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OBJECTIVES: This study aims to assess pharmacodynamic target attainment in critically ill patients and identify factors influencing target attainment and mortality outcomes. METHODS: We analysed data from the DOLPHIN trial. Beta-lactam and ciprofloxacin peak and trough concentration were measured within the first 36 h (T1) after initiation of treatment. The study outcome included the rate of pharmacodynamic target attainment of 100 % ƒT>1xEpidemiological cut-off value (ECOFF) for beta-lactams, and of fAUC0-24h/ECOFF>125 for ciprofloxacin at T1. RESULTS: The target attainment rates were 78.1 % (n = 228/292) for beta-lactams, and 41.5 % (n = 39/94) for ciprofloxacin, respectively. Lower estimated glomerular filtration rate and higher SOFA score were associated with target attainment. In patients receiving beta-lactams, 28-day mortality was significantly higher in patients who attained 100 % ƒT>1xECOFF (28.9 % vs. 12.5 %; p = 0.01). In the multivariate analysis, attainment of 100 % ƒT>4xECOFF, but not 100 % ƒT>1xECOFF, was associated with a higher 28-day mortality (OR 2.70, 95 % CI 1.36-5.48 vs. OR 1.28, 95 % CI 0.53-3.34). CONCLUSIONS: A high rate of target attainment (100 % ƒT>1xECOFF) for beta-lactams and a lower rate for ciprofloxacin was observed. Achieving exposures of 100 % ƒT>4xECOFF was associated with 28-day mortality. The impact of antibiotic target attainment on clinical outcome needs to be a focus of future research.

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OBJECTIVES: This study aimed to provide new insights into the impact of emergency department (ED) to ICU time on hospital mortality, stratifying patients by academic and nonacademic teaching (NACT) hospitals, and considering Acute Physiology and Chronic Health Evaluation (APACHE)-IV probability and ED-triage scores. DESIGN, SETTING, AND PATIENTS: We conducted a retrospective cohort study (2009-2020) using data from the Dutch National Intensive Care Evaluation registry. Patients directly admitted from the ED to the ICU were included from four academic and eight NACT hospitals. Odds ratios (ORs) for mortality associated with ED-to-ICU time were estimated using multivariable regression, both crude and after adjusting for and stratifying by APACHE-IV probability and ED-triage scores. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 28,455 patients were included. The median ED-to-ICU time was 1.9 hours (interquartile range, 1.2-3.1 hr). No overall association was observed between ED-to-ICU time and hospital mortality after adjusting for APACHE-IV probability (p = 0.36). For patients with an APACHE-IV probability greater than 55.4% (highest quintile) and an ED-to-ICU time greater than 3.4 hours the adjusted OR (ORsadjApache) was 1.24 (95% CI, 1.00-1.54; p < 0.05) as compared with the reference category (< 1.1 hr). In the academic hospitals, the ORsadjApache for ED-to-ICU times of 1.6-2.3, 2.3-3.4, and greater than 3.4 hours were 1.21 (1.01-1.46), 1.21 (1.00-1.46), and 1.34 (1.10-1.64), respectively. In NACT hospitals, no association was observed (p = 0.07). Subsequently, ORs were adjusted for ED-triage score (ORsadjED). In the academic hospitals the ORsadjED for ED-to-ICU times greater than 3.4 hours was 0.98 (0.81-1.19), no overall association was observed (p = 0.08). In NACT hospitals, all time-ascending quintiles had ORsadjED values of less than 1.0 (p < 0.01). CONCLUSIONS: In patients with the highest APACHE-IV probability at academic hospitals, a prolonged ED-to-ICU time was associated with increased hospital mortality. We found no significant or consistent unfavorable association in lower APACHE-IV probability groups and NACT hospitals. The association between longer ED-to-ICU time and higher mortality was not found after adjustment and stratification for ED-triage score.

