Enzymatic glycosylation of aloesone performed by plant UDP-dependent glycosyltransferases.

Aloesone is a bioactive natural product and biosynthetic precursor of rare glucosides found in rhubarb and some aloe plants including Aloe vera. This study aimed to investigate biocatalytic aloesone glycosylation and more than 400 uridine diphosphate-dependent glycosyltransferase (UGT) candidates, including multifunctional and promiscuous enzymes from a variety of plant species were assayed. As a result, 137 selective aloesone UGTs were discovered, including four from the natural producer rhubarb. Rhubarb UGT72B49 was further studied and its catalytic constants (kcat = 0.00092 ± 0.00003 s-1, KM = 30 ± 2.5 µM) as well as temperature and pH optima (50 °C and pH 7, respectively) were determined. We further aimed to find an efficient aloesone glycosylating enzyme with potential application for biocatalytic production of the glucoside. We discovered UGT71C1 from Arabidopsis thaliana as an efficient aloesone UGT showing a 167-fold higher catalytic efficiency compared to that of UGT72B49. Interestingly, sequence analysis of all the 137 newly identified aloesone UGTs showed that they belong to different phylogenetic groups, with the highest representation in groups B, D, E, F and L. Finally, our study indicates that aloesone C-glycosylation is highly specific and rare, since it was not possible to achieve in an efficient manner with any of the 422 UGTs assayed, including multifunctional GTs and 28 known C-UGTs.

An SMS chatbot digital educational program to increase healthy eating behaviors in adolescence: A multifactorial randomized controlled trial among 7,890 participants in the Danish National Birth Cohort.

BACKGROUND: Few cost-effective strategies to shift dietary habits of populations in a healthier direction have been identified. We examined if participating in a chatbot health education program transmitted by Short Messages Service ("SMS-program") could improve adolescent dietary behaviors and body weight trajectories. We also explored possible added effects of maternal or peer involvement. METHODS AND FINDINGS: We conducted a randomized controlled trial (RCT) among adolescents from the Danish National Birth Cohort (DNBC). Eligible were adolescents who during 2015 to 2016 at age 14 years had completed a questionnaire assessing height, weight, and dietary habits. Two thirds were offered participation in an SMS-program, whereas 1/3 ("non-SMS group") received no offer. The SMS program aimed to improve 3 key dietary intake behaviors: sugar-sweetened beverages (SSBs), fruit and vegetables (FV), and fish. The offered programs had 3 factorially randomized schemes; the aims of these were to test effect of asking the mother or a friend to also participate in the health promotion program, and to test the effect of a 4-week individually tailored SMS program against the full 12-week SMS program targeting all 3 dietary factors. Height and weight and intakes of SSB, FV, and fish were assessed twice by a smartphone-based abbreviated dietary questionnaire completed at 6 months (m) and 18 m follow-up. Main outcome measures were (1) body mass index (BMI) z-score; and (2) an abbreviated Healthy Eating Index (mini-HEI, 1 m window, as mean of z-scores for SSB, FV, and fish). Among the 7,890 randomized adolescents, 5,260 were assigned to any SMS program; 63% (3,338) joined the offered program. Among the 7,890 randomized, 74% (5,853) and 68% (5,370) responded to follow-ups at 6 m and 18 m, respectively. Effects were estimated by intention-to-treat (ITT) analyses and inverse probability weighted per-protocol (IPW-PP) analyses excluding adolescents who did not join the program. Mean (standard deviation (SD)) mini-HEI at baseline, 6 m and 18 m was -0.01 (0.64), 0.01 (0.59), and -0.01 (0.59), respectively. In ITT-analyses, no effects were observed, at any time point, in those who had received any SMS program compared to the non-SMS group, on BMI z-score (6 m: -0.010 [95% confidence interval (CI) -0.035, 0.015]; p = 0.442, 18 m: 0.002 [95% CI -0.029, 0.033]; p = 0.901) or mini-HEI (6 m: 0.016 [95% CI -0.011, 0.043]; p = 0.253, 18m: -0.016 [95% CI -0.045, 0.013]; p = 0.286). In IPW-PP analyses, at 6 m, a small decrease in BMI z-score (-0.030 [95% CI -0.057, -0.003]; p = 0.032) was observed, whereas no significant effect was observed in mini-HEI (0.027 [95% CI -0.002, 0.056]; p = 0.072), among those who had received any SMS program compared to the non-SMS group. At 18 m, no associations were observed (BMI z-score: -0.006 [95% CI -0.039, 0.027]; p = 0.724, and mini-HEI: -0.005 [95% CI -0.036, 0.026]; p = 0.755). The main limitations of the study were that DNBC participants, though derived from the general population, tend to have higher socioeconomic status than average, and that outcome measures were self-reported. CONCLUSIONS: In this study, a chatbot health education program delivered through an SMS program had no effect on dietary habits or weight trajectories in ITT analyses. However, IPW-PP-analyses, based on those 63% who had joined the offered SMS program, suggested modest improvements in weight development at 6 m, which had faded at 18 m. Future research should focus on developing gender-specific messaging programs including "booster" messages to obtain sustained engagement. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02809196 https://clinicaltrials.gov/study/NCT02809196.

