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Introduction: Lipopolysaccharide (LPS) stimulation of human whole blood ex vivo has been widely used to investigate human innate immune responses. However, there are uncertainties regarding the reproducibility and reliability of this assay. Methods: In this prospective, single-center study, cytokine responses (interleukin 8, interferon-α, interferon-γ, interleukin 10, interleukin 1-ß, interleukin 6, and tumor necrosis factor-α) to ex vivo whole blood LPS stimulation were assessed in 12 healthy volunteers. Cytokine levels were measured at 0, 2, and 4 h using a multiplex immunoassay (Luminex ®). Stimulation was repeated after six weeks. We examined reproducibility across technical and biological replicates at baseline and between repeated experiments after 6 weeks based on the area under the curve (AUC) of the individual cytokines using Pearson's correlation coefficient and the mean coefficient of variation. Results: The lowest mean coefficients of variation were observed for the technical replicates (5.4 to 9.2%), followed by the biological replicates (8.1 to 24.8%), and the repeated experiments after 6 weeks (17 to 31.2%). Between the baseline and 6-week AUCs, the following Pearson correlation coefficients R were observed: interleukin 10, 0.97; interferon-α, 0.84; interleukin 1-ß, 0.83; interleukin 8, 0.79; interleukin 6, 0.73; interferon-γ, 0.73; and tumor necrosis factor-α, 0.63. Discussion: The level of agreement between the baseline and week-6 cytokine response to ex vivo LPS stimulation was high across the seven cytokines analyzed. While interleukin 10 exhibited the lowest level of variability over time, tumor necrosis factor-α showed the highest variability in repeated experiments, which should be considered in the design and interpretation of future studies.
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BACKGROUND: Early fluid management in patients with advanced chronic kidney disease (CKD) and sepsis-induced hypotension is challenging with limited evidence to support treatment recommendations. We aimed to compare an early restrictive versus liberal fluid management for sepsis-induced hypotension in patients with advanced CKD. METHODS: This post-hoc analysis included patients with advanced CKD (eGFR of less than 30 mL/min/1.73 m2 or history of end-stage renal disease on chronic dialysis) from the crystalloid liberal or vasopressor early resuscitation in sepsis (CLOVERS) trial. The primary endpoint was death from any cause before discharge home by day 90. RESULTS: Of 1563 participants enrolled in the CLOVERS trial, 196 participants had advanced CKD (45% on chronic dialysis), with 92 participants randomly assigned to the restrictive treatment group and 104 assigned to the liberal fluid group. Death from any cause before discharge home by day 90 occurred significantly less often in the restrictive fluid group compared with the liberal fluid group (20 [21.7%] vs. 41 [39.4%], HR 0.5, 95% CI 0.29-0.85). Participants in the restrictive fluid group had more vasopressor-free days (19.7 ± 10.4 days vs. 15.4 ± 12.6 days; mean difference 4.3 days, 95% CI, 1.0-7.5) and ventilator-free days by day 28 (21.0 ± 11.8 vs. 16.5 ± 13.6 days; mean difference 4.5 days, 95% CI, 0.9-8.1). CONCLUSIONS: In patients with advanced CKD and sepsis-induced hypotension, an early restrictive fluid strategy, prioritizing vasopressor use, was associated with a lower risk of death from any cause before discharge home by day 90 as compared with an early liberal fluid strategy. TRIAL REGISTRATION: NCT03434028 (2018-02-09), BioLINCC 14149.
