The COVID-19 pandemic has led to an ongoing increase in the use of remote consultations in general practice in England. Although the evidence is limited, there are concerns that the increase in remote consultations could lead to more antibiotic prescribing.In this cohort study, we used patient-level primary care data from the Clinical Practice Research Datalink to estimate the association between consultation mode (remote versus face-to-face) and antibiotic prescribing in England for acute respiratory infections (ARI) between April 2021 and March 2022. Eligibility criteria were applied at both practice-level and patient-level. 400 practices in England were sampled at random and then 600,000 patients were randomly sampled from the eligible patients (whose sex was recorded). Consultations for acute respiratory infections were identified. All antibiotic prescriptions were included, with the exception of antituberculosis drugs and antileprotic drugs, as identified through chapter 5.1 of the British National Formulary. The CPRD Aurum data was linked to the COVID-19 ONS infection survey by region. All analyses were done at the individual level. Repeated consultations from the same patient within 7 days were grouped together. We used targeted maximum likelihood estimation, a causal machine learning method with adjustment for infection type and patient-level, clinician-level and practice-level factors.There were 45,997 ARI consultations  within the study period, of which 28,127 were remote and 17,870 were face-to-face. For children, 48% of consultations were remote and, for adults, 66% were remote. For children, 42% of remote and 43% of face-to-face consultations led to an antibiotic prescription; the equivalent values for adults were 52% and 42%, respectively. After adjustment with TMLE, adults with a remote consultation had 23%  higher chance of being prescribed antibiotics than if they had been seen face-to-face. We found no significant association between consultation mode and antibiotic prescribing in children (OR 1.04 95% CI: 0.98–1.11).The higher rates of antibiotic prescribing in remote consultations for adults are cause for concern. We see no significant difference in antibiotic prescribing between consultation mode for children. These findings should inform antimicrobial stewardship activities for health-care professionals and policy makers. Future research should examine differences in guideline-compliance between remote and face-to-face consultations to understand the factors driving antibiotic prescribing in different consultation modes.None. Use of remote consultations in general practice has increased rapidly since the onset of the COVID-19 pandemic. Concerns have been raised that antibiotic prescribing rates may be higher in remote compared with face-to-face consultations. Acute respiratory infection (ARI) is the most common reason for an antibiotic prescription in adults making it one of the most important areas of prescription practice for antibiotic use. Empirical studies investigating the differences in antibiotic prescribing rates between online and remote consultations have produced mixed findings, in general and for ARIs specifically. Recent review-type articles on the topic–including a 2020 qualitative systematic review and a 2021 meta-analytic systematic review—have reported mixed results when comparing online and face-to-face consultations with some showing higher and others lower antibiotic prescribing in remote consultations. Furthermore, many of the studies that were included in the reviews were at risk of bias due to a failure to control for demographic and clinical differences between patients in remote versus face-to-face consultations.This is the first England-wide study estimating the difference in antibiotic prescribing between consultations modes since the start of the COVID pandemic, where both remote and face-to-face consultations are now commonly used. It is also the first study in this setting to apply TMLE—doubly robust causal machine learning method. We found that an adult was 23% more likely to be prescribed an antibiotic for an ARI in a remote compared with a face-to-face consultation with a general practitioner in England. There was no evidence for a difference in children. Our findings are based on an analysis of a representative sample of almost 46,000 GP consultations for ARIs in general practice in England and control for patient, clinician- and practice-level factors that are associated with both consultation mode and with antibiotic prescribing. As such, our findings are at a smaller risk of bias from unobserved confounding than the previous research examining this issue and, therefore, represent an important contribution to the evidence base.This study uses rich patient-level data and robust statistical methods and represents an important contribution to the evidence base on antibiotic prescribing in primary care since the start of the COVID pandemic. Taken together with the existing body of evidence on this topic, our results showing higher prescribing in remote consultations are cause for concern. The factors affecting antibiotic prescribing and the interaction with consultation mode are complex and will require further research to unpick. The existing evidence, including this study, have largely focused on prescribing rates, and do not investigate the appropriateness of antibiotics prescribing in remote compared to face-to-face consultations. Further investigation is required to explain the discrepancy in antibiotic prescribing between consultation modes. The growing body of evidence in this area has relevance for future antimicrobial stewardship activities and should be used to inform the ongoing development of antibiotic prescribing guidelines for remote consultations.The development of antibiotic resistance is a global public health issue largely fuelled by antibiotic overprescribing. Most antibiotic prescribing in England happens in general practice: 72.1% of total antibiotic prescribing in 2021,Acute respiratory infections (ARIs) account for the greatest number of antibiotic prescriptions in UK general practice.,,,,,,There is limited evidence on the differences in ARI antibiotic prescribing between patients seen face-to-face and those seen remotely–in particular, in a post-pandemic setting where close to 50% of consultations are remote. Some observational studies have shown increases in prescribing in remote consultations for certain ARIsIn this study, we compare antibiotic prescribing in patients that were seen remotely by a GP for an ARI compared to patients that were seen face-to-face or using a mix of face-to-face and remote consultations. Analyses were conducted separately for adults and children under 16.We performed a cohort study using person-level data from the Clinical Practice Research Datalink (CPRD) Aurum between January 2018 and July 2022. The study protocol was approved by CPRD's Research Data Governance (protocol number: 21_000357).CPRD Aurum is a database with routinely collected data from primary care practices that uses EMIS Web®. CPRD contains data for over 40 million patients from 1332 practices in England as of May 2022. Patients are broadly representative of the English population based on age, sex, and deprivation. CPRD also linked their data to the 2015 indices of multiple deprivation (IMD) at the patient-level, and to the 2011 urban-rural classification at the practice-level. The data was linked to the COVID-19 ONS infection survey by region (23 September 2022 release). The COVID-19 ONS infection survey was a large-scale, nationally representative survey that was conducted in the United Kingdom between December 2020 to March 2023 and collected data on the prevalence of COVID-19 infection in the community. This was included to control for changes in the prevalence of COVID-19 during the study period.We selected the 600,000 patients from 400 practices rather than sample from all practices as we wanted to be able to calculate the proportion of remote consultations per practice. By sampling from 400 practices, we expected to get 10–15% of the list size at each practice and therefore the practice-level variables would be more reliable. This enabled us to check for practices with a very high proportion of remote or face-to-face consultations as this would be a sign of poor coding. Cohort eligibility criteria.We studied patients registered at general practices that participated in CPRD Aurum. Eligibility criteria were applied at both practice- and patient-level. 400 practices in England were sampled at random. Eligible patients were those with acceptable data quality (verified by CPRD); registered at one of the 400 practices at any point between January 2018 and March 2021; recorded as either male or female sex; and eligible for area-level linkage to the index of multiple deprivation (IMD). 600,000 patients were then randomly sampled from the eligible patients. Three GP practices were further identified by CPRD as having duplication issues and were excluded from the analysis.Consultations for acute respiratory infections were identified  with the exclusion of antituberculosis drugs (5.1.9) and antileprotic drugs (5.1.10) were included. Antibiotic prescriptions were linked to a consultation either using the observation and problem IDs provided by CPRD, or if they were issued on the same date as an ARI consultation.Consultations were classified by mode of delivery as either remote  or face-to-face (at the GP surgery or at home) consultations based on information in the consultation table for consultation mode or observations recorded during the consultation. Where a consultation's mode was unclear, it was assumed to be face-to-face. For a more comprehensive description of these classification methods, readers are referred toNo data was imputed for any variables. A very small number of patients (less than 15) that did not have IMD recorded were excluded from the analysis.,To optimise the potential for variable adjustment as well as to ensure the exchangeability at baseline of the treatment arms, as many characteristics as possible were included in the dataset at several covariate levels: consultation-, patient-, clinician-, and practice-level. We adjusted for factors (or their proxies) known to be associated with antibiotic prescribing. These included comorbidities such as asthma or COPD,We also adjusted for variables that were identified through conversations with practising GPs to be associated with either antibiotic prescribing or having a remote consultation. The selection of GPs and the identification of additional variables was not systematic. These included COVID-19 infection in the last 7, 30 or 365 days before the consultation, number of remote or face-to-face consultations in the last 7, 30 or 365 days before the consultation and regional ONS COVID-19 infection prevalence.All covariates were included in both the treatment and outcome models. See To identify the treatment effect of consultation mode on antibiotic prescribing, we made the following causal assumptions. The stable unit treatment value assumption, i.e., the treatment status of any individual did not affect the potential outcomes of other individuals. This likely holds as one patient having a remote consultation is unlikely to have an impact on the decision to prescribe antibiotics to a different patient. The second assumption was no unmeasured confounding. In other words, the exposure mechanism and potential outcomes were independent after conditioning on our defined set of covariates. We have minimised the risk of unmeasured confounding through our inclusion of a large selection of relevant patient-, clinician- and practice-level factors that could be linked to both exposure  and outcome (antibiotic prescribing). Thirdly, we assumed positivity, i.e., within strata of the set of covariates, all consultations had a nonzero probability of receiving either exposure condition. By design, only patients with a respiratory infection were included and those can be seen both remotely or face-to-face unlike consultations for other purposes such as vaccinations or wound management. We checked minimum and maximum of the propensity scores from the treatment model for violations of the positivity assumption.We defined the statistical target parameters as the average treatment effect (ATE) and the odds ratio (OR).The standardised mean difference (SMD) was used to assess how similar the distribution of covariates was between remote and face-to-face consultations. A 10% difference was considered large enough to be noteworthy. For statistical disclosure reasons, summary statistics were suppressed in groups with fewer than 10 consultations.The exposure is a binary consultation mode variable (remote codes as 1 and