A register and questionnaire study of long-term general health symptoms following SARS-CoV-2 vaccination in Denmark.

Many individuals who refuse COVID-19 vaccination have concerns about long-term side effects. Here, we report findings on self-reported symptoms from a Danish survey- and register study. The study included 34,868 vaccinated primary course recipients, 95.8% of whom received mRNA vaccines, and 1,568 unvaccinated individuals. Participants had no known history of SARS-CoV-2 infection. Using g-computation on logistic regression, risk differences (RDs) for symptoms between vaccinated and unvaccinated persons were estimated with adjustments for possible confounders. Within six weeks after vaccination, higher risks were observed for physical exhaustion (RD 4.9%, 95% CI 1.1% to 8.4%), fever or chills (RD 4.4%, 95% CI 2.1% to 6.7%), and muscle/joint pain (RD 7.0%, 95% CI 3.1% to 10.7%), compared to unvaccinated individuals. Beyond twenty-six weeks, risks were higher among the vaccinated for sleeping problems (RD 3.0, 95% 0.2 to 5.8), fever or chills (RD 2.0, 95% CI 0.4 to 3.6), reduced/altered taste (RD 1.2, 95% CI 0.2 to 2.3) and shortness of breath (RD 2.6, 95% CI 0.9 to 4.0). However, when examining pre-omicron responses only, the difference for reduced/altered taste was significant. As expected, the risk of experiencing physical exhaustion, fever or chills, and muscle/joint pain was higher among persons who responded within six weeks of completing the primary course. No significant differences were observed for the 7-25-week period after vaccination. Associations for the period beyond 26 weeks must be interpreted with caution and in the context of undetected SARS-CoV-2 infection, wide confidence intervals, and multiple testing. Overall, we observe no concerning signs of long-term self-reported physical, cognitive, or fatigue symptoms after vaccination.

SARS-CoV-2 Infection and Risk of Postacute Psychiatric and Neurologic Diagnoses: A Nationwide Danish Cohort Study.

BACKGROUND AND OBJECTIVES: The extent and burden of postacute psychiatric and neurologic manifestations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are not yet fully understood. To evaluate the association between SARS-CoV-2 infection and postacute manifestations of psychiatric and neurologic disorders, we conducted a nationwide cohort study including the entire Danish population aged 12 years or older on March 1, 2020. METHODS: Individuals were followed up for SARS-CoV-2 infection and diagnosis of subsequent psychiatric and neurologic disorders from March 1, 2020, to January 31, 2023, using the Danish nationwide coronavirus disease 2019 (COVID-19) test surveillance database and the Danish National Patient Registry. The main period of interest was 1-12 months after infection. Incidence rate ratios (IRRs) of new onset of 11 psychiatric and 30 neurologic disorders were calculated by comparing incidence rates of disorders between SARS-CoV-2-positive individuals and individuals without a positive test (nonpositive individuals). Stratified analyses were conducted according to COVID-19 vaccination status, variant period, age, sex, and severity of infection. RESULTS: Overall, 1,775,639 individuals in the study cohort (n = 3,239,008) were tested SARS-CoV-2 positive during follow-up. SARS-CoV-2-positive individuals compared with nonpositive individuals were at 24% reduced risk of any psychiatric disease (IRR 0.76, 95% CI 0.74-0.78) in the postacute period. The risk of any neurologic disorder was slightly higher among SARS-CoV-2-positive individuals than among those without a positive test (IRR 1.05, 95% CI 1.04-1.07). IRRs for specific disorders varied considerably from a 3.9-fold increased risk of change in sense of smell or taste (IRR 3.91, 95% CI 2.77-5.53) to a 29% reduced risk of dementia (IRR 0.71, 95% CI 0.65-0.78). The severity of infection and vaccination status, more so than age, sex, and variant, were found to significantly influence the stratified IRRs. Compared with nonpositive individuals, hospitalized patients with COVID-19 were at a 2.1-fold (IRR 2.05, 95% CI 1.78-2.37) increased risk of psychiatric disorders and at a 2.4-fold increased risk of neurologic disorders (IRR 2.44, 95% CI 2.29-2.60). DISCUSSION: Our study does not support previous findings of substantial postacute neurologic and psychiatric morbidities among the general population of SARS-CoV-2-infected individuals, but does corroborate an elevated risk among the most severe cases with COVID-19.

Booster vaccination with SARS-CoV-2 mRNA vaccines and myocarditis in adolescents and young adults: a Nordic cohort study.

