To explore the perspectives of nurses regarding pain and its management during routine infant vaccination at the Child Welfare Clinics in Ghana.Qualitative descriptive design.Qualitative in depth, in‐person interviews using a semistructured interview guide were conducted with 19 Registered Nurses who were were purposively sampled from three selected Child Welfare Clinics in hospitals in the Greater Accra Region of Ghana, The Tesch cotent analysis procedure was followed for the analysis of interview data.Nurses were aware that the injections they give infants are painful. They described how infants exhibit certain behaviours to express pain. Although nurses support infant pain management during vaccination, they rarely use evidenced‐based pain interventions. Table Most of the nurses were in the age range of 30–39 years. All but one of the 19 nurses were females, with 16 (84.2%) having certificate educational qualifications in nursing. Over a quarter of the interviewed nurses were community health nurses  Vaccinations are painful for infants and (b) The current pain assessment and management practices by nurses in Ghana during vaccination are inadequate. The first theme consisted of three subthemes namely (i) infants can experience pain during vaccination, (ii) infants express pain in different ways during vaccination, and (iii) nurses' beliefs about factors that make vaccination painful. The second theme consists of four subthemes namely (i) nurses do not assess pain using a validated tool, (ii) nurses do rate pain informally, (iii) nurses are supportive of managing infant pain, and (iv) current pain management practices are limited.4.1Nurses reported that infants feel pain during vaccination and may express pain in a variety of ways, as well as their beliefs about factors that make vaccination painful.4.1.1n = 19) were very aware that infants can and do experience pain during vaccination. Their demonstration of awareness focused on their observation that infants showed signs of pain when injected.PARTICIPANT 3 SITE 1.When they are on their mother's lap, they do not cry but the moment you inject them, they start crying; that means that they felt the painAll nurses (4.1.2n = 19) reported that infants expressed pain through behaviour, including vocal expressions, negative facial expressions and body movements during vaccination.Vocal expressionAll participants (n = 19) reported that vocal expressions such as crying or screaming were the most common signs of infant pain during vaccination.PARTICIPANT 5 SITE 1.Immediately you inject them they tremble and start cryingiiFacial expressionAll nurses (n = 14) reported that all infants exhibited pain in their facial expressions during immunization, characterized in most cases by frowns or grimaces, tightly closed eyes and opening their mouths wide when they cry.PARTICIPANT 3 SITE 3.Some of them frown their faces or grimace immediately you injected themPARTICIPANT 1 SITE 1.When they cry, they open their mouths wide and close their eyes tightly to tell you they are in painiiiBody movementsMost nurses (n = 7) reported that infants usually cannot keep still when they are in pain. Limb movement is one of the ways they communicate the pain they are going through. They described how some infants withdraw their limbs in response to pain during vaccination.Some nurses  noted that the number of injections and both tissue damage and deposition of vaccine components in the skin cause infants to feel pain during vaccination.Number of injectionsAll nurses (n = 14) firmly believed that multiple injections per visit were the cause of the pain. They mentioned that infants could have up to three injections per visit, which they felt was too painful, and they complained about the frequency. A nurse feared even more painful vaccines could be introduced due to emerging diseases.PARTICIPANT 6 SITE 3.My biggest concern is the fact that every time new diseases emerge, new vaccines are added to the existing ones. As before, we only gave pentavalent vaccine on the left thigh. Now they've added IPV, so for example at 14 weeks we give the babies three injections and that causes excruciating pain for the babiesPARTICIPANT 2 SITE 2.The mothers complain about the multiple injections because of the pain their babies experience, they are usually not happy when their babies are due for multiple injectionsiiBoth tissue damage and deposition of vaccine constituents into the skin.Most nurses (n = 5) believed the cause of pain the infants feel during vaccination is the result of both tissue damage and deposition of vaccine constituents into the skin.PARTICIPANT 4 SITE 1.The needle that is going through the skin gives pain and pushing the vaccine constituents into the skin gives pain, so both together are very painful for the childA few of the participants  reported that no formal assessment of the infant's pain was performed during vaccination. Most participants were unaware of their role in pain assessment, while others did not even know how to assess pain.SITE 3 PARTICIPANT 5.I do not know that I have to assess pain during immunization, I think my duty is to immunize babiesiiLack of timeAll nurses (n = 9) explained that their reasons for not doing formal assessments were due to the lack of time during vaccination. The lack of time usually arose from the high number of infants they (nurses) must serve, making it difficult for them to assess pain.PARTICIPANT 4 SITE 3.There is no time to assess vaccination pain even if we are educated in vaccination pain assessmentPARTICIPANT 5 SITE 3.The mothers who bring their infants to vaccinated are in a hurry. So, if you spend time on one baby assessing the pain, they will throw insults at you (laughs) so the time will be a challenge even if we knew how to conduct the assessmentiiiLack of knowledgeAlmost half of the participants (n = 19) said they lacked knowledge on how to assess pain.PARTICIPANT 2 SITE 3.{Hesitant} no we do not assess pain during vaccination, I am not sure how to assess pain during vaccinationAll of the nurses (4.2.2n = 11) perceive the intensity of pain that infants experience as moderate, even though they did not use any formal way of assessing.Nurses do rate pain as moderateNurses perceive pain intensity without using a formal assessment tool. Responses from nurses indicate that most nurses  usually attributed this rating to the duration of infants' cries after the vaccination and the type of procedure. To them, vaccination is a minor procedure that will not bring about severe pain.n = 8) viewed infant pain to be of high intensity. This is attributed to several injections administered to the infant at one time, causing much pain.PARTICIPANT 7 SITE 1.Due to the multiple injections, I rate it as high, three injections per visit lead to severe painSome of the nurses (4.2.3n = 19) agreed that they supported managing infant pain during vaccination. They explained that since pain is a natural phenomenon for humans, its management is necessary as it helps to reduce the pain the infant feels.PARTICIPANT 2 SITE 1.Yes, it should be managed so that their pain will be lessened, and crying will stop. The pain increases the temperature of the babies and sometimes they have to be hospitalized which will incur a cost for the parentsAll the participants (4.2.4Most nurses did not use evidence‐based interventions to manage infant pain during vaccination.n = 15) did not use evidence‐based interventions to manage infant pain. Rather, they (nurses) usually advised parents to use paracetamol syrup, shea butter and apologetic words to reduce pain.The use of paracetamol syrupMost nurses (n = 7) told mothers at the site to give paracetamol syrup to their babies after the injections.PARTICIPANT 1 SITE 3.Mm (pause) when they come here, we mostly tell them to give them some paracetamol when they get home, paracetamol is mostly for their feveriiThe use of shea butterNurses (n = 3) advised the mothers to use shea at the site of the injection to help reduce pain.PARTICIPANT 6 SITE 1.Sometimes we tell the mothers that if their babies develop an abscess at the injection site, they should put an ice pack on the injection site. After that, they can smear shea butter to relieve the pain of the injectioniiiApologetic wordsSome nurses (n = 5) spoke about how apologies were rendered to infants after injection. These apologies  are said by the mothers and/or nurses to manage the pain. Apologies are thought to be effective in managing pain as it calms the infant down.PARTICIPANT 1 SITE 1.Sometimes when we inject the babies, we tell them ‘Sorry, sorry’ or try to pamper themSome of the nurses (4.2.4.1n = 4) explained that they did nothing to reduce infants' pain during vaccination. Rather, they left the pain management to the mothers. Mothers will have to use their knowledge to manage the pain of their infants, be it right or wrong.PARTICIPANT 4 SITE 1.Currently, just after the injections, we do not do anything for them. Some of the mothers have older children so they know what to do. They have paracetamol syrup in their bags so immediately you inject the babies they administer it. Some mothers even administer it at home before coming herePARTICIPANT 7 SITE 1.We don't do anything here, the only thing we do is to put the cotton at the site because we have opened the skin. So, we put the cotton wool there to stop the bleeding after the injectionSome of the nurses .Although all nurses in this study supported the management of infant pain during vaccination (Chan et al., Mothers have expressed concern about the pain associated with vaccinations in infants, which would lead to vaccination delays. Applying these evidence‐based strategies during infant vaccination has been shown to be an effective strategy to overcome parental vaccination reluctance and ultimately improve the quality of infant care (World Health Organization, Some of the nurses reported that they did nothing to relieve the infants' pain during vaccination. Rather, they left pain management to the mothers. There is evidence that parents may not receive the support of healthcare providers when it comes to pain interventions. (Parvez et al., As all Ghanaian infants need to be vaccinated and the consequence of unmanaged infant vaccination pain, there is an urgent need for KT efforts such as didactic workshops, reminders, audits and feedback for Ghanaian nurses to implement WHO recommendations during infant vaccination will provide better patient experience, increase vaccination compliance, help address short‐ and long‐term consequences associated with vaccine‐associated pain and build trust between nurses and mothers Taddio, .6Nurses should be equipped with the knowledge, resources and support needed to assist mothers in applying WHO evidence‐based recommended strategies during infant vaccination. KT strategies such as reminders, educational sessions, educational materials, audits and feedback can be used to train nurses in the clinics that provide infant vaccine injections. These strategies aim to implement the knowledge that will help nurses avoid pain during painful events such as immunization. They should also encourage the use of recommended strategies such as breastfeeding, administration of oral sweet‐tasting solutions, proper position, caregiver presence, and distraction with adequate time and resources for effective pain management in infants during vaccination while addressing their barriers. The use of these strategies can successfully reduce vaccination‐associated pain in infants and improve vaccination compliance in the Ghanaian context.7The study was contextual; the sites of the study were limited to the Greater Accra Region of Ghana, and therefore, findings may not reflect the views of mothers who bring their babies to be vaccinated and nurses who vaccinate infants at the CWCs in other regions, particularly the rural areas. Hence, the study findings may not be widely generalizable to other contexts in Ghana. However, transferability may be considered when the context is similar.8Vaccination is of paramount importance to prevent short‐term and long‐term consequences of disease that can last a lifetime. Infant pain is a source of concern for both the nurse vaccinating the infant and the mother watching her baby in pain. Addressing this issue can positively impact nurses' management practices and improve child and system outcomes. Nurses must be trained and supported with the necessary resources to effectively manage infant vaccine‐related pain. Breastfeeding during vaccinations should be facilitated whenever possible, sweet solutions vaccinations should be given prior to injections, and infants should be properly positioned during infant vaccinations in Ghana. There should be national guidelines focusing on the application of WHO recommendations in Ghana.This study was conceptualized by EA. The data were collected by EA and analysed by EA, TSR and BJS. The manuscript was drafted and reviewed by all the authors. All the authors read and approved the manuscript.This research received no specific grant from any funding agency in the public, commercial or not‐for‐profit.The authors have declared that no conflicts of interest exist.


