Host space, not energy or symbiont size, constrains feather mite abundance across passerine bird species.

Comprehending symbiont abundance among host species is a major ecological endeavour, and the metabolic theory of ecology has been proposed to understand what constrains symbiont populations. We parameterized metabolic theory equations to investigate how bird species' body size and the body size of their feather mites relate to mite abundance according to four potential energy (uropygial gland size) and space constraints (wing area, total length of barbs and number of feather barbs). Predictions were compared with the empirical scaling of feather mite abundance across 106 passerine bird species (26,604 individual birds sampled), using phylogenetic modelling and quantile regression. Feather mite abundance was strongly constrained by host space (number of feather barbs) but not by energy. Moreover, feather mite species' body size was unrelated to the body size of their host species. We discuss the implications of our results for our understanding of the bird-feather mite system and for symbiont abundance in general.

The Mitogenome Relationships and Phylogeography of Barn Swallows (Hirundo rustica).

The barn swallow (Hirundo rustica) poses a number of fascinating scientific questions, including the taxonomic status of postulated subspecies. Here, we obtained and assessed the sequence variation of 411 complete mitogenomes, mainly from the European H. r. rustica, but other subspecies as well. In almost every case, we observed subspecies-specific haplogroups, which we employed together with estimated radiation times to postulate a model for the geographical and temporal worldwide spread of the species. The female barn swallow carrying the Hirundo rustica ancestral mitogenome left Africa (or its vicinity) around 280 thousand years ago (kya), and her descendants expanded first into Eurasia and then, at least 51 kya, into the Americas, from where a relatively recent (<20 kya) back migration to Asia took place. The exception to the haplogroup subspecies specificity is represented by the sedentary Levantine H. r. transitiva that extensively shares haplogroup A with the migratory European H. r. rustica and, to a lesser extent, haplogroup B with the Egyptian H. r. savignii. Our data indicate that rustica and transitiva most likely derive from a sedentary Levantine population source that split at the end of the Younger Dryas (YD) (11.7 kya). Since then, however, transitiva received genetic inputs from and admixed with both the closely related rustica and the adjacent savignii. Demographic analyses confirm this species' strong link with climate fluctuations and human activities making it an excellent indicator for monitoring and assessing the impact of current global changes on wildlife.

Evolutionary dynamics in the Anthropocene: Life history and intensity of human contact shape antipredator responses.

Humans profoundly impact landscapes, ecosystems, and animal behavior. In many cases, animals living near humans become tolerant of them and reduce antipredator responses. Yet, we still lack an understanding of the underlying evolutionary dynamics behind these shifts in traits that affect animal survival. Here, we used a phylogenetic meta-analysis to determine how the mean and variability in antipredator responses change as a function of the number of generations spent in contact with humans under 3 different contexts: urbanization, captivity, and domestication. We found that any contact with humans leads to a rapid reduction in mean antipredator responses as expected. Notably, the variance among individuals over time observed a short-term increase followed by a gradual decrease, significant for domesticated animals. This implies that intense human contact immediately releases animals from predation pressure and then imposes strong anthropogenic selection on traits. In addition, our results reveal that the loss of antipredator traits due to urbanization is similar to that of domestication but occurs 3 times more slowly. Furthermore, the rapid disappearance of antipredator traits was associated with 2 main life-history traits: foraging guild and whether the species was solitary or gregarious (i.e., group-living). For domesticated animals, this decrease in antipredator behavior was stronger for herbivores than for omnivores or carnivores and for solitary than for gregarious species. By contrast, the decrease in antipredator traits was stronger for gregarious, urbanized species, although this result is based mostly on birds. Our study offers 2 major insights on evolution in the Anthropocene: (1) changes in traits occur rapidly even under unintentional human "interventions" (i.e., urbanization) and (2) there are similarities between the selection pressures exerted by domestication and by urbanization. In all, such changes could affect animal survival in a predator-rich world, but through understanding evolutionary dynamics, we can better predict when and how exposure to humans modify these fitness-related traits.

