Higher beta-hydroxybutyrate ketone levels associated with a slower kidney function decline in ADPKD.

BACKGROUND AND HYPOTHESIS: Dysregulated energy metabolism is a recently discovered key feature of Autosomal Dominant Polycystic Kidney Disease (ADPKD). Cystic cells depend on glucose and are poorly able to use other energy sources such as ketone bodies. Raising ketone body concentration reduced disease progression in animal models of polycystic kidney diseases. Therefore, we hypothesized that higher endogenous plasma beta-hydroxybutyrate concentrations are associated with reduced disease progression in patients with ADPKD. METHODS: We analyzed data from 670 patients with ADPKD participating in the DIPAK cohort, a multi-center prospective observational cohort study. Beta-hydroxybutyrate was measured at baseline using nuclear magnetic resonance spectroscopy. Participants were excluded if they had type 2 diabetes, were using disease-modifying drugs (e.g. tolvaptan, somatostatin analogs), were not fasting, or had missing beta-hydroxybutyrate levels, leaving 521 participants for the analyses. Linear regression analyses were used to study cross-sectional associations and linear mixed-effect modeling for longitudinal associations. RESULTS: Of the participants, 61% were female, with an age of 47.3 ± 11.8 years, a height-adjusted total kidney volume (htTKV) of 834 (IQR 495-1327) ml/m, and an estimated glomerular filtration rate (eGFR) of 63.3 ± 28.9 mL/min/1.73m2. The median concentration of beta-hydroxybutyrate was 94 (IQR 68-147) µmol/L. Cross-sectionally, beta-hydroxybutyrate was neither associated with eGFR nor with htTKV. Longitudinally, beta-hydroxybutyrate was positively associated with eGFR slope (B = 0.35 ml/min/1.73m2 (95% CI 0.09 to 0.61), p = 0.007), but not with kidney growth. After adjustment for potential confounders, every doubling in beta-hydroxybutyrate concentration was associated with an improvement in the annual rate of eGFR by 0.33 ml/min/1.73m2 (95% CI 0.09 to 0.57, p = 0.008). CONCLUSION: These observational analyses support the hypothesis that interventions that raise beta-hydroxybutyrate concentration could reduce the rate of kidney function decline in patients with ADPKD.

"Boy, what are we all doing? We are crazy, really crazy": a qualitative study of psychosocial processes around an atypical one-time smoking cessation course.

BACKGROUND: Smoking prevalence is still high, which requires effective interventions that help many people who smoke at once in addition to time-consuming individual interventions. 'I Quit' is a large-scale smoking cessation course in The Netherlands. This qualitative study explored I Quit participants' experiences during and after the course, and perceptions of whether and how the course may have altered their smoking behavior. METHODS: We performed individual semi-structured interviews with course participants (N = 21) who had either quit successfully, attempted to quit but relapsed, or had continued to smoke after 'I Quit'. Shortly after qualitative data collection was completed, Foundation I Quit was accused in the media of a number of misbehaviors. Although unplanned, this provided a unique opportunity to explore participants' views on alleged fraud in a second round of interviews (N = 16). Data were collected from 2016 to 2018. RESULTS: Qualitative findings showed two psychosocial processes that may explain smoking cessation after course attendance. First, the confrontation with a large group of people who smoke, of whom some had already developed smoking-related complaints, triggered identity processes both towards and away from quitting smoking. Unorthodox methods used in the course appeared to trigger identity processes. Second, social support after the course from participants' own social network facilitated maintenance of successful quitting. The study also found that interview participants' opinions on I Quit did not change much after allegations of fraud in the media. CONCLUSIONS: Findings suggest that a one-time course might initiate psychosocial processes that could help certain smokers to gain motivation to quit, requiring a minimum of resources. Identity processes triggered by the course seem tricky as people have different ways of dealing with identity threat, some of which can be counterproductive and even result in more difficulty quitting. More research is needed to examine who can benefit from a one-time course, and who needs more support in order to quit successfully.

Hapten/Myristoyl Functionalized Poly(propyleneimine) Dendrimers as Potent Cell Surface Recruiters of Antibodies for Mediating Innate Immune Killing.