Heterogeneous catalysis is inseparable from interfacial mass transfer and chemical reaction processes determined by the structure and microenvironment. Different from high‐temperature thermochemical processes, photo‐ and electrocatalysis operated at mild conditions often involve both gas and liquid phases, making it important but challenging to characterize the reaction process typically occurring at the gas–liquid–solid interface. Herein, we review the scope, feasibility, and limitation of ten types of currently available technologies used to characterize interfacial wettability and mass transfer properties of various triple‐phase catalytic reactions. The review summarizes techniques from macroscopic contact angle measurement to microscopic environment electron microscopy for investigating the wettability‐controlled structure of triple‐phase interfaces. Experimental and computational methods in revealing the interfacial mass transfer process have also been systematically discussed, followed by a perspective on the opportunities and challenges of advanced characterization methods to help understand the fundamental reaction mechanism of triple‐phase catalysis. The review focuses on the strategies for evaluating the wettability‐controlled mass transfer process at triple‐phase interfaces. Ten types of characterizations are described based on photocatalytic and electrocatalytic reactions involving water and gas molecules. Finally, the review discusses the tasks of advanced characterizations to help understand the fundamental reaction mechanism for triple‐phase catalysis. This is a tough challenge from a chemical reaction kinetics viewpoint. Lower reaction temperature indicates a weaker collision between reactants and catalysts, thus leading to less opportunity to overcome the reaction barriers. Thousands of literature have been published each year to understand and optimize the intrinsic reaction kinetics over well‐designed catalytic active sites. Actually, low reaction temperatures and pressures can also result in poor reactant diffusivity and concentration, leading to an insufficient supply of reactants to the surface of catalysts. This limitation in physical mass transfer kinetics may cause limited molecule collisions, further hindering the catalytic activity enhancement at mild conditions. In addition, different from various gas–solid double‐phase reaction systems in thermocatalytic processes , most energy and environmental catalysis driven by renewable light or electric energies  needs water as the most important clean proton sources. Water exists in the liquid state at low temperatures with poor saturated vapor pressure and shows limited diffusion coefficient and saturated solubility toward gas molecules. Therefore, the effective contact between gas/liquid reactants and solid catalysts becomes an essential scientific and engineering task for gas‐consuming and gas‐evolving catalytic reactions.As an important branch of interface science, heterogeneous catalysis has been widely studied and applied to the modern chemical industry in the past century.3 One  In contrast to conventional double‐phase photo‐ and electrocatalytic systems, which consist of catalysts immersed in a bulk liquid phase, triple‐phase catalytic systems by supporting catalysts at gas–liquid boundaries have been developed and exhibited outstanding performance. A couple of reviews have focused on the rational design of triple‐phase catalysts and reactors. The enhancement is typically ascribed to the fast gaseous reactants supply and products departure. Although pioneer works have shown the great opportunity of triple‐phase catalysis in promoting the reaction kinetics at mild conditions, the fundamental reaction process at the interface has yet to be well understood. The exact answer relies on developing advanced characterization technologies to unveil the wettability of nanostructured triple‐phase interfaces and their influence on the interfacial mass transfer and chemical reaction properties.The contact between gas, liquid, and solid substances as a basic phenomenon in nature has been studied for centuries. Since the first theoretical framework done by Wenzel in the 1930s, physicochemical processes over triple‐phase interfaces have gradually become a research hotspot, including superwettability, one of the top ten emerging technologies in chemistry 2021 established by IUPAC.15 In In this review, we summarize ten types of experimental and computational methods that have been or are expected to be applied in characterizing the interfacial wettability and the mass transfer process in triple‐phase catalysis Figure . The dis2 The former can be well‐controlled during material preparation procedures and characterized by conventional material characterization technologies, such as X‐ray spectrum and electron microscopy. While the latter is highly dependent on the wettability and wetting state of the catalyst and is very sensitive to the reaction environment, thus providing new opportunities and challenges for the characterization. Beginning with contact angle (CA) measurements, the characterizations of triple‐phase interfaces are discussed in the order of spatial resolution from macro to micro in the following sections.The overall reaction process on the surface of heterogeneous catalysts typically includes (1) reactants transport; (2) reactants adsorption; (3) intermediates conversion; (4) products desorption; and (5) products transport. The interfacial structure plays a key role in determining the efficiency of the catalytic reaction. For triple‐phase catalysis, the interfacial structure refers to structures of both the catalyst and the gas–liquid–solid interface.23 The2.1 It is a universal method to observe the wettability of nanostructured catalysts due to their simplicity and compatibility. The result can reflect the intrinsic or apparent wettability for smooth and rough materials, respectively. CA measurements can be sorted as air phase water droplet and underwater gas bubble measurements  prevented the infiltration of water, thus allowing the formation of abundant triple‐phase interfaces over titanium oxide nanoparticles. A couple of the following works proved the advantages of the triple‐phase photocatalytic system in achieving higher reactivity, apparent quantum yields, and photothermal effects than the double‐phase system without a gas‐phase connection. Besides, the CA of carbon nitride nanosheets can be modified from near zero to 120° by grafting with 1H,1H,2H,2H‐perfluorodecanethiol. The hydrophobic surface could adsorb CO2 bubbles when the carbon nitride nanosheets were immersed in a CO2‐saturated aqueous phase, thus leading to the formation of triple‐phase interfaces and improved photocatalytic CO2 reduction activity.For photocatalysis, most semiconductor nanomaterials such as titanium oxide and carbon nitride are hydrophilic and show a water CA close to zero.44 It  One common characteristic of these reactions is the involvement of H2O/H2O2 as reactants, intermediates, or products. For instance, coating molecular sieves with an organosilanes hydrophobic layer could confine the in situ generated hydrogen peroxide, contributing to enhanced methanol productivity. Similarly, a significantly increased water CA from ∼40° to ∼138° was obtained for surface‐modified iron catalysts. The improved hydrophobicity protected the catalyst surface from water generated during CO hydrogenation, thus achieving an olefin yield of up to 36.6% with suppressed side reactions related to water.Recently, interfacial wettability has also attracted attention in low‐temperature thermocatalytic processes, including methane oxidation, CO hydrogenation, and water–gas shift reactions.52 One2.1.2 The vertically oriented MoS2 nanosheet array on the electrode provided more electrochemical active surface area and, in particular, showed a substantially larger gas bubble CA (153.6°) than the flat electrode (135.2°). The superaerophobic behavior allows the immediate departure of small hydrogen bubbles from the surface of the electrode, therefore contributing to efficiently exposed active sites for the following cathodic reaction. This property is significant for improving the energy efficiency and electrode stability of a water splitting system operated at industrial level current densities.For gas‐evolving reactions, such as oxygen evolution reaction and hydrogen evolution reaction, gas bubbles are generated and detached from the surface of catalysts immersed in aqueous media. This stimulates the observation of underwater triple‐phases, where small gas bubbles rather than continuous gas phases are exposed to the catalyst. The underwater gas bubble CA measurement for hydrogen evolution reaction was firstly reported in 2014 to reveal the superaerophobic behavior of a nanostructured electrode.53 The The underwater triple‐phase system typically consists of hydrophobic catalysts with porous or array nanostructures. Teflon‐modified gas diffusion electrode typically shows a gas bubble bursting effect during underwater CA measurement (CA ≈ 0°), indicating that gas pockets would fill in the pores or intervals of the nanoarrays. In this case, gaseous reactants can directly diffuse to the surface of catalysts until all reactants in gas pockets are consumed up. Nevertheless, constructing an underwater triple‐phase system is a trade‐off process. More gas pockets surrounding the catalyst indicate less connection to the water phase, which was evidenced from carbon and copper nanoarray electrodes for oxygen and CO2 reduction reactions, respectively. Besides, an aerophilic surface modification toward catalysts is often at the cost of covered active sites and increased internal resistance. Theoretically, a catalyst with moderate wettability is desirable to optimize the contact of both gas and liquid phases and provide abundant triple‐phase interfaces. CA measurement alone, however, can hardly give detailed structural information about the abundance and the shape of interfaces, stimulating the extension and collaboration with other characterizations.Beyond gas‐evolving reactions represented by water splitting, the CA measurement of underwater gas bubbles is also useful to evaluate the interfacial wettability of gas‐consuming reactions, especially for those underwater aerophilic triple‐phase systems.55 The2.1.3 For example, a moderate adhesive force to a gas bubble indicates the formation of a stable triple‐phase interface, which is suitable for gas‐consuming reactions in the