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Annals of Intensive Care Jun 2024Previous retrospective research has shown that maintaining prone positioning (PP) for an average of 40 h is associated with an increase of survival rates in intubated...
BACKGROUND
Previous retrospective research has shown that maintaining prone positioning (PP) for an average of 40 h is associated with an increase of survival rates in intubated patients with COVID-19-related acute respiratory distress syndrome (ARDS). This study aims to determine whether a cumulative PP duration of more than 32 h during the first 2 days of intensive care unit (ICU) admission is associated with increased survival compared to a cumulative PP duration of 32 h or less.
METHODS
This study is an ancillary analysis from a previous large international observational study involving intubated patients placed in PP in the first 48 h of ICU admission in 149 ICUs across France, Belgium and Switzerland. Given that PP is recommended for a 16-h daily duration, intensive PP was defined as a cumulated duration of more than 32 h during the first 48 h, whereas standard PP was defined as a duration equal to or less than 32 h. Patients were followed-up for 90 days. The primary outcome was mortality at day 60. An Inverse Probability Censoring Weighting (IPCW) Cox model including a target emulation trial method was used to analyze the data.
RESULTS
Out of 2137 intubated patients, 753 were placed in PP during the first 48 h of ICU admission. The intensive PP group (n = 79) had a median PP duration of 36 h, while standard PP group (n = 674) had a median of 16 h during the first 48 h. Sixty-day mortality rate in the intensive PP group was 39.2% compared to 38.7% in the standard PP group (p = 0.93). Twenty-eight-day and 90-day mortality as well as the ventilator-free days until day 28 were similar in both groups. After IPCW, there was no significant difference in mortality at day 60 between the two-study groups (HR 0.95 [0.52-1.74], p = 0.87 and HR 1.1 [0.77-1.57], p = 0.61 in complete case analysis or in multiple imputation analysis, respectively).
CONCLUSIONS
This secondary analysis of a large multicenter European cohort of intubated patients with ARDS due to COVID-19 found that intensive PP during the first 48 h did not provide a survival benefit compared to standard PP.
PubMed: 38935175
DOI: 10.1186/s13613-024-01340-z -
Angewandte Chemie (International Ed. in... Jun 2024Herein we have evidenced the formation of favorable π-hole Br···metal noncovalent interactions (NCIs) involving elements from groups 9, 11 and 12. More in detail, M...
Herein we have evidenced the formation of favorable π-hole Br···metal noncovalent interactions (NCIs) involving elements from groups 9, 11 and 12. More in detail, M (M = Co2+, Ni2+, Cu2+ and Zn2+) containing porphyrins have been synthesized and their supramolecular assemblies structurally characterized by means of single crystal X-ray diffraction and Hirshfeld surface analyses, revealing the formation of directional Br···M contacts in addition to ancillary hydrogen bond and lone pair-π bonds. Computations at the PBE0-D3/def2-TZVP level of theory revealed the π-hole nature of the Br···M interaction. In addition, the physical nature of these NCIs was studied using Quantum Chemistry methodologies, providing evidence of π-hole Spodium and Regium bonds in Zn2+ and Cu2+ porphyrins, in addition to unveiling the presence of a π-hole for group 9 (Co2+). On the other hand, group 10 (Ni2+) acted as both electron donor and acceptor moiety without showing an electropositive π-hole. Owing to the underexplored potential of π-hole interactions in transition metal chemistry, we believe the results reported herein will be useful in supramolecular chemistry, organometallics, and solid-state chemistry by i) putting under the spotlight the π-hole chemistry involving first row transition metals and ii) unlocking a new tool to direct the self-assembly of metalloporphyrins.
PubMed: 38934220
DOI: 10.1002/anie.202409963 -
Neonatology Jun 2024The SafeBoosC-III trial investigated the effect of cerebral oximetry-guided treatment in the first 72 h after birth on mortality and severe brain injury diagnosed by...
Effect of Cerebral Oximetry-Guided Treatment on Brain Injury in Preterm Infants as Assessed by Magnetic Resonance Imaging at Term Equivalent Age: An Ancillary SafeBoosC-III Study.
INTRODUCTION
The SafeBoosC-III trial investigated the effect of cerebral oximetry-guided treatment in the first 72 h after birth on mortality and severe brain injury diagnosed by cranial ultrasound in extremely preterm infants (EPIs). This ancillary study evaluated the effect of cerebral oximetry on global brain injury as assessed by magnetic resonance imaging (MRI) at term equivalent age (TEA).
METHODS
MRI scans were obtained between 36 and 44.9 weeks PMA. The Kidokoro score was independently evaluated by two blinded assessors. The intervention effect was assessed using the nonparametric Wilcoxon rank sum test for median difference and 95% Hodges-Lehmann (HL) confidence intervals (CIs). The intraclass correlation coefficient (ICC) was used to assess the agreement between the assessors.
