INFLUENCE OF AGE, PERIOD, AND BIRTH COHORT EFFECTS ON SECULAR TREND IN GOUT INCIDENCE IN THE UNITED KINGDOM

BackgroundThe risk of incident gout in the United Kingdom (UK) appears to have declined since 2013.[1] However, whether this is temporary or likely to continue is unclear.ObjectivesTo examine the influence of age, calendar year, and year of birth on recent gout incidence in the UK.MethodsUsing data from IQVIA Medical Research Database in the UK, we identified incident gout by READ codes from 1999 to 2019. We grouped age, calendar year, and year of birth into 3-year categories. We assessed the effect of age, calendar year, and birth cohort categories on the incidence rate of gout using the age-period-cohort model among all participants and in men and women separately.ResultsOver the 21 years, there were 164,588 incident gout cases. The incidence rate of gout increased with age until age 80, then leveled off (P for trend <0.001) (Figure 1A). The gout incidence increased from 1999 to 2013, then declined (Figure 1B). The incidence rate of gout was higher in the late birth cohorts than in the early birth cohorts from the Year 1999 to the Year 2013 (Figure 1C);however, such a trend was reversed after the Year 2013, with the incidence rate of gout being higher in the early birth cohorts than that in the late birth cohorts (Figure 1D). Similar patterns were observed in men and women.ConclusionUsing the age-period-cohort model, we found that the risk of gout in the UK increased from 1999 to 2013 and then declined afterward. These findings suggest that some environmental factors occurring after 2013 may play role. Such a downward trend of the risk of gout may continue if these environmental factors are still present.Reference[1]Abhishek A, Tata LJ, Mamas M, et al. Has the gout epidemic peaked in the UK? A nationwide cohort study using data from the Clinical Practice Research Datalink, from 1997 to across the COVID-19 pandemic in 2021. Ann Rheum Dis 2022 Jan 27.Figure 1.(A) Age rate ratios and the corresponding 95% confidence intervals of gout incidence. The relative risk of each age category compared with the reference age category (57-59) was adjusted for the calendar year and birth cohort. (B) Calendar year rate ratios and 95% confidence intervals of gout incidence. The relative risk of each calendar year compared with the reference calendar year (2008-2010) was adjusted for age and birth cohort. (C) Cohort rate ratios and the corresponding 95% confidence intervals of gout incidence. The relative risk of each birth cohort (1911-1982) compared with the reference birth cohort (1950-1952) was adjusted for age and calendar year. (D) Cohort rate ratios and the corresponding 95% confidence intervals of gout incidence. The relative risk of each birth cohort (1923-1988) compared with the reference birth cohort (1950-1952) was adjusted for age and calendar year.[Figure omitted. See PDF]AcknowledgementsThis work was supported by the National Natural Science Foundation of China (81930071, 82072502, U21A20352), Project Program of National Clinical Research Center for Geriatric Disorders (2021LNJJ06, 2022LNJJ07), the Natural Science Foundation of Hunan Province (2022JJ20100), and the Science and Technology Innovation Program of Hunan Province (2022RC3075, 2022RC1009).Disclosure of InterestsNone Declared.

Longitudinal single-cell epitope and RNA-sequencing reveals the immunological impact of type 1 interferon autoantibodies in critical COVID-19 (preprint)

Type I interferon (IFN-I) neutralizing autoantibodies have been found in some critical COVID-19 patients; however, their prevalence and longitudinal dynamics across the disease severity scale, and functional effects on circulating leukocytes remain unknown. Here, in 284 COVID-19 patients, we found IFN-I autoantibodies in 19% of critical, 6% of severe and none of the moderate cases. Longitudinal profiling of over 600,000 peripheral blood mononuclear cells using multiplexed single-cell epitope and transcriptome sequencing from 54 COVID-19 patients, 15 non-COVID-19 patients and 11 non-hospitalized healthy controls, revealed a lack of IFN-I stimulated gene (ISG-I) response in myeloid cells from critical cases, including those producing anti-IFN-I autoantibodies. Moreover, surface protein analysis showed an inverse correlation of the inhibitory receptor LAIR-1 with ISG-I expression response early in the disease course. This aberrant ISG-I response in critical patients with and without IFN-I autoantibodies, supports a unifying model for disease pathogenesis involving ISG-I suppression via convergent mechanisms.