EVI and NDVI as proxies for multifaceted avian diversity in urban areas.

Most ecological studies use remote sensing to analyze broad-scale biodiversity patterns, focusing mainly on taxonomic diversity in natural landscapes. One of the most important effects of high levels of urbanization is species loss (i.e., biotic homogenization). Therefore, cost-effective and more efficient methods to monitor biological communities' distribution are essential. This study explores whether the Enhanced Vegetation Index (EVI) and the Normalized Difference Vegetation Index (NDVI) can predict multifaceted avian diversity, urban tolerance, and specialization in urban landscapes. We sampled bird communities among 15 European cities and extracted Landsat 30-meter resolution EVI and NDVI values of the pixels within a 50-m buffer of bird sample points using Google Earth Engine (32-day Landsat 8 Collection Tier 1). Mixed models were used to find the best associations of EVI and NDVI, predicting multiple avian diversity facets: Taxonomic diversity, functional diversity, phylogenetic diversity, specialization levels, and urban tolerance. A total of 113 bird species across 15 cities from 10 different European countries were detected. EVI mean was the best predictor for foraging substrate specialization. NDVI mean was the best predictor for most avian diversity facets: taxonomic diversity, functional richness and evenness, phylogenetic diversity, phylogenetic species variability, community evolutionary distinctiveness, urban tolerance, diet foraging behavior, and habitat richness specialists. Finally, EVI and NDVI standard deviation were not the best predictors for any avian diversity facets studied. Our findings expand previous knowledge about EVI and NDVI as surrogates of avian diversity at a continental scale. Considering the European Commission's proposal for a Nature Restoration Law calling for expanding green urban space areas by 2050, we propose NDVI as a proxy of multiple facets of avian diversity to efficiently monitor bird community responses to land use changes in the cities.

Defensive tolerance to parasitism is correlated with sexual selection in swallows.

Parasite-mediated sexual selection has been the topic of extensive research and enthusiastic debate for more than three decades. Here, we suggest that secondary sexual characters may not only signal parasite resistance but also defensive tolerance. We exemplify this possibility by analysing information on two sexually selected traits, annual reproductive success, and ectoparasitism in a barn swallow Hirundo rustica population followed for more than 30 years. For each individual, we estimated the slope of the association between reproductive success and parasitism as an index of tolerance and subsequently explored the association with the expression of the sexually selected traits. In accordance with expectations of parasites playing a role in sexual selection, tail length was negatively related to load of chewing lice and nest size was positively related to tolerance to chewing lice. We discuss the importance of considering defensive tolerance for understanding the role of parasite-mediated sexual selection.

Long-term consistency in susceptibility of prey species to predation by an avian predator.

Selection by predators affects prey through competition for limiting resources. This not only has consequences for direct mortality but also indirectly affects disturbance. Changes in the intensity of selection on prey by predators may affect the size of prey populations, with consequences for their short- or long-term interactions. We assessed whether predation by northern goshawks Accipiter gentilis modified the composition of prey communities consistently along a temporal gradient, showing long-term consistency in susceptibility of prey species to predation. We followed six populations of the goshawk in two biomes in Denmark and Finland during 1949-2019. Susceptibility to goshawk predation in 2005-2017 in Denmark was only weakly related to susceptibility to goshawk predation in 1977-2004. In Finland, susceptibility of shared prey species to goshawk predation was positively related between periods. The average difference in susceptibility to goshawk predation between periods was considerably higher in Denmark than in Finland. Susceptibility of prey species to predation in goshawks increased with latitude and body mass of prey species, and decreased with period of time and population density of prey species. The changes in susceptibility to predation suggest changes in the characteristics of the local prey pools.

A survey of preferences for respiratory support in the intensive care unit for patients with acute hypoxaemic respiratory failure.