RESULTS
A total of 210 patients from 8 centers were included, of whom 121 underwent MRI at TEA (75.6% of alive patients): 57 in the cerebral oximetry group and 64 in the usual care group. There was an excellent correlation between the assessors for the Kidokoro score (ICC agreement: 0.93, 95% CI: 0.91-0.95). The results showed no significant differences between the cerebral oximetry group (median 2, interquartile range [IQR]: 1-4) and the usual care group (median 3, IQR: 1-4; median difference -1 to 0, 95% HLCI: -1 to 0; p value 0.1196).
CONCLUSIONS
In EPI, the use of cerebral oximetry-guided treatment did not lead to significant alterations in brain injury, as determined by MRI at TEA. The strong correlation between the assessors highlights the potential of the Kidokoro score in multicenter trials.
PubMed: 38934161
DOI: 10.1159/000539175 -
Cureus May 2024The erythroblastosis transformation-specific regulated gene 1 (ERG) is a transcription factor that can be used as an immunohistochemical (IHC) marker in the diagnosis...
INTRODUCTION
The erythroblastosis transformation-specific regulated gene 1 (ERG) is a transcription factor that can be used as an immunohistochemical (IHC) marker in the diagnosis and prognostication of malignancy. ERG was initially used in prostate cancer; however, it is a useful marker in extramedullary myeloid disease. Patients with acute myeloid leukemia (AML), dry bone marrow aspirate, and CD34, CD117-negative blast cells can be in a diagnostic dilemma. This audit aimed to (a) validate ERG IHC in bone marrow trephine samples, (b) quantify ERG IHC positivity in an AML cohort, and correlate concordance with CD34 and CD117 IHC, when available, and (c) to see whether ERG is a useful adjunct in the diagnosis of cases of AML.
METHODS
A retrospective audit was completed of all new and relapsed cases of AML over one year at a single center. For inclusion, patients needed a trephine specimen at presentation, and all had a hematoxylin and eosin(H&E) specimen, ERG IHC, and at least one or both of CD34 and CD117 IHC. Four pathologists independently assessed the stains quantitatively and qualitatively in comparison to the morphology seen on the H&E sample. The kappa value was used to assess agreement.
RESULTS
Seventeen patients with AML met the inclusion criteria. All specimens had H&E, CD34, and ERG stains; 9/17 (53%) had CD117 IHC. ERG demonstrated high concordance with blast cells on H&E morphology, with a high agreement among pathologists. Qualitatively, pathologists recognized that ERG spared lymphoid nodules; however, it also stained granulocytes at various maturation stages.
CONCLUSION
ERG is a sensitive marker for the diagnosis of AML. ERG can help visualize blast cells that have been confirmed by ancillary tests. More research into the utility of ERG in AML diagnostics is recommended.
PubMed: 38933637
DOI: 10.7759/cureus.61168 -
Cureus May 2024Introduction Cardiac rehabilitation (CR) is an underutilized resource in patients with ischemic heart disease, despite being a Class IA recommendation. In this study, a...
Introduction Cardiac rehabilitation (CR) is an underutilized resource in patients with ischemic heart disease, despite being a Class IA recommendation. In this study, a multidisciplinary quality improvement (QI) team aimed to improve CR referrals by standardizing the ordering process at our hospital system. Method By using a collaborative approach involving the electronic medical record (EMR), medical provider education, and hospital protocols, our two-hospital healthcare system was able to successfully identify barriers to CR referral rates and implement interventions for these barriers. All physicians and medical providers, including ancillary staff, were educated on the EMR order sets to improve compliance by using automated order sets in the EMR. The CR referral order in the EMR included a statement regarding the application of evidence-based medicine, and a computerized provider order entry was included as a reminder to the ordering provider. The use of EMR was monitored monthly by the QI committee. Chi-square test and odds ratios were obtained for statistical analysis. Results Through provider-EMR education and patient education on discharge, CR referral rates significantly improved from 51.2 to 87.1% (p = 0.0001) in a 12-month period. The study included 1,499 patients in total. The improvement was statistically significant regardless of patient gender, race, or insurance coverage. Additionally, subgroup analysis in this study found that prior to standardization of the ordering process, African American patients were significantly less likely to be referred to CR compared to Caucasian patients. (51.2% vs. 41.0%, p=0.01). There was no statistically significant difference in the likelihood of CR referral between Caucasian and African American patients following the intervention (84.0% vs. 78.0%, p = 0.166). Conclusion This study shows that CR is an underutilized resource and that effective QI initiatives may not only increase CR referral rates but also close the gap between racial inequities in referral rates. Future research with multi-center randomized control trials is needed to further enhance its external generalizability to other institutions.