BACKGROUND AND AIMS: The SARS-CoV-2 mRNA vaccines are associated with an increased risk of myocarditis. This association appears to be strongest in male adolescents and younger males and after the second dose. The aim was to evaluate the risk of myocarditis following SARS-CoV-2 mRNA booster vaccination in 12-to-39-year-olds. METHODS: A multinational cohort study was conducted using nationwide register data in Denmark, Finland, Norway, and Sweden and comprising all 8.9 million individuals residing in each of the four countries. Participants were followed for an inpatient diagnosis of myocarditis. In each of the four countries, Poisson regression was used to estimate adjusted incidence rate ratios (IRRs) of myocarditis comparing vaccination schedules, with associated 95% confidence intervals (CIs). Country-specific results were combined in meta-analyses. RESULTS: A total of 8.9 million residents were followed for 12 271 861 person-years and 1533 cases of myocarditis were identified. In 12-to-39-year-old males, the 28-day acute risk period following the third dose of BNT162b2 or mRNA-1273 was associated with an increased incidence rate of myocarditis compared to the post-acute risk period 28 days or more after the second dose [IRR 2.08 (95% CI 1.31-3.33) and 8.89 (2.26-35.03), respectively]. For females, the corresponding IRR was only estimable for BNT162b2, 3.99 (0.41-38.64). The corresponding absolute risks following the third dose of BNT162b2 and mRNA-1273 in males were 0.86 (95% CI 0.53-1.32) and 1.95 (0.53-4.99) myocarditis events within 28 days per 100 000 individuals vaccinated, respectively. In females, the corresponding absolute risks following the third dose of BNT162b2 were 0.15 (0.04-0.39) events per 100 000 individuals vaccinated. No deaths occurred within 30 days of vaccine-related cases. CONCLUSIONS: The results suggest that a booster dose is associated with increased myocarditis risk in adolescents and young adults. However, the absolute risk of myocarditis following booster vaccination is low.

Environmental drivers of Arctic communities based on metabarcoding of marine sediment eDNA.

Our ability to assess biodiversity at relevant spatial and temporal scales for informing management is of increasing importance given this is foundational to identify and mitigate the impacts of global change. Collecting baseline information and tracking ecological changes are particularly important for areas experiencing rapid changes and representing data gaps such as Arctic marine ecosystems. Environmental DNA has the potential to provide such data. We extracted environmental DNA from 90 surface sediment samples to assess eukaryote diversity around Greenland and Svalbard using two separate primer pairs amplifying different sections of the 18S rRNA gene. We detected 27 different phyla and 99 different orders and found that temperature and the change in temperature explained the most variation in the community in a single linear model, while latitude, sea ice cover and change in temperature explained the most variation in the community when assessed by individual non-linear models. We identified potential indicator taxa for Arctic climate change, including a terebellid annelid worm. In conclusion, our study demonstrates that environmental DNA offers a feasible method to assess biodiversity and identifies warming as a key driver of differences in biodiversity across these remote ecosystems.

SARS-CoV-2 Infection and Postacute Risk of Non-Coronavirus Disease 2019 Infectious Disease Hospitalizations: A Nationwide Cohort Study of Danish Adults Aged ≥50 Years.

BACKGROUND: Reports suggest that the potential long-lasting health consequences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may involve persistent dysregulation of some immune populations, but the potential clinical implications are unknown. We investigated the associated risk of hospitalization due to non-coronavirus disease 2019 (COVID-19) infectious diseases following the postacute phase of SARS-CoV-2 infection. METHODS: By cross-linking data from the comprehensive Danish test and surveillance system for COVID-19 together with nationwide healthcare and demographic registers, we established a study cohort of 2 430 694 individuals aged ≥50 years, from 1 January 2021 to 10 December 2022, with no evidence of SARS-CoV-2 infection prior to study entry. Using Poisson regression, we compared the outcome rates of non-COVID-19 infectious disease hospitalizations following the acute phase of (a first) SARS-CoV-2 infection (defined as ≥29 days since the day of infection) in recovered individuals with rates among SARS-CoV-2-uninfected individuals. RESULTS: Among 2 430 694 included individuals (mean age, 66.8 [standard deviation, 11.3] years), 930 071 acquired SARS-CoV-2 infection during follow-up totaling 4 519 913 person-years. The postacute phase of SARS-CoV-2 infection was associated with an incidence rate ratio (IRR) of 0.90 (95% confidence interval [CI]: .88-.92) for any infectious disease hospitalization. Findings (IRR [95% CI]) were similar for upper respiratory tract (1.08 [.97-1.20]), lower respiratory tract (0.90 [.87-.93]), influenza (1.04 [.94-1.15]), gastrointestinal (1.28 [.78-2.09]), skin (0.98 [.93-1.03]), urinary tract (1.01 [.96-1.08]), certain invasive bacterial (0.96 [.91-1.01]), and other (0.96 [.92-1.00]) infectious disease hospitalizations and in subgroups. CONCLUSIONS: Our study does not support an increased susceptibility to non-COVID-19 infectious disease hospitalization following SARS-CoV-2 infection.

