Evaluation of the Fill-it-up-design to use historical control data in randomized clinical trials with two arm parallel group design.

PURPOSE: In the context of clinical research, there is an increasing need for new study designs that help to incorporate already available data. With the help of historical controls, the existing information can be utilized to support the new study design, but of course, inclusion also carries the risk of bias in the study results. METHODS: To combine historical and randomized controls we investigate the Fill-it-up-design, which in the first step checks the comparability of the historical and randomized controls performing an equivalence pre-test. If equivalence is confirmed, the historical control data will be included in the new RCT. If equivalence cannot be confirmed, the historical controls will not be considered at all and the randomization of the original study will be extended. We are investigating the performance of this study design in terms of type I error rate and power. RESULTS: We demonstrate how many patients need to be recruited in each of the two steps in the Fill-it-up-design and show that the family wise error rate of the design is kept at 5 % . The maximum sample size of the Fill-it-up-design is larger than that of the single-stage design without historical controls and increases as the heterogeneity between the historical controls and the concurrent controls increases. CONCLUSION: The two-stage Fill-it-up-design represents a frequentist method for including historical control data for various study designs. As the maximum sample size of the design is larger, a robust prior belief is essential for its use. The design should therefore be seen as a way out in exceptional situations where a hybrid design is considered necessary.

Intensive care unit caseload and workload and their association with outcomes in critically unwell patients: a large registry-based cohort analysis.

BACKGROUND: Too high or too low patient volumes and work amounts may overwhelm health care professionals and obstruct processes or lead to inadequate personnel routine and process flow. We sought to evaluate, whether an association between current caseload, current workload, and outcomes exists in intensive care units (ICU). METHODS: Retrospective cohort analysis of data from an Austrian ICU registry. Data on patients aged ≥ 18 years admitted to 144 Austrian ICUs between 2013 and 2022 were included. A Cox proportional hazards model with ICU mortality as the outcome of interest adjusted with patients' respective SAPS 3, current ICU caseload (measured by ICU occupancy rates), and current ICU workload (measured by median TISS-28 per ICU) as time-dependent covariables was constructed. Subgroup analyses were performed for types of ICUs, hospital care level, and pre-COVID or intra-COVID period. RESULTS: 415 584 patient admissions to 144 ICUs were analysed. Compared to ICU caseloads of 76 to 100%, there was no significant relationship between overuse of ICU capacity and risk of death [HR (95% CI) 1.06 (0.99-1.15), p = 0.110 for > 100%], but for lower utilisation [1.09 (1.02-1.16), p = 0.008 for ≤ 50% and 1.10 (1.05-1.15), p < 0.0001 for 51-75%]. Exceptions were significant associations for caseloads > 100% between 2020 and 2022 [1.18 (1.06-1.30), p = 0.001], i.e., the intra-COVID period. Compared to the reference category of median TISS-28 21-30, lower [0.88 (0.78-0.99), p = 0.049 for ≤ 20], but not higher workloads were significantly associated with risk of death. High workload may be associated with higher mortality in local hospitals [1.09 (1.01-1.19), p = 0.035 for 31-40, 1.28 (1.02-1.60), p = 0.033 for > 40]. CONCLUSIONS: In a system with comparably high intensive care resources and mandatory staffing levels, patients' survival chances are generally not affected by high intensive care unit caseload and workload. However, extraordinary circumstances, such as the COVID-19 pandemic, may lead to higher risk of death, if planned capacities are exceeded. High workload in ICUs in smaller hospitals with lower staffing levels may be associated with increased risk of death.

Quantitative Comparisons of Progressive Supranuclear Palsy Rating Scale Versions Using Item Response Theory.

