Body Mass Index and Mortality in Coronavirus Disease 2019 and Other Diseases:A Cohort Study in 35,506 ICU Patients

OBJECTIVES: Obesity is a risk factor for severe coronavirus disease 2019 and might play a role in its pathophysiology. It is unknown whether body mass index is related to clinical outcome following ICU admission, as observed in various other categories of critically ill patients. We investigated the relationship between body mass index and inhospital mortality in critically ill coronavirus disease 2019 patients and in cohorts of ICU patients with non-severe acute respiratory syndrome coronavirus 2 viral pneumonia, bacterial pneumonia, and multiple trauma. DESIGN: Multicenter observational cohort study. SETTING: Eighty-two Dutch ICUs participating in the Dutch National Intensive Care Evaluation quality registry. PATIENTS: Thirty-five-thousand five-hundred six critically ill patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patient characteristics and clinical outcomes were compared between four cohorts (coronavirus disease 2019, nonsevere acute respiratory syndrome coronavirus 2 viral pneumonia, bacterial pneumonia, and multiple trauma patients) and between body mass index categories within cohorts. Adjusted analyses of the relationship between body mass index and inhospital mortality within each cohort were performed using multivariable logistic regression. Coronavirus disease 2019 patients were more likely male, had a higher body mass index, lower Pao2/Fio2 ratio, and were more likely mechanically ventilated during the first 24 hours in the ICU compared with the other cohorts. Coronavirus disease 2019 patients had longer ICU and hospital length of stay, and higher inhospital mortality. Odds ratios for inhospital mortality for patients with body mass index greater than or equal to 35 kg/m2 compared with normal weight in the coronavirus disease 2019, nonsevere acute respiratory syndrome coronavirus 2 viral pneumonia, bacterial pneumonia, and trauma cohorts were 1.15 (0.79- 1.67), 0.64 (0.43-0.95), 0.73 (0.61-0.87), and 0.81 (0.57-1.15), respectively. CONCLUSIONS: The obesity paradox, which is the inverse association between body mass index and mortality in critically ill patients, is not present in ICU patients with coronavirus disease 2019-related respiratory failure, in contrast to nonsevere acute respiratory syndrome coronavirus 2 viral and bacterial respiratory infections

Intrinsic DNA damage repair deficiency results in progressive microglia loss and replacement

The DNA excision repair protein Ercc1 is important for nucleotide excision, double strand DNA break, and interstrand DNA crosslink repair. In constitutiveErcc1-knockout mice, microglia display increased phagocytosis, proliferation and an enhanced responsiveness to lipopolysaccharide (LPS)-induced peripheral inflammation. However, the intrinsic effects ofErcc1-deficiency on microglia are unclear. In this study,Ercc1was specifically deleted from Cx3cr1-expressing cells and changes in microglia morphology and immune responses at different times after deletion were determined. Microglia numbers were reduced with approximately 50% at 2-12 months afterErcc1deletion. Larger and more ramified microglia were observed followingErcc1deletion both in vivo and in organotypic hippocampal slice cultures.Ercc1-deficient microglia were progressively lost, and during this period, microglia proliferation was transiently increased.Ercc1-deficient microglia were gradually replaced by nondeficient microglia carrying a functionalErcc1allele. In contrast to constitutiveErcc1-deficient mice, microglia-specific deletion ofErcc1did not induce microglia activation or increase their responsiveness to a systemic LPS challenge. Gene expression analysis suggested thatErcc1deletion in microglia induced a transient aging signature, which was different from a priming or disease-associated microglia gene expression profile.</p

Distinct amyloid-beta and tau-associated microglia profiles in Alzheimer's disease

Alzheimer's disease (AD) is the most prevalent form of dementia and is characterized by abnormal extracellular aggregates of amyloid-beta and intraneuronal hyperphosphorylated tau tangles and neuropil threads. Microglia, the tissue-resident macrophages of the central nervous system (CNS), are important for CNS homeostasis and implicated in AD pathology. In amyloid mouse models, a phagocytic/activated microglia phenotype has been identified. How increasing levels of amyloid-beta and tau pathology affect human microglia transcriptional profiles is unknown. Here, we performed snRNAseq on 482,472 nuclei from non-demented control brains and AD brains containing only amyloid-beta plaques or both amyloid-beta plaques and tau pathology. Within the microglia population, distinct expression profiles were identified of which two were AD pathology-associated. The phagocytic/activated AD1-microglia population abundance strongly correlated with tissue amyloid-beta load and localized to amyloid-beta plaques. The AD2-microglia abundance strongly correlated with tissue phospho-tau load and these microglia were more abundant in samples with overt tau pathology. This full characterization of human disease-associated microglia phenotypes provides new insights in the pathophysiological role of microglia in AD and offers new targets for microglia-state-specific therapeutic strategies

Profiling Microglia From Alzheimer's Disease Donors and Non-demented Elderly in Acute Human Postmortem Cortical Tissue

Microglia are the tissue-resident macrophages of the central nervous system (CNS). Recent studies based on bulk and single-cell RNA sequencing in mice indicate high relevance of microglia with respect to risk genes and neuro-inflammation in Alzheimer's disease (AD). Here, we investigated microglia transcriptomes at bulk and single-cell levels in non-demented elderly and AD donors using acute human postmortem cortical brain samples. We identified seven human microglial subpopulations with heterogeneity in gene expression. Notably, gene expression profiles and subcluster composition of microglia did not differ between AD donors and non-demented elderly in bulk RNA sequencing nor in single-cell sequencing

