Pseudomonas aeruginosa infections are a serious threat in intensive care units (ICUs). The aim of this confirmatory, randomized, multicenter, placebo-controlled, double-blind, phase 2/3 study was to ...assess the efficacy, immunogenicity, and safety of IC43 recombinant Pseudomonas aeruginosa vaccine in non-surgical ICU patients.
Eight hundred patients aged 18 to 80 years admitted to the ICU with expected need for mechanical ventilation for ≥ 48 h were randomized 1:1 to either IC43 100 μg or saline placebo, given in two vaccinations 7 days apart. The primary efficacy endpoint was all-cause mortality in patients 28 days after the first vaccination. Immunogenicity and safety were also evaluated.
All-cause mortality rates at day 28 were 29.2% vs 27.7% in the IC43 and placebo groups, respectively (P = .67). Overall survival (Kaplan-Meier survival estimates, P = .46) and proportion of patients with ≥ one confirmed P. aeruginosa invasive infection or respiratory tract infection also did not differ significantly between both groups. The geometric mean fold increase in OprF/I titers was 1.5 after the first vaccination, 20 at day 28, after the second vaccination, and 2.9 at day 180. Significantly more patients in the placebo group (96.5%) had ≥ one adverse event (AE) versus the IC43 100 μg group (93.1%) (P = .04). The most frequently reported severe AEs in the IC43 and placebo groups were respiratory failure (6.9% vs 5.7%, respectively), septic shock (4.1% vs 6.5%), cardiac arrest (4.3% vs 5.7%), multiorgan failure (4.6% vs 5.5%), and sepsis (4.6% vs 4.2%). No related serious AEs were reported in the IC43 group.
The IC43 100 μg vaccine was well tolerated in this large population of medically ill, mechanically ventilated patients. The vaccine achieved high immunogenicity but provided no clinical benefit over placebo in terms of overall mortality.
https://clinicaltrials.gov (NCT01563263). Registration was sent to ClinicalTrials.gov on March 14, 2012, but posted by ClinicalTrials.gov on March 26, 2012. The first subject was included in the trial on March 22, 2012.
Objective
Patients’ olfactory function after autoimmune encephalitis (AE) involving limbic structures may be impaired. This study aimed to characterize olfactory function in patients after autoimmune ...encephalitides.
Methods
A case–control study was performed including 11 AE patients with antibodies against NMDAR (
n
= 4), GAD (
n
= 3), VGKC (
n
= 3) and antibody-negative AE (
n
= 1) and a control group of 12 patients with pneumococcal meningo-encephalitis (PC). In subgroup analyses, AE patients with and without NMDAR-antibodies were compared. Olfactory function was assessed using the Sniffin Sticks test and the resulting TDI-score (threshold, discrimination, identification). Involvement of limbic structures was evaluated on imaging data (MRI). Statistical analyses were performed to test for correlations of TDI-score and MRI results.
Results
The overall olfactory function of the AE-group and the PC-group was comparable (mean TDI 32.0 CI 27.3–36.7, 32.3 CI 28.5–36.0). The proportions of hyposmic patients were similar compared to the general population. However, AE patients of the non-NMDAR group had significantly lower TDI-scores (28.9 ± 6,8) than NMDAR patients (37.4 ± 3.5) (
p
= 0.046) and a significantly lower discrimination capability than the NMDAR patients (9.9 ± 2.0 vs. 14.5 ± 0.6) (
p
= 0.002). The non-NMDAR patients had significantly more limbic MRI pathologies (6/7) compared to the NMDAR patients (0/4) (
p
= 0.015). Furthermore, a correlation between limbic MRI pathologies and worse capability of smelling discrimination was found (
p
= 0.016,
r
= −0.704,
n
= 11).
Conclusion
Our results indicate that patients with NMDAR autoimmune encephalitis have normal long term olfactory function. However, patients with non-NMDAR autoimmune encephalitis appear to have a persistently impaired olfactory function, probably mediated by encephalitic damage to limbic structures.
High-mobility group box 1 (HMGB1) protein is a critical mediator of neutrophil extracellular trap (NET) formation (NETosis). Myeloperoxidase (MPO)-DNA complexes, a biomarker of NETs, and HMGB1 have ...been associated with delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH). Additional mechanistic NET-related biomarkers and their role in the neuroinflammatory cascade surrounding DCI remain to be explored.
A post-hoc analysis of a prospective, blinded, single-center biomarker observational study was performed.
measurements of serum citrullinated histone H3-DNA complexes (H3Cit-DNA), peptidylarginine deiminase 4 (PAD4), cell-free DNA (cf-DNA), and DNase 1 activity were conducted on admission (D0) and day 4 (D4). Delayed cerebral infarction (DCI) was defined as new cerebral infarction on CT head not present on the post-treatment scan.
