Efficacy and Safety of Tirzepatide in Adults With Type 2 Diabetes: A Perspective for Primary Care Providers.

This article reviews the efficacy and safety data of tirzepatide, a once-weekly, novel glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 (GLP-1) receptor agonist approved in the United States, the European Union, and other regions for the treatment of type 2 diabetes. All doses of tirzepatide demonstrated superiority in reducing A1C and body weight from baseline versus placebo or active comparators. The safety profile of tirzepatide was consistent with that of the GLP-1 receptor agonist class, with mild to moderate and transient gastrointestinal side effects being the most common adverse events. With clinically and statistically significant reductions in A1C and body weight without increased risk of hypoglycemia in various populations, tirzepatide has demonstrated potential as a first-in-class treatment option for many people with type 2 diabetes.

Achievement of glycaemic targets with weight loss and without hypoglycaemia in type 2 diabetes with the once-weekly glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist tirzepatide: A post hoc analysis of the SURPASS-1 to -5 studies.

AIM: To assess composite endpoints combining glycaemic control (HbA1c < 7.0%, ≤ 6.5% or < 5.7%) with weight loss (≥ 5%, ≥ 10% or ≥ 15%) and without hypoglycaemia with tirzepatide in type 2 diabetes (T2D). MATERIALS AND METHODS: Data from the phase 3 SURPASS programme were evaluated post hoc by trial. Participants with T2D were randomized to tirzepatide (5, 10 and 15 mg), placebo (SURPASS-1,5), semaglutide 1 mg (SURPASS-2) or titrated basal insulin (SURPASS-3,4). The proportions of participants achieving the composite endpoints were compared between tirzepatide and the respective comparator groups at week 40/52. RESULTS: The proportions of participants achieving an HbA1c value of less than 7.0% with 5% or more weight loss and without hypoglycaemia ranged from 43% to 82% with tirzepatide across the SURPASS-1 to -5 trials versus 4%-5% with placebo, 51% with semaglutide 1 mg and 5% with basal insulin (P < .001 vs. all comparators). The proportions of participants achieving an HbA1c value of less than 7.0% with 10% or more, or 15% or more weight loss and without hypoglycaemia were significantly higher with all tirzepatide doses versus comparators across trials (P < .001 or P < .05). Similar results were observed for all other combinations of endpoints with an HbA1c value of 6.5% or less, or less than 5.7%, with more tirzepatide-treated participants achieving these endpoints versus those in the comparator groups, including semaglutide. CONCLUSIONS: Across the SURPASS-1 to -5 clinical trials, more tirzepatide-treated participants with T2D achieved clinically meaningful composite endpoints, which included reaching glycaemic targets with various degrees of weight loss and without hypoglycaemia, than those in the comparator groups.

Influence of the particle size of encapsulated chia oil on the oil release and bioaccessibility during in vitro gastrointestinal digestion.

Among vegetable oils, chia oil has been gaining interest in recent years due to its high linolenic acid content (ALA, 18:3 ω3). The aim of this work was to study the influence of the particle size of encapsulated purified chia oil (PCO) on the encapsulation efficiency and PCO release during in vitro digestion. PCO micro- and nano-sized particles with sodium alginate (SA) as an encapsulating agent (ME-PCO-SA and NE-PCO-SA) were designed by micro and nano spray-drying, respectively, applying a central composite plus star point experimental design. NE-PCO-SA showed a smaller particle size and higher encapsulation efficiency of PCO than ME-PCO-SA (0.16 µm vs. 3.5 µm; 98.1% vs. 92.0%). Emulsions (NE-PCO and ME-PCO) and particles (NE-PCO-SA and ME-PCO-SA) were subjected to in vitro static gastrointestinal digestion. ME-PCO and NE-PCO showed sustained oil release throughout the three phases of digestion (oral, gastric and intestinal phases), whereas the PCO release from ME-PCO-SA and NE-PCO-SA occurred mainly in the intestinal phase, showing the suitability of sodium alginate as an intestine-site release polymer. Nano-sized particles showed a significantly higher PCO release after in vitro digestion (NE-PCO-SA, 78.4%) than micro-sized particles (ME-PCO-SA, 69.8%), and also higher bioaccessibility of individual free fatty acids, such as C18:3 ω-3 (NE-PCO-SA, 23.6%; ME-PCO-SA, 7.9%), due to their greater surface area. However, when ME-PCO-SA and NE-PCO-SA were incorporated into yogurt, the PCO release from both particle systems after the digestion of the matrix was similar (NE-PCO-SA, 58.8%; ME-PCO-SA-Y, 61.8%), possibly because the calcium ions contained in the yogurt induced partial ionic gelation of SA, impairing the PCO release. Sodium alginate spray-dried micro and nanoparticles showed great potential for vehiculation of omega-3 rich oils in the design of functional foods.