face-to-face/mixed as 0) and the outcome is a binary antibiotic prescription variable (antibiotics prescribed coded as 1/antibiotics not prescribed coded as 0).We used targeted maximum likelihood estimation (TMLE) to estimate the difference in prescribing rates between patients seen remotely and those seen face-to-face. TMLE is a semi-parametric approach used to estimate causal effects in observational data. TMLE is often referred to as a causal machine learning method as it combines elements of machine learning and causal inference. First it creates initial estimates of the treatment and outcome models. Through the construction of a “clever covariate,” which is a function of the treatment, outcome, and propensity score (the probability of treatment assignment given a set of observed covariates), TMLE refines the initial estimate of the causal effect optimising the bias-variance trade-off and estimating the statistical target parameters of interest, in this study the ATE and OR. This double robustness property of TMLE provides protection against potential model misspecifications, thus offering reliable causal effect estimation. TMLE relies on cross-validation to minimise overfitting. When used in combination with a superlearner, it can handle high-dimensional data, which makes it a powerful tool to estimate causal effects.We used 10-fold cross-validation. We clustered the cross-validation by GP practice so that all observations from the same practice would be within the same cross-validation fold, accounting for intra-practice correlations. In addition to this, we clustered at the individual level in the relevant models comprising the ensemble model, to account for patients appearing multiple times in the data. To ensure consistent prevalence of the binary outcome across cross-validation folds, stratification was performed based on the outcome variable , of which 61%  were remote and 39%  face-to-face. For children, 48% of consultations were remote whereas for adults 66% were remote. Antibiotics were prescribed in 48% of all consultations for adults, and in 52% of remote and 42% of face-to-face consultations. For children, 43% of all consultations led to antibiotic prescriptions with 42% in remote and 43% in face-to-face consultations . The medMost consultations were only associated with one infection type (97.5% adults and 97.4% children). The proportion of consultations only associated with one infection was marginally higher in face-to-face compared to remote consultations for both adults and children (2.9% versus 2.3% for adults and 2.6% versus 3.5% for children). Regardless of the type of infection, adults had a higher proportion of remote consultations compared to children. For a URTI, 71% of adults were seen remotely compared with just 53% of children . The mosThere were some differences in the baseline characteristics of patients having remote compared with face-to-face consultations , Fig. 2.The minimum and the maximum propensity scores were 0.037 and 0.944, respectively, for children; and 0.039 and 0.962, respectively, for adults which suggests the positivity assumption is reasonable.Using TMLE, we estimated that 44.7%  of adults would have been prescribed antibiotics if they had all been seen face-to-face with 49.9%  if seen remotely, which corresponds to a difference in average treatment effect of 5.1%  and an odds ratio of 1.23 .In children, we estimated that 41.8%  would have been prescribed antibiotics if they had all been seen face-to-face with 42.8%  if seen remotely. This corresponds to a non-significant difference in average treatment effect of 1%  and an odds ratio of 1.04 .The results without mixed mode consultations are consistent with the main analysis .Using data from almost 46,000 GP consultations for ARIs in general practice in England we estimated differences in antibiotic prescribing between remote and face-to-face ARI consultations. After adjusting for a variety of factors, we found that an adult who had a remote consultation was 23% more likely to be prescribed antibiotics compared to if they had had a face-to-face consultation. In contrast, we found no evidence of an association between consultation mode and antibiotic prescribing in children.,The overall antibiotic prescribing rates by infection type are broadly similar to previously published estimates.Our finding that antibiotics are more likely to be prescribed to adults in remote rather than face to face consultations represents an important contribution to the field. The existing evidence from observational studies on remote consultations and antibiotic prescribing is mixedWe do not observe a difference by consultation mode in antibiotic prescribing for children. This could mean that there is no difference or that we were unable to detect it. Previous studies have found a difference in children but in different settings.Including both adults and children in the same study provides us with a unique opportunity to compare results from the same practices during the same time period. A potential explanation for why we see a difference in adults but not in children could be that GPs are more risk averse when consulting with children and prefer to bring them in for a face-to-face consultation before prescribing. We do observe a higher proportion of both face-to-face and mixed consultations in children.The factors affecting antibiotic prescribing for ARIs, and the interaction with consultation mode are complex and will require further research to disentangle. Both patients and GPs might behave differently in a face-to-face compared with a remote consultation. Total triage (patients are remotely assessed before booking into a consultation) should ensure that patients have the right type of consultation for their concern, but this system is not used by all practices, and is not perfect, especially when there is high demand for appointments. Patients may exert particular pressure on GPs in certain types of appointments. Clinical examinations, which may help to determine the need for antibiotics—such as listening to a chest or looking in an ear—are not possible in a remote consultation, which may influence prescribing. Increased GP workload has also been associated with increased prescribing of broad-spectrum antibiotics,There are implications for both antibiotic prescribing and the use of remote consultations. Increased prescribing in adults could have a substantial impact on the UK's commitment to reduce antibiotic prescribing by 15% by 2024, given ∼70% of antibiotics prescribing happens in primary care and that ARIs are the most common condition that antibiotics are prescribed for.There should be continued focus on educating the public on the importance of responsible use of antibiotics. Some antimicrobial stewardship activities such as the Treat Antibiotics Responsibly, Guidance, Education and Tools initiative have been adapted to work better for both prescribers and patients in remote consultations.The risks and benefits of remote consultations in general practice are not fully understood. Further research is required to understand differences in quality of care and outcomes between remote and face-to-face consultations across a range of clinical scenarios. This study raises a concern that antibiotic prescribing rates for adults are significantly higher in remote consultations, but we do not know whether this is clinically appropriate. More work is needed to explore the appropriateness of antibiotic prescriptions across consultation modes and in different clinical contexts. That work may in turn inform our approaches to triage, by aiding understanding of clinical indications for directing patients to one consultation type over another. More research is required to investigate if any difference in antibiotic prescribing rates based on consultation mode varies across demographic groups .Further quantitative analysis is needed to explore whether our findings hold true for other prescribers. This is especially important given the rapid rise in numbers of nurse practitioners, pharmacists and paramedics working in general practice. Qualitative investigation of the issue, including speaking to clinicians and patients, and observing ARI consultations to explore how antibiotic prescribing plays out in practice in remote versus face-to-face environments is also needed.We have used a large patient-level dataset that is representative of the English population. We controlled for patient-, clinician- and practice-level factors known to be associated with antibiotic prescribing using a doubly-robust causal machine learning method. In addition, the way we classified consultations into remote, mixed and face-to-face and then grouped mixed and face-to-face consultations together, more accurately reflects the way consultations take place in general practice in England rather than using only face-to-face consultations as the comparator.Although we included a wide range of factors, there may still be unobserved confounding, such as urgency, acuity, or staffing levels, that could influence both consultation mode and antibiotic prescribing, but we are unable to measure them in this study. This could impact the results but it is unlikely to fully remove the relationship we observe between consultation mode and antibiotic prescribing in adults.The practices that participate in CPRD Aurum could be different to those that do not. We further limited inclusion in the study to only practices that have consented to take part in further data linkage . At patient level, only patients that had valid postcode recorded were included as this was necessary for the linkage. Patients in CPRD Aurum have been shown to be representative of the broader English population but it is not possible to check to what extent, if at all, the exclusion criteria applied at the practice and patient level would change this.We are unlikely to capture all ARIs due to poor clinical coding–some studies found that only 69% of antibiotics prescribed could be linked to a specific part of the body and/or clinical condition.Our results are concerning because of the potential implications for antibiotic consumption and resistance. Further research is needed to understand the causes of increased antibiotic prescribing in remote consultations, and to determine whether the observed increase is appropriate.On a broader level, the effect of increased remote consulting in general practice needs to be considered in the round. While the rapid introduction of remote consultations was a great success in the sense that it allowed general practice to keep functioning in the first few months of the pandemic, there may be unintended consequences that follow. Careful and thorough evaluation of interventions takes on an even greater importance when changes are instituted rapidly, as was the case with the accelerated rollout of remote consultations.EV and GC conceived the study. EV and KDC developed the study design and analytical approach, in consultation with other project team members. EC, EV and KDC accessed and verified the underlying data. EC processed the data sources. EV and KDC performed the statistical analyses. EV, KDC and PC drafted the initial version of the manuscript. All authors contributed to the interpretation of the findings and reviewed and edited the manuscript for intellectual content. All authors approved the final version of the manuscript and agreed to be accountable for all aspects of the work. EV is the guarantor. The corresponding author attests that all listed authors meet authorship criteria and no others meeting criteria have been omitted.https://www.cprd.com/Data-access, and enquiries can be emailed to enquiries@cprd.gov.uk. Scientific approval for this study was given by the CPRD Independent Scientific Advisory Committee (ISAC). The primary care data can be requested via application to the Clinical Practice Research Datalink. The following link to codelists can be used to identify ARIs:https://github.com/THF-evaluative-analytics/antibiotic-prescribing-cprd/tree/main/Codelists.We used deidentified primary care data from the Clinical Practice Research Datalink (CPRD). For more information, please visit: CPRD has ethics approval from the Health Research Authority to support research using anonymised patient data. Requests by researchers to access the data are reviewed via the CPRD Research Data Governance (RDG) and the protocol number for this study is: 21_000357. The RDG process is to ensure that the proposed research is of benefit to patients and public health. The data used in this study were obtained from practices that had consented to participate in CPRD research, and all data were handled in accordance with CPRD guidelines for data management and confidentiality.We declare no competing interests.