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Fluidoterapia , Hipotensión , Insuficiencia Renal Crónica , Sepsis , Humanos , Sepsis/complicaciones , Sepsis/terapia , Masculino , Femenino , Persona de Mediana Edad , Insuficiencia Renal Crónica/terapia , Insuficiencia Renal Crónica/complicaciones , Anciano , Fluidoterapia/métodos , Hipotensión/etiología , Hipotensión/terapiaRESUMEN
PURPOSE: Severe burn injuries are often accompanied by infections and associated with high morbidity and mortality. This study aimed to compare the prevalence and clinical impact of bacteremia between patients receiving intensive care with and without burns. METHODS: This single-center retrospective cohort study at the University Hospital Vienna, Austria, analyzed blood cultures from intensive care unit (ICU) patients with and without burns (2012-2022) to assess the prevalence of bacteremia, the associated pathogen distribution and the 60-day all-cause mortality. RESULTS: In 1170 ICU patients, 303 with burns and 867 without, the prevalence of bacteremia was similar among patients with at least one blood culture (31/157 [19.7%] versus 44/213 [20.7%], OR [95%CI] = 0.95 [0.57-1.57]). Burn patients exhibited a significantly higher frequency of microbiological sampling (51.5% versus 24.5%, p < 0.001), resulting in a higher overall prevalence of bacteremia (10.2% versus 5.1%, p = 0.002). 16.2% of all identified pathogens were multidrug-resistant (MDR). The 60-day all-cause mortality was higher in patients with MDR pathogens than in patients without bacteremia (41.7% versus 10.6%, p = 0.026). CONCLUSION: Bacteremia prevalence was similar in burn and non-burn patients, with high rates of multidrug-resistant Gram-negative pathogens. The 60-day all-cause mortality was significantly higher in patients with MDR pathogens than in patients without bacteremia.
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Bacteriemia , Quemaduras , Unidades de Cuidados Intensivos , Humanos , Quemaduras/complicaciones , Quemaduras/microbiología , Quemaduras/epidemiología , Quemaduras/mortalidad , Estudios Retrospectivos , Bacteriemia/epidemiología , Bacteriemia/microbiología , Bacteriemia/mortalidad , Masculino , Femenino , Persona de Mediana Edad , Prevalencia , Anciano , Unidades de Cuidados Intensivos/estadística & datos numéricos , Austria/epidemiología , Adulto , Farmacorresistencia Bacteriana Múltiple , Cuidados Críticos/estadística & datos numéricos , Antibacterianos/uso terapéuticoRESUMEN
BACKGROUND: Various SARS-CoV-2 variants of concerns (VOCs) characterized by higher transmissibility and immune evasion have emerged. Despite reduced vaccine efficacy against VOCs, currently available vaccines provide protection. Population-based evidence on the humoral immune response after booster vaccination is crucial to guide future vaccination strategies and in preparation for imminent COVID-19 waves. METHODS: This multicenter, population-based cohort study included 4697 individuals ≥18 years of age who received a booster vaccination. Antibody levels against SARS-CoV-2 receptor binding domain (RBD) and neutralizing antibodies against wild-type (WT) virus and Omicron variants were assessed at baseline (day of booster vaccination) and after four weeks. Safety was evaluated daily within the first week using a participant-completed electronic diary. Antibody levels were compared across different vaccination strategies, taking into account individual host factors. RESULTS: Our main model including 3838 participants revealed that individuals who received a booster with mRNA-1273 compared to BNT162b2 vaccine had a significantly higher increase (95 %CI) in anti-RBD-antibody levels (37,707 BAU/mL [34,575-40,839] vs. 27,176 BAU/mL [26,265-28,087]), and of neutralization levels against WT (1,681 [1490-1872] vs. 1141 [1004-1278] and Omicron variant (422 [369-474] vs. 329 [284-374]). Neutralizing antibody titres highly correlated with anti-RBD antibodies, with neutralizing capacity 4.4 fold higher against WT compared to Omicron. No differences in safety were found between the two booster vaccines. CONCLUSION: Our study underlines the superiority of a booster vaccination with mRNA-1273, independent of the primary vaccination and therefore provides guidance on the vaccination strategy.