Recruiting endogenous antibodies to the surface of cancer cells using antibody-recruiting molecules has the potential to unleash innate immune effector killing mechanisms against antibody-bound cancer cells. The affinity of endogenous antibodies is relatively low, and many currently explored antibody-recruiting strategies rely on targeting over-expressed receptors, which have not yet been identified in most solid tumors. Here, both challenges are addressed by functionalizing poly(propyleneimine) (PPI) dendrimers with both multiple dinitrophenyl (DNP) motifs, as anti-hapten antibody-recruiting motifs, and myristoyl motifs, as universal phospholipid cell membrane anchoring motifs, to recruit anti-hapten antibodies to cell surfaces. By exploiting the multivalency of the ligand exposure on the dendrimer scaffold, it is demonstrated that dendrimers featuring ten myristoyl and six DNP motifs exhibit the highest antibody-recruiting capacity in vitro. Furthermore, it is shown that treating cancer cells with these dendrimers in vitro marks them for phagocytosis by macrophages in the presence of anti-hapten antibodies. As a proof-of-concept, it is shown that intratumoral injection of these dendrimers in vivo in tumor-bearing mice results in the recruitment of anti-DNP antibodies to the cell surface in the tumor microenvironment. These findings highlight the potential of dendrimers as a promising class of novel antibody-recruiting molecules for use in cancer immunotherapy.

Temperature Directs the Majority-Rules Principle in Supramolecular Copolymers Driven by Triazine-Benzene Interactions.

Supramolecular copolymers have typically been studied in the extreme cases, such as self-sorting or highly mixed copolymer systems, while the intermediate systems have been less understood. We have reported the temperature-dependent microstructure in copolymers of triazine- and benzene-derivatives based on charge-transfer interactions with a highly alternating microstructure at low temperatures. Here, we investigate the temperature-dependent copolymerization further and increase the complexity by combining triazine- and benzene-derivatives with opposite preferred helicities. In this case, intercalation of the benzene-derivative into the triazine-derivative assemblies causes a helical inversion. The inversion of the net helicity was rationalized by comparing the mismatch penalties of the individual monomers, which indicated that the benzene-derivative dictates the helical screw-sense of the supramolecular copolymers. Surprisingly, this was not reflected in further investigations of slightly modified triazine- and benzene-derivatives, thus highlighting that the outcome is a subtle balance between structural features, where small differences can be amplified due to the competitive nature of the interactions. Overall, these findings suggest that the temperature-dependent microstructure of triazine- and benzene-based supramolecular copolymers determines the copolymer helicity of the presented system in a similar way as the mixed majority-rules phenomenon.

Ferro- and ferrielectricity and negative piezoelectricity in thioamide-based supramolecular organic discotics.

Amide-based discotic supramolecular organic materials are of interest for fundamental understanding of cooperative self-assembly and collective dipole switching mechanisms as well as for practically relevant ferroelectric and piezoelectric properties. Here, we show how replacing amides (dipole moment of ∼3.5 D) with thioamides (∼5.1 D) as dipolar moieties in the archetypal C3-symmetric discotic molecule BTA leads to ferroelectric materials with a higher remnant polarization and lower coercive field. The thioamide-based materials also demonstrate a rare negative piezoelectricity and a previously predicted, yet never experimentally observed, polarization reversal via asymmetric intermediate states, that is, ferrielectric switching.

Identified or conflicted: a latent class and regression tree analysis explaining how identity constructs cluster within smokers.

Identity, or 'who I am', is important for smoking behaviour. Identity constructs (parts of a person's identity) are typically examined as separate entities, but emerging evidence suggests that the multifaceted nature of identity is relevant in the context of smoking. This cross-sectional study examined how smoking-related self- and group-identity constructs cluster within adult daily smokers (N = 231), whether classes of smokers can be distinguished based on clusters of identity constructs, and which factors explain class membership. Data were collected online in The Netherlands and Belgium, 2017-2018. Latent class and regression tree analyses showed that participants in Class 1 of 'Identified smokers' (estimated population share 54%) reported stronger smoker self- and group-identities, stronger expected identity loss when quitting smoking, and weaker quitter self-identities and non-smoker self- and group-identities (vs. Class 2 of 'Conflicted smokers'). Class membership was explained by the interaction between mental smoking dependence (dominant explanatory variable), consideration of future consequences, age of smoking onset, self-efficacy, and future self thought clarity. Models had good fit. The identity of more dependent smokers is more strongly oriented toward smoking. Smoking is also more strongly embedded in the identity of smokers who started smoking young, are less inclined to think about the future, and have lower self-efficacy.

