Phenotypic and functional heterogeneity of human intermediate monocytes based on HLA-DR expression

Human blood monocytes are subclassified as classical, intermediate and nonclassical. In this study, it was shown that conventionally defined human intermediate monocytes can be divided into two distinct subpopulations with mid- and high-level surface expression of HLA-DR (referred to as DRmid and DRhi intermediate monocytes). These IM subpopulations were phenotypically and functionally characterized in healthy adult blood by flow cytometry, migration assays and lipoprotein uptake assays. Their absolute numbers and proportions were then compared in blood samples from obese and nonobese adults. DRmid and DRhi intermediate monocytes differentially expressed several proteins including CD62L, CD11a, CX3CR1 and CCR2. Overall, the DRmid intermediate monocytes surface profile more closely resembled that of classical monocytes while DRhi intermediate monocytes were more similar to nonclassical. However, in contrast to classical monocytes, DRmid intermediate monocytes migrated weakly to CCL2, had reduced intracellular calcium flux following CCR2 ligation and favored adherence to TNF alpha-activated endothelium over transmigration. In lipid uptake assays, DRmid intermediate monocytes demonstrated greater internalization of oxidized and acetylated low-density lipoprotein than DRhi intermediate monocytes. In obese compared to nonobese adults, proportions and absolute numbers of DRmid, but not DRhi intermediate monocytes, were increased in blood. The results are consistent with phenotypic and functional heterogeneity within the intermediate monocytes subset that may be of specific relevance to lipoprotein scavenging and metabolic health.The authors acknowledge the kind contribution of time and samples by study participants, as well as the assistance of the nursing and medical staff at the Centre for Diabetes, Endocrinology and Metabolism (CDEM) at Galway University Hospital. We also acknowledge assistance provided by Dr Paula O\u27Shea, Consultant Biochemist and staff at the Department of Biochemistry, Galway University Hospital. EPC, SN and SMS were supported by the Molecular Medicine Ireland Clinical and Translational Research Scholars Programme which was funded by the Irish Government\u27s Programme for Research in Third Level Institutions, Cycle 5 and by NUI Galway. MCD was supported by the Health Services Executive (HSE) of Ireland, Medical Education, Training & Research (METR) Section and the Health Research Board (HRB) of Ireland under the National Specialist Registrar/Senior Registrar Academic Fellowship Program (NSAFP). JKE was partly‐funded by grants from the Irish Research Council for Science, Engineering and Technology (IRCSET EMPOWER fellowship) and the Health Research Board (grant number RP2006182N). Funding support was also received from Science Foundation Ireland [Regenerative Medicine Institute Strategic Research Cluster, grant number 09/SRC‐B1794; CÚRAM Research Centre, grant number 13/RC/2073 (MDG, TO\u27B, RC) and Principal Investigators grant numbers 07/IN1/B958 and 13/IA/1954 (NFL)], from the European Commission [Horizon 2020 Collaborative Health Project NEPHSTROM (Novel Stromal Cell Therapy for Diabetic Kidney Disease; grant 634086 (MDG, TO\u27B)] and from the European Regional Development Fund (all authors). All flow cytometry and cell sorting experiments were performed in the NUI Galway Flow Cytometry Core Facility which is supported by funds from NUI Galway, Science Foundation Ireland, the Irish Government\u27s Programme for Research in Third Level Institutions, Cycle 5 and the European Regional Development Fund

Effect of lower tidal volume ventilation facilitated by extracorporeal carbon dioxide removal vs standard care ventilation on 90-day mortality in patients with acute hypoxemic respiratory failure

Importance In patients who require mechanical ventilation for acute hypoxemic respiratory failure, further reduction in tidal volumes, compared with conventional low tidal volume ventilation, may improve outcomes. Objective To determine whether lower tidal volume mechanical ventilation using extracorporeal carbon dioxide removal improves outcomes in patients with acute hypoxemic respiratory failure. Design, Setting, and Participants This multicenter, randomized, allocation-concealed, open-label, pragmatic clinical trial enrolled 412 adult patients receiving mechanical ventilation for acute hypoxemic respiratory failure, of a planned sample size of 1120, between May 2016 and December 2019 from 51 intensive care units in the UK. Follow-up ended on March 11, 2020. Interventions Participants were randomized to receive lower tidal volume ventilation facilitated by extracorporeal carbon dioxide removal for at least 48 hours (n = 202) or standard care with conventional low tidal volume ventilation (n = 210). Main Outcomes and Measures The primary outcome was all-cause mortality 90 days after randomization. Prespecified secondary outcomes included ventilator-free days at day 28 and adverse event rates. Results Among 412 patients who were randomized (mean age, 59 years; 143 [35%] women), 405 (98%) completed the trial. The trial was stopped early because of futility and feasibility following recommendations from the data monitoring and ethics committee. The 90-day mortality rate was 41.5% in the lower tidal volume ventilation with extracorporeal carbon dioxide removal group vs 39.5% in the standard care group (risk ratio, 1.05 [95% CI, 0.83-1.33]; difference, 2.0% [95% CI, −7.6% to 11.5%]; P = .68). There were significantly fewer mean ventilator-free days in the extracorporeal carbon dioxide removal group compared with the standard care group (7.1 [95% CI, 5.9-8.3] vs 9.2 [95% CI, 7.9-10.4] days; mean difference, −2.1 [95% CI, −3.8 to −0.3]; P = .02). Serious adverse events were reported for 62 patients (31%) in the extracorporeal carbon dioxide removal group and 18 (9%) in the standard care group, including intracranial hemorrhage in 9 patients (4.5%) vs 0 (0%) and bleeding at other sites in 6 (3.0%) vs 1 (0.5%) in the extracorporeal carbon dioxide removal group vs the control group. Overall, 21 patients experienced 22 serious adverse events related to the study device. Conclusions and Relevance Among patients with acute hypoxemic respiratory failure, the use of extracorporeal carbon dioxide removal to facilitate lower tidal volume mechanical ventilation, compared with conventional low tidal volume mechanical ventilation, did not significantly reduce 90-day mortality. However, due to early termination, the study may have been underpowered to detect a clinically important difference