BACKGROUND: When caring for mechanically ventilated adults with acute hypoxaemic respiratory failure (AHRF), clinicians are faced with an uncertain choice between ventilator modes allowing for spontaneous breaths or ventilation fully controlled by the ventilator. The preferences of clinicians managing such patients, and what motivates their choice of ventilator mode, are largely unknown. To better understand how clinicians' preferences may impact the choice of ventilatory support for patients with AHRF, we issued a survey to an international network of intensive care unit (ICU) researchers. METHODS: We distributed an online survey with 32 broadly similar and interlinked questions on how clinicians prioritise spontaneous or controlled ventilation in invasively ventilated patients with AHRF of different severity, and which factors determine their choice. RESULTS: The survey was distributed to 1337 recipients in 12 countries. Of these, 415 (31%) completed the survey either fully (52%) or partially (48%). Most respondents were identified as medical specialists (87%) or physicians in training (11%). Modes allowing for spontaneous ventilation were considered preferable in mild AHRF, with controlled ventilation considered as progressively more important in moderate and severe AHRF. Among respondents there was strong support (90%) for a randomised clinical trial comparing spontaneous with controlled ventilation in patients with moderate AHRF. CONCLUSIONS: The responses from this international survey suggest that there is clinical equipoise for the preferred ventilator mode in patients with AHRF of moderate severity. We found strong support for a randomised trial comparing modes of ventilation in patients with moderate AHRF.

Nest size matters: common cuckoos prefer to parasitize larger nests of Oriental reed warblers.

Avian brood parasites leave parental care of their offspring to foster parents. Theory predicts that parasites should select for large host nests when they have sufficient available host nests at a given time. We developed an empirical experimental design to test cognitive ability of female cuckoos in nest size by studying nest choice of common cuckoos (Cuculus canorus) among nests of its Oriental reed warbler (Acrocephalus orientalis) hosts. We presented three groups of experimental nests: 1) nest dyads tied together including one large and one small artificial nest from reed leaves, 2) nest triads tied together used the old modified warbler's own nests including enlarged, reduced and medium-sized nests, and 3) nest dyads are similar to group 1, but not tied together to elicit parasitism by common cuckoos. We predict that cuckoos prefer larger nest than medium one, the next is smaller nest. Our findings showed that common cuckoo females generally prefer large nests over medium or small sized nests in all three experimental groups. Furthermore, cuckoo parasitism was significantly more common than in previous studies of the same warbler population, implying that larger, higher and more exposed host nests effectively increased the probability of cuckoo parasitism.

Interpretation of gut microbiota data in the 'eye of the beholder': A commentary and re-evaluation of data from 'Impacts of radiation exposure on the bacterial and fungal microbiome of small mammals in the Chernobyl Exclusion Zone'.

Evidence that exposure to environmental pollutants can alter the gut microbiota composition of wildlife includes studies of rodents exposed to radionuclides. Antwis et al. (2021) used amplicon sequencing to characterise the gut microbiota of four species of rodent (Myodes glareolus, Apodemus agrarius, A. flavicollis and A. sylvaticus) inhabiting the Chernobyl Exclusion Zone (CEZ) to examine possible changes in gut bacteria (microbiota) and gut fungi (mycobiota) associated with exposure to radionuclides and whether the sample type (from caecum or faeces) affected the analysis. The conclusions derived from the analyses of gut mycobiota are based on data that represent a mixture of ingested fungi (e.g. edible macrofungi, polypores, lichens and ectomycorrhizae) and gut mycobiota (e.g. microfungi and yeasts), which mask the patterns of inter- and intraspecific variation in the authentic gut mycobiota. Implying that 'faecal samples are not an accurate indicator of gut composition' creates an unnecessary controversy about faecal sampling because the comparison of samples from the caecum and faeces confounds many other possible drivers (including different animals from different locations, sampled in different years) of variation in gut microbiota. It is relevant also that Antwis et al.'s (2021) data lack statistical power to detect an effect of exposure to radionuclides on the gut microbiota because (1) all of their samples of Apodemus mice had experienced a medium or high total absorbed dose rate and (2) they did not collect samples of bank voles (M. glareolus) from replicate contaminated and uncontaminated locations. Discussion of Antwis et al.'s (2021) analysis, especially the claims presented in the Abstract, is important to prevent controversy about the outcome of research on the biological impacts of wildlife inhabiting the CEZ.