A Danish questionnaire study of acute symptoms of SARS-CoV-2 infection by variant, vaccination status, sex and age.

It is not well-described how the acute symptoms of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) differ by variant, vaccination, sex and age. A cross-sectional questionnaire study linked to national testing- and registry data was conducted among 148,874 SARS-CoV-2 first time reverse transcription polymerase chain reaction (RT-PCR) test-positive individuals and corresponding date-matched symptomatic test-negative controls. Major SARS-CoV-2 variants (Index/wild type, Alpha, Delta and Omicron) were defined using periods of predominance. Risk differences (RDs) were estimated for each of 21 predefined acute symptoms comparing: (1) test-positive and -negative individuals, by variant period, (2) vaccinated and unvaccinated test-positives, by variant period, (3) individuals tested positive during the Omicron and Delta periods, by vaccination status, and (4) vaccinated Omicron test-positive and -negative individuals, by age and sex. Compared to pre-Omicron, RDs between test-positive and test-negative individuals during the Omicron period were lower for most symptoms. RDs for altered sense of smell (dysosmia) and taste (dysgeusia) were highest for Delta (RD = 50.8 (49.4-52.0) and RD = 54.7 (53.4-56.0), respectively) and lowest for Omicron (RD = 12.8 (12.1-13.5) and RD = 11.8 (11.1-12.4), respectively). Across variants, vaccinated individuals reported fewer symptoms. During Omicron, females and 30-59 year-old participants reported more symptoms.

Post-acute symptoms 4 months after SARS-CoV-2 infection during the Omicron period: a nationwide Danish questionnaire study.

Post-acute symptoms are not uncommon after SARS-CoV-2 infection with pre-Omicron variants. How Omicron and COVID-19 booster vaccination influence the risk of post-acute symptoms is less clear. We analyzed data from the nationwide Danish questionnaire study EFTER-COVID comprising 44,553 individuals ≥15 years old, tested between July 2021 and January 2022, in order to evaluate the association of the Omicron variant and COVID-19 booster vaccination with post-acute symptoms and new-onset general health problems, four months after infection with SARS-CoV-2. Risk differences (RDs) were estimated by comparing Omicron -cases to controls, Omicron to Delta -cases, and Omicron vaccinated cases with three to -two doses, adjusted for age, sex, BMI, self-reported chronic diseases, Charlson comorbidity index, healthcare occupation, and vaccination status. Four months after testing for SARS-CoV-2 during the Omicron period, cases experienced substantial post-acute symptoms and new-onset health problems compared to controls; the largest RD was observed for memory issues (RD=7.2%, 95%CI: 6.4 to 8.1). However, risks were generally lower than in the Delta period, particularly for dysosmia (RD=-15.0%, 95%CI: -17.0 to -13.2) and dysgeusia (RD=-11.2%, 95%CI: -13.2 to -9.5). Booster vaccination was associated with fewer post-acute symptoms and new-onset health problems, four months after Omicron infection, compared to two COVID-19 vaccine doses.

A hybrid register and questionnaire study of Covid-19 and post-acute sick leave in Denmark.

Post-acute sick leave is an underexplored indicator of the societal burden of SARS-CoV-2. Here,  we report findings about self-reported sick leave and risk factors thereof from a hybrid survey and register study, which include 37,482 RT-PCR confirmed SARS-CoV-2 cases and 51,336 test-negative controls who were tested during the index- and alpha-dominant waves. We observe that an additional 33 individuals per 1000 took substantial sick leave following acute infection compared to persons with no known history of infection, where substantial sick leave is defined as >1 month of sick leave within the period 1-9 months after the RT-PCR test date. Being female, 50-65 years, or having certain pre-existing health conditions such as obesity, chronic lung diseases, and fibromyalgia each increase risk for taking substantial sick leave. Altogether, these results may help motivate improved diagnostic and treatment options for persons living with post-Covid conditions.

Effect of Biokos, a natural lipopeptide surfactant extracted from a bacterium of the Pseudomonas genus, on infection of Cryptocaryon irritans.

Cryptocaryoniasis (marine white spot disease), caused by Cryptocaryon irritans, is a major threat to marine fish cultures in tropical and subtropical waters, and a serious nuisance to hobbyists with saltwater fish tanks. With only classical treatment schedules such as copper salts or hyposaline baths being available, control of the disease remains a challenge. In this study, we investigated the effect of Biokos, a viscosin-like lipopeptide surfactant extracted from a bacterium of the Pseudomonas genus, on the external life stages of C. irritans, including theronts, protomonts and tomonts. The present study demonstrated that the compound has an antiparasitic effect on all tested external stages of the parasite. In particular, when Biokos was used at 48 mg/L, it was able to kill almost all theronts and protomonts within 1 h in in vitro experiments, and using the same concentration in an in vivo challenge experiment, the parasitic load was reduced by more than 95% compared to the control group with no Biokos. Additionally, cultured fish cells were able to proliferate, and fish showed no adverse signs at Biokos concentrations that were effective in killing the parasite. Thus, Biokos may be a promising way for preventing or reducing the burden of this parasitic disease in the future.

