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Sclerostin inhibitors protect against osteoporotic fractures, but their cardiovascular safety remains unclear. We conducted a cis-Mendelian randomisation analysis to estimate the causal effect of sclerostin levels on cardiovascular risk factors. We meta-analysed three GWAS of sclerostin levels including 49,568 Europeans and selected 2 SNPs to be used as instruments. We included heel bone mineral density and hip fracture risk as positive control outcomes. Public GWAS and UK Biobank patient-level data were used for the study outcomes, which include cardiovascular events, risk factors, and biomarkers. Lower sclerostin levels were associated with higher bone mineral density and 85% reduction in hip fracture risk. However, genetically predicted lower sclerostin levels led to 25-85% excess coronary artery disease risk, 40% to 60% increased risk of type 2 diabetes, and worse cardiovascular biomarkers values, including higher triglycerides, and decreased HDL cholesterol levels. Results also suggest a potential (but borderline) association with increased risk of myocardial infarction. Our study provides genetic evidence of a causal relationship between reduced levels of sclerostin and improved bone health and fracture protection, but increased risk of cardiovascular events and risk factors., Competing Interests: Competing interests DPA’s department has received grant/s from Amgen, Chiesi-Taylor, Lilly, Janssen, Novartis, and UCB Biopharma. His research group has received consultancy fees from Astra Zeneca and UCB Biopharma. Amgen, Astellas, Janssen, Synapse Management Partners and UCB Biopharma have funded or supported training programmes organised by DPA’s department. The views expressed in this study are the personal views of MGM and do not represent the views of her current employer, the European Medicines Agency. All other authors declare no conflicts of interest. Ethics approval & consent to participate All participants provided informed consent to participate in each one of the GWAS we have used. UK Biobank received ethical approval from the North West Multi-centre Research Ethics Committee (REC reference: 16/NW/0274). All participants provided informed consent to participate., (© 2024. The Author(s).)

Understanding the genetic basis of COVID-19 vaccine seroconversion is crucial to study the role of genetics on vaccine effectiveness. In our study, we used UK Biobank data to find the genetic determinants of COVID-19 vaccine-induced seropositivity and breakthrough infections. We conducted four genome-wide association studies among vaccinated participants for COVID-19 vaccine seroconversion and breakthrough susceptibility and severity. Our findings confirmed a link between the HLA region and seroconversion after the first and second doses. Additionally, we identified 10 genomic regions associated with breakthrough infection (SLC6A20, ST6GAL1, MUC16, FUT6, MXI1, MUC4, HMGN2P18-KRTCAP2, NFKBIZ and APOC1), and one with breakthrough severity (APOE). No significant evidence of genetic colocalisation was found between those traits. Our study highlights the roles of individual genetic make-up in the varied antibody responses to COVID-19 vaccines and provides insights into the potential mechanisms behind breakthrough infections occurred even after the vaccination., (© 2024. The Author(s).)

Effective prevention strategies for post-COVID complications are crucial for patients, clinicians, and policy makers to mitigate their cumulative burden. This study evaluated the association of modifiable lifestyle factors (smoking, alcohol intake, BMI, physical activity, sedentary time, sleep duration, and dietary habits) with COVID-19 multisystem sequelae, death, and hospitalization in the UK Biobank cohort (n = 68,896). A favorable lifestyle (6-10 healthy factors; 46.4%) was associated with a 36% lower risk of multisystem sequelae (HR, 0.64; 95% CI, 0.58-0.69; ARR at 210 days, 7.08%; 95% CI, 5.98-8.09) compared to an unfavorable lifestyle (0-4 factors; 12.3%). Risk reductions spanned all 10 organ systems, including cardiovascular, coagulation, metabolic, gastrointestinal, kidney, mental health, musculoskeletal, respiratory disorders, and fatigue. This beneficial effect was largely attributable to direct lifestyle impacts independent of corresponding pre-infection comorbidities (71% for any sequelae). A favorable lifestyle was also related to the risk of post-COVID death (HR 0.59, 0.52-0.66) and hospitalization (HR 0.78, 0.73-0.84). These associations persisted across acute and post-acute infection phases, irrespective of hospitalization status, vaccination, or SARS-CoV-2 variant. These findings underscore the clinical and public health importance of adhering to a healthy lifestyle in mitigating long-term COVID-19 adverse impacts and enhancing future pandemic preparedness., (© 2024. The Author(s).)

