Collateral effects of the COVID-19 pandemic on endocrine treatments for breast and prostate cancer in the UK: a cohort study.

Background: The COVID-19 pandemic affected cancer screening, diagnosis and treatments. Many surgeries were substituted with bridging therapies during the initial lockdown, yet consideration of treatment side effects and their management was not a priority. Objectives: To examine how the changing social restrictions imposed by the pandemic affected incidence and trends of endocrine treatment prescriptions in newly diagnosed (incident) breast and prostate cancer patients and, secondarily, endocrine treatment-related outcomes (including bisphosphonate prescriptions, osteopenia and osteoporosis), in UK clinical practice from March 2020 to June 2022. Design: Population-based cohort study using UK primary care Clinical Practice Research Datalink GOLD database. Methods: There were 13,701 newly diagnosed breast cancer patients and 12,221 prostate cancer patients with ⩾1-year data availability since diagnosis between January 2017 and June 2022. Incidence rates (IR) and incidence rate ratios (IRR) were calculated across multiple time periods before and after lockdown to examine the impact of changing social restrictions on endocrine treatments and treatment-related outcomes, including osteopenia, osteoporosis and bisphosphonate prescriptions. Results: In breast cancer patients, aromatase inhibitor (AI) prescriptions increased during lockdown versus pre-pandemic [IRR: 1.22 (95% confidence interval (CI): 1.11-1.34)], followed by a decrease post-first lockdown [IRR: 0.79 (95% CI: 0.69-0.89)]. In prostate cancer patients, first-generation antiandrogen prescriptions increased versus pre-pandemic [IRR: 1.23 (95% CI: 1.08-1.4)]. For breast cancer patients on AIs, diagnoses of osteopenia, osteoporosis and bisphosphonate prescriptions were reduced across all lockdown periods versus pre-pandemic (IRR range: 0.31-0.62). Conclusion: During the first 2 years of the pandemic, newly diagnosed breast and prostate cancer patients were prescribed more endocrine treatments compared to pre-pandemic due to restrictions on hospital procedures replacing surgeries with bridging therapies. But breast cancer patients had fewer diagnoses of osteopenia and osteoporosis and bisphosphonate prescriptions. These patients should be followed up in the coming years for signs of bone thinning. Evidence of poorer management of treatment-related side effects will help assess resource allocation for patients at high risk for bone-related complications.

Effects of the COVID-19 pandemic on hormone treatments for breast and prostate cancer in the UK: implications for bone health The COVID-19 pandemic has had a big impact on health, going beyond just causing illness. One area it has influenced is how patients with breast cancer or prostate cancer are treated. Surgeries and radiotherapies were delayed from the first lockdown as hospitals reduced non-covid related procedures. Some patients with breast or prostate cancer were instead given some medications to help stop their cancers from growing until they were able to have surgery or radiotherapy. These medications (called endocrine treatments) have important side effects, such as conditions that affect the bones. Patients on these medications should be monitored by doctors for signs of bone thinning and should, in some cases, be given other medications to help stop this happening. This study used doctors' records from more than 5 million people to find out whether the pandemic affected the number of endocrine medications being prescribed in patients with breast or prostate cancer, and also looked at the number of these patients that were diagnosed with conditions that affect their bones and whether they were given medications that could protect their bone health. We found that during the first lockdown, patients with breast cancer or prostate cancer had more of some types of endocrine treatments compared to before the lockdown. However, they had fewer diagnoses of conditions related to bone health and fewer medications to protect their bones. It is possible that appointments and tests that are usually carried out to diagnose conditions relating to bone health were not performed in the months after the first lockdown, and so these conditions were underdiagnosed. The use of medications to protect their bones was also reduced, likely because this was not considered a priority during the pandemic. This highlights that such patients should be followed up in the coming years for signs of bone thinning, given the relatively poorer management of these side effects in these people after the pandemic.

Mathematical modeling of SARS-CoV-2 variant substitutions in European countries: transmission dynamics and epidemiological insights.