During the COVID-19 pandemic, online media were the most widely used sources of scientific information. Often, they are also the only ones on science-related topics. Research has shown that much of the information available on the Internet about the health crisis lacked scientific rigor, and that misinformation about health issues can pose a threat to public health. In turn, millions of Catholics were found to be demonstrating against vaccination against COVID-19 based on “false” and misleading religious arguments. This research analyses publications about the vaccine in Catholic online media with the aim of understanding the presence of information (and misinformation) in this community. An algorithm designed for each media outlet collected COVID-19 vaccine-related publications from 109 Catholic media outlets in five languages. In total, 970 publications were analysed for journalistic genres, types of headlines and sources of information. The results show that most publications are informative and most of their headlines are neutral. However, opinion articles have mostly negative headlines. Furthermore, a higher percentage of the opinion authors come from the religious sphere and most of the sources cited are religious. Finally, 35% of the publications relate the vaccine to the framing issue of abortion. The COVID-19 pandemic grabbed the attention of all digital news media, as it matches almost all newsworthy criteria . The unpDuring the COVID-19 pandemic, information consumption on the Internet increased dramatically. In Europe, for example, consumption peaks were recorded on the dates when the first governmental measures were taken to curb the spread of the virus . DespiteHealth professionals have always faced misinformation, as it has existed since awareness of the media’s influence on public opinion. However, both the digital era and the COVID-19 pandemic have evidenced a substantial growth of fake news or manipulated information. Both factors have made these contents gain even more strength, potentially posing a risk to public health .Such was the extent of misinformation generated around the disease, that it was described by the World Health Organization (WHO) as an “infodemic” and, given that misinformation on health issues can represent a threat to public health , the ageThe media has a relevant role in emergency situations, as citizens trust them to provide truthful and evidence-based information . FurtherLikewise, the media is a powerful tool for shaping the public agenda, including during the COVID-19 pandemic. Multiple recent investigations have shown its impact on the public perception of the virus. Some of them reveal that the media played an essential role in slowing the spread of the disease ,17 and oThe citizenry tends to seek information that aligns with and sustains their beliefs and ways of understanding reality, seeking evidence that confirms their opinions by consuming information that is consistent with their views, even if it is biased. Previous studies argue that this in turn is intensified by dogmatisms and the difficulty of dealing with complexity, as well as by the tendencies of people with very conservative positions, who present greater resistance to revising their beliefs ,21. In tOn their part, digital platforms and social media, through the use of algorithmic recommendations, show each person the information that may be of most interest to them ,23,24. TSome research, such as that developed by the Massachusetts Institute of Technology , points Disinformation favours the monetisation and profitability of digital platforms, at the same time as it benefits their producers with audience and visibility beyond profitability, and thus, it ends up being a strategy of the business model of each platform which, as Zuboff  tells usThe fact is that the power of misinformation to go viral on digital platforms is exploited to the fullest by antivaccine movements that use fake science as a template and guide for the narratives that reach their audiences. The US Center for Countering Digital Hate conducted extensive research and identified the earnings of the top twelve antivaccine figures in the US and concluded that the market for antivaccine communication and disinformation is highly lucrative .There is a high volume of misinformation regarding COVID-19 vaccines, which has been fuelled by conspiracy ideas such as the nonexistence of the virus, the idea that vaccines contain microchips to control the population, or the implementation of 5G , and rumTo carry out this research, all publications mentioning the COVID-19 vaccine were collected from 109 Catholic websites in five different languages: 30 in Spanish, 15 in French, 26 in English, 18 in Italian and 20 in Portuguese see . All pubThe collection of posts was conducted using an algorithm designed based on each website studied to collect all posts that, up to 1 April 2021, included certain keywords related to the COVID-19 vaccine. Since the algorithm retrieved some duplicate publications , a manual monitoring of each of the automatically collected publications was performed. Ambiguous content or content that did not meet the objective of this research was discarded. A third check was performed by the analysts, who verified that each publication in the sample addressed the COVID-19 vaccine topic, while also verifying that it was published within the established study period. This resulted in a total of 970 publications, which were then analysed quantitatively and qualitatively. The quantitative method was used to identify the basic data of the publications and the qualitative method was used to study the journalistic genres, headlines, and the publication in general. The sample was recorded in spreadsheets where, in addition to quantifying the total number of publications collected, categories of analysis were proposed. The categorisation scheme used in this study was based on categorisations used in previous studies ,37. The After having studied the publications with the forms, we proceeded to work with the data. Through quantitative analysis and the use of data visualisation techniques, we looked for trends and patterns ,40,41 thCrux (135 articles) and ACN web (102). Almost half of the publications were retrieved from Catholic News Agency (61), American Magazine (53), Catholic Philly (51), National Catholic Register (51) and Catholic Newspaper (51). Fewer than 50 publications were retrieved from the remaining websites . Almost a third were retrieved from Spanish websites (27.6%) and significantly fewer from Italian (5.6%), French (2.8%) and Portuguese (1.7%) websites. Of the 109 websites consulted, publications were retrieved from 58 websites. The sites from which the most publications were retrieved are websites .Aciprensa, Gaudium Press, Catholic News Service and Cisa News Africa. About half of the publications retrieved, and thus analysed, (48.7%) come from US websites. The remaining half is distributed among the rest of the territories detected, including the “Global” category  . This caThroughout the study period, peaks of information production on the COVID-19 vaccine can be observed. When analysing the total number of publications, two dates show the highest number of articles published on this topic, with English and Spanish websites producing the highest volumes of publications on these dates .21 December 2020This news spike responded to a statement issued by the Congregation for the Doctrine of Faith, approved by Pope Francis, in which he announced: “All vaccines recognised as clinically safe and effective can be used in conscience with the certainty that the use of such vaccines does not constitute a formal cooperation with the abortion from which the cells used in the production of the vaccines are derived”. The text stated that the reason is that the abortion from which the cell lines were extracted “is, on the part of those who make use of the resulting vaccines, remote”. However, the Congregation clarified that this thumbs-up does not equate to approval of abortion or the use of cell lines derived from aborted foetuses in scientific testing.23 February 2021Among Spanish-language publications, several unrelated issues are identified, so the increase in news output is believed to be rather coincidental. In English publications, however, two recurring themes can be observed. One is the call by Europe’s Catholic leaders (Caritas Europa and the Commission of Bishops’ Conferences of the European Union) for the EU to be guided by solidarity, fraternity, and social justice in distributing and administering the COVID-19 vaccine. “Commitment and solidarity must be the decisive criterion at this historic moment,” they said in a joint statement. The other, meanwhile, was the prayer offered by Cardinal Wilton D. Gregory of Washington for those who had died of COVID-19 on CNN’s programme marking 500,000 deaths from the disease.14 December 2020Three informative peaks can be observed in the Spanish publications:Publications on this date are linked to the start of vaccination against COVID-19 in the United States, with a nurse in New York City being the first person to receive the vaccine. This event prompted a joint statement from the chairs of the Doctrine and Pro-Life Committees of the United States Conference of Catholic Bishops, in which they argued that vaccination is “a moral responsibility”. Receiving one of the COVID-19 vaccines should be understood as an act of charity towards other members of our community. “In this way, being safely vaccinated against COVID-19 should be considered an act of love of neighbour and part of our moral responsibility for the common good,” wrote prelates Kevin C. Rhoades and Joseph F. Naumann, while not obviating the “moral concerns” of vaccines. The bishops of the state of Colorado also spoke out, stating in a letter that the use of vaccines is morally acceptable under certain circumstances. In this sense, they recalled that “a good end cannot justify bad means” and that vaccines “must be developed according to ethical criteria”. The Canadian government warned that those allergic to any ingredient should not use the Pfizer vaccine. Another event that was identified in the publications on this date was the demonstration of some twenty COVID-19 denialists around Seville Cathedral. “The mask makes us sick”, “COVID-19 vaccine = genetic engineering” and “The vaccine kills you” were some of the messages of the demonstrators.21 December 2020Postings on this date relate to the Vatican’s declaration that it is morally acceptable to vaccinate against COVID-19. 