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Vacuna nCoV-2019 mRNA-1273 , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Vacuna BNT162 , Vacunas contra la COVID-19 , COVID-19 , Inmunización Secundaria , Inmunogenicidad Vacunal , SARS-CoV-2 , Humanos , Masculino , COVID-19/prevención & control , COVID-19/inmunología , Femenino , Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , SARS-CoV-2/inmunología , Persona de Mediana Edad , Adulto , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/administración & dosificación , Vacunas contra la COVID-19/efectos adversos , Vacuna BNT162/inmunología , Vacuna BNT162/administración & dosificación , Vacuna nCoV-2019 mRNA-1273/inmunología , Anciano , Estudios de Cohortes , Vacunación , Glicoproteína de la Espiga del Coronavirus/inmunología , Adulto JovenRESUMEN
BACKGROUND: Invasive aspergillosis is a severe fungal infection that affects multiple organ systems including the CNS and the lungs. Isavuconazole, a novel triazole antifungal agent, has demonstrated promising activity against Aspergillus spp. However, data on the penetration of isavuconazole into the CNS and ELF and intracellular accumulation remain limited. MATERIALS AND METHODS: We conducted a prospective single-centre pharmacokinetic (PK) study in 12 healthy volunteers. Subjects received seven doses of 200 mg isavuconazole to achieve an assumed steady-state. After the first and final infusion, plasma sampling was conducted over 8 and 12 h, respectively. All subjects underwent one lumbar puncture and bronchoalveolar lavage, at either 2, 6 or 12 h post-infusion of the final dose. PBMCs were collected in six subjects from blood to determine intracellular isavuconazole concentrations at 6, 8 or 12 h. The AUC/MIC was calculated for an MIC value of 1 mg/L, which marks the EUCAST susceptibility breakpoint for Aspergillus fumigatus and Aspergillus flavus. RESULTS: C max and AUC0-24h of isavuconazole in plasma under assumed steady-state conditions were 6.57â±â1.68 mg/L (meanâ±âSD) and 106â±â32.1 h·mg/L, respectively. The average concentrations measured in CSF, ELF and in PBMCs were 0.07â±â0.03, 0.94â±â0.46 and 27.1â±â17.8 mg/L, respectively. The AUC/MIC in plasma, CSF, ELF and in PBMCs under steady-state conditions were 106â±â32.1, 1.68â±â0.72, 22.6â±â11.0 and 650â±â426 mg·h/L, respectively. CONCLUSION: Isavuconazole demonstrated moderate penetration into ELF, low penetrability into CSF and high accumulation in PBMCs. Current dosing regimens resulted in sufficient plasma exposure in all subjects to treat isolates with MICsâ≤â1 mg/L.
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Antifúngicos , Voluntarios Sanos , Nitrilos , Piridinas , Triazoles , Humanos , Triazoles/farmacocinética , Triazoles/administración & dosificación , Piridinas/farmacocinética , Piridinas/administración & dosificación , Antifúngicos/farmacocinética , Antifúngicos/administración & dosificación , Masculino , Adulto , Nitrilos/farmacocinética , Nitrilos/administración & dosificación , Estudios Prospectivos , Femenino , Infusiones Intravenosas , Adulto Joven , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Aspergillus fumigatus/efectos de los fármacos , Aspergillus flavus/efectos de los fármacos , Líquido del Lavado Bronquioalveolar/química , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/efectos de los fármacosRESUMEN
Background: APN01 is a soluble recombinant human angiotensin-converting enzyme 2 (rhACE2), a key player in the renin-aldosterone-angiotensin system (RAAS). In clinical studies, APN01 was administered intravenously only, so far. The aim of this study (ClinicalTrials.gov: NCT05065645) was to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of inhaled APN01. Methods: This was a phase I, double-blind, placebo-controlled, dose-escalation study. Inhalation was conducted via a nebuliser over 15 min in three single ascending dose (SAD) cohorts (n=24) and two multiple ascending dose (MAD) cohorts (n=16: every 12 h for 7 days). Doses in the SAD cohort were 1.25, 2.5 and 5 mg·mL-1; doses in the MAD cohort were 2.5 and 5 mg·mL-1. Safety (including adverse events (AEs), laboratory findings and lung function results), PK and PD data were assessed. Results: In the SAD and MAD cohorts, treatment-related AEs were slightly more frequent in the active treatment group than in the placebo group. AEs were mild to moderate, with no dose-limiting toxicities. No clinically relevant changes in lung function and laboratory results were observed. The mean maximum observed plasma concentration (Cmax) values after single and multiple doses of 5 mg·mL-1 APN01 were 1.88 and 6.61 ng·mL-1, respectively. Among the PD variables, significance was found for ACE2 and angiotensin 1-5. Conclusions: The application of aerosolised APN01 is safe and well tolerated after single and multiple doses. By achieving a high local concentration in the lungs and low systemic bioavailability, inhaled rhACE2 may present a therapeutic option in ACE2-related diseases.
