Uncovering the heritable components of multimorbidities and disease trajectories using a nationwide cohort.

Quantifying the contribution of genetics and environmental effects on disease initiation and progression, as well as the shared genetics of different diseases, is vital for the understanding of the disease etiology of multimorbidities. In this study, we leverage nationwide Danish registries to provide a granular atlas of the genetic origin of disease phenotypes for a cohort of all Danes 1978-2018 with partially known pedigree (n = 6.3 million). We estimate the heritability and genetic correlation between thousands of disease phenotypes using a novel approach that can be scaled to nationwide data. Our findings confirm the importance of genetics for a number of known associations and increase the resolution of heritability by adding numerous associations, some of which point to shared biologically origin of different phenotypes. We also establish the heritability of disease trajectories and the importance of sex-specific genetic contributions. Results can be accessed at https://h2.cpr.ku.dk/ .

Perspective: multi-configurational methods in bio-inorganic chemistry.

Transition metal ions play crucial roles in the structure and function of numerous proteins, contributing to essential biological processes such as catalysis, electron transfer, and oxygen binding. However, accurately modeling the electronic structure and properties of metalloproteins poses significant challenges due to the complex nature of their electronic configurations and strong correlation effects. Multiconfigurational quantum chemistry methods are, in principle, the most appropriate tools for addressing these challenges, offering the capability to capture the inherent multi-reference character and strong electron correlation present in bio-inorganic systems. Yet their computational cost has long hindered wider adoption, making methods such as density functional theory (DFT) the method of choice. However, advancements over the past decade have substantially alleviated this limitation, rendering multiconfigurational quantum chemistry methods more accessible and applicable to a wider range of bio-inorganic systems. In this perspective, we discuss some of these developments and how they have already been used to answer some of the most important questions in bio-inorganic chemistry. We also comment on ongoing developments in the field and how the future of the field may evolve.

Simulating X-ray Absorption Spectroscopy in Challenging Environments: Methodological Insights from Water-Solvated Ammonia and Ammonium Systems.

Core-electron excitations in solvated systems, influenced by solvent geometry and hydrogen bonding, make X-ray absorption spectroscopy (XAS) a valuable tool for assessing solvent-solute interactions. However, calculating XAS spectra with electronic-structure methods has proven challenging due to a delicate interplay between correlation and solvation effects. This study provides a computational procedure for XAS modeling in solvated systems, with water-solvated ammonia and ammonium systems serving as probes. Exploring methodological challenges, we investigate explicit embedding models, specifically the polarizable embedding family, including polarizable density embedding and extended polarizable density embedding. Our linear-response time-dependent density functional theory (LR-TDDFT) XAS calculations reveal the efficiency of this approach, with extended polarizable density embedding emerging as a robust improvement over polarizable density embedding. Contrary to some recent literature, our study challenges the belief that LR-TDDFT cannot accurately describe XAS spectra of ammonia and ammonium solvated in water.

The COVID-19 pandemic eroded system support but not social solidarity.

While the World was busy mitigating the disastrous health and economic effects of the novel coronavirus, a less direct, but not less concerning peril has largely remained unexplored: the COVID-19 crisis may have disrupted some of the most fundamental social and political relationships in democratic societies. We interviewed samples resembling the national population of Denmark, Hungary, Italy and the US three times: in April, June and December of 2020 (14K observations). We show that multiple (but not all) measures of support for the political system decreased between April and December. Exploiting the panel setup, we demonstrate that within-respondent increases in indicators of pandemic fatigue (specifically, the perceived subjective burden of the pandemic and feelings of anomie) correspond to decreases in system support and increases in extreme anti-systemic attitudes. At the same time, we find no systematic trends in feelings of social solidarity, which are largely unaffected by changes in pandemic burden.

Epidemic modelling of monitoring public behavior using surveys during pandemic-induced lockdowns.