Background: Countries across Europe have faced similar evolutions of SARS-CoV-2 variants of concern, including the Alpha, Delta, and Omicron variants. Materials and methods: We used data from GISAID and applied a robust, automated mathematical substitution model to study the dynamics of COVID-19 variants in Europe over a period of more than 2 years, from late 2020 to early 2023. This model identifies variant substitution patterns and distinguishes between residual and dominant behavior. We used weekly sequencing data from 19 European countries to estimate the increase in transmissibility ( Δ ß ) between consecutive SARS-CoV-2 variants. In addition, we focused on large countries with separate regional outbreaks and complex scenarios of multiple competing variants. Results: Our model accurately reproduced the observed substitution patterns between the Alpha, Delta, and Omicron major variants. We estimated the daily variant prevalence and calculated Δ ß between variants, revealing that: ( i ) Δ ß increased progressively from the Alpha to the Omicron variant; ( i i ) Δ ß showed a high degree of variability within Omicron variants; ( i i i ) a higher Δ ß was associated with a later emergence of the variant within a country; ( i v ) a higher degree of immunization of the population against previous variants was associated with a higher Δ ß for the Delta variant; ( v ) larger countries exhibited smaller Δ ß , suggesting regionally diverse outbreaks within the same country; and finally ( v i ) the model reliably captures the dynamics of competing variants, even in complex scenarios. Conclusion: The use of mathematical models allows for precise and reliable estimation of daily cases of each variant. By quantifying Δ ß , we have tracked the spread of the different variants across Europe, highlighting a robust increase in transmissibility trend from Alpha to Omicron. Additionally, we have shown that the geographical characteristics of a country, as well as the timing of new variant entrances, can explain some of the observed differences in variant substitution dynamics across countries.

Calculating daily dose in the Observational Medical Outcomes Partnership Common Data Model.

PURPOSE: We aimed to develop a standardized method to calculate daily dose (i.e., the amount of drug a patient was exposed to per day) of any drug on a global scale using only drug information of typical observational data in the Observational Medical Outcomes Partnership Common Data Model (OMOP CDM) and a single reference table from Observational Health Data Sciences And Informatics (OHDSI). MATERIALS AND METHODS: The OMOP DRUG_STRENGTH reference table contains information on the strength or concentration of drugs, whereas the OMOP DRUG_EXPOSURE table contains information on patients' drug prescriptions or dispensations/claims. Based on DRUG_EXPOSURE data from the primary care databases Clinical Practice Research Datalink GOLD (United Kingdom) and Integrated Primary Care Information (IPCI, The Netherlands) and healthcare claims from PharMetrics® Plus for Academics (USA), we developed four formulas to calculate daily dose given different DRUG_STRENGTH reference table information. We tested the dose formulas by comparing the calculated median daily dose to the World Health Organization (WHO) Defined Daily Dose (DDD) for six different ingredients in those three databases and additional four international databases representing a variety of healthcare settings: MAITT (Estonia, healthcare claims and discharge summaries), IQVIA Disease Analyzer Germany (outpatient data), IQVIA Longitudinal Patient Database Belgium (outpatient data), and IMASIS Parc Salut (Spain, hospital data). Finally, in each database, we assessed the proportion of drug records for which daily dose calculations were possible using the suggested formulas. RESULTS: Applying the dose formulas, we obtained median daily doses that generally matched the WHO DDD definitions. Our dose formulas were applicable to >85% of drug records in all but one of the assessed databases. CONCLUSION: We have established and implemented a standardized daily dose calculation in OMOP CDM providing reliable and reproducible results.

The impact of the UK COVID-19 lockdown on the screening, diagnostics and incidence of breast, colorectal, lung and prostate cancer in the UK: a population-based cohort study.

Introduction: The COVID-19 pandemic had collateral effects on many health systems. Cancer screening and diagnostic tests were postponed, resulting in delays in diagnosis and treatment. This study assessed the impact of the pandemic on screening, diagnostics and incidence of breast, colorectal, lung, and prostate cancer; and whether rates returned to pre-pandemic levels by December, 2021. Methods: This is a cohort study of electronic health records from the United Kingdom (UK) primary care Clinical Practice Research Datalink (CPRD) GOLD database. The study included individuals registered with CPRD GOLD between January, 2017 and December, 2021, with at least 365 days of clinical history. The study focused on screening, diagnostic tests, referrals and diagnoses of first-ever breast, colorectal, lung, and prostate cancer. Incidence rates (IR) were stratified by age, sex, and region, and incidence rate ratios (IRR) were calculated to compare rates during and after lockdown with rates before lockdown. Forecasted rates were estimated using negative binomial regression models. Results: Among 5,191,650 eligible participants, the first lockdown resulted in reduced screening and diagnostic tests for all cancers, which remained dramatically reduced across the whole observation period for almost all tests investigated. There were significant IRR reductions in breast (0.69 [95% CI: 0.63-0.74]), colorectal (0.74 [95% CI: 0.67-0.81]), and prostate (0.71 [95% CI: 0.66-0.78]) cancer diagnoses. IRR reductions for lung cancer were non-significant (0.92 [95% CI: 0.84-1.01]). Extrapolating to the entire UK population, an estimated 18,000 breast, 13,000 colorectal, 10,000 lung, and 21,000 prostate cancer diagnoses were missed from March, 2020 to December, 2021. Discussion: The UK COVID-19 lockdown had a substantial impact on cancer screening, diagnostic tests, referrals, and diagnoses. Incidence rates remained significantly lower than pre-pandemic levels for breast and prostate cancers and associated tests by December, 2021. Delays in diagnosis are likely to have adverse consequences on cancer stage, treatment initiation, mortality rates, and years of life lost. Urgent strategies are needed to identify undiagnosed cases and address the long-term implications of delayed diagnoses.

