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Despite much research on the topic, little work has been done comparing the use of methods to control for confounding in the estimation of COVID-19 vaccine effectiveness in routinely collected medical record data. We conducted a trial emulation study to replicate the ChAdOx1 (Oxford/AstraZeneca) and BNT162b2 (BioNTech/Pfizer) COVID-19 phase 3 efficacy studies. We conducted a cohort study including individuals aged 75+ from UK CPRD AURUM (N = 916,128) in early 2021. Three different methods were assessed: Overlap weighting, inverse probability treatment weighting, and propensity score matching. All three methods successfully replicated the findings from both phase 3 trials, and overlap weighting performed best in terms of confounding, systematic error, and precision. Despite lack of trial data beyond 3 weeks, we found that even 1 dose of BNT162b2 was effective against SARS-CoV-2 infection for up to 12 weeks before a second dose was administered. These results support the UK Joint Committee on Vaccination and Immunisation modelling and related UK vaccination strategies implemented in early 2021. Key messagesO_LIReal world evidence generated using weighting (overlapping weights and inverse probability of treatment weights) and propensity score matching: all methods successfully replicate the findings of Phase 3 trials for COVID-19 vaccine effectiveness. C_LIO_LIOverlap weighting provides the least biased estimates in our study and should be considered amongst the most suitable methods for future COVID-19 vaccine effectiveness research. C_LIO_LIDespite a lack of trial data, our findings suggest that first-dose BNT162b2 provides effective protection against SARS-COV-2 infection for up to 12 weeks, in line with UKs Joint Committee on Vaccination and Immunisation modelling and subsequent vaccination strategies. C_LI
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Clinical determinants for cardiovascular and thromboembolic (CVE) complications of COVID-19 are well-understood, but the roles of genetics and lifestyle remain unknown. We performed a prospective cohort study using UK Biobank, including 25,335 participants with confirmed SARS-CoV-2 infection between March 1, 2020, and September 3, 2021. Outcomes were hospital-diagnosed atrial fibrillation (AF), coronary artery disease (CAD), ischemic stroke (ISS), and venous thromboembolism (VTE) within 90 days post-infection. Heritable risk was represented by validated polygenic risk scores (PRSs). Lifestyle was defined by a composite of nine variables. We estimated adjusted hazard ratios (aHR) and confidence intervals (CI) using Cox proportional hazards models. In the COVID-19 acute phase, PRSs linearly predicted a higher risk of AF (aHR 1.52 per standard deviation increase, 95% CI 1.39 to 1.67), CAD (1.59, 1.40 to 1.81), and VTE (1.30, 1.11 to 1.53), but not ISS (0.92, 0.64 to 1.33). A healthy lifestyle was associated with a substantially lower risk of post-COVID-19 AF (0.70, 0.53 to 0.92), CAD (0.64, 0.44 to 0.91), and ISS (0.28, 0.12 to0.64), but not VTE (0.82, 0.48 to 1.39), compared with an unhealthy lifestyle. No evidence for interactions between genetics and lifestyle was found. Our results demonstrated that population genetics and lifestyle considerably influence cardiovascular complications following COVID-19, with implications for future personalised thromboprophylaxis and healthy lifestyle campaigns to offset the elevated cardiovascular disease burden imposed by the ongoing pandemic.
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Despite previous evidence from retrospective cohorts suggest that survivors of COVID-19 may be at increased risk of psychiatric sequelae, questions remain on the incidence and absolute risk of psychiatric outcomes, and on the potential protective effect of vaccination. Addressing these knowledge gaps will help public health and clinical service planning during the ongoing pandemic. Based on UK Biobank prospective data, we constructed a SARS-CoV-2 infection cohort including participants with a positive PCR test for SARS-CoV-2 between March 1, 2020 and September 30, 2021; a contemporary control cohort with no evidence of SARS-CoV-2, and a historical control cohort predating the COVID-19 pandemic. Additional control cohorts were constructed for benchmarking, including participants diagnosed with other respiratory tract infection, or with a negative SARS-CoV-2 test. We used propensity score weighting using predefined (clinically informed) and data-driven covariates to minimize confounding. We then estimated incidence rates and risk of first psychiatric disorders diagnosed by ICD-10 codes and psychotropic prescriptions after SARS-CoV-2 infection using cause-specific Cox models. In this prospective cohort including 406,579 adults (224,681 women, 181,898 men; mean [SD] age 66.1 [8.4] years), 26,181 had a SARS-CoV-2 infection. Compared with contemporary controls (n=380,398), COVID-19 survivors had increased risks of subsequent psychiatric diagnoses (HR: 2.02, 95% CI 1.85-2.21; difference in incidence rate: 24.85, 95 CI 20.69-29.39 per 1000 person-years) and psychotropic prescriptions (HR: 1.61, 95% CI 1.48-1.75; difference in incidence rate: 21.77, 95% CI 16.59-27.54 per 1000 person-years). Regarding individual mental health related outcomes, the SARS-CoV-2 infection cohort showed an increased risk of psychotic disorders (2.26, 1.28-3.98), mood disorders (2.19, 1.92-2.50), anxiety disorders (2.08, 