Arachidonic Acid Mobilization and Peroxidation Promote Microglial Dysfunction in Aß Pathology.

Aberrant increase of arachidonic acid (ARA) has long been implicated in the pathology of Alzheimer's disease (AD), while the underlying causal mechanism remains unclear. In this study, we revealed a link between ARA mobilization and microglial dysfunction in Aß pathology. Lipidomic analysis of primary microglia from AppNL-GF mice showed a marked increase in free ARA and lysophospholipids (LPLs) along with a decrease in ARA-containing phospholipids, suggesting increased ARA release from phospholipids (PLs). To manipulate ARA-containing PLs in microglia, we genetically deleted lysophosphatidylcholine acyltransferase 3 (Lpcat3), the main enzyme catalyzing the incorporation of ARA into PLs. Loss of microglial Lpcat3 reduced the levels of ARA-containing PLs, free ARA and LPLs, leading to a compensatory increase in monounsaturated fatty acid (MUFA)-containing PLs in both male and female App NL-GF mice. Notably, the reduction of ARA in microglia significantly ameliorated oxidative stress and inflammatory responses while enhancing the phagocytosis of Aß plaques and promoting the compaction of Aß deposits. Mechanistically, scRNA seq suggested that LPCAT3 deficiency facilitates phagocytosis by facilitating de novo lipid synthesis while protecting microglia from oxidative damage. Collectively, our study reveals a novel mechanistic link between ARA mobilization and microglial dysfunction in AD. Lowering brain ARA levels through pharmacological or dietary interventions may be a potential therapeutic strategy to slow down AD progression.

Secondary-Electrospray Ionization Mass Spectrometry-Based Online Analyses of Mouse Volatilome Uncover Gut Microbiome-Dictated Metabolic Changes in the Host.

The symbiotic relationship between the gut microbial population is capable of regulating numerous aspects of host physiology, including metabolism. Bacteria can modulate the metabolic processes of the host by feeding on nutritional components within the lumen and releasing bioactive components into circulation. Endogenous volatile organic compound (VOC) synthesis is dependent on the availability of precursors found in mammalian metabolism. Herein, we report that microbial-mediated metabolic influences can alter the host volatilome and the prominent volatile changes can be uncovered by a novel volatile analysis technique named secondary electrospray ionization mass spectrometry. Mice were subjected to an antibiotic cocktail to deplete the microbiome and then inoculated with either single strain bacteria or fecal matter transplantation (FMT) to replete the microbial population in the gut. VOC sampling was achieved by using an advanced secondary electrospray ionization (SESI) source that directly mounted onto a Thermo Q-Exactive high-resolution mass spectrometer (HRMS). A principal component analysis summarizing the volatile profiles of the mice revealed independent clustering of each strain of the FMT-inoculated groups, suggesting unique volatile profiles. The Mummichog algorithm uncovered phenylalanine metabolism as a significantly altered metabolic profile in the volatilome of the microbiome-repleted mice. Our results indicated that the systemic metabolic changes incurred by the host are translated to unique volatile profiles correlated to the diversity of the microbial population colonized within the host. It is thus possible to take advantage of SESI-HRMS-based platforms for noninvasive screening of VOCs to determine the contribution of various microbial colonization within human gut that may impact host health.

The influence of patient position on ultrasound examination of the sciatic nerve in the popliteal fossa: A cross-sectional study.

Introduction/Purpose: Ultrasound-guided popliteal fossa sciatic nerve (PFSN) blocks are performed with patients in the supine, lateral or prone position. No known studies compare the quality of images obtained from each approach. This study examines the quality of supine and prone PFSN ultrasound images. Methods: Thirty-eight adult volunteers were sorted into two groups. Five regional anaesthesiologists performed ultrasound examinations of the PFSN on volunteers in supine and prone positions. Popliteal fossa sciatic nerve image quality was analysed with grayscale techniques and peer evaluation. Popliteal fossa sciatic nerve depth, distance from the popliteal crease and time until optimal imaging were recorded. Results: The grayscale ratio of the PFSN vs. the background was 1.83 (supine) and 1.75 (prone) (P = 0.034). Similarly, the grayscale ratio of the PFSN vs. the immediately adjacent area was 1.65 (supine) and 1.55 (prone) (P = 0.004). Mean depth of the PFSN was 1.6 cm (supine) and 1.7 cm (prone) (P = 0.009). Average distance from the popliteal crease to the PFSN was 5.9 cm (supine) and 6.6 cm (prone) (P = 0.02). Mean time to acquire optimal imaging was 36 s (supine) and 47 s (prone) (P = 0.002). Observers preferred supine positioning 53.8%, prone positioning 22.5% and no preference 23.7% of the time. Observers with strong preferences preferred supine imaging in 70.9% of cases. Conclusions: Supine ultrasound examination offered quicker identification of the PFSN, in a more superficial location, closer to the popliteal crease and with enhanced contrast to surrounding tissue, correlating with observer preferences for supine positioning. These results may influence ultrasound-guided PFSN block success rates, especially in difficult-to-image patients.