Exploring transdiagnostic stress and trauma-related symptoms across the world: a latent class analysis

Background: Although trauma exposure is universally prevalent, the ways in which individuals respond to potentially traumatic events vary. Between-country differences have been identified as affecting the development and manifestation of transdiagnostic psychological symptoms, but it remains unclear how stress and trauma-related transdiagnostic symptoms and risk patterns differ based on geographic region. Objective: To explore whether there are distinct classes of stress and trauma-related transdiagnostic symptoms and to determine predictors of class membership in a global sample. Method: Participants (N = 8675) from 115 different countries were recruited online between 2020–2022 and completed the Global Psychotrauma Screen, which assesses stress and trauma exposure, related symptoms, and risk factors. A latent class analysis (LCA) was used to identify classes of stress and trauma-related symptoms per world region (African States, Asia-Pacific States, Eastern European States, Latin American and Caribbean States, Western European and Other States, and North America) and the total sample. Likelihood of class membership was assessed based on demographics, characteristics of the potentially traumatic event, and potential risk factors across the world regions. Results: Similar class compositions were observed across regions. A joint latent class analysis identified three classes that differed by symptom severity (i.e. high, moderate, low). Multinomial logistic regression analyses revealed several factors that conferred greater risk for experiencing higher levels of symptoms, including geographic region, gender, and lack of social support, among others. Conclusions: Stress and trauma-related symptoms seem to be similarly transdiagnostic across the world, supporting the value of a transdiagnostic assessment. A latent class analysis of transdiagnostic stress and trauma-related symptoms in a global sample showed high, medium, and low symptom classes.Class compositions were similar across global geographic regions.Several factors were associated with high symptom class membership globally, including gender, geographic region, and lack of social support. A latent class analysis of transdiagnostic stress and trauma-related symptoms in a global sample showed high, medium, and low symptom classes. Class compositions were similar across global geographic regions. Several factors were associated with high symptom class membership globally, including gender, geographic region, and lack of social support.</p

Safety and Efficacy of Human Chorionic Gonadotropin Hormone-Derivative EA-230 in Cardiac Surgery Patients: A Randomized Double-Blind Placebo-Controlled Study

OBJECTIVES: To determine the safety and efficacy of human chorionic gonadotropin hormone-derivative EA-230 in cardiac surgery patients. Cardiac surgery induces systemic inflammation and may impair renal function, affecting patient outcome. EA-230 exerted immunomodulatory and renoprotective effects in preclinical models and was safe and showed efficacy in phase I and II human studies. DESIGN: Double-blinded, placebo-controlled, randomized study. SETTING: Collaboration of the Cardiothoracic Surgery, Anesthesiology, and the Intensive Care departments of a tertiary hospital in the Netherlands. PATIENTS: One hundred eighty patients undergoing an on-pump coronary artery bypass procedure with or without concomitant valve surgery. INTERVENTIONS: Ninety mg/kg/hr EA-230 or placebo administered during surgery. MEASUREMENTS AND MAIN RESULTS: During the study, no safety concerns emerged. EA-230 did not modulate interleukin-6 plasma concentrations (area under the curve 2,730 pg/mL × hr [1,968-3,760] vs 2,680 pg/mL × hr [2,090-3,570] for EA-230 and placebo group, respectively; p = 0.80). Glomerular filtration rate increased following surgery (mean ± sem increase in the EA-230 vs placebo groups: glomerular filtration rateiohexolmeasured using iohexol plasma clearance: 19 ± 2 vs 16 ± 2 mL/min/1.73 m2; p = 0.13 and estimated glomerular filtration rate with the Modification of Diet in Renal Disease equation using creatinine: 6 ± 1 vs 2 ± 1 mL/min/1.73 m2; p = 0.01). The "injury" stage of the Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease criteria for acute kidney injury was 7% in the EA-230 group versus 18% in the placebo group (p = 0.07). In addition, EA-230-treated patients had a less positive fluid balance compared with placebo-treated patients (217 ± 108 vs 605 ± 103 mL; p = 0.01), while the use of vasoactive agents was similar in both groups (p = 0.39). Finally, hospital length of stay was shorter in EA-230 treated patients (8 d [7-11] vs 10 d [8-12]; p = 0.001). Efficacy results were more pronounced in patients that had longer duration of surgery and thus longer duration of study drug infusion. CONCLUSIONS: EA-230 was safe in patients undergoing on-pump cardiac surgery. It did not modulate interleukin-6 plasma concentrations but appeared to exert beneficial renal and cardiovascular effects and shortened in-hospital length of stay

Brain macrophages acquire distinct transcriptomes in multiple sclerosis lesions and normal appearing white matter

Multiple sclerosis (MS) is a disease of the central nervous system that is characterized by inflammation and focal areas of demyelination, ultimately resulting in axonal degradation and neuronal loss. Several lines of evidence point towards a role for microglia and other brain macrophages in disease initiation and progression, but exactly how lesion formation is triggered is currently unknown. Here, we characterized early changes in MS brain tissue through transcriptomic analysis of normal appearing white matter (NAWM). We found that NAWM was characterized by enriched expression of genes associated with inflammation and cellular stress derived from brain macrophages. Single cell RNA sequencing confirmed a stress response in brain macrophages in NAWM and identified specific microglia and macrophage subsets at different stages of demyelinating lesions. We identified both phagocytic/activated microglia and CAM clusters that were associated with various MS lesion types. These overall changes in microglia and macrophages associated with lesion development in MS brain tissue may provide therapeutic targets to limit lesion progression and demyelination