BACKGROUND: Implementing a lockdown for disease mitigation is a balancing act: Non-pharmaceutical interventions can reduce disease transmission significantly, but interventions also have considerable societal costs. Therefore, decision-makers need near real-time information to calibrate the level of restrictions. METHODS: We fielded daily surveys in Denmark during the second wave of the COVID-19 pandemic to monitor public response to the announced lockdown. A key question asked respondents to state their number of close contacts within the past 24 hours. Here, we establish a link between survey data, mobility data, and hospitalizations via epidemic modelling of a short time-interval around Denmark's December 2020 lockdown. Using Bayesian analysis, we then evaluate the usefulness of survey responses as a tool to monitor the effects of lockdown and then compare the predictive performance to that of mobility data. RESULTS: We find that, unlike mobility, self-reported contacts decreased significantly in all regions before the nation-wide implementation of non-pharmaceutical interventions and improved predicting future hospitalizations compared to mobility data. A detailed analysis of contact types indicates that contact with friends and strangers outperforms contact with colleagues and family members (outside the household) on the same prediction task. CONCLUSIONS: Representative surveys thus qualify as a reliable, non-privacy invasive monitoring tool to track the implementation of non-pharmaceutical interventions and study potential transmission paths.

Mobile phone data obtained from companies such as Google and Apple have often been used to monitor public compliance with pandemic lockdowns and make predictions of future disease spread. Survey data obtained by asking people a series of questions can provide an alternative source of information. We undertook daily surveys of a representative subset of the Danish population immediately before, and during, a lockdown during the COVID19 pandemic. We compared the modeling results obtained from the surveys with data derived from the movement of mobile phones. The self-reported survey data was more predictive of future hospitalizations due to COVID than mobility data. Our data suggest that surveys can be used to monitor compliance during lockdowns.

Discriminatory attitudes against unvaccinated people during the pandemic.

During the COVID-19 pandemic, sizeable groups of unvaccinated people persist even in countries with high vaccine access1. As a consequence, vaccination became a controversial subject of debate and even protest2. Here we assess whether people express discriminatory attitudes in the form of negative affectivity, stereotypes and exclusionary attitudes in family and political settings across groups defined by COVID-19 vaccination status. We quantify discriminatory attitudes between vaccinated and unvaccinated citizens in 21 countries, covering a diverse set of cultures across the world. Across three conjoined experimental studies (n = 15,233), we demonstrate that vaccinated people express discriminatory attitudes towards unvaccinated individuals at a level as high as discriminatory attitudes that are commonly aimed at immigrant and minority populations3-5. By contrast, there is an absence of evidence that unvaccinated individuals display discriminatory attitudes towards vaccinated people, except for the presence of negative affectivity in Germany and the USA. We find evidence in support of discriminatory attitudes against unvaccinated individuals in all countries except for Hungary and Romania, and find that discriminatory attitudes are more strongly expressed in cultures with stronger cooperative norms. Previous research on the psychology of cooperation has shown that individuals react negatively against perceived 'free-riders'6,7, including in the domain of vaccinations8,9. Consistent with this, we find that contributors to the public good of epidemic control (that is, vaccinated individuals) react with discriminatory attitudes towards perceived free-riders (that is, unvaccinated individuals). National leaders and vaccinated members of the public appealed to moral obligations to increase COVID-19 vaccine uptake10,11, but our findings suggest that discriminatory attitudes-including support for the removal of fundamental rights-simultaneously emerged.

Nuclear Magnetic Shielding Constants with the Polarizable Density Embedding Model.