Persistent symptoms following the acute phase of COVID-19 present a major burden to both the affected and the wider community. We conducted a cohort study including over 856,840 first COVID-19 cases, 72,422 re-infections and more than 3.1 million first negative-test controls from primary care electronic health records from Spain and the UK (Sept 2020 to Jan 2022 (UK)/March 2022 (Spain)). We characterised post-acute COVID-19 symptoms and identified key symptoms associated with persistent disease. We estimated incidence rates of persisting symptoms in the general population and among COVID-19 patients over time. Subsequently, we investigated which WHO-listed symptoms were particularly differential by comparing their frequency in COVID-19 cases vs. matched test-negative controls. Lastly, we compared persistent symptoms after first infections vs. reinfections.Our study shows that the proportion of COVID-19 cases affected by persistent post-acute COVID-19 symptoms declined over the study period. Risk for altered smell/taste was consistently higher in patients with COVID-19 vs test-negative controls. Persistent symptoms were more common after reinfection than following a first infection. More research is needed into the definition of long COVID, and the effect of interventions to minimise the risk and impact of persistent symptoms., (© 2023. The Author(s).)

Current understanding of determinants for COVID-19-related cardiovascular and thromboembolic (CVE) complications primarily covers clinical aspects with limited knowledge on genetics and lifestyles. Here, we analysed a prospective cohort of 106,005 participants from UK Biobank with confirmed SARS-CoV-2 infection. We show that higher polygenic risk scores, indicating individual's hereditary risk, were linearly associated with increased risks of post-COVID-19 atrial fibrillation (adjusted HR 1.52 [95% CI 1.44 to 1.60] per standard deviation increase), coronary artery disease (1.57 [1.46 to 1.69]), venous thromboembolism (1.33 [1.18 to 1.50]), and ischaemic stroke (1.27 [1.05 to 1.55]). These genetic associations are robust across genders, key clinical subgroups, and during Omicron waves. However, a prior composite healthier lifestyle was consistently associated with a reduction in all outcomes. Our findings highlight that host genetics and lifestyle independently affect the occurrence of CVE complications in the acute infection phrase, which can guide tailored management of COVID-19 patients and inform population lifestyle interventions to offset the elevated cardiovascular burden post-pandemic., (© 2023. Springer Nature Limited.)

Population-based studies can provide important evidence on the safety of COVID-19 vaccines. Using data from the United Kingdom, here we compare observed rates of thrombosis and thrombocytopenia following vaccination against SARS-CoV-2 and infection with SARS-CoV-2 with background (expected) rates in the general population. First and second dose cohorts for ChAdOx1 or BNT162b2 between 8 December 2020 and 2 May 2021 in the United Kingdom were identified. A further cohort consisted of people with no prior COVID-19 vaccination who were infected with SARS-Cov-2 identified by a first positive PCR test between 1 September 2020 and 2 May 2021. The fourth general population cohort for background rates included those people in the database as of 1 January 2017. In total, we included 3,768,517 ChAdOx1 and 1,832,841 BNT162b2 vaccinees, 401,691 people infected with SARS-CoV-2, and 9,414,403 people from the general population. An increased risk of venous thromboembolism was seen after first dose of ChAdOx1 (standardized incidence ratio: 1.12 [95% CI: 1.05 to 1.20]), BNT162b2 (1.12 [1.03 to 1.21]), and positive PCR test (7.27 [6.86 to 7.72]). Rates of cerebral venous sinus thrombosis were higher than otherwise expected after first dose of ChAdOx1 (4.14 [2.54 to 6.76]) and a SARS-CoV-2 PCR positive test (3.74 [1.56 to 8.98]). Rates of arterial thromboembolism after vaccination were no higher than expected but were increased after a SARS-CoV-2 PCR positive test (1.39 [1.21 to 1.61]). Rates of venous thromboembolism with thrombocytopenia were higher than expected after a SARS-CoV-2 PCR positive test (5.76 [3.19 to 10.40])., (© 2022. The Author(s).)

Population-based studies can provide important evidence on the safety of COVID-19 vaccines. Here we compare rates of thrombosis and thrombocytopenia following vaccination against SARS-CoV-2 with the background (expected) rates in the general population. In addition, we compare the rates of the same adverse events among persons infected with SARS-CoV-2 with background rates. Primary care and linked hospital data from Catalonia, Spain informed the study, with participants vaccinated with BNT162b2 or ChAdOx1 (27/12/2020-23/06/2021), COVID-19 cases (01/09/2020-23/06/2021) or present in the database as of 01/01/2017. We included 2,021,366 BNT162b2 (1,327,031 with 2 doses), 592,408 ChAdOx1, 174,556 COVID-19 cases, and 4,573,494 background participants. Standardised incidence ratios for venous thromboembolism were 1.18 (95% CI 1.06-1.32) and 0.92 (0.81-1.05) after first- and second dose BNT162b2, and 0.92 (0.71-1.18) after first dose ChAdOx1. The standardised incidence ratio for venous thromboembolism in COVID-19 was 10.19 (9.43-11.02). Standardised incidence ratios for arterial thromboembolism were 1.02 (0.95-1.09) and 1.04 (0.97-1.12) after first- and second dose BNT162b2, 1.06 (0.91-1.23) after first-dose ChAdOx1 and 4.13 (3.83-4.45) for COVID-19. Standardised incidence ratios for thrombocytopenia were 1.49 (1.43-1.54) and 1.40 (1.35-1.45) after first- and second dose BNT162b2, 1.28 (1.19-1.38) after first-dose ChAdOx1 and 4.59 (4.41- 4.77) for COVID-19. While rates of thrombosis with thrombocytopenia were generally similar to background rates, the standardised incidence ratio for pulmonary embolism with thrombocytopenia after first-dose BNT162b2 was 1.70 (1.11-2.61). These findings suggest that the safety profiles of BNT162b2 and ChAdOx1 are similar, with rates of adverse events seen after vaccination typically similar to background rates. Meanwhile, rates of adverse events are much increased for COVID-19 cases further underlining the importance of vaccination., (© 2022. The Author(s).)