Simulating human digestion: developing our knowledge to create healthier and more sustainable foods.

The gold standard for nutrition studies is clinical trials but they are expensive and variable, and do not always provide the mechanistic information required, hence the increased use of in vitro and increasingly in silico simulations of digestion. In this review, we give examples of the main simulations being used to model upper gastrointestinal tract digestion. This review ranges from the selection of enzymes to the interpretation of results from static models to fully dynamic models. We describe the modifications made to accommodate different demographic groups (infants, the elderly, etc.). We list examples of the application of the different models as well as giving the advantages and disadvantages. A model is only useful if it predicts or aids the understanding of physiological behaviour. Thus, the final section of the review makes a comparison of results obtained from experiments undertaken using in vitro simulations with those obtained in vivo. This comparison will help the reader understand the appropriateness of each model for the type of measurement to be undertaken. In particular, human studies tend to measure bioactive concentrations in blood and not in the gastrointestinal tract whereas in vitro studies often only produce data on release of nutrients into the gut lumen. This is the difficulty of comparing bioaccessibility as generated in vitro with bioavailability as generated in vivo. It is apparent that the models being used are increasingly being validated with in vivo data and this bodes well for the future.

Human gastrointestinal conditions affect in vitro digestibility of peanut and bread proteins.

As plant proteins are increasingly used as a source of amino acids in the diet, studies on in vitro digestion of plant proteins are key to understand the different factors affecting proteolysis, with the ultimate goal of optimising the nutritional composition/intake of plant protein-rich products. More realistic scenarios including the most likely food matrix and physiologically relevant gastrointestinal (GI) conditions should be considered when assessing the in vitro digestion of proteins. The research described here compares the extent of hydrolysis of proteins from peanuts and wheat bread, in particular the vicilin-like 7S globulin (Ara h 1) and gliadin, respectively, with three GI scenarios simulating either infant, early phase adult (fed state) or late phase adult (fasted state) conditions. The digestibility of these proteins, in isolation or when naturally present in the respective food matrix, has been evaluated with SDS-PAGE, LC-MS/MS and a spectrophotometric assay. Results from the food matrices showed lower extent of total protein GI digestion under simulated infant conditions, intermediate behaviour under fed state adult conditions and larger extent under fasted state adult conditions. This was also the case for isolated gliadin. However, isolated Ara h 1 only showed lower extent of proteolysis in the gastric phase under infant conditions, reaching a similar extent to both adult conditions over the course of the intestinal phase. The food matrix seems to have delayed the proteolysis. Choosing an appropriate GI scenario as well as the matrix of the end food product is paramount when assessing in vitro protein digestion.

The pattern of peptides released from dairy and egg proteins is highly dependent on the simulated digestion scenario.

Evaluating the gastrointestinal (GI) fate of proteins is part of the assessment to determine whether proteins are safe to consume. In vitro digestion tests are often used for screening purposes in the evaluation of potential allergenicity. However, the current pepsin resistant test used by the European Food Safety Authority, only corresponds to fasted gastric conditions representative of a late phase adult stomach. In addition, these tests are performed on isolated proteins and the effect of the food matrix and processing are not systematically considered. The aim of this research is to compare three different static in vitro GI scenarios that are physiologically relevant. Namely, an infant, early phase (fed state) adult and late phase (fasted state) adult model. These protocols are applied to well-characterised isolated dairy (ß-lactoglobulin and ß-casein) and egg (lysozyme and ovalbumin) proteins and the impact of food matrix/processing on their proteolysis is also investigated. A combination of SDS-PAGE, LC-MS/MS and spectrophotometric assay was used for the evaluation of the proteolysis. Results highlight differences across the three GI scenarios whether on isolated proteins or within food matrices. The infant model led to incomplete digestion, leaving intact egg proteins, either isolated or in the food matrix, and intact ß-lactoglobulin in the milk. In addition, peptides greater than 9 amino acids were found throughout the intestinal phase for all proteins studied, regardless of the scenario. This reinforces the difficulty of linking protein digestibility to potential allergenicity because many other factors are involved that need further investigation.