BACKGROUND: Progressive supranuclear palsy (PSP) is a neurodegenerative, late-onset disease that is challenging in terms of assessment. The Progressive Supranuclear Palsy Rating Scale (PSPRS), a 28-item clinician-reported scale, is the most established clinical outcome assessment method. Recently, the U.S. Food and Drug Administration (FDA) has proposed a subscale of 10 items as an alternative to full PSPRS. OBJECTIVES: To quantitatively evaluate and compare the properties of full PSPRS and the FDA subscale using item response theory. To develop a progression model of the disease and assess relative merits of study designs and analysis options. METHODS: Data of 979 patients from four interventional trials and two registries were available for analysis. Our investigation was divided into: (1) estimating informativeness of the 28 items; (2) estimating disease progression; and (3) comparing the scales, trial designs, and analysis options with respect to power to detect a clinically relevant treatment effect. RESULTS: PSPRS item scores had a low pairwise correlation (r = 0.17 ± 0.14) and the items irritability, sleep difficulty, and postural tremor were uncorrelated with the other items. The FDA-selected items displayed higher correlation (r = 0.35 ± 0.14) and were the basis for a longitudinal item response model including disease progression. Trial simulations indicated that identification of a disease-modifying treatment effect required less than half the study size if the analysis was based on longitudinal item information compared with total scores at end-of-treatment. CONCLUSION: A longitudinal item response model based on the FDA-selected PSPRS items is a promising tool in evaluating treatments for PSP. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Innovative approaches for vaccine trials as a key component of pandemic preparedness - a white paper.

BACKGROUND: WHO postulates the application of adaptive design features in the global clinical trial ecosystem. However, the adaptive platform trial (APT) methodology has not been widely adopted in clinical research on vaccines. METHODS: The VACCELERATE Consortium organized a two-day workshop to discuss the applicability of APT methodology in vaccine trials under non-pandemic as well as pandemic conditions. Core aspects of the discussions are summarized in this article. RESULTS: An "ever-warm" APT appears ideally suited to improve efficiency and speed of vaccine research. Continuous learning based on accumulating APT trial data allows for pre-planned adaptations during its course. Given the relative design complexity, alignment of all stakeholders at all stages of an APT is central. Vaccine trial modelling is crucial, both before and in a pandemic emergency. Various inferential paradigms are possible (frequentist, likelihood, or Bayesian). The focus in the interpandemic interval may be on research gaps left by industry trials. For activation in emergency, template Disease X protocols of syndromal design for pathogens yet unknown need to be stockpiled and updated regularly. Governance of a vaccine APT should be fully integrated into supranational pandemic response mechanisms. DISCUSSION: A broad range of adaptive features can be applied in platform trials on vaccines. Faster knowledge generation comes with increased complexity of trial design. Design complexity should not preclude simple execution at trial sites. Continuously generated evidence represents a return on investment that will garner societal support for sustainable funding. Adaptive design features will naturally find their way into platform trials on vaccines.

Immunogenicity, reactogenicity, and safety of a second booster with BNT162b2 or full-dose mRNA-1273: A randomized VACCELERATE trial in adults aged ≥75 years (EU-COVAT-1-AGED Part B).

OBJECTIVES: To assess the safety and immunogenicity of a fourth vaccination (second booster) in individuals aged ≥75 years. METHODS: Participants were randomized to BNT162b2 (Comirnaty, 30 µg) or messenger RNA (mRNA)-1273 (Spikevax, 100 µg). The primary end point was the rate of two-fold antibody titer increase 14 days after vaccination, targeting the receptor binding domain (RBD) region of wild-type SARS-CoV-2. The secondary end points included changes in neutralizing activity against wild-type and 25 variants. Safety was assessed by monitoring solicited adverse events (AEs) for 7 days. RESULTS: A total of 269 participants (mean age 81 years, mRNA-1273 n = 135/BNT162b2 n = 134) were included. Two-fold anti-RBD immunoglobulin (Ig) G titer increase was achieved by 101 of 129 (78%) and 116 of 133 (87%) subjects in the BNT162b2 and the mRNA-1273 group, respectively (P = 0.054). A second booster of mRNA-1273 provided higher anti-RBD IgG geometric mean titer: 21.326 IU/mL (95% confidence interval: 18.235-24.940) vs BNT162b2: 15.181 IU/mL (95% confidence interval: 13.172-17.497). A higher neutralizing activity was noted for the mRNA-1273 group. The most frequent AE was pain at the injection site (51% in mRNA-1273 and 48% in BNT162b2). Participants in the mRNA-1273 group had less vaccine-related AEs (30% vs 39%). CONCLUSIONS: A second booster of either BNT162b2 or mRNA-1273 provided substantial IgG increase. Full-dose mRNA-1273 provided higher IgG levels and neutralizing capacity against SARS-CoV-2, with similar safety profile for subjects of advanced age.

Methods for non-proportional hazards in clinical trials: A systematic review.