Prevalent fingerprint of marine macroalgae in arctic surface sediments.

Macroalgal forests export much of their production, partly supporting food webs and carbon stocks beyond their habitat, but evidence of their contribution in sediment carbon stocks is poor. We test the hypothesis that macroalgae contribute to carbon stocks in arctic marine sediments. We used environmental DNA (eDNA) fingerprinting on a large-scale set of surface sediment samples from Greenland and Svalbard. We evaluated eDNA results by comparing with traditional survey and tracer methods. The eDNA-based survey identified macroalgae in 94 % of the sediment samples covering shallow nearshore areas to 1460 m depth and 350 km offshore, with highest sequence abundance nearshore and with dominance of brown macroalgae. Overall, the eDNA results reflected the potential source communities of macroalgae and eelgrass assessed by traditional surveys, with the most abundant orders being common among different methods. A stable isotope analysis showed a considerable contribution from macroalgae in sediments although with high uncertainty, highlighting eDNA as a great improvement and supplement for documenting macroalgae as a contributor to sediment carbon stocks. Conclusively, we provide evidence for a prevalent contribution of macroalgal forests in arctic surface sediments, nearshore as well as offshore, identifying brown algae as main contributors.

Safety of BA.4-5 or BA.1 bivalent mRNA booster vaccines: nationwide cohort study.

OBJECTIVE: To examine the association between the omicron adapted bivalent mRNA covid-19 booster vaccines received as a fourth dose and risk of adverse events. DESIGN: Nationwide cohort study. SETTING: Denmark. PARTICIPANTS: 2 225 567 adults aged ≥50 years who received three covid-19 vaccine doses during the study period, 1 January 2021 to 10 December 2022. MAIN OUTCOME MEASURES: The main outcome measure was rates of hospital visits for 27 different adverse events in a 28 day main risk period after vaccination with a bivalent omicron adapted mRNA booster vaccine as a fourth dose compared with reference period rates from day 29 after the third or fourth vaccine dose and onward. RESULTS: 1 740 417 adults (mean age 67.8 years, standard deviation 10.7 years) received a bivalent mRNA vaccine as a fourth dose. Fourth dose vaccination with a bivalent mRNA vaccine was not associated with a statistically significant increased rate of any of the 27 adverse outcomes within 28 days (eg, incidence rate ratio of 0.95, 95% confidence interval of 0.87 to 1.04 for ischaemic cardiac events based on 672 v 9992 events during the compared 28 day risk and reference period, respectively), nor when analysed according to age, sex, or vaccine type, or when using alternative analytical approaches. However, post hoc analysis detected signals for myocarditis (statistically significant in female participants), although the outcome was rare and findings were based on few cases. No risk of cerebrovascular infarction was found (incidence rate ratio 0.95, 95% confidence interval 0.87 to 1.05; 644 v 9687 events). CONCLUSIONS: The use of bivalent mRNA vaccines as a fourth vaccine dose against covid-19 was not associated with an increased risk of 27 different adverse events in adults aged ≥50 years.

Clinical outcomes of myocarditis after SARS-CoV-2 mRNA vaccination in four Nordic countries: population based cohort study.