Incident Use of Hydroxychloroquine for the Treatment of Rheumatoid Arthritis and Systemic Lupus Erythematosus During the COVID-19 Pandemic.

OBJECTIVE: We studied whether the use of hydroxychloroquine (HCQ) for COVID-19 resulted in supply shortages for patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). METHODS: We used US claims data (IQVIA PHARMETRICS® Plus for Academics [PHARMETRICS]) and hospital electronic records from Spain (Institut Municipal d'Assistència Sanitària Information System [IMASIS]) to estimate monthly rates of HCQ use between January 2019 and March 2022, in the general population and in patients with RA and SLE. Methotrexate (MTX) use was estimated as a control. RESULTS: More than 13.5 million individuals (13,311,811 PHARMETRICS, 207,646 IMASIS) were included in the general population cohort. RA and SLE cohorts enrolled 135,259 and 39,295 patients, respectively, in PHARMETRICS. Incidence of MTX and HCQ were stable before March 2020. On March 2020, the incidence of HCQ increased by 9- and 67-fold in PHARMETRICS and IMASIS, respectively, and decreased in May 2020. Usage rates of HCQ went back to prepandemic trends in Spain but remained high in the United States, mimicking waves of COVID-19. No significant changes in HCQ use were noted among patients with RA and SLE. MTX use rates decreased during HCQ approval period for COVID-19 treatment. CONCLUSION: Use of HCQ increased dramatically in the general population in both Spain and the United States during March and April 2020. Whereas Spain returned to prepandemic rates after the first wave, use of HCQ remained high and followed waves of COVID-19 in the United States. However, we found no evidence of general shortages in the use of HCQ for both RA and SLE in the United States.

The role of COVID-19 vaccines in preventing post-COVID-19 thromboembolic and cardiovascular complications.

OBJECTIVE: To study the association between COVID-19 vaccination and the risk of post-COVID-19 cardiac and thromboembolic complications. METHODS: We conducted a staggered cohort study based on national vaccination campaigns using electronic health records from the UK, Spain and Estonia. Vaccine rollout was grouped into four stages with predefined enrolment periods. Each stage included all individuals eligible for vaccination, with no previous SARS-CoV-2 infection or COVID-19 vaccine at the start date. Vaccination status was used as a time-varying exposure. Outcomes included heart failure (HF), venous thromboembolism (VTE) and arterial thrombosis/thromboembolism (ATE) recorded in four time windows after SARS-CoV-2 infection: 0-30, 31-90, 91-180 and 181-365 days. Propensity score overlap weighting and empirical calibration were used to minimise observed and unobserved confounding, respectively.Fine-Gray models estimated subdistribution hazard ratios (sHR). Random effect meta-analyses were conducted across staggered cohorts and databases. RESULTS: The study included 10.17 million vaccinated and 10.39 million unvaccinated people. Vaccination was associated with reduced risks of acute (30-day) and post-acute COVID-19 VTE, ATE and HF: for example, meta-analytic sHR of 0.22 (95% CI 0.17 to 0.29), 0.53 (0.44 to 0.63) and 0.45 (0.38 to 0.53), respectively, for 0-30 days after SARS-CoV-2 infection, while in the 91-180 days sHR were 0.53 (0.40 to 0.70), 0.72 (0.58 to 0.88) and 0.61 (0.51 to 0.73), respectively. CONCLUSIONS: COVID-19 vaccination reduced the risk of post-COVID-19 cardiac and thromboembolic outcomes. These effects were more pronounced for acute COVID-19 outcomes, consistent with known reductions in disease severity following breakthrough versus unvaccinated SARS-CoV-2 infection.