Impact of caseins and whey proteins ratio and lipid content on in vitro digestion and ex vivo absorption.

Caseins and whey proteins are known as 'slow' and 'fast' proteins, respectively, based on their amino acid absorption rate. However, there is limited understanding of the mechanisms controlling their behaviour during gastro-intestinal transit. A protein model system (8% total protein) with varying casein:whey protein ratios (0:100, 20:80, 50:50 and 80:20) were subjected to in vitro gastro-intestinal digestion using a semi-dynamic gastric model, a static intestinal model and an ex vivo absorption model (Ussing chambers). The casein-rich (≥50%) samples showed the formation of solid coagula that were persistent throughout gastric digestion, which caused a delay in nutrient emptying, slower digestion and leucine absorption kinetics. In contrast, whey proteins formed more soluble aggregates during the gastric phase, which led to faster gastric emptying, rapid intestinal hydrolysis, and higher and faster leucine absorption. This work shows the key role of the gastric restructuring for the overall digestive mechanism and kinetics of food, in particular proteins.

The antibiotic vancomycin induces complexation and aggregation of gastrointestinal and submaxillary mucins.

Vancomycin, a branched tricyclic glycosylated peptide antibiotic, is a last-line defence against serious infections caused by staphylococci, enterococci and other Gram-positive bacteria. Orally-administered vancomycin is the drug of choice to treat pseudomembranous enterocolitis in the gastrointestinal tract. However, the risk of vancomycin-resistant enterococcal infection or colonization is significantly associated with oral vancomycin. Using the powerful matrix-free assay of co-sedimentation analytical ultracentrifugation, reinforced by dynamic light scattering and environmental scanning electron microscopy, and with porcine mucin as the model mucin system, this is the first study to demonstrate strong interactions between vancomycin and gastric and intestinal mucins, resulting in very large aggregates and depletion of macromolecular mucin and occurring at concentrations relevant to oral dosing. In the case of another mucin which has a much lower degree of glycosylation (~60%) - bovine submaxillary mucin - a weaker but still demonstrable interaction is observed. Our demonstration - for the first time - of complexation/depletion interactions for model mucin systems with vancomycin provides the basis for further study on the implications of complexation on glycopeptide transit in humans, antibiotic bioavailability for target inhibition, in situ generation of resistance and future development strategies for absorption of the antibiotic across the mucus barrier.

Bile salts in digestion and transport of lipids.

Because of their unusual chemical structure, bile salts (BS) play a fundamental role in intestinal lipid digestion and transport. BS have a planar arrangement of hydrophobic and hydrophilic moieties, which enables the BS molecules to form peculiar self-assembled structures in aqueous solutions. This molecular arrangement also has an influence on specific interactions of BS with lipid molecules and other compounds of ingested food and digestive media. Those comprise the complex scenario in which lipolysis occurs. In this review, we discuss the BS synthesis, composition, bulk interactions and mode of action during lipid digestion and transport. We look specifically into surfactant-related functions of BS that affect lipolysis, such as interactions with dietary fibre and emulsifiers, the interfacial activity in facilitating lipase and colipase anchoring to the lipid substrate interface, and finally the role of BS in the intestinal transport of lipids. Unravelling the roles of BS in the processing of lipids in the gastrointestinal tract requires a detailed analysis of their interactions with different compounds. We provide an update on the most recent findings concerning two areas of BS involvement: lipolysis and intestinal transport. We first explore the interactions of BS with various dietary fibres and food emulsifiers in bulk and at interfaces, as these appear to be key aspects for understanding interactions with digestive media. Next, we explore the interactions of BS with components of the intestinal digestion environment, and the role of BS in displacing material from the oil-water interface and facilitating adsorption of lipase. We look into the process of desorption, solubilisation of lipolysis, products and formation of mixed micelles. Finally, the BS-driven interactions of colloidal particles with the small intestinal mucus layer are considered, providing new findings for the overall assessment of the role of BS in lipid digestion and intestinal transport. This review offers a unique compilation of well-established and most recent studies dealing with the interactions of BS with food emulsifiers, nanoparticles and dietary fibre, as well as with the luminal compounds of the gut, such as lipase-colipase, triglycerides and intestinal mucus. The combined analysis of these complex interactions may provide crucial information on the pattern and extent of lipid digestion. Such knowledge is important for controlling the uptake of dietary lipids or lipophilic pharmaceuticals in the gastrointestinal tract through the engineering of novel food structures or colloidal drug-delivery systems.

