Plasma immune signatures can predict rejection-free survival in the first year after pediatric liver transplantation.

BACKGROUND & AIMS: After pediatric liver transplantation (pLT), children undergo life-long immunosuppression since reliable biomarkers for the assessment of rejection probability are scarce. In the multicentre (n=7) prospective clinical cohort "ChilSFree" study, we aimed to characterize longitudinal dynamics of soluble and cellular immune mediators during the first year after pLT and identify early biomarkers associated with outcome. METHODS: Using paired Luminex-based multiplex technique and flow cytometry, we characterized longitudinal dynamics of soluble immune mediators (SIM, n=50) and immune cells in the blood of 244 patients at 8 visits over one year: before, 7/14/21/28 days, 3/6/12 months after pLT. RESULTS: The unsupervised clustering of patients based on SIM profiles revealed 6 unique SIM signatures associated with clinical outcome. From 3 signatures linked to improved outcome, one was associated with one-year-long rejection-free survival and stable graft function and was characterized by low levels of pro-inflammatory (CXCL8/9/10/12, CCL7, SCGF-ß, sICAM-1), high levels of regenerative (SCF, TNF-ß), and pro-apoptotic (TRAIL) SIM (all, p<0.001, fold change >100). Of note, this SIM signature appeared two weeks after pLT and remained stable over the entire year, pointing towards its potential as a novel early biomarker for minimizing or weaning immunosuppression. In the blood of these patients, a higher frequency of CD56bright NK cells (p<0.01), a known hallmark also associated with operationally tolerant pLT patients, was detected. The concordance of the model for prediction of rejection based on identified SIM signatures was 0.715, and 0.795, in combination with living-related transplantation as co-variate, respectively. CONCLUSIONS: SIM blood signatures may enable the non-invasive and early assessment of rejection risks in the first year after pLT, paving the way to improved therapeutic options.

The impact of inaccurate assumptions about antibody test accuracy on the parametrisation and results of infectious disease models of epidemics.

The parametrisation of infectious disease models is often done based on epidemiological studies that use diagnostic and serology tests to establish disease prevalence or seroprevalence in the population being modelled. During outbreaks of an emerging infectious disease, tests are often used, both for disease control and epidemiological studies, before studies evaluating their accuracy in the population have concluded, with assumptions made about accuracy parameters like sensitivity and specificity. In this simulation study, we simulated such an outbreak, based on the case study of COVID-19, and found that inaccurate parametrisation of infectious disease models due to assumptions about antibody test accuracy in a seroprevalence study can cause modelling results that inform public health decisions to be inaccurate; for example, in our simulation setup, assuming that antibody test specificity was 0.99 instead of 0.90 when it was in fact 0.90 led to an average relative difference of 0.78 in model-projected peak hospitalisations, even when test sensitivity and all other parameters were accurately characterised. We therefore suggest that methods to speed up test evaluation studies are vitally important in the public health response to an emerging outbreak.

Effect of SARS-CoV-2 Incidence and Immunisation Rates on Sporadic Creutzfeldt-Jakob Disease Incidence.

BACKGROUND: Recent case studies and media outlets have hypothesised an effect of SARS-CoV-2 infection and immunisation on the development or progression of neurodegenerative diseases such as Alzheimer's disease or sporadic Creutzfeldt-Jakob disease (sCJD). OBJECTIVES: This study aims to identify potential associations of SARS-CoV-2 infections and SARS-CoV-2 immunisation with sCJD incidence, disease duration, and age of onset. METHOD: We used data from a prospective sCJD surveillance study in Germany (2016-2022) and publicly available datasets of SARS-CoV-2 cases and vaccination numbers in Germany for the years 2020-2022. Associations of SARS-CoV-2 incidence and immunisation rates with sCJD incidence were assessed by comparing quarterly and annual cumulative sCJD incidences in the periods before (2016-2019) and during the pandemic (2020-2022). RESULTS: We could not identify any time-related effect of SARS-CoV-2 incidence or immunisation rate on the sCJD incidence. Moreover, we did not find any sCJD incidence alterations before and during the SARS-CoV-2 pandemic on a federal or state level. The overall sCJD incidence was within expected ranges in the years 2020-2022. There were no changes in age of onset and clinical disease duration in these years. CONCLUSIONS: We found no evidence supporting a short-term effect of the pandemic on sCJD incidence. However, considering the extended pre-clinical phase of sCJD, continued surveillance is needed to identify potential future incidence alterations.