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BACKGROUND: Electronic informed consent (eConsent) usage has expanded in recent years in Europe, especially during the pandemic. Slow recruitment rate and limitations in participant outreach are the challenges often faced in clinical research. Given the benefits of eConsent and group counselling reported in the literature, group eConsent was implemented in recruitment for the SWITCH-ON study. We aim to explore the experience of participants who attended group eConsent for the SWITCH-ON study and evaluate its potential for future use. METHODS: SWITCH-ON study aims to analyse the immunogenicity of a healthy population following bivalent COVID-19 booster vaccination. Four hundred thirty-four healthcare workers aged 18-65 were successfully recruited and sent a questionnaire about their experience with group eConsent. Out of 399 completed questionnaires (response rate 92%), 39 participants did not join group eConsent. The remaining 360 responses were included in the final analysis. Quantitative and qualitative data were reported using descriptive statistical analysis and thematic analysis respectively. RESULTS: Participants found that group eConsent was an efficient method that it allowed them to hear each other's questions and concerns and created a sense of togetherness. However, limited privacy, barriers to asking questions in a group, and peer pressure can limit the use of group eConsent. One hundred sixty-five (46%) participants thought that group eConsent was suitable to recruit participants with diseases or conditions, while 87 (24%) reported limitations with this method. The remaining participants suggested that applicability of group eConsent depended on the diseases or conditions of the study population, and one-to-one conversation should always be available. Participants who had experienced both one-to-one and group eConsent shared different preferred consent formats for future studies. CONCLUSION: Group eConsent was positively evaluated by the participants of a low-risk vaccination study. Participants advised using webinars to provide general information about the study, followed by an individual session for each participant, would retain the benefits of group eConsent and minimise the limitations it posed. This proposed setting addresses privacy questions and makes group eConsent easier to implement. TRIAL REGISTRATION: ClinicalTrials.gov NCT05471440 (registered on 22nd of July, 2022).

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BACKGROUND: Insight into cellular immune responses to COVID-19 vaccinations is crucial for optimizing booster programs in kidney transplant recipients (KTRs). METHODS: In an immunologic substudy of a multicenter randomized controlled trial (NCT05030974) investigating different repeated vaccination strategies in KTR who showed poor serological responses after 2 or 3 doses of an messenger RNA (mRNA)-based vaccine, we compared SARS-CoV-2-specific interleukin-21 memory T-cell and B-cell responses by enzyme-linked immunosorbent spot (ELISpot) assays and serum IgG antibody levels. Patients were randomized to receive: a single dose of mRNA-1273 (100 µg, n = 25), a double dose of mRNA-1273 (2 × 100 µg, n = 25), or a single dose of adenovirus type 26 encoding the SARS-CoV-2 spike glycoprotein (Ad26.COV2.S) (n = 25). In parallel, we also examined responses in 50 KTR receiving 100 µg mRNA-1273, randomized to continue (n = 25) or discontinue (n = 25) mycophenolate mofetil/mycophenolic acid. As a reference, the data were compared with KTR who received 2 primary mRNA-1273 vaccinations. RESULTS: Repeated vaccination increased the seroconversion rate from 21% to 66% in all patients, which was strongly associated with enhanced levels of SARS-CoV-2-specific interleukin-21 memory T cells (odd ratio, 3.84 [1.89-7.78]; P < 0.001) and B cells (odd ratio, 35.93 [6.94-186.04]; P < 0.001). There were no significant differences observed in these responses among various vaccination strategies. In contrast to KTR vaccinated with 2 primary vaccinations, the number of antigen-specific memory B cells demonstrated potential for classifying seroconversion after repeated vaccination (area under the curve, 0.64; 95% confidence interval, 0.37-0.90; P = 0.26 and area under the curve, 0.95; confidence interval, 0.87-0.97; P < 0.0001, respectively). CONCLUSIONS: Our study emphasizes the importance of virus-specific memory T- and B-cell responses for comprehensive understanding of COVID-19 vaccine efficacy among KTR.

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Waning antibody responses after COVID-19 vaccination combined with the emergence of the SARS-CoV-2 Omicron lineage led to reduced vaccine effectiveness. As a countermeasure, bivalent mRNA-based booster vaccines encoding the ancestral spike protein in combination with that of Omicron BA.1 or BA.5 were introduced. Since then, different BA.2-descendent lineages have become dominant, such as XBB.1.5, JN.1, or EG.5.1. Here, we report post-hoc analyses of data from the SWITCH-ON study, assessing how different COVID-19 priming regimens affect the immunogenicity of bivalent booster vaccinations and breakthrough infections (NCT05471440). BA.1 and BA.5 bivalent vaccines boosted neutralizing antibodies and T-cells up to 3 months after boost; however, cross-neutralization of XBB.1.5 was poor. Interestingly, different combinations of prime-boost regimens induced divergent responses: participants primed with Ad26.COV2.S developed lower binding antibody levels after bivalent boost while neutralization and T-cell responses were similar to mRNA-based primed participants. In contrast, the breadth of neutralization was higher in mRNA-primed and bivalent BA.5 boosted participants. Combined, our data further support the current use of monovalent vaccines based on circulating strains when vaccinating risk groups, as recently recommended by the WHO. We emphasize the importance of the continuous assessment of immune responses targeting circulating variants to guide future COVID-19 vaccination policies.