We extend the polarizable density embedding (PDE) model to support the calculation of nuclear magnetic resonance (NMR) shielding constants using gauge-including atomic orbitals (GIAOs) within a density functional theory (DFT) framework. The PDE model divides the total system into fragments, describing some by quantum mechanics (QM) and the others through an embedding model. The PDE model uses anisotropic polarizabilities, inter-fragment two-electron Coulomb integrals, and a non-local repulsion operator to emulate the QM effects. The terms involving Coulomb integrals are straightforwardly extended with GIAOs. In contrast, we consider two approaches to handle the gauge dependency of the non-local operator, employing either simple symmetrization or a gauge transformation. We find the latter approach to be most stable with respect to increasing the basis set size of the QM region. We examine the accuracy of the PDE model for calculating NMR shielding constants on several solutes in a water solution. The performance is compared with the classical polarizable embedding (PE) model in addition to supermolecular reference calculations. Based on these systems, we address the basis set convergence characteristics and the QM region size requirements. Furthermore, we investigate the performance of the PDE model for a system with significant electron spill-out. In many cases, we find that the PDE model outperforms the PE model, especially regarding the accuracy of nuclear shielding constants when using small QM region sizes and in systems with significant electron spill-out.

Multiconfigurational short-range density functional theory for nuclear magnetic resonance shielding constants with gauge-including atomic orbitals.

In this paper, we present the theory and implementation of nuclear magnetic resonance shielding constants with gauge-including atomic orbitals for the hybrid multiconfigurational short-range density functional theory model. As a special case, this implementation also includes Hartree-Fock srDFT (HF-srDFT). Choosing a complete-active space (CAS) wave function as the multiconfigurational parameterization of the wave function, we investigate how well CAS-srDFT reproduces experimental trends of nuclear shielding constants compared to DFT and complete active space self-consistent field (CASSCF). Calculations on the nucleobases adenine and thymine show that CAS-srDFT performs on average the best of the tested methods, much better than CASSCF but only marginally better than HF-srDFT. The performance, compared to regular DFT, is similar when functionals containing exact exchange are used. We generally find that the inclusion of exact exchange is important for an accurate description of the shielding constants. In cases where no exact exchange is included, we observe that the HF- and CAS-srDFT often outperform regular DFT. For calculations on transition metal nuclei in organometallic compounds with significant static correlation, the CAS-srDFT method again outperforms CASSCF compared to experimental shielding constants, and the change from HF-srDFT is substantial. In conclusion, the static correlation posed by the metal complexes seems to be captured by CAS-srDFT, which is promising since this type of correlation is not well described by regular DFT.

Pandemic fatigue fueled political discontent during the COVID-19 pandemic.

Health authorities have highlighted "pandemic fatigue" as a psychological consequence of the COVID-19 pandemic and warned that "fatigue" could demotivate compliance with health-related policies and mandates. Yet, fatigue from following the policies of authorities may have consequences far beyond the health domain. Theories from the social sciences have raised that real and perceived costs of policies can also drive sentiments of discontent with the entire political establishment. Integrating theories from the health and social sciences, we ask how pandemic fatigue (i.e., perceived inability to "keep up" with restrictions) developed over the pandemic and whether it fueled political discontent. Utilizing longitudinal and panel surveys collected from September 2020 to July 2021 in eight Western countries (N = 49,116), we analyze: 1) fatigue over time at the country level, 2) associations between pandemic fatigue and discontent, and 3) the effect of pandemic fatigue on political discontent using panel data. Pandemic fatigue significantly increased with time and the severity of interventions but also decreased with COVID-19 deaths. When triggered, fatigue elicited a broad range of discontent, including protest support and conspiratorial thinking. The results demonstrate the significant societal impact of the pandemic beyond the domain of health and raise concerns about the stability of democratic societies, which were already strained by strife prior to the pandemic.

Moralizing the COVID-19 Pandemic: Self-Interest Predicts Moral Condemnation of Other's Compliance, Distancing, and Vaccination.

