Rapid development of an evidence- and consensus-based guideline for controlling transmission of SARS-CoV-2 in schools during a public health emergency - A process evaluation.

Introduction: Different measures to prevent and control the spread of SARS-CoV-2 have been implemented in German schools. Decisions regarding such measures should be informed by evidence regarding their effectiveness, and their unintended consequences for health and society. A multi-stakeholder panel was convened to develop an evidence- and consensus-based guideline for school measures, using the novel WHO-INTEGRATE framework. Developing a guideline to inform decision-making outside of the clinical realm during a public health emergency was unprecedented in Germany. This study aims to identify lessons learnt for similar endeavours by addressing the following research question: What were the strengths and weaknesses of the guideline development process as perceived by the different groups involved? Methods: Fifteen semi-structured interviews were conducted virtually. We recruited participants aiming to include the perspectives of all groups contributing to the guideline development, including both panel members (scientists, practitioners, school family and observers) and the guideline secretariat. For analysis, we carried out deductive-inductive thematic qualitative text analysis according to Kuckartz, structuring findings using a category system. Results: Due to time pressure, the guideline secretariat was heavily involved not only in synthesising the evidence but also in developing and drafting recommendations. Participants critically reflected on certain methods-related decisions, including the development of draft recommendations and application of the WHO-INTEGRATE framework by scientists only. The full potential of the framework might not have been harnessed. Participants' understanding of relevant and valid evidence varied, and the available evidence base was limited. Participants represented different types of expertise, notably expertise informed by scientific evidence and expertise grounded in lived experience, influencing their involvement in the guideline development process and discussions during meetings. Conclusion: Developing an evidence- and consensus-based public health guideline in only three months was challenging, notably because of the involvement of a broad range of stakeholders and the use of a novel Evidence-to-Decision framework, both unprecedented in Germany. Learning from this process with a view to "institutionalising" the development of public health guidelines and refining methods can contribute to more evidence-informed public health decision-making in Germany and beyond, in general and during a public health emergency.

Public health and social measures during health emergencies such as the COVID‐19 pandemic: An initial framework to conceptualize and classify measures

Background Public health and social measures (PHSM) intend to reduce the transmission of infectious diseases and to reduce the burden on health systems, economies and societies. During the COVID‐19 pandemic, PHSM have been selected, combined and implemented in a variable manner and inconsistently categorized in policy trackers. This paper presents an initial conceptual framework depicting how PHSM operate in a complex system, enabling a wide‐reaching description of these measures and their intended and unintended outcomes. Methods In a multi‐stage development process, we combined (i) a complexity perspective and systems thinking;(ii) literature on existing COVID‐19 PHSM frameworks, taxonomies and policy trackers;(iii) expert input and (iv) application to school and international travel measures. Results The initial framework reflects our current understanding of how PHSM are intended to achieve transmission‐related outcomes in a complex system, offering visualizations, definitions and worked examples. First, PHSM operate through two basic mechanisms, that is, reducing contacts and/or making contacts safer. Second, PHSM are defined not only by the measures themselves but by their stringency and application to specific populations and settings. Third, PHSM are critically influenced by contextual factors. The framework provides a tool for structured thinking and further development, rather than a ready‐to‐use tool for practice. Conclusions This conceptual framework seeks to facilitate coordinated, interdisciplinary research on PHSM effectiveness, impact and implementation;enable consistent, coherent PHSM monitoring and evaluation;and contribute to evidence‐informed decision‐making on PHSM implementation, adaptation and de‐implementation. We expect this framework to be modified and refined over time.

Measuring the Burden of Infodemics: Summary of the Methods and Results of the Fifth WHO Infodemic Management Conference.