More than Meets the Eye: Untargeted Metabolomics and Lipidomics Reveal Complex Pathways Spurred by Activation of Acid Resistance Mechanisms in Escherichia coli.

Escherichia coli is a ubiquitous group of bacteria that can be either commensal gut microbes or enterohemorrhagic food-borne pathogens. Regardless, both forms must survive acidic environments in the stomach and intestines to reach and colonize the gut, a process that partially relies on amino acid-dependent acid resistance (AR) mechanisms and modifications to membrane phospholipids. However, only the basic tenets of these mechanisms have been elucidated. In this paper, we aim to conduct a full-scale metabolic and lipidomic characterization of E. coli's adaptations to acid stress. We hypothesized that the use of untargeted metabolomics and lipidomics would reveal mechanisms downstream of AR processes that provide novel contributions to acid stress survival. We detected significant differences in the extracellular metabolome and the lipidome induced by amino acid supplementation (glutamine, arginine, or lysine) and contextualized these results using real-time quantitative polymerase chain reaction (RT-qPCR). We additionally identified several metabolic pathways as well as a significant alteration in phospholipid synthetic pathways induced by differential amino acid supplementation. These results demonstrate that AR may extend beyond canonical mechanisms to a coordinated metabolic phenotype. Future studies may benefit from our analysis to further elucidate distinct targets for prebiotic supplements to cultivate commensal strains or therapies to combat pathogenic ones.

Not just a gut feeling: a deep exploration of functional bacterial metabolites that can modulate host health.

Bacteria have been known to reside in the human gut for roughly two centuries, but their modulatory effects on host health status are still not fully characterized. The gut microbiota is known to interact with dietary components and nutrients, producing functional metabolites that may alter host metabolic processes. The majority of thoroughly researched and understood gut microbial metabolites fall into two categories: short-chain fatty acids (SCFAs) and bacterial derivatives of dietary tryptophan. Despite the heavy emphasis on these metabolites, other metabolites stemming from microbial origin have significant impacts on host health and disease states. In this narrative review, we summarize eight recent studies elucidating novel bacterial metabolites, detailing the process by which these metabolites are identified, their actions within specific categories of human health, and how diet may impact production of these metabolites. With similar future mechanistic research, a more complete picture of bacterial impact on host metabolism may be constructed.

The Application of Metabolomics in Recent Colorectal Cancer Studies: A State-of-the-Art Review.

Colorectal cancer (CRC) is a highly prevalent disease with poor prognostic outcomes if not diagnosed in early stages. Current diagnosis techniques are either highly invasive or lack sufficient sensitivity. Thus, identifying diagnostic biomarkers of CRC with high sensitivity and specificity is desirable. Metabolomics represents an analytical profiling technique with great promise in identifying such biomarkers and typically represents a close tie with the phenotype of a specific disease. We thus conducted a systematic review of studies reported from January 2012 to July 2021 relating to the detection of CRC biomarkers through metabolomics to provide a collection of knowledge for future diagnostic development. We identified thirty-seven metabolomics studies characterizing CRC, many of which provided metabolites/metabolic profile-based diagnostic models with high sensitivity and specificity. These studies demonstrated that a great number of metabolites can be differentially regulated in CRC patients compared to healthy controls, adenomatous polyps, or across stages of CRC. Among these metabolite biomarkers, especially dysregulated were certain amino acids, fatty acids, and lysophosphatidylcholines. Additionally, we discussed the contribution of the gut bacterial population to pathogenesis of CRC through their modulation to fecal metabolite pools and summarized the established links in the literature between certain microbial genera and altered metabolite levels in CRC patients. Taken together, we conclude that metabolomics presents itself as a promising and effective method of CRC biomarker detection.

