Restoring the infected powerhouse: Mitochondrial quality control in sepsis.

Sepsis is a dysregulated host response to an infection, characterized by organ failure. The pathophysiology is complex and incompletely understood, but mitochondria appear to play a key role in the cascade of events that culminate in multiple organ failure and potentially death. In shaping immune responses, mitochondria fulfil dual roles: they not only supply energy and metabolic intermediates crucial for immune cell activation and function but also influence inflammatory and cell death pathways. Importantly, mitochondrial dysfunction has a dual impact, compromising both immune system efficiency and the metabolic stability of end organs. Dysfunctional mitochondria contribute to the development of a hyperinflammatory state and loss of cellular homeostasis, resulting in poor clinical outcomes. Already in early sepsis, signs of mitochondrial dysfunction are apparent and consequently, strategies to optimize mitochondrial function in sepsis should not only prevent the occurrence of mitochondrial dysfunction, but also cover the repair of the sustained mitochondrial damage. Here, we discuss mitochondrial quality control (mtQC) in the pathogenesis of sepsis and exemplify how mtQC could serve as therapeutic target to overcome mitochondrial dysfunction. Hence, replacing or repairing dysfunctional mitochondria may contribute to the recovery of organ function in sepsis. Mitochondrial biogenesis is a process that results in the formation of new mitochondria and is critical for maintaining a pool of healthy mitochondria. However, exacerbated biogenesis during early sepsis can result in accumulation of structurally aberrant mitochondria that fail to restore bioenergetics, produce excess reactive oxygen species (ROS) and exacerbate the disease course. Conversely, enhancing mitophagy can protect against organ damage by limiting the release of mitochondrial-derived damage-associated molecules (DAMPs). Furthermore, promoting mitophagy may facilitate the growth of healthy mitochondria by blocking the replication of damaged mitochondria and allow for post sepsis organ recovery through enabling mitophagy-coupled biogenesis. The remaining healthy mitochondria may provide an undamaged scaffold to reproduce functional mitochondria. However, the kinetics of mtQC in sepsis, specifically mitophagy, and the optimal timing for intervention remain poorly understood. This review emphasizes the importance of integrating mitophagy induction with mtQC mechanisms to prevent undesired effects associated with solely the induction of mitochondrial biogenesis.

Circulating monocytes expressing senescence-associated features are enriched in COVID-19 patients with severe disease.

Accurate biomarkers for predicting COVID-19 severity have remained an unmet need due to an incomplete understanding of virus pathogenesis and heterogeneity among patients. Cellular senescence and its pro-inflammatory phenotype are suggested to be a consequence of SARS-CoV-2 infection and potentially drive infection-dependent pathological sequelae. Senescence-associated markers in infected individuals have been identified primarily in the lower respiratory tract, while little is known about their presence in more easily accessible bio-specimens. Here, we measured the abundance of senescence-associated signatures in whole blood, plasma and peripheral blood mononuclear cells (PBMCs) of COVID-19 patients and patients without an infection. Bulk transcriptomic and targeted proteomic assays revealed that the level of senescence-associated markers, including the senescence-associated secretory phenotype (SASP), is predictive of SARS-CoV-2 infection. Single-cell RNA-sequencing data demonstrated that a senescence signature is particularly enriched in monocytes of COVID-19 patients, partially correlating with disease severity. Our findings suggest that monocytes are prematurely induced to senescence by SARS-CoV-2 infection, might contribute to exacerbating a SASP-like inflammatory response and can serve as markers and predictors for COVID-19 and its sequelae.

Plasma proteomic characterization of the development of acute kidney injury in early sepsis patients.