Estimates of protection levels against SARS-CoV-2 infection and severe COVID-19 in Germany before the 2022/2023 winter season: the IMMUNEBRIDGE project.

PURPOSE: Despite the need to generate valid and reliable estimates of protection levels against SARS-CoV-2 infection and severe course of COVID-19 for the German population in summer 2022, there was a lack of systematically collected population-based data allowing for the assessment of the protection level in real time. METHODS: In the IMMUNEBRIDGE project, we harmonised data and biosamples for nine population-/hospital-based studies (total number of participants n = 33,637) to provide estimates for protection levels against SARS-CoV-2 infection and severe COVID-19 between June and November 2022. Based on evidence synthesis, we formed a combined endpoint of protection levels based on the number of self-reported infections/vaccinations in combination with nucleocapsid/spike antibody responses ("confirmed exposures"). Four confirmed exposures represented the highest protection level, and no exposure represented the lowest. RESULTS: Most participants were seropositive against the spike antigen; 37% of the participants ≥ 79 years had less than four confirmed exposures (highest level of protection) and 5% less than three. In the subgroup of participants with comorbidities, 46-56% had less than four confirmed exposures. We found major heterogeneity across federal states, with 4-28% of participants having less than three confirmed exposures. CONCLUSION: Using serological analyses, literature synthesis and infection dynamics during the survey period, we observed moderate to high levels of protection against severe COVID-19, whereas the protection against SARS-CoV-2 infection was low across all age groups. We found relevant protection gaps in the oldest age group and amongst individuals with comorbidities, indicating a need for additional protective measures in these groups.

Bridging the gap - estimation of 2022/2023 SARS-CoV-2 healthcare burden in Germany based on multidimensional data from a rapid epidemic panel.

OBJECTIVES: Throughout the SARS-CoV-2 pandemic, Germany like other countries lacked adaptive population-based panels to monitor the spread of epidemic diseases. METHODS: To fill a gap in population-based estimates needed for winter 2022/23 we resampled in the German SARS-CoV-2 cohort study MuSPAD in mid-2022, including characterization of systemic cellular and humoral immune responses by interferon-γ-release assay (IGRA) and CLIA/IVN assay. We were able to confirm categorization of our study population into four groups with differing protection levels against severe COVID-19 courses based on literature synthesis. Using these estimates, we assessed potential healthcare burden for winter 2022/23 in different scenarios with varying assumptions on transmissibility, pathogenicity, new variants, and vaccine booster campaigns in ordinary differential equation models. RESULTS: We included 9921 participants from eight German regions. While 85% of individuals were located in one of the two highest protection categories, hospitalization estimates from scenario modeling were highly dependent on viral variant characteristics ranging from 30-300% compared to the 02/2021 peak. Our results were openly communicated and published to an epidemic panel network and a newly established modeling network. CONCLUSIONS: We demonstrate feasibility of a rapid epidemic panel to provide complex immune protection levels for inclusion in dynamic disease burden modeling scenarios.

Estimating fine age structure and time trends in human contact patterns from coarse contact data: The Bayesian rate consistency model.

Since the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), large-scale social contact surveys are now longitudinally measuring the fundamental changes in human interactions in the face of the pandemic and non-pharmaceutical interventions. Here, we present a model-based Bayesian approach that can reconstruct contact patterns at 1-year resolution even when the age of the contacts is reported coarsely by 5 or 10-year age bands. This innovation is rooted in population-level consistency constraints in how contacts between groups must add up, which prompts us to call the approach presented here the Bayesian rate consistency model. The model can also quantify time trends and adjust for reporting fatigue emerging in longitudinal surveys through the use of computationally efficient Hilbert Space Gaussian process priors. We illustrate estimation accuracy on simulated data as well as social contact data from Europe and Africa for which the exact age of contacts is reported, and then apply the model to social contact data with coarse information on the age of contacts that were collected in Germany during the COVID-19 pandemic from April to June 2020 across five longitudinal survey waves. We estimate the fine age structure in social contacts during the early stages of the pandemic and demonstrate that social contact intensities rebounded in an age-structured, non-homogeneous manner. The Bayesian rate consistency model provides a model-based, non-parametric, computationally tractable approach for estimating the fine structure and longitudinal trends in social contacts and is applicable to contemporary survey data with coarsely reported age of contacts as long as the exact age of survey participants is reported.