Leveraging Telemedicine for Quality Improvement Video Review of Critical ICU Events: A Novel Multidisciplinary Form of Education.

The objectives of this study were to codify the events triggering bedside recording and to report the types of performance issues identified that were then used to inform dedicated ICU quality improvement efforts. DESIGN: This is a retrospective descriptive analysis of a video review program conducted at a single institution from July 2016 to November 2019. SETTING: Surgical and Trauma ICU at a single urban academic quaternary care center. PATIENTS: All patients admitted to the surgical and trauma ICU between July 2016 and November 2019 were eligible for the study as all ICU beds in our health system institutions are equipped with closed circuit video/audio monitoring. Through an institutional review board approved program, any event triggering the immediate bedside presence of a provider in the ICU is routinely recorded at the discretion of the care team or tele-intensivist. INTERVENTIONS: A database of these events was created over a 3-year period, and cases were reviewed for content, quality improvement, and educational opportunities. Select recordings were analyzed and shared at multidisciplinary/multiprofessional video review sessions. MEASUREMENTS AND MAIN RESULTS: There were 286 critical events video recorded and reviewed in the ICUs between July 2016 and November 2019. The most commonly recorded events included: cardiopulmonary arrests (n = 75), intubations (n = 71), and acute clinical decompensation triggered by nonreassuring vital signs (n = 57) or arrhythmias (n = 13). Of these recordings, 59 were shared at video review conferences, where quality of care was assessed and thematic opportunities for improvement were characterized. Recurrent quality improvement themes that were identified included adherence to protocols, the importance of teamwork and closed-loop communication, clearly designated team leadership, and the use of universal precautions. CONCLUSIONS: Video review in the ICU is feasible and presents valuable opportunities for quality improvement and educational discussions.

Respiratory mechanics and mortality in coronavirus disease 2019 acute respiratory distress syndrome: A retrospective cohort study.

BACKGROUND: The association between commonly monitored respiratory parameters, including compliance and oxygenation and clinical outcomes in acute respiratory distress syndrome (ARDS) from coronavirus disease 2019 (COVID-19) remains unclear, limiting prognostication and the delivery of targeted treatments. Our project aim was to identify if any such associations exist between clinical outcomes and respiratory parameters. METHODS: We performed a retrospective observational cohort study of confirmed COVID-19 positive patients admitted to a single dedicated intensive care unit at a university hospital from March 27 to April 26, 2020. We collected information on baseline clinical and demographic characteristics and initial respiratory parameters. Our primary outcome was in-hospital mortality. RESULTS: A total of 22 patients met criteria for ARDS and were included in our study. Nine of the 22 (40.9%) patients with ARDS died during hospitalization. The initial static respiratory system compliance of survivors was 39 (interquartile range [IQR] 34, 55) and nonsurvivors was 27 (IQR 24, 33, P < 0.01). A lower respiratory system compliance was associated with an increased adjusted odd of in-hospital mortality (odds ratio 1.2, 95% confidence interval 1.01, 1.45 P = 0.04). CONCLUSION: In our cohort of 22 patients mechanically ventilated with ARDS from COVID-19, having lower respiratory system compliance after intubation was associated with an increased risk of in-hospital mortality, consistent with ARDS from non-COVID etiologies.

The Year in Vascular Anesthesia: Selected Highlights From 2018.

This special article is the second in an annual series for the Journal of Cardiothoracic and Vascular Anesthesia that is specifically dedicated to highlights in vascular anesthesiology published in 2018. This review begins with 2 updates in preoperative medicine in the vascular surgery population, including recent publications regarding the management of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers and antiplatelet medications in the perioperative period. The next section focuses on complications related to thoracic endovascular aortic surgery, particularly as technology advances allow for endovascular repair of more complex anatomy. The final section focuses on quality in vascular surgery and evaluates recent publications that examine the safety and feasibility of fast-track endovascular aortic surgery. Even though this is only a sampling of the literature published in 2018 relevant to the cardiovascular anesthesiologist, these themes represent some of the topics most clinically relevant to the perioperative period.