Objective: To investigate the clinical outcomes of myocarditis associated with mRNA vaccines against the SARS-CoV-2 virus compared with other types of myocarditis. Design: Population based cohort study. Setting: Nationwide register data from four Nordic countries (Denmark, Finland, Norway, and Sweden), from 1 January 2018 to the latest date of follow-up in 2022. Participants: The Nordic myocarditis cohort; 7292 individuals aged ≥12 years who had an incident diagnosis of myocarditis as a main or secondary diagnosis, in a population of 23 million individuals in Denmark, Finland, Norway, and Sweden. Main outcome measures: Heart failure, or death from any cause within 90 days of admission to hospital for new onset myocarditis, and hospital readmission within 90 days of discharge to hospital for new onset myocarditis. Clinical outcomes of myocarditis associated with SARS-CoV-2 mRNA vaccination, covid-19 disease, and conventional myocarditis were compared. Results: In 2018-22, 7292 patients were admitted to hospital with new onset myocarditis, with 530 (7.3%) categorised as having myocarditis associated with SARS-CoV-2 mRNA vaccination, 109 (1.5%) with myocarditis associated with covid-19 disease, and 6653 (91.2%) with conventional myocarditis. At the 90 day follow-up, 62, nine, and 988 patients had been readmitted to hospital in each group (vaccination, covid-19, and conventional myocarditis groups, respectively), corresponding to a relative risk of readmission of 0.79 (95% confidence interval 0.62 to 1.00) and 0.55 (0.30 to 1.04) for the vaccination type and covid-19 type myocarditis groups, respectively, compared with the conventional myocarditis group. At the 90 day follow-up, 27, 18, and 616 patients had a diagnosis of heart failure or died in the vaccination type, covid-19 type, and conventional myocarditis groups, respectively. The relative risk of heart failure within 90 days was 0.56 (95% confidence interval 0.37 to 0.85) and 1.48 (0.86 to 2.54) for myocarditis associated with vaccination and covid-19 disease, respectively, compared with conventional myocarditis; the relative risk of death was 0.48 (0.21 to 1.09) and 2.35 (1.06 to 5.19), respectively. Among patients aged 12-39 years with no predisposing comorbidities, the relative risk of heart failure or death was markedly higher for myocarditis associated with covid-19 disease than for myocarditis associated with vaccination (relative risk 5.78, 1.84 to 18.20). Conclusions: Compared with myocarditis associated with covid-19 disease and conventional myocarditis, myocarditis after vaccination with SARS-CoV-2 mRNA vaccines was associated with better clinical outcomes within 90 days of admission to hospital.

Skull and Neck Lesions in a Long-Finned Pilot Whale (Globicephala melas): A Result of Ship Collision?

Necropsy on an adult male pilot whale stranded in Denmark in an area with heavy boat traffic revealed internal lesions in the head and neck region, while the exterior did not show any visible lesions. We found multiple fractured bones, muscle trauma and extensive hemorrhage including a fractured occipital bone with several fragments and bone pieces deeply embedded into the cerebrum of the brain. The brain was literally smashed while the third and partially fourth cervical vertebrae were almost pulverized surrounded by large amounts of blood and muscle contusion. The whale was likely killed due to a ship collision, and this particular case substantiates the value of always performing full necropsies including incisions in head and neck regions on all stranded whales-especially in areas with heavy boat traffic. This case demonstrates the importance of veterinarians performing full necropsies of whales to rule out other causes of death. Otherwise, ship collisions may be an overlooked issue having implications for population health.

A nationwide questionnaire study of post-acute symptoms and health problems after SARS-CoV-2 infection in Denmark.

A considerable number of individuals infected with SARS-CoV-2 continue to experience symptoms after the acute phase. Here, we report findings from a nationwide questionnaire study in Denmark including 61,002 RT-PCR confirmed SARS-CoV-2 cases and 91,878 test-negative controls aged 15-years or older. Six to twelve months after the test, the risks of 18 out of 21 symptoms were elevated among test-positives. The largest adjusted risk differences (RD) were observed for dysosmia (RD = 10.92%, 95% CI 10.68-11.21%), dysgeusia (RD = 8.68%, 95% CI 8.43-8.93%), fatigue/exhaustion (RD = 8.43%, 95%CI 8.14-8.74%), dyspnea (RD = 4.87%, 95% CI 4.65-5.09%) and reduced strength in arms/legs (RD = 4.68%, 95% CI 4.45-4.89%). During the period from the test and until completion of the questionnaire, new diagnoses of anxiety (RD = 1.15%, 95% CI 0.95-1.34%) or depression (RD = 1.00%, 95% CI 0.81-1.19%) were also more common among test-positives. Even in a population where the majority of test-positives were not hospitalized, a considerable proportion experiences symptoms up to 12 months after infection. Being female or middle-aged increases risks.

Analysis of Thromboembolic and Thrombocytopenic Events After the AZD1222, BNT162b2, and MRNA-1273 COVID-19 Vaccines in 3 Nordic Countries.