Chloroplast-rich material from the physical fractionation of pea vine (Pisum sativum) postharvest field residue (Haulm).

An innovative procedure for plant chloroplasts isolation has been proposed, which consists of juice extraction by physical fractionation from plant material and recovery of its chloroplast-rich fraction (CRF) by centrifugation. This simple method has been applied to pea vine haulm subjected to different post-harvest treatments: blanching, storage at different relative humidity values and fermentation. Additionally, freeze storage of the extracted juice was carried out. The macronutrient (total lipids, proteins, ash and carbohydrates) and micronutrient (fatty acids, chlorophylls, ß-carotene, α-tocopherol and ascorbic acid) content and composition of the CRF have been determined. The CRF isolated from fresh pea vine haulm is a potential source of essential micronutrients (α-linolenic acid, ß-carotene, α-tocopherol) and carbohydrates, whereas the post-harvest treatments trialled have a detrimental effect on the nutritional content. Industrial applications for the recovered nutritionally rich fraction, such as food supplement ingredient or animal feeding, are likely envisaged, while optimising the use of green haulm.

Calcium Alters the Interfacial Organization of Hydrolyzed Lipids during Intestinal Digestion.

Calcium plays an important dual role in lipid digestion: promoting removal of long-chain fatty acids from the oil-water interface by forming insoluble calcium soaps while also limiting their bioaccessibility. This becomes more significant in food containing high calcium concentration, such as dairy products. Nevertheless, scarce attention has been paid to the effect of calcium on the interfacial properties during lipid digestion, despite this being largely an interfacial reaction. This study focused on the dynamics of the formation of calcium soaps at the oil-water interface during lipolysis by pancreatic lipase in the absence and presence of the two primary human bile salts (sodium glycocholate or sodium glycochenodeoxycholate). The competitive adsorption of lipase, bile salts, and lipolysis products, as well as the formation of calcium soaps in the presence of increasing concentrations of calcium were mainly characterized by recording the interfacial tension and dilatational modulus in situ. In the absence of bile salts, calcium complexes with fatty acids at the oil-water interface forming a relatively strong viscoelastic network of calcium soaps over time. The dilatational modulus of the calcium soap network is directly related to the interfacial concentration of lipolysis products and the calcium bulk concentration. Calcium soaps are also visualized forming a continuous rough layer on the surface of oil droplets immersed in simulated intestinal aqueous phase. Despite bile salts having different surface activity, they play a similar role on the interfacial competition with lipase and lipolysis products although altering their kinetics. The presence of bile salts disrupts the network of calcium soaps, as suggested by the decrease in the dilatational modulus and the formation of calcium soap islands on the surface of the oil droplets. The accelerant effect of calcium on lipolysis is probably because of fatty acid complexation and subsequent removal from the interface rather than reduced electrostatic repulsion between lipase and bile salt molecules and promoted lipase adsorption. The work shown here has implications for the delivery of oil-soluble bioactives in the presence of calcium.

Instant polysaccharide-based emulsions: impact of microstructure on lipolysis.