Acute kidney injury (AKI) develops frequently in the course of patients with sepsis and strongly associates with in-hospital mortality. However, diagnosing AKI involves a considerable lag-time because it depends on assessing an increase in serum creatinine, and offers no insight in the underlying pathophysiology. Consequently, identifying a set of proteins reflecting the development of AKI may improve earlier recognition of AKI and the understanding of its pathophysiology. A targeted plasma proteomic approach was performed in early sepsis patients with and without subsequent AKI development in a matched pair design (n = 19 each). Principal component analysis identified 53 proteins associated with development of AKI, which were further analysed using Enrichr gene ontology and pathway analysis. Nine differentially expressed proteins from the targeted proteomics were increased among patients who subsequently developed AKI and correlated with principal components, namely CALCA, CALR, CA12, CLEC1A, PTK7, KIM-1, NPPC, NUCB2 and PGF. We demonstrated the biological insight in the development of AKI in early sepsis compared to non-AKI sepsis.

Mild hypothermia during cardiopulmonary bypass assisted CABG is associated with improved short- and long-term survival, a 18-year cohort study.

Data substantiating the optimal patient body temperature during cooling procedures in cardiac operations are currently unavailable. To explore the optimal temperature strategy, we examined the association between temperature management and survival among patients during cardiopulmonary bypass assisted coronary artery bypass grafting (CABG) procedures on 30-days and 5-year postoperative survival. Adult patients (n = 5,672, 23.6% female and mean (SD) age of 66 (10) years) operated between 1997 and 2015 were included, with continuous measured intraoperative nasopharyngeal temperatures. The association between mortality and patient characteristics, laboratory parameters, the lowest intraoperative plateau temperature and intraoperative cooling/rewarming rates were examined by multivariate Cox regression analysis. Machine learning-based cluster analysis was used to identify patient subgroups based on pre-cooling parameters and explore whether specific subgroups benefitted from a particular temperature management. Mild hypothermia (32-35°C) was independently associated with improved 30-days and 5-year survival compared to patients in other temperature categories regardless of operation year. 30 days and 5-year survival were 98% and 88% in the mild hypothermia group, whereas it amounted 93% and 80% in the severe hypothermia (<30°C). Normothermia (35-37°C) showed the lowest survival after 30 days and 5 years amounting 93% and 72%, respectively. Cluster analysis identified 8 distinct patient subgroups principally defined by gender, age, kidney function and weight. The full cohort and all patient subgroups displayed the highest survival at a temperature of 32°C. Given these associations, further prospective randomized controlled trials are needed to ascertain optimal patient temperatures during CPB.

Hospital-related costs of sepsis around the world: A systematic review exploring the economic burden of sepsis.

AIM: The aim of this study was to examine the quality of manuscripts reporting sepsis health care costs and to provide an overview of hospital-related expenditures for sepsis in adult patients around the world. METHODS: We systematically searched the PubMed, EMBASE, Cochrane and Google Scholar to identify relevant studies between January 2010 and January 2022. We selected articles that provided costs and cost-effectiveness analyses, defined sepsis and described their cost calculation method. All costs were adjusted to 2020 US dollars. Medians and interquartile ranges (IQRs) for various costs of sepsis were calculated. The quality of economic studies was assessed using the Drummond 10-item checklist. RESULTS: Overall, 26 studies met our eligibility criteria. The mean total hospital costs per patient varied largely, between €1101 and €91,951. The median (IQR) of the total sepsis costs per country were €36,191 (€17,158 - €53,349), which equals €50 (€34 - €84) per capita annually. The relative amount of healthcare budget spent on sepsis was 2.65%, which equals 0.33% of the gross national product (GNP). CONCLUSION: While general sepsis costs are high, there is considerable variability between countries regarding the costs of sepsis. Further studies examining the impact on sepsis costs, especially on the general ward, can help justify, design and monitor initiatives on prevention, diagnosis, and treatment of this time-critical and potentially preventable disease.

The validation of a serious game for teaching ultrasound skills.