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Corticoesteroides , Infecciones Comunitarias Adquiridas , Neumonía , Humanos , Infecciones Comunitarias Adquiridas/tratamiento farmacológico , Corticoesteroides/uso terapéutico , Corticoesteroides/administración & dosificación , Neumonía/tratamiento farmacológico , Resultado del Tratamiento , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: Bacterial co-infections are believed to be less frequent in patients with Covid-19 than influenza, but frequencies varied between studies. METHODS: This single-center retrospective, propensity score-matched analysis included adult patients with Covid-19 or influenza admitted to normal-care wards between 02/2014 and 12/2021. Covid-19 cases were propensity score matched to influenza cases at a 2:1 ratio. Community-acquired and hospital-acquired bacterial co-infections were defined as positive blood or respiratory cultures ≤ 48 h or > 48 h after hospital admission, respectively. The primary outcome was comparison of community-acquired and hospital-acquired bacterial infections between patients with Covid-19 and influenza in the propensity score-matched cohort. Secondary outcomes included frequency of early and late microbiological testing. RESULTS: A total of 1337 patients were included in the overall analysis, of which 360 patients with Covid-19 were matched to 180 patients with influenza. Early (≤ 48 h) microbiological sampling was performed in 138 (38.3%) patients with Covid-19 and 75 (41.7%) patients with influenza. Community-acquired bacterial co-infections were found in 14 (3.9%) of 360 patients with Covid-19 and 7 (3.9%) of 180 patients with influenza (OR 1.0, 95% CI 0.3-2.7). Late (> 48 h) microbiological sampling was performed in 129 (35.8%) patients with Covid-19 and 74 (41.1%) patients with influenza. Hospital-acquired bacterial co-infections were found in 40 (11.1%) of 360 patients with Covid-19 and 20 (11.1%) of 180 patients with influenza (OR 1.0, 95% CI 0.5-1.8). CONCLUSION: The rate of community-acquired and hospital-acquired bacterial co-infections was similar in hospitalized Covid-19 and influenza patients. These findings contrast previous literature reporting that bacterial co-infections are less common in Covid-19 than influenza.
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Infecciones Bacterianas , COVID-19 , Coinfección , Infecciones Comunitarias Adquiridas , Infección Hospitalaria , Gripe Humana , Adulto , Humanos , COVID-19/epidemiología , Gripe Humana/epidemiología , Estudios Retrospectivos , Coinfección/epidemiología , Infecciones Bacterianas/epidemiología , Infección Hospitalaria/epidemiología , Infecciones Comunitarias Adquiridas/epidemiología , HospitalesRESUMEN
BACKGROUND: Pathophysiological changes in severely burned patients alter the pharmacokinetics (PK) of anti-infective agents, potentially leading to subtherapeutic concentrations at the target site. Albumin supplementation, to support fluid resuscitation, may affect pharmacokinetic properties by binding drugs. This study aimed to investigate the PK of piperacillin/tazobactam in burn patients admitted to the ICU before and after albumin substitution as total and unbound concentrations in plasma. PATIENTS AND METHODS: Patients admitted to the ICU and scheduled for 4.5 g piperacillin/tazobactam administration and 200 mL of 20% albumin substitution as part of clinical routine were included. Patients underwent IV microdialysis, and simultaneous arterial plasma sampling, at baseline and multiple timepoints after drug administration. PK analysis of total and unbound drug concentrations under steady-state conditions was performed before and after albumin supplementation. RESULTS: A total of seven patients with second- to third-degree burns involving 20%-60% of the total body surface were enrolled. Mean (SD) AUC0-8 (h·mg/L) of total piperacillin/tazobactam before and after albumin substitution were 402.1 (242)/53.2 (27) and 521.8 (363)/59.7 (32), respectively. Unbound mean AUC0-8 before and after albumin supplementation were 398.9 (204)/54.5 (25) and 456.4 (439)/64.5 (82), respectively. CONCLUSIONS: Albumin supplementation had little impact on the PK of piperacillin/tazobactam. After albumin supplementation, there was a numerical increase in mean AUC0-8 of total and unbound piperacillin/tazobactam, whereas similar Cmax values were observed. Future studies may investigate the effect of albumin supplementation on drugs with a higher plasma protein binding.