Importance: Vaccinations are paramount to halt the COVID-19 pandemic, and safety data are essential to determine the risk-benefit ratio of each COVID-19 vaccine. Objective: To evaluate the association between the AZD1222, BNT162b2, and mRNA-1273 vaccines and subsequent thromboembolic and thrombocytopenic events. Design, Setting, and Participants: This self-controlled case series used individual-level data from national registries in Norway, Finland, and Denmark. Participants included individuals with hospital contacts because of coronary artery disease, coagulation disorders, or cerebrovascular disease between January 1, 2020, and May 16, 2021. Exposures: AZD1222, BNT162b2, or mRNA-1273 vaccine. Main Outcomes and Measure: Relative rate (RR) of hospital contacts for coronary artery disease, coagulation disorders, or cerebrovascular disease in a 28-day period following vaccination compared with the control period prior to vaccination. Results: We found 265 339 hospital contacts, of whom 112 984 [43%] were for female patients, 246 092 [93%] were for patients born in 1971 or earlier, 116 931 [44%] were for coronary artery disease, 55 445 [21%] were for coagulation disorders, and 92 963 [35%] were for cerebrovascular disease. In the 28-day period following vaccination, there was an increased rate of coronary artery disease following mRNA-1273 vaccination (RR, 1.13 [95% CI, 1.02-1.25]), but not following AZD1222 vaccination (RR, 0.92 [95% CI, 0.82-1.03]) or BNT162b2 vaccination (RR, 0.96 [95% CI, 0.92-0.99]). There was an observed increased rate of coagulation disorders following all 3 vaccines (AZD1222: RR, 2.01 [95% CI, 1.75-2.31]; BNT162b2: RR, 1.12 [95% CI, 1.07-1.19]; and mRNA-1273: RR, 1.26 [95% CI, 1.07-1.47]). There was also an observed increased rate of cerebrovascular disease following all 3 vaccines (AZD1222: RR, 1.32 [95% CI, 1.16-1.52]; BNT162b2: RR, 1.09 [95% CI, 1.05-1.13]; and mRNA-1273: RR, 1.21 [95% CI, 1.09-1.35]). For individual diseases within the main outcomes, 2 notably high rates were observed: 12.04 (95% CI, 5.37-26.99) for cerebral venous thrombosis and 4.29 (95% CI, 2.96-6.20) for thrombocytopenia, corresponding to 1.6 (95% CI, 0.6-2.6) and 4.9 (95% CI, 2.9-6.9) excess events per 100 000 doses, respectively, following AZD1222 vaccination. Conclusions and Relevance: In this self-controlled case series, there was an increased rate of hospital contacts because of coagulation disorders and cerebrovascular disease, especially for thrombocytopenia and cerebral venous thrombosis, following vaccination with AZD1222. Although increased rates of several thromboembolic and thrombocytopenic outcomes following BNT162b2 and mRNA-1273 vaccination were observed, these increases were less than the rates observed after AZD1222, and sensitivity analyses were not consistent. Confirmatory analysis on the 2 mRNA vaccines by other methods are warranted.

SARS-CoV-2 Vaccination and Myocarditis in a Nordic Cohort Study of 23 Million Residents.

Importance: Reports of myocarditis after SARS-CoV-2 messenger RNA (mRNA) vaccination have emerged. Objective: To evaluate the risks of myocarditis and pericarditis following SARS-CoV-2 vaccination by vaccine product, vaccination dose number, sex, and age. Design, Setting, and Participants: Four cohort studies were conducted according to a common protocol, and the results were combined using meta-analysis. Participants were 23 122 522 residents aged 12 years or older. They were followed up from December 27, 2020, until incident myocarditis or pericarditis, censoring, or study end (October 5, 2021). Data on SARS-CoV-2 vaccinations, hospital diagnoses of myocarditis or pericarditis, and covariates for the participants were obtained from linked nationwide health registers in Denmark, Finland, Norway, and Sweden. Exposures: The 28-day risk periods after administration date of the first and second doses of a SARS-CoV-2 vaccine, including BNT162b2, mRNA-1273, and AZD1222 or combinations thereof. A homologous schedule was defined as receiving the same vaccine type for doses 1 and 2. Main Outcomes and Measures: Incident outcome events were defined as the date of first inpatient hospital admission based on primary or secondary discharge diagnosis for myocarditis or pericarditis from December 27, 2020, onward. Secondary outcome was myocarditis or pericarditis combined from either inpatient or outpatient hospital care. Poisson regression yielded adjusted incidence rate ratios (IRRs) and excess rates with 95% CIs, comparing rates of myocarditis or pericarditis in the 28-day period following vaccination with rates among unvaccinated individuals. Results: Among 23 122 522 Nordic residents (81% vaccinated by study end; 50.2% female), 1077 incident myocarditis events and 1149 incident pericarditis events were identified. Within the 28-day period, for males and females 12 years or older combined who received a homologous schedule, the second dose was associated with higher risk of myocarditis, with adjusted IRRs of 1.75 (95% CI, 1.43-2.14) for BNT162b2 and 6.57 (95% CI, 4.64-9.28) for mRNA-1273. Among males 16 to 24 years of age, adjusted IRRs were 5.31 (95% CI, 3.68-7.68) for a second dose of BNT162b2 and 13.83 (95% CI, 8.08-23.68) for a second dose of mRNA-1273, and numbers of excess events were 5.55 (95% CI, 3.70-7.39) events per 100 000 vaccinees after the second dose of BNT162b2 and 18.39 (9.05-27.72) events per 100 000 vaccinees after the second dose of mRNA-1273. Estimates for pericarditis were similar. Conclusions and Relevance: Results of this large cohort study indicated that both first and second doses of mRNA vaccines were associated with increased risk of myocarditis and pericarditis. For individuals receiving 2 doses of the same vaccine, risk of myocarditis was highest among young males (aged 16-24 years) after the second dose. These findings are compatible with between 4 and 7 excess events in 28 days per 100 000 vaccinees after BNT162b2, and between 9 and 28 excess events per 100 000 vaccinees after mRNA-1273. This risk should be balanced against the benefits of protecting against severe COVID-19 disease.