Social contact patterns during the COVID-19 pandemic in 21 European countries - evidence from a two-year study.

BACKGROUND: Most countries have enacted some restrictions to reduce social contacts to slow down disease transmission during the COVID-19 pandemic. For nearly two years, individuals likely also adopted new behaviours to avoid pathogen exposure based on personal circumstances. We aimed to understand the way in which different factors affect social contacts - a critical step to improving future pandemic responses. METHODS: The analysis was based on repeated cross-sectional contact survey data collected in a standardized international study from 21 European countries between March 2020 and March 2022. We calculated the mean daily contacts reported using a clustered bootstrap by country and by settings (at home, at work, or in other settings). Where data were available, contact rates during the study period were compared with rates recorded prior to the pandemic. We fitted censored individual-level generalized additive mixed models to examine the effects of various factors on the number of social contacts. RESULTS: The survey recorded 463,336 observations from 96,456 participants. In all countries where comparison data were available, contact rates over the previous two years were substantially lower than those seen prior to the pandemic (approximately from over 10 to < 5), predominantly due to fewer contacts outside the home. Government restrictions imposed immediate effect on contacts, and these effects lingered after the restrictions were lifted. Across countries, the relationships between national policy, individual perceptions, or personal circumstances determining contacts varied. CONCLUSIONS: Our study, coordinated at the regional level, provides important insights into the understanding of the factors associated with social contacts to support future infectious disease outbreak responses.

Effect of risk status for severe COVID-19 on individual contact behaviour during the SARS-CoV-2 pandemic in 2020/2021-an analysis based on the German COVIMOD study.

BACKGROUND: One of the primary aims of contact restriction measures during the SARS-CoV-2 pandemic has been to protect people at increased risk of severe disease from the virus. Knowledge about the uptake of contact restriction measures in this group is critical for public health decision-making. We analysed data from the German contact survey COVIMOD to assess differences in contact patterns based on risk status, and compared this to pre-pandemic data to establish whether there was a differential response to contact reduction measures. METHODS: We quantified differences in contact patterns according to risk status by fitting a generalised linear model accounting for within-participant clustering to contact data from 31 COVIMOD survey waves (April 2020-December 2021), and estimated the population-averaged ratio of mean contacts of persons with high risk for a severe COVID-19 outcome due to age or underlying health conditions, to those without. We then compared the results to pre-pandemic data from the contact surveys HaBIDS and POLYMOD. RESULTS: Averaged across all analysed waves, COVIMOD participants reported a mean of 3.21 (95% confidence interval (95%CI) 3.14,3.28) daily contacts (truncated at 100), compared to 18.10 (95%CI 17.12,19.06) in POLYMOD and 28.27 (95%CI 26.49,30.15) in HaBIDS. After adjusting for confounders, COVIMOD participants aged 65 or above had 0.83 times (95%CI 0.79,0.87) the number of contacts as younger age groups. In POLYMOD, this ratio was 0.36 (95%CI 0.30,0.43). There was no clear difference in contact patterns due to increased risk from underlying health conditions in either HaBIDS or COVIMOD. We also found that persons in COVIMOD at high risk due to old age increased their non-household contacts less than those not at such risk after strict restriction measures were lifted. CONCLUSIONS: Over the course of the SARS-CoV-2 pandemic, there was a general reduction in contact numbers in the German population and also a differential response to contact restriction measures based on risk status for severe COVID-19. This differential response needs to be taken into account for parametrisations of mathematical models in a pandemic setting.

Native liver survival in bile salt export pump deficiency: results of a retrospective cohort study.

