Impact of Red Blood Cell Transfusion on In-hospital Mortality of Isolated Coronary Artery Bypass Graft Surgery: A Retrospective Observational Study of French Nationwide 3-year Cohort.

OBJECTIVE: To assess the relationship between red blood cell (RBC) transfusion exposure and in-hospital mortality after isolated coronary artery bypass graft (CABG) surgery. BACKGROUND: RBC transfusion was commonly used to treat anemia in isolated CABG surgery, but transfusion was found an independent risk factor of postoperative mortality; recent guidelines on patient blood management strategy issued in the last decade may have changed transfusion incidence and related mortality. METHODS: A retrospective cohort study was conducted from the National database on patients' hospital discharge reports. Consecutive adult patients who underwent isolated CABG surgery in France from January 1, 2016, to December 31, 2018, were included. The primary outcome was the in-hospital mortality rate. RBC transfusion during the hospital stay was identified by specific codes and ordered as categorical variables (no, moderate, or massive transfusion). RESULTS: A total of 37,498 participants were studied [mean (SD) age, 66.5 (9.6) years, 31,587 (84.2%) were men]. In-hospital mortality rate was 1.45% (n=541) and RBC transfusion rate was 9.4% (n=3521). In-hospital deaths were more frequent among transfused patients [1.06% (361) if no transfusion up to 10.2% (n=113) if massive transfusion]. After adjustment for confounding variables, RBC transfusion remained a significant independent factor of in-hospital mortality: odds ratio=1.66 (95% confidence interval: 1.27-2.19, P <0.001) for moderate transfusion, 6.40 (95% confidence interval: 5.07-8.09, P <0.001) if massive. CONCLUSIONS AND RELEVANCE: Despite a modest patients' exposure to transfusion, this study suggests that RBC administration is an independent factor of in-hospital mortality in isolated CABG surgery.

Empathy across cultures - one size does not fit all: from the ego-logical to the eco-logical of relational empathy.

Empathy is extolled in Western healthcare and medical education as an exemplary quality to cultivate in trainees and providers. Yet it remains an elusive and inadequately understood attribute. It posits a "one size fits all" unidimensional attribute applicable across contexts with scant attention given to its multifaceted dimensions in intercultural contexts. In this article, we uncloak the shortcomings of this conventional empathy in intercultural settings, and instead propound an expanded "relational empathy".

Control of intestinal homeostasis, colitis, and colitis-associated colorectal cancer by the inflammatory caspases.

Inflammatory caspases are essential effectors of inflammation and cell death. Here, we investigated their roles in colitis and colorectal cancer and report a bimodal regulation of intestinal homeostasis, inflammation and tumorigenesis by caspases-1 and -12. Casp1(-/-) mice exhibited defects in mucosal tissue repair and succumbed rapidly after dextran sulfate sodium administration. This phenotype was rescued by administration of exogenous interleukin-18 and was partially reproduced in mice deficient in the inflammasome adaptor ASC. Casp12(-/-) mice, in which the inflammasome is derepressed, were resistant to acute colitis and showed signs of enhanced repair. Together with their increased inflammatory response, the enhanced repair response of Casp12(-/-) mice rendered them more susceptible to colorectal cancer induced by azoxymethane (AOM)+DSS. Taken together, our results indicate that the inflammatory caspases are critical in the induction of inflammation in the gut after injury, which is necessary for tissue repair and maintenance of immune tolerance.

Sexual dimorphism in the cerebrovascular network: Brain MRI shows lower arterial density in women.

BACKGROUND AND PURPOSE: Accumulating evidence suggests that there is a sexual dimorphism in brain health, with women exhibiting greater disability following strokes of comparable size and having a higher prevalence of cognitive impairment later in life. Despite the critical implication of the cerebrovascular architecture in brain perfusion and brain health, it remains unclear whether structural differences in vessel density exist across the sexes. METHODS: In this study, we used high-density MRI imaging to characterize the intracerebral arterial and venous density of 28 (14 women) sex-matched healthy young volunteers in vivo. Using an in-house vessel segmentation algorithm, we quantified and compared these vascular features across the cortical and subcortical deep gray matter, white matter, and periventricular white matter. RESULTS: We found that, on average, women have reduced intracerebral arterial density in comparison to men (F 2.34 ± 0.48%, M 2.67 ± 0.39%; p<.05). This difference was most pronounced in the subcortical deep gray matter (F 1.78 ± 0.53%, M 2.38 ± 0.82%; p<.05) and periventricular white matter (F 0.68 ± 0.15%, M 1.14 ± 0.33%; p<.0005), indicating a potential sex-specific vulnerability to hypoperfusion in areas critical to core cerebral functions. In contrast, venous density did not exhibit a significant difference between sexes. CONCLUSIONS: While this research remains exploratory, it raises important pathophysiological considerations for brain health, adverse cerebrovascular events, and dementia across the sexes. Our findings also highlight the need to take into account sex differences when investigating cerebral characteristics in humans.