PubMed: 38933616
DOI: 10.7759/cureus.61157 -
Frontiers in Medicine 2024Links have been established between SARS-CoV-2 and endoplasmic reticulum stress (ERS). However, the relationships between inflammation, ERS, and the volume of organ...
INTRODUCTION
Links have been established between SARS-CoV-2 and endoplasmic reticulum stress (ERS). However, the relationships between inflammation, ERS, and the volume of organ damage are not well known in humans. The aim of this study was to explore whether ERS explains lung damage volume (LDV) among COVID-19 patients admitted to the intensive care unit (ICU).
MATERIALS AND METHODS
We conducted a single-center retrospective study (ancillary analysis of a prospective cohort) including severe COVID-19 ICU patients who had a chest computed tomography (CT) scan 24 h before/after admission to assess LDV. We performed two multivariate linear regression models to identify factors associated with plasma levels of 78 kDa-Glucose-Regulated Protein (GRP78; ERS marker) and Interleukin-6 (IL-6; inflammation marker) at admission.
RESULTS
Among 63 patients analyzed, GRP78 plasma level was associated with LDV in both multivariate models (β = 22.23 [4.08;40.38]; = 0.0179, β = 20.47 [0.74;40.20]; = 0.0423) but not with organ failure (Sequential Organ Failure Assessment (SOFA) score) at admission (r = 0.03 [-0.22;0.28]; = 0.2559). GRP78 plasma level was lower among ICU survivors (1539.4 [1139.2;1941.1] vs. 1714.2 [1555.2;2579.1] pg./mL. respectively; = 0.0297). IL-6 plasma level was associated with SOFA score at admission in both multivariate models (β = 136.60 [65.50;207.70]; = 0.0003, β = 193.70 [116.60;270.90]; < 0.0001) but not with LDV ( = 0.13 [-0.14;0.39]; = 0.3219). IL-6 plasma level was not different between ICU survivors and non-survivors (12.2 [6.0;43.7] vs. 30.4 [12.9;69.7] pg./mL. respectively; = 0.1857). There was no correlation between GRP78 and IL-6 plasma levels ( = 0.13 [-0.13;0.37]; = 0.3106).
CONCLUSION
Among severe COVID-19 patients, ERS was associated with LDV but not with systemic inflammation, while systemic inflammation was associated with organ failure but not with LDV.
PubMed: 38933109
DOI: 10.3389/fmed.2024.1368031 -
Pharmaceutics Jun 2024The tyrosine kinase Inhibitor (TKI) imatinib is approved for the treatment of the chronic phase of chronic myeloid leukemia (CP-CML). Pharmacokinetic studies have...
The tyrosine kinase Inhibitor (TKI) imatinib is approved for the treatment of the chronic phase of chronic myeloid leukemia (CP-CML). Pharmacokinetic studies have highlighted the importance of inter-patient variability on imatinib plasma trough concentrations (ima[C]min). In the OPTIM-imatinib trial, we demonstrated that therapeutic drug monitoring (TDM) is able to improve the molecular response of CP-CML patients treated with imatinib. Here, we analyzed the constitutional exomes and RNAseq data of these patients. We performed an association analysis between the constitutional genetic variants of the patients and their ima[C]min, measured after 12 weeks of treatment with 400 mg once daily. Using linear regression, we identified 50 SNPs that showed excess heterozygosity depending on the ima[C]min. Ten SNPs were from non-coding sequences, and among the 40 remaining, 30 (from 25 genes) could be split into two categories. The first group of 16 SNPs concerns genes encoding extracellular matrix, cell junction, and membrane proteins. Coincidentally, cell adhesion proteins were also identified by RNA-seq as being overexpressed in patients with high ima[C]min. The other group of 14 SNPs were from genes encoding proteins involved in transcription/translation. Although most of the SNPs are intronic variants (28), we also identified missense (3), synonymous (4), 5'/3' (2), splicing (1), and upstream (4) variants. A haplotype analysis of four genes showed a significant association with high ima[C]min. None of the SNPs were significantly associated with the response. In conclusion, we identified a number of ima[C]min-associated SNPs, most of which correspond to genes encoding proteins that could play a role in the diffusion and transit of imatinib through membranes or epithelial barriers.