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Antibacterianos , Quemaduras , Humanos , Antibacterianos/uso terapéutico , Piperacilina/farmacocinética , Ácido Penicilánico/farmacocinética , Combinación Piperacilina y Tazobactam/farmacocinética , Quemaduras/complicaciones , Quemaduras/tratamiento farmacológico , Unidades de Cuidados IntensivosRESUMEN
BACKGROUND: Community-acquired pneumonia (CAP) is associated with high morbidity and mortality. In the present study, we aimed to assess the effect of corticosteroids on all-cause mortality in patients hospitalized with CAP. METHODS: For this meta-analysis and meta-regression, we conducted a systematic search of trials that evaluated the effect of corticosteroid therapy in patients hospitalized with CAP through March 2023. We included randomized, controlled trials, comparing adjunctive corticosteroid therapy with the standard of care alone for treatment of patients hospitalized with CAP and reporting all-cause mortality. We excluded retrospective analyses, observational data, and trial protocols. The primary outcome was all-cause mortality within 30 days after hospital admission. The safety analysis included the frequency of adverse events and steroid-associated adverse events. RESULTS: The literature search identified 35 713 citations, of which 15 studies and 3367 patients were eligible for the final analysis. The all-cause mortality at 30 days was significantly lower in the corticosteroid group (104 of 1690, 6.15%) than in the control group (152 of 1677, 9.06%; risk ratio [RR], 0.67; 95% confidence interval [CI], .53 to .85; P = .001; I2 = 0%). In 9 studies (2549 patients) that reported the occurrence of adverse events, corticosteroid therapy was not associated with an increased risk of developing any adverse event compared with standard care (RR, 0.90; 95% CI, .65 to 1.24; P = .5; I2 = 88%). CONCLUSIONS: Adjunctive systemic corticosteroid therapy in patients hospitalized with CAP was associated with a reduction in all-cause mortality by day 30. The benefits were more pronounced in patients with severe pneumonia.
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Infecciones Comunitarias Adquiridas , Neumonía , Humanos , Corticoesteroides/efectos adversos , Neumonía/tratamiento farmacológico , Infecciones Comunitarias Adquiridas/tratamiento farmacológico , Infecciones Comunitarias Adquiridas/epidemiología , Hospitalización , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
OBJECTIVES: Although generic medicinal products are required to have the same qualitative and quantitative composition of the active substance as their reference originator product, patients and health care professionals express concerns about their interchangeability and safety. Therefore, the present study investigated the antimicrobial activity and pathogen mutation prevention of original and generic cefepime, linezolid and piperacillin/tazobactam against Staphylococcus aureus. METHODS: Two generic formulations of cefepime, linezolid and piperacillin/tazobactam were tested against their respective originator products. Susceptibility testing was performed with twenty-one clinical isolates of S. aureus and ATCC-29213 using broth microdilution. Time kill curves (TKC) were performed with ATCC-29213 at drug concentrations above and below the respective minimum inhibitory concentrations (MIC). Mutation prevention concentration was determined for each drug formulation against ATCC-29213. All experiments were performed in triplicate. Mutant colonies from mutation prevention concentration (MPC) experiments were genotypically tested by sequence analysis. RESULTS: MIC ratios between contiguous originator and generic drugs were similar for each isolate. No visual differences were observed in TKCs between originator and generic substances. The MPC did not differ between different formulations of the same substance. Although sequence analysis of mutant colonies revealed genomic differences compared with the original ATCC-29213, no differences in mutation frequencies were observed between clinical isolates and ATCC-29213 treated with originator or generic substances. CONCLUSIONS: Similar antimicrobial activity and pathogen mutation prevention was observed between contiguous substances. These results support the interchangeability of generic and originator drug formulations with the same active ingredient.