1.82-2.38), substance use disorders (1.59, 1.34-1.90), sleep disorders (1.95, 1.60-2.39); and prescriptions for antipsychotics (3.78, 2.74-5.21), antidepressants (1.55, 1.29-1.87), benzodiazepines (1.82, 1.58-2.11), and opioids (1.40, 1.26-1.55). Overall, the risk of any mental health outcome was increased with a HR of 1.58, 95% CI 1.47-1.70; and difference in incidence rate of 32.04, 25.76-38.81 per 1000 person-years. These results were consistent when comparing to a historical control cohort. Additionally, mental health risks were increased even further in participants who tested positive in hospital settings. Finally, participants who were fully vaccinated had a lower risk of mental health outcomes compared to those infected when unvaccinated or partially vaccinated. All observed risks of mental health outcomes were attenuated or even lower after SARS-CoV-2 infection compared with those with other respiratory infections, or with participants in the test-negative control cohort. In this prospective cohort study, people who survived COVID-19 were at increased risk of psychiatric outcomes and related psychotropic medications. These risks were higher in those with more severe disease, treated in hospital settings, and were significantly reduced in fully vaccinated people. Of note, compared to participants with other respiratory infections or with only negative testing results, those infected with SARS-CoV-2 had an even lower risk of mental health outcomes, warranting further research into causation. The early identification and treatment of psychiatric disorders among survivors of COVID-19 should be a priority in the long-term management of COVID-19. Particular attention might be needed for those with severe (hospitalized) disease and those who were not fully vaccinated at the time of infection.
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BACKGROUNDCovid-19 vaccination has been associated with an increased risk of venous thromboembolism (VTE). However, it is unknown whether genetic predisposition to VTE is associated with an increased risk of thrombosis following vaccination. METHODSUsing data from the UK Biobank, which contains in-depth genotyping data and linked vaccination and health outcomes information, we generated a polygenic risk score (PRS) using 299 genetic variants identified from a previous large genome-wide association study. We prospectively assessed associations between PRS and incident VTE after first and the second-dose vaccination separately. We conducted sensitivity analyses stratified by vaccine type (adenovirus- and mRNA-based) and using two historical unvaccinated cohorts. We estimated hazard ratios (HR) for PRS-VTE associations using Cox models. RESULTSOf 359,310 individuals receiving one dose of a Covid-19 vaccine, 160,327 (44.6%) were males, and the mean age at the vaccination date was 69.05 (standard deviation [SD] 8.04) years. After 28- and 90-days follow-up, 88 and 299 individuals developed VTE respectively, equivalent to an incidence rate of 0.88 (95% confidence interval [CI] 0.70 to 1.08) and 0.92 (95% CI 0.82 to 1.04) per 100,000 person-days. The PRS was significantly associated with a higher risk of VTE (HR per 1 SD increase in PRS, 1.41 (95% CI 1.15 to 1.73) in 28 days and 1.36 (95% CI 1.22 to 1.52) in 90 days). Similar associations were found after stratification by vaccine type, in the two-dose cohort and across the historical unvaccinated cohorts. CONCLUSIONSThe genetic determinants of post-Covid-19-vaccination VTE are similar to those seen in historical data. This suggests that, at the population level, post-vaccine VTE has similar aetiology to conventional VTE. Additionally, the observed PRS-VTE associations were equivalent for adenovirus- and mRNA-based vaccines.
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BackgroundSubstantial evidence suggests that severe Covid-19 leads to an increased risk of Venous Thromboembolism (VTE). We aimed to quantify the risk of VTE associated with ambulatory Covid-19, study the potential protective role of vaccination, and establish key clinical and genetic determinants of post-Covid VTE. MethodsWe analyzed a cohort of ambulatory Covid-19 patients from UK Biobank, and compared their 30-day VTE risk with propensity-score-matched non-infected participants. We fitted multivariable models to study the associations between age, sex, ethnicity, socio-economic status, obesity, vaccination status and inherited thrombophilia with post-Covid VTE. ResultsOverall, VTE risk was nearly 20-fold higher in Covid-19 vs matched non-infected participants (hazard ratio [HR] 19.49, 95% confidence interval [CI] 11.50 to 33.05). However, the risk was substantially attenuated amongst the vaccinated (HR: 2.79, 95% CI 0.82 to 9.54). Older age, male sex, and obesity were independently associated with higher risk, with adjusted HRs of 2.00 (1.61 to 2.47) per 10 years, 1.66 (1.28 to 2.15), and 1.85 (1.29 to 2.64), respectively. Further, inherited thrombophilia led to an HR 2.05, 95% CI 1.15 to 3.66. ConclusionsAmbulatory Covid-19 was associated with a striking 20-fold increase in incident VTE, but no elevated risk after breakthrough infection in the fully vaccinated. Older age, male sex, and obesity were clinical determinants of Covid-19-related VTE. Additionally, inherited thrombophilia doubled risk further, comparable to the effect of 10-year ageing. These findings reinforce the need for vaccination, and call for targeted strategies to prevent VTE during outpatient care of Covid-19.