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Recently, the importance of efficient and effective health care has been recognized, especially during the acute phase of the Coronavirus Disease-2019 (COVID-19) pandemic. Intensive care units (ICUs) have faced an immense workload, with massive numbers of patients being treated in a very short period of time. In general, ICUs are required to deliver high-quality care at all times during the year. At the same time, high-quality organizational goals may not be aligned with the interests, motivation, and development of individual staff members (eg, nurses, and doctors). For management of the ICU, it is important to balance the organizational goals and development of the staff members ("their human capital"), usually referred to as human resource management. Although many studies have considered this area, no holistic view of the topic has been presented. Such a holistic view may help leadership and/or other stakeholders at the ICU to design a better learning health system. This pragmatic review aims to provide a conceptual model for the management of ICUs. Future research may also use this conceptual model for studying important factors for designing and understanding human resources in an ICU.

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AIMS: This randomized controlled pilot study aimed to assess the differences in the frequency, type and severity of prescribing errors made by medical students when assessed in an electronic (e-)prescribing system compared to a traditional prescribing method (e.g., typing out a prescription). METHODS: Fourth year medical students in the period of 1 November to 31 July 2023, were asked to participate in this single-centre prospective, randomized, controlled intervention study. Participants performed a prescribing assessment in either an e-prescribing system (intervention group) or in a more traditional prescribing platform (control group). The prescriptions were checked for errors, graded and categorized. Differences in prescribing errors, error categories and severity were analysed. RESULTS: Out of 334 students, 84 participated in the study. Nearly all participants (98.8%) made 1 or more prescribing errors, primarily involving inadequate information errors. In the intervention group, more participants made prescribing errors involving the prescribed amount (71.4 vs. 19.0%; P < .01), but fewer involving administrative errors (2.4 vs. 19.0%; P = .03). Prescribing-method-specific errors were identified in 4.8 and 40.5% of the intervention and control group, respectively, with significant differences in overlapping errors as well. CONCLUSION: This pilot study shows the importance of training e-prescribing competencies in medical curricula, in addition to traditional prescribing methods. It identifies prescribing-method-specific prescribing errors and emphasizes the need for further research to define e-prescribing competencies. Additionally, the need for an accessible real-life-like e-prescribing environment tailored to educators and students is essential for effective learning and incorporation of e-prescribing into medical curricula.

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Model-informed precision dosing (MIPD) might be used to optimize antibiotic treatment. Procalcitonin (PCT) is a biomarker for severity of infection and response to antibiotic treatment. The aim of this study was to assess the impact of MIPD on the course of PCT and to investigate the association of PCT with pharmacodynamic target (PDT) attainment in critically ill patients. This is a secondary analysis of the DOLPHIN trial, a multicentre, open-label, randomised controlled trial. Patients with a PCT value available at day 1 (T1), day 3 (T3), or day 5 (T5) after randomisation were included. The primary outcome was the absolute difference in PCT concentration at T1, T3, and T5 between the MIPD and the standard dosing group. In total, 662 PCT concentrations from 351 critically ill patients were analysed. There was no statistically significant difference in PCT concentration between the trial arms at T1, T3, or T5. The median PCT concentration was highest in patients who exceeded 10× PDT at T1 [13.15 ng/mL (IQR 5.43-22.75)]. In 28-day non-survivors and in patients that exceeded PDT at T1, PCT decreased significantly between T1 and T3, but plateaued between T3 and T5. PCT concentrations were not significantly different between patients receiving antibiotic treatment with or without MIPD guidance. The potential of PCT to guide antibiotic dosing merits further investigation.