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Infecciones Estafilocócicas , Staphylococcus aureus , Humanos , Linezolid/farmacología , Staphylococcus aureus/genética , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Cefepima/farmacología , Medicamentos Genéricos/farmacología , Combinación Piperacilina y Tazobactam , Infecciones Estafilocócicas/tratamiento farmacológico , MutaciónAsunto(s)
COVID-19 , Ritonavir , Humanos , Ritonavir/uso terapéutico , Tratamiento Farmacológico de COVID-19RESUMEN
OBJECTIVES: A weak correlation between symptom severity and antibody levels after primary immunization against COVID-19 has already been shown. This study aimed to describe the association between reactogenicity and immunogenicity after booster vaccination. METHODS: This secondary analysis of a prospective cohort study included 484 healthcare workers who received a booster vaccination with BNT162b2. Anti-receptor binding domain (RBD) antibodies were assessed at baseline and 28 days after booster vaccination. Side effects were graded (none, mild, moderate, or severe) and reported daily for 7 days after booster vaccination. Spearman correlation coefficient (rho) was used to determine the correlations between the severity of each symptom and anti-RBD levels before vaccination and 28 days after. The Bonferroni method was used to adjust p values for multiple comparisons. RESULTS: Most of the 484 participants reported at least one local (451 [93.2%]) or systemic (437 [90.3%]) post-booster symptom. No correlations between the severity of local symptoms and antibody levels were found. Except for nausea, systemic symptoms showed weak but statistically significant correlations with 28-day anti-RBD levels (fatigue [rho = 0.23, p < 0.01], fever [rho = 22, p < 0.01], headache [rho = 0.15, p 0.03], arthralgia [rho = 0.2, p < 0.01], myalgia [rho = 0.17, p < 0.01]). There was no association between post-booster symptoms and pre-booster antibody levels. DISCUSSION: This study showed only a weak correlation between the severity of systemic post-booster symptoms and anti-SARS-CoV-2 antibody levels at 28 days. Therefore, self-reported symptom severity cannot be used to predict immunogenicity after booster vaccination.
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Anticuerpos Antivirales , Vacunas contra la COVID-19 , COVID-19 , Humanos , Anticuerpos Antivirales/sangre , Vacuna BNT162 , COVID-19/prevención & control , Estudios Prospectivos , Vacunación/efectos adversos , Vacunas contra la COVID-19/efectos adversos , Inmunización SecundariaRESUMEN
Previous findings suggest that bacterial coinfections are less common in ICU patients with COVID-19 than with influenza, but evidence is limited. OBJECTIVES: This study aimed to compare the rate of early bacterial coinfections in ICU patients with COVID-19 or influenza. DESIGN SETTING AND PARTICIPANTS: Retrospective propensity score matched cohort study. We included patients admitted to ICUs of a single academic center with COVID-19 or influenza (January 2015 to April 2022). MAIN OUTCOMES AND MEASURES: The primary outcome was early bacterial coinfection (i.e., positive blood or respiratory culture within 2 d of ICU admission) in the propensity score matched cohort. Key secondary outcomes included frequency of early microbiological testing, antibiotic use, and 30-day all-cause mortality. RESULTS: Out of 289 patients with COVID-19 and 39 patients with influenza, 117 (n = 78 vs 39) were included in the matched analysis. In the matched cohort, the rate of early bacterial coinfections was similar between COVID-19 and influenza (18/78 [23%] vs 8/39 [21%]; odds ratio, 1.16; 95% CI, 0.42-3.45; p = 0.82). The frequency of early microbiological testing and antibiotic use was similar between the two groups. Within the overall COVID-19 group, early bacterial coinfections were associated with a statistically significant increase in 30-day all-cause mortality (21/68 [30.9%] vs 40/221 [18.1%]; hazard ratio, 1.84; 95% CI, 1.01-3.32). CONCLUSIONS AND RELEVANCE: Our data suggest similar rates of early bacterial coinfections in ICU patients with COVID-19 and influenza. In addition, early bacterial coinfections were significantly associated with an increased 30-day mortality in patients with COVID-19.