Delineation of Nitrate Reduction Hotspots in Artificially Drained Areas through Assessment of Small-Scale Spatial Variability of Electrical Conductivity Data.

Identification of nitrate reduction hotspots (NRH) can be instrumental in implementing targeted strategies for reducing nitrate loading from agriculture. In this study, we aimed to delineate possible NRH areas from soil depths of 80 to 180 cm in an artificially drained catchment by utilizing electrical conductivity (EC) values derived by the inversion of apparent electrical conductivity data measured by an electromagnetic induction instrument. The NRH areas were derived from the subzones generated from clustering the EC values via two methods, unsupervised ISODATA clustering and the Optimized Hot Spot Analysis, that highly complement each other. The clustering of EC values generated three classes, wherein the classes with high EC values correspond to NRH areas as indicated by their low redox potential values and nitrate (NO3-) concentrations. Nitrate concentrations in the NRH were equal to 13 to 17% of the concentrations in non-NRH areas and occupied 26% of the total area of the drainage catchments in the study. It is likely that, with the identification of NRH areas, the degree of nitrogen reduction in the vadose zone may be higher than initially estimated at the subcatchment scale.

Evaluating a digital life story app in a nursing home context - A qualitative study.

AIMS AND OBJECTIVES: To evaluate how digital life stories can be used to support person-centred care focusing on benefits and challenges experienced by the staff and the management team in a nursing home context. BACKGROUND: Life story work can be used to support person-centred care and help people with dementia maintain their identity. The use of digital life stories provides opportunities to easily share the content between staff and relatives and combine different types of multimedia, for example pictures, videos, text and sound. DESIGN: Six healthcare professionals and two members of the management team at a nursing home were recruited. Participant observations with informal interviews of the formal health career were conducted in two day shifts and two night shifts. Field notes were taken during the observations. Also, individual semi-structured interviews were held with four of the recruited participants. This article adheres to the Standards for Reporting Qualitative Research (SRQR). RESULTS: Themes revealed were (1) person-centred care and life story work as interrelated approaches; (2) Pros and cons related to the My Life Story app; and how (3) Time and information and communication technology (ICT) can restrict life story work. CONCLUSION: Digital life stories can be used to support a person-centred care approach. However, a number of challenges exist related to digital life story work. When using digital life stories, it is important to ensure the staff time and competences needed to work with, for example an app and that visible support and encouragement are provided by the management team. RELEVANCE TO CLINICAL PRACTICE: Challenges are revealed when life story work is embedded in the culture and everyday work of a nursing home. It is of great importance to clinical practice to be aware of and address these challenges in order to succeed with digital life story work.

Pantoprazole in Patients at Risk for Gastrointestinal Bleeding in the ICU.

BACKGROUND: Prophylaxis for gastrointestinal stress ulceration is frequently given to patients in the intensive care unit (ICU), but its risks and benefits are unclear. METHODS: In this European, multicenter, parallel-group, blinded trial, we randomly assigned adults who had been admitted to the ICU for an acute condition (i.e., an unplanned admission) and who were at risk for gastrointestinal bleeding to receive 40 mg of intravenous pantoprazole (a proton-pump inhibitor) or placebo daily during the ICU stay. The primary outcome was death by 90 days after randomization. RESULTS: A total of 3298 patients were enrolled; 1645 were randomly assigned to the pantoprazole group and 1653 to the placebo group. Data on the primary outcome were available for 3282 patients (99.5%). At 90 days, 510 patients (31.1%) in the pantoprazole group and 499 (30.4%) in the placebo group had died (relative risk, 1.02; 95% confidence interval [CI], 0.91 to 1.13; P=0.76). During the ICU stay, at least one clinically important event (a composite of clinically important gastrointestinal bleeding, pneumonia, Clostridium difficile infection, or myocardial ischemia) had occurred in 21.9% of patients assigned to pantoprazole and 22.6% of those assigned to placebo (relative risk, 0.96; 95% CI, 0.83 to 1.11). In the pantoprazole group, 2.5% of patients had clinically important gastrointestinal bleeding, as compared with 4.2% in the placebo group. The number of patients with infections or serious adverse reactions and the percentage of days alive without life support within 90 days were similar in the two groups. CONCLUSIONS: Among adult patients in the ICU who were at risk for gastrointestinal bleeding, mortality at 90 days and the number of clinically important events were similar in those assigned to pantoprazole and those assigned to placebo. (Funded by Innovation Fund Denmark and others; SUP-ICU ClinicalTrials.gov number, NCT02467621 .).