Background: An infodemic is excess information, including false or misleading information, that spreads in digital and physical environments during a public health emergency. The COVID-19 pandemic has been accompanied by an unprecedented global infodemic that has led to confusion about the benefits of medical and public health interventions, with substantial impact on risk-taking and health-seeking behaviors, eroding trust in health authorities and compromising the effectiveness of public health responses and policies. Standardized measures are needed to quantify the harmful impacts of the infodemic in a systematic and methodologically robust manner, as well as harmonizing highly divergent approaches currently explored for this purpose. This can serve as a foundation for a systematic, evidence-based approach to monitoring, identifying, and mitigating future infodemic harms in emergency preparedness and prevention. Objective: In this paper, we summarize the Fifth World Health Organization (WHO) Infodemic Management Conference structure, proceedings, outcomes, and proposed actions seeking to identify the interdisciplinary approaches and frameworks needed to enable the measurement of the burden of infodemics. Methods: An iterative human-centered design (HCD) approach and concept mapping were used to facilitate focused discussions and allow for the generation of actionable outcomes and recommendations. The discussions included 86 participants representing diverse scientific disciplines and health authorities from 28 countries across all WHO regions, along with observers from civil society and global public health-implementing partners. A thematic map capturing the concepts matching the key contributing factors to the public health burden of infodemics was used throughout the conference to frame and contextualize discussions. Five key areas for immediate action were identified. Results: The 5 key areas for the development of metrics to assess the burden of infodemics and associated interventions included (1) developing standardized definitions and ensuring the adoption thereof; (2) improving the map of concepts influencing the burden of infodemics; (3) conducting a review of evidence, tools, and data sources; (4) setting up a technical working group; and (5) addressing immediate priorities for postpandemic recovery and resilience building. The summary report consolidated group input toward a common vocabulary with standardized terms, concepts, study designs, measures, and tools to estimate the burden of infodemics and the effectiveness of infodemic management interventions. Conclusions: Standardizing measurement is the basis for documenting the burden of infodemics on health systems and population health during emergencies. Investment is needed into the development of practical, affordable, evidence-based, and systematic methods that are legally and ethically balanced for monitoring infodemics; generating diagnostics, infodemic insights, and recommendations; and developing interventions, action-oriented guidance, policies, support options, mechanisms, and tools for infodemic managers and emergency program managers.

Public health and social measures during health emergencies such as the COVID-19 pandemic: An initial framework to conceptualize and classify measures.

Background: Public health and social measures (PHSM) intend to reduce the transmission of infectious diseases and to reduce the burden on health systems, economies and societies. During the COVID-19 pandemic, PHSM have been selected, combined and implemented in a variable manner and inconsistently categorized in policy trackers. This paper presents an initial conceptual framework depicting how PHSM operate in a complex system, enabling a wide-reaching description of these measures and their intended and unintended outcomes. Methods: In a multi-stage development process, we combined (i) a complexity perspective and systems thinking; (ii) literature on existing COVID-19 PHSM frameworks, taxonomies and policy trackers; (iii) expert input and (iv) application to school and international travel measures. Results: The initial framework reflects our current understanding of how PHSM are intended to achieve transmission-related outcomes in a complex system, offering visualizations, definitions and worked examples. First, PHSM operate through two basic mechanisms, that is, reducing contacts and/or making contacts safer. Second, PHSM are defined not only by the measures themselves but by their stringency and application to specific populations and settings. Third, PHSM are critically influenced by contextual factors. The framework provides a tool for structured thinking and further development, rather than a ready-to-use tool for practice. Conclusions: This conceptual framework seeks to facilitate coordinated, interdisciplinary research on PHSM effectiveness, impact and implementation; enable consistent, coherent PHSM monitoring and evaluation; and contribute to evidence-informed decision-making on PHSM implementation, adaptation and de-implementation. We expect this framework to be modified and refined over time.

[A new understanding of risk communication in public health emergencies]. / Ein neues Verständnis von Risikokommunikation in Public-Health-Notlagen.

Risk communication of public institutions should support the population in the decision-making process in the event of existing risks. It plays a particularly important role in health emergencies such as the SARS-CoV­2 pandemic. After the SARS outbreak in 2003, the World Health Organization (WHO) revised its International Health Regulations (IHR 2005) and called for risk communication to be established as a core area of health policy in all member countries. While the emphasis on health policy was welcomed, the potential for risk communication in this area has not yet been fully exploited. Reasons include discrepancies in the understanding of risk communication and the large number of available methods.This discussion article is intended to help establish a new understanding of risk communication in public health emergencies (emergency risk communication - ERC). It is suggested that, in addition to the risks, the opportunities of the crisis should be included more and that risk communication should be understood more as a continuous process that can be optimized at various points. The "Earlier-Faster-Smoother-Smarter" approach and in particular the earlier detection of health risks ("Earlier") could support the management of public health emergencies in the future.