BACKGROUND: Bile salt export pump (ABCB11) deficiency [Progressive familial intrahepatic cholestasis (PFIC2)] is the most common genetic cause of PFIC and is associated with pruritus and progressive liver disease. Surgical biliary diversion or pharmacological [ileal bile acid transporter inhibitor (IBATi)] approaches can be used to block the recirculation of bile acids to the liver. There is a paucity of detailed data on the natural history and, in particular, the longitudinal evolution of bile acid levels to predict treatment response. Cross-sectional data from large international consortia suggested a maximum cutoff value of bile acids after the intervention to predict a successful outcome. METHODS: This retrospective, single-center, cohort study included all patients with confirmed biallelic pathogenic ABCB11 genotype PFIC2 treated at our institution with ≥2 years follow-up. The outcomes of interventions and predictors of long-term health were analyzed. RESULTS: Forty-eight cases were identified with PFIC2. Eighteen received partial external biliary diversion (PEBD) surgery, and 22 patients underwent liver transplantation. Two patients developed HCC and 2 died. Improved survival with native liver was closely associated with genotype, complete normalization of serum bile acids following PEBD, and alleviation of pruritus. Persistence of mild-to-moderate elevation of bile acids or a secondary rise following normalization was associated with liver disease progression and led to transplantation, suggesting that any prolonged elevation of bile acids worsens the chance of native liver survival. Higher-grade fibrosis at the time of PEBD was not associated with reduced long-term native liver survival. Patients with PFIC2 benefit from PEBD even at a stage of advanced fibrosis. CONCLUSION: Serum bile acid levels are an early predictor of treatment response and might serve as the gold standard in the evaluation of novel therapies including IBATi.

The Impact of Thrombophilic Factors on Disease Progression in Children with Biliary Atresia-A Single-Centre Cohort Study.

Epidemiological evidence suggests that thrombophilic factors, including male sex, non-O blood type, MTHFRnt677TT mutation, factor V Leiden G1691A mutation, and prothrombin G20210A polymorphism, may contribute to the progression of fibrosis and occurrence of portal vein thrombosis in liver disease. We retrospectively investigated the effect of potentially thrombophilic factors on native liver survival as a patient-relevant endpoint of disease progression in a cohort of 142 children being followed up for biliary atresia at Hannover Medical School from April 2017 to October 2019. No significant association could be determined. There was no evidence for relevant differences in native liver survival for the Factor V Leiden G1691A mutation (hazard ratio [HR] = 0.86, 95% confidence interval [CI] 0.38-1.98, p = 0.73), prothrombin G20210A polymorphism (HR = 0.96, 95%CI 0.24-3.65, p = 0.96), non-O blood type (HR = 0.79, 95%CI 0.51-1.21, p = 0.28) or MTHFRnt677TT mutation (HR = 1.24, 95%CI 0.60-2.56, p = 0.56). A certain, albeit not strong, evidence of reduced native liver survival in male patients after Kasai hepatoportoenterostomy, particularly during the first 2000 days (42%; HR = 1.41, 95%CI 0.92-2.18, p = 0.11) was found. All children with pre-transplant portal vein thrombosis (n = 7) had non-O blood types. Larger multi-centre studies are necessary to show if the male sex or other thrombophilic factors could be potentially associated with reduced native liver survival.

Diagnosing Acute Cellular Rejection after Paediatric Liver Transplantation-Is There Room for Interleukin Profiles?

BACKGROUND: The current gold standard to diagnose T-cell-mediated acute rejection (TCMR) requires liver histology. Using data from the ChilSFree study on immune response after paediatric liver transplantation (pLT), we aimed to assess whether soluble cytokines can serve as an alternative diagnostic tool in children suspected to have TCMR. METHODS: A total of n = 53 blood samples obtained on the day of or up to 3 days before liver biopsy performed for suspected TCMR at median 18 days (range 7-427) after pLT in n = 50 children (38% female, age at pLT 1.8 (0.5-17.5) years) were analysed for circulating cytokine levels using Luminex-based Multiplex technology. Diagnostic accuracy of cytokine concentrations was assessed using a multivariable model based on elastic net regression and gradient boosting machine analysis. RESULTS: TCMR was present in 68% of biopsies. There was strong evidence that patients with TCMR had increased levels of soluble CXCL8, CXCL9, CXCL10, IL-16, IL-18, HGF, CCL4, MIF, SCGF-ß, and HGF before biopsy. There was some evidence for increased levels of sCD25, ICAM-1, IL-6, IL-3, and CCL11. Diagnostic value of both single cytokine levels and a combination of cytokines and clinical markers was poor, with AUROCs not exceeding 0.7. CONCLUSION: Patients with TCMR showed raised levels of cytokines and chemokines reflective of T-cell activation and chemotaxis. Despite giving insight into the mechanisms of TCMR, the diagnostic value of soluble cytokines for the confirmation of TCMR in a clinical scenario of suspected TCMR is poor.

Age-specific contribution of contacts to transmission of SARS-CoV-2 in Germany.