For the analysis of time-to-event data, frequently used methods such as the log-rank test or the Cox proportional hazards model are based on the proportional hazards assumption, which is often debatable. Although a wide range of parametric and non-parametric methods for non-proportional hazards has been proposed, there is no consensus on the best approaches. To close this gap, we conducted a systematic literature search to identify statistical methods and software appropriate under non-proportional hazard. Our literature search identified 907 abstracts, out of which we included 211 articles, mostly methodological ones. Review articles and applications were less frequently identified. The articles discuss effect measures, effect estimation and regression approaches, hypothesis tests, and sample size calculation approaches, which are often tailored to specific non-proportional hazard situations. Using a unified notation, we provide an overview of methods available. Furthermore, we derive some guidance from the identified articles.

Regulatory Issues of Platform Trials: Learnings from EU-PEARL.

Although platform trials have many benefits, the complexity of these designs may result not only in increased methodological but also regulatory and ethical challenges. These aspects were addressed as part of the IMI project EU Patient-Centric Clinical Trial Platforms (EU-PEARL). We reviewed the available guidelines on platform trials in the European Union and the United States. This is supported and complemented by feedback received from regulatory interactions with the European Medicines Agency and the US Food and Drug Administration. Throughout the project we collected the needs of all relevant stakeholders including ethics committees, regulators, and health technology assessment bodies through active dialog and dedicated stakeholder workshops. Furthermore, we focused on methodological aspects and where applicable identified the corresponding guidance. Learnings from the guideline review, regulatory interactions, and workshops are provided. Based on these, a master protocol template was developed. Issues that still need harmonization or clarification in guidelines or where further methodological research is needed are also presented. These include questions around clinical trial submissions in Europe, the need for multiplicity control across the whole master protocol, the use of non-concurrent controls, and the impact of different randomization schemes. Master protocols are an efficient and patient-centered clinical trial design that can expedite drug development. However, they can also introduce additional operational and regulatory complexities. It is important to understand the different requirements of stakeholders upfront and address them in the trial. While relevant guidance is increasing, early dialog with relevant stakeholders can help to further support such designs.

Optimal allocation strategies in platform trials with continuous endpoints.

Platform trials are randomized clinical trials that allow simultaneous comparison of multiple interventions, usually against a common control. Arms to test experimental interventions may enter and leave the platform over time. This implies that the number of experimental intervention arms in the trial may change as the trial progresses. Determining optimal allocation rates to allocate patients to the treatment and control arms in platform trials is challenging because the optimal allocation depends on the number of arms in the platform and the latter typically varies over time. In addition, the optimal allocation depends on the analysis strategy used and the optimality criteria considered. In this article, we derive optimal treatment allocation rates for platform trials with shared controls, assuming that a stratified estimation and a testing procedure based on a regression model are used to adjust for time trends. We consider both, analysis using concurrent controls only as well as analysis methods using concurrent and non-concurrent controls and assume that the total sample size is fixed. The objective function to be minimized is the maximum of the variances of the effect estimators. We show that the optimal solution depends on the entry time of the arms in the trial and, in general, does not correspond to the square root of k allocation rule used in classical multi-arm trials. We illustrate the optimal allocation and evaluate the power and type 1 error rate compared to trials using one-to-one and square root of k allocations by means of a case study.

Simultaneous inference procedures for the comparison of multiple characteristics of two survival functions.

Survival time is the primary endpoint of many randomized controlled trials, and a treatment effect is typically quantified by the hazard ratio under the assumption of proportional hazards. Awareness is increasing that in many settings this assumption is a priori violated, for example, due to delayed onset of drug effect. In these cases, interpretation of the hazard ratio estimate is ambiguous and statistical inference for alternative parameters to quantify a treatment effect is warranted. We consider differences or ratios of milestone survival probabilities or quantiles, differences in restricted mean survival times, and an average hazard ratio to be of interest. Typically, more than one such parameter needs to be reported to assess possible treatment benefits, and in confirmatory trials, the according inferential procedures need to be adjusted for multiplicity. A simple Bonferroni adjustment may be too conservative because the different parameters of interest typically show considerable correlation. Hence simultaneous inference procedures that take into account the correlation are warranted. By using the counting process representation of the mentioned parameters, we show that their estimates are asymptotically multivariate normal and we provide an estimate for their covariance matrix. We propose according to the parametric multiple testing procedures and simultaneous confidence intervals. Also, the logrank test may be included in the framework. Finite sample type I error rate and power are studied by simulation. The methods are illustrated with an example from oncology. A software implementation is provided in the R package nph.

Red blood cell transfusion-related dynamics of extracellular vesicles in intensive care patients: a prospective subanalysis.