The effectiveness of COVID-19 vaccines to prevent long COVID symptoms: staggered cohort study of data from the UK, Spain, and Estonia.

BACKGROUND: Although vaccines have proved effective to prevent severe COVID-19, their effect on preventing long-term symptoms is not yet fully understood. We aimed to evaluate the overall effect of vaccination to prevent long COVID symptoms and assess comparative effectiveness of the most used vaccines (ChAdOx1 and BNT162b2). METHODS: We conducted a staggered cohort study using primary care records from the UK (Clinical Practice Research Datalink [CPRD] GOLD and AURUM), Catalonia, Spain (Information System for Research in Primary Care [SIDIAP]), and national health insurance claims from Estonia (CORIVA database). All adults who were registered for at least 180 days as of Jan 4, 2021 (the UK), Feb 20, 2021 (Spain), and Jan 28, 2021 (Estonia) comprised the source population. Vaccination status was used as a time-varying exposure, staggered by vaccine rollout period. Vaccinated people were further classified by vaccine brand according to their first dose received. The primary outcome definition of long COVID was defined as having at least one of 25 WHO-listed symptoms between 90 and 365 days after the date of a PCR-positive test or clinical diagnosis of COVID-19, with no history of that symptom 180 days before SARS-Cov-2 infection. Propensity score overlap weighting was applied separately for each cohort to minimise confounding. Sub-distribution hazard ratios (sHRs) were calculated to estimate vaccine effectiveness against long COVID, and empirically calibrated using negative control outcomes. Random effects meta-analyses across staggered cohorts were conducted to pool overall effect estimates. FINDINGS: A total of 1 618 395 (CPRD GOLD), 5 729 800 (CPRD AURUM), 2 744 821 (SIDIAP), and 77 603 (CORIVA) vaccinated people and 1 640 371 (CPRD GOLD), 5 860 564 (CPRD AURUM), 2 588 518 (SIDIAP), and 302 267 (CORIVA) unvaccinated people were included. Compared with unvaccinated people, overall HRs for long COVID symptoms in people vaccinated with a first dose of any COVID-19 vaccine were 0·54 (95% CI 0·44-0·67) in CPRD GOLD, 0·48 (0·34-0·68) in CPRD AURUM, 0·71 (0·55-0·91) in SIDIAP, and 0·59 (0·40-0·87) in CORIVA. A slightly stronger preventative effect was seen for the first dose of BNT162b2 than for ChAdOx1 (sHR 0·85 [0·60-1·20] in CPRD GOLD and 0·84 [0·74-0·94] in CPRD AURUM). INTERPRETATION: Vaccination against COVID-19 consistently reduced the risk of long COVID symptoms, which highlights the importance of vaccination to prevent persistent COVID-19 symptoms, particularly in adults. FUNDING: National Institute for Health and Care Research.

IncidencePrevalence: An R package to calculate population-level incidence rates and prevalence using the OMOP common data model.

PURPOSE: Real-world data (RWD) offers a valuable resource for generating population-level disease epidemiology metrics. We aimed to develop a well-tested and user-friendly R package to compute incidence rates and prevalence in data mapped to the observational medical outcomes partnership (OMOP) common data model (CDM). MATERIALS AND METHODS: We created IncidencePrevalence, an R package to support the analysis of population-level incidence rates and point- and period-prevalence in OMOP-formatted data. On top of unit testing, we assessed the face validity of the package. To do so, we calculated incidence rates of COVID-19 using RWD from Spain (SIDIAP) and the United Kingdom (CPRD Aurum), and replicated two previously published studies using data from the Netherlands (IPCI) and the United Kingdom (CPRD Gold). We compared the obtained results to those previously published, and measured execution times by running a benchmark analysis across databases. RESULTS: IncidencePrevalence achieved high agreement to previously published data in CPRD Gold and IPCI, and showed good performance across databases. For COVID-19, incidence calculated by the package was similar to public data after the first-wave of the pandemic. CONCLUSION: For data mapped to the OMOP CDM, the IncidencePrevalence R package can support descriptive epidemiological research. It enables reliable estimation of incidence and prevalence from large real-world data sets. It represents a simple, but extendable, analytical framework to generate estimates in a reproducible and timely manner.

Observational methods for COVID-19 vaccine effectiveness research: an empirical evaluation and target trial emulation.