55% of the publications on this date report the content of the Vatican’s statement with headlines that refer to the vaccine in a positive or neutral way, such as “Holy See calls COVID-19 vaccines “morally acceptable””, or “Moral assessment of the use of COVID-19 vaccines”. The remaining 45% tend towards the negative tone and criticism of this note issued by the Vatican, either with headlines such as “Christians should never take vaccine contaminated by abortions, says bishop” or “Vatican applies vaccine contaminated by abortions”. You can also find headlines on this date where no reference was made to the fact of the note issued by the Vatican, but in which the vaccine was associated with negative side effects and even death from the vaccine.11 March 2021On this date, although a peak of publications can be observed, they are not related to each other. Nor has it been possible to find an informative event or fact that justifies the increase in publications on this date, so it could be considered a chance occurrence, with no identified causality.14 January 2021In the English-language publications, a greater number of information peaks about the COVID-19 vaccine are identified, which coincide with the following dates:Growth in publication volume is recorded due to Catholic websites reporting that a Vatican spokesperson confirmed that Popes Francis and Benedict XVI received the first dose of the COVID-19 vaccine on the previous Wednesday and Thursday, respectively.18 February 2021Most publications on this date report a decree issued by the Cardinal Governor of Vatican City State warning that employees who refuse to receive the COVID-19 vaccine could face sanctions or dismissal.4 March 2021On this day, the chairman of the US bishops’ Committee on Doctrine, Bishop Kevin C. Rhoades, released a video in which he said the Johnson & Johnson vaccine “can be used with a good moral conscience”. The bishop said the Vatican “has made it clear that all COVID-19 vaccines recognised as clinically safe and effective can be used in good conscience”. He also said that if there is a choice of vaccines available, “we recommend that you choose one with the least connection to abortion-derived cell lines”.10 March 2021On this date, a group of leading Catholic academics announced that they believed it was morally acceptable for anyone to receive any of the vaccines available in the United States. “Catholics, and indeed all people of good will who embrace a culture of life for the whole human family, born and unborn, can use these vaccines without fear of moral culpability” for abortion, they said. The variation in the news output of the Portuguese, French and Italian websites is not significant, as in no cases are their peak days more than three publications. Therefore, no correlations with specific current events were established.Regarding the journalistic genres, in the news sites analysed, publications of the informative genre had the greater presence, representing 90%, compared to 10% of the opinion genre. Comparing by language, publications in Italian contained the highest percentage of the opinion genre (14%). In the rest of the languages, publications in this genre are between 7% and 13%. In all the languages, publications in the informative genre are the majority, exceeding 85% .Among the publications of the informative genre, 83% are news, that is, journalistic texts that consist of the narration of a fact or current event. This is followed by the report subgenre with 10%, these being journalistic texts that include news elements and declarations of various personalities, and which are mainly descriptive. To a much lesser extent, 4% were identified as chronicles, which are composed of interpretative accounts told from the scene of the events, including evaluative elements. Finally, there were 3% identified as interviews, i.e., dialogues with people who can provide data on a particular event.It can be observed that news reports and chronicles were only identified among publications in Spanish and English. In addition, only news items were found in Portuguese-language publications. This subgenre was the majority in all the studied languages, representing more than 80% of the publications in all the languages .Aciprensa, 11 January 2021);In Spanish: “Biólogo molecular católico: Vacunas contra el COVID-19 son seguras y eficaces” ;In English: “‘We need the Lord to cast out demon of division in our nation’, cardinal says” ;In Portuguese: “Anvisa aprova registro definitivo da vacina de Oxford no Brasil” ;In French: “COVID-19: «La dimension géopolitique est centrale dans la course au vaccin»” .In Italian: “Coronavirus COVID-19: vescovi statunitensi, ‘dubbi su ammissibilità morale uso vaccini sviluppati, testati o prodotti con linee cellulari derivate da aborto’” , that is, of an objective order, insofar as they are true or not false see . Example.In Spanish: “Los bebés por nacer utilizados para el desarrollo de las vacunas estaban vivos en el momento de la extracción de tejido” Church Militant, 10 August 2020).In English: “Aborted baby vaccine backfires” .In French: “COVID-19: un vaccin, un espoir et des questions” .In Italian: “Vaccino anti COVID: perché si continua a fare allarmismo?” . In publications in Spanish (7%), English (6%), and Italian (4%), a lower use of this type of headline was detected, while no publications in Portuguese were identified with this type of headline .The largest number of opinion publications on the COVID-19 vaccine were in the column format (81%), which means that they were signed and offered a point of view or disquisition on the subject in question. This type of publication predominated in all the languages studied, since in all of them they represent almost or more than 80% of the opinion publications and in both Portuguese and French, 100% .The second largest format in the total number of opinion publications was editorial (17%), that is, unsigned publications that express the opinions of the media itself, which do not contain personal positions, but rather those of the collective intellectual who is behind the publication of the website. This format, however, was only present in opinion publications in Spanish and English, where it represented 20% and 19%, respectively .Opinion publications in the reader’s letter format appeared in a much lower percentage (2%); these publications are written by the readers of the media and are intended to express their opinion on the topic in question. This format was identified in 12.5% of the publications in Italian and 1.7% of the publications in English. It was not detected in the publications in Spanish, Portuguese and French .More than half of the headlines of opinion publications were of a valuative nature (61%), so it can be said that they include an interpretation, evaluation, or judgment of the journalist on certain facts of reference, while attributing a contextual meaning to them. The remaining percentage (39%) was thematic, which means that they only indicate the issue addressed in the publication.In all languages, half or more than half of the opinion publications were of an evaluative type, with Spanish publications having the highest percentage of this type of headline (64%). In Portuguese and French publications, an equal distribution is observed: 50% of opinion publications had thematic headlines and 50% were evaluative . HoweverSixty one percent of the evaluative headlines corresponding to opinion publications were negative. A breakdown of the evaluative headlines by language shows that opinion headlines in Spanish (87%), French (100%) and Italian (100%) contained the highest percentages of negative evaluative headlines. Conversely, in English (57%) and Portuguese (100%), there were mostly positive evaluative headlines .Most of the authors who wrote opinion articles have a journalistic profile (34%) linked to the media, or a religious profile (18%) linked to the Catholic community. A smaller percentage of opinion publications were signed by an author with expertise in different disciplines (13%). A significant percentage of authors have a mixed profile (28%), that is, they are linked to more than one of the specified fields. To a much lesser extent, there are profiles related to other fields (4%), and other (3%).This trend is observed in both Spanish and English publications. However, this does not occur in Portuguese, French and Italian publications . In PortAICA, entitled “The initiative is carried out by the Apostolic Limosneria and responds to the repeated appeals of Pope Francis so that no one is excluded from the vaccination campaign against COVID-19”.The most recurrent theme among the total number of publications analysed was the access to COVID-19 vaccines, i.e., their distribution among the population . The pubThe second most recurrent theme was information and misinformation on COVID-19 vaccines, i.e., publications that aimed to provide useful data on vaccines. The third most frequent topic was related to vaccine composition. The rest of the categorised topics occupied a considerably smaller space.Although most of the publications analysed did not link COVID-19 vaccines to abortion (69%), a third of them did (31%). This link proposed that vaccines are composed of cells from aborted foetuses and/or that they can cause spontaneous abortions.A difference is observed between the percentage of publications that, in each language, linked vaccines against COVID-19 with the topic of abortion. The language with the highest percentage of publications linking COVID-19 vaccines to abortion was English (38%). This was followed by publications in Spanish (26%) and, to a much lesser extent, in Italian (9%), French (7%) and Portuguese (6%) . It coulThe most cited sources of information among the analysed publications came from the health field. They corresponded to health personnel and experts in health sciences. The second type of sources most frequently used came from the religious sphere, i.e., from the Catholic community.Twenty percent of the publications that addressed the subject of the composition of the vaccine contained only religious sources, and 76% contained at least one of them, even though they also contained other types of sources. Only 4% of the publications on this topic used only health personnel and health science experts as sources, and 58% included them as one of the types of sources see .Thirteen percent of the publications whose subject is vaccine information/disinformation contained only religious sources, while 2% mentioned only sources of information from health personnel and experts. However, 61% of the publications dealing with this topic contained at least one source of this type, among others. This same percentage corresponds to the use of religious sources among other types of sources see .The results of the conducted research reveal that disinformation also reached the Catholic community through its own communication vehicles, and considering the five languages analysed, highlight the complexity of the phenomenon in the midst of the pandemic process and the potential health risks for this population. Disinformation in this context goes beyond a market that runs through digital platforms and social networks and is established within Catholic journalistic platforms, where the ethics and aesthetics of journalism are in line with Catholicism, emphasizing aspects of personal and collective belief in an environment marked by the undeniable word of God. In this research, comparisons were made by language, considering those mostly spoken by catholic communities, but not by country or region. However, this may also bring interesting results to compare with the present study, and thus is a suggested line for future research.Crux (135) and ACN web (102). In addition, noteworthy numbers of the publications were analysed from Catholic News Agency (61), American Magazine (53), Catholic Philly (51), National Catholic Register (51) and Diario Católico (51). Less than 50 publications were recovered and analysed from the rest of the websites covered in this research. Moreover, almost half of the publications analysed (49%) come from U.S. websites . In second place comes the report (10%) and then, to a much lesser extent, the chronicle (4%) and the interview (3%). Reports and chronicles were only identified among publications in Spanish and English, while publications in Portuguese were only news.Most of the headlines among informative publications were referential (93%), meaning that they intended to be objective, and they are true or not false. A minor percentage of informative headlines (7%) were of an evaluative type , which embody an interpretative