Extracellular vesicles (EVs) accumulate during packed red blood cell (PRBC) storage. To date, the involvement of EVs in transfusion-related immunomodulation (TRIM) has not been prospectively evaluated in intensive care unit (ICU) patients. This was a prospective subanalysis of a recent observational feasibility study in postoperative ICU patients after: (1) open aortic surgery (Aorta), (2) bilateral lung transplantation (LuTx), and (3) other types of surgery (Comparison). Patient plasma was collected three times each before and after leukoreduced PRBC transfusion at 30-min intervals. The total number of EVs and EVs derived from erythrocytes (EryEVs), total platelets (total PEVs), activated platelets, granulocytes (GEVs), monocytes, and myeloid cells in PRBC samples and patient plasma were analyzed by flow cytometry. Statistical analysis was performed by Spearman's correlation test, linear mixed models and pairwise comparisons by Wilcoxon matched-pairs test. Twenty-three patients (Aorta n = 5, LuTx n = 9, Comparison n = 9) were included in the final analysis. All EV subgroups analyzed were detectable in all PRBCs samples (n = 23), but concentrations did not correlate with storage time. Moreover, all EVs analyzed were detectable in all plasma samples (n = 138), and EV counts were consistent before transfusion. Concentrations of total EVs, EryEVs, total PEVs, and GEVs increased after transfusion compared with baseline in the entire cohort but not in specific study groups. Furthermore, the change in plasma EV counts (total EVs and EryEVs) after transfusion correlated with PRBC storage time in the entire cohort. Extracellular vesicles were detectable in all PRBC and plasma samples. Individual EV subtypes increased after transfusion in the entire cohort, and in part correlated with storage duration. Future clinical studies to investigate the role of EVs in TRIM are warranted and should anticipate a larger sample size.Trial registration: Clinicaltrials.gov: NCT03782623.

Current state-of-the-art and gaps in platform trials: 10 things you should know, insights from EU-PEARL.

Platform trials bring the promise of making clinical research more efficient and more patient centric. While their use has become more widespread, including their prominent role during the COVID-19 pandemic response, broader adoption of platform trials has been limited by the lack of experience and tools to navigate the critical upfront planning required to launch such collaborative studies. The European Union-Patient-cEntric clinicAl tRial pLatform (EU-PEARL) initiative has produced new methodologies to expand the use of platform trials with an overarching infrastructure and services embedded into Integrated Research Platforms (IRPs), in collaboration with patient representatives and through consultation with U.S. Food and Drug Administration and European Medicines Agency stakeholders. In this narrative review, we discuss the outlook for platform trials in Europe, including challenges related to infrastructure, design, adaptations, data sharing and regulation. Documents derived from the EU-PEARL project, alongside a literature search including PubMed and relevant grey literature (e.g., guidance from regulatory agencies and health technology agencies) were used as sources for a multi-stage collaborative process through which the 10 more important points based on lessons drawn from the EU-PEARL project were developed and summarised as guidance for the setup of platform trials. We conclude that early involvement of critical stakeholder such as regulatory agencies or patients are critical steps in the implementation and later acceptance of platform trials. Addressing these gaps will be critical for attaining the full potential of platform trials for patients. Funding: Innovative Medicines Initiative 2 Joint Undertaking with support from the European Union's Horizon 2020 research and innovation programme and EFPIA.

Immunogenicity and reactogenicity of a first booster with BNT162b2 or full-dose mRNA-1273: A randomised VACCELERATE trial in adults ≥75 years (EU-COVAT-1).

