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PurposeThe ENFORCE cohort is a national Danish prospective cohort of adults who received a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine as part of the Danish National SARS-CoV-2 vaccination programme. It was designed to investigate the long-term effectiveness, safety and durability of SARS-CoV-2 vaccines used in Denmark.ParticipantsA total of 6943 adults scheduled to receive a SARS-CoV-2 vaccine in the Danish COVID-19 vaccination programme were enrolled in the study prior to their first vaccination. Participants will be followed for a total of 2 years with five predetermined follow-up visits and additional visits in relation to any booster vaccination. Serology measurements are performed after each study visit. T-cell immunity is evaluated at each study visit for a subgroup of 699 participants. Safety information is collected from participants at visits following each vaccination. Data on hospital admissions, diagnoses, deaths and SARS-CoV-2 PCR results are collected from national registries throughout the study period. The median age of participants was 64 years (IQR 53–75), 56.6% were women and 23% were individuals with an increased risk of a serious course of COVID-19. A total of 340 (4.9%) participants tested positive for SARS-CoV-2 spike IgG at baseline.Findings to dateResults have been published on risk factors for humoral hyporesponsiveness and non-durable response to SARS-CoV-2 vaccination, the risk of breakthrough infections at different levels of SARS-CoV-2 spike IgG by viral variant and on the antibody neutralising capacity against different SARS-CoV-2 variants following primary and booster vaccinations.Future plansThe ENFORCE cohort will continuously generate studies investigating immunological response, effectiveness, safety and durability of the SARS-CoV-2 vaccines.Trial registration numberNCT04760132.

Limited data are available on breakthrough COVID-19 in patients with hematologic malignancy (HM) after anti–severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. Adult patients with HM, ≥1 dose of anti-SARS-CoV-2 vaccine, and breakthrough COVID-19 between January 2021 and March 2022 were analyzed. A total of 1548 cases were included, mainly lymphoid malignancies (1181 cases, 76%). After viral sequencing in 753 cases (49%), the Omicron variant was prevalent (517, 68.7%). Most of the patients received ≤2 vaccine doses before COVID-19 (1419, 91%), mostly mRNA-based (1377, 89%). Overall, 906 patients (59%) received COVID-19-specific treatment. After 30-day follow-up from COVID-19 diagnosis, 143 patients (9%) died. The mortality rate in patients with the Omicron variant was 7.9%, comparable to other variants, with a significantly lower 30-day mortality rate than in the prevaccine era (31%). In the univariable analysis, older age (P < .001), active HM (P < .001), and severe and critical COVID-19 (P = .007 and P < .001, respectively) were associated with mortality. Conversely, patients receiving monoclonal antibodies, even for severe or critical COVID-19, had a lower mortality rate (P < .001). In the multivariable model, older age, active disease, critical COVID-19, and 2-3 comorbidities were correlated with a higher mortality, whereas monoclonal antibody administration, alone (P < .001) or combined with antivirals (P = .009), was protective. Although mortality is significantly lower than in the prevaccination era, breakthrough COVID-19 in HM is still associated with considerable mortality. Death rate was lower in patients who received monoclonal antibodies, alone or in combination with antivirals. EPICOVIDEHA has received funds from Optics COMMIT (COVID-19 Unmet Medical Needs and Associated Research Extension) COVID-19 RFP program by GILEAD Science, United States (Project 2020-8223).