liquid phase. On the contrary, a small bubble adhesive force is required for gas‐evolving reactions to keep active sites exposed to the liquid reactants. According to reported literature in catalysis, the results of adhesive force are always in good agreement with the CA measurements, where a big CA toward droplet/bubble refers to a weak adhesive force and vice versa. A more intriguing reverse combination, which is often observed in nature , has yet to be discovered in triple‐phase catalysis. It should be noted that the adhesive force measurement has a limitation in the repeatability due to the inconsistent experimental details, such as the structure of the pallet, and the initial extrusion strength of the droplet/bubble, therefore cannot be directly used for quantitative study and comparison between different works.Adhesive force is a widely used extension of CA measurements to analyze the relative bonding strength of catalysts to water and gas phases. The adhesive force of a water droplet or a gas bubble to a solid surface is ranged from near zero to hundreds of micro‐newton.57 For In addition, owing to the simplicity and compatibility, CA measurements can be used as an operando technique to investigate the wettability during catalytic reactions. Although few examples can be found from literature up to date, one can easily find the feasibility of adding a series of variables to the measurement, such as light intensity, wavelength, bias potential, time, temperature, pressure, and gas/liquid composition, thus greatly extending the innovation of this method in triple‐phase catalysis.For a superwetting system, where regular CA and adhesive force measurements can only give limited information, dynamic CA hysteresis measurements, including advancing, receding, and sliding CAs, are often used as alternatives to characterize the interfacial wettability.59 In 2.2 Although optical microscopy shows relatively lower resolution than electron microscopy, it offers faster response and better environmental compatibility that can be used to image triple‐phase interfaces under catalytic conditions.Optical microscopy is an optical instrument that uses the optical principle to magnify and image material's microstructures that cannot be distinguished by human eyes. For triple‐phase catalysis, it is typically used to observe microscale gas bubbles and local liquid phase connected to catalysts and can be divided into ultrafast digital cameras and confocal laser scanning microscopy (CLSM). The resolution of optical microscopy ranges from micrometers to nanometers according to the light source selection and optical path setting.60 Alt2.2.1 The wetting state of a rough surface can be classified as three models: (1) Cassie model: non‐wetted contact between the liquid and the rough surface; (2) Wenzel model: fully wetted contact between the liquid and the rough surface; and (3) Cassie‐Wenzel coexistence model: an intermediate state between Cassie and Wenzel models. For electrocatalytic oxygen reduction, Liu and co‐workers revealed the different wetting states of the surface‐modified Pt/Si array cathode by comparing the different reflection contrast  from top‐view optical images. The observation demonstrates the structure of the triple‐phase catalytic interface and correlates well with the CA and adhesive force measurements.Digital camera imaging has been applied to reveal the wetting state of nanostructured electrodes Figure .57]57t Figure .[59] This feature makes ionic liquids more feasible than water for ESEM imaging. Ionic liquids can be divided into hydrophilic and hydrophobic according to their compositions, making the interfacial structure between them and catalysts an exciting but challenging research topic. A Cassie wetting state of 1‐hydroxyethyl‐3‐methylimidazolium tetrafluoroborate ionic liquids on –CF3 terminated nanostructured surfaces have been successfully observed by ESEM, which sheds light on the characterization of the gas‐ionic liquids‐electrode interface in non‐aqueous electrocatalysis.Ionic liquids, a significant kind of non‐molecular compounds in the liquid state that has been investigated for high‐performance electrocatalysis, typically have a much higher boiling point than water.87 Thi By coupling SEM with optical microscopy, it is possible to get high‐resolution images of nanocatalysts and the corresponding triple‐phase interfaces. For example, an oil–silica–water triple‐phase nanostructure can be well‐confirmed by combining SEM (imaging hollow silica nanospheres) with dark‐field optical microscopy (imaging oil nanodroplets). The nanostructure acts as an oxygen nanocarrier and shows enhanced interfacial oxygen diffusion for biocatalytic oxidation of glucose, choline, lactate, and sucrose. Coupling with CLSM has also been demonstrated to be useful in determining the penetration depth of the water phase into the photocatalytic nanoarrays  and its relative position to the photocatalytic nanoarrays through the comparison between SEM and CLSM images.A combination of SEM and optical microscopy can make full use of the advantages of the two techniques  and has been applied for the spectrum analysis of individual nanocrystals. Such combination requires the alignment of the sample, which is typically achieved by orientation correction to a marked substrate.90 By s Figure .[47]3For a specific triple‐phase catalytic system, its interfacial wettability and molecular mass transfer are the two sides of a coin. Mass transfer characterization helps build the relationship between interfacial structures and catalytic activities, thus guiding the design of advanced catalytic systems. Both experimental and computational methods have been developed to investigate the interfacial mass transfer process. The following sections introduce three kinds of experimental measurements and two kinds of computational simulations and discuss their capabilities in detecting the mass transfer process at triple‐phase interfaces.3.13.1.1Ea). For most chemical reactions, the logarithm of the reaction rate is linearly correlated with the reciprocal of temperature, indicating a kinetic control regime. The Ea can be measured from the slope of the fitted curve −Ea/R, where R is the gas constant. However, a non‐linear relationship also exists in some conditions. For example, a convex curve was detected for dimethyl oxalate hydrogenation in a porous nanocage reactor. The curve's curvature gradually reduced with the decrease of the size of the nanocage, accompanied by a reduced dimethyl oxalate diffusion flux. Therefore, the downward deviation from the Arrhenius linear relationship can be understood from a diffusion control regime that the accelerated activity at higher temperatures would induce a more severe diffusion limitation and cause the curve to bend.The Arrhenius plot shows the temperature‐dependent reaction rate of chemical processes, which is typically used to evaluate apparent activation energies Ea.[92 But for photo‐ and electrocatalytic reactions involving slow mass transfer processes of gas molecules in liquid phases, the Arrhenius plot is a useful tool to determine the rate‐determining step of the reaction. Electrochemical acetylene reduction to ethylene has recently become a hot research topic owing to its advantages in removing trace amounts of acetylene from ethylene gas feed compared to the conventional hydrogenation route. For a triple‐phase electrochemical flow‐cell, an Arrhenius linear relationship was observed between the logarithm of the reaction rate and the reciprocal of temperature. However, a double‐phase control system immersing the electrode into an acetylene‐saturated electrolyte showed a non‐linear relationship. Interestingly, a concave curve was formed that reaction rate was primarily unchanged at temperatures between 5 and 15℃. This phenomenon was deemed as an abnormal diffusion‐controlled regime because of the higher acetylene solubility in the electrolyte at lower temperatures.This phenomenon is rarely seen in gas–solid catalysis at low temperatures due to the fast mass transfer of gas reactants in the gas phase.94 ButTherefore, the Arrhenius plot or the relationship between reaction rates and temperatures is one of the few experimental approaches for qualitatively investigating the interfacial mass transfer process. It can be used to make a preliminary judgment on the mass transfer process as the potential rate‐determining step of the reaction.3.1.2 For example, electrochemical impedance spectroscopy (EIS) can give semi‐quantitative interfacial mass transfer information of an electrochemical system. Nyquist plots detected from EIS typically involve high‐frequency and low‐frequency regions. The high‐frequency region reflects the electrode's internal resistance and charges transfer resistance, while the low‐frequency is linked to the diffusion behavior of electrolyte ions at catalytic interfaces. For example, a porous electrode with higher hydrophilicity  typically shows a higher low‐frequency resistance due to the less diffusivity of ions into the interlayer of the electrode. The relaxation time constant obtained from the Nyquist plots can reflect how fast ions can transport inside the porous electrode. Hydrophobic porous electrode processes shorter relaxation time constant than the hydrophilic one because of the smaller electrolyte penetration and apparent viscosity at electrolyte/electrode interfaces. But it is still challenging to establish an appropriate model to fix the EIS results and give accurate meaning to the Nyquist plot in triple‐phase electrocatalysis. Besides, the EIS measurement is mainly used for charge carrier transportation in electrochemical energy storage. It should be noted that the dissolution and consumption of gas reactants at triple‐phase interfaces can also affect the interfacial transport of electrolyte ions. Therefore, researchers should deserve more attention to the EIS measurement in evaluating the interfacial mass transfer property in triple‐phase electrocatalysis.The mass transfer process of reactants and products on the surface of electrode has been investigated for decades based on electrochemical measurements.100 Fo Typically, photocatalysts were grown or immobilized on conductive glass substrates for the measurement  is a function of mass transfer coefficient (k) and the concentration difference between the bulk phase (C0) and the interface (Ci).From the interfacial mass transfer equation (Equation ), one cak phase C0 and the2 concentration during CO2 electroreduction reaction , of which the fluorescence intensity can be measured and converted to the interfacial CO2 concentration during the reaction. FES results demonstrated a stable interfacial CO2 concentration for the triple‐phase electrochemical CO2 reduction system at a current density of 100 mA cm–2. The CO2 mass transfer coefficients were determined to be 0.27 cm–2, which is over ten times higher than the double‐phase control system.The reactant concentration in the bulk phase is a known constant. Therefore, mass transfer flux and interfacial concentration should be measured to quantitatively evaluate the interfacial mass transfer coefficient of a catalytic system. For heterogeneous catalysis, it is reasonable to make an approximation that the reactant's interfacial mass transfer flux equals its consumption rate per unit area to reach a dynamic reaction equilibrium. Generally, the reactant consumption rate is proportional to the (photo)current and other detectable reaction signals. Therefore, quantifying the mass transfer coefficient as the intrinsic property of a catalytic system becomes possible by further measuring the interfacial concentration of the reactant. Recently, fluorescent labeling has been used for the in situ detection of interfacial COn Figure .