H3Cit-DNA, PAD4, cf-DNA, and DNase 1 activity were within quantifiable ranges in all serum samples analyzed at D0 and D4. Admission biomarker levels were not associated with DCI development. From D0 to D4, in both the DCI and the non-DCI groups, H3Cit-DNA levels significantly decreased, cf-DNA levels significantly increased, and PAD4 levels remained stable. In contrast, DNase 1 activity significantly decreased from D0 to D4 in the DCI group (
< 0.001) but not in the non-DCI group.
This exploratory analysis demonstrated NET-related biomarkers such as H3Cit-DNA, PAD4, cf-DNA, and DNase 1 activity in all aSAH patients. A decline of systemic DNase 1 activity in the early phase might increase the risk of delayed cerebral ischemia.
Moderate hypothermia after decompressive surgery might not be beneficial for stroke patients. However, normothermia may prove to be an effective method of enhancing neurological outcomes. The study ...aims were to evaluate the application of a pre-specified normothermia protocol in stroke patients after decompressive surgery and its impact on temperature load, and to describe the functional outcome of patients at 12 months after treatment.
We analysed patients with space-occupying middle cerebral artery (MCA) infarction treated with decompressive surgery and a pre-specified temperature management protocol. Patients treated primarily with device-controlled normothermia or hypothermia were excluded. The individual temperature load above 36.5 °C was calculated for the first 96 h after hemicraniectomy as the Area Under the Curve, using °C x hours. The effect of temperature load on functional outcome at 12 months was analysed by logistic regression.
We included 40 stroke patients treated with decompressive surgery (mean SD age: 58.9 10.1 years; mean SD time to surgery: 30.5 16.7 hours). Fever (temperature > 37.5 °C) developed in 26 patients during the first 96 h after surgery and mean (SD) temperature load above 36.5 °C in this time period was 62,3 (+/- 47,6) °C*hours. At one year after stroke onset, a moderate to moderately severe disability (modified Rankin Scale score of 3 or 4) was observed in 32% of patients, and a severe disability (score of 5) in 37% of patients, respectively. The lethality in the cohort at 12 months was 32%. The temperature load during the first 96 h was not an independent predictor for 12 month lethality (OR 0.986 95%-CI:0.967-1.002; p < 0.12).
Temperature control in surgically treated patients with space-occupying MCA infarction using a pre-specified protocol excluding temperature management systems resulted in mild hyperthermia between 36.8 °C and 37.2 °C and a low overall temperature load. Future prospective studies on larger cohorts comparing different strategies for normothermia treatment including temperature management devices are needed.
Myeloperoxidase (MPO)-DNA complexes, biomarkers of neutrophil extracellular traps (NETs), have been associated with arterial and venous thrombosis. Their role in aneurysmal subarachnoid hemorrhage ...(aSAH) is unknown.
To assess whether serum MPO-DNA complexes are present in patients with aSAH and whether they are associated with delayed cerebral ischemia (DCI).
Post-hoc analysis of a prospective, observational single-center study, with de novo serum biomarker measurements in consecutive patients with aSAH between July 2018 and September 2020, admitted to a tertiary care neuroscience ICU.
We analyzed serum obtained at admission and hospital day 4 for concentrations of MPO-DNA complexes. The primary outcome was DCI, defined as new infarction on brain CT. The secondary outcome was clinical vasospasm, a composite of clinical and transcranial Doppler parameters. We used Wilcoxon signed-rank-test to assess for differences between paired measures.
Among 100 patients with spontaneous subarachnoid hemorrhage, mean age 59 years (sd ± 13 yr), 55% women, 78 had confirmed aSAH. Among these, 29 (37%) developed DCI. MPO-DNA complexes were detected in all samples. The median MPO-DNA level was 33 ng/mL (interquartile range IQR, 18-43 ng/mL) at admission, and 22 ng/mL (IQR, 11-31 ng/mL) on day 4 (unpaired test;
= 0.015). We found a significant reduction in MPO-DNA levels from admission to day 4 in patients with DCI (paired test;
= 0.036) but not in those without DCI (
= 0.17). There was a similar reduction in MPO-DNA levels between admission and day 4 in patients with (
= 0.006) but not in those without clinical vasospasm (
= 0.47).
This is the first study to detect the NET biomarkers MPO-DNA complexes in peripheral serum of patients with aSAH and to associate them with DCI. A pronounced reduction in MPO-DNA levels might serve as an early marker of DCI. This diagnostic potential of MPO-DNA complexes and their role as potential therapeutic targets in aSAH should be explored further.