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BACKGROUND AND IMPORTANCE: Sudden cardiac arrest has a high incidence and often leads to death. A treatment option that might improve the outcomes in refractory cardiac arrest is Extracorporeal Cardiopulmonary Resuscitation (ECPR). OBJECTIVES: This study investigates the number of in-hospital cardiac arrest (IHCA) and out-of-hospital cardiac arrest (OHCA) patients eligible to ECPR and identifies clinical characteristics that may help to identify which patients benefit the most from ECPR. DESIGN, SETTINGS AND PARTICIPANTS: A retrospective two-centre study was conducted in Rotterdam, the Netherlands. All IHCA and OHCA patients between 1 January 2017 and 1 January 2020 were screened for eligibility to ECPR. The primary outcome was the percentage of patients eligible to ECPR and patients treated with ECPR. The secondary outcome was the comparison of the clinical characteristics and outcomes of patients eligible to ECPR treated with conventional Cardiopulmonary Resuscitation (CCPR) vs. those of patients treated with ECPR. MAIN RESULTS: Out of 1246 included patients, 412 were IHCA patients and 834 were OHCA patients. Of the IHCA patients, 41 (10.0%) were eligible to ECPR, of whom 20 (48.8%) patients were actually treated with ECPR. Of the OHCA patients, 83 (9.6%) were eligible to ECPR, of whom 23 (27.7%) were actually treated with ECPR. In the group IHCA patients eligible to ECPR, no statistically significant difference in survival was found between patients treated with CCPR and patients treated with ECPR (hospital survival 19.0% vs. 15.0% respectively, 4.0% survival difference 95% confidence interval -21.3 to 28.7%). In the group OHCA patients eligible to ECPR, no statistically significant difference in-hospital survival was found between patients treated with CCPR and patients treated with ECPR (13.3% vs. 21.7% respectively, 8.4% survival difference 95% confidence interval -30.3 to 10.2%). CONCLUSION: This retrospective study shows that around 10% of cardiac arrest patients are eligible to ECPR. Less than half of these patients eligible to ECPR were actually treated with ECPR in both IHCA and OHCA.

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BACKGROUND: The role of haloperidol as treatment for ICU delirium and related symptoms remains controversial despite two recent large controlled trials evaluating its efficacy and safety. We sought to determine whether haloperidol when compared to placebo in critically ill adults with delirium reduces days with delirium and coma and improves delirium-related sequelae. METHODS: This multi-center double-blind, placebo-controlled randomized trial at eight mixed medical-surgical Dutch ICUs included critically ill adults with delirium (Intensive Care Delirium Screening Checklist ≥ 4 or a positive Confusion Assessment Method for the ICU) admitted between February 2018 and January 2020. Patients were randomized to intravenous haloperidol 2.5 mg or placebo every 8 h, titrated up to 5 mg every 8 h if delirium persisted until ICU discharge or up to 14 days. The primary outcome was ICU delirium- and coma-free days (DCFDs) within 14 days after randomization. Predefined secondary outcomes included the protocolized use of sedatives for agitation and related behaviors, patient-initiated extubation and invasive device removal, adverse drug associated events, mechanical ventilation, ICU length of stay, 28-day mortality, and long-term outcomes up to 1-year after randomization. RESULTS: The trial was terminated prematurely for primary endpoint futility on DSMB advice after enrolment of 132 (65 haloperidol; 67 placebo) patients [mean age 64 (15) years, APACHE IV score 73.1 (33.9), male 68%]. Haloperidol did not increase DCFDs (adjusted RR 0.98 [95% CI 0.73-1.31], p = 0.87). Patients treated with haloperidol (vs. placebo) were less likely to receive benzodiazepines (adjusted OR 0.41 [95% CI 0.18-0.89], p = 0.02). Effect measures of other secondary outcomes related to agitation (use of open label haloperidol [OR 0.43 (95% CI 0.12-1.56)] and other antipsychotics [OR 0.63 (95% CI 0.29-1.32)], self-extubation or invasive device removal [OR 0.70 (95% CI 0.22-2.18)]) appeared consistently more favorable with haloperidol, but the confidence interval also included harm. Adverse drug events were not different. Long-term secondary outcomes (e.g., ICU recall and quality of life) warrant further study. CONCLUSIONS: Haloperidol does not reduce delirium in critically ill delirious adults. However, it may reduce rescue medication requirements and agitation-related events in delirious ICU patients warranting further evaluation. TRIAL REGISTRATION: ClinicalTrials.gov (#NCT03628391), October 9, 2017.