Low vs high hemoglobin trigger for transfusion in vascular surgery: a randomized clinical feasibility trial.

Current guidelines advocate to limit red blood cell (RBC) transfusion during surgery, but the feasibility and safety of such a strategy remain unclear, as the majority of evidence is based on postoperatively stable patients. We assessed the effects of a protocol aiming to restrict RBC transfusion throughout hospitalization for vascular surgery. Fifty-eight patients scheduled for lower limb bypass or open abdominal aortic aneurysm repair were randomly assigned, on hemoglobin drop below 9.7 g/dL, to either a low-trigger (hemoglobin < 8.0 g/dL) or a high-trigger (hemoglobin < 9.7 g/dL) group for RBC transfusion. Near-infrared spectroscopy assessed intraoperative oxygen desaturation in brain and muscle. Explorative outcomes included nationwide registry data on death and major vascular complications. The primary outcome, mean hemoglobin within 15 days of surgery, was significantly lower in the low-trigger group, at 9.46 vs 10.33 g/dL in the high-trigger group (mean difference, -0.87 g/dL; P = .022), as were units of RBCs transfused (median [interquartile range (IQR)], 1 [0-2] vs 3 [2-6]; P = .0015). Although the duration and magnitude of cerebral oxygen desaturation increased in the low-trigger group (median [IQR], 421 [42-888] vs 127 [11-331] minutes × %; P = .0036), muscle oxygenation was unaffected. The low-trigger group associated to a higher rate of death or major vascular complications (19/29 vs 8/29; hazard ratio, 3.20; P = .006) and fewer days alive outside the hospital within 90 days (median [IQR], 76 [67-82] vs 82 [76-84] days; P = .049). In conclusion, a perioperative protocol restricting RBC transfusion successfully separated hemoglobin levels and RBC units transfused. Exploratory outcomes suggested potential harm with the low-trigger group and warrant further trials before such a strategy is universally adopted. This trial was registered at www.clinicaltrials.gov as #NCT02465125.

Long-term trends in the phylogenetic and functional diversity of Anatidae in South China coastal wetlands.

Species loss has attracted much attention among scientists for more than half a century. However, we have little information on the trends in phylogenetic and functional changes behind the species loss although this information is always asynchronous and important for conservation and management. We measured community trends in Anatidae (ducks and geese) for the last 50 yr to quantify trends in phylogenetic and functional diversity patterns coinciding with taxonomic historical dynamics. We used one-way ANOVAs to test if there was a significant historical trend in communities of Anatidae. We characterized taxonomic, phylogenetic, and functional diversity of communities. For taxonomic diversity, we used species richness (SR). For phylogenetic diversity, we calculated the standardized effect size of mean pairwise distances (ses.MPD) and the standard effect size of mean nearest taxon distances (ses.MNTD) in communities. For functional diversity, we calculated functional richness (FRic), functional evenness (FEve), functional divergence (FDiv), and the community-level weighted means (CWM) of trait values for diet, foraging stratum, and body mass, separately. From the 1950s to 2010s, species richness declined without significant trends. The ses.MNTD of Anatidae communities showed no clear trends. However, ses.MPD of Anatidae communities declined dramatically during this period. For functional diversity, functional evenness of diet, foraging stratum, body mass, and functional dispersion of diet, foraging stratum did not increase or decline significantly. However, functional evenness of all traits, functional richness, and functional dispersion of body mass showed declined trends. The basic phylogenetic diversity and species body mass of Anatidae communities declined significantly because of a declining trend in the relative independent branch of geese. This makes it more challenging for implement community recovery in the future. More attention in conservation biology should consider taxonomic diversity and asynchrony in phylogenetic and functional diversity.