order insofar as they reflect an interpretation of the journalist or author of the publication in accordance with his or her values, interests, or ideology. French-language publications used the greatest number of valuative headlines (24%) .Within the opinion publications, 81% were columns, i.e., signed journalistic texts that offered a point of view or disquisition on a particular topic. Columns prevailed as the majority of the opinion publications, with at least an 80% in all the studied languages, and in the cases of Portuguese and French, the opinion genre represented 100% of the publications . The secMost of the opinion headlines were of a valuative nature; a total of 61% of the headlines of publications of this type included an interpretation, evaluation, or judgment by the journalist with respect to certain facts of reference. Thus, less than 40% of opinion headlines were thematic, indicating only the issue addressed in the publication. When dividing per language, this trend can also be observed among Spanish and English publications . On their hand, Portuguese and French publications presented a 50–50 distribution of thematic and valuative headlines, whereas Italian presented 75% valuative headlines in contraposition to 25% of the thematic type. It is interesting to note how the Italian language presents some differences with regards to the rest of the languages. On the one hand, it had the highest percentage of opinion publications (14%), and within opinion publications, it had the highest percentage of evaluative headlines (75%). This result could suggest a more explicit tendency from the Italian Catholic media to present their opinions when referring to the COVID-19 vaccine, while the media analysed in English or Spanish, for example, showed a greater tendency towards communicating vaccine-related issues in a format that seeks to present (or pretend) neutrality and information, even when false information is given, as in the case of linking the vaccine to abortion. In any case, even counting Italian publications, the majority of publications in all languages tended to be presented in an informative format, representing more than 80% across all languages. Moreover, within the informative publications, the vast majority were of the news type and had referential headlines; therefore, the tendency of all the Catholic media analysed is to present information on the COVID-19 vaccine with facts in a neutral referential news format.Another result that is worth highlighting is the fact that within the informative publications, French publications presented 24% evaluative headlines. The language that used the most headlines of this type after French was Spanish with 7%, which shows a difference between French and the rest of the languages. Sixty-one percent of the evaluative headlines had a negative connotation. However, this majority is not observed in all languages. The language division shows how this majority is observed in French and Italian evaluative headlines, in 100% of the cases, and in the Spanish evaluative headlines, in 87% of the cases. However, in evaluative headlines in English, 57% of the headlines contained a positive connotation, and in the case of the evaluative headlines of the opinion publications in Portuguese, 100% were positive .When analysing the profiles of the authors of the opinion publications, it can be observed how the majority have a journalistic profile, with a 34% of authors belonging to the media sector. A mixed profile represents 28% of opinion publications’ authors, 17% of these publications were written by authors with a religious profile, and 13% of the profiles belong to experts in different disciplines. The present study did not analyse whether author profiles had any correlation with the tone, stance or persuasiveness of opinion publications, nor the impact of each author on the recognition of his or her publications, an interesting line of research to explore in the future.Access to COVID-19 vaccines and the capacity to provide the vaccine was the subject of most of the publications of all types. The second most frequent subject was the misinformation regarding the COVID-19 vaccines, and the third, the composition of the vaccines . RegardiWith regards to the sources of the publications, the type of source most frequently cited corresponds to health personnel and experts in health sciences. In the second place, we see sources coming from the religious sphere. Among the publications that communicated about vaccine composition, one-fifth contained only religious sources, and in 76% of these cases, some of the sources were religious even if they included other types of sources. Four percent of the publications on this topic used health personnel and health science experts as their only source, and 58% of these publications used at least one such source . LikewisIn conclusion, the tendency among the Catholic media analysed was to present the information related to the COVID-19 vaccine in an informative, newsworthy format with referential headlines, using health and religious sources. Likewise, the topic that most occupied the analysed publications was access to the vaccine and the ethics or morality of getting vaccinated. This study focused on the news production from Catholic media, which opens a clear future research venue with focus on the consumption of these media and the influence of their formats on readers’ attitudes, as well as the role that different formats play in shaping their perceptions and beliefs. Overall, this research opens a deeper reflection on what happens when journalism and religion meet, the former being a field in which professionals are expected to convey facts based on evidence and research ,14,15.


The current understanding of the genetic determinants of thoracic aortic aneurysms and dissections (TAAD) has largely been informed through studies of rare, Mendelian forms of disease. Here, we conducted a genome-wide association study (GWAS) of TAAD, testing ~25 million DNA sequence variants in 8,626 participants with and 453,043 participants without TAAD in the Million Veteran Program, with replication in an independent sample of 4,459 individuals with and 512,463 without TAAD from six cohorts. We identified 21 TAAD risk loci, 17 of which have not been previously reported. We leverage multiple downstream analytic methods to identify causal TAAD risk genes and cell types and provide human genetic evidence that TAAD is a non-atherosclerotic aortic disorder distinct from other forms of vascular disease. Our results demonstrate that the genetic architecture of TAAD mirrors that of other complex traits and that it is not solely inherited through protein-altering variants of large effect size. A genome-wide association study of thoracic aortic aneurysms and dissections (TAAD) in the Million Veteran Program identifies 17 new risk loci and demonstrates that the genetic architecture of TAAD mirrors that of other complex traits. Despite the lethality of these conditions, the genetic determinants of TAAD remain largely unknown, with published GWAS having revealed only four loci reaching genome-wide significance5. As a result, most of what is understood about the genetics of TAAD has been derived from studies examining rare, pathogenic variants resulting in heritable aortopathy 6.TAAD encompass a spectrum of aortic pathology affecting the aortic root, the ascending aorta, the aortic arch and the descending thoracic aorta. Thoracic aortic aneurysms, a dilation of the proximal aorta, are known to progressively enlarge over time, ultimately leading to rupture and death if not surgically repaired. In addition, dissections of the ascending (Stanford type A) or descending (Stanford type B) thoracic aorta are life-threatening conditions requiring emergency treatment, often including surgical repair, and are associated with high short-term and long-term mortality risk7 and allows for the elucidation of causal biology and mechanisms. Leveraging the MVP resource, we sought to (1) perform a genetic discovery analysis for TAAD across multiple ancestries, (2) explore the spectrum of phenotypes associated with TAAD risk variants through a phenome-wide association study (PheWAS), (3) examine the genetic relationship between TAAD and its epidemiologic risk factors, (4) map causal variants and genes for disease, (5) identify causal tissues and cell types and (6) construct and test a polygenic risk score (PRS) for TAAD  is a genomic and precision medicine cohort established in 2011 by the Department of VA Healthcare System to study how genes affect health and disease. We recently demonstrated that a VA Healthcare System-based biobank can aid in the genetic discovery of aortic diseaseWe designed a two-phased GWAS. The initial MVP discovery analysis was composed of 8,626 individuals  with TAAD and 453,043 disease-free individuals from the same ancestral groups , ULK4 (ref. 4) and LRP1 (ref. 4) loci at genome-wide significance and the recently identified TCF7L2 (ref. 5) locus with P < 5 × 10−5 , with the four known and 17 new loci demonstrating a directionally consistent replication P value < 0.05  = 1.35; 95% confidence interval (CI), 1.41–1.30; P = 2.5 × 10−47). All five signals that did not replicate failed to meet the pre-specified threshold (P < 0.05) for independent replication  and were taken forward for replication. Following replication, 21 loci continued to exceed genome-wide significance (P < 0.05) in individuals of African ancestry, and six did likewise in participants of Hispanic ancestry (Supplementary Table 9 and an ancestry-matched linkage disequilibrium (LD) reference panel identified a total of five additional independent variants across the 21 replicated TAAD GWAS loci 10. We found that all 21 lead variants demonstrated an association with ascending aortic diameter with Bonferroni P < 0.0012 , respectively  OpenGWAS project14, we performed a PheWAS of the 21 TAAD lead risk variants across a range of over 2,000 conditions, diseases and metabolites. In total, we identified 167 statistically significant (P < 5.0 × 10−8) PheWAS associations across the 21 genetic variants. In particular, several of the TAAD risk variants were associated with a range of anthropometric traits such as height and conditions including asthma and migraine with genome-wide significance  analyses using genetic instruments for a lifetime smoking index17, lipids  and low-density lipoprotein (LDL) cholesterol)18, blood pressure  and mean arterial pressure (MAP) (https://pan.ukbb.broadinstitute.org)) and height19 . Our results remained robust to multiple sensitivity analyses, including the weighted median20 as well as MR-PRESSO21 and MR-Egger22 tests for evidence of horizontal pleiotropy, although MR-PRESSO outlier-corrected results demonstrated effect estimates slightly smaller in magnitude  at a genome-wide significance level . PP and DBP emerged as the most highly prioritized causal blood pressure traits for TAAD risk  analysis, a recently developed analytic tool that applies Bayesian principles to prioritize causal risk factors among correlated exposures with shared genetic predictors FBN1 (ref. 24), ELN25 and LRP1 (refs. 27) are the causal genes at three of the identified loci, and a recent report provided evidence that TCF7L2 is the likely causal gene acting at the locus5 (Supplementary Table R2 > 0.8). In addition, we hypothesized that TAAD risk variants may be acting by inducing expression changes locally in the proximal aortic wall and performed a fine-mapping transcriptome-wide association study (TWAS)28 and colocalization analyses using aortic expression quantitative