Current estimates of pandemic SARS-CoV-2 spread in Germany using infectious disease models often do not use age-specific infection parameters and are not always based on age-specific contact matrices of the population. They also do usually not include setting- or pandemic phase-based information from epidemiological studies of reported cases and do not account for age-specific underdetection of reported cases. Here, we report likely pandemic spread using an age-structured model to understand the age- and setting-specific contribution of contacts to transmission during different phases of the COVID-19 pandemic in Germany. We developed a deterministic SEIRS model using a pre-pandemic contact matrix. The model was optimized to fit age-specific SARS-CoV-2 incidences reported by the German National Public Health Institute (Robert Koch Institute), includes information on setting-specific reported cases in schools and integrates age- and pandemic period-specific parameters for underdetection of reported cases deduced from a large population-based seroprevalence studies. Taking age-specific underreporting into account, younger adults and teenagers were identified in the modeling study as relevant contributors to infections during the first three pandemic waves in Germany. For the fifth wave, the Delta to Omicron transition, only age-specific parametrization reproduces the observed relative and absolute increase in pediatric hospitalizations in Germany. Taking into account age-specific underdetection did not change considerably how much contacts in schools contributed to the total burden of infection in the population (up to 12% with open schools under hygiene measures in the third wave). Accounting for the pandemic phase and age-specific underreporting is important to correctly identify those groups of the population in which quarantine, testing, vaccination, and contact-reduction measures are likely to be most effective and efficient. Age-specific parametrization is also highly relevant to generate informative age-specific output for decision makers and resource planers.

Long-term persistence of antibodies after diphtheria/tetanus vaccination in immunosuppressed patients with inflammatory rheumatic diseases and healthy controls.

Many vaccines demonstrate high effectiveness for years. This prospective multicentre study was conducted in Switzerland to assess the long-term persistence of antibodies to the diphtheria/tetanus (dT)-vaccine in adult patients with rheumatic diseases (PRDs). 163 PRDs and 169 controls were included in the study. The median age of all participants was 50 years (range: 18-83 years) and 56% were female. After a median time interval of 16 years after vaccination, the median anti-vaccine antibody concentrations were lower in PRDs than in controls for tetanus (1.68 vs 2.01; p = 0.049) and diphtheria (0.05 vs 0.22; p = 0.002). Based on the currently accepted seroprotection threshold (antibody concentration ≥ 0.1 IU/ml), PRDs had lower proportions of short-term tetanus and diphtheria protection as demonstrated by crude odds ratios (OR) of 0.30 (p = 0.017) and OR: 0.52 (p = 0.004), respectively. After adjusting for 'age' and 'time since last dT vaccination', the strength of associations became weaker; for tetanus, borderline evidence remained for a true difference between PRDs and controls (OR: 0.36 [p = 0.098]), however, not for diphtheria (OR: 0.86 [p = 0.58]). We hypothesize that in the presence of rheumatic diseases and its immunosuppressive treatment, vaccine-specific long-lived plasma cells (LLPCs) may be diminished or competitively displaced by rheumatism-specific LLPCs, a process which may decrease the persistence of vaccine-specific antibodies. Novel studies should be designed by incorporating methodologies allowing to determine the attributable fraction of immunosuppressive/immunomodulatory medications and rheumatic disease itself on long-lasting vaccine-specific antibody persistence, as well as, further study the role of LLPCs.

Sexual Contact Patterns in High-Income Countries-A Comparative Analysis Using Data From Germany, the United Kingdom, and the United States.

Sexual contact patterns determine the spread of sexually transmitted infections and are a central input parameter for mathematical models in this field. We evaluated the importance of country-specific sexual contact pattern parametrization for high-income countries with similar cultural backgrounds by comparing data from two independent studies (HaBIDS and SBG) in Germany, a country without systematic sexual contact pattern data, with data from the National Survey of Sexual Attitudes and Lifestyles (Natsal) in the UK, and the National Survey of Family Growth (NSFG) in the US, the two longest running sexual contact studies in high-income countries. We investigated differences in the distribution of the reported number of opposite-sex partners, same-sex partners and both-sex partners using weighted negative binomial regression adjusted for age and sex (as well as stratified by age). In our analyses, UK and US participants reported a substantially higher number of lifetime opposite-sex sexual partners compared to both German studies. The difference in lifetime partners was caused by a higher proportion of individuals with many partners in the young age group (<24 years) in the UK and the US. Partner acquisition in older age groups was similar. The number of same-sex partners was similar across countries, while there was heterogeneity in the reported experience with partners from both sexes, consistent with the differences observed for opposite-sex sexual partners. These patterns can lead to substantially different dynamics of sexually transmitted infections across ages, and have strong impact on the results of modeling studies.