BACKGROUND: Vaccination remains crucial for protection against severe SARS-CoV-2 infection, especially for people of advanced age, however, optimal dosing regimens are as yet lacking. METHODS: EU-COVAT-1-AGED Part A is a randomised controlled, adaptive, multicentre phase II trial evaluating safety and immunogenicity of a 3rd vaccination (1st booster) in individuals ≥75 years. Fifty-three participants were randomised to full-doses of either mRNA-1273 (Spikevax®, 100 µg) or BNT162b2 (Comirnaty®, 30 µg). The primary endpoint was the rate of 2-fold circulating antibody titre increase 14 days post-vaccination measured by quantitative electrochemiluminescence (ECL) immunoassay, targeting RBD region of Wuhan wild-type SARS-CoV-2. Secondary endpoints included the changes in neutralising capacity against wild-type and 25 variants of concern at 14 days and up to 12 months. Safety was assessed by monitoring of solicited adverse events (AEs) for seven days after on-study vaccination. Unsolicited AEs were collected until the end of follow-up at 12 months, SAEs were pursued for a further 30 days. RESULTS: Between 08th of November 2021 and 04th of January 2022, 53 participants ≥75 years received a COVID-19 vaccine as 1st booster. Fifty subjects (BNT162b2 n = 25/mRNA-1273 n = 25) were included in the analyses for immunogenicity at day 14. The primary endpoint of a 2-fold anti-RBD IgG titre increase 14 days after vaccination was reached for all subjects. A 3rd vaccination of full-dose mRNA-1273 provided higher anti-RBD IgG titres (Geometric mean titre) D14 mRNA-127310711 IU/mL (95 %-CI: 8003;14336) vs. BNT162b2: 7090 IU/mL (95 %-CI: 5688;8837). We detected a pattern showing higher neutralising capacity of full-dose mRNA-1273 against wild-type as well as for 23 out of 25 tested variants. INTERPRETATION: Third doses of either BNT162b2 or mRNA-1273 provide substantial circulating antibody increase 14 days after vaccination. Full-dose mRNA-1273 provides higher antibody levels with an overall similar safety profile for people ≥75 years. FUNDING: This trial was funded by the European Commission (Framework Program HORIZON 2020).

The impact of religion on changes in end-of-life practices in European intensive care units: a comparative analysis over 16 years.

PURPOSE: Religious beliefs affect end-of-life practices in intensive care units (ICUs). Changes over time in end-of-life practices were not investigated regarding religions. METHODS: Twenty-two European ICUs (3 regions: Northern, Central, and Southern Europe) participated in both Ethicus-1 (years 1999-2000) and Ethicus-2 studies (years 2015-2016). Data of ICU patients who died or had limitations of life-sustaining therapy were analysed regarding changes in end-of-life practices and patient/physician religious affiliations. Frequencies, timing of decision-making, and religious affiliations of physicians/patients were compared using the same definitions. RESULTS: In total, 4592 adult ICU patients (n = 2807 Ethicus-1, n = 1785 Ethicus-2) were analysed. In both studies, patient and physician religious affiliations were mostly Catholic, Greek Orthodox, Jewish, Protestant, or unknown. Treating physicians (but not patients) commonly reported no religious affiliation (18%). Distribution of end-of-life practices with respect to religion and geographical regions were comparable between the two studies. Withholding [n = 1143 (40.7%) Ethicus-1 and n = 892 (50%) Ethicus-2] and withdrawing [n = 695 (24.8%) Ethicus-1 and n = 692 (38.8%) Ethicus-2] were most commonly decided. No significant changes in end-of-life practices were observed for any religion over 16 years. The number of end-of-life discussions with patients/ families/ physicians increased, while mortality and time until first decision decreased. CONCLUSIONS: Changes in end-of-life practices observed over 16 years appear unrelated to religious affiliations of ICU patients or their treating physicians, but the effects of religiosity and/or culture could not be assessed. Shorter time until decision in the ICU and increased numbers of patient and family discussions may indicate increased awareness of the importance of end-of-life decision-making in the ICU.

Comparing maximum diameter and volume when assessing the growth of small abdominal aortic aneurysms using longitudinal CTA data: cohort study.

BACKGROUND: Monitoring of abdominal aortic aneurysms (AAAs) is currently based on serial measurements of maximum aortic diameter. Additional assessment of aneurysm volume has previously been proposed to possibly improve growth prediction and treatment decisions. To evaluate the use of supplementing volume measurements, the authors aimed to characterise the growth distribution of AAA volume and to compare the growth rates of the maximum diameter and volume at the patient level. METHODS: Maximum diameter and volume were monitored every 6 months in 84 patients with small AAAs, with a total of 331 computed tomographic angiographies (with initial maximum diameters of 30-68 mm). A previously developed statistical growth model for AAAs was applied to assess the growth distribution of volume and to compare individual growth rates for volume and for maximum diameter. RESULTS: The median (25-75% quantile) expansion in volume was 13.4 (6.5-24.7) % per year. Cube root transformed volume and maximum diameter showed a closely linear association with a within-subject correlation of 0.77. At the surgery threshold maximum diameter of 55 mm, the median (25-75% quantile) volume was 132 (103-167) ml. In 39% of subjects, growth rates for volume and maximum diameter were equivalent, in 33% growth was faster in volume and in 27% growth was faster in maximum diameter. CONCLUSION: At the population level, volume and maximum diameter show a substantial association such that the average volume is approximately proportional to the average maximum diameter raised to a power of three. At the individual level, however, in the majority of patient's AAAs grow at different pace in different dimensions. Hence, closer monitoring of aneurysms with sub-critical diameter but suspicious morphology may benefit from complementing maximum diameter by volume or related measurements.

