 10-bed respiratory care unit for patients with chronic respiratory failure in a tertiary university hospital. PATIENTS: Ventilator dependent patients who are otherwise medically stable. All subjects had a tracheostomy in place, were colonized with gram-negative organisms, and produced purulent secretions which could be sampled daily. INTERVENTIONS: Six patients received nine courses of nebulized therapy, which consisted of treatments every 8 hrs of gentamicin (80 mg) or amikacin (400 mg) for 14 to 21 days. MEASUREMENTS AND MAIN RESULTS: Doses to the lung were measured using radiolabeled aerosols and antibiotic concentrations in sputum. The response was assessed by a) changes in the volume of respiratory secretions; b) effect on bacterial cultures; and c) changes in the inflammatory cells and mediators of inflammation of the respiratory secretions (interleukin-1beta [IL-1beta], tumor necrosis factor-alpha [TNF-alpha], soluble intercellular adhesion molecule-1 [sICAM-1], and human leukocyte elastase). On average, patients inhaled 35.4 +/- 5.08% (SD) of the initial drug placed in the nebulizer (neb-charge). Of this neb-charge, 9.50 +/- 2.78% was found on the respirator tubing and tracheostomy tube and 21.9 +/- 7.15% was actually deposited in the lungs. The remainder of the neb-charge was sequestered in the nebulizer or exhaled. Trough sputum concentrations averaged 4.3 +/- 3.2 microg/mL/mg neb-charge (range 234 to 520 microg/mL) and increased to 16.6 +/- 8.1 microg/mL/mg neb-charge (range 1005 to 5839 microg/mL) immediately after therapy (p = .011). Serum concentrations were undetectable in most determinations except for a single patient who was in renal failure (8.7 microg/mL amikacin). Treatment caused a significant reduction in the volume of secretions (p = .002). Weekly cultures revealed eradication of Pseudomonas species, Serratia marcescens, and Enterobacter aerogenes in most of the trials. Before antibiotic treatment, concentrations of IL-1beta were higher than those reported in acute respiratory distress syndrome. Throughout the duration of the study, IL-1beta correlated significantly with the absolute number of macrophages, neutrophils, and lymphocytes, respectively (r2 = .55, p = .002; r2 = .50, p < .0004, r2 = .36, p = .005). TNF-alpha concentrations correlated with lymphocytes and neutrophils, respectively (r2 =.27, p = .013, r2 = .21, p = .033). sICAM-1 concentrations increased two-fold (p < .001) during treatment and then returned to baseline. The volume of secretions was related to neutrophil and IL-1beta concentrations, respectively (r2 = .25, p = .008, r2= .35, p = .006). CONCLUSIONS: Nebulizer delivery of aerosolized aminoglycosides is efficient and predictable. In our clinical model, aerosolized antibiotics can make a significant impact on respiratory secretions. Their efficacy in treatment of critically ill patients remains to be determined.

Adult↗

PubMed2000

Plastic bronchitis occurring late after the Fontan procedure: treatment with aerosolized urokinase.

OBJECTIVE: To describe the use of aerosolized urokinase in a patient with plastic bronchitis after a Fontan procedure. DESIGN: Case report. SETTING: Pediatric intensive care unit in a university-affiliated children's hospital. PATIENTS: Report of one patient with acute respiratory failure secondary to plastic bronchitis. INTERVENTIONS: Aerosolized urokinase, multiple bronchoscopies, corticosteroids, mucolytics, bronchodilators, and atrial pacing. MEASUREMENTS AND MAIN RESULTS: Airway obstruction secondary to recurring casts improved with the treatments. Histologic analysis of the casts demonstrated less fibrin after treatments with aerosolized urokinase. No adverse events were noted. CONCLUSIONS: The addition of aerosolized urokinase to this patient's treatment regimen helped to resolve life-threatening airway obstruction secondary to fibrin casts.

Acute Disease↗

PubMed1992

A continuous sampler with background suppression for monitoring alpha-emitting aerosol particles.

A continuous air monitor has been developed that includes provisions for improving the detection of alpha-emitting aerosol particles in the presence of radon/thoron progeny that are unattached to ambient aerosol particles. Wind tunnel tests show that 80% of 10-microns aerodynamic equivalent diameter particles penetrate the flow system from the ambient air to the collection filter when the flow rate is 57 L min-1 (2 cfm) and the wind speed is 1 m s-1. Uniformity of aerosol collection on the filter, as characterized by the coefficient of variation of the areal density deposits, is less than 15% for 10-microns aerodynamic-equivalent-diameter aerosol particles. Tests with unattached radon daughters in a flow-through chamber showed that approximately 99% of the 218Po was removed by an inlet screen that is designed to collect radon daughters that are in the size range of molecular clusters. The inlet screen offers the opportunity to improve the signal-to-noise ratio of energy spectra in the regions of interest (subranges of the energy spectrum) of transuranic elements and thereby enhance the performance of background compensation algorithms.

Aerosols↗

PubMed1993

Analyses of radioactive aerosols to support accurate internal dose assessments at Chin-Shan nuclear power plant.

Studies of the physical and chemical properties of radioactive aerosols produced in different work environments were made at Chin-Shan nuclear power plant in Taiwan. These properties, including particle mass- and activity-size distributions, elemental and radionuclide compositions, and solubility lung class, are essential for the assessment of internal dose equivalents from the inhalation of radioactive aerosols. Several practices and environments studied include thermal arc cutting, grinding, sandblasting, and noble gas progeny. For physical analyses, cascade impactors, scanning electron microscopy with energy-dispersive x-ray analysis, inductively coupled plasma atomic emission spectrometry, and neutron activation analysis were applied. For chemical analyses, the solubility lung class was determined, in vitro, with the measurement of aerosol dissolution rates in simulated biological fluids. Results of these analyses were used to calculate the annual limit on intake, the derived air concentration, and committed dose equivalents for radiological protection against radioactive aerosols produced at Chin-Shan nuclear power plant.

Aerosols↗

PubMed1987

Aerosolized gadolinium-DTPA enhances the magnetic resonance signal of extravascular lung water.

Gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA), a contrast agent for magnetic resonance imaging, was administered by either aerosol or intravenous injection to rats. Proton relaxation times in excised lungs and kidneys were then measured. With increasing concentrations of aerosolized Gd-DTPA, the spin-lattice relaxation time (T1) of lungs decreased (enhanced) significantly (P less than .001), an effect that persisted for at least 80 minutes; there was no change in kidney T1. After intravenous injection of Gd-DTPA, lung T1 did not change, but kidney T1 decreased significantly (P less than .001), confirming previous observations of renal clearance. It is concluded that aerosolized Gd-DTPA is a more efficacious method of delivery of paramagnetic contrast agent to the lungs than intravenous injection, and that the lack of systemic effect after aerosolization indicates that enhancement was limited to the extravascular compartment.

Administration, Inhalation↗