Association of AZD1222 and BNT162b2 COVID-19 Vaccination With Thromboembolic and Thrombocytopenic Events in Frontline Personnel : A Retrospective Cohort Study.

BACKGROUND: In March 2021, several European countries suspended the use of the AZD1222 (Oxford-AstraZeneca) COVID-19 vaccine because of thromboembolic safety concerns. Reports from Norway and Germany subsequently described patients with venous thrombosis and thrombocytopenia within 5 to 16 days of vaccination. OBJECTIVE: To evaluate the risk for outcomes related to thrombosis and thrombocytopenia after AZD1222 or BNT162b2 (Pfizer-BioNTech) COVID-19 vaccination. DESIGN: Nationwide exploratory retrospective cohort study. SETTING: Danish linkable registers on vaccinations, hospitalizations, occupation, and other covariates. PARTICIPANTS: 355 209 Danish frontline personnel designated for priority COVID-19 vaccination followed from 27 December 2020 (the day of the first COVID-19 vaccination in Denmark) to 13 April 2021. MEASUREMENTS: Study outcomes were cerebral venous sinus thrombosis, splanchnic vein thrombosis, pulmonary embolism, deep venous thrombosis, arterial thrombosis, thrombocytopenia, and death. Cumulative incidences of study outcomes within 28 days of vaccination and unvaccinated risk time were compared using adjusted survival curves resulting in risk differences (RDs) at day 28 after vaccination. Adjustment for birth cohort, sex, calendar period, occupation, comorbid conditions, and prescription drug use was included. RESULTS: Vaccination with AZD1222 versus no vaccination was associated with a significant RD at day 28 for deep venous thrombosis (RD, 8.35 [95% CI, 0.21 to 16.49] per 100 000 vaccinations). The RDs for cerebral venous sinus thrombosis (RD, 1.68 [CI, -0.64 to 4.00] per 100 000 vaccinations) and thrombocytopenia (RD, 2.39 [CI, -1.09 to 5.87] per 100 000 vaccinations) were not significant. No adverse associations were seen for BNT162b2 vaccination. LIMITATION: No medical record review; surveillance bias. CONCLUSION: In this exploratory retrospective cohort study among frontline personnel in Denmark, receipt of the AZD1222 vaccine was associated with a small excess risk for deep venous thrombosis. Although the corresponding risks for the more rare and severe thrombotic outcomes (such as cerebral venous sinus thrombosis) were not statistically significantly increased, statistical precision was low, and clinically relevant risks could not be excluded with certainty. There was no statistically significant association of BNT162b2 vaccination with thrombotic or thrombocytopenic events. PRIMARY FUNDING SOURCE: Lundbeck Foundation.

Decision support system to evaluate ventilation in the acute respiratory distress syndrome (DeVENT study)-trial protocol.

BACKGROUND: The acute respiratory distress syndrome (ARDS) occurs in response to a variety of insults, and mechanical ventilation is life-saving in this setting, but ventilator-induced lung injury can also contribute to the morbidity and mortality in the condition. The Beacon Caresystem is a model-based bedside decision support system using mathematical models tuned to the individual patient's physiology to advise on appropriate ventilator settings. Personalised approaches using individual patient description may be particularly advantageous in complex patients, including those who are difficult to mechanically ventilate and wean, in particular ARDS. METHODS: We will conduct a multi-centre international randomised, controlled, allocation concealed, open, pragmatic clinical trial to compare mechanical ventilation in ARDS patients following application of the Beacon Caresystem to that of standard routine care to investigate whether use of the system results in a reduction in driving pressure across all severities and phases of ARDS. DISCUSSION: Despite 20 years of clinical trial data showing significant improvements in ARDS mortality through mitigation of ventilator-induced lung injury, there remains a gap in its personalised application at the bedside. Importantly, the protective effects of higher positive end-expiratory pressure (PEEP) were noted only when there were associated decreases in driving pressure. Hence, the pressures set on the ventilator should be determined by the diseased lungs' pressure-volume relationship which is often unknown or difficult to determine. Knowledge of extent of recruitable lung could improve the ventilator driving pressure. Hence, personalised management demands the application of mechanical ventilation according to the physiological state of the diseased lung at that time. Hence, there is significant rationale for the development of point-of-care clinical decision support systems which help personalise ventilatory strategy according to the current physiology. Furthermore, the potential for the application of the Beacon Caresystem to facilitate local and remote management of large numbers of ventilated patients (as seen during this COVID-19 pandemic) could change the outcome of mechanically ventilated patients during the course of this and future pandemics. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04115709. Registered on 4 October 2019, version 4.0.