Individual social contact data and population mobility data as early markers of SARS-CoV-2 transmission dynamics during the first wave in Germany-an analysis based on the COVIMOD study.

BACKGROUND: The effect of contact reduction measures on infectious disease transmission can only be assessed indirectly and with considerable delay. However, individual social contact data and population mobility data can offer near real-time proxy information. The aim of this study is to compare social contact data and population mobility data with respect to their ability to reflect transmission dynamics during the first wave of the SARS-CoV-2 pandemic in Germany. METHODS: We quantified the change in social contact patterns derived from self-reported contact survey data collected by the German COVIMOD study from 04/2020 to 06/2020 (compared to the pre-pandemic period from previous studies) and estimated the percentage mean reduction over time. We compared these results as well as the percentage mean reduction in population mobility data (corrected for pre-pandemic mobility) with and without the introduction of scaling factors and specific weights for different types of contacts and mobility to the relative reduction in transmission dynamics measured by changes in R values provided by the German Public Health Institute. RESULTS: We observed the largest reduction in social contacts (90%, compared to pre-pandemic data) in late April corresponding to the strictest contact reduction measures. Thereafter, the reduction in contacts dropped continuously to a minimum of 73% in late June. Relative reduction of infection dynamics derived from contact survey data underestimated the one based on reported R values in the time of strictest contact reduction measures but reflected it well thereafter. Relative reduction of infection dynamics derived from mobility data overestimated the one based on reported R values considerably throughout the study. After the introduction of a scaling factor, specific weights for different types of contacts and mobility reduced the mean absolute percentage error considerably; in all analyses, estimates based on contact data reflected measured R values better than those based on mobility. CONCLUSIONS: Contact survey data reflected infection dynamics better than population mobility data, indicating that both data sources cover different dimensions of infection dynamics. The use of contact type-specific weights reduced the mean absolute percentage errors to less than 1%. Measuring the changes in mobility alone is not sufficient for understanding the changes in transmission dynamics triggered by public health measures.

Negative SARS-CoV-2 PCR or rapid antigen test result and the subsequent risk of being infectious: a mathematical simulation study.

BACKGROUND: A considerable proportion of SARS-CoV-2 transmission occurs from asymptomatic and pre-symptomatic cases. Therefore, different polymerase chain reaction (PCR)- or rapid antigen test (RAT)-based approaches are being discussed and applied to identify infectious individuals that would have otherwise gone undetected. In this article, we provide a framework to estimate the time-dependent risk of being infectious after a negative SARS-CoV-2 test, and we simulate the number of expected infectious individuals over time in populations who initially tested negative. METHODS: A Monte Carlo approach is used to simulate asymptomatic infections over a 10-days period in populations of 1000 individuals following a negative SARS-CoV-2 test. Parameters representing the application of PCR tests or RATs are utilized, and SARS-CoV-2 cumulative 7-day incidences between 25 and 200 per 100,000 people are considered. Simulation results are compared to case numbers predicted via a mathematical equation. RESULTS: The simulations showed a continuous increase in infectious individuals over time in populations of individuals who initially tested SARS-CoV-2 negative. The interplay between false negative rates of PCR tests or RATs, and the time that has passed since testing determines the number of infectious individuals. The simulated and the mathematically predicted number of infectious individuals were comparable. However, Monte Carlo simulations highlight that, due to random variation, theoretically observed infectious individuals can considerably exceed predicted case numbers even shortly after a test was conducted. CONCLUSIONS: This study demonstrates that the number of infectious individuals in a screened group of asymptomatic people can be effectively reduced, and this effect can be described mathematically. However, the false negative rate of a test, the time since the negative test and the underlying SARS-CoV-2 incidence are critical parameters in determining the observed subsequent number of cases in tested population groups.

Discontinuation of biologic DMARDs in a real-world population of patients with rheumatoid arthritis in remission: outcome and risk factors.