Small trials have suggested that heterologous vaccination with first-dose ChAdOx1 and second-dose BNT162b2 may generate a better immune response than homologous vaccination with two doses of ChAdOx1. In this cohort analysis, we use linked data from Catalonia (Spain), where those aged <60 who received a first dose of ChAdOx1 could choose between ChAdOx1 and BNT162b2 for their second dose. Comparable cohorts were obtained after exact-matching 14,325/17,849 (80.3%) people receiving heterologous vaccination to 14,325/149,386 (9.6%) receiving homologous vaccination by age, sex, region, and date of second dose. Of these, 464 (3.2%) in the heterologous and 694 (4.8%) in the homologous groups developed COVID-19 between 1st June 2021 and 5th December 2021. The resulting hazard ratio (95% confidence interval) is 0.66 [0.59-0.74], favouring heterologous vaccination. The two groups had similar testing rates and safety outcomes. Sensitivity and negative control outcome analyses confirm these findings. In conclusion, we demonstrate that a heterologous vaccination schedule with ChAdOx1 followed by BNT162b2 was more efficacious than and similarly safe to homologous vaccination with two doses of ChAdOx1. Most of the infections in our study occurred when Delta was the predominant SARS-CoV-2 variant in Spain. These data agree with previous phase 2 randomised trials., (© 2022. The Author(s).)

Although pivotal trials with varying populations and study methods suggest higher efficacy for mRNA than adenoviral Covid-19 vaccines, not many studies have directly compared vaccine effectiveness in the population. Here, we conduct a head-to-head comparison of BNT162b2 versus ChAdOx1 against Covid-19. We analyse 235,181 UK Biobank participants aged 50 years or older and vaccinated with one or two doses of BNT162b2 or ChAdOx1. People are followed from the vaccination date until 18/10/2021. Inverse probability weighting is used to minimise confounding and the Cox models to derive hazard ratio. We find that, compared with one dose of ChAdOx1, vaccination with BNT162b2 is associated with a 28% (95% CI, 12-42) decreased risk of SARS-CoV-2 infection. Also, two doses of BNT162b2 vs ChAdOx1 confers 30% (95% CI, 25-35) and 29% (95% CI, 10-45) lower risks of both infection and hospitalisation during the study period when the Delta variant is dominant. Furthermore, the comparative protection against the infection persists for at least six months among the fully vaccinated, suggesting no differential waning between the two vaccines. These findings can inform evidence-based Covid-19 vaccination campaigns and booster strategies., (© 2022. The Author(s).)

The natural history of coronavirus disease 2019 (COVID-19) has yet to be fully described. Here, we use patient-level data from the Information System for Research in Primary Care (SIDIAP) to summarise COVID-19 outcomes in Catalonia, Spain. We included 5,586,521 individuals from the general population. Of these, 102,002 had an outpatient diagnosis of COVID-19, 16,901 were hospitalised with COVID-19, and 5273 died after either being diagnosed or hospitalised with COVID-19 between 1st March and 6th May 2020. Older age, being male, and having comorbidities were all generally associated with worse outcomes. These findings demonstrate the continued need to protect those at high risk of poor outcomes, particularly older people, from COVID-19 and provide appropriate care for those who develop symptomatic disease. While risks of hospitalisation and death were lower for younger populations, there is a need to limit their role in community transmission.

Comorbid conditions appear to be common among individuals hospitalised with coronavirus disease 2019 (COVID-19) but estimates of prevalence vary and little is known about the prior medication use of patients. Here, we describe the characteristics of adults hospitalised with COVID-19 and compare them with influenza patients. We include 34,128 (US: 8362, South Korea: 7341, Spain: 18,425) COVID-19 patients, summarising between 4811 and 11,643 unique aggregate characteristics. COVID-19 patients have been majority male in the US and Spain, but predominantly female in South Korea. Age profiles vary across data sources. Compared to 84,585 individuals hospitalised with influenza in 2014-19, COVID-19 patients have more typically been male, younger, and with fewer comorbidities and lower medication use. While protecting groups vulnerable to influenza is likely a useful starting point in the response to COVID-19, strategies will likely need to be broadened to reflect the particular characteristics of individuals being hospitalised with COVID-19.