Measures implemented in the school setting to contain the COVID-19 pandemic

BACKGROUND: In response to the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the impact of coronavirus disease 2019 (COVID-19), governments have implemented a variety of measures to control the spread of the virus and the associated disease. Among these, have been measures to control the pandemic in primary and secondary school settings. OBJECTIVES: To assess the effectiveness of measures implemented in the school setting to safely reopen schools, or keep schools open, or both, during the COVID-19 pandemic, with particular focus on the different types of measures implemented in school settings and the outcomes used to measure their impacts on transmission-related outcomes, healthcare utilisation outcomes, other health outcomes as well as societal, economic, and ecological outcomes.  SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and the Educational Resources Information Center, as well as COVID-19-specific databases, including the Cochrane COVID-19 Study Register and the WHO COVID-19 Global literature on coronavirus disease (indexing preprints) on 9 December 2020. We conducted backward-citation searches with existing reviews. SELECTION CRITERIA: We considered experimental (i.e. randomised controlled trials; RCTs), quasi-experimental, observational and modelling studies assessing the effects of measures implemented in the school setting to safely reopen schools, or keep schools open, or both, during the COVID-19 pandemic. Outcome categories were (i) transmission-related outcomes (e.g. number or proportion of cases); (ii) healthcare utilisation outcomes (e.g. number or proportion of hospitalisations); (iii) other health outcomes (e.g. physical, social and mental health); and (iv) societal, economic and ecological outcomes (e.g. costs, human resources and education). We considered studies that included any population at risk of becoming infected with SARS-CoV-2 and/or developing COVID-19 disease including students, teachers, other school staff, or members of the wider community.  DATA COLLECTION AND ANALYSIS: Two review authors independently screened titles, abstracts and full texts. One review author extracted data and critically appraised each study. One additional review author validated the extracted data. To critically appraise included studies, we used the ROBINS-I tool for quasi-experimental and observational studies, the QUADAS-2 tool for observational screening studies, and a bespoke tool for modelling studies. We synthesised findings narratively. Three review authors made an initial assessment of the certainty of evidence with GRADE, and several review authors discussed and agreed on the ratings. MAIN RESULTS: We included 38 unique studies in the analysis, comprising 33 modelling studies, three observational studies, one quasi-experimental and one experimental study with modelling components. Measures fell into four broad categories: (i) measures reducing the opportunity for contacts; (ii) measures making contacts safer; (iii) surveillance and response measures; and (iv) multicomponent measures. As comparators, we encountered the operation of schools with no measures in place, less intense measures in place, single versus multicomponent measures in place, or closure of schools. Across all intervention categories and all study designs, very low- to low-certainty evidence ratings limit our confidence in the findings. Concerns with the quality of modelling studies related to potentially inappropriate assumptions about the model structure and input parameters, and an inadequate assessment of model uncertainty. Concerns with risk of bias in observational studies related to deviations from intended interventions or missing data. Across all categories, few studies reported on implementation or described how measures were implemented. Where we describe effects as 'positive', the direction of the point estimate of the effect favours the intervention(s); 'negative' effects do not favour the intervention.  We found 23 modelling studies assessing measures reducing the opportunity for contacts (i.e. alternating attendance, reduced class size). Most of these studies assessed transmission and healthcare utilisation outcomes, and all of these studies showed a reduction in transmission (e.g. a reduction in the number or proportion of cases, reproduction number) and healthcare utilisation (i.e. fewer hospitalisations) and mixed or negative effects on societal, economic and ecological outcomes (i.e. fewer number of days spent in school). We identified 11 modelling studies and two observational studies assessing measures making contacts safer (i.e. mask wearing, cleaning, handwashing, ventilation). Five studies assessed the impact of combined measures to make contacts safer. They assessed transmission-related, healthcare utilisation, other health, and societal, economic and ecological outcomes. Most of these studies showed a reduction in transmission, and a reduction in hospitalisations; however, studies showed mixed or negative effects on societal, economic and ecological outcomes (i.e. fewer number of days spent in school). We identified 13 modelling studies and one observational study assessing surveillance and response measures, including testing and isolation, and symptomatic screening and isolation. Twelve studies focused on mass testing and isolation measures, while two looked specifically at symptom-based screening and isolation. Outcomes included transmission, healthcare utilisation, other health, and societal, economic and ecological outcomes. Most of these studies showed effects in favour of the intervention in terms of reductions in transmission and hospitalisations, however some showed mixed or negative effects on societal, economic and ecological outcomes (e.g. fewer number of days spent in school). We found three studies that reported outcomes relating to multicomponent measures, where it was not possible to disaggregate the effects of each individual intervention, including one modelling, one observational and one quasi-experimental study. These studies employed interventions, such as physical distancing, modification of school activities, testing, and exemption of high-risk students, using measures such as hand hygiene and mask wearing. Most of these studies showed a reduction in transmission, however some showed mixed or no effects.   As the majority of studies included in the review were modelling studies, there was a lack of empirical, real-world data, which meant that there were very little data on the actual implementation of interventions. AUTHORS' CONCLUSIONS: Our review suggests that a broad range of measures implemented in the school setting can have positive impacts on the transmission of SARS-CoV-2, and on healthcare utilisation outcomes related to COVID-19. The certainty of the evidence for most intervention-outcome combinations is very low, and the true effects of these measures are likely to be substantially different from those reported here. Measures implemented in the school setting may limit the number or proportion of cases and deaths, and may delay the progression of the pandemic. However, they may also lead to negative unintended consequences, such as fewer days spent in school (beyond those intended by the intervention). Further, most studies assessed the effects of a combination of interventions, which could not be disentangled to estimate their specific effects. Studies assessing measures to reduce contacts and to make contacts safer consistently predicted positive effects on transmission and healthcare utilisation, but may reduce the number of days students spent at school. Studies assessing surveillance and response measures predicted reductions in hospitalisations and school days missed due to infection or quarantine, however, there was mixed evidence on resources needed for surveillance. Evidence on multicomponent measures was mixed, mostly due to comparators. The magnitude of effects depends on multiple factors. New studies published since the original search date might heavily influence the overall conclusions and interpretation of findings for this review.