BACKGROUND: There are scarce data on best practices to control for confounding in observational studies assessing vaccine effectiveness to prevent COVID-19. We compared the performance of three well-established methods [overlap weighting, inverse probability treatment weighting and propensity score (PS) matching] to minimize confounding when comparing vaccinated and unvaccinated people. Subsequently, we conducted a target trial emulation to study the ability of these methods to replicate COVID-19 vaccine trials. METHODS: We included all individuals aged ≥75 from primary care records from the UK [Clinical Practice Research Datalink (CPRD) AURUM], who were not infected with or vaccinated against SARS-CoV-2 as of 4 January 2021. Vaccination status was then defined based on first COVID-19 vaccine dose exposure between 4 January 2021 and 28 January 2021. Lasso regression was used to calculate PS. Location, age, prior observation time, regional vaccination rates, testing effort and COVID-19 incidence rates at index date were forced into the PS. Following PS weighting and matching, the three methods were compared for remaining covariate imbalance and residual confounding. Last, a target trial emulation comparing COVID-19 at 3 and 12 weeks after first vaccine dose vs unvaccinated was conducted. RESULTS: Vaccinated and unvaccinated cohorts comprised 583 813 and 332 315 individuals for weighting, respectively, and 459 000 individuals in the matched cohorts. Overlap weighting performed best in terms of minimizing confounding and systematic error. Overlap weighting successfully replicated estimates from clinical trials for vaccine effectiveness for ChAdOx1 (57%) and BNT162b2 (75%) at 12 weeks. CONCLUSION: Overlap weighting performed best in our setting. Our results based on overlap weighting replicate previous pivotal trials for the two first COVID-19 vaccines approved in Europe.

"The burden of post-acute COVID-19 symptoms in a multinational network cohort analysis".

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.

Supporting Pharmacovigilance Signal Validation and Prioritization with Analyses of Routinely Collected Health Data: Lessons Learned from an EHDEN Network Study.

INTRODUCTION: Individual case reports are the main asset in pharmacovigilance signal management. Signal validation is the first stage after signal detection and aims to determine if there is sufficient evidence to justify further assessment. Throughout signal management, a prioritization of signals is continually made. Routinely collected health data can provide relevant contextual information but are primarily used at a later stage in pharmacoepidemiological studies to assess communicated signals. OBJECTIVE: The aim of this study was to examine the feasibility and utility of analysing routine health data from a multinational distributed network to support signal validation and prioritization and to reflect on key user requirements for these analyses to become an integral part of this process. METHODS: Statistical signal detection was performed in VigiBase, the WHO global database of individual case safety reports, targeting generic manufacturer drugs and 16 prespecified adverse events. During a 5-day study-a-thon, signal validation and prioritization were performed using information from VigiBase, regulatory documents and the scientific literature alongside descriptive analyses of routine health data from 10 partners of the European Health Data and Evidence Network (EHDEN). Databases included in the study were from the UK, Spain, Norway, the Netherlands and Serbia, capturing records from primary care and/or hospitals. RESULTS: Ninety-five statistical signals were subjected to signal validation, of which eight were considered for descriptive analyses in the routine health data. Design, execution and interpretation of results from these analyses took up to a few hours for each signal (of which 15-60 minutes were for execution) and informed decisions for five out of eight signals. The impact of insights from the routine health data varied and included possible alternative explanations, potential public health and clinical impact and feasibility of follow-up pharmacoepidemiological studies. Three signals were selected for signal assessment, two of these decisions were supported by insights from the routine health data. Standardization of analytical code, availability of adverse event phenotypes including bridges between different source vocabularies, and governance around the access and use of routine health data were identified as important aspects for future development. CONCLUSIONS: Analyses of routine health data from a distributed network to support signal validation and prioritization are feasible in the given time limits and can inform decision making. The cost-benefit of integrating these analyses at this stage of signal management requires further research.

Association between ethnic background and COVID-19 morbidity, mortality and vaccination in England: a multistate cohort analysis using the UK Biobank.