Inactivation of Interferon Regulatory Factor 1 Causes Susceptibility to Colitis-Associated Colorectal Cancer.

The mechanisms linking chronic inflammation of the gut (IBD) and increased colorectal cancer susceptibility are poorly understood. IBD risk is influenced by genetic factors, including the IBD5 locus (human 5q31), that harbors the IRF1 gene. A cause-to-effect relationship between chronic inflammation and colorectal cancer, and a possible role of IRF1 were studied in Irf1-/- mice in a model of colitis-associated colorectal cancer (CA-CRC) induced by azoxymethane and dextran sulfate. Loss of Irf1 causes hyper-susceptibility to CA-CRC, with early onset and increased number of tumors leading to rapid lethality. Transcript profiling (RNA-seq) and immunostaining of colons shows heightened inflammation and enhanced enterocyte proliferation in Irf1-/- mutants, prior to appearance of tumors. Considerable infiltration of leukocytes is seen in Irf1-/- colons at this early stage, and is composed primarily of proinflammatory Gr1+ Cd11b+ myeloid cells and other granulocytes, as well as CD4+ lymphoid cells. Differential susceptibility to CA-CRC of Irf1-/- vs. B6 controls is fully transferable through hematopoietic cells as observed in bone marrow chimera studies. Transcript signatures seen in Irf1-/- mice in response to AOM/DSS are enriched in clinical specimens from patients with IBD and with colorectal cancer. In addition, IRF1 expression in the colon is significantly decreased in late stage colorectal cancer (stages 3, 4) and is associated with poorer prognosis. This suggests that partial or complete loss of IRF1 expression alters the type, number, and function of immune cells in situ during chronic inflammation, possibly via the creation of a tumor-promoting environment.

Postoperative Rehabilitation May Reduce the Risk of Readmission After Groin Hernia Repair.

Thirty-day readmission after surgery has been proposed as a quality-of-care indicator. We explored the effect of postoperative rehabilitation on readmission risk after groin hernia repair. We used the French National Discharge Database to identify all index hospitalizations for groin hernia repair in 2011. Readmissions within 30 days of discharge were clinically classified in terms of their relationship to the index stay. We used logistic regression to adjust the risk of readmission for patient, procedure and hospital factors. Among 122,952 index hospitalizations for inguinal hernia repair, 3,357 (2.7%) related 30-day readmissions were recorded. Reiterated analyses indicated that readmission risk was consistently associated with patient complexity: age (per year after 60 years, OR 1.03, 95% CI 1.02-1.03, P < 0.001), hospitalization within the previous year (OR 1.56, 95% CI 1.44-1.69, P < 0.001), and increasing severity and combination of co-morbidities. Postoperative rehabilitation was identified as a protective factor (OR 0.56, 95% CI 0.46-0.69, P < 0.001). Older patients and those with greater comorbidity are at elevated risk of readmission after inguinal hernia repair. Postoperative rehabilitation may reduce this risk. Further studies are warranted to confirm the protective effect of postoperative rehabilitation.

Large-scale identification of coregulated enhancer networks in the adult human brain.

Understanding the complexity of the human brain and its functional diversity remain a major challenge. Distinct anatomical regions are involved in an array of processes, including organismal homeostasis, cognitive functions, and susceptibility to neurological pathologies, many of which define our species. Distal enhancers have emerged as key regulatory elements that acquire histone modifications in a cell- and species-specific manner, thus enforcing specific gene expression programs. Here, we survey the epigenomic landscape of promoters and cis-regulatory elements in 136 regions of the adult human brain. We identify a total of 83,553 promoter-distal H3K27ac-enriched regions showing global characteristics of brain enhancers. We use coregulation of enhancer elements across many distinct regions of the brain to uncover functionally distinct networks at high resolution and link these networks to specific neuroglial functions. Furthermore, we use these data to understand the relevance of noncoding genomic variations previously linked to Parkinson's disease incidence.

CCDC88B is a novel regulator of maturation and effector functions of T cells during pathological inflammation.