OBJECTIVES: Data from randomized controlled trials have shown the feasibility of discontinuation of bDMARD therapy in patients with RA that have reached remission. Criteria for selecting patients that are likely to remain in remission are still incompletely defined. We aimed to identify predictors of successful discontinuation of bDMARD therapy in the Swiss Clinical Quality Management (SCQM) registry, a real-world cohort of RA patients. METHODS: RA patients in DAS28-ESR remission who stopped bDMARD/tsDMARD treatment were included. Loss of remission was defined as a DAS28-ESR > 2.6 or restart of a bDMARD/tsDMARD. Time to loss of remission was the main outcome. Kaplan-Meier methods were applied and Cox regression was used for multivariable analyses adjusting for confounding factors. Missing data were imputed using multiple imputation. RESULTS: A total of 318 patients in a bDMARD/tsDMARD-free remission were followed between 1997 and 2017. In total, 241 patients (76%) lost remission after a median time of 0.9 years (95% CI: 0.7, 1.0). The time to loss of remission was shorter in women, in patients with a longer disease duration >4yrs and in patients who did not meet clinical disease activity index (CDAI) remission criteria at baseline. Remission was longer in patients with csDMARD therapy during b/tsDMARD free remission [hazard ratio (HR) 0.8, P =0.05, 95% CI: 0.6, 1.0]. CONCLUSION: In a real-world patient population, the majority of patients who discontinued b/tsDMARD treatment lost remission within <1 year. Our study confirms that fulfilment of more rigorous remission criteria and csDMARD treatment increases the chance of maintaining b/tsDMARD-free remission.

Impact of assessing patient-reported outcomes with mobile apps on patient-provider interaction.

OBJECTIVE: To explore the effect of apps measuring patient-reported outcomes (PROs) on patient-provider interaction in the rheumatic diseases in an observational setting. METHODS: Patients in the Swiss Clinical Quality Management in Rheumatic Diseases Registry were offered mobile apps (iDialog and COmPASS) to track disease status between rheumatology visits using validated PROs (Rheumatoid Arthritis Disease Activity Index-5 score, Bath Ankylosing Spondylitis Disease Activity Index score, Routine Assessment of Patient Index Data-3 score and Visual Analogue Scale score for pain, disease activity and skin symptoms). We assessed two aspects of patient-provider interaction: shared decision making (SDM) and physician awareness of disease fluctuations. We used logistic regressions to compare outcomes among patients who (1) used an app and discussed app data with their physician (app+discussion group), (2) used an app without discussing the data (app-only group) or (3) did not use any app (non-app users). RESULTS: 2111 patients were analysed, including 1799 non-app users, 150 app-only users and 162 app+discussion users (43% male; with 902 patients with rheumatoid arthritis, 766 patients with axial spondyloarthritis and 443 patients with psoriatic arthritis). App users were younger than non-app users (mean age of 47 vs 51 years, p<0.001). Compared with non-app users, the app+discussion group rated their rheumatologist more highly in SDM (OR 1.7, 95% CI 1.1 to 2.4) and physician awareness of disease fluctuations (OR 2.0, 95% CI 1.3 to 3.1). This improvement was absent in the app-only group. CONCLUSION: App users who discussed app data with their rheumatologist reported more favourably on patient-provider interactions than app users who did not and non-app users. Apps measuring PROs may contribute little to patient-provider interactions without integration of app data into care processes.

Risk estimation for air travel-induced malaria transmission in central Europe - A mathematical modelling study.

BACKGROUND: Aim of our study was to identify conditions under which malaria transmission caused by imported infectious mosquitoes or travellers could occur at large central European airports, and if such transmission could be sustained by indigenous mosquitoes. METHODS: We developed a deterministic and a stochastic compartmental Susceptible-Exposed-Infectious-Recovered-Susceptible (humans)/Susceptible-Exposed-Infectious (mosquitoes) model with two mosquito (imported Anopheles gambiae, indigenous A. plumbeus) and three human (travellers, airport personnel exposed/not exposed to imported A. gambiae) populations. We assessed various scenarios to identify combinations of model parameters leading to ongoing malaria transmission at the airport. RESULTS: The number of infected airport personnel was low (five infected employees/six months) under assumptions reflecting possible future climatic conditions, current passenger mobility and no desinsection of airports/aircraft. Almost all infections among airport personnel were directly due to bites by imported A. gambiae. Indigenous mosquitoes would need to have comparable transmission parameters to A. gambiae to sustain disease transmission. Incoming infectious passengers play only a minor role in malaria transmission. Use of aircraft/airport desinsection led to no transmission events in the model. CONCLUSION: Our study shows that sustainable air travel-induced malaria transmission in central Europe is unlikely under current conditions or conditions which might become realistic in the next century.