Measures implemented in the school setting to contain the COVID-19 pandemic: a scoping review.

BACKGROUND: In response to the spread of SARS-CoV-2 and the impact of COVID-19, national and subnational governments implemented a variety of measures in order to control the spread of the virus and the associated disease. While these measures were imposed with the intention of controlling the pandemic, they were also associated with severe psychosocial, societal, and economic implications on a societal level. One setting affected heavily by these measures is the school setting. By mid-April 2020, 192 countries had closed schools, affecting more than 90% of the world's student population. In consideration of the adverse consequences of school closures, many countries around the world reopened their schools in the months after the initial closures. To safely reopen schools and keep them open, governments implemented a broad range of measures. The evidence with regards to these measures, however, is heterogeneous, with a multitude of study designs, populations, settings, interventions and outcomes being assessed. To make sense of this heterogeneity, we conducted a rapid scoping review (8 October to 5 November 2020). This rapid scoping review is intended to serve as a precursor to a systematic review of effectiveness, which will inform guidelines issued by the World Health Organization (WHO). This review is reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) checklist and was registered with the Open Science Framework. OBJECTIVES: To identify and comprehensively map the evidence assessing the impacts of measures implemented in the school setting to reopen schools, or keep schools open, or both, during the SARS-CoV-2/COVID-19 pandemic, with particular focus on the types of measures implemented in different school settings, the outcomes used to measure their impacts and the study types used to assess these. SEARCH METHODS: We searched the Cochrane COVID-19 Study Register, MEDLINE, Embase, the CDC COVID-19 Research Articles Downloadable Database for preprints, and the WHO COVID-19 Global literature on coronavirus disease on 8 October 2020. SELECTION CRITERIA: We included studies that assessed the impact of measures implemented in the school setting. Eligible populations were populations at risk of becoming infected with SARS-CoV-2, or developing COVID-19 disease, or both, and included people both directly and indirectly impacted by interventions, including students, teachers, other school staff, and contacts of these groups, as well as the broader community. We considered all types of empirical studies, which quantitatively assessed impact including epidemiological studies, modelling studies, mixed-methods studies, and diagnostic studies that assessed the impact of relevant interventions beyond diagnostic test accuracy. Broad outcome categories of interest included infectious disease transmission-related outcomes, other harmful or beneficial health-related outcomes, and societal, economic, and ecological implications. DATA COLLECTION AND ANALYSIS: We extracted data from included studies in a standardized manner, and mapped them to categories within our a priori logic model where possible. Where not possible, we inductively developed new categories. In line with standard expectations for scoping reviews, the review provides an overview of the existing evidence regardless of methodological quality or risk of bias, and was not designed to synthesize effectiveness data, assess risk of bias, or characterize strength of evidence (GRADE). MAIN RESULTS: We included 42 studies that assessed measures implemented in the school setting. The majority of studies used mathematical modelling designs (n = 31), while nine studies used observational designs, and two studies used experimental or quasi-experimental designs. Studies conducted in real-world contexts or using real data focused on the WHO European region (EUR; n = 20), the WHO region of the Americas (AMR; n = 13), the West Pacific region (WPR; n = 6), and the WHO Eastern Mediterranean Region (EMR; n = 1). One study conducted a global assessment and one did not report on data from, or that were applicable to, a specific country. Three broad intervention categories emerged from the included studies: organizational measures to reduce transmission of SARS-CoV-2 (n = 36), structural/environmental measures to reduce transmission of SARS-CoV-2 (n = 11), and surveillance and response measures to detect SARS-CoV-2 infections (n = 19). Most studies assessed SARS-CoV-2 transmission-related outcomes (n = 29), while others assessed healthcare utilization (n = 8), other health outcomes (n = 3), and societal, economic, and ecological outcomes (n = 5). Studies assessed both harmful and beneficial outcomes across all outcome categories. AUTHORS' CONCLUSIONS: We identified a heterogeneous and complex evidence base of measures implemented in the school setting. This review is an important first step in understanding the available evidence and will inform the development of rapid reviews on this topic.