The emergence of the novel coronavirus has put societies under tremendous pressure to instigate massive and rapid behavior change. Throughout history, an effective strategy to facilitate novel behaviors has been to morally condemn those who do not behave in an appropriate way. Accordingly, here, we investigate if complying with the advice of health authorities-for example, to physically distance or vaccinate-has emerged as a moralized issue during the COVID-19 pandemic. In Study 1, we rely on data (N = 94K) from quota-sampled rolling cross-sectional online surveys from eight countries (Denmark, Sweden, Germany, France, Italy, Hungary, the United Kingdom, and the United States). We find that large majorities find it justified to condemn those who do not keep a distance to others in public and around half of respondents blame ordinary citizens for the severity of the pandemic. Furthermore, we identify the most important predictors of condemnation to be behavior change and personal concern, while institutional trust and social distrust also play large but less consistent roles. Study 2 offers a registered replication of our findings on a representative sample of Britons (N = 1.5K). It shows that both moralization and condemnation of both vaccination and general compliance are best predicted by self-interested considerations.

Willingness to Take the Booster Vaccine in a Nationally Representative Sample of Danes.

We estimate the willingness to take the booster dose in a representative sample of Danes. We estimate an overall willingness in the adult Danish population of about 87 percent and a willingness of about 95.5 percent among primary vaccine takers. Moreover, we show that these percentages are significantly lower among younger populations, as well as among groups who do not see COVID-19 as a threat to society, those who do not feel that they have the ability to follow recommendations ('self-efficacy'), those who do not perceive the advice of the health authorities as effective against disease spread ('response efficacy'), and those who feel that the costs of following recommendations are high ('response cost').

Communicate hope to motivate the public during the COVID-19 pandemic.

How should health authorities communicate to motivate the public to comply with health advice during a prolonged health crisis such as a pandemic? During the SARS-CoV-2 pandemic, for example, people have had to comply with successive restrictions as the world faced multiple races between controlling new waves of the virus and the development and implementation of vaccines. Here, we examine how health authorities and governments most effectively motivate the public by focusing on a specific race: between the Alpha variant and the implementation of the first generation of COVID-19 vaccinations in the winter of 2021. Following prior research on crisis communication, we focus on appeals to fear and hope using communicative aids in the form of visualizations based on epidemiological modelling. Using a population-based experiment conducted in United States ([Formula: see text]), we demonstrate that a hope-oriented visual communication aid, depicting the competing effects on the epidemic curve of (1) a more infectious variant and (2) vaccinations, motivates public action more effectively than a fear-oriented visual communication, focusing exclusively on the threat of the new variant. The importance of the implementation of such hope-oriented messages is further highlighted by cross-national representative surveys from eight countries ([Formula: see text]), which demonstrate that feelings of fear towards the Alpha variant alone were insufficient to activate strong compliance. Overall, these findings provide general insights into the importance of hope as a health communication strategy during the COVID-19 pandemic and beyond.

Did the European suspension of the AstraZeneca vaccine decrease vaccine acceptance during the COVID-19 pandemic?

On March 11, 2021, the AstraZeneca vaccine against COVID-19 was suspended in three Nordic countries and, on subsequent days, in other European countries. Using data on vaccine acceptance in eight Western countries obtained on a daily basis, we show that these decisions - and associated news - decreased public vaccine acceptance in several countries and part of this decrease happened in response to suspensions in other countries. The findings demonstrate the importance of international coordination between health authorities during a pandemic such that local authorities are able to put the decisions of foreign authorities into perspective.

The Psychological Burden of the COVID-19 Pandemic Is Associated With Antisystemic Attitudes and Political Violence.

What are the consequences of the COVID-19 pandemic for people's political attitudes and behavior? We tested, specifically, whether the psychological burden of the COVID-19 pandemic relates to antisystemic attitudes (dissatisfaction with the fundamental social and political order), peaceful political activism, and political violence. Nationally representative two-wave panel data were collected via online surveys of adults in the United States, Denmark, Italy, and Hungary (ns = 6,131 and 4,568 in Waves 1 and 2, respectively). Overall, levels of antisystemic attitudes were low, and only a small share of interviewees reported behavioral intentions to participate in and actual participation in political violence. However, preregistered analyses indicated that perceived COVID-19 burden was associated with antisystemic attitudes and intentions to engage in political violence. In the United States, the burden of COVID-19 was also associated with self-reported engagement in violence surrounding the Black Lives Matter protests and counterprotests. We found less robust evidence that perceived COVID-19 burden was associated with peaceful activism.