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with persistent symptoms (“long COVID”). We assessed the burden of long COVID among nonhospitalized adults with polymerase chain reaction (PCR)–confirmed SARS-CoV-2 infection.MethodsIn the fall of 2020, a cross-sectional survey was performed in the adult Danish general population. This included a self-administered point-of-care test for SARS-CoV-2 antibodies, the Short Form Health Survey (SF-12), and coronavirus disease 2019 (COVID-19)–associated symptom questions. Nonhospitalized respondents with a positive SARS-CoV-2 PCR test ≥12 weeks before the survey (cases) were matched (1:10) to seronegative controls on age, sex, and body mass index. Propensity score–weighted odds ratios (ORs) and ORs for risk factors were estimated for each health outcome.ResultsIn total, 742 cases and 7420 controls were included. The attributable risk of at least 1 long-COVID symptom was 25.0 per 100 cases (95% confidence interval [CI], 22.2–27.4). Compared to controls, cases reported worse general health (OR, 5.9 [95% CI, 5.0–7.0]) and had higher odds for a broad range of symptoms, particularly loss of taste (OR, 11.8 [95% CI, 9.5–14.6]) and smell (OR, 11.2 [95% CI, 9.1–13.9]). Physical and Mental Component Summary scores were also significantly reduced with differences of −2.5 (95% CI, −3.1 to −1.8) and −2.0 (95% CI, −2.7 to −1.2), respectively. Female sex and severity of initial infection were major risk factors for long COVID.ConclusionsNonhospitalized SARS-CoV-2 PCR–positive individuals had significantly reduced physical and mental health, and 1 in 4 reported persistence of at least 1 long-COVID symptom Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with persistent symptoms ("long COVID"). We assessed the burden of long COVID among nonhospitalized adults with polymerase chain reaction (PCR)-confirmed SARS-CoV-2 infection. Methods In the fall of 2020, a cross-sectional survey was performed in the adult Danish general population. This included a self-administered point-of-care test for SARS-CoV-2 antibodies, the Short Form Health Survey (SF-12), and coronavirus disease 2019 (COVID-19)-associated symptom questions. Nonhospitalized respondents with a positive SARS-CoV-2 PCR test >= 12 weeks before the survey (cases) were matched (1:10) to seronegative controls on age, sex, and body mass index. Propensity score-weighted odds ratios (ORs) and ORs for risk factors were estimated for each health outcome. Results In total, 742 cases and 7420 controls were included. The attributable risk of at least 1 long-COVID symptom was 25.0 per 100 cases (95% confidence interval [CI], 22.2-27.4). Compared to controls, cases reported worse general health (OR, 5.9 [95% CI, 5.0-7.0]) and had higher odds for a broad range of symptoms, particularly loss of taste (OR, 11.8 [95% CI, 9.5-14.6]) and smell (OR, 11.2 [95% CI, 9.1-13.9]). Physical and Mental Component Summary scores were also significantly reduced with differences of -2.5 (95% CI, -3.1 to -1.8) and -2.0 (95% CI, -2.7 to -1.2), respectively. Female sex and severity of initial infection were major risk factors for long COVID. Conclusions Nonhospitalized SARS-CoV-2 PCR-positive individuals had significantly reduced physical and mental health, and 1 in 4 reported persistence of at least 1 long-COVID symptom.In this national cross-sectional survey, long-COVID symptoms after SARS-CoV-2 infection are common compared to seronegative controls, affecting both physical and mental health. Female sex and severity of infection are dominant risk factors. Informed interdisciplinary management strategies for long COVID are needed.

The oral protease inhibitor nirmatrelvir is of key importance for prevention of severe coronavirus disease 2019 (COVID-19). To facilitate resistance monitoring, we studied severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) escape from nirmatrelvir in cell culture. Resistant variants harbored combinations of substitutions in the SARS-CoV-2 main protease (Mpro). Reverse genetics revealed that E166V and L50F + E166V conferred high resistance in infectious culture, replicon, and Mpro systems. While L50F, E166V, and L50F + E166V decreased replication and Mpro activity, L50F and L50F + E166V variants had high fitness in the infectious system. Naturally occurring L50F compensated for fitness cost of E166V and promoted viral escape. Molecular dynamics simulations revealed that E166V and L50F + E166V weakened nirmatrelvir-Mpro binding. Polymerase inhibitor remdesivir and monoclonal antibody bebtelovimab retained activity against nirmatrelvir-resistant variants, and combination with nirmatrelvir enhanced treatment efficacy compared to individual compounds. These findings have implications for monitoring and ensuring treatments with efficacy against SARS-CoV-2 and emerging sarbecoviruses.