[Expert committees in German public health policymaking during the SARS-CoV-2 pandemic: a document analysis]. / Politikberatung durch Expert*innenräte in der SARS-CoV-2-Pandemie in Deutschland: Eine Dokumentenanalyse aus Public-Health-Perspektive.

INTRODUCTION: During the SARS-CoV-2 pandemic, policymakers have to make far-reaching decisions that should be supported by scientific evidence. This presents a major challenge, given the limited availability of evidence, especially in the early phases of the pandemic. Decision-makers thus turned to scientific experts to help to convey and contextualize the evidence for public health policymaking. The way in which these experts were consulted varied widely. Some decision-makers called on expert committees in which they convened multiple experts from different disciplines. However, the composition and role of these committees have raised questions of transparency and representation. This study examines whether and how expert committees in Germany were convened at the federal and national level to advise governments and ministries during the SARS-CoV-2 pandemic. We investigated the disciplinary composition, gender representation and the transparency related to the convening of these bodies, work processes and the accessibility of results. METHODS: We performed a multi-stage document analysis. Between May and July 2020, we submitted freedom-of-information requests to the governmental institutions at both a federal and a national level. In addition to analysing the responses to these requests, we conducted a thorough search and analysis of the i) pandemic preparedness plans, (ii) official press releases and (iii) minor interpellations ("Kleine Anfragen") at the federal and state level. We included documents on expert committees in the SARS-CoV-2 context for the period from January to the beginning of December 2020 and carried out a qualitative content analysis. RESULTS: We identified a total of 21 expert committees that were established in ten federal states and four federal ministries. In eleven committees, the members were known by name, with women making up 26 % of the members. Biomedical disciplines such as virology, hygiene, medicine, and biology were the most commonly represented. Other disciplines including economics, law and sociology, and non-scientific experts were represented in seven federal states. The members of ten committees were not known by name. These committees covered different thematic areas (school and day-care, civil participation, medicine and care, economic topics), and their members were more commonly practitioners or came from affected populations. DISCUSSION: The SARS-CoV-2 pandemic has led to an increased consultation of experts in public health policymaking. However, expert committees in Germany are not sufficiently representative and interdisciplinary to take different perspectives into account and ultimately advise politicians in complex pandemic situations. Furthermore, the work of these committees is not sufficiently transparent because access to information is limited. CONCLUSION: Due to this lack of transparency, it is unclear whether and how the expert committees exerted an influence on politics. Transparency of political decision-making processes and the consideration of pluralistic perspectives are considered essential for the legitimation and quality of political decisions in a pandemic and should therefore be strengthened in pandemic management in Germany.