BACKGROUND: Point-of-care ultrasound (POCUS) is an important bedside diagnostic tool and is being taught in several specialties. However, mastering the required psychomotor skills takes time and learning curves are different between students. Especially learning to make the right probe movements with the corresponding changes of the ultrasound image on screen, and integrating it into a 3D mental model takes time. This precious bedside-time of trainers and physicians may be reduced using other learning methods for mastering the psychomotor skills, for example the use of serious games. Such a game is under development but it needs to be validated before widespread use can be advised. In this article we describe the development and the first three steps in the validation of a serious game for ultrasound skills. RESULTS: We have included 18 ultrasound experts and 24 ultrasound novices who played the serious game 'Underwater" and provided feedback. They concluded that "underwater" is fun to play and that movement of the 3D-printed probe resembled real ultrasound probe movements. Participants highly valued the potential of the game for training eye-hand coordination and stability of probe handling, two very important skills in performing ultrasound in real practice. Although we compared several in-game parameters such as distance and speed, no difference was observed between novices and experts. This means that content- and face validity of the serious game is demonstrated but optimal parameters to measure differences between novices and experts still have to be determined. CONCLUSIONS: Our study shows solid content- and face validity of the serious game "UnderWater" for training ultrasound skills, although construct validity could not be demonstrated yet. The game is appreciated as a promising serious game for training eye-hand coordination and learning ultrasound, which may reduce expensive bed-side teaching.

Life after a point-of-care ultrasound course: setting up the right conditions!

BACKGROUND: Point-of-care Ultrasound (POCUS) is becoming an important diagnostic tool for internal medicine and ultrasound educational programs are being developed. An ultrasound course is often included in such a curriculum. We have performed a prospective observational questionnaire-based cohort study consisting of participants of a POCUS course for internal medicine in the Netherlands in a 2-year period. We investigated the usefulness of an ultrasound course and barriers participants encountered after the course. RESULTS: 55 participants (49%) completed the pre-course questionnaire, 29 (26%) completed the post-course questionnaire, 11 participants (10%) finalized the third questionnaire. The number of participants who performs POCUS was almost doubled after the course (from 34.5 to 65.5%). Almost all participants felt insufficiently skilled before the course which declined to 34.4% after the course. The majority (N = 26 [89.7%]) stated that this 2-day ultrasound course was sufficient enough to perform POCUS in daily practice but also changed daily practice. The most important barriers withholding them from performing ultrasound are lack of experts for supervision, insufficient practice time and absence of an ultrasound machine. CONCLUSIONS: This study shows that a 2-day hands-on ultrasound course seems a sufficient first step in an ultrasound curriculum for internal medicine physicians to obtain enough knowledge and skills to perform POCUS in clinical practice but it also changes clinical practice. However, there are barriers in the transfer to clinical practice that should be addressed which may improve curriculum designing.

A Systematic Review of the Effects of Hyperoxia in Acutely Ill Patients: Should We Aim for Less?

INTRODUCTION: Despite widespread and liberal use of oxygen supplementation, guidelines about rational use of oxygen are scarce. Recent data demonstrates that current protocols lead to hyperoxemia in the majority of the patients and most health care professionals are not aware of the negative effects of hyperoxemia. METHOD: To investigate the effects of hyperoxemia in acutely ill patients on clinically relevant outcomes, such as neurological and functional status as well as mortality, we performed a literature review using Medline (PubMed) and Embase. We used the following terms: hyperoxemia OR hyperoxemia OR ["oxygen inhalation therapy" AND (mortality OR death OR outcome OR survival)] OR [oxygen AND (mortality OR death OR outcome OR survival)]. Original studies about the clinical effects of hyperoxemia in adult patients suffering from acute or emergency illnesses were included. RESULTS: 37 articles were included, of which 31 could be divided into four large groups: cardiac arrest, traumatic brain injury (TBI), stroke, and sepsis. Although a single study demonstrated a transient protective effect of hyperoxemia after TBI, other studies revealed higher mortality rates after cardiac arrest, stroke, and TBI treated with oxygen supplementation leading to hyperoxemia. Approximately half of the studies showed no association between hyperoxemia and clinically relevant outcomes. CONCLUSION: Liberal oxygen therapy leads to hyperoxemia in a majority of patients and hyperoxemia may negatively affect survival after acute illness. As a clinical consequence, aiming for normoxemia may limit negative effects of hyperoxemia in patients with acute illness.