trait locus (eQTL) data from the Genotype–Tissue Expression Project (GTEx)29. When combining the above strategies, we identified seven additional putative causal genes: THSD4, COL6A3, CDH13, NOC3L, SCAI, PRDM6 and ADAMTS8  to evaluate for significant enrichment of specific tissues or cell types with genetic TAAD risk-association signals across 205 different tissues and cell types. Not surprisingly, the aorta demonstrated the strongest enrichment . Human myometrium is primarily composed of smooth muscle cells, consistent with the well-recognized critical role of vascular smooth muscle cells (VSMCs) in TAAD pathogenesis. Much like fibroblasts, chondrocytes produce and maintain collagen and proteoglycans, and, in cell culture, osteoblasts are nearly indistinguishable from fibroblasts33, providing evidence for a key role of fibroblasts in TAAD development.We next sought to identify the critical tissues and cell types for TAAD risk variants. At the genome-wide level, we first used stratified LD score regression6. Of note, FBN1 was present both in our GWAS gene set and in the HTAAD gene set. We then tested whether the 21 putative causal TAAD risk genes were enriched in specific cell types identified from publicly available single-nuclear RNA-sequencing (snRNA-seq) expression data from ascending and descending thoracic aorta10. Using the Fast Gene Set Enrichment software34, we observed that the causal TAAD gene set was significantly enriched in VSMCs (P = 0.0078), and a suggestive enrichment was also observed with fibroblasts (P = 0.02), although this was no longer significant after Bonferroni correction 35 and snRNA-seq data from normal ascending and descending thoracic aortas10. For the nine genes that we hypothesized promote TAAD risk through changes in aortic gene expression  was prioritized to be acting in fibroblasts, mesenchymal–stromal cells and endothelial cells. Cadherin 13 signaling has been shown to be protective for endothelial cells in the setting of oxidative stress38, and its reported role in angiogenesis39 suggests that it may play a role in aortic remodeling during aneurysmal degeneration across multiple cell types. In total, we prioritized at least one candidate causal cell type for eight of the nine genes thought to be acting through changes in gene expression in the thoracic aorta.Finally, we sought to identify relevant cell types for the individual putative causal TAAD risk genes leveraging single-cell RNA-sequencing (scRNA-seq) data from normal and aneurysmal ascending aortic aneurysm tissue 36 Fig. . Integra 36 Fig. . For exa40 whole-genome-sequencing data. To increase the number of independent variants included in our score, we used the PRS-CSx software, which uses Bayesian methods to generate posterior genetic variant effect sizes under coupled continuous shrinkage priors41. We first validated the PRS using prevalent data from the Mass General Brigham Biobank . We observed that the TAAD PRS was strongly associated with prevalent TAAD, with a 1-s.d. increase in PRS associated with a 57% increased risk of disease . Individuals with a PRS in the 95th percentile or higher were 2.67 times more likely to be diagnosed with TAAD  and an LD panel from 1000 GenomesPPRS = 1.8 × 10−47; Fig. 42. While the effect estimate of these pathogenic variants was substantially larger than that observed for the top 5% PRS , we noted that, when modeling TAAD risk, the addition of the PRS improved the AUC value by a similar amount as the presence of a pathogenic TAAD risk variant  cohort . We again observed an effect estimate greater than 2.0 for the top 5% PRS  using Cox proportional hazard models. We observed that those in the top 5% of the PRS were 2.5-fold more likely to experience an incident TAAD event during a median of 11.2 years of follow up and demonstrated more than fourfold higher risk of TAAD-related mortality Fig. .In the current study, we identified 17 new TAAD loci and localized the anatomic distribution of these TAAD risk variants. We examined the phenotypic consequences of TAAD lead risk variants with PheWAS, and, through MR, we demonstrate that elevated PP and DBP, taller standing height and smoking are likely causal epidemiologic risk factors for TAAD. Leveraging bulk and scRNA-seq and snRNA-seq data, we identified causal tissues and cell types for TAAD. Lastly, we developed a genome-wide PRS for TAAD that identifies a subset of the population at substantially greater risk for TAAD.6. While prior GWAS have identified four TAAD risk loci5, given the relatively rare incidence of TAAD in the population, it remained unclear whether common or rare variants were the primary driver of TAAD heritability. In the current study, we increase the number of TAAD risk loci by a factor of five and identify putative causal risk genes that likely affect disease through changes in gene expression, akin to other common complex traits. These findings offer new potential targets for therapeutic intervention as well as firmly establish TAAD as a complex trait.These findings permit several conclusions. First, we provide substantial evidence that the genetic architecture of TAAD mirrors that of other complex traits. Current understanding of the pathophysiology of TAAD has largely been informed through the investigation and identification of rare deleterious variants within what are now termed HTAAD genes. These identified genetic variants, generally missense or nonsense mutations, substantially alter a gene’s protein product and subsequently disrupt critical functions in VSMC contraction, extracellular matrix stabilization or transforming growth factor (TGF)-β signaling16, and suggested common risk factors for both diseases included hypertension, smoking and hyperlipidemia. While an association between atherosclerosis and ascending aortic aneurysms has been observed45, whether the two pathologic processes share underlying causal mechanisms remained unknown. Here, through causal inference methods, we provide genetic support for a causal role of smoking and hypertension on TAAD risk. However, unlike for abdominal aortic aneurysm47 and other cardiovascular diseases49, circulating lipoproteins do not appear to play a substantial role in TAAD development. The loci revealed in our genetic discovery analysis highlight the role of extracellular matrix integrity in TAAD, and the tissue and cell type enrichment analyses underscore the importance of VSMCs in TAAD risk. Prior lineage-mapping studies suggest that the embryologic origin of VSMCs in the thoracic aorta differing from that of the rest of the arterial tree may play a role in susceptibility to atherogenic conditions50. In light of these findings, we hypothesize that therapies focusing on restoring extracellular matrix stability rather than on atherosclerotic risk factor modification will be more likely to provide a substantial impact on TAAD prevention.Second, despite its morphologic similarities with infrarenal abdominal aortic aneurysm, our results support the notion that TAAD is a distinct disorder from the rest of the atherosclerotic cardiovascular disease spectrum. Early observational studies of TAAD often studied abdominal and thoracic aortic aneurysms together51, critics have highlighted that this research has focused on diseases in which genetic testing is seldom indicated52, unlikely to substantially alter clinical outcomes53, or that may not be justified within current healthcare cost structures7. However, unlike other diseases, testing for heritable causes of TAAD is already performed, typically through exome sequencing in those with familial or early-onset TAAD syndromes to identify pathogenic variants54. Here, we demonstrate that individuals within the upper tail of the PRS distribution are at substantially greater risk to experience TAAD or TAAD-related mortality. Furthermore, we observed similar gains in the calculated AUC statistic when adding pathogenic or likely pathogenic TAAD risk variants or PRSs (TAAD PRS) to risk-prediction models, suggesting that there is an additional benefit for PRS testing to include common variation beyond current targeted or exome-sequencing panels. In sum, our data suggest that extending current genetic panels to include testing for polygenic TAAD risk may be warranted and deserves further study.Third, our data provide additional evidence for the clinical utility of TAAD PRSs. Although recent literature focusing on PRS application has demonstrated an ability to risk stratify the population at large55, rather than a true causal association. Similarly, when examining the scatterplots for each of the significant MR associations, it is possible that the positive results may not necessarily be attributable to a true causal effect but rather that the MR association results may reflect shared biological pathways between the risk factor and TAAD. Finally, a number of the TAAD risk loci demonstrate genome-wide significant associations with increased DBP. Our MR results support a causal role for DBP in TAAD susceptibility; however, our sensitivity analysis suggests that DBP is not the sole driver of TAAD risk at these regions of the genome. Disentangling the effects of hypertension on proximal aortic dilation and dissection, a pathologic process that alters human blood pressure homeostasis, is likely to require model systems to completely elucidate the complex mechanisms at work.Our study should be interpreted in the context of its limitations. First, our TAAD phenotype is based on EHR diagnosis and procedural code data and may result in misclassification of case status. However, such misclassification should, on average, reduce statistical power for discovery and bias results toward the null. Second, the VA Healthcare System population is overwhelmingly male, and our ability to detect sex-specific genetic associations in discovery was limited. Third, power to detect differential expression associations and identify causal TAAD cell types in scRNA-seq and snRNA-seq data may be limited by sequencing depth, sample size or tissue-processing techniques. Fourth, while we observe a significant MR result for height exposure and TAAD, we cannot rule out the possibility that this association is driven by the pleiotropy of height-associated variantsIn conclusion, our data provide new mechanistic insights into TAAD risk and demonstrate that its genetic architecture is akin to that of other complex traits. We identify causal risk factors, cell types and genes that may be used to inform clinical care.P < 5 × 10−8) in the MVP, we sought replication of our findings with data from a meta-analysis of six external datasets comprising 4,459 TAAD cases and 512,463 controls  individuals from the Penn Medicine BioBank. Before this conditional analysis, we aligned our summary statistics with the ancestry-matched reference panel using the DENTIST software56. We set a threshold P < 5 × 10−8 (genome-wide significance) to declare statistical significance.We used the COJO-GCTA software14 is a publicly available online repository of a wide array of summary statistics from previously published GWAS and the UK Biobank. For TAAD lead variants identified in our GWAS analysis, we queried the phenotypes available in the IEU OpenGWAS project to perform a PheWAS12 across a range of over 2,000 conditions, diseases and metabolites. Details of the sensitivity analysis re-examining DBP and height-associated variants with TAAD accounting for blood pressure and height using individual-level data in the MVP are described in the The IEU OpenGWAS projectP < 5 × 10−8) with an R2 < 0.001. All clumping was performed using the TwoSampleMR R package57. Genetic instruments