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BACKGROUND: It is unclear whether thrombectomy alone is non-inferior to thrombectomy with intravenous thrombolysis in patients with acute ischemic stroke due to large-vessel occlusion. PURPOSE: To perform a comprehensive, trial-level data, non-inferiority meta-analysis of randomised controlled trials comparing endovascular thrombectomy with and without intravenous thrombolysis in patients with ischemic stroke due to large-vessel occlusion of anterior circulation. METHODS: The prespecified primary efficacy outcome was functional independence, defined as a modified Rankin scale (mRS)score of 0 to 2 at 90 days. The two prespecified non-inferiority margins were risk differences of -10% and - 5%. The study was registered in PROSPERO (CRD42022361110) and conducted according to PRISMA guidelines. RESULTS: Six trials were included in this analysis (DIRECT-MT, DEVT, SKIP, MR CLEAN-NO IV, DIRECT-SAFE and SWIFT DIRECT) comprising a total of 2334 patients. Functional independence at 90 days was achieved by 570 (49·0%) of 1164 patients in the thrombectomy alone group and 595 (50·9%) of 1170 patients in the thrombectomy with thrombolysis group (pooled risk difference - 0·02, [95% CI -0·06-0·02]). Combined thrombectomy and thrombolysis were associated with significantly higher rates of successful reperfusion (pooled risk ratio 0·96 [95% CI, 0·93-0·99], p = 0·006) but at the expense of a significantly increased risk of overall - but not symptomatic - intracranial haemorrhage (pooled risk ratio 0·87 [95% CI, 0·77-0·98], p = 0·02). CONCLUSIONS: Compared with a combined treatment approach, thrombectomy alone was non-inferior at -10% non-inferiority margin, but not at a - 5% inferiority margin for functional independence. Current evidence cannot exclude clinically important differences between the two treatment approaches.
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Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Humanos , Accidente Cerebrovascular Isquémico/diagnóstico , Accidente Cerebrovascular Isquémico/terapia , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/terapia , Fibrinolíticos/efectos adversos , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/terapia , Isquemia Encefálica/complicaciones , Resultado del Tratamiento , Trombectomía/efectos adversos , Terapia Trombolítica/efectos adversos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
COVID-19-associated pulmonary aspergillosis (CAPA) is a life-threatening fungal infection that mainly affects critically ill patients. The aim of this study was to assess the incidence and clinical outcomes of putative CAPA in critically ill COVID-19 patients. This retrospective observational cohort study included 181 cases from 5 ICUs at Vienna General Hospital between January 2020 and April 2022. Patients were diagnosed with putative CAPA according to the AspICU classification, which included a positive Aspergillus culture in a bronchoalveolar lavage sample, compatible signs and symptoms, and abnormal medical imaging. The primary outcome was adjusted 60-day all-cause mortality from ICU admission in patients with vs. without putative CAPA. Secondary outcomes included time from ICU admission to CAPA diagnosis and pathogen prevalence and distribution. Putative CAPA was identified in 35 (19.3%) of 181 COVID-19 patients. The mean time to diagnosis was 9 days. Death at 60 days occurred in 18 of 35 (51.4%) patients with CAPA and in 43 of 146 (29.5%) patients without CAPA (adjusted HR (95%CI) = 2.15 (1.20-3.86, p = 0.002). The most frequently isolated Aspergillus species was Aspergillus fumigatus. The prevalence of putative pulmonary aspergillosis in critically ill COVID-19 patients was high and was associated with significantly higher mortality.
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BACKGROUND: An understanding vaccine-dependent effects on protective and sustained humoral immune response is crucial to planning future vaccination strategies against coronavirus disease 2019 (COVID-19). METHODS: In this multicenter, population-based, cohort study including 4601 individuals after primary vaccination against COVID-19 ≥ 4 months earlier we compared factors associated with residual antibody levels against severe acute respiratory syndrome coronavirus-2 receptor-binding domain (RBD) across different vaccination strategies (BNT162b2, mRNA-1273, or ChAdOx1). RESULTS: Our main model including 3787 individuals (2 × BNT162b2, n = 2271; 2 × mRNA-1273, n = 251; 2 × ChAdOx1, n = 1265), predicted significantly lower levels of anti-RBD antibodies after 6 months in individuals vaccinated with ChAdOx1 (392.7 binding antibody units per milliliter [BAU/mL]) compared with those vaccinated with BNT162b2 (1179.5 BAU/mL) or mRNA-1273 (2098.2 BAU/mL). Vaccine-dependent association of antibody levels was found for age with a significant predicted difference in BAU/ml per year for BNT162b2 (-21.5; 95% confidence interval [CI], -24.7 to -18.3) and no significant association for mRNA-1273 (-4.0; 95% CI, -20.0 to 12.1) or ChAdOx1 (1.7; 95% CI, .2 to 3.1). The predicted decrease over time since full immunization was highest in mRNA-1273 (-23.4; 95% CI, -31.4 to -15.4) compared with BNT162b2 (-5.9; 95% CI, -7 to -4.8). CONCLUSIONS: Our study revealed population-based evidence of vaccine-dependent effects of age and time since full immunization on humoral immune response. Findings underline the importance of individualized vaccine selection, especially in elderly individuals.