Eiders, nutrients and eagles: Bottom-up and top-down population dynamics in a marine bird.

The main objective of this long-term study (1978-2016) was to find the underlying factors behind the declining trends of eider Somateria mollissima in the Baltic/Wadden Sea. Specifically, we aimed at quantifying the bottom-up effect of nutrients, through mussel stocks, on reproduction and abundance of eider, and the top-down effects caused by white-tailed eagle Haliaeetus albicilla predation. Bottom-up effects increase marine primary productivity with subsequent effects on food availability for a major mussel predator. Top-down effects may also regulate eider populations because during incubation female eiders are vulnerable to predation by eagles. Our structural equation modelling explained a large percentage of the variance in eider abundance. We conclude that the Baltic/Wadden Sea eider population was regulated directly by white-tailed sea eagle predation on incubating females and indirectly by the amount of nutrients in seawater affecting both mussel stocks and the breeding success of eiders, reflecting density dependence. These findings may explain the decreasing trend in the Baltic/Wadden Sea eider population during the last decades as an additive effect of top-down and bottom-up factors, and likely as an interaction between them.

Effect of low vs high haemoglobin transfusion trigger on cardiac output in patients undergoing elective vascular surgery: Post-hoc analysis of a randomized trial.

BACKGROUND: During vascular surgery, restricted red-cell transfusion reduces frontal lobe oxygen (ScO2 ) saturation as determined by near-infrared spectroscopy. We evaluated whether inadequate increase in cardiac output (CO) following haemodilution explains reduction in ScO2 . METHODS: This is a post-hoc analysis of data from the Transfusion in Vascular surgery (TV) Trial where patients were randomized on haemoglobin drop below 9.7 g/dL to red-cell transfusion at haemoglobin below 8.0 (low-trigger) vs 9.7 g/dL (high-trigger). Fluid administration was guided by optimizing stroke volume. We compared mean intraoperative levels of CO, haemoglobin, oxygen delivery, and CO at nadir ScO2 with linear regression adjusted for age, operation type and baseline. Data for 46 patients randomized before end of surgery were included for analysis. RESULTS: The low-trigger resulted in a 7.1% lower mean intraoperative haemoglobin level (mean difference, -0.74 g/dL; P < .001) and reduced volume of red-cell transfused (median [inter-quartile range], 0 [0-300] vs 450 mL [300-675]; P < .001) compared with the high-trigger group. Mean CO during surgery was numerically 7.3% higher in the low-trigger compared with the high-trigger group (mean difference, 0.36 L/min; 95% confidence interval (CI.95), -0.05 to 0.78; P = .092; n = 42). At the nadir ScO2 -level, CO was 11.9% higher in the low-trigger group (mean difference, 0.58 L/min; CI.95, 0.10-1.07; P = .024). No difference in oxygen delivery was detected between trial groups (MD, 1.39 dLO2 /min; CI.95, -6.16 to 8.93; P = .721). CONCLUSION: Vascular surgical patients exposed to restrictive RBC transfusion elicit the expected increase in CO making it unlikely that their potentially limited cardiac capacity explains the associated ScO2 decrease.

Higher vs Lower Doses of Dexamethasone in Patients with COVID-19 and Severe Hypoxia (COVID STEROID 2) trial: Protocol for a secondary Bayesian analysis.