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BACKGROUND: Out-of-hospital cardiac arrest (OHCA) is a leading cause of death worldwide. Cardiac rhythms of OHCA patients can change during transportation and transfer from emergency medical services (EMS) to the emergency department (ED). OBJECTIVE: Our objective was to study the prevalence of cardiac rhythm changes during transfer from the EMS to the ED in OHCA patients and the possible association with clinical outcomes. METHODS: We retrospectively studied adult OHCA patients admitted to the ED between January 2017 and December 2019. The primary outcome was the incidence of cardiac rhythm changes during transfer from EMS to the ED. Secondary outcomes were: ED survival, intensive care unit survival, hospital survival, and maximum Glasgow Coma Scale score during admission. RESULTS: We included 625 patients, of whom there were 49 (7.8%) in the rhythm change group and 576 in the no rhythm change group. ED survival was significantly lower in the rhythm change group (26.5%) vs. the no rhythm change group (78.5%, p < 0.01). CONCLUSION: Cardiac rhythm changes can occur in OHCA patients during transfer from EMS to the ED. Our results showed some evidence that these changes are associated with a lower ED survival.

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OBJECTIVES: Antibiotic dosing is not optimal in the ICU. Our recent trial investigated the effect of model-informed precision dosing (MIPD) of beta-lactam antibiotics and ciprofloxacin and showed no significant differences in clinical outcomes in all patients. This study aimed to identify subgroups of patients in which the MIPD of these antibiotics could be beneficial for clinical outcomes. METHODS: We analysed data from the DOLPHIN randomized controlled trial, which compared MIPD to standard dosing of beta-lactam antibiotics and ciprofloxacin in 388 ICU patients. We divided patients into subgroups based on baseline characteristics and assessed the effect of MIPD on 28-day mortality, 6-month mortality, change in sequential organ failure assessment (delta-SOFA), and ICU length of stay (LOS). RESULTS: We found a lower 28-day mortality in patients with a SOFA below 8 randomized to MIPD (OR 0.40; 95% CI 0.17-0.88). However, patients with a higher SOFA show an increased 28-day mortality (OR 1.94; 95% CI 1.07-3.59) in the MIPD group. ICU LOS was increased in patients receiving MIPD with a SOFA below 8 (IRR 1.36; 95% CI 1.01-1.83) and those receiving MIPD for ceftriaxone (IRR 1.76; 95% CI 1.24-2.51). Patients receiving a dose recommendation within 24 hours show a trend towards decreased ICU LOS (IRR 0.77; 95% CI 0.52-1.16) and higher delta-SOFA (estimate -1.19; 95% CI -2.98-0.60). CONCLUSIONS: ICU patients with a SOFA below 8 using MIPD had an increased ICU LOS but a lower 28-day mortality. Fast dose recommendations using MIPD of beta-lactam antibiotics and ciprofloxacin needs to be investigated in ICU patients.

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INTRODUCTION: Vancomycin is used in intensive care unit (ICU) patients for the treatment of infections caused by gram-positive bacteria. The vancomycin pharmacokinetic/pharmacodynamic index is a ratio of the area under the concentration to the minimum inhibitory concentration ≥400-600 h*mg/L. This target can generally be achieved by a plasma concentration of 20-25 mg/L. Together with the pathophysiological alterations and pharmacokinetic variability associated with critical illness, the use of continuous renal replacement therapy (CRRT) may complicate the attainment of adequate vancomycin concentrations. The primary objective was the prevalence of attainment of vancomycin concentrations 20-25 mg/L after 24 h in adult ICU patients receiving CRRT. Secondary outcomes were to evaluate target attainment at days 2 and 3 and to calculate vancomycin clearance (CL) by CRRT and residual diuresis. METHODS: We performed a prospective observational study in adult ICU patients on CRRT, which received at least 24 h continuous infusion of vancomycin. Between May 2020 and February 2021, daily vancomycin residual blood gas and dialysate samples were collected from 20 patients, every 6 h and if possible vancomycin urine samples. Vancomycin was analysed with an immunoassay method. The CL by CRRT was calculated by a different approach correcting for the downtime and providing insight into the degree of filter patency. RESULTS: The proportion of patients with vancomycin concentrations <20 mg/L was 50% 24 h after starting vancomycin (n = 10). No differences were observed in patient characteristics. The target vancomycin concentration 20-25 mg/L was only achieved in 30% of the patients. On days 2 and 3, despite the use of TDM and albeit in lower percentages, sub- and supratherapeutic levels were still observed. Taking downtime and filter patency into account resulted in lower vancomycin CL. CONCLUSIONS: 50% of the studied ICU patients on CRRT showed subtherapeutic vancomycin concentrations 24 h after starting therapy. The results reveal that optimization of vancomycin dosage during CRRT therapy is needed.