Porcine epidemic diarrhea virus (PEDV), belonging to the genus Alphacoronavirus, can cause serious disease in pigs of all ages, especially in suckling pigs. Differences in virulence have been observed between various strains of this virus. In this study, four pigs were inoculated with PEDV from Germany (intestine/intestinal content collected from pigs in 2016) and four pigs with PEDV from Italy (intestine/intestinal material collected from pigs in 2016). The pigs were re-inoculated with the same virus on multiple occasions to create a more robust infection and enhance the antibody responses. The clinical signs and pathological changes observed were generally mild. Two distinct peaks of virus excretion were seen in the group of pigs inoculated with the PEDV from Germany, while only one strong peak was seen for the group of pigs that received the virus from Italy. Seroconversion was seen by days 18 and 10 post-inoculation with PEDV in all surviving pigs from the groups that received the inoculums from Germany and Italy, respectively. Attempts to infect pigs with a swine enteric coronavirus (SeCoV) from Slovakia were unsuccessful, and no signs of infection were observed in the inoculated animals.

This article's main contributions are twofold: 1) to demonstrate how to apply the general European Union's High-Level Expert Group's (EU HLEG) guidelines for trustworthy AI in practice for the domain of healthcare and 2) to investigate the research question of what does "trustworthy AI" mean at the time of the COVID-19 pandemic. To this end, we present the results of a post-hoc self-assessment to evaluate the trustworthiness of an AI system for predicting a multiregional score conveying the degree of lung compromise in COVID-19 patients, developed and verified by an interdisciplinary team with members from academia, public hospitals, and industry in time of pandemic. The AI system aims to help radiologists to estimate and communicate the severity of damage in a patient's lung from Chest X-rays. It has been experimentally deployed in the radiology department of the ASST Spedali Civili clinic in Brescia, Italy, since December 2020 during pandemic time. The methodology we have applied for our post-hoc assessment, called Z-Inspection®, uses sociotechnical scenarios to identify ethical, technical, and domain-specific issues in the use of the AI system in the context of the pandemic.

Changes in lifestyle, finances and work status during COVID-19 lockdownsmay have led to biopsychosocial changes in people with pre-existing vulnerabilities such as MajorDepressive Disorders (MDDs) and Multiple Sclerosis (MS). Methods: Data were collected as a part the RADAR-CNS (Remote Assessment of Disease and Relapse-Central Nervous System) program.We analyzed the following data from long-term participants in a decentralized multinational study:J. Clin. Med. 2022, 11, 7163. https://doi.org/10.3390/jcm11237163 https://www.mdpi.com/journal/jcm J. Clin. Med. 2022, 11, 7163 2 of 20 symptoms of depression, heart rate (HR) during the day and night; social activity; sedentary state,steps and physical activity of varying intensity. Linear mixed-effects regression analyses with repeated measures were fitted to assess the changes among three time periods (pre, during and post-lockdown) across the groups, adjusting for depression severity before the pandemic and gender. Results: Participants with MDDs (N = 255) and MS (N = 214) were included in the analyses. Overall,depressive symptoms remained stable across the three periods in both groups. A lower mean HR and HR variation were observed between pre and during lockdown during the day for MDDs and during the night for MS. HR variation during rest periods also decreased between pre- and post-lockdown in both clinical conditions. We observed a reduction in physical activity for MDDs and MS upon the introduction of lockdowns. The group with MDDs exhibited a net increase in social interaction via social network apps over the three periods. Conclusions: Behavioral responses to the lockdown measured by social activity, physical activity and HR may reflect changes in stress in people with MDDs and MS. Remote technology monitoring might promptly activate an early warning of physical and social alterations in these stressful situations. Future studies must explore how stress does or does not impact depression severity