BACKGROUND: Coronavirus disease 2019 (COVID-19) can lead to severe hypoxic respiratory failure and death. Corticosteroids decrease mortality in severely or critically ill patients with COVID-19. However, the optimal dose remains unresolved. The ongoing randomised COVID STEROID 2 trial investigates the effects of higher vs lower doses of dexamethasone (12 vs 6 mg intravenously daily for up to 10 days) in 1,000 adult patients with COVID-19 and severe hypoxia. METHODS: This protocol outlines the rationale and statistical methods for a secondary, pre-planned Bayesian analysis of the primary outcome (days alive without life support at day 28) and all secondary outcomes registered up to day 90. We will use hurdle-negative binomial models to estimate the mean number of days alive without life support in each group and present results as mean differences and incidence rate ratios with 95% credibility intervals (CrIs). Additional count outcomes will be analysed similarly and binary outcomes will be analysed using logistic regression models with results presented as probabilities, relative risks and risk differences with 95% CrIs. We will present probabilities of any benefit/harm, clinically important benefit/harm and probabilities of effects smaller than pre-defined clinically minimally important differences for all outcomes analysed. Analyses will be adjusted for stratification variables and conducted using weakly informative priors supplemented by sensitivity analyses using sceptic priors. DISCUSSION: This secondary, pre-planned Bayesian analysis will supplement the primary, conventional analysis and may help clinicians, researchers and policymakers interpret the results of the COVID STEROID 2 trial while avoiding arbitrarily dichotomised interpretations of the results. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04509973; EudraCT: 2020-003363-25.

Higher vs lower doses of dexamethasone in patients with COVID-19 and severe hypoxia (COVID STEROID 2) trial: Protocol and statistical analysis plan.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has resulted in millions of deaths and overburdened healthcare systems worldwide. Systemic low-dose corticosteroids have proven clinical benefit in patients with severe COVID-19. Higher doses of corticosteroids are used in other inflammatory lung diseases and may offer additional clinical benefits in COVID-19. At present, the balance between benefits and harms of higher vs. lower doses of corticosteroids for patients with COVID-19 is unclear. METHODS: The COVID STEROID 2 trial is an investigator-initiated, international, parallel-grouped, blinded, centrally randomised and stratified clinical trial assessing higher (12 mg) vs. lower (6 mg) doses of dexamethasone for adults with COVID-19 and severe hypoxia. We plan to enrol 1,000 patients in Denmark, Sweden, Switzerland and India. The primary outcome is days alive without life support (invasive mechanical ventilation, circulatory support or renal replacement therapy) at day 28. Secondary outcomes include serious adverse reactions at day 28; all-cause mortality at day 28, 90 and 180; days alive without life support at day 90; days alive and out of hospital at day 90; and health-related quality of life at day 180. The primary outcome will be analysed using the Kryger Jensen and Lange test adjusted for stratification variables and reported as adjusted mean differences and median differences. The full statistical analysis plan is outlined in this protocol. DISCUSSION: The COVID STEROID 2 trial will provide evidence on the optimal dosing of systemic corticosteroids for COVID-19 patients with severe hypoxia with important implications for patients, their relatives and society.

Low-dose hydrocortisone in patients with COVID-19 and severe hypoxia: The COVID STEROID randomised, placebo-controlled trial.