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T-cell-mediated help to B cells is required for the development of humoral responses, in which the cytokine interleukin (IL)-21 is key. Here, we studied the mRNA-1273 vaccine-induced SARS-CoV-2-specific memory T-cell IL-21 response, memory B cell response, and immunoglobulin (Ig)G antibody levels in peripheral blood at 28 days after the second vaccination by ELISpot and the fluorescent bead-based multiplex immunoassay, respectively. We included 40 patients with chronic kidney disease (CKD), 34 patients on dialysis, 63 kidney transplant recipients (KTR), and 47 controls. We found that KTR, but not patients with CKD and those receiving dialysis, showed a significantly lower number of SARS-CoV-2-specific IL-21 producing T cells than controls (P < .001). KTR and patients with CKD showed lower numbers of SARS-CoV-2-specific IgG-producing memory B cells when compared with controls (P < .001 and P = .01, respectively). The T-cell IL-21 response was positively associated with the SARS-CoV-2-specific B cell response and the SARS-CoV-2 spike S1-specific IgG antibody levels (both Pearson r = 0.5; P < .001). In addition, SARS-CoV-2-specific B cell responses were shown to be IL-21 dependent. Taken together, we show that IL-21 signaling is important in eliciting robust B cell-mediated immune responses in patients with kidney disease and KTR.

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Cytokines are regulators of the immune response against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). However, the contribution of cytokine-secreting CD4+ and CD8+ memory T cells to the SARS-CoV-2-specific humoral immune response in immunocompromised kidney patients is unknown. Here, we profiled 12 cytokines after stimulation of whole blood obtained 28 days post second 100 µg mRNA-1273 vaccination with peptides covering the SARS-CoV-2 spike (S)-protein from patients with chronic kidney disease (CKD) stage 4/5, on dialysis, kidney transplant recipients (KTR), and healthy controls. Unsupervised hierarchical clustering analysis revealed two distinct vaccine-induced cytokine profiles. The first profile was characterized by high levels of T-helper (Th)1 (IL-2, TNF-α, and IFN-γ) and Th2 (IL-4, IL-5, IL-13) cytokines, and low levels of Th17 (IL-17A, IL-22) and Th9 (IL-9) cytokines. This cluster was dominated by patients with CKD, on dialysis, and healthy controls. In contrast, the second cytokine profile contained predominantly KTRs producing mainly Th1 cytokines upon re-stimulation, with lower levels or absence of Th2, Th17, and Th9 cytokines. Multivariate analyses indicated that a balanced memory T cell response with the production of Th1 and Th2 cytokines was associated with high levels of S1-specific binding and neutralizing antibodies mainly at 6 months after second vaccination. In conclusion, seroconversion is associated with the balanced production of cytokines by memory T cells. This emphasizes the importance of measuring multiple T cell cytokines to understand their influence on seroconversion and potentially gain more information about the protection induced by vaccine-induced memory T cells.