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Vacunas contra la COVID-19 , COVID-19 , Anciano , Humanos , Vacuna BNT162 , Vacuna nCoV-2019 mRNA-1273 , Estudios de Cohortes , COVID-19/prevención & controlRESUMEN
OBJECTIVE: To investigate the immunogenicity and safety of BNT162b2 booster vaccination with and without a tetravalent influenza vaccine. METHODS: A prospective, open-label cohort study on immunogenicity and safety of COVID-19 booster vaccination with or without a tetravalent influenza vaccine was performed. Eight hundred thirty-eight health care workers were included in the following study arms: BNT162b2 booster-only, influenza-vaccine-only or combination of both. Levels of antibodies against SARS-CoV-2 spike receptor binding domain, and haemagglutinin inhibition tested for four different influenza strains (A(H1N1)pdm09, A(H3N2), B/Victoria, B/Yamagata) were measured at the time of vaccination and 4 weeks later. RESULTS: After 4 weeks, median (interquartile range) levels of antibodies against the receptor binding domain of the viral spike (S) protein and relative change from baseline were high in individuals who received BNTb162b2 booster vaccination only (absolute: 16 600 [10 980-24 360] vs. 12 630 [8198-18 750] BAU/mL [p < 0.0001]; relative increase: 49% [23.6-95.3] vs. 40% [21.9-80.6] [p 0.048]; booster-only n = 521 vs. combination-arm n = 229 respectively). Results were confirmed after matching for sex, age, body mass index, baseline antibody levels and vaccine compound received for primary immunization (absolute: 13 930 [10 610-22 760] vs. 12 520 [8710-17 940]; [p 0.031]; relative increase: 55.7% [27.8-98.5] vs. 42.2% [22.9-74.5]; p 0.045). Adverse events were almost identical in the booster-only and the combination-arm, but numerically low in the influenza arm (525/536 [97.9%] vs. 235/240 [97.9%] vs. 26/33 [78.8 %]). DISCUSSION: Although no safety concerns occurred, our study provides evidence on reduced immunogenicity of a BNT162b2 booster vaccination in combination with a tetravalent influenza vaccine. Further studies investigating new influenza variants as well as potential differences vaccine effectiveness are needed.
Asunto(s)
COVID-19 , Subtipo H1N1 del Virus de la Influenza A , Vacunas contra la Influenza , Gripe Humana , Humanos , Anticuerpos Antivirales , Vacuna BNT162 , Estudios de Cohortes , COVID-19/etiología , Subtipo H3N2 del Virus de la Influenza A , Vacunas contra la Influenza/efectos adversos , Gripe Humana/prevención & control , Estudios Prospectivos , SARS-CoV-2 , Vacunación/efectos adversos , Vacunas de Productos InactivadosRESUMEN
Background: Microdialysis sampling after drug microdosing may provide tissue pharmacokinetic data early in clinical drug development. However, low administered doses and small sample volumes pose an analytical challenge, particularly for highly protein-bound drugs. Materials & methods: Carbon-14 [14C]diclofenac was used as a model drug to assess the technical and analytical feasibility of in vivo microdialysis after microdose administration in an in vitro setup. Results: [14C]diclofenac dialysate concentrations were accurately quantified with accelerator MS. [14C]diclofenac dialysate recoveries were similar in the presence and absence of therapeutic diclofenac concentrations but were considerably decreased when albumin was added to the immersion solution, suggesting high protein binding. Conclusion: These results demonstrate the feasibility of combining microdosing and microdialysis to assess tissue pharmacokinetics.