PubMed: 38931954
DOI: 10.3390/pharmaceutics16060834 -
Diagnostics (Basel, Switzerland) Jun 2024This review aims to provide a comprehensive overview of the diagnosis of brain death/death by neurologic criteria (BD/DNC) by emphasizing the clinical criteria... (Review)
Review
This review aims to provide a comprehensive overview of the diagnosis of brain death/death by neurologic criteria (BD/DNC) by emphasizing the clinical criteria established by the American Academy of Neurology (AAN) in light of their updated guidelines released in 2023. In this review, we will focus on the current implementation of ancillary tests including the catheter cerebral angiogram, nuclear scintigraphy, and transcranial Doppler, which provide support in diagnoses when clinical examination and apnea tests are inconclusive. Finally, we will also provide examples to discuss the implementation of certain imaging studies in the context of diagnosing BD/DNC. Recent developments in the field of neurology have emphasized the importance of clinical criteria for diagnosing BD/DNC, with the AAN providing clear updated guidelines that include coma, apnea, and the absence of brainstem reflexes. Current ancillary tests, including the catheter cerebral angiogram, nuclear scintigraphy, and transcranial Doppler play a crucial role in confirming BD/DNC when the clinical assessment is limited. The role of commonly used imaging studies including computed tomography and magnetic resonance angiographies of the brain as well as CT/MR perfusion studies will also be discussed in the context of these new guidelines. BD/DNC represents the permanent cessation of brain functions, including the brainstem. This review article provides the historical context, clinical criteria, and pathophysiology that goes into making this diagnosis. Additionally, it explores the various ancillary tests and selected imaging studies that are currently used to diagnose BD/DNC under the newly updated AAN guidelines. Understanding the evolution of how to effectively use these diagnostic tools is crucial for healthcare professionals who encounter these BD/DNC cases in their practice.
PubMed: 38928702
DOI: 10.3390/diagnostics14121287 -
Cancers Jun 2024The aim of this study was to assess the potential value of circulating active and inactive IL-18 levels in distinguishing pseudo and true tumor progression among NSCLC...
UNLABELLED
The aim of this study was to assess the potential value of circulating active and inactive IL-18 levels in distinguishing pseudo and true tumor progression among NSCLC patients receiving immune checkpoint inhibitor treatments (ICIs).
METHODS
This ancillary study includes 195 patients with metastatic non-small-cell lung cancer (NSCLC) treated with ICI in monotherapy, either pembrolizumab or nivolumab. Plasmatic levels of IL-18-related compounds, comprising the inhibitor IL-18 binding protein (IL-18BP), the inactive IL-18 (corresponding to IL-18/IL-18BP complex), and the active free IL-18, were assayed by ELISA. Objective tumoral response was analyzed by FDG PET-CT at baseline, 7 weeks, and 3 months post treatment induction, using PERCIST criteria.
RESULTS
Plasmatic IL-18BP and total IL-18 levels are increased at baseline in NSCLC patients compared with healthy controls, whereas IL-18/IL-18BP complexes are decreased, and free IL-18 levels remain unchanged. Neither of the IL-18-related compounds allowed to discriminate ICI responding to nonresponding patients. However, inactive IL-18 levels allowed to discriminate patients with a first tumor progression, assessed after 7 weeks of treatment, with worse overall survival. In addition, we showed that neutrophil concentration is also a predictive indicator of patients' outcomes with OS (HR = 2.6, = 0.0001) and PFS (HR = 2.2, = 0.001).
CONCLUSIONS
Plasmatic levels of inactive IL-18, combined with circulating neutrophil concentrations, can effectively distinguish ICI nonresponding patients with better overall survival (OS), potentially guiding rapid decisions for therapeutic intensification.
PubMed: 38927931
DOI: 10.3390/cancers16122226 -
NPJ Parkinson's Disease Jun 2024The Movement Disorder Society developed research criteria for the detection of the prodromal phase of Parkinson's disease (PD). Accurate identification of this phase is...
The Movement Disorder Society developed research criteria for the detection of the prodromal phase of Parkinson's disease (PD). Accurate identification of this phase is essential for early interventions. Therefore, we investigated the diagnostic value of these research criteria in the general population. Lifelines is an ongoing cohort study of 167,000 participants from the general population of the Northern Netherlands. 160 participants self-reported to have developed PD during three rounds of follow-up of five years each. Data were available to infer six out of eleven risk markers, and six out of twelve prodromal markers. We retrospectively compared the criteria in the prodromal stage of a group of 160 'converters' with 320 age- and sex-matched controls. The overall incidence rate of PD was 0.20 per 1.000 person-years (95% CI: 0.049-0.36), increasing with age and rates were higher in men. The median probability for prodromal PD in PD-converters was 1.29% (interquartile range: 0.46-2.9), compared to 0.83% (0.39-1.8) for controls (P = 0.014). The MDS set of criteria for prodromal PD had an ROC-AUC of 0.577, and was therefore not sufficient to adequately predict conversion to PD. We were unable to predict conversion to PD in the general population using a selection of the prodromal PD research criteria. Ancillary investigations are required to improve the diagnostic accuracy of the criteria, but most are precluded from large-scale use. Strategies, including olfactory tests or alpha-synuclein seeding amplification assays may improve the detection of prodromal PD in the general population.
PubMed: 38926405
DOI: 10.1038/s41531-024-00739-6