OBJECTIVES: Despite growing evidence suggesting increased COVID-19 mortality among people from ethnic minorities, little is known about milder forms of SARS-CoV-2 infection. We sought to explore the association between ethnic background and the probability of testing, testing positive, hospitalisation, COVID-19 mortality and vaccination uptake. DESIGN: A multistate cohort analysis. Participants were followed between 8 April 2020 and 30 September 2021. SETTING: The UK Biobank, which stores medical data on around half a million people who were recruited between 2006 and 2010. PARTICIPANTS: 405 541 subjects were eligible for analysis, limited to UK Biobank participants living in England. 23 891 (6%) of participants were non-white. PRIMARY AND SECONDARY OUTCOME MEASURES: The associations between ethnic background and testing, testing positive, hospitalisation and COVID-19 mortality were studied using multistate survival analyses. The association with single and double-dose vaccination was also modelled. Multistate models adjusted for age, sex and socioeconomic deprivation were fitted to estimate adjusted HRs (aHR) for each of the multistate transitions. RESULTS: 18 172 (4.5%) individuals tested positive, 3285 (0.8%) tested negative and then positive, 1490 (6.9% of those tested positive) were hospitalised, and 129 (0.6%) tested positive at the moment of hospital admission (ie, direct hospitalisation). Finally, 662 (17.4%) died after admission. Compared with white participants, Asian participants had an increased risk of negative to positive transition (aHR 1.24 (95% CI 1.02 to 1.52)), testing positive (95% CI 1.44 (1.33 to 1.55)) and direct hospitalisation (1.61 (95% CI 1.28 to 2.03)). Black participants had an increased risk of hospitalisation following a positive test (1.71 (95% CI 1.29 to 2.27)) and direct hospitalisation (1.90 (95% CI 1.51 to 2.39)). Although not the case for Asians (aHR 1.00 (95% CI 0.98 to 1.02)), black participants had a reduced vaccination probability (0.63 (95% CI 0.62 to 0.65)). In contrast, Chinese participants had a reduced risk of testing negative (aHR 0.64 (95% CI 0.57 to 0.73)), of testing positive (0.40 (95% CI 0.28 to 0.57)) and of vaccination (0.78 (95% CI 0.74 to 0.83)). CONCLUSIONS: We identified inequities in testing, vaccination and COVID-19 outcomes according to ethnicity in England. Compared with whites, Asian participants had increased risks of infection and admission, and black participants had almost double hospitalisation risk, and a 40% lower vaccine uptake.

The impact of COVID-19 certification mandates on the number of cases of and hospitalizations with COVID-19 in the UK: A difference-in-differences analysis.

Background: Mandatory COVID-19 certification, showing proof of vaccination, negative test, or recent infection to access to public venues, was introduced at different times in the four countries of the UK. We aim to study its effects on the incidence of cases and hospital admissions. Methods: We performed Negative binomial segmented regression and ARIMA analyses for four countries (England, Northern Ireland, Scotland and Wales), and fitted Difference-in-Differences models to compare the latter three to England, as a negative control group, since it was the last country where COVID-19 certification was introduced. The main outcome was the weekly averaged incidence of COVID-19 cases and hospital admissions. Results: COVID-19 certification led to a decrease in the incidence of cases and hospital admissions in Northern Ireland, as well as in Wales during the second half of November. The same was seen for hospital admissions in Wales and Scotland during October. In Wales the incidence rate of cases in October already had a decreasing tendency, as well as in England, hence a particular impact of COVID-19 certification was less obvious. Method assumptions for the Difference-in-Differences analysis did not hold for Scotland. Additional NBSR and ARIMA models suggest similar results, while also accounting for correlation in the latter. The assessment of the effect in England itself leads one to believe that this intervention might not be strong enough for the Omicron variant, which was prevalent at the time of introduction of COVID-19 certification in the country. Conclusions: Mandatory COVID-19 certification reduced COVID-19 transmission and hospitalizations when Delta predominated in the UK, but lost efficacy when Omicron became the most common variant.

Immunoregulatory Biomarkers of the Remission Phase in Type 1 Diabetes: miR-30d-5p Modulates PD-1 Expression and Regulatory T Cell Expansion.

The partial remission (PR) phase of type 1 diabetes (T1D) is an underexplored period characterized by endogenous insulin production and downmodulated autoimmunity. To comprehend the mechanisms behind this transitory phase and develop precision medicine strategies, biomarker discovery and patient stratification are unmet needs. MicroRNAs (miRNAs) are small RNA molecules that negatively regulate gene expression and modulate several biological processes, functioning as biomarkers for many diseases. Here, we identify and validate a unique miRNA signature during PR in pediatric patients with T1D by employing small RNA sequencing and RT-qPCR. These miRNAs were mainly related to the immune system, metabolism, stress, and apoptosis pathways. The implication in autoimmunity of the most dysregulated miRNA, miR-30d-5p, was evaluated in vivo in the non-obese diabetic mouse. MiR-30d-5p inhibition resulted in increased regulatory T cell percentages in the pancreatic lymph nodes together with a higher expression of CD200. In the spleen, a decrease in PD-1+ T lymphocytes and reduced PDCD1 expression were observed. Moreover, miR-30d-5p inhibition led to an increased islet leukocytic infiltrate and changes in both effector and memory T lymphocytes. In conclusion, the miRNA signature found during PR shows new putative biomarkers and highlights the immunomodulatory role of miR-30d-5p, elucidating the processes driving this phase.