Does face mask use elicit risk-compensation? Quasi-experimental evidence from Denmark during the SARS-CoV-2 pandemic.

BACKGROUND: Public use of face masks has been widely adopted to halter the SARS-CoV-2 pandemic, but a key concern has been whether the effectiveness of face mask use is limited due to the elicitation of false feelings of security that decrease the observance of other protective behaviors, the so-called risk-compensation. METHODS: We exploit quasi-experimental variation, prompted by three major changes in policy, to assess whether public use of face masks elicit risk-compensation by increasing the number of close contacts or decreasing attention to distancing and hygiene measured in daily nationally representative surveys (N = 106 880). RESULTS: Number of close contacts: face mask use prompted by the policy changes decrease the number of contacts in two of the three interventions. In the remaining intervention, it has no effect. Attention to hygiene: across the changes, face masks use does not affect people's attention to hygiene. Attention to distancing: in two of three interventions, face mask use increase attention to distancing. In the remaining intervention, we see a decrease in attention. CONCLUSIONS: Overall, public use of face masks may occasionally elicit a narrow form of risk-compensation; specifically, reducing engagement in physical distancing. However, such narrow forms of risk-compensation are limited: the results do not reveal any effects on the actual number of physical contacts, only on the psychological attention to distancing advice. Moreover, the negative effect only appears for one of three interventions. The other two interventions suggest that face mask use increases attention to physical distancing.

Transparent communication about negative features of COVID-19 vaccines decreases acceptance but increases trust.

During the rapid development and rolling out of vaccines against COVID-19, researchers have called for an approach of "radical transparency," in which vaccine information is transparently disclosed to the public, even if negative information can decrease vaccine uptake. Consistent with theories about the psychology of conspiracy beliefs, these calls predict that a lack of transparency may reduce trust in health authorities and may facilitate the spread of conspiracy theories, which may limit the long-term capabilities of health authorities during and after the pandemic. On the basis of preregistered experiments conducted on large, representative samples of Americans and Danes (N > 13,000), the current study contrasts the effects of vague vaccine communication with transparent communication, which discloses either positive or negative vaccine features. The evidence demonstrates that transparent negative communication may indeed harm vaccine acceptance here and now but that it increases trust in health authorities. Furthermore, the alternative of vague, reassuring communication does not increase vaccine acceptance either and leads to both lower trust and higher endorsement of conspiracy theories.

Public acceptance of COVID-19 vaccines: cross-national evidence on levels and individual-level predictors using observational data.

OBJECTIVES: The management of the COVID-19 pandemic hinges on the approval of safe and effective vaccines but, equally importantly, on high vaccine acceptance among people. To facilitate vaccine acceptance via effective health communication, it is key to understand levels of vaccine scepticism and the demographic, psychological and political predictors. To this end, we examine the levels and predictors of acceptance of an approved COVID-19 vaccine. DESIGN, SETTING AND PARTICIPANTS: We examine the levels and predictors of acceptance of an approved COVID-19 vaccine in large online surveys from eight Western democracies that differ in terms of the severity of the pandemic and their response: Denmark, France, Germany, Hungary, Sweden, Italy, UK and USA (total N=18 231). Survey respondents were quota sampled to match the population margins on age, gender and geographical location for each country. The study was conducted from September 2020 to February 2021, allowing us to assess changes in acceptance and predictors as COVID-19 vaccine programmes were rolled out. OUTCOME MEASURE: The outcome of the study is self-reported acceptance of a COVID-19 vaccine approved and recommended by health authorities. RESULTS: The data reveal large variations in vaccine acceptance that ranges from 83% in Denmark to 47% in France and Hungary. Lack of vaccine acceptance is associated with lack of trust in authorities and scientists, conspiratorial thinking and a lack of concern about COVID-19. CONCLUSION: Most national levels of vaccine acceptance fall below estimates of the required threshold for herd immunity. The results emphasise the long-term importance of building trust in preparations for health emergencies such as the current pandemic. For health communication, the results emphasise the importance of focusing on personal consequences of infections and debunking of myths to guide communication strategies.