Protective Effects of STI-2020 Antibody Delivered Post-Infection by the Intranasal or Intravenous Route in a Syrian Golden Hamster COVID-19 Model (preprint)

We have previously reported that the SARS-CoV-2 neutralizing antibody, STI-2020, potently inhibits cytopathic effects of infection by genetically diverse clinical SARS-CoV-2 pandemic isolates in vitro, and has demonstrated efficacy in a hamster model of COVID-19 when administered by the intravenous route immediately following infection. We now have extended our in vivo studies of STI-2020 to include disease treatment efficacy, profiling of biodistribution of STI-2020 in mice when antibody is delivered intranasally (IN) or intravenously (IV), as well as pharmacokinetics in mice following IN antibody administration. Importantly, SARS-CoV-2-infected hamsters were treated with STI-2020 using these routes, and treatment effects on severity and duration of COVID-19-like disease in this model were evaluated. In SARS-CoV-2 infected hamsters, treatment with STI-2020 12 hours post-infection using the IN route led to a decrease in severity of clinical disease signs and a more robust recovery during 9 days of infection as compared to animals treated with an isotype control antibody. Treatment via the IV route using the same dose and timing regimen resulted in a decrease in the average number of consecutive days that infected animals experienced weight loss, shortening the duration of disease and allowing recovery to begin more rapidly in STI-2020 treated animals. Following IN administration in mice, STI-2020 was detected within 10 minutes in both lung tissue and lung lavage. The half-life of STI-2020 in lung tissue is approximately 25 hours. We are currently investigating the minimum effective dose of IN-delivered STI-2020 in the hamster model as well as establishing the relative benefit of delivering neutralizing antibodies by both IV and IN routes.

Novel SARS-CoV-2 Whole-genome sequencing technique using Reverse Complement PCR enables fast and accurate outbreak analysis (preprint)

Current transmission rates of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are still increasing and many countries are facing second waves of infections. Rapid SARS-CoV-2 whole genome sequencing (WGS) is often unavailable but could support public health organizations and hospitals in monitoring and determining transmission links. Here we report a novel reverse complement polymerase chain reaction (RC-PCR) technology for WGS of SARS-CoV-2. This technique is unique as it enables library preparation in a single PCR saving time, resources and enables high throughput screening. A total of 173 samples tested positive for SARS-CoV-2 between March and September 2020 were included. RC-PCR WGS applicability for outbreak analysis in public health service and hospital settings was tested on six predefined clusters containing samples of healthcare workers and patients. RC-PCR resulted in WGS data for 146 samples. It showed a genome coverage of up to 98,2% for samples with a maximum Ct value of 32. Three out of six suspected clusters were fully confirmed, while in other clusters four healthcare workers were not associated. Importantly, a previously unknown chain of transmission was confirmed in the public health service samples. These findings confirm the reliability and applicability of the RC-PCR technology for SARS-CoV-2 sequencing in outbreak analysis and surveillance.

Global Absence and Targeting of Protective Immune States in Severe COVID-19. (preprint)

While SARS-CoV-2 infection has pleiotropic and systemic effects in some patients, many others experience milder symptoms. We sought a holistic understanding of the severe/mild distinction in COVID-19 pathology, and its origins. We performed a whole-blood preserving single-cell analysis protocol to integrate contributions from all major cell types including neutrophils, monocytes, platelets, lymphocytes and the contents of serum. Patients with mild COVID-19 disease display a coordinated pattern of interferon-stimulated gene (ISG) expression across every cell population and these cells are systemically absent in patients with severe disease. Severe COVID-19 patients also paradoxically produce very high anti-SARS-CoV-2 antibody titers and have lower viral load as compared to mild disease. Examination of the serum from severe patients demonstrates that they uniquely produce antibodies with multiple patterns of specificity against interferon-stimulated cells and that those antibodies functionally block the production of the mild disease-associated ISG-expressing cells. Overzealous and auto-directed antibody responses pit the immune system against itself in many COVID-19 patients and this defines targets for immunotherapies to allow immune systems to provide viral defense. One Sentence SummaryIn severe COVID-19 patients, the immune system fails to generate cells that define mild disease; antibodies in their serum actively prevents the successful production of those cells.