[38,  The only difference lies in selecting suitable fluorescent dyes for the specific reactant/product response. Experimentally detecting interfacial concentration and mass transfer coefficient is helpful to illustrate the interfacial molecular mass transfer property in triple‐phase catalysis and could give strong support to the widely applied theoretical simulations introduced in the next section.Theoretically, the FES measurement is suitable for other gas‐consuming reactions .115 Th3.23.2.12 as an important greenhouse gas and chemical feedstock has been intensively investigated for decades. The chemical equilibrium between CO2, bicarbonate, and carbonate in the water phase often causes difficulties in precisely estimating the actual CO2 concentration for a series of photo‐ and electrocatalytic CO2 conversion reactions. More importantly, this issue cannot be ignored in triple‐phase CO2 electrolysis using an alkaline electrolyte, since the non‐faradaic consumption of CO2 will lead to severe CO2 loss and composition change of the electrolyte. Therefore, estimating the CO2 concentration at gas–electrolyte–cathode interfaces is important in understanding the overall process of CO2 mass transfer and chemical conversion.CO decades.116 Th Different from the above discussed experimental methods that the diffusion time and distance from the phase boundary cannot be precisely controlled, PDEs can provide time‐dependent concentration gradient as a function of diffusion distance from the catalytic interface. The concept of phase and interface is simplified as a one‐dimensional virtual space  with designated diffusion coefficients, reaction rate constants, and the initial concentration of solutes  is a primary driving force for the interfacial mass transfer of dissolved CO2 molecules. The size of desorbed gas bubbles was highly dependent on the morphology of the electrode and can greatly affect the mass transfer efficiency and the CO2 reduction limiting current density.Partial differential equations (PDEs) take into account interactions (reaction and diffusion) between molecules and ions to model their interfacial mass transfer processes.119 Dis Figure . For CO2n Figure .[1172 supply and prevent non‐faradaic consumption by the OH–. PDEs played an irreplaceable role in estimating the interfacial pH and CO2 concentration during the reaction‐diffusion dynamic equilibrium process. The CO2 concentration in alkaline electrolytes decreases exponentially from the gas–liquid interface. Therefore, an ultrathin catalyst layer at the gas–electrolyte boundary was required to keep a relatively high local CO2 concentration in alkaline electrolyte and to achieve a high CO2 conversion selectivity with suppressed hydrogen evolution reaction at large current densities.When the electrolyte is switched to KOH, a well‐designed gas–electrolyte–cathode interface is required to facilitate CO process.120 Th2 in porous media  cannot be directly obtained from the literature. The collision between gas molecules and pore walls diminishes the effective diffusion coefficient of CO2 in nanoporous compared to CO2 in bulk. Bosanquet's effective diffusivity was employed to calculate the effective diffusion coefficient according to the Knudsen diffusion model approximation.The application of PDEs requires the determination of a series of initial conditions. However, the diffusion coefficient of COterature.121 ThThe exact solution of PDEs might not exist in complicated systems, such as the nanostructured 2D/3D triple‐phase catalytic interface, and we will discuss the alternative simulation method in the next section.3.2.2 The complex system transforms into a series of simple solvable systems with relevant PDEs and dependent variables to simulate the mass transfer process at any point inside each element and over the whole system.Finite element method (FEM) is a modern computational method to find solutions to complex engineering problems. It is used to find approximate PDEs solutions of systems with complex geometry and boundary conditions by dividing the model into several subdivisions.122 Th4 and 109 times higher than in liquid and solid phases. It means that constructing a gas phase highway directly to the surface of catalysts is the best way to solve the mass transfer issue for gas‐consuming reactions. However, the actual mass transfer process over triple‐phase interfaces is highly dependent on the wettability and nanostructure of the interface, often leading to a massive deviation from the ideal expectation. For example, the limiting CO2 reduction current density over the gas diffusion layer‐based triple‐phase system only increased about ten times compared to the double‐phase control sample. FEM provides a theoretical model to show the temporal and spatial distribution of a nanostructured boundary condition. Recently, Sargent et al. investigated the influence of an ionomer layer on the CO2 diffusion behavior across gas‐electrolyte‐catalyst triple‐phase interfaces  suppressed charge recombination caused by the poor supply of oxygen; (2) broad oxygen concentration tolerance to keep a considerable reaction rate; (3) flow reaction feasibility. Recently, two FEM models have been built to simulate the local oxygen concentration over the photocatalyst layers immobilized at the air–water boundary and immersed in the water phase, respectively. The result showed that the local oxygen concentration dramatically decreased to near zero in the immersed double‐phase system, while the triple‐phase system kept a stable oxygen concentration over the photocatalyst layer during the reaction.Photocatalytic aerobic oxidation is another important reaction involving both oxygen and water as reactants. It shows a broad application in environmental catalysis, such as antibacterial, air purification, and organics degradation.126 Ho4In this review, we focused on state‐of‐the‐art approaches in characterizing the interfacial wettability and mass transfer properties in triple‐phase catalysis. Ten types of currently available experimental and computational methods have been summarized. We discussed the advantages, limitations, and applicable scenarios of each method based on their working principle and practical cases. As the emerging of triple‐phase catalysis, this review aims to show the importance and capability of various technologies in evaluating the physicochemical process at catalytic interfaces. However, the characterization still faces several tasks at the current stage. The unstable triple‐phase interface often causes poor operational stability, which is one major disadvantage of triple‐phase catalytic systems reported so far. Imaging technologies reported so far have difficulties giving online characterizations on triple‐phase catalysis. Ultrafast cameras have shown the feasibility in revealing the gas bubble adhesion and departure process for gas‐evolving reactions, but cannot provide detailed interfacial structure information due to their relatively low resolution.Optical imaging methods have limited spatial resolution to reveal the fine structure of triple‐phase interfaces at the nanoscale. In contrast, high‐resolution electron microscopy requires a complex preparation process with limited tolerance for low boiling liquid phases. As a result, the experiments can only deliver vague and distorted images, which can hardly reflect the actual structure of a catalytic interface. Besides, the wettability of the catalysts undergoes destruction during catalysis, often leading to significantly changed interfacial structures .85 TheFor interfacial molecular transfer analysis, most characterizations rely on computational simulations with a large amount of approximate fitting and guesswork. FEM is mainly based on the solution of relevant PDEs according to a series of reaction‐diffusion equilibrium. And empirical correlations are still required in some cases to estimate the interfacial diffusion‐related properties for the simulation. However, the real mass transfer process in triple‐phase catalysis is far more complicated and involves multiple molecule interactions . For example, FEM cannot distinguish boundary conditions sharing the same structure but different wettability and surface energies. Although some experimental methods have been used as compensation to the computational simulations, they can only provide side evidence for the interfacial mass transfer process through detectable signals such as reaction rate, current density, and fluorescence intensity. The integration of two or more characterizations, such as the CLSM‐SEM combination discussed in Section Beyond the physical mass transfer process, it is also important to consider the chemical reaction process at triple‐phase interfaces. A deep understanding of the essence of interfacial wettability and its influence on chemical adsorption and activation energies relies on detecting molecule‐catalyst interactions with high temporal and spatial resolutions. The application of environmental transmission electron microscopy and molecular dynamics simulation might be the next breakthrough in characterizing the nature of wettability‐controlled reaction over triple‐phase interfaces at sub‐nano or molecular scale.130 ThThe authors declare no conflict of interest.