were constructed for the lifetime smoking index 17, lipid levels 18, blood pressure  and height 19 using publicly available summary statistics  the global test for horizontal pleiotropy, (2) the outlier-corrected causal estimate, which corrects for the detected horizontal pleiotropy and (3) the distortion test, which tests whether the causal estimate is significantly different after outlier adjustment. Given the high genetic correlation among blood pressure traits, we then used the MR-BMA methodology23 to generate multivariable models for analysis to prioritize the most likely causal blood pressure traits. Further details of the MR-BMA methods are contained in the MR analyses for smoking (through a lifetime smoking index), lipid levels , blood pressure  and height exposure were performed with TAAD as the outcome. Given that some of the above exposure summary statistics included UK Biobank data, the TAAD outcome summary data included all of the studies in our analysis except the UK Biobank, encompassing 12,422 TAAD cases and 578,768 controls. Genetic instruments were selected as DNA sequence variants that were associated with the exposure at genome-wide significance (R2 > 0.8) with the lead TAAD risk variant, (4) cis eQTL from the GTEx dataset in aortic tissue29 with association P < 5 × 10−6, (5) results from FOCUS28 version 0.5, a fine-mapping technique to identify causal genes in a TWAS58 using bulk RNA-seq data from post-mortem aortic tissue  and TAAD meta-analysis (discovery and replication) summary statistics and (6) results of a colocalization analysis from our TAAD GWAS meta-analysis and eQTL data from GTEx bulk RNA-seq data in aortic tissue using the coloc R package59. Further methodologic details of these analyses and an analysis identifying putative causal TAAD risk variants are described in the FBN1 (ref. 24), ELN25, LRP1 (refs. 27) and TCF7L2 (ref. 5) where prior literature has established these as the likely causal genes) were identified based on having (1) three prioritization strategies highlighting it as a likely causal gene and (2) plausible biological evidence for a role in TAAD pathogenesis based on prior genetic, clinical or functional studies.We prioritized candidate causal genes at each of the identified TAAD risk loci by aggregating evidence from (1) prior genetic, clinical or functional studies, (2) the closest gene to the lead risk variant, (3) genes with protein-altering variants in high LD . For this analysis, we approximated the LD structure from Europeans within the 1000 Genomes40 reference panel and set Bonferroni-corrected P < 0.00024 (0.05 ÷ 205 annotations) for statistical significance.As an initial enrichment analysis, we partitioned the heritability of TAAD using stratified LD score regression6 and overlapped our gene set with publicly available snRNA-seq data from ascending and descending thoracic aorta specimens10. We downloaded single-nucleus expression data and existing t-SNE cluster annotations for each cell from the Broad Institute Single Cell Portal (https://singlecell.broadinstitute.org/single_cell) and combined the clusters into five overarching cell categorizations: VSMCs, fibroblasts, endothelial cells, leukocytes and other cells  was used to declare statistical significance.We generated a gene set of 21 putative causal TAAD risk genes: the 11 candidate causal genes identified from our GWAS as well as ten additional previously identified definitive or strong HTAAD genes (‘category A’)n = 3) and ascending thoracic aortic aneurysm cases (n = 8) were reanalyzed using Seurat (version 4)60. Briefly, dimensionality reduction was previously performed using t-SNE, and identification of cluster-defining genes was performed using the FindAllMarkers function. Feature plots , violin plots , dot plots and heat maps were generated using Seurat (version 4). Within each cluster, differential gene expression based on case–control status was performed with FindAllMarkers (group.by = ‘stim’), and a Bonferroni P value < 0.005 (0.05 ÷ 9 maximum genes per cluster) was set for statistical significance. Previously published snRNA-seq data from the thoracic aorta were downloaded from the Broad Single Cell Portal10. Data from the cells were processed in R Studio with Seurat (version 4) according to the pipeline described above, with metadata of the original clustering added. Briefly, cells were filtered based on the following parameters: 250 < nFeatureRNA < 2,500, nCount_RNA > 500 and percent.mt < 0.5%. Variable features were scaled using ScaleData for percent.mt. Dimensionality reduction with UMAP was performed, and dot plots were generated with group.by = ‘Category’ corresponding to the original clusters from Pirruccello et al.10.For nine genes that we hypothesized influence TAAD risk through alterations in gene expression . Individuals are then additively scored in a weighted fashion based on the number of risk alleles that they carry for each variant in the PRS.A weighted PRS represents an individual’s risk of a given disease conferred by the sum of the effects of many common DNA sequence variants. A weight is assigned to each genetic variant based on its strength of association with disease risk  and an LD panel from 1000 Genomes43 score >0.5 and high-confidence LOFTEE44 predicted loss-of-function variants in one of the 11 HTAAD genes. Lastly, we examined whether the TAAD PRS was associated with an increase in risk of incident TAAD and TAAD-related mortality within the UK Biobank among 281 participants with incident TAAD, 22 participants with TAAD-related deaths and 359,000 participants without TAAD of European ancestry.We then tested our scores in three separate datasets. For initial validation, we tested the normalized PRS using prevalent data from the Mass General Brigham Biobank in 775 individuals with and 24,518 individuals without TAAD of European ancestry. Next, we assessed the performance of the PRS in an updated freeze of the CHIP–MGI cohort  and subsequently compared these results (in terms of effect estimate and AUC) to the effects of a set of previously curated, pathogenic or likely pathogenic TAAD risk variants among individuals with exome-sequencing data available . In a sensitivity analysis, we also examined the effects of rare missense variants with a REVEL62. We included in step 1 of REGENIE  variants that were directly genotyped and had a minor allele frequency >1%, <10% missingness and a Hardy–Weinberg equilibrium test P value > 10−15. The association model used in step 2 of REGENIE included as covariates age, sex and five principal components of ancestry. Next, associated statistics across MVP participants of European, African and Hispanic ancestry were meta-analyzed using an inverse-variance-weighted fixed-effect method as implemented in the METAL software program63. We excluded variants with a high amount of heterogeneity (I2 statistic > 75%) across the three ancestries.In our primary discovery analysis, genotyped and imputed DNA sequence variants in individuals of European, African and Hispanic ancestry were tested for association with TAAD using logistic mixed models as performed in the REGENIE version 2.0 statistical software programP < 5 × 10−8), we sought replication of our findings from a combination of six external cohorts representing 4,459 individuals with TAAD and 512,463 individuals without TAAD. Details of participant selection, quality control, phenotyping and statistical analysis are presented in Supplementary Table For variants meeting genome-wide significance for TAAD (P < 0.05), were directionally consistent in both cohorts and had an overall P < 5 × 10−8 (genome-wide significance) in the discovery and replication cohorts combined. New loci were defined as being more than 500,000 bp away from a known TAAD genome-wide associated lead variant. Additionally, LD information from the 1000 Genomes Project38 was used to determine independent variants for which the association peak extended beyond 500,000 bp. All logistic regression P values were two sided.We defined significant new TAAD associations as those that were at least nominally significant in replication  to declare statistical significance.In the PheWAS analysis, DNA sequence variants were queried in the IEU OpenGWAS projectP value < 0.0055 (0.05 ÷ 9 traits) for statistical significance. For the MR-BMA analysis, the Nyholt procedure of effective tests64 was used to account for the strong correlation among the blood pressure traits, with a multiple-testing-adjusted P value = 0.05 set as the significance threshold.In our MR analyses, a random-effect inverse-variance-weighted method was used as the primary analysis, with sensitivity analyses performed for the statistically significant associations as described above. We set a two-sided 10. We used a Bonferroni-corrected two-sided P value < 0.0012 (0.05(2 phenotypes × 21 variants)−1) to declare statistical significance. In the analysis examining the association of previously published aortic diameter10 loci with TAAD, we tested the 81 ascending and 46 descending aortic diameter autosomal loci with MAF > 0.01. We used a Bonferroni-corrected two-sided P value < 0.0004 (0.05(81 ascending + 46 descending loci)−1) to declare statistical significance.In the association analysis of TAAD risk variants with ascending and descending aortic diameters, we queried previously published GWAS summary statistics from the UK Biobank in which these measurements were extracted from MRI images using a deep learning model43 score >0.5 and high-confidence LOFTEE44 predicted loss-of-function variants in one of the 11 HTAAD genes. Following analysis, an AUC statistic was generated for each of these models.In our PRS analysis, logistic regression models  were used to estimate ORs and 95% CIs for associations of the continuous PRS (1 s.d. unit) with TAAD in the Mass General Brigham Biobank and CHIP–MGI adjusting for age, sex and five principal components. We additionally calculated the prevalence of TAAD for the 5% of individuals with the highest PRS relative to the rest of the population and generated CIs using R (version 4.1). In CHIP–MGI, we also tested the association of rare, pathogenic variants with TAAD risk using logistic regression and adjusting for age, sex and principal components. In a sensitivity analysis, we examined the TAAD risk conferred through rare missense variants with a REVELP value < 0.0125 for statistical significance (0.05 ÷ 4 tests: associations for (1) the continuous PRS, (2) the top 5% PRS, (3) rare TAAD risk variants and (4) TAAD-related death). All P values were two-sided.In the UK Biobank, we tested the association of the 5% of individuals with the highest TAAD PRS relative to the rest of the population with incident TAAD events and incident TAAD-related mortality using Cox proportional hazard models adjusting for age, sex and five principal components of ancestry in the white British subset of UK Biobank participants. Prevalent cases were excluded, and individuals were censored upon death, when experiencing the relevant event or at the end of follow up (a median of 11.1 years). We declared a Further information on research design is available in the Any methods, additional references, Nature Portfolio reporting summaries, source data, extended data, supplementary information, acknowledgements, peer review information; details of author contributions and competing interests; and statements of data and code availability are available at 10.1038/s41588-023-01420-z.Supplementary InformationSupplementary Figs. 1–7, Tables 1 and 2, Acknowledgements and Methods.Reporting SummarySupplementary Tables 3–25Supplementary Tables 3–25.


