Association between preoperative anemia optimization and major complications after non-cardiac surgery: a retrospective analysis.

BACKGROUND: Anemia is common in the preoperative setting and associated with increased postoperative complications and mortality. However, it is unclear if preoperative anemia optimization reduces postoperative complications. We aimed to assess the association between preoperative anemia optimization and a composite endpoint of major cardiovascular, renal, and pulmonary complications and all-cause mortality within 30 days after noncardiac surgery in adult patients. METHODS: In this retrospective analysis preoperative anemia was defined as hemoglobin concentration below 12.0 g.dl-1 in women and 13.0 g.dl-1 in men within 6 months before surgery. A propensity score-based generalized estimating equation analysis was used to determine the association between preoperative anemia optimization and the primary outcome. Moreover, mediation analysis was conducted to investigate whether intraoperative red blood cell transfusion or duration of intraoperative hypotension were mediators of the relation between anemia optimization and the primary outcome. RESULTS: Fifty-seven hundred anemia optimized, and 8721 non-optimized patients met study criteria. The proportion of patients having any component of the composite of major complications and all-cause mortality was 21.5% in the anemia-optimized versus 18.0% in the non-optimized, with confounder-adjusted odds ratio estimate of 0.99 (95% CI 0.86‒1.15) for anemia optimization versus non-optimization, p = 0.90. Intraoperative red blood cell transfusion had a minor mediation effect on the relationship between preoperative anemia optimization and the primary outcome, whereas duration of intraoperative hypotension was not found to be a mediator. CONCLUSION: Preoperative anemia optimization did not appear to be associated with a composite outcome of major in-hospital postoperative cardiovascular, renal, and pulmonary complications and all-cause in-hospital mortality.

Non-canonical Targets of HIF1a Impair Oligodendrocyte Progenitor Cell Function.

Mammalian cells respond to insufficient oxygen through transcriptional regulators called hypoxia-inducible factors (HIFs). Although transiently protective, prolonged HIF activity drives distinct pathological responses in different tissues. Using a model of chronic HIF1a accumulation in pluripotent-stem-cell-derived oligodendrocyte progenitors (OPCs), we demonstrate that HIF1a activates non-canonical targets to impair generation of oligodendrocytes from OPCs. HIF1a activated a unique set of genes in OPCs through interaction with the OPC-specific transcription factor OLIG2. Non-canonical targets, including Ascl2 and Dlx3, were sufficient to block differentiation through suppression of the oligodendrocyte regulator Sox10. Chemical screening revealed that inhibition of MEK/ERK signaling overcame the HIF1a-mediated block in oligodendrocyte generation by restoring Sox10 expression without affecting canonical HIF1a activity. MEK/ERK inhibition also drove oligodendrocyte formation in hypoxic regions of human oligocortical spheroids. This work defines mechanisms by which HIF1a impairs oligodendrocyte formation and establishes that cell-type-specific HIF1a targets perturb cell function in response to low oxygen.

Cell Type-Specific Intralocus Interactions Reveal Oligodendrocyte Mechanisms in MS.

Multiple sclerosis (MS) is an autoimmune disease characterized by attack on oligodendrocytes within the central nervous system (CNS). Despite widespread use of immunomodulatory therapies, patients may still face progressive disability because of failure of myelin regeneration and loss of neurons, suggesting additional cellular pathologies. Here, we describe a general approach for identifying specific cell types in which a disease allele exerts a pathogenic effect. Applying this approach to MS risk loci, we pinpoint likely pathogenic cell types for 70%. In addition to T cell loci, we unexpectedly identified myeloid- and CNS-specific risk loci, including two sites that dysregulate transcriptional pause release in oligodendrocytes. Functional studies demonstrated inhibition of transcriptional elongation is a dominant pathway blocking oligodendrocyte maturation. Furthermore, pause release factors are frequently dysregulated in MS brain tissue. These data implicate cell-intrinsic aberrations outside of the immune system and suggest new avenues for therapeutic development. VIDEO ABSTRACT.