A 67‐year‐old woman was referred to our hospital for further evaluation of a positive fecal occult blood test. Colonoscopy revealed an elevated rectal lesion (10 mm in size) with a central depression. A rod‐like object was noted in the center of the lesion. Magnifying endoscopy with narrow‐band imaging showed obscure surface structures and dilated vessels. Magnifying endoscopy with crystal violet staining showed that the pit pattern had disappeared. These endoscopic findings suggested that the lesion was comprised of granulation tissue. A detailed medical history revealed that she had undergone a total hysterectomy with mesh placement for bladder prolapse. We reasoned that the mesh used during pelvic surgery might have penetrated the rectum. She underwent subsequent surgery to remove the mesh. Although most foreign bodies in the rectum are swallowed or self‐inserted, pelvic surgery is another source of foreign bodies in the rectum. Although rectal foreign bodies (RFBs) are rarely encountered in clinical practice, RFBs can cause bleeding, mucosal ulceration, and perforation.A 67‐year‐old woman was referred to our hospital for further evaluation of a positive fecal occult blood test. The physical examination and laboratory data were normal. A colonoscopy revealed an elevated lesion (10 mm in size) with a central depression in the anterior wall of the lower part of the rectum. A rod‐like and hard object was observed in the center of the lesion Figure . MagnifyWe attempted to grasp and remove the rod‐like object with biopsy forceps , but the object was firmly implanted in the center of the lesion. Computed tomography showed a high‐density, linear material that had migrated through the right vulva to penetrate the rectum Figure . Under bA detailed medical history revealed that she had undergone a total hysterectomy for uterine prolapse and placement of mesh for bladder prolapse at 53 and 66 years of age, respectively. Based on her medical history and endoscopic and radiographic findings, we diagnosed this case as an RFB, and the RFB was presumed to be the penetrating mesh used in pelvic surgery. Considering the risk of bleeding and abscess formation due to RFB, we chose surgical removal of the material. The surgical procedure consisted of transanal removal and suture closure, during which it was noted that one of the six supporting legs applied to fix the mesh had penetrated the rectum. The patient was discharged to home without complications after surgery.n = 199 [68.4%]); self‐inserted RFB (n = 87 [29.9%]); and iatrogenic (n = 5 [1.7%]). Of the five iatrogenic RFBs, four occurred following a procedure for prolapse and hemorrhoids in which staples were left in the rectum, and one case involved a uterine contraceptive device retained in the rectum. An online search in PubMed of reports published between 2012 and 2022 identified seven cases of iatrogenic RFBs, including the report by Zhang et al.  procedure was performed to stabilize the pelvic organs.In conclusion, we have reported a case of an iatrogenic RFB diagnosed by medical history and unique endoscopic findings. Our experience suggests that although rare, pelvic surgery can be the cause of an iatrogenic RFB.DEN Open. The other authors declare no conflict of interest.Takayuki Matsumoto is a responsible and executive JGES member for


As the development of the Internet of Things (IoT) continues, Federated Learning (FL) is gaining popularity as a distributed machine learning framework that does not compromise the data privacy of each participant. However, the data held by enterprises and factories in the IoT often have different distribution properties (Non-IID), leading to poor results in their federated learning. This problem causes clients to forget about global knowledge during their local training phase and then tends to slow convergence and degrades accuracy. In this work, we propose a method named FedRAD, which is based on relational knowledge distillation that further enhances the mining of high-quality global knowledge by local models from a higher-dimensional perspective during their local training phase to better retain global knowledge and avoid forgetting. At the same time, we devise an entropy-wise adaptive weights module (EWAW) to better regulate the proportion of loss in single-sample knowledge distillation versus relational knowledge distillation so that students can weigh losses based on predicted entropy and learn global knowledge more effectively. A series of experiments on CIFAR10 and CIFAR100 show that FedRAD has better performance in terms of convergence speed and classification accuracy compared to other advanced FL methods. With the growth of the Internet of Things and advances in Big Data-driven artificial intelligence, the network’s data are increasingly created by geographically distributed enterprise endpoints and IoT devices. The IoT in the context of Big Data is growing rapidly in the industrial sector. However, centralized aggregation of industrial Big Data to cloud servers leads to unaffordable transmission overheads and also violates the data privacy of each enterprise or client, which results in distributed databases consisting of multiple “data islands”. In light of the challenges posed by “data islands” in the development and application of the Internet of Things, Federated Learning (FL)  was firsAlthough federated learning does not require centralized data aggregation to the cloud, however, there will be skewed distribution of data across enterprises during practical applications, which will lead to degradation of FL performance. For example, the data collected for mobile terminal input methods have different distributions for people with different operating habits. There are also many differences in the distribution of sensor acquisition data used by different plants to classify equipment faults or detect quality defects, both in terms of sensor type acquisition differences and fault type distribution differences. Wearable IoT sensor data for monitoring patient vital signs in the medical field are also heavily used for artificial intelligence learning to enable online diagnostics such as expert systems. However, the data collected by these edge IoT devices still suffer from inconsistencies in the distribution of features and labels. In summary, this huge challenge called Non-IID hinders the application of federated learning in IoT in the context of Big Data, and this work aims to propose a generalized method to address this challenge in federal learning for IoT applications.Similar to the problem in continuous learning , this vaInspired by above considerations, we propose a relational adaptive distillation paradigm called Relational Adaptive Distillation for Heterogeneous Federated Learning, abbreviated as FedRAD. The aggregated global model is downloaded by the selected clients during each round of communication and collaboratively distilled  with theOur main contributions:1.To address the phenomenon of drift and forgetting arising from local training of FL algorithms in IoT application deployment. This work incorporates an auxiliary constraint on loss in the local training phase in conjunction with relational knowledge distillation, enabling the local model to learn and retain global knowledge with a higher dimensional view to avoid forgetting.2.To further improve model stability and robustness, this work proposes a robust local learning method named entropy-wise adaptive weights (EWAW), where the penalty weights between distillation losses are determined adaptively by the prediction entropy of global model on each local data model, which can further improve the model performance in each scenario by dynamically adjusting the loss weights.3.By performing comprehensive experiments on CIFAR10 and CIFAR100, we validate that FedRAD has superior accuracy and convergence speed compared to FedAvg, FedProx and FedMD for scenarios with different levels of data heterogeneity and different percentages of active clients.With the emergence of various data privacy protection requirements, secure multi-party computing ,19 is coKnowledge distillation can transfer knowledge from large teacher models to small student models and is widely used for model compression ,27 and cIn summary, to eliminate the dependence of the above knowledge distillation-based federated learning on public datasets and to fully exploit the potential of knowledge distillation to improve the performance of federated learning under data heterogeneity, this paper proposes FedRAD, which incorporates both relational knowledge and single-sample knowledge into the loss function in a collaborative distillation way between models, and adds adaptive weights based on prediction entropy to automatically control the penalty weights of the two distillation losses.To address the inconsistency of learning and the consequent drift caused by the forgetting phenomenon in federated learning, this paper proposes a novel federated learning method called FedRAD from the perspective of expanding the dimension of knowledge distillation. To confirm the conjecture of incoherent learning due to forgetting in federation learning, we first built an image classification system using FedAvg as the federated learning framework. CIFAR10  of the N clients 5.    for each clientsdo6.      7.    end for8.    Server Aggregation: 9.   end for10.    Client update 11.    for eachdo12.    for batchdo13.      14.      15.      16.      17.    end for18.    end for1.  Initialize model parameters Algorithm 1 shows a detailed description for FedRAD. In each round In detail, on the basis of local dataset training in Equation (2), i.e., minimizing the CIFAR10 and CIFAR100 are selected to serve as benchmark datasets for evaluating FedRAD and other baselines. CIFAR10/100 are 10/100 classification datasets, respectively. CIFAR10 consists of 50,000 training images and 10,000 test images in 10 classes, which have 5000 and 1000 images per class. CIFAR100 has the same total number of images as CIFAR10, but it has 100 classes. CIFAR100 has 500 training images and 100 testing images per class. All images of CIFAR10/100 are 3-channel color images (32 × 32). These two datasets have moderate classification difficulty, sufficient categories and a span of difficulty between them. It is also easy to divide the classes into different distributions and there is no potential structure to influence the experimental results. Therefore, these two datasets are widely used in federated learning. This work uses Dirichlet distribution to simulate different data distribution scenarios with unbalanced label classes, controlling the degree of Non-IID by a parameterproaches ,39. We d+ [+, we also share the parameters of client models like FedAvg in order to make a fair comparison instead of just using FedDistill. The network of the generator used in FedGen is composed of two embedding layers  and two fully connected (FC) layers with LeakyReLU and BatchNorm layers between them, while the noise data FedRAD is designed to improve the forgetting phenomenon in federated learning with heterogeneous data, and we select some representative algorithms as baselines: FedAvg , FedProx+  . For methods involving distillation, the distillation temperature T is set uniformly to 1. In local training phase, the batch size is set to 128 and the learning rate is set to 0.01 with an exponential decrease of 0.98. For FedProx, we adjust its proximal term in the range . The aggregation of knowledge in FedMD is performed using the averaging process used in the original paper.+ combines parameter aggregation and knowledge distillation, the lack of dissemination of high-dimensional relational knowledge continues to make its performance weaker than FedRAD. Since FedGen uses a lightweight generator to add proxy data and it chooses to generate pseudo data on the feature level, its performance depends heavily on the generator’s quality. Meanwhile, the feature space of the data, although more compact than the input space, often does not carry enough knowledge to outperform other feature mining approaches, e.g., relational knowledge distillation. + aggregates the client model parameters and performs one-sample knowledge distillation for the global model, but it is also weaker than FedRAD in different distribution scenarios, which further illustrates the need for relational knowledge distillation in a Non-IID environment. FedGen’s performance in different Non-IID scenarios depends on the inductive bias it conveys to the clients, and the effect often depends on the quality of the feature space provided by the generator.In order to assess the robustness of FedRAD under different degrees of data heterogeneity, the accuracy of different methods is tested under different Non-IID scenarios , FedRAD achieves a large advantage over other baselines, especially in extreme distribution heterogeneity cases. In terms of privacy protection, all training is done on the local side and no user data will be leaked. Overall, FedRAD is suitable for various scenarios of IoT application deployments due to its excellent performance in different scenarios, and it is able to solve the challenges caused by data heterogeneity such as intelligent transportation and industrial IoT collaboration.In this work, the proposed FedRAD makes full use of the knowledge distillation mining capability and achieves good performance in terms of model convergence speed and accuracy. For application scenarios with different degrees of data heterogeneity  is introduced to dynamically trade-off the constraint capacity between different distillation knowledge in different distribution scenarios. Experiments on two benchmark datasets, CIFAR10 and CIFAR100, demonstrate the well-adapted nature of FedRAD and its superiority in accuracy and convergence speed compared with the rest of the SOTA methods.The future work will focus on how to reduce the communication overhead between IoT edge endpoints and server; one possible idea is to combine split learning to reduce the proportion of weights while making better use of knowledge distillation. Meanwhile, the method focuses on the local training phase, which is orthogonal to some of the methods used to improve the global aggregation phase, which could be combined with GAN in the future to improve the global model on the server side and further improve the forgetting phenomenon from the global side.