During COVID-19 there was an increase in antibiotic utilization across all settings. West Virginia has the highest outpatient antibiotic prescribing rate in the country. As part of our outpatient antibiotic stewardship initiative, we developed and utilized a dashboard to track and report prescribing data in two pediatric clinics in a large health system.We reviewed prescribing data from Oct 2020- Mar 2022 in two outpatient pediatric clinics using a dashboard within the electronic medical record. Both clinics are affiliated with a large health system but clinic A was academic and clinic B was non-academic clinic. We also collected data on total number of visits and visits that had antibiotics prescribed. We reviewed prescription data on visits that were diagnosed with upper respiratory tract illness (URI) like acute otitis media, acute sinusitis, acute pharyngitis etc. We compared URI antibiotic prescriptions in Jan 2021-Mar 2021 with Jan 2022- Mar 2022.There were more than 15,000 visits during the study period. A steady increase in antibiotic prescriptions written per visit was noted in both clinics . There was a significant increase in percentage of prescriptions for URI in the respiratory season for 2021 and 2022 . The most common diagnosis for antibiotic prescription in both clinics was acute otitis media . However, clinic B wrote cefdinir prescriptions for 38 % cases of otitis media vs. 12% in clinic A.There was an increase in overall prescriptions for antibiotics and prescriptions for URI in both clinic sites. This was most likely due to the prolonged viral season following cessation of COVID-19 mitigation measures. There were significant differences noted in prescribing practices, like cefdinir overuse for treatment of otitis media, which will guide our antimicrobial stewardship interventions in future.All Authors: No reported disclosures


The utility of geotechnical centrifuge tests depends on how correctly they predict the physical and mechanical behaviour of concrete. In this study, a model concrete material that consisted of α-gypsum plaster, fine silica sand, and water was developed. An orthogonal test design was used to evaluate the effect of the mix proportion on the model concrete performance. The physical  and mechanical  characteristics were considered as indices. Various mix ratios resulted in remarkable relative contributions to model concrete performance, and each raw material dosage exhibited positive or negative synergy. The water–plaster ratio (W/P) and aggregate–plaster ratio (A/P) strongly influenced the mechanical and physical characteristics, respectively. Multiple linear regression analysis (MLRA) was carried out to determine a forecast model for various small-scale test demands. Finally, the applicability and outlines of the presented forecasting method in proportioning design were evaluated by typical use of model concrete in small-scale model tests. Simple concrete, which has relatively high strength and stiffness, is an efficient and effective solution for geotechnical infrastructure in soft soil ,2,3,4,5.A gypsum-based mixture mortar is useful in small-scale modelling and can reflect the quasi-brittle nature of concrete; especially in centrifuge model tests, which require large-scale factors ,12. KnapIn this study, a total of 20 groups of gypsum-based mortar samples with various water–plaster ratios and silica sand dosages were tested by orthogonal test design. The flowability, bleeding rate, and compressive and flexural strength were considered as evaluation indices of model concrete materials. Prediction models of the relationship between the evaluation indices and various mix proportions are proposed by using multiple linear regression analysis (MLRA). Finally, by typical application in a centrifuge model test, guidance for general application of gypsum-based materials for modelling concrete elements in small-scale physical tests are provided.To satisfy the spatial and physical scaling laws between small-scale test and those of a corresponding prototype, the raw materials of the emulation model concrete column consisted of α-gypsum plaster , water, and fine silica sand . The chemical composition of the α-gypsum plaster was analysed with an X-ray fluorescence spectrometer  , as showTo investigate the effect of various mixing ratios on the performance of model concrete, an orthogonal test design was used. The advantage of orthogonal testing was to select representative test points from a comprehensive test plan for minimizing the experimental quantity and obtaining comprehensive test results. Thus, the water/plaster (W/P) ratio and coarse aggregate content were considered as the pertinent variables in the orthogonal tests. Remarkably, the mass fraction of plaster (A/P) was used as the content of fine silica sand, which served as the coarse aggregate for model concrete. In accordance with relevant research and previous experiments, the standards of each mixing ratio were determined by choosing typical values . Table 3All 20 groups of model concrete mortar samples  consisteThe weighted powder, including the alpha-gypsum plaster and fine silica sand, was added into the mixer and dry-mixed for about 60 s.The sand plaster mixture was poured into the water and quickly stirred in the mixer for 120 s.Fresh paste and casted samples were prepared for further testing.The flowability characteristic of the model concrete mortar was determined by measuring the spread diameter of fresh mixture slurry by a mini-slump test ,22. A 40The standing observation method indicates the stability of the mixture paste by measurement of the percentage of the upper bleeding water volume of fresh slurry compared with the total volume . A largeCubic model concrete specimens of a standard size (50 × 50 × 50 mm) were prepared for unconfined compression tests. The specimens were made by pouring the sand plaster mixture into the mould and were subsequently demoulded. Afterwards, the standard cubes were cured for 3, 7, 14, and 28 days under standard curing conditions at a temperature of 25 ± 2 °C and a relative humidity of 95% . The comfr) was considered to be more suitable for representing the flexural behaviour of concrete under bending-induced flexural stress [fr has a substantial size effect. For each bending test, prismoid-shaped specimens (size: 20 mm × 20 mm × 450 mm) were used to obtain the average fr for each mixing composition. These dimensions can provide corresponding values of fr for subsequent centrifuge model tests of a model concrete pile at 1:40 scale [Compared with the direct flexural strength using standard specimens, the modulus of rupture  > (RA/P).To describe the behaviour of the concrete under bending-induced flexural stress , the modulus of rupture was used . Figure X, Y are the two datasets of indices; and σx and σy are the standard deviation of X, Y, respectively. A large coefficient indicates a significant relationship between the two indices.The correlation between various indices in this study was further investigated by Pearson correlation analysis . PearsonThe significance of each composition on the performance indices could be determined by an analysis of the orthogonal test results, and then the most appropriate ratio can be selected to simulate the concrete structure behaviour in small-scale models. However, the specific mixing ratio of model concrete is frequently modified to satisfy the requirements for various small-scale model test conditions. To conveniently determine the optimum mixing ratio, MLRA was performed to forecast the ratio parameters of the model concrete in this study. SPSS statistics  were used to develop the predicting regression models by MLRA by 20 set results of orthogonal tests.2) reveal excellent linear relationships between the independent and dependent variables. Moreover, the significance of variance analysis in To verify the feasibility of the MLRA models developed in this study, all of the test indices  should be statistically verified. Fflowability, the standardized coefficients of the A/P and W/P ratios were −0.82 and 0.48, respectively. Thus, the aggregate contents negatively influenced the flowability of the slurry, whereas the water/plaster ratio exhibited positive synergy. In addition, the significance of the two mix proportions on the flowability—which considers the absolute value of standardized coefficients—was A/P > W/P, and it is consistent with the orthogonal test result analysis. On the basis of the regression coefficients in Fflowability, Fbleeding, F7-d compressive, and F7-d flexural are the prediction equations of the flowability, bleeding rate, and 7 days compressive and flexural strength of model concrete, respectively.To verify the feasibility of the prediction model and further explain the guidelines for parameter selection of the model concrete for small-scale modelling, a typical application of model concrete piles in a geotechnical centrifuge test is presented. The aim of the presented centrifuge test is to investigate the failure behaviour of a concrete column-supported embankment. In general, concrete columns undergo bending failure in practice, which causes global failure of the embankment ,34. TherIn this study, orthogonal test design was applied to quantitatively evaluate the effects of various compositions on model concrete performance. On the basis of the test results, a forecast model for determining the optimal formulations of model concrete was proposed to satisfy various small-scale model test requirements. The following conclusions were drawn.(i) The effects of aggregate content and water/plaster ratio on the performance of model concrete were interdependent. The aggregate content negatively influenced the flowability and the bleeding rate of the slurry, whereas the water/plaster ratio exhibited positive synergy. Increasing the aggregate content and water/plaster ratio negatively corresponded to the mechanical characteristics, which was pertinent to compressive and flexural strength.(ii) The correlation between the flowability and bleeding rate was significant (Pearson correlation coefficient: 0.92) because of the high content of free water in the mixture slurry. Moreover, the correlation between the compressive and flexural strength was positive; a significant correlation coefficient was found after curing for 14 days.(iii) On the basis of the MLRA, a prediction model for the performance of model concrete was proposed. The significance level of each mix was proposed in the following sequence: for optimum flowability and bleeding rate, A/P > W/P. However, regarding the compressive and flexural strength, A/P < W/P.(iv) Outlines for parameter selection of the model concrete were summarized based on a typical application case in geotechnical centrifuge testing. Combined with the specific test target, a reasonable range of water/gypsum ratios and aggregate content can be precisely determined by the prediction model.