We used a genome-wide screen in mutagenized mice to identify genes which inactivation protects against lethal neuroinflammation during experimental cerebral malaria (ECM). We identified an ECM-protective mutation in coiled-coil domain containing protein 88b (Ccdc88b), a poorly annotated gene that is found expressed specifically in spleen, bone marrow, lymph nodes, and thymus. The CCDC88B protein is abundantly expressed in immune cells, including both CD4(+) and CD8(+) T lymphocytes, and in myeloid cells, and loss of CCDC88B protein expression has pleiotropic effects on T lymphocyte functions, including impaired maturation in vivo, significantly reduced activation, reduced cell division as well as impaired cytokine production (IFN-γ and TNF) in response to T cell receptor engagement, or to nonspecific stimuli in vitro, and during the course of P. berghei infection in vivo. This identifies CCDC88B as a novel and important regulator of T cell function. The human CCDC88B gene maps to the 11q13 locus that is associated with susceptibility to several inflammatory and auto-immune disorders. Our findings strongly suggest that CCDC88B is the morbid gene underlying the pleiotropic effect of the 11q13 locus on inflammation.

Positional mapping and candidate gene analysis of the mouse Ccs3 locus that regulates differential susceptibility to carcinogen-induced colorectal cancer.

The Ccs3 locus on mouse chromosome 3 regulates differential susceptibility of A/J (A, susceptible) and C57BL/6J (B6, resistant) mouse strains to chemically-induced colorectal cancer (CRC). Here, we report the high-resolution positional mapping of the gene underlying the Ccs3 effect. Using phenotype/genotype correlation in a series of 33 AcB/BcA recombinant congenic mouse strains, as well as in groups of backcross populations bearing unique recombinant chromosomes for the interval, and in subcongenic strains, we have delineated the maximum size of the Ccs3 physical interval to a ∼2.15 Mb segment. This interval contains 12 annotated transcripts. Sequencing of positional candidates in A and B6 identified many either low-priority coding changes or non-protein coding variants. We found a unique copy number variant (CNV) in intron 15 of the Nfkb1 gene. The CNV consists of two copies of a 54 bp sequence immediately adjacent to the exon 15 splice site, while only one copy is found in CRC-susceptible A. The Nfkb1 protein (p105/p50) expression is much reduced in A tumors compared to normal A colonic epithelium as analyzed by immunohistochemistry. Studies in primary macrophages from A and B6 mice demonstrate a marked differential activation of the NfκB pathway by lipopolysaccharide (kinetics of stimulation and maximum levels of phosphorylated IκBα), with a more robust activation being associated with resistance to CRC. NfκB has been previously implicated in regulating homeostasis and inflammatory response in the intestinal mucosa. The interval contains another positional candidate Slc39a8 that is differentially expressed in A vs B6 colons, and that has recently been associated in CRC tumor aggressiveness in humans.

Genetic control of susceptibility to carcinogen-induced colorectal cancer in mice: the Ccs3 and Ccs5 loci regulate different aspects of tumorigenesis.

Colorectal cancer (CRC) is a multistep disease that involves a two-way interaction between a complex genetic pre-disposition component, and a set of poorly understood extrinsic environmental factors. In mice, CRC can be induced by treatment with azoxymethane (AOM). Using a set of AcB/BcA recombinant congenic strains derived from CRC-susceptible A/J and CRC-resistant C57Bl/6J (B6) progenitors, we previously detected the Ccs3 locus (colon cancer susceptibility locus 3) as a major regulator of CRC susceptibility. Phenotyping of additional AcB/BcA strains for susceptibility to AOM-induced CRC has refined the Ccs3 interval to a 6.7 Mb segment on chromosome 3. In addition, the presence of intermediate susceptibility phenotypes in individual AcB/BcA strains suggested additional gene effects regulating CRC susceptibility in A/J and B6 strains. Those were investigated by linkage analysis and whole genome scanning in a set of 208 informative (B6 x A/J)F2 progeny, using tumor multiplicity as a quantitative measure of susceptibility. This analysis validated the important role of Ccs3 in regulating this trait, and additionally detected contribution from a second locus on the distal portion of chromosome 9 (LOD = 3.76), that was given the temporary designation of Ccs5. Ccs5 modulates tumor multiplicity in F2 animals bearing at least one A/J-derived susceptibility allele at Ccs3, with A/J-derived Ccs5 susceptibility alleles being inherited in a recessive manner. There is a strong additive effect of Ccs3 and Ccs5 on tumor multiplicity in F2 mice: mice doubly homozygotes for A/J or B6 alleles at Ccs3 and Ccs5 show tumor numbers similar to those of parental A/J and B6, respectively. Interestingly, the Ccs5 region overlaps several quantitative trait loci previously reported to regulate intestinal homeostasis and susceptibility to intestinal colitis in mice and humans. Our findings identify a novel two-locus system regulating CRC susceptibility in mice, of which the relevance to human CRC can now be tested experimentally.