On the use of non-concurrent controls in platform trials: a scoping review.

BACKGROUND: Platform trials gained popularity during the last few years as they increase flexibility compared to multi-arm trials by allowing new experimental arms entering when the trial already started. Using a shared control group in platform trials increases the trial efficiency compared to separate trials. Because of the later entry of some of the experimental treatment arms, the shared control group includes concurrent and non-concurrent control data. For a given experimental arm, non-concurrent controls refer to patients allocated to the control arm before the arm enters the trial, while concurrent controls refer to control patients that are randomised concurrently to the experimental arm. Using non-concurrent controls can result in bias in the estimate in case of time trends if the appropriate methodology is not used and the assumptions are not met. METHODS: We conducted two reviews on the use of non-concurrent controls in platform trials: one on statistical methodology and one on regulatory guidance. We broadened our searches to the use of external and historical control data. We conducted our review on the statistical methodology in 43 articles identified through a systematic search in PubMed and performed a review on regulatory guidance on the use of non-concurrent controls in 37 guidelines published on the EMA and FDA websites. RESULTS: Only 7/43 of the methodological articles and 4/37 guidelines focused on platform trials. With respect to the statistical methodology, in 28/43 articles, a Bayesian approach was used to incorporate external/non-concurrent controls while 7/43 used a frequentist approach and 8/43 considered both. The majority of the articles considered a method that downweights the non-concurrent control in favour of concurrent control data (34/43), using for instance meta-analytic or propensity score approaches, and 11/43 considered a modelling-based approach, using regression models to incorporate non-concurrent control data. In regulatory guidelines, the use of non-concurrent control data was considered critical but was deemed acceptable for rare diseases in 12/37 guidelines or was accepted in specific indications (12/37). Non-comparability (30/37) and bias (16/37) were raised most often as the general concerns with non-concurrent controls. Indication specific guidelines were found to be most instructive. CONCLUSIONS: Statistical methods for incorporating non-concurrent controls are available in the literature, either by means of methods originally proposed for the incorporation of external controls or non-concurrent controls in platform trials. Methods mainly differ with respect to how the concurrent and non-concurrent data are combined and temporary changes handled. Regulatory guidance for non-concurrent controls in platform trials are currently still limited.

Nationwide analysis of hospital admissions and outcomes of patients with SARS-CoV-2 infection in Austria in 2020 and 2021.

This retrospective study evaluated temporal and regional trends of patient admissions to hospitals, intensive care units (ICU), and intermediate care units (IMCU) as well as outcomes during the COVID-19 pandemic in Austria. We analysed anonymous data from patients admitted to Austrian hospitals with COVID-19 between January 1st, 2020 and December 31st, 2021. We performed descriptive analyses and logistic regression analyses for in-hospital mortality, IMCU or ICU admission, and in-hospital mortality following ICU admission. 68,193 patients were included, 8304 (12.3%) were primarily admitted to ICU, 3592 (5.3%) to IMCU. Hospital mortality was 17.3%; risk factors were male sex (OR 1.67, 95% CI 1.60-1.75, p < 0.001) and high age (OR 7.86, 95% CI 7.07-8.74, p < 0.001 for 90+ vs. 60-64 years). Mortality was higher in the first half of 2020 (OR 1.15, 95% CI 1.04-1.27, p = 0.01) and the second half of 2021 (OR 1.11, 95% CI 1.05-1.17, p < 0.001) compared to the second half of 2020 and differed regionally. ICU or IMCU admission was most likely between 55 and 74 years, and less likely in younger and older age groups. We find mortality in Austrian COVID-19-patients to be almost linearly associated with age, ICU admission to be less likely in older individuals, and outcomes to differ between regions and over time.

Red blood cell transfusion-related eicosanoid profiles in intensive care patients-A prospective, observational feasibility study.