A conserved intracellular allosteric binding site (IABS) has recently been identified at several G protein‐coupled receptors (GPCRs). Ligands targeting the IABS, so‐called intracellular allosteric antagonists, are highly promising compounds for pharmaceutical intervention and currently evaluated in several clinical trials. Beside co‐crystal structures that laid the foundation for the structure‐based development of intracellular allosteric GPCR antagonists, small molecule tools that enable an unambiguous identification and characterization of intracellular allosteric GPCR ligands are of utmost importance for drug discovery campaigns in this field. Herein, we discuss recent approaches that leverage cellular target engagement studies for the IABS and thus play a critical role in the evaluation of IABS‐targeted ligands as potential therapeutic agents. A druggable intracellular allosteric binding site (IABS) has recently been identified at several GPCRs. Ligands targeting the IABS are promising drugs and currently evaluated in several clinical trials. Herein, we review small molecule tools that enable an unambiguous identification and characterization of cellular target engagement for intracellular allosteric GPCR ligands. This new mode of specific GPCR modulation is characterized by a stabilization of the inactive receptor conformation and a steric blockage of intracellular transducer (G protein and/or β‐arrestin) binding.4, 5 T7–9 was guided by binding assay data generated with hand‐tailored molecular tools targeting the IABS of the respective receptor.‐CCR2‐RA‐[R],3H]‐vercirnon, and the CXCR1/2‐targeted [3H]‐Sch5271233H]‐navarixin) were successfully applied in radioligand binding assays to assess drug interactions with the IABS of the respective GPCR. However, in the case of intracellular target binding sites, such as the IABS, the application of radioligand binding assays is mainly limited to cell‐free conditions and not well‐suited for cell‐based studies. The reason for that is, that radioligand binding assays mostly rely on a heterogeneous assay protocol, which means that washing steps are required to remove the unbound radioligand prior to assay readout via scintillation counting. Whereas the removal of the extracellular unbound ligand fraction can easily be accomplished by buffer exchange, the separation of intracellular unbound ligand fraction is not straightforward, due to the membrane barrier. More general drawbacks of radioligand binding assays are high infrastructure requirements according to radiation protection measures and the production of radioactive waste. In order to provide new approaches enabling non‐isotopic and cell‐based binding studies for the IABS of GPCRs, we and others have recently developed new small molecule‐based tools that are discussed below.Radioligands are among the most commonly used molecular tools for studying drug–target binding interactions in the field of GPCR research. One reason for their wide application is that radioligand binding assays allow measurements with native target proteins. This has the advantage that no modifications of the target protein, which eventually affect its druggability, subcellular distribution or expression level, are required. In addition, to transform a small molecule ligand into a radioactive tracer, usually only minor structural modifications are sufficient, such as the replacement of a hydrogen atom . A conjugation of the cell‐permeable tetramethylrhodamine (TAMRA) fluorophore to the vercirnon‐based pharmacophore was enabled by a final stage Cu(I)‐catalyzed Huisgen cycloaddition.10 allowed the identification and characterization of drug‐like as well as low molecular weight CCR9 ligands in a highly accurate and straightforward manner. Kinetic binding studies with 10 revealed that the interaction between CCR9 and the vercirnon scaffold is characterized by a long residence time of 90 min, which rationalizes the high affinity and outstanding CCR9 selectivity of vercirnon (5). Most importantly, by applying 10 in a cellular NanoBRET assay, we were able to detect and accurately quantify target engagement for the IABS of CCR9 in a live cell environment. Intracellular CCR9 binding of 10 and its displacement by non‐fluorescent competitors, such as vercirnon (5), was also monitored by fluorescence microscopy. Thus, 10 represents an unprecedented tool that enables the quantification as well as visualization of ligand binding to the IABS of CCR9 in a cellular environment. In addition, the application of 10 as a screening tool in cell‐free and cellular NanoBRET assays enabled the discovery of the 4‐aminopyrimidine AAA30 (9) as a new intracellular CCR9 antagonist with improved affinity and antagonistic activity compared to the clinical candidate vercirnon (5).Similar to radioligands, fluorescent ligands have had a major impact on drug discovery campaigns in the field of GPCR research over the past years.0 Figure A, was ba11  and CCR9, respectively, have been reported thus far.[12), we developed the first GPCR‐targeted PROTAC that utilizes the IABS as a drug target site.12 evoked a limited but statistically significant and selective degradation of CCR9 , thereby demonstrating that PROTACs are indeed suitable tools to study cellular target engagement for the IABS of GPCRs.Over the last years, the approach of targeted protein degradation (TPD), induced by means of so‐called proteolysis‐targeting chimeras (PROTACs), has gained much attention, due to several key advantages compared to standard inhibition of protein function by small molecules. The two most relevant advantages of PROTACs are their catalytic mode of action and a durable inhibition of protein function as a consequence of irreversible target protein degradation.thus far.13, 247  and received his license as a pharmacist in 2020. Currently, he is a PhD student in the Schiedel group at the FAU. His PhD project is focused on the development of small molecule ligands and molecular tools targeting the intracellular allosteric binding site of the chemokine receptor CCR9.Lara Toy studied Molecular Science (MSc) at the FAU. Currently, she is a PhD student in the Schiedel group at the FAU. Her PhD project is focused on the development of small molecule ligands and molecular tools targeting the intracellular allosteric binding site of the chemokine receptor CCR2.Maximilian F. Schmidt studied pharmacy at the FAU and received his license as a pharmacist in 2017. During his doctoral studies under the supervision of Peter Gmeiner and Tim Clark, his work was focussed on molecular modelling and molecular dynamics simulations of GPCR‐ligand complexes. Currently, he is working in the hospital pharmacy at the University Hospital Erlangen.Dorothee Weikert is a junior group leader at the Department of Chemistry and Pharmacy of the FAU. During her PhD at the FAU under the supervision of Kristina Friedland and Peter Gmeiner, she joined the lab of Michael Bouvier at the University of Montreal for a research stay. A second research stay, in the lab of Brian Kobilka at the Stanford University, followed her PhD. In 2016, she returned to the FAU and is working with her group on BRET‐based studies of GPCR activation and protein‐protein interactions, like receptor dimerization, especially in the context of bivalent ligands.Matthias Schiedel is a junior group leader (Liebig Fellow) at the Department of Chemistry and Pharmacy of the FAU Erlangen‐Nürnberg. After working in the field of epigenetic drug discovery for his PhD at the University of Freiburg with Manfred Jung and his postdoc at the University of Oxford with Stuart Conway, he joined the field of GPCR research and is now working with his group on novel approaches for targeting the intracellular allosteric binding site of GPCRs.


Early life adversity predicts shorter adult lifespan in several animal taxa. Yet, work on long‐lived primate populations suggests the evolution of mechanisms that contribute to resiliency and long lives despite early life insults. Here, we tested associations between individual and cumulative early life adversity and lifespan on rhesus macaques at the Cayo Santiago Biological Field Station using 50 years of demographic data. We performed sex‐specific survival analyses at different life stages to contrast short‐term effects of adversity  with long‐term effects . Female infants showed vulnerability to multiple adversities at birth, but affected females who survived to adulthood experienced a reduced risk later in life. In contrast, male infants showed vulnerability to a lower number of adversities at birth, but those who survived to adulthood were negatively affected by both early life individual and cumulative adversity. Our study shows profound immediate effects of insults  on female infant cohorts and suggests that affected female adults are more robust. In contrast, adult males who experienced harsh conditions early in life showed an increased mortality risk at older ages as expected from hypotheses within the life course perspective. Our analysis suggests sex‐specific selection pressures on life histories and highlights the need for studies addressing the effects of early life adversity across multiple life stages. Recent work on long‐lived primate populations suggests the evolution of mechanisms that contribute to resiliency and long lives despite early life insults. Our study shows profound immediate effects of insults at birth on female infant cohorts and suggests that affected female adults are more robust. In contrast, adult males who experienced harsh conditions early in life showed an increased mortality risk at older ages as expected from hypotheses within the life course perspective. Data on social mammals are further limited to the non‐dispersing sex. Studies on primate populations with social dispersal suffer from the limitation of being biased toward a single sex, which often results in hypotheses being tested only in females  is a 15.2 ha island located 1 km off the southeastern coast of Puerto Rico  that serves as biological field station for behavioral and noninvasive research of free‐ranging rhesus macaques , we added all variables to a global model. As maternal age and infant mortality may be associated . Monkeys that survived to age one were treated as censored individuals who at least survived the infancy period. For each sex, we used the Kaplan–Meier estimator and the log‐rank test to estimate and compare survival functions followed by the Cox proportional hazards regression to estimate and compare hazard ratios. As the Kaplan–Meier estimator can only consider groups as explanatory variables, we binarized density. For this, we evaluated the observed distribution of the annual number of adult females at the onset of each birth season. Individuals born in a year where the number of adult females was above the 3rd quartile of the distribution  were classified as experiencing high density. This is in line with prior reports on density effects on births  over time and recorded the age at death or age at right censorship . For each sex, we used the Kaplan–Meier estimator and the log‐rank test to estimate and compare survival functions followed by a mixed‐effects Cox proportional hazards regression to estimate and compare hazard ratios. As described above, we estimated survival functions for adult monkeys experiencing each adversity relative to those who did not experience such adversity. To test whether experiencing any of the five sources of adversity early in life increased mortality risk during adulthood, we fitted sex‐specific mixed‐effects Cox proportional hazards models using each adversity as a fixed effect and maternal ID as a random intercept. Because the PH assumption was not met for the hurricane covariate in our initial global model for male adults, we extended the Cox analysis using time‐varying covariates by stratifying the hurricane covariate into two age periods (3–8 and >8 years) following visual inspection of the estimated coefficient across time  following visual inspection of the estimated coefficient across time ; data curation (lead); formal analysis (lead); investigation ; methodology ; validation ; visualization ; writing – original draft ; writing – review and editing . Anthony J. Sherer: Data curation (supporting); formal analysis (supporting); investigation (supporting); validation (supporting); writing – review and editing (supporting). Raisa Hernández‐Pacheco: Conceptualization ; funding acquisition (lead); investigation ; methodology ; project administration (lead); resources (lead); supervision (lead); validation ; visualization ; writing – original draft ; writing – review and editing .We declare no conflict of interest.Appendix S1.Click here for additional data file.