Compliance without fear: Individual-level protective behaviour during the first wave of the COVID-19 pandemic.

OBJECTIVES: The outbreak of the COVID-19 pandemic required rapid public compliance with advice from health authorities. Here, we ask who was most likely to do so during the first wave of the pandemic. DESIGN: Quota-sampled cross-sectional and panel data from eight Western democracies (Denmark, France, Germany, Hungary, Italy, Sweden, the United Kingdom, and the United States). METHODS: We fielded online public opinion surveys to 26,508 citizens between 19 March and 16 May. The surveys included questions about protective behaviour, perceptions of the pandemic (threat and self-efficacy), as well as broader attitudes towards society (institutional and interpersonal trust). We employ multilevel and fixed-effects regression models to analyse the relationship between these variables. RESULTS: Consistent with prior research on epidemics, perceptions of threat turn out as culturally uniform determinants of both avoidant and preventive forms of protective behaviour. On this basis, authorities could foster compliance by appealing to fear of COVID-19, but there may be normative and practical limits to such a strategy. Instead, we find that another major source of compliance is a sense of self-efficacy. Using individual-level panel data, we find evidence that self-efficacy is amendable to change and exerts an effect on protective behaviour. Furthermore, the effects of fear are small among those who feel efficacious, creating a path to compliance without fear. In contrast, two other major candidates for facilitating compliance from the social sciences, interpersonal trust and institutional trust, have surprisingly little motivational power during the first wave of the COVID-19 pandemic. CONCLUSIONS: To address future waves of the pandemic, health authorities should thus focus on facilitating self-efficacy in the public.

Polarizable Density Embedding for Large Biomolecular Systems.

We present an efficient and robust fragment-based quantum-classical embedding model capable of accurately capturing effects from complex environments such as proteins and nucleic acids. This is realized by combining the molecular fractionation with conjugate caps (MFCC) procedure with the polarizable density embedding (PDE) model at the level of Fock matrix construction. The PDE contributions to the Fock matrix of the core region are constructed using the local molecular basis of the individual fragments rather than the supermolecular basis of the entire system. Thereby, we avoid complications associated with the application of the MFCC procedure on environment quantities such as electronic densities and molecular-orbital energies. Moreover, the computational cost associated with solving self-consistent field (SCF) equations of the core region remains unchanged from that of purely classical polarized embedding models. We analyze the performance of the resulting model in terms of the reproduction of the electrostatic potential of an insulin monomer protein and further in the context of solving problems related to electron spill-out. Finally, we showcase the model for the calculation of one- and two-photon properties of the Nile red molecule in a protein environment. Based on our analyses, we find that the combination of the MFCC approach with the PDE model is an efficient, yet accurate approach for calculating molecular properties of molecules embedded in structured biomolecular environments.

Design and Combinatorial Development of Shield-1 Peptide Mimetics Binding to Destabilized FKBP12.

On the basis of computational design, a focused one-bead one-compound library has been prepared on microparticle-encoded PEGA1900 beads consisting of small tripeptides with a triazole-capped N-terminal. The library was screened towards a double point-mutated version of the human FKBP12 protein, known as the destabilizing domain (DD). Inspired by the decoded library hits, unnatural peptide structures were screened in a novel on-bead assay, which was useful for a rapid structure evaluation prior to off-bead resynthesis. Subsequently, a series of 19 compounds were prepared and tested using a competitive fluorescence polarization assay, which led to the discovery of peptide ligands with low micromolar binding affinity towards the DD. The methodology represents a rapid approach for identification of a novel structure scaffold, where the screening and initial structure refinement was accomplished using small quantities of library building blocks.