IntroductionThe COVID-19 pandemic caused by the virus SARS-CoV has spread rapidly and caused damage worldwide. Data suggest a major overrepresentation of hypertension and diabetes among patients experiencing severe courses of COVID-19 including COVID-19-related deaths. Many of these patients receive renin-angiotensin system (RAS) inhibiting therapy, and evidence suggests that treatment with angiotensin II receptor blockers (ARBs) could attenuate SARS-CoV-induced acute respiratory distress syndrome, and ACE inhibitors and ARBs have been suggested to alleviate COVID-19 pulmonary manifestations. This randomised clinical trial will address whether RAS inhibiting therapy should be continued or discontinued in hospitalised patients with COVID-19.Methods and analysisThis trial is a 30-day randomised parallel-group non-inferiority clinical trial with an embedded mechanistic substudy. In the main trial, 215 patients treated with a RAS inhibitor will be included. The participants will be randomly assigned in a 1:1 ratio to either discontinue or continue their RAS inhibiting therapy in addition to standard care. The patients are included during hospitalisation and followed for a period of 30 days. The primary end point is number of days alive and out of hospital within 14 days after recruitment. In a mechanistic substudy, 40 patients treated with RAS inhibition, who are not in hospital and not infected with COVID-19 will be randomly assigned to discontinue or continue their RAS inhibiting therapy with the primary end point of serum ACE2 activity.Ethics and disseminationThis trial has been approved by the Scientific-Ethical Committee of the Capital Region of Denmark (identification no. H-20026484), the Danish Medicines Agency (identification no. 2020040883) and by the Danish Data Protection Agency (P-2020-366). The results of this project will be compiled into one or more manuscripts for publication in international peer-reviewed scientific journals.Trial registration number2020-001544-26;NCT04351581.

Abstract Introduction Significant mortality amongst vulnerable populations, such as people living with dementia, might go undetected during pandemic conditions due to refocus of care efforts. There is an urgent need to fully evaluate the pandemic impact on mortality amongst people living with dementia in order to facilitate future healthcare reforms and prevent deaths. The purpose of this study was to determine whether there was any significant difference in mortality amongst people with dementia without COVID-19 during the COVID-19 pandemic compared to previous years. Methods A literature search was conducted in 5 databases. The relative risk ratio and confidence interval was used to estimate the change in mortality rates amongst people with dementia during the COVID-19 pandemic. The I2 value was used to assess heterogeneity, publication bias, and sensitivity analyses were performed. Results Pooled analysis of 11 studies showed that mortality amongst people living with dementia was significantly increased during the COVID-19 pandemic for people with dementia without COVID-19. Mortality risk increased by 25% during the time period studied. Subgroup analysis was not performed due the low number of included studies. Conclusions The results of this study suggest that people with dementia had a significant increased mortality during the pandemic even if they did not have COVID-19. People with dementia should participate in efforts that reduce general social spread and pandemic impact on healthcare system such as vaccinations, mask mandates, and testing. These results have clinical implications as preventing direct COVID-19 infection is not enough to adequately protect people living with dementia from increased mortality. Measures to limit social spread of infections and help support patients should also be a focus for clinicians. Further research should focus on the identification of mechanisms and other explanations for increased mortality as well as contributing factors such as living in care homes and differences between countries with various pandemic strategies.

The ongoing COVID-19 pandemic has exposed the fragility of current food systems to feed populations around the world. Particularly in urban centers, consumers have been confronted with this vulnerability, highlighting reliance on just-in-time logistics, imports and distant primary production. Urban food demand, regional food supply, land use change, and transport strategies are considered key factors for reestablishing resilient landscapes as part of a sustainable food system. Improving the sustainability of food systems in such circumstances entails working on the interrelations between food supply and demand, rural and urban food commodity production sites, and groups of involved actors and consumers. Of special significance is the agricultural land in close proximity to urban centers. Calling for more holistic approaches in the sense of inclusiveness, food security, citizen involvement and ecological principles, this article describes the use of a new decision support tool, the Metropolitan Foodscape Planner (MFP). The MFP features up-to-date European datasets to assess the potential of current agricultural land use to provide food resources (with special attention to both plant- and animal-based products) and meet the demand of city dwellers, and help to empower citizens, innovators, companies, public authorities and other stakeholders of regional food systems to build a more regionalized food supply network. The tool was tested in the context of the food system of the Copenhagen City Region in two collaborative workshops, namely one workshop with stakeholders of the Copenhagen City Region representing food consultancies, local planning authorities and researchers, and one in-person workshop masterclass with MSc students from the University of Copenhagen. Workshop participants used the tool to learn about the impacts of the current food system at the regional and international level with regard to the demand-supply paradigm of city-regions. The ultimate goal was to develop a participatory mapping exercise and test three food system scenarios for a more regionalized and sustainable food system and, therefore, with increased resilience to crises. Results from this implementation also demonstrated the potential of the tool to identify food production sites at local level that are potentially able to feed the city region in a more sustainable, nutritious and way.