SNCA) gene was identified in families with Parkinson's disease (PD).GBA) and leucine‐rich repeat kinase (LRRK2) pathogenic variants, as they are the most commonly known PD risk and causal variants and the most targeted in gene‐specific interventional trials?In 1997, Mihael H. Polymeropoulos and colleagues announced to the world that a mutation in the α‐synuclein –approved gene‐targeted therapy available, so genetic testing in the present climate would not affect management. However, in certain circumstances, our answer would be different, and we would offer genetic testing to our patients with PD. These circumstances would include an uncertain diagnosis with atypical features before more invasive investigations are considered, an earlier age of onset to help with prognosis, and counseling of patients and their families about disease progression, patients' interests, and inclusion in clinical trials.GBA and LRRK2 genes together account for most of the known strong genetic contributions to PD, with variants in LRRK2 being the most frequent causeGBA being the most frequent risk factorLRRK2 pathogenic variant: It is found in 10% of familial PD cases, 1% to 2% of all PD cases,GBA variants have been identified in various populations but are most frequently detected among people of Ashkenazi Jewish descent.LRKK2 and GBA mutations bridge the etiological gap between sporadic and hereditary PD, being both risk and causal factors to variable degrees on a continuum of reduced penetrance of a causative variant and increased risk. This phenomenon has been confirmed in genome‐wide association studies, cumulative burden tests, and in family studies for LRRK2.GBA‐PD is a non‐Mendelian form of PD, but GBA mutations markedly increase the risk of developing PD.GBA mutations on the risk and age at onset (AAO) of PD, and the odds ratio for PD ranged between 2.84 and 4.94 for mild GBA mutations and 9.92 and 21.29 for severe GBA mutations with a 5‐year earlier AAO for severe mutations.Pathogenic variants in the LRRK2 variant and whose father, with PD, had tested positive earlier for this variant. The incomplete penetrance and degree of conferred risk of PD in LRRK2 and GBA mutation carriers make it difficult to predict the development of disease in asymptomatic carriers and should be considered when counseling patients with PD and their families. When neuroprotective therapies become available, we must learn more about the penetrance of PD in these mutation carriers and their predictive value. The only way we can achieve this goal is through widespread genotyping and deep phenotyping of patients with PD and the investigation of genetic modifiers. The French PD Genetic Study group estimated that PD penetrance in GBA mutation carriers was 29.7% at 80 years using a dominant model,LRRK2 G2019S variantGBA as an autosomal dominant condition with reduced penetrance.“What is my risk of developing PD?” asked a young, healthy, asymptomatic lady who tested positive for a pathogenic There are 2 groups to consider when discussing routine genetic testing: people with PD and people at risk of developing PD with a positive family history. In both groups, we would argue against routine testing, and this will only change if gene‐targeted therapy is available in the PD group and if neuroprotective treatment is available in the group at risk for PD. With this in mind, are there any benefits, and what are the drawbacks of testing unaffected family members? The knowledge of one's mutation carrier status can assist with reproductive decisions, counseling about their risk of disease development, and the identification of individuals for neuroprotective trials when they are available. But this will come at a price, as insurance may not cover the costs of genetic testing and counseling as the result may not be an actionable finding. The other important drawbacks of genetic testing in this group are the negative social, psychological, and economic implications, as asymptomatic mutation carriers may be denied life insurance or future employment opportunities.LRRK2‐PD and GBA‐PD from idiopathic PD (iPD) ?Are there clinical clues that can distinguish LRRK2‐PDMDS gene) and GBA‐PDLRRK2 variant carriers and 55.8 years in GBA variant carriers.GBA‐PD, the phenotype is largely dependent on the severity of the variant type, with severe variant carriers displaying a more severe phenotype than mild variant carriers and iPD. This severe phenotype in GBA‐PD includes an earlier AAO, more severe cognitive decline, more frequently developed Lewy body dementia, rapid motor progression, and reduced survival.LRRK2‐PD and GBA‐PD that would make routine genetic testing justifiable? Because LRRK2‐PD and GBA‐PD can look similar to iPD and their presentation can be equally heterogeneous, no single clinical sign can adequately indicate a particular gene mutation. Thus, the only way to definitively rule out or rule in a genetic cause is by genetic testing, and this is also the only strategy to identify participants for clinical trials. Consider the following scenario: a 50‐year‐old man presents to a neurology clinic, and he has mild motor features of PD with normal cognition and a negative family history. He could have an LRRK2 or GBA pathogenic variant or just have iPD. Although routine testing for LRRK2 pathogenic variants does not significantly alter clinical management, testing for the type of GBA variant a patient has can affect the way we plan management and counsel the patients and their families already today. A patient diagnosed with GBA‐PD is often afraid of developing dementia; however, the risk of dementia and development of Lewy body dementia is higher with severe GBA mutations,GBA mutation does put the patient in a higher risk group for developing dementia, and genetic testing may be beneficial in these cases to better inform counseling and prognosis despite the aforementioned uncertainties in an individual patient. In the same way, there is evidence that shows cognitive impairment worsened after deep brain stimulation (DBS) in patients with GBA mutations,GBA carriers and did not always specify which GBA variant was associated with this outcome. Therefore, the detection of a GBA mutation in a patient being considered for DBS should not be used as a strict exclusion criterion, and more large‐scale studies investigating the differential effect of GBA mutation types and DBS are needed before a firm conclusion can be drawn about DBS in these patients.Are there important clinical consequences of LRRK2 and GBA mutations are the most advanced targets in several trials because they are considerably more common than the other monogenic forms of PD attributed to SNCA, PINK1, Parkin, and DJ1 mutations, for which it will be difficult to achieve an adequately powered clinical trial.https://www.parkinson.org/PDGENEration; NCT04057794) that provides free CLIA‐certified genetic testing and counseling to patients with PD, or industry‐sponsored interventional studiesLRRK2 and GBA‐PD in clinical trials, but the incomplete and variable penetrance of these mutations would also pose a major hurdle.Insight into the pathophysiological pathways involved in the genetic forms of PDLRRK2. LRRK2‐PD pathogenic variants cause a toxic gain‐of‐function increase in LRRK2 kinase activity, which has been targeted by the development of kinase inhibitors.LRRK2 kinase inhibitors, DNL201 (NCT03710707) and DNL151 (NCT04056689), will soon enter late‐stage clinical trials, with DNL151 being advanced first . There are other inhibitors in preclinical phases and include MLi‐2, PF‐06685360,LRRK2 mRNA transmission. A mouse PD modelLRRK2 ASOs injected into the brain reduce LRRK2 protein levels and the formation of α‐synuclein inclusions. A phase I trial is underway to assess the safety, tolerability, and pharmacokinetics of intrathecal administration of an ASO called BIIB094 that targets LRRK2 mRNA expression in patients with PD . For GBA‐PD, there are 3 gene‐targeted approaches.GBA pathogenic variant and those without.There are 2 main gene‐targeted approaches to 30 Of the respondents, 41% had not referred any PD patient for genetic testing, and the most common reason included cost or lack of insurance coverage, lack of perceived clinical utility, and lack of confidence in their genetic knowledge. These are major barriers that need to be overcome before genetic testing is routine in patients with PD. When clinicians’ attitudes toward general screening of the Ashkenazi Jewish population for the breast cancer (BRCA1/2) gene and LRRK2 mutations were compared,BRCA screening, being an actionable finding, but 86% opposed LRRK2 screening, which currently has no specific treatment available. However, this will likely change should a gene‐targeted therapy for LRRK2 become available and may even have a disease‐modifying effect. Genetic testing raises social and ethical concerns. Many clinicians are concerned about the implications of the genetic test results for their patients and families and need to consider their patients' attitudes and beliefs,With the advent of gene‐specific clinical trials, are clinicians and patients with PD and their families ready for routine genetic testing as a standard of care, and are their knowledge, interests, and attitudes toward genetic testing in PD aligned? In 2019, 178 movement disorder specialists at 146 clinical sites in Canada and the United States completed a questionnaire evaluating their current practice, knowledge, attitudes, and barriers to genetic testing in PD.LRRK2 and GBA mutations on the same panel. A potential solution would be to create a high‐quality sequencing panel covering both the LRRK2 and GBA genes that is easily accessible and low cost.Genetic tests available for PD include targeted testing in which a single or few variants in (a) gene(s) are tested, multigene panels in which multiple PD genes are tested by next‐generation sequencing together with deletion/duplication analysis offered by commercial companies, and direct‐to‐consumer testing.As genetic testing is evolving, the costs are declining. In countries where health insurance is standard, different insurance companies offer different coverage depending on a patient's/relative's personal risk and family history. Genetic testing and counseling are billed separately, so overall costs are greater with counseling included. Patients or relatives may have to pay out of pocket or get payment plans with the genetic laboratories. When gene‐targeted therapy is available, insurance companies will have an incentive to pay for genetic testing as there will be an actionable finding. There are a few research studiesIn the hypothetical situation that a gene‐targeted therapy is FDA approved and available, how would our approach to genetic testing in PD change? We would recommend initiating genetic testing using a stepwise approach, where we first test patients for the specific pathogenic variant(s) or gene(s) that the therapy is directed against and where this therapy is available. Table In conclusion, the multitude of clinical trials ongoing infuses hope of a gene‐targeted therapy being available to patients with PD soon. However, we do not feel it is time to offer genetic testing routinely until such gene‐targeted treatment is available to patients with PD and neuroprotective therapy is available to asymptomatic mutation carriers. We would recommend genetic testing in patients with PD with atypical features, early age of onset, significant family history, and in the research setting for inclusion in clinical trials.