The development of emulsion-based products through optimisation of ingredients, reduction in energy-input during manufacture, while fulfilling healthy attributes, are major objectives within the food industry. Instant emulsions can meet these features, but comprehensive studies are necessary to investigate the effect of the initial formulation on the final microstructure and, in turn, on the in vitro lipolysis, comprising the double aim of this work. The instant emulsion is formed within 1.5-3 min after pouring the aqueous phase into the oil phase which contains a mixture of emulsifier (Tween 20), swelling particles (Sephadex) and thickeners (hydroxypropylmethylcellulose, HPMC, and guar gum, GG) under mild shearing (180 rpm). The creation of oil-in-water emulsions is monitored in situ by viscosity analysis, the final microstructure visualised by microscopy and the release of free fatty acids under simulated intestinal conditions quantified by titration. Increasing the concentration and molecular weight (Mw) of GG leads to smaller emulsion droplets due to increased bulk viscosity upon shearing. This droplet size reduction is magnified when increasing the Mw of HPMC or swelling capacity of viscosifying particles. In addition, in the absence of the emulsifier Tween 20, the sole use of high-Mw HPMC is effective in emulsification due to combined increased bulk viscosity and interfacial activity. Hence, optimisation of the ingredient choice and usage level is possible when designing microstructures. Finally, emulsions with larger droplet size (>20 µm) display a slower rate and lower extent of lipolysis, while finer emulsions (droplet size ≤20 µm) exhibit maximum rate and extent profiles. This correlates with the extent of emulsion destabilisation observed under intestinal conditions.

Influence of interfacial and bulk properties of cellulose ethers on lipolysis of oil-in-water emulsions.

Cellulose ethers are usually used as secondary emulsifiers. Different types of commercial hydroxypropylmethylcellulose (HPMC) have been used here as the main emulsifier of oil-in-water emulsions to probe their impact on the lipid digestibility under simulated intestinal conditions. The droplet size distribution and ζ-potential of the emulsions subjected to in-vitro lipolysis have been compared with that of control samples (non-digested). The lipolysis has been quantified over time by means of the pH-stat method. The displacement of HPMC from the oil-water interface by bile salts has been assessed by interfacial tension technique. Results show that HPMC delays the lipid digestion of emulsions regardless of the Mw and methoxyl content. The destabilisation of emulsions under intestinal conditions as well as the resistance of HPMC to be displaced from the emulsion interface by bile salts may contribute to this feature. This provides new insights into the mechanisms whereby dietary fibre reduces fat absorption.

Effect of substituent pattern and molecular weight of cellulose ethers on interactions with different bile salts.

Some known mechanisms proposed for the reduction of blood cholesterol by dietary fibre are: binding with bile salts in the duodenum and prevention of lipid absorption, which can be partially related with the bile salt binding. In order to gain new insights into the mechanisms of the binding of dietary fibre to bile salts, the goal of this work is to study the main interactions between cellulose derivatives and two types of bile salts. Commercial cellulose ethers: methyl (MC), hydroxypropyl (HPC) and hydroxypropylmethyl cellulose (HPMC), have been chosen as dietary fibre due to their highly functional properties important in manufactured food products. Two types of bile salts: sodium taurocholate (NaTC) and sodium taurodeoxycholate (NaTDC), have been chosen to understand the effect of the bile salt type. Interactions in the bulk have been investigated by means of differential scanning calorimetry (DSC) and linear mechanical spectroscopy. Results show that both bile salts have inhibitory effects on the thermal structuring of cellulose ethers and this depends on the number and type of substitution in the derivatised celluloses, and is not dependent upon molecular weight. Concerning the bile salt type, the more hydrophobic bile salt (NaTDC) has greater effect on these interactions, suggesting more efficient adsorption onto cellulose ethers. These findings may have implications in the digestion of cellulose-stabilised food matrices, providing a springboard to develop new healthy cellulose-based food products with improved functional properties.

Subphase exchange experiments with the pendant drop technique.

INTRODUCTION: The development of the coaxial double capillary 15 years ago opened up the possibility to undertake accurate desorption and penetration studies of interfacial layers in the pendant drop technique. Drop and bubble methods offer several advantages with respect to other interfacial techniques. They allow a more stringent control of the environmental conditions, use smaller amounts of material and provide a much higher interface/volume ratio than in conventional Langmuir Troughs. EXPERIMENTAL: The coaxial capillary was developed 15 years ago at the University of Granada as an accessory for the pendant drop surface film balance. It allows exchanging the subphase of the drop without disturbing the surface film and preserving the drop volume throughout the subphase exchange. Hence, this methodology enables one to carry out a great variety of interfacial studies well beyond the usual adsorption profiles. Penetration studies, sequential adsorption measurements, desorption kinetics, reversibility of adsorption and testing of enzymatic treatments on interfacial layers are amongst the principal applications. The coaxial capillary has been recently upgraded to a multi-exchange device which has boosted its applicability. It can be now used to address multilayer formation, create soft interfacial nano-composites such as membranes, polyelectrolyte assemblies and simulate in vitro digestion in a single droplet. APPLICATIONS: This review aims to compile the experimental work done, using the pendant drop subphase exchange in the last decade, and how its use has provided new insights into the surface/interfacial properties of many different materials. Special emphasis is placed on recent work regarding simulation of in vitro digestion in order to address issues relating to metabolism degradation profiles. The use of this methodology when dealing with interfacial studies allows setting the foundations of interfacial engineering technology. Based on subphase exchange experiments, we aim to develop models for competitive adsorption of different compounds at the interface and build up layer-by-layer interfacial structures. Future challenges comprise the design of finely adjusted nanoengineering systems, based on multilayer assemblies with tailored functionalities, to match the application demand.