Introduction: Eicosanoids are bioactive lipids present in packed red blood cells (PRBCs), and might play a role in transfusion-related immunomodulation (TRIM). We tested the feasibility of analyzing eicosanoid profiles in PRBC supernatant and in plasma samples of postoperative intensive care unit (ICU) patients transfused with one unit of PRBCs. Methods: We conducted a prospective, observational feasibility study enrolling postoperative ICU patients: 1) patients treated with acetylsalicylic acid following abdominal aortic surgery (Aorta); 2) patients on immunosuppressants after bilateral lung transplantation (LuTx); and 3) patients undergoing other types of major surgery (Comparison). Abundances of arachidonic acid (AA) and seven pre-defined eicosanoids were assessed by liquid chromatography and tandem mass spectrometry. PRBC supernatant was sampled directly from the unit immediately prior to transfusion. Spearman's correlations between eicosanoid abundance in PRBCs and storage duration were assessed. Patient plasma was collected at 30-min intervals: Three times each before and after transfusion. To investigate temporal changes in eicosanoid abundances, we fitted linear mixed models. Results: Of 128 patients screened, 21 were included in the final analysis (Aorta n = 4, LuTx n = 8, Comparison n = 9). In total, 21 PRBC and 125 plasma samples were analyzed. Except for 20-hydroxyeicosatetraenoic acid (HETE), all analyzed eicosanoids were detectable in PRBCs, and their abundance positively correlated with storage duration of PRBCs. While 5-HETE, 12-HETE/8-HETE, 15-HETE, 20-HETE, and AA were detectable in virtually all plasma samples, 9-HETE and 11-HETE were detectable in only 57% and 23% of plasma samples, respectively. Conclusions: Recruitment of ICU patients into this transfusion study was challenging but feasible. Eicosanoid abundances increased in PRBC supernatants during storage. In plasma of ICU patients, eicosanoid abundances were ubiquitously detectable and showed limited fluctuations over time prior to transfusion. Taken together, larger clinical studies seem warranted and feasible to further investigate the role of PRBC-derived eicosanoids in TRIM.

Online error rate control for platform trials.

Platform trials evaluate multiple experimental treatments under a single master protocol, where new treatment arms are added to the trial over time. Given the multiple treatment comparisons, there is the potential for inflation of the overall type I error rate, which is complicated by the fact that the hypotheses are tested at different times and are not necessarily pre-specified. Online error rate control methodology provides a possible solution to the problem of multiplicity for platform trials where a relatively large number of hypotheses are expected to be tested over time. In the online multiple hypothesis testing framework, hypotheses are tested one-by-one over time, where at each time-step an analyst decides whether to reject the current null hypothesis without knowledge of future tests but based solely on past decisions. Methodology has recently been developed for online control of the false discovery rate as well as the familywise error rate (FWER). In this article, we describe how to apply online error rate control to the platform trial setting, present extensive simulation results, and give some recommendations for the use of this new methodology in practice. We show that the algorithms for online error rate control can have a substantially lower FWER than uncorrected testing, while still achieving noticeable gains in power when compared with the use of a Bonferroni correction. We also illustrate how online error rate control would have impacted a currently ongoing platform trial.

Association of immediate versus delayed extubation of patients admitted to intensive care units postoperatively and outcomes: A retrospective study.

AIM OF THIS STUDY: This study seeks to investigate, whether extubation of tracheally intubated patients admitted to intensive care units (ICU) postoperatively either immediately at the day of admission (day 1) or delayed at the first postoperative day (day 2) is associated with differences in outcomes. MATERIALS AND METHODS: We performed a retrospective analysis of data from an Austrian ICU registry. Adult patients admitted between January 1st, 2012 and December 31st, 2019 following elective and emergency surgery, who were intubated at the day 1 and were extubated at day 1 or day 2, were included. We performed logistic regression analyses for in-hospital mortality and over-sedation or agitation following extubation. RESULTS: 52 982 patients constituted the main study population. 1 231 (3.3%) patients extubated at day 1 and 958 (5.9%) at day 2 died in hospital, 464 (1.3%) patients extubated at day 1 and 613 (3.8%) at day 2 demonstrated agitation or over-sedation after extubation during ICU stay; OR (95% CI) for in-hospital mortality were OR 1.17 (1.01-1.35, p = 0.031) and OR 2.15 (1.75-2.65, p<0.001) for agitation or over-sedation. CONCLUSIONS: We conclude that immediate extubation as soon as deemed feasible by clinicians is associated with favourable outcomes and may thus be considered preferable in tracheally intubated patients admitted to ICU postoperatively.