Bacterial proteases are a promising post-translational regulation strategy in synthetic circuits because they recognize specific amino acid degradation tags (degrons) that can be fine-tuned to modulate the degradation levels of tagged proteins. For this reason, recent efforts have been made in the search for new degrons. Here we review the up-to-date applications of degradation tags for circuit engineering in bacteria. In particular, we pay special attention to the effects of degradation bottlenecks in synthetic oscillators and introduce mathematical approaches to study queueing that enable the quantitative modelling of proteolytic queues.

Background: The impact of respiratory syncytial virus (RSV) in older adults is underrecognized, and the limited existing studies on the incidence of hospitalizations show great variability. This study aims to estimate the seasonal incidence rates (IRs) of RSV hospitalizations among adults aged ≥60 years and evaluate how different case definitions influence these estimates. Methods: A prospective, multicenter observational study with active monitoring was conducted over 10 seasons (2010–2011 to 2019–2020) in 4–10 hospitals (depending on the season) and covered 21%–46% of the region's total population (about 5 million people). RSV hospitalization IRs per 100 000 person-years and 95% confidence intervals were calculated with the exact Poisson method and were stratified by age group (≥60, ≥70, or ≥80 years), RSV season, sex, and the entire study period. Two case definitions were compared: influenzalike illness (ILI) and the combined use of ILI and extended severe acute respiratory infection (ILI/SARI). Results: A total of 40 600 hospitalizations of individuals aged ≥60 years were included. The RSV hospitalization IRs ranged from 21 to 402 per 100 000 person-years, varying by season, age group, and case definition. The highest IRs were observed in those aged ≥80 years. The ILI case definition underestimated RSV hospitalizations by 13%–40% when compared with the ILI/SARI case definition. Conclusions: On average, approximately 1 in every 1000 adults aged ≥60 years is hospitalized due to RSV. The risk of a severe RSV infection increases with age and varies significantly between seasons. These are key results for the estimation of the potential impact of the new available RSV vaccines.

Respiratory syncytial virus (RSV) is a substantial cause of hospital admission in young children and leads to seasonal pressure on pediatric emergency units in most countries. This study aims to assemble national or large-scale data on RSV hospitalisations from six European countries with a standardised approach to provide recent burden data for all children and assess changes since SARS-CoV-2's emergence. We analysed 2016-2023 hospital records from national registries in Denmark, England, Finland, The Netherlands, and Scotland, and from a hospital surveillance network in Spain-Valencia for children below 18 years. We considered separately RSV-coded and RSV laboratory-confirmed cases, comparing them to respiratory tract infections. We studied the temporal evolution of incidence rates and case reporting practices, comparing pre- and post-COVID-19 periods. Post-COVID-19 observed RSV hospital burden was similar to the pre-COVID-19 one for younger children but higher for the 1-2 years, 3-4 years, and 5-17 years age groups. No change in terms of coding-neither diagnosis nor RSV-coding when RSV was laboratory-confirmed-was detected. Hospital RSV burden in children is significant but currently not fully monitorable. Further efforts to harmonise coding practices both within and across countries would improve the quality of future analyses. Additional data in future seasons should complement current outcomes to inform decisions regarding RSV prevention.

The aim of this study was to assess the possible extent of bias due to violation of a core assumption (event-dependent exposures) when using self-controlled designs to analyse the association between COVID-19 vaccines and myocarditis. We used data from five European databases (Spain: BIFAP, FISABIO VID, and SIDIAP; Italy: ARS-Tuscany; England: CPRD Aurum) converted to the ConcePTION Common Data Model. Individuals who experienced both myocarditis and were vaccinated against COVID-19 between 1 September 2020 and the end of data availability in each country were included. We compared a self-controlled risk interval study (SCRI) using a pre-vaccination control window, an SCRI using a post-vaccination control window, a standard SCCS and an extension of the SCCS designed to handle violations of the assumption of event-dependent exposures. We included 1,757 cases of myocarditis. For analyses of the first dose of the Pfizer vaccine, to which all databases contributed information, we found results consistent with a null effect in both of the SCRI and extended SCCS, but some indication of a harmful effect in a standard SCCS. For the second dose, we found evidence of a harmful association for all study designs, with relatively similar effect sizes (SCRI pre = 1.99, 1.40 - 2.82; SCRI post 2.13, 95 %CI - 1.43, 3.18; standard SCCS 1.79, 95 %CI 1.31 - 2.44, extended SCCS 1.52, 95 %CI = 1.08 - 2.15). Adjustment for calendar time did not change these conclusions. Findings using all designs were also consistent with a harmful effect following a second dose of the Moderna vaccine. In the context of the known association between COVID-19 vaccines and myocarditis, we have demonstrated that two forms of SCRI and two forms of SCCS led to largely comparable results, possibly because of limited violation of the assumption of event-dependent exposures.

We test the robustness of the self-controlled risk interval (SCRI) design in a setting where time between doses may introduce time-varying confounding, using both negative control outcomes (NCOs) and quantitative bias analysis (QBA). All vaccinated cases identified from 5 European databases between 1 September 2020 and end of data availability were included. Exposures were doses 1-3 of the Pfizer, Moderna, AstraZeneca, and Janssen COVID-19 vaccines; outcomes were myocarditis and otitis externa (NCO). The SCRI used a 60-day control window and dose-specific 28-day risk windows, stratified by vaccine brand and adjusted for calendar time. The QBA included two scenarios: (i) baseline probability of the confounder was higher in the control window and (ii) vice versa. The NCO was not associated with any of the COVID-19 vaccine types or doses except Moderna dose 1 (IRR = 1.09, 95%CI 1.01-1.09). The QBA suggested even the strongest literature-reported confounder (COVID-19; RR_myocarditis = 18.3) could only explain away part of the observed effect from IRR = 3 to IRR = 1.40. The SCRI seems robust to unmeasured confounding in the COVID-19 setting, although a strong unmeasured confounder could bias the observed effect upward. Replication of our findings for other safety signals would strengthen this conclusion.

Introduction: Respiratory Syncytial Virus (RSV) is a major cause of morbidity in older adults. With the emergence of the coronavirus disease 2019 (COVID-19) and the subsequent changes in respiratory viral circulation, it is crucial to reassess RSV-associated healthcare burden in adults. This study assessed RSV-associated healthcare burden in adults in six European countries before and during the COVID-19 pandemic. Methods: We conducted a retrospective analysis using national hospital admissions data from Denmark, England, Finland, the Netherlands, Scotland, and regional surveillance data from the Valencia region (Spain). We included patients aged ≥18 years hospitalised for respiratory tract infections (RTIs) from 2016 to 2023. We assessed RSV-coded and laboratory-confirmed hospitalisations, intensive care unit (ICU) admissions, in-hospital length of stay (LOS), and mortality. Results: RSV-associated hospitalisations significantly reduced during the 2020/2021 season across all countries, coinciding with strict COVID-19 preventive measures, but resurged in subsequent seasons. We observed the highest hospitalisation rates in adults aged ≥85 years. RSV-coded hospitalisations were found to underestimate the true burden when compared with laboratory-confirmed cases. Underestimation factors ranged from 1.1 to 4.3 times across countries. No significant differences were observed in LOS or ICU admission rates for RSV-associated hospitalisations compared to RTIs. Discussion: Our findings underscore the complex epidemiology of RSV in older adults. The differences between RSV-coded and laboratory-confirmed cases highlight the critical need for improved surveillance and diagnostic practices to better assess the true burden. Our findings could be vital for guiding public health strategies, particularly with the recent introduction of RSV vaccines for older adults.