(1) Manuscript: A. Writing of the First Draft, B. Review and Critique.K.R.: 1AC.K.: 1BEthical Compliance Statement: The authors confirm that the approval of an institutional review board and patient consent was not required for this work. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.Funding Sources and Conflict of Interest: Christine Klein has received grants from the German Research Foundation, Bundesministerium für Bildung und Forschung (BMBF), The Michael J. Fox Foundation, and Aligning Science Across Parkinson's (ASAP); is employed by the University of Luebeck and University Hospital Schleswig‐Holstein; has received speaking honoraria from Desitin; provides consultancies for Centogene and Lundbeck; has received royalties from Oxford University Press; and is on the advisory board of Retromer Therapeutics. K.R. is a PhD student at the University of Luebeck and University Hospital Schleswig‐Holstein, has received a PhD scholarship from ASAP, and has no conflicts of interest.Financial Disclosures for the Previous 12 Months: Christine Klein would like to acknowledge support from Deutsche Forschungsgemeinschaft (DFG) FOR 2488 and the Global Parkinson's Disease Genetics Program (GP2) funded by the Aligning Science Across Parkinson's initiative and implemented by The Michael J. Fox Foundation. Karisha Roopnarain would like to acknowledge support from the GP2 funded by the Aligning Science Across Parkinson's initiative and implemented by The Michael J. Fox Foundation.


Here, we seek to validate differentiation as an independent predictor of later mental health conditions, and to explore its aetiology.An individual's overall burden of behavioural and emotional problems across childhood is associated with increased likelihood of later mental health conditions. However, the We analysed data from ~79,000 children in the population‐based Norwegian Mother, Father, and Child Cohort Study, and linked health‐care registries. In preregistered analyses, we modelled the extent and rate of differentiation of behavioural and emotional problems between ages 1.5–5 years, and estimated associations with later symptoms (age 8) and diagnoses (after age 8). We also explored the aetiology of differentiation by estimating associations with early life exposures and, in a subset of 23,945 full siblings, assessing the impact of accounting for unobserved familial confounding.β = 0.04 ) and parental relationship problems  were associated with higher behavioural relative to emotional problems at age 5. Maternal prenatal distress , concurrent distress  and parental education  predicted higher emotional relative to behavioural problems at age 5. Estimates for maternal prenatal distress and at‐risk drinking were consistent across both unadjusted and adjusted analyses accounting for unobserved familial risk.Differentiation of behavioural and emotional problems was associated with later symptoms and diagnoses of mental health conditions, independent of total problems. Maternal at‐risk drinking (Differentiation of behavioural and emotional problems in early childhood represents a valid source of inter‐individual variability linked to the later emergence of psychopathology and may be relevant for early detection and prevention strategies for mental health. Co‐occurring behavioural and emotional problems in early life are strongly associated with later mental health conditions. However, the relative extent of problems in these domains  may provide additional information about who is at risk and for which disorders, essential to detecting and preventing the emergence of psychopathology.Findings show that differentiation of behavioural and emotional problems in early life strongly associates with the development of mental health conditions later in childhood and adolescence.We identify potentially modifiable environmental factors predicting differentiation in early life, while accounting for confounding by unobserved familial risk.differentiated from one another ‐ may provide additional information about who is at risk of developing specific mental health conditions.Behavioural and emotional problems often co‐occur in young children. It is also well established that behavioural problems  and emotional problems  in early childhood are associated with an increased risk of mental disorders later in development , a national health registry containing information about all births in Norway. In addition, we obtained data on diagnoses of specific mental health conditions from the Norwegian Patient Registry (NPR) and “Kontroll og utbetaling av helserefusjoner” (KUHR).The data in MoBa was collected by questionnaires from early pregnancy to middle childhood, provided primarily by mothers . Phenotype data from the fathers were collected by questionnaire around week 17 of the pregnancy.We used the Child Behaviour Checklist (CBCL) to assess behavioural problems (8 items) and emotional problems (5 items), at ages 1.5, 3, and 5 years. Information about psychometric properties of the CBCL subscales are provided in Appendix We also combined behavioural and emotional problems as a sum score in order to provide a point of reference for analyses of the differentiation scores described above. Total levels of emotional and behavioural problems were computed by adding up standardised scores of the two dimensions in the overall sample . By definition, these scores are completely orthogonal to the differentiation scores.We used the 13‐item Short Mood and Feelings Questionnaire  and parity as time‐invariant covariates and the child's age at questionnaire return as a time‐varying covariate. Mother ID was used for clustering in all models.https://github.com/psychgen/phenotools). We used the False Discovery Rate (FDR) to preserve the Type 1 error rates at 5% in all models , we parameterised the development of behavioural‐emotional differentiation across three time points . Individual differences in the extent and rate of differentiation of behavioural and emotional problems were captured by latent slope and intercept factors .We entered the 16 early life exposures into the LGMs, initially allowing them to influence both slope and intercept factors to derive estimates of the observational exposure‐outcome associations in the full sample. We then tested sub‐models in which all exposures influenced the growth process via, alternately, only the slope or intercept factors. Finally, we restricted to the sibling sub‐sample  and ran multilevel LGMs, where variance in the exposure variables is decomposed into variance that is specific to a given mother for a given child (level 1) and variance that is specific to a given mother but shared across siblings (level 2). Effects of the exposures on the growth factor(s) were estimated in two versions of this model: (1) unadjusted for familial confounding  and (2) adjusted for nuclear family‐level confounding. Whilst only controlling for 50% of genetic effects at the child level, this design completely adjusts associations for family‐wide factors. This includes most plausible “third variable” confounders of associations between early environmental exposures and child outcomes .To account for differences between the sibling sub‐sample and the overall sample, due to within‐sample selection bias , we included inverse probability weights based on a logistic regression of sibling‐singleton status on all other study variables in all sibling‐only models , Tucker‐Lewis index (TLI), standardised root mean square residual (SRMR), and root mean square error of approximation (RMSEA). By convention, an SRMR below 0.1 and an RMSEA of less than 0.05 implies a good fit, as well as CFI and TLI values over 0.95 Kline, . We alsoWe included all MoBa children with available CBCL data on at least one measurement occasion fhi.no. Access to datasets requires approval from The Regional Committee for Medical and Health Research Ethics in Norway and an agreement with MoBa.https://github.com/psychgen/childhood‐differentiation.Data preparation and analysis code for all elements of the project is publicly available on Github: rrange: −0.01–0.01).Descriptive statistics for all symptom measures are presented in Table r = 0.64 ). There was evidence of sex differences where males showed greater extent of behavioural relative to emotional problems at age 5  but similar rates of differentiation over time compared to females . Later birth order was associated with greater extent  and rate  of differentiation toward behavioural problems. For total problems, a growth model with both slope and intercept factors also provided excellent fit  and extent  of total problems and the rate  and extent  of differentiation toward behavioural problems in relation to a diagnosis of ADHD. Similar associations were observed between the extent of total problems , differentiation toward behavioural problems at age 5 , and later diagnosed DBD.We then estimated the likelihood of having received relevant diagnoses based on the rate and extent of differentiation during early childhood  and rate  of differentiation toward emotional problems. In addition, maternal prenatal and concurrent distress were predictive of the extent and/or rate of differentiation toward emotional problems after FDR correction  and emotional problems . In contrast to observational links between differentiation and parental education or relationship problems, these associations appeared not to be inflated by unobserved familial confounding.There has recently been much emphasis on the stability and co‐occurrence of mental health conditions in childhood, which can be captured by a general “p” factor  by confounders not shared by siblings , results were inconsistent across the observational analyses in the whole sample and the unadjusted analyses in the sibling sub‐sample. In this sub‐sample, some selection effects remained after weighting .Supplementary Information S1Click here for additional data file.