BACKGROUND: In the early phase of the pandemic, some guidelines recommended the use of corticosteroids for critically ill patients with COVID-19, whereas others recommended against the use despite lack of firm evidence of either benefit or harm. In the COVID STEROID trial, we aimed to assess the effects of low-dose hydrocortisone on patient-centred outcomes in adults with COVID-19 and severe hypoxia. METHODS: In this multicentre, parallel-group, placebo-controlled, blinded, centrally randomised, stratified clinical trial, we randomly assigned adults with confirmed COVID-19 and severe hypoxia (use of mechanical ventilation or supplementary oxygen with a flow of at least 10 L/min) to either hydrocortisone (200 mg/d) vs a matching placebo for 7 days or until hospital discharge. The primary outcome was the number of days alive without life support at day 28 after randomisation. RESULTS: The trial was terminated early when 30 out of 1000 participants had been enrolled because of external evidence indicating benefit from corticosteroids in severe COVID-19. At day 28, the median number of days alive without life support in the hydrocortisone vs placebo group were 7 vs 10 (adjusted mean difference: -1.1 days, 95% CI -9.5 to 7.3, P = .79); mortality was 6/16 vs 2/14; and the number of serious adverse reactions 1/16 vs 0/14. CONCLUSIONS: In this trial of adults with COVID-19 and severe hypoxia, we were unable to provide precise estimates of the benefits and harms of hydrocortisone as compared with placebo as only 3% of the planned sample size were enrolled. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04348305. European Union Drug Regulation Authorities Clinical Trials (EudraCT) Database: 2020-001395-15.

Effect of 12 mg vs 6 mg of Dexamethasone on the Number of Days Alive Without Life Support in Adults With COVID-19 and Severe Hypoxemia: The COVID STEROID 2 Randomized Trial.

Importance: A daily dose with 6 mg of dexamethasone is recommended for up to 10 days in patients with severe and critical COVID-19, but a higher dose may benefit those with more severe disease. Objective: To assess the effects of 12 mg/d vs 6 mg/d of dexamethasone in patients with COVID-19 and severe hypoxemia. Design, Setting, and Participants: A multicenter, randomized clinical trial was conducted between August 2020 and May 2021 at 26 hospitals in Europe and India and included 1000 adults with confirmed COVID-19 requiring at least 10 L/min of oxygen or mechanical ventilation. End of 90-day follow-up was on August 19, 2021. Interventions: Patients were randomized 1:1 to 12 mg/d of intravenous dexamethasone (n = 503) or 6 mg/d of intravenous dexamethasone (n = 497) for up to 10 days. Main Outcomes and Measures: The primary outcome was the number of days alive without life support (invasive mechanical ventilation, circulatory support, or kidney replacement therapy) at 28 days and was adjusted for stratification variables. Of the 8 prespecified secondary outcomes, 5 are included in this analysis (the number of days alive without life support at 90 days, the number of days alive out of the hospital at 90 days, mortality at 28 days and at 90 days, and ≥1 serious adverse reactions at 28 days). Results: Of the 1000 randomized patients, 982 were included (median age, 65 [IQR, 55-73] years; 305 [31%] women) and primary outcome data were available for 971 (491 in the 12 mg of dexamethasone group and 480 in the 6 mg of dexamethasone group). The median number of days alive without life support was 22.0 days (IQR, 6.0-28.0 days) in the 12 mg of dexamethasone group and 20.5 days (IQR, 4.0-28.0 days) in the 6 mg of dexamethasone group (adjusted mean difference, 1.3 days [95% CI, 0-2.6 days]; P = .07). Mortality at 28 days was 27.1% in the 12 mg of dexamethasone group vs 32.3% in the 6 mg of dexamethasone group (adjusted relative risk, 0.86 [99% CI, 0.68-1.08]). Mortality at 90 days was 32.0% in the 12 mg of dexamethasone group vs 37.7% in the 6 mg of dexamethasone group (adjusted relative risk, 0.87 [99% CI, 0.70-1.07]). Serious adverse reactions, including septic shock and invasive fungal infections, occurred in 11.3% in the 12 mg of dexamethasone group vs 13.4% in the 6 mg of dexamethasone group (adjusted relative risk, 0.83 [99% CI, 0.54-1.29]). Conclusions and Relevance: Among patients with COVID-19 and severe hypoxemia, 12 mg/d of dexamethasone compared with 6 mg/d of dexamethasone did not result in statistically significantly more days alive without life support at 28 days. However, the trial may have been underpowered to identify a significant difference. Trial Registration: ClinicalTrials.gov Identifier: NCT04509973 and ctri.nic.in Identifier: CTRI/2020/10/028731.