SARS-CoV-2 transmission in teenagers and young adults in Fútbol Club Barcelona's Multidisciplinary Sports Training Academy.

Most studies, aimed at determining the incidence and transmission of SARS-CoV-2 in children and teenagers, have been developed in school settings. Our study conducted surveillance and inferred attack rates focusing on the practice of sports. Prospective and observational study of those attending the sports facilities of Fútbol Club Barcelona (FCB), in Barcelona, Spain, throughout the 2020-2021 season. Participants were young players (from five different sports) and adult workers, who belonged to stable teams (shared routines and were involved in same quarantine rules). Biweekly health questionnaires and SARS-CoV-2 screening were conducted. From the 234 participants included, 70 (30%) both lived and trained in the FCB facilities (Recruitment Pathway 1;RP1) and 164 (70%) lived at their own household and just came to the facilities to train (RP2). During the study, 38 positive cases were identified; none had severe symptoms or needed hospitalization. The overall weekly incidence in the cohorts did not differ compared to the one expected in the community, except for 2 weeks when an outbreak occurred. The attack rate (AR) was three times higher for the participants from RP1, in comparison to those from RP2 (p < 0.01). A Basketball team showed a significant higher AR.  Conclusion: Physical activities in stable teams are not related to an increased risk of transmission of SARS-CoV-2, since there were the same observed cases than expected in the community. The risk is higher in indoor sports (Basketball vs. Football), and in closed cohort living settings (RP1 vs. RP2). The fulfilment of preventive measures is essential. What is Known: • Despite the low numerical impact caused in paediatric hospitalizations during COVID-19 pandemic, the social impact has been maximum. • The transmission potential in children and teenagers is limited, and it had been widely demonstrated in school settings. What is New: • Group physical activities in children and teenagers are not also related to an increased risk of transmission of SARS-CoV-2, when preventive measures, such as washing hands, and screening protocols are applied. • Routine and semi-professional sports activities seem safe environments to promote during this pandemic.

Surveillance of Daughter Micronodule Formation Is a Key Factor for Vaccine Evaluation Using Experimental Infection Models of Tuberculosis in Macaques.

Tuberculosis (TB) is still a major worldwide health problem and models using non-human primates (NHP) provide the most relevant approach for vaccine testing. In this study, we analysed CT images collected from cynomolgus and rhesus macaques following exposure to ultra-low dose Mycobacterium tuberculosis (Mtb) aerosols, and monitored them for 16 weeks to evaluate the impact of prior intradermal or inhaled BCG vaccination on the progression of lung disease. All lesions found (2553) were classified according to their size and we subclassified small micronodules (<4.4 mm) as 'isolated', or as 'daughter', when they were in contact with consolidation (described as lesions ≥ 4.5 mm). Our data link the higher capacity to contain Mtb infection in cynomolgus with the reduced incidence of daughter micronodules, thus avoiding the development of consolidated lesions and their consequent enlargement and evolution to cavitation. In the case of rhesus, intradermal vaccination has a higher capacity to reduce the formation of daughter micronodules. This study supports the 'Bubble Model' defined with the C3HBe/FeJ mice and proposes a new method to evaluate outcomes in experimental models of TB in NHP based on CT images, which would fit a future machine learning approach to evaluate new vaccines.

Unravelling the role of the mandatory use of face covering masks for the control of SARS-CoV-2 in schools: a quasi-experimental study nested in a population-based cohort in Catalonia (Spain).

