Phosphatidylserine is a global immunosuppressive signal in efferocytosis, infectious disease, and cancer

Apoptosis is an evolutionarily conserved and tightly regulated cell death modality. It serves important roles in physiology by sculpting complex tissues during embryogenesis and by removing effete cells that have reached advanced age or whose genomes have been irreparably damaged. Apoptosis culminates in the rapid and decisive removal of cell corpses by efferocytosis, a term used to distinguish the engulfment of apoptotic cells from other phagocytic processes. Over the past decades, the molecular and cell biological events associated with efferocytosis have been rigorously studied, and many eat-me signals and receptors have been identified. The externalization of phosphatidylserine (PS) is arguably the most emblematic eat-me signal that is in turn bound by a large number of serum proteins and opsonins that facilitate efferocytosis. Under physiological conditions, externalized PS functions as a dominant and evolutionarily conserved immunosuppressive signal that promotes tolerance and prevents local and systemic immune activation. Pathologically, the innate immunosuppressive effect of externalized PS has been hijacked by numerous viruses, microorganisms, and parasites to facilitate infection, and in many cases, establish infection latency. PS is also profoundly dysregulated in the tumor microenvironment and antagonizes the development of tumor immunity. In this review, we discuss the biology of PS with respect to its role as a global immunosuppressive signal and how PS is exploited to drive diverse pathological processes such as infection and cancer. Finally, we outline the rationale that agents targeting PS could have significant value in cancer and infectious disease therapeutics

O027 The combination of mandibular advancement devices (MAD) and supplemental oxygen dramatically improves OSA severity: preliminary results from the MADOX trial

Abstract Introduction Patients with obstructive sleep apnoea (OSA) considered ‘non-responders’ to mandibular advancement device (MAD) therapy, typically have a high loop gain contributing to their OSA physiology. While MAD does not improve loop gain, other treatments such as supplemental oxygen can have a strong effect on this pathogenic trait. Therefore, we conducted a randomised controlled trial (RCT) to determine whether the administration of supplemental oxygen in combination with a MAD, was associated with greater improvements in OSA severity compared to MAD therapy alone. Methods Patients recently diagnosed with OSA underwent an initial screening sleep study to confirm the presence of moderate-severe OSA (Apnoea-hypopnoea index [AHI]&amp;gt;20events/hr). Eligible patients were then enrolled in a randomised single-blind cross-over trial involving 4 sleep studies with the following treatments; MAD, oxygen (4L/min), MAD+oxygen and room-air/sham (control). The primary outcome was the reduction in AHI (%baseline). Results Of the 57 participants screened, 35 met the eligibility criteria (Baseline/Screening AHI = 52±22 events/hr). Compared to the sham night, all treatments significantly reduced the AHI; a 35% [CI: 18–48] was seen with oxygen (p&amp;lt;0.0002), a 53% [CI: 40–64] was seen with MAD (p&amp;lt;0.0001) and a 67% [CI: 56–76] was seen with MAD+oxygen (p&amp;lt;0.0001). Importantly, the combination of MAD+oxygen was associated with a significant reduction in AHI relative to MAD alone (15% [CI:4–24] p=0.01). Discussion In a population with moderate-severe OSA, preliminary analyses from this trial suggests that the addition of supplemental oxygen in combination with MAD therapy provided greater reductions in OSA severity than either treatment alone. </jats:sec

The Combination of an Oral Appliance and Supplemental Oxygen Markedly Improves Obstructive Sleep Apnea Severity: A Randomized Controlled Trial

Introduction: Obstructive sleep apnea (OSA) is challenging to treat due to limited tolerance of the leading therapy, continuous positive airway pressure. A leading second line therapy, oral appliances, are well tolerated but have limited efficacy. On the basis that oral appliance efficacy is lowest in patients with a high chemoreflex "loop gain", the current study tested the hypothesis that administration of supplemental oxygen (to lower loop gain) in combination with an oral appliance provides greater OSA treatment efficacy compared to oral appliance therapy alone. Methods: In a multicentre randomized crossover trial, 41 patients with moderate-to-severe OSA (apnea-hypopnea index [AHI] >20 events/hr) underwent in-laboratory polysomnography to assess the impact of a night of supplemental oxygen (4 L/min), oral appliance, both therapies in combination, compared to sham (air) on AHI. For primary analysis, hypopneas were scored regardless of desaturation/arousal criteria. Mixed model analysis compared treatment efficacy (change in AHI from baseline) between combination therapy and oral appliance alone (primary outcome). Sensitivity analysis reported AHI changes using standard 3% desaturation or arousal criteria (AHI3pa). Key secondary outcomes were arousal index and visual analog scale for sleep quality (VASSQ); higher score reflects improved sleep (0-10 units). Results: Of the 41 randomized patients (14F:27M, baseline AHI = 49 [29, 62] events/hr; median [interquartile range]), 38 completed all four interventions. Compared to sham, AHI was lowered with oxygen (−33% [CI: −46, −17]), oral appliances (−53% [−64, −41]), and the combination (−67% [−77, −57]): the combination provided a greater reduction compared to oral appliance alone (difference = −14% [−23, −4], P=0.009) confirming the study hypothesis. Sensitivity analysis using AHI3pa yielded a −73% change with the combination vs. sham (difference vs. oral appliance = −17% [−25, −7]). In secondary analysis, arousal index was lowered with oxygen (−19% [−28, −9]), oral appliances (−29% [−37, −20]), and the combination (−36% [−43, −27]; difference vs. oral appliance = −7% [−14, 2], P=0.11). VASSQ increased with oxygen (0.52 [−0.08, 1.1], borderline change), oral appliances (0.71 [0.11, 1.30]), and with the combination (0.98 [0.39, 1.58]; difference vs. oral appliance = 0.28 [−0.31, 0.86]). Conclusion: In moderate-severe OSA, the combination of supplemental oxygen and oral appliance therapy provides a greater OSA treatment efficacy compared to oral appliances alone. Combining a loop gain intervention with oral appliances is a promising approach to markedly attenuate the severity of OSA