Depolymerization of supramolecular polymers by a covalent reaction; transforming an intercalator into a sequestrator.

Controlling the reciprocity between chemical reactivity and supramolecular structure is a topic of great interest in the emergence of molecular complexity. In this work, we investigate the effect of a covalent reaction as a trigger to depolymerize a supramolecular assembly. We focus on the impact of an in situ thiol-ene reaction on the (co)polymerization of three derivatives of benzene-1,3,5-tricarboxamide (BTA) monomers functionalized with cysteine, hexylcysteine, and alkyl side chains: Cys-BTA, HexCys-BTA, and a-BTA. Long supramolecular polymers of Cys-BTA can be depolymerized into short dimeric aggregates of HexCys-BTA via the in situ thiol-ene reaction. Analysis of the system by time-resolved spectroscopy and light scattering unravels the fast dynamicity of the structures and the mechanism of depolymerization. Moreover, by intercalating the reactive Cys-BTA monomer into an unreactive inert polymer, the in situ thiol-ene reaction transforms the intercalator into a sequestrator and induces the depolymerization of the unreactive polymer. This work shows that the implementation of reactivity into supramolecular assemblies enables temporal control of depolymerization processes, which can bring us one step closer to understanding the interplay between non-covalent and covalent chemistry.

Unraveling the Complexity of Supramolecular Copolymerization Dictated by Triazine-Benzene Interactions.

Supramolecular copolymers formed by the noncovalent synthesis of multiple components expand the complexity of functional molecular systems. However, varying the composition and microstructure of copolymers through tuning the interactions between building blocks remains a challenge. Here, we report a remarkable discovery of the temperature-dependent supramolecular copolymerization of the two chiral monomers 4,4',4″-(1,3,5-triazine-2,4,6-triyl)tribenzamide (S-T) and 4,4',4″-(benzene-1,3,5-triyl)tribenzamide (S-B). We first demonstrate in the homopolymerization of the two individual monomers that a subtle change from the central triazine to benzene in the chemical structure of the monomers significantly affects the properties of the resulting homopolymers in solution. Homopolymers formed by S-T exhibit enhanced stability in comparison to S-B. More importantly, through a combination of spectroscopic analysis and theoretical simulation, we reveal the complex process of copolymerization: S-T aggregates into homopolymers at elevated temperature, and upon slow cooling S-B gradually intercalates into the copolymers, to finally give copolymers with almost 80% alternating bonds at 10 °C. The formation of the predominantly alternating copolymers is plausibly contributed by preferred heterointeractions between triazine and benzene cores in S-T and S-B, respectively, at lower temperatures. Overall, this work unravels the complexity of a supramolecular copolymerization process where an intermediate heterointeraction (higher than one homointeraction and lower than the other homointeraction) presents and proposes a general method to elucidate the microstructures of copolymers responsive to temperature changes.

Lacking willpower? A latent class analysis of healthcare providers' perceptions of smokers' responsibility for smoking.

OBJECTIVE: Healthcare providers' (HCPs) perceptions of smokers' responsibility for smoking may affect implementation of smoking cessation care (SCC), but are understudied. This study examined Dutch HCPs' perceptions of smokers' responsibility for smoking, and how many and which subgroups exist with regard to these perceptions. METHODS: Observational cross-sectional study among physicians and other HCPs (N = 570). Latent class analysis was used to analyse data. RESULTS: Results showed two latent classes of HCPs: a majority (77 %) that appeared to hold smokers themselves more accountable for their smoking, and a minority (23 %) that seemed more inclined to believe that people smoked as a consequence of factors such as addiction, and smoking initiation when people were young and could not foresee consequences. The two-class model showed excellent certainty in classification. Class membership was associated with age, working experience, and smoking status. The majority class experienced more barriers to SCC than the minority class and provided SCC tasks to fewer patients. CONCLUSIONS: HCPs' perceptions of smokers' responsibility for smoking relate to HCP background characteristics, barriers to SCC and implementation of SCC. PRACTICE IMPLICATIONS: New approaches to improving SCC might be needed that take HCP's perceptions of smokers' responsibility into account.