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Although pivotal trials with varying populations and study methods suggest higher efficacy for mRNA than adenoviral Covid-19 vaccines, no direct evidence is available. Here, we conducted a head-to-head comparison of BNT162b2 versus ChAdOx1 against Covid-19. We analysed 235,181 UK Biobank participants aged 50 years or older and vaccinated with one or two doses of BNT162b2 or ChAdOx1. People were followed from the vaccination date until 18/10/2021. Inverse probability weighting was used to minimise confounding and the Cox models to derive hazard ratio. We found that, compared with two doses of ChAdOx1, vaccination with BNT162b2 was associated with 30% lower risks of both SARS-CoV-2 infection and related hospitalisation during the period dominated by the delta variant. Also, this comparative effectiveness was consistent across several subgroups and persisted for at least six months, suggesting no differential waning between the two vaccines. Our findings can inform evidence-based Covid-19 vaccination campaigns and booster strategies.
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Alpha-1 blockers, often used to treat benign prostate hyperplasia (BPH), have been hypothesized to prevent COVID-19 complications by minimising cytokine storms release. We conducted a prevalent-user active-comparator cohort study to assess association between alpha-1 blocker use and risks of three COVID-19 outcomes: diagnosis, hospitalization, and hospitalization requiring intensive services. Our study included 2.6 and 0.46 million users of alpha-1 blockers and of alternative BPH therapy during the period between November 2019 and January 2020, found in electronic health records from Spain (SIDIAP) and the United States (Department of Veterans Affairs, Columbia University Irving Medical Center, IQVIA OpenClaims, Optum DOD, Optum EHR). We estimated hazard ratios using state-of-the-art techniques to minimize potential confounding, including large-scale propensity score matching/stratification and negative control calibration. We found no differential risk for any of COVID-19 outcome, pointing to the need for further research on potential COVID-19 therapies.
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AIM: To explore the effect of microRNA-146a (miR-146a) on apoptosis of human gastric cancer SGC-7901 cells and the underluing mechanism.METHODS: miR-146a mimic (up-regulated miR-146a expression) and miR-146a inhibitor (down-regulated miR-146a expression) were transfected into the SGC-7901 cells by liposome method.At the same time, miRNA nonsense sequence transfection group as the negative control group (NC group) was set up.RT-qPCR was used to evaluate the levels of miR-146a in the SGC-7901 cells after transfection.The effects of miR-146a on the cell apoptosis and growth were assessed by flow cytometry analysis and CCK-8 assay, respectively.The effect of over-expression or knockdown of miR-146a on transforming growth factor-β-activated kinase 1 (TAK1)/ nuclear factor-kappa B (NF-κB) signaling was evaluated by RT-qPCR and Western blot.RESULTS: miR-146a modulated apoptosis of SGC-7901 cells.Over-expression of miR-146a significantly increased apoptosis, whereas knockdown of miR-146a inhibited the apoptosis of SGC-7901 cells.The expression of TAK1 at mRNA and protein levels was significantly decreased when miR-146a mimic was transfected into the SGC-7901 cells (P<0.05).On the contrast, the expression of TAK1 at mRNA and protein were significantly higher in miR-146a inhibitor transfection group than that in NC group (P<0.05), suggesting that miR-146a negatively regulated TAK1 expression.Moreover, knockdown of TAK1 enhanced the apoptosis of SGC-7901 cells (P<0.01), while over-expression of TAK1 inhibited the apoptosis of SGC-7901 cells(P<0.01).Additionally, both over-expression of miR-146a and knockdown of TAK1 led to a prominent increase in the expression of NF-κB inhibitor protein alpha (IκBα) and a significat decrease in B cell lymphoma-2 (Bcl-2) level in the SGC-7901 cells.CONCLUSION: miR-146a significantly promotes apoptosis of SGC-7901 cells by inhibition of NF-κB pathway via targeting TAK1.