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BACKGROUND: Bivalent mRNA-based COVID-19 vaccines encoding the ancestral and omicron spike (S) protein were developed as a countermeasure against antigenically distinct SARS-CoV-2 variants. We aimed to assess the (variant-specific) immunogenicity and reactogenicity of mRNA-based bivalent omicron (BA.1) vaccines in individuals who were primed with adenovirus-based or mRNA-based vaccines encoding the ancestral spike protein. METHODS: We analysed results of the direct boost group of the SWITCH ON study, an open-label, multicentre, randomised controlled trial. Health-care workers from four academic hospitals in the Netherlands aged 18-65 years who had completed a primary COVID-19 vaccination regimen and received one booster of an mRNA-based vaccine, given no later than 3 months previously, were eligible. Participants were randomly assigned (1:1) using computer software in block sizes of 16 and 24 to receive an omicron BA.1 bivalent booster straight away (direct boost group) or a bivalent omicron BA.5 booster, postponed for 90 days (postponed boost group), stratified by priming regimen. The BNT162b2 OMI BA.1 boost was given to participants younger than 45 years, and the mRNA-1273.214 boost was given to participants 45 years or older, as per Dutch guidelines. The direct boost group, whose results are presented here, were divided into four subgroups for analysis: (1) Ad26.COV2.S (Johnson & Johnson) prime and BNT162b2 OMI BA.1 (BioNTech-Pfizer) boost (Ad/P), (2) mRNA-based prime and BNT162b2 OMI BA.1 boost (mRNA/P), (3) Ad26.COV2.S prime and mRNA-1273.214 (Moderna) boost (Ad/M), and (4) mRNA-based prime and mRNA-1273.214 boost (mRNA/M). The primary outcome was fold change in S protein S1 subunit-specific IgG antibodies before and 28 days after booster vaccination. The primary outcome and safety were assessed in all participants except those who withdrew, had a SARS-CoV-2 breakthrough infection, or had a missing blood sample at day 0 or day 28. This trial is registered with ClinicalTrials.gov, NCT05471440. FINDINGS: Between Sept 2 and Oct 4, 2022, 219 (50%) of 434 eligible participants were randomly assigned to the direct boost group; 187 participants were included in the primary analyses; exclusions were mainly due to SARS-CoV-2 infection between days 0 and 28. From the 187 included participants, 138 (74%) were female and 49 (26%) were male. 42 (22%) of 187 participants received Ad/P and 44 (24%) mRNA/P (those aged <45 years), and 45 (24%) had received Ad/M and 56 (30%) mRNA/M (those aged ≥45 years). S1-specific binding antibody concentrations increased 7 days after bivalent booster vaccination and remained stable over 28 days in all four subgroups (geometric mean ratio [GMR] between day 0 and day 28 was 1·15 [95% CI 1·12-1·19] for the Ad/P group, 1·17 [1·14-1·20] for the mRNA/P group, 1·20 [1·17-1·23] for the Ad/M group, and 1·16 [1·13-1·19] for the mRNA/M group). We observed no significant difference in the GMR between the Ad/P and mRNA/P groups (p=0·51). The GMR appeared to be higher in the Ad/M group than in the mRNA/M group, but was not significant (p=0·073). Most side-effects were mild to moderate in severity and resolved within 48 h in most individuals. INTERPRETATION: Booster vaccination with mRNA-1273.214 or BNT162b2 OMI BA.1 in adult healthcare workers resulted in a rapid recall of humoral and cellular immune responses independent of the priming regimen. Monitoring of SARS-CoV-2 immunity at the population level, and simultaneously antigenic drift at the virus level, remains crucial to assess the necessity and timing of COVID-19 variant-specific booster vaccinations. FUNDING: The Netherlands Organization for Health Research and Development (ZonMw).

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INTRODUCTION: In cardiac arrest, cerebral ischemia and reperfusion injury mainly determine the neurological outcome. The aim of this study was to investigate the relation between the course of cerebral oxygenation and regain of consciousness in patients treated with extracorporeal cardiopulmonary resuscitation (ECPR). We hypothesized that rapid cerebral oxygenation increase causes unfavorable outcomes. METHODS: This prospective observational study was conducted in three European hospitals. We included adult ECPR patients between October 2018 and March 2020, in whom cerebral regional oxygen saturation (rSO2 ) measurements were started minutes before ECPR initiation until 3 h after. The primary outcome was regain of consciousness, defined as following commands, analyzed using binary logistic regression. RESULTS: The sample consisted of 26 ECPR patients (23% women, Agemean 46 years). We found no significant differences in rSO2 values at baseline (49.1% versus 49.3% for regain versus no regain of consciousness). Mean cerebral rSO2 values in the first 30 min after ECPR initiation were higher in patients who regained consciousness (38%) than in patients who did not regain consciousness (62%, odds ratio 1.23, 95% confidence interval 1.01-1.50). CONCLUSION: Higher mean cerebral rSO2 values in the first 30 min after initiation of ECPR were found in patients who regained consciousness.

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