Cerebral venous drainage might influence brain edema characteristics and functional outcome of patients with severe ischemic stroke. The purpose of the study was to evaluate whether hypoplasia of ...transverse sinuses or the internal jugular veins is associated with poor functional outcome in patients with space-occupying middle cerebral artery (MCA) infarction who underwent decompressive surgery.
We performed a retrospective analysis of patients with space-occupying MCA infarction treated with decompressive surgery at our university hospital. The transverse sinuses and the internal jugular veins were evaluated on baseline images and categorized as normal, hypoplastic or occluded. We defined composite variables for ipsilateral, contralateral or any abnormal cerebral venous drainage. We assessed the functional outcome at 12 months with the modified Rankin scale (mRS) score and defined poor functional outcome as mRS scores 5 and 6.
We analyzed 88 patients with available baseline imaging data mean SD patient age 53 (±9) years; medianIQR time to decompressive surgery 31(22-51) h. At 12 months 44 patients (50%) had a poor outcome. In univariate analysis neither ipsilateral (OR 1.98;95%CI: 0.75-5.40), nor contralateral (OR 1.56;95%CI: 0.59-4.24) or any (OR 1.6; 95%CI: 0.68-3.79) hypoplasia or occlusion of venous drainage were significantly associated with poor functional outcome. In multivariate analyses, higher patient age (OR 1.07;95%CI 1.01-1.14) and baseline stroke severity (OR 3.42;95%CI 1.31-9.40) were independent predictors of poor functional outcome, but not ipsilateral hypoplasia or occlusion of venous drainage (OR 1.31;95%CI 0.47-3.67).
The cerebral venous drainage pattern was not significantly associated with poor functional outcome in our cohort of patients with space-occupying MCA infarction who underwent decompressive surgery.
ABSTRACT Background. Dental disorders and dental treatment are among the variety of causes of brain abscess. Case Description. The authors present the case of a patient who developed multiple brain ...abscesses after undergoing professional tooth cleaning. The results of a diagnostic work-up ruled out an underlying immunodeficiency. After receiving neurosurgical intervention and intensive care treatment by means of local and intravenous antibiotics for 24 days, the patient was transferred to another hospital for rehabilitation. Six months after the treatment, the patient still had moderate residual paresis of the left leg. Practical Implications. Although it happens rarely, professional tooth cleaning may be considered a cause of brain abscesses even in otherwise healthy patients.
Mutations of the gene encoding the mitochondrial enzyme sterol 27-hydroxylase (CYP27A1 gene) cause defects in the cholesterol pathway to bile acids that lead to the storage of cholestanol and ...cholesterol in tendons, lenses and the central nervous system. This disorder is the cause of a clinical syndrome known as cerebrotendinous xanthomatosis (CTX). Since 1991 several mutations of the CYP27A1 gene have been reported. We diagnosed the clinical features of CTX in a caucasian woman. Serum levels of cholestanol and 7α-hydroxycholesterol were elevated and the concentration of 27-hydroxycholesterol was reduced. Bile alcohols in the urine and faeces were increased. The analysis of the CYP27A1 gene showed that the patient was a compound heterozygote carrying two mutations both located in exon 8. One mutation is a novel four nucleotide deletion (c.1330-1333delTTCC) that results in a frameshift and the occurrence of a premature stop codon leading to the formation of a truncated protein of 448 amino acids. The other mutation, previously reported, is a C - > T transition (c. c.1381C > T) that converts the glutamine codon at position 461 into a termination codon (p.Q461X). These truncated proteins are expected to have no biological function being devoid of the cysteine residue at position 476 of the normal enzyme that is crucial for heme binding and enzyme activity.
In patients older than 60 years of age with extensive middle-cerebral-artery strokes, early hemicraniectomy improved survival as compared with treatment in the ICU alone. The majority of survivors ...had substantial disability and required assistance with most bodily needs.
Large space-occupying middle-cerebral-artery or hemispheric ischemic brain infarcts are associated with the development of massive brain edema, which may lead to herniation and early death. This condition, which has been described as malignant middle-cerebral-artery infarction, is associated with 80% mortality due to herniation during the first week, despite maximal conservative treatment in the intensive care unit (ICU), including osmotherapy, barbiturates, and hyperventilation.
1
–
8
Conservative therapies for ischemic brain edema are not supported by sufficient evidence from clinical trials.
9
,
10
Decompressive hemicraniectomy (temporary removal of a large part of the skull) combined with duraplasty allows edematous tissue to expand outside the . . .
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