Neuroprotective hypothermia - Why keep your head cool during ischemia and reperfusion.

BACKGROUND: Targeted temperature management (TTM) is the induced cooling of the entire body or specific organs to help prevent ischemia and reperfusion (I/R) injury, as may occur during major surgery, cardiac resuscitation, traumatic brain injury and stroke. Ischemia and reperfusion induce neuronal damage by mitochondrial dysfunction and oxidative injury, ER stress, neuronal excitotoxicity, and a neuroinflammatory response, which may lead to activation of apoptosis pathways. SCOPE OF REVIEW: The aim of the current review is to discuss TTM targets that convey neuroprotection and to identify potential novel pharmacological intervention strategies for the prevention of cerebral ischemia and reperfusion injury. MAJOR CONCLUSIONS: TTM precludes I/R injury by reducing glutamate release and oxidative stress and inhibiting release of pro-inflammatory factors and thereby counteracts mitochondrial induced apoptosis, neuronal excitotoxicity, and neuroinflammation. Moreover, TTM promotes regulation of the unfolded protein response and induces SUMOylation and the production of cold shock proteins. These advantageous effects of TTM seem to depend on the clinical setting, as well as type and extent of the injury. Therefore, future aims should be to refine hypothermia management in order to optimize TTM utilization and to search for pharmacological agents mimicking the cellular effects of TTM. GENERAL SIGNIFICANCE: Bundling knowledge about TTM in the experimental, translational and clinical setting may result in better approaches for diminishing I/R damage. While application of TTM in the clinical setting has some disadvantages, targeting its putative protective pathways may be useful to prevent I/R injury and reduce neurological complications.

Blood cell dynamics during hibernation in the European Ground Squirrel.

Hibernation is a unique natural model to study large and specific modulation in numbers of leukocytes and thrombocytes, with potential relevance for medical application. Hibernating animals cycle through cold (torpor) and warm (arousal) phases. Previous research demonstrated clearance of leukocytes and thrombocytes from the circulation during torpor, but did not provide information regarding the timing during torpor or the subtype of leukocytes affected. To study the influence of torpor-bout duration on clearance of circulating cells, we measured blood cell dynamics in the European Ground Squirrel. Numbers of leukocytes and thrombocytes decreased within 24h of torpor by 90% and remained unchanged during the remainder of the torpor-bout. Differential counts demonstrated that granulocytes, lymphocytes and monocytes are all affected by torpor. Although a decreased production might explain the reduced number of thrombocytes, granulocytes and monocytes, this cannot explain the observed lymphopenia since lymphocytes have a much lower turnover rate than thrombocytes, granulocytes and monocytes. In conclusion, although underlying biochemical signaling pathways need to be unraveled, our data show that the leukocyte count drops dramatically after entrance into torpor and that euthermic cell counts are restored within 1.5h after onset of arousal, even before body temperature is fully normalized.

Signal transduction pathways involved in brain death-induced renal injury.

Kidneys derived from brain death organ donors show an inferior survival when compared to kidneys derived from living donors. Brain death is known to induce organ injury by evoking an inflammatory response in the donor. Neuronal injury triggers an inflammatory response in the brain, leading to endothelial dysfunction and the release of cytokines in the circulation. Serum levels of interleukin-6, -8, -10, and monocyte chemoattractant protein-1 (MCP-1) are increased after brain death. Binding with cytokine-receptors in kidneys stimulates activation of nuclear factor-kappa B (NF-kappaB), selectins, adhesion molecules and production of chemokines leading to cellular influx. Mitogen-activated protein kinases (MAP-kinases) mediate inflammatory responses and together with NF-kappaB they seem to play an important role in brain death induced renal injury. Altering the activation state of MAP-kinases could be a promising drug target for early intervention to reduce cerebral injury related donor kidney damage and improve outcome after transplantation.