Interactions between cellulose ethers and a bile salt in the control of lipid digestion of lipid-based systems.

In order to gain new insights into the potential of specific dietary fibres to control lipid digestion, the goal of this work is to study the main interactions between commercial cellulose ethers, as dietary fibre, and a bile salt, as an important duodenal component present during the digestibility of lipids. These interactions have been evaluated in two different scenarios found for an oil-in-water emulsion on its transit through the duodenum. Namely, interactions in the continuous phase and competitive adsorption at the oil-water interface have been looked at by means of micro-differential scanning calorimetry (micro-DSC) and interfacial tension (IT). Micro-DSC revealed that the presence of the bile salt affects the thermogelation process of cellulose derivatives, suggesting binding to cellulose ethers. The effect on thermogelation seems to be cellulose type-dependent. IT measurements proved the ability of cellulose ethers to compete for the oil-water interface in the presence of the bile salt. Interactions in the bulk might have an impact on this interfacial scenario. These findings may have implications in the digestion of emulsified lipids, hence providing a springboard to develop new cellulose-based food products with improved functional properties.

Block copolymers at interfaces: interactions with physiological media.

Triblock copolymers (also known as Pluronics or poloxamers) are biocompatible molecules composed of hydrophobic and hydrophilic blocks with different lengths. They have received much attention recently owing to their applicability for targeted delivery of hydrophobic compounds. Their unique molecular structure facilitates the formation of dynamic aggregates which are able to transport lipid soluble compounds. However, these structures can be unstable and tend to solubilize within the blood stream. The use of nanoemulsions as carriers for the lipid soluble compounds appears as a new alternative with improved protection against physiological media. The interfacial behavior of block copolymers is directly related to their peculiar molecular structure and further knowledge could provide a rational use in the design of poloxamer-stabilized nanoemulsions. This review aims to combine the new insights gained recently into the interfacial properties of block copolymers and their performance in nanoemulsions. Direct studies dealing with the interactions with physiological media are also reviewed in order to address issues relating metabolism degradation profiles. A better understanding of the physico-chemical and interfacial properties of block copolymers will allow their manipulation to modulate lipolysis, hence allowing the rational design of nanocarriers with efficient controlled release.

Interactions between Pluronics (F127 and F68) and bile salts (NaTDC) in the aqueous phase and the interface of oil-in-water emulsions.

Pluronics are being introduced in food research in order to delay lipid digestion, with the length of hydrophilic and hydrophobic chains playing an important role in the rate of such a process. Since bile salts play a crucial role in the lipid digestion process, the aim of this work is to analyze the interactions between Pluronic F127 or F68 and the bile salt NaTDC when the latter is added at physiological concentrations. These interactions are studied at the Pluronic-covered oil-water interface and in the aqueous phase of Pluronic-stabilized emulsions. This work has been carried out with techniques such as differential scanning calorimetry, interfacial tension, dilatational rheology, and scanning electron microscopy. As a result, Pluronic F127 was shown to be more resistant to displacement by bile salt than F68 at the oil-water interface due to the larger steric hindrance and interfacial coverage provided. In addition, Pluronics have the ability to compete for the oil-water interface and interact in the bulk with the bile salt. Concretely, Pluronic F127 seems to interact with more molecules of bile salt in the bulk, thus hindering their adsorption onto the oil-water interface. As a conclusion, Pluronic F127 affects to a larger extent the ability of bile salt to promote the further cascade of lipolysis in the presence of lipase owing to a combination of interfacial and bulk events.