OBJECTIVE: To assess the effectiveness of mandatory use of face covering masks (FCMs) in schools during the first term of the 2021-2022 academic year. DESIGN: A retrospective population-based study. SETTING: Schools in Catalonia (Spain). POPULATION: 599 314 children aged 3-11 years attending preschool (3-5 years, without FCM mandate) and primary education (6-11 years, with FCM mandate). STUDY PERIOD: From 13 September to 22 December 2021 (before Omicron variant). INTERVENTIONS: A quasi-experimental comparison between children in the last grade of preschool (5 years old), as a control group, and children in year 1 of primary education (6 years old), as an interventional group. MAIN OUTCOME MEASURES: Incidence of SARS-CoV-2, secondary attack rates (SARs) and effective reproductive number (R*). RESULTS: SARS-CoV-2 incidence was significantly lower in preschool than in primary education, and an increasing trend with age was observed. Six-year-old children showed higher incidence than 5 year olds (3.54% vs 3.1%; OR 1.15 (95% CI 1.08 to 1.22)) and slightly lower but not statistically significant SAR (4.36% vs 4.59%; incidence risk ratio 0.96 (95% CI 0.82 to 1.11)) and R* (0.9 vs 0.93; OR 0.96 (95% CI 0.87 to 1.09)). Results remained consistent using a regression discontinuity design and linear regression extrapolation approaches. CONCLUSIONS: We found no significant differences in SARS-CoV-2 transmission due to FCM mandates in Catalonian schools. Instead, age was the most important factor in explaining the transmission risk for children attending school.

A semi-empirical risk panel to monitor epidemics: multi-faceted tool to assist healthcare and public health professionals.

Introduction: Bronchiolitis, mostly caused by Respiratory Syncytial Virus (RSV), and influenza among other respiratory infections, lead to seasonal saturation at healthcare centers in temperate areas. There is no gold standard to characterize the stages of epidemics, nor the risk of respiratory infections growing. We aimed to define a set of indicators to assess the risk level of respiratory viral epidemics, based on both incidence and their short-term dynamics, and considering epidemical thresholds. Methods: We used publicly available data on daily cases of influenza for the whole population and bronchiolitis in children <2 years from the Information System for Infection Surveillance in Catalonia (SIVIC). We included a Moving Epidemic Method (MEM) variation to define epidemic threshold and levels. We pre-processed the data with two different nowcasting approaches and performed a 7-day moving average. Weekly incidences (cases per 105 population) were computed and the 5-day growth rate was defined to create the effective potential growth (EPG) indicator. We performed a correlation analysis to define the forecasting ability of this index. Results: Our adaptation of the MEM method allowed us to define epidemic weekly incidence levels and epidemic thresholds for bronchiolitis and influenza. EPG was able to anticipate daily 7-day cumulative incidence by 4-5 (bronchiolitis) or 6-7 (influenza) days. Discussion: We developed a semi-empirical risk panel incorporating the EPG index, which effectively anticipates surpassing epidemic thresholds for bronchiolitis and influenza. This panel could serve as a robust surveillance tool, applicable to respiratory infectious diseases characterized by seasonal epidemics, easy to handle for individuals lacking a mathematical background.

Low transmission of SARS-CoV-2 derived from children in family clusters: An observational study of family households in the Barcelona Metropolitan Area, Spain.

BACKGROUND: Family clusters offer a good opportunity to study viral transmission in a stable setting. We aimed to analyze the specific role of children in transmission of SARS-CoV-2 within households. METHODS: A prospective, longitudinal, observational study, including children with documented acute SARS-CoV-2 infection attending 22 summer-schools in Barcelona, Spain, was performed. Moreover, other patients and families coming from other school-like environments that voluntarily accessed the study were also studied. A longitudinal follow-up (5 weeks) of the family clusters was conducted to determine whether the children considered to be primary cases were able to transmit the virus to other family members. The household reproduction number (Re*) and the secondary attack rate (SAR) were calculated. RESULTS: 1905 children from the summer schools were screened for SARS-CoV-2 infection and 22 (1.15%) tested positive. Moreover, 32 additional children accessed the study voluntarily. Of these, 37 children and their 26 households were studied completely. In half of the cases (13/26), the primary case was considered to be a child and secondary transmission to other members of the household was observed in 3/13, with a SAR of 14.2% and a Re* of 0.46. Conversely, the SAR of adult primary cases was 72.2% including the kids that gave rise to the contact tracing study, and 61.5% without them, and the estimated Re* was 2.6. In 4/13 of the paediatric primary cases (30.0%), nasopharyngeal PCR was persistently positive > 1 week after diagnosis, and 3/4 of these children infected another family member (p<0.01). CONCLUSIONS: Children may not be the main drivers of the infection in household transmission clusters in the study population. A prolonged positive PCR could be associated with higher transmissibility.