Exploring the Potential of Benzene-1,3,5-tricarboxamide Supramolecular Polymers as Biomaterials.

The fast dynamics occurring in natural processes increases the difficulty of creating biomaterials capable of mimicking Nature. Within synthetic biomaterials, water-soluble supramolecular polymers show great potential in mimicking the dynamic behavior of these natural processes. In particular, benzene-1,3,5-tricaboxamide (BTA)-based supramolecular polymers have shown to be highly dynamic through the exchange of monomers within and between fibers, but their suitability as biomaterials has not been yet explored. Herein we systematically study the interactions of BTA supramolecular polymers bearing either tetraethylene glycol or mannose units at the periphery with different biological entities. When BTA fibers were incubated with bovine serum albumin (BSA), the protein conformation was only affected by the fibers containing tetraethylene glycol at the periphery (BTA-OEG4). Coarse-grained molecular simulations showed that BSA interacted with BTA-OEG4 fibers rather than with BTA-OEG4 monomers that are present in solution or that may exchange out of the fibers. Microscopy studies revealed that, in the presence of BSA, BTA-OEG4 retained their fiber conformation although their length was slightly shortened. When further incubated with fetal bovine serum (FBS), both long and short fibers were visualized in solution. Nevertheless, in the hydrogel state, the rheological properties were remarkably preserved. Further studies on the cellular compatibility of all the BTA assemblies and mixtures thereof were performed in four different cell lines. A low cytotoxic effect at most concentrations was observed, confirming the suitability of utilizing functional BTA supramolecular polymers as dynamic biomaterials.

Facilitating smoking cessation in patients who smoke: a large-scale cross-sectional comparison of fourteen groups of healthcare providers.

BACKGROUND: Although healthcare providers are well placed to help smokers quit, implementation of smoking cessation care is still suboptimal. The Ask-Advise-Refer tasks are important aspects of smoking cessation care. We examined to which extent a large and diverse sample of healthcare providers expressed the intention to implement smoking cessation care and which barriers they encountered. We moreover examined to which extent the Ask-Advise-Refer tasks were implemented as intended, and which determinants (in interaction) influenced intentions and the implementation of Ask-Advise-Refer. METHODS: Cross-sectional survey among addiction specialists, anaesthesiologists, cardiologists, general practitioners, internists, neurologists, paediatricians, pulmonologists, ophthalmologists, surgeons, youth specialists, dental hygienists, dentists, and midwives (N = 883). Data were analysed using multivariate linear and logistic regression analyses and regression tree analyses. RESULTS: The Ask-Advice-Refer tasks were best implemented among general practitioners, pulmonologists, midwives, and addiction specialists. Overall we found a large discrepancy between asking patients about smoking status and advising smokers to quit. Participants mentioned lack of time, lack of training, lack of motivation to quit in patients, and smoking being a sensitive subject as barriers to smoking cessation care. Regression analyses showed that the most important determinants of intentions and implementation of Ask-Advise-Refer were profession, role identity, skills, guideline familiarity and collaboration agreements for smoking cessation care with primary care. Determinants interacted in explaining outcomes. CONCLUSIONS: There is much to be gained in smoking cessation care, given that implementation of Ask-Advise-Refer is still relatively low. In order to improve smoking cessation care, changes are needed at the level of the healthcare provider (i.e., facilitate role identity and skills) and the organization (i.e., facilitate collaboration agreements and guideline familiarity). Change efforts should be directed towards the specific barriers encountered by healthcare providers, the contexts that they work in, and the patients that they work with.

DNA-Functionalized Supramolecular Polymers: Dynamic Multicomponent Assemblies with Emergent Properties.

Recent years have witnessed an increasing interest in hybrid molecular systems in which the programmability of DNA hybridization is used to introduce enhanced molecular control in synthetic systems. The first examples of DNA-functionalized supramolecular polymers have been reported only recently, but have already revealed structural and functional properties that are not easily obtained in either synthetic supramolecular polymers or DNA-only based systems. In this Topical Review, we provide an overview of the various forms of additional control offered by DNA hybridization for different types of supramolecular polymers and discuss how orthogonal supramolecular interactions in these hybrid systems can give rise to emergent structural and functional properties.

"It's on everyone's plate": a qualitative study into physicians' perceptions of responsibility for smoking cessation.