Travel-related control measures to contain the COVID-19 pandemic: an evidence map.

OBJECTIVES: To comprehensively map the existing evidence assessing the impact of travel-related control measures for containment of the SARS-CoV-2/COVID-19 pandemic. DESIGN: Rapid evidence map. DATA SOURCES: MEDLINE, Embase and Web of Science, and COVID-19 specific databases offered by the US Centers for Disease Control and Prevention and the WHO. ELIGIBILITY CRITERIA: We included studies in human populations susceptible to SARS-CoV-2/COVID-19, SARS-CoV-1/severe acute respiratory syndrome, Middle East respiratory syndrome coronavirus/Middle East respiratory syndrome or influenza. Interventions of interest were travel-related control measures affecting travel across national or subnational borders. Outcomes of interest included infectious disease, screening, other health, economic and social outcomes. We considered all empirical studies that quantitatively evaluate impact available in Armenian, English, French, German, Italian and Russian based on the team's language capacities. DATA EXTRACTION AND SYNTHESIS: We extracted data from included studies in a standardised manner and mapped them to a priori and (one) post hoc defined categories. RESULTS: We included 122 studies assessing travel-related control measures. These studies were undertaken across the globe, most in the Western Pacific region (n=71). A large proportion of studies focused on COVID-19 (n=59), but a number of studies also examined SARS, MERS and influenza. We identified studies on border closures (n=3), entry/exit screening (n=31), travel-related quarantine (n=6), travel bans (n=8) and travel restrictions (n=25). Many addressed a bundle of travel-related control measures (n=49). Most studies assessed infectious disease (n=98) and/or screening-related (n=25) outcomes; we found only limited evidence on economic and social outcomes. Studies applied numerous methods, both inferential and descriptive in nature, ranging from simple observational methods to complex modelling techniques. CONCLUSIONS: We identified a heterogeneous and complex evidence base on travel-related control measures. While this map is not sufficient to assess the effectiveness of different measures, it outlines aspects regarding interventions and outcomes, as well as study methodology and reporting that could inform future research and evidence synthesis.

Adverse effects of non-steroidal anti-inflammatory drugs in patients with viral respiratory infections: rapid systematic review.

OBJECTIVES: To assess the effects of non-steroidal anti-inflammatory drugs (NSAIDs) in patients with viral respiratory infections on acute severe adverse outcomes, healthcare utilisation, quality of life and long-term survival. DESIGN: Rapid systematic review. PARTICIPANTS: Humans with viral respiratory infections, exposed to systemic NSAIDs. PRIMARY OUTCOMES: Acute severe adverse outcomes, healthcare utilisation, quality of life and long-term survival. RESULTS: We screened 10 999 titles and abstracts and 738 full texts, including 87 studies. No studies addressed COVID-19, Severe Acute Respiratory Syndrome or Middle East Respiratory Syndrome; none examined inpatient healthcare utilisation, quality of life or long-term survival. Effects of NSAIDs on mortality and cardiovascular events in adults with viral respiratory infections are unclear (three observational studies; very low certainty). Children with empyema and gastrointestinal bleeding may be more likely to have taken NSAIDs than children without these conditions (two observational studies; very low certainty). In patients aged 3 years and older with acute respiratory infections, ibuprofen is associated with a higher rate of reconsultations with general practitioners than paracetamol (one randomised controlled trial (RCT); low certainty). The difference in death from all causes and hospitalisation for renal failure and anaphylaxis between children with fever receiving ibuprofen versus paracetamol is likely to be less than 1 per 10 000 (1 RCT; moderate/high certainty). Twenty-eight studies in adults and 42 studies in children report adverse event counts. Most report that no severe adverse events occurred. Due to methodological limitations of adverse event counts, this evidence should be interpreted with caution. CONCLUSIONS: It is unclear whether the use of NSAIDs increases the risk of severe adverse outcomes in patients with viral respiratory infections. This absence of evidence should not be interpreted as evidence for the absence of such risk. This is a rapid review with a number of limitations. PROSPERO REGISTRATION NUMBER: CRD42020176056.