BACKGROUND: Little research has investigated in-depth how physicians perceive their role in smoking cessation care. This qualitative study sought to understand physicians' perceptions of responsibility for smoking cessation. METHODS: Data were collected through individual semi-structured interviews and focus group interviews between June and November 2017 in The Netherlands. We interviewed 5 addiction specialists, 5 anesthesiologist, 4 cardiologists, 8 GPs, 5 internists, 5 neurologists, 2 pediatricians, 6 pulmonologists, 7 surgeons, and 8 youth healthcare physicians (N = 55). Data analysis followed the framework approach. RESULTS: The analysis showed that three actors were perceived as responsible for smoking cessation: physicians, patients, and the government. Participants perceived physicians as responsible for facilitating smoking cessation -albeit to different extents-, patients as carrying the ultimate responsibility for quitting smoking, and the government as responsible for creating a society in which smoking uptake is more difficult and quitting smoking easier. Perceptions of smoking itself were found to be important for how participants viewed responsibility for smoking cessation. It remained unclear for many participants which healthcare provider is responsible for smoking cessation care. CONCLUSIONS: The organization of smoking cessation care within health systems should be a focus of intervention, to better define physician roles and perceptions of responsibility. In addition, it seems important to target perceptions of smoking itself on the level of physicians and -as suggested by comments by several participants- the government.

Impact of the water-compatible periphery on the dynamic and structural properties of benzene-1,3,5-tricarboxamide based amphiphiles.

The consequences of using saccharides versus tetra(ethyleneglycol) chains as water-compatible moieties on the morphology and dynamics of supramolecular polymers in aqueous solutions are investigated. The saccharides form many H-bonds with other saccharides within the polymer and with water, increasing the hydration of the fiber and changing its dynamics.

Polymorphism in Benzene-1,3,5-tricarboxamide Supramolecular Assemblies in Water: A Subtle Trade-off between Structure and Dynamics.

In biology, polymorphism is a well-known phenomenon by which a discrete biomacromolecule can adopt multiple specific conformations in response to its environment. The controlled incorporation of polymorphism into noncovalent aqueous assemblies of synthetic small molecules is an important step toward the development of bioinspired responsive materials. Herein, we report on a family of carboxylic acid functionalized water-soluble benzene-1,3,5-tricarboxamides (BTAs) that self-assemble in water to form one-dimensional fibers, membranes, and hollow nanotubes. Interestingly, one of the BTAs with the optimized position of the carboxylic group in the hydrophobic domain yields nanotubes that undergo reversible temperature-dependent dynamic reorganizations. SAXS and Cryo-TEM data show the formation of elongated, well-ordered nanotubes at elevated temperatures. At these temperatures, increased dynamics, as measured by hydrogen-deuterium exchange, provide enough flexibility to the system to form well-defined nanotube structures with apparently defect-free tube walls. Without this flexibility, the assemblies are frozen into a variety of structures that are very similar at the supramolecular level, but less defined at the mesoscopic level.

Clinical predictors of escalating care in hepatic and renal cyst infection in autosomal dominant polycystic kidney and liver disease.

BACKGROUND: Cyst infection may occur in autosomal dominant polycystic kidney disease (ADPKD) and autosomal dominant polycystic liver disease (ADPLD). Antimicrobial agents often fail to control infection, leading to invasive action. We aimed to identify factors predicting escalation of care. METHODS: ADPKD and ADPLD patients were identified from local/national databases (2001-2013). Records were screened for patients meeting criteria for cyst infection (positive cyst aspirate and/or clinical findings). Factors that predict escalated care were identified with multivariate modified Poisson regression. RESULTS: We screened 1773 patients. A total of 77 patients with cyst infection (4.3%) were included for analysis (hepatic 36%; male 49%; age 54 ±; 13 years; ADPKD 95%; dialysis 9%, diabetes 18%, renal transplant 56%, eGFR [IQR 24-78] ml/min/1.73 m2 (excluding patients with a history of renal transplant or receiving dialysis)). A pathogen was identified in 71% of cases. Escherichia coli was the most common pathogen and accounted for 69% of cases. Initial treatment was limited to antibiotics in 87% of patients (n = 67), 40% included a fluoroquinolone. Ultimately, 48% of patients underwent some form of invasive action (escalation of care). Increasing white blood cell count (WBC) (RR 1.04 95%-CI 1.01-1.07, p = 0.008) was associated with escalating care, whereas an increase in time between transplant and infection (RR 0.92 95% CI 0.86-0.97, p = 0.005) and E. coli isolation (RR 0.55 95% CI 0.34-0.89, p = 0.02) were protective. CONCLUSION: High serum WBC, isolation of atypical pathogens and early infection after transplantation are factors that increase the risk of escalation of care in hepatic and renal cyst infection patients.

Supramolecular Platform Stabilizing Growth Factors.

High concentrations of supplemented growth factors can cause oversaturation and adverse effects in in vitro and in vivo studies, though these supraphysiological concentrations are often required due to the low stability of growth factors. Here we demonstrate the stabilization of TGF-ß1 and BMP4 using supramolecular polymers. Inspired by heparan sulfate, sulfonated peptides were presented on a supramolecular polymer to allow for noncovalent binding to growth factors in solution. After mixing with excipient molecules, both TGF-ß1 and BMP4 were shown to have a prolonged half-life compared to the growth factors free in solution. Moreover, high cellular response was measured by a luciferase assay, indicating that TGF-ß1 remained highly active upon binding to the supramolecular assembly. The results demonstrate that significant lower concentrations of growth factors can be used when supramolecular polymers bearing growth factor binding moieties are implemented. This approach can also be exploited in hydrogel systems to control growth factor release.

Catalytically Active Single-Chain Polymeric Nanoparticles: Exploring Their Functions in Complex Biological Media.

Dynamic single-chain polymeric nanoparticles (SCPNs) are intriguing, bioinspired architectures that result from the collapse or folding of an individual polymer chain into a nanometer-sized particle. Here we present a detailed biophysical study on the behavior of dynamic SCPNs in living cells and an evaluation of their catalytic functionality in such a complex medium. We first developed a number of delivery strategies that allowed the selective localization of SCPNs in different cellular compartments. Live/dead tests showed that the SCPNs were not toxic to cells while spectral imaging revealed that SCPNs provide a structural shielding and reduced the influence from the outer biological media. The ability of SCPNs to act as catalysts in biological media was first assessed by investigating their potential for reactive oxygen species generation. With porphyrins covalently attached to the SCPNs, singlet oxygen was generated upon irradiation with light, inducing spatially controlled cell death. In addition, Cu(I)- and Pd(II)-based SCPNs were prepared and these catalysts were screened in vitro and studied in cellular environments for the carbamate cleavage reaction of rhodamine-based substrates. This is a model reaction for the uncaging of bioactive compounds such as cytotoxic drugs for catalysis-based cancer therapy. We observed that the rate of the deprotection depends on both the organometallic catalysts and the nature of the protective group. The rate reduces from in vitro to the biological environment, indicating a strong influence of biomolecules on catalyst performance. The Cu(I)-based SCPNs in combination with the dimethylpropargyloxycarbonyl protective group showed the best performances both in vitro and in biological environment, making this group promising in biomedical applications.

A longitudinal study into the reciprocal effects of identities and smoking behaviour: Findings from the ITC Netherlands Survey.

OBJECTIVE: Although it has been found that identity constructs related to smoking are associated with changes in smoking behaviour, the direction of causal associations is as yet unclear. This study aims to clarify the nature and direction of these associations. METHODS: In this longitudinal study we examined the reciprocal relations between identity constructs (i.e., smoker self-identity, quitter self-identity and smoker group-identity), intention to quit and smoking and quitting behaviour among a sample of 1036 smokers and ex-smokers, using cross-lagged structural equation modelling. Moreover, we tested whether these relations differed by socio-economic status (SES). RESULTS: Identity and smoking behaviour were reciprocally related in that in intention to quit and smoking behaviour consistently predicted identity change, and identity predicted (changes in) intentions to quit and smoking behaviour. Behaviour appears more important for identity change than identity for behaviour change. Furthermore, quitter self-identity appears more important than smoker self- and group-identity. Relationships did not differ significantly between SES-groups. The findings were replicated using a cross-validation sample. CONCLUSION: Results imply that changing smoking behaviour may be a vehicle to change smoking-related identity. Moreover, strengthening identification with quitting is more crucial for quit success than decreasing smoker identities. The finding that behaviour may be more important for identity than vice versa, if replicated, may call for additions to identity theories.