Serial and regional assessment of the right ventricular molecular and functional response to pressure-loading.

BACKGROUND: Right ventricular(RV) function determines outcomes in RV pressure-loading. A better understanding of the time-course and regional distribution of RV remodeling may help optimize targets and timing for therapeutic intervention. We sought to characterize RV remodeling between zero and 6-weeks after initiation of RV pressure-loading. METHODS AND RESULTS: Thirty-six rats were randomized to either sham surgery or to pulmonary artery banding(PAB). After echocardiography and conductance catheter studies, groups of rats were euthanized at 1-week, 3-weeks and 6-weeks after sham surgery, or induction of RV pressure-loading, for RV histological, RNA and molecular analysis. A vigorous inflammatory response characterized by increased RV inflammatory cytokines, chemokines and macrophage markers was observed at 1-week following PAB. Metabolic changes, TGF-ß1 canonical signaling, collagenous fibrosis deposition and apoptosis were already significantly increased by 1-week after PAB. Genes marking fibroblast activation were upregulated at 1-week but not 6-week post-PAB surgery. Mitochondrial dysfunction as evidenced by increased PDK activity and decreased PDH phosphorylation significantly at 6-week post PAB. These processes preceded the development of overt myocardial hypertrophy and impaired echo parameters of systolic and diastolic function which occurred significantly from 3-weeks after PAB. CONCLUSION: RV myocardial inflammation, metabolic shift, metabolic gene transcription and pro-fibrotic signaling occur early after initiation of pressure-loading when RV pressures are only moderately elevated, before the development of overt myocardial hypertrophy and dysfunction, suggesting that adaptive hypertrophy and maladaptive remodeling occur simultaneously. These results suggest that therapeutic intervention to reduce adverse RV remodeling may be needed earlier and at lower thresholds than currently employed.

Compassion fatigue in healthcare providers: a scoping review.

The detrimental impacts of COVID-19 on healthcare providers' psychological health and well-being continue to affect their professional roles and activities, leading to compassion fatigue. The purpose of this review was to identify and summarize published literature on compassion fatigue among healthcare providers and its impact on patient care. Six databases were searched: MEDLINE (Ovid), PsycINFO (Ovid), Embase (Ovid), CINAHL, Scopus, Web of Science, for studies on compassion fatigue in healthcare providers, published in English from the peak of the pandemic in 2020 to 2023. To expand the search, reference lists of included studies were hand searched to locate additional relevant studies. The studies primarily focused on nurses, physicians, and other allied health professionals. This scoping review was registered on Open Science Framework (OSF), using the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) extension to scoping review. From 11,715 search results, 24 met the inclusion criteria. Findings are presented using four themes: prevalence of compassion fatigue; antecedents of compassion fatigue; consequences of compassion fatigue; and interventions to address compassion fatigue. The potential antecedents of compassion fatigue are grouped under individual-, organization-, and systems-level factors. Our findings suggest that healthcare providers differ in risk for developing compassion fatigue in a country-dependent manner. Interventions such as increasing available personnel helped to minimize the occurrence of compassion fatigue. This scoping review offers important insight on the common causes and potential risks for compassion fatigue among healthcare providers and identifies potential strategies to support healthcare providers' psychological health and well-being.

Cost-effectiveness analysis of consolidation with brentuximab vedotin for high-risk Hodgkin lymphoma after autologous stem cell transplantation.

BACKGROUND: In a recent randomized, placebo-controlled trial, consolidation treatment with brentuximab vedotin (BV) decreased the risk of Hodgkin lymphoma (HL) progression after autologous stem cell transplantation (ASCT). However, the impact of BV consolidation on overall survival, quality of life, and health care costs remain unclear. METHODS: A Markov decision-analytic model was constructed to measure the costs and clinical outcomes for BV consolidation therapy compared with active surveillance in a cohort of patients aged 33 years who were at risk for HL relapse after ASCT. Life-time costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) were calculated for each post-ASCT strategy. RESULTS: After quality-of-life adjustments and standard discounting, upfront BV consolidation was associated with an improvement of 1.07 QALYs compared with active surveillance plus BV as salvage. However, the strategy of BV consolidation led to significantly higher health care costs ($378,832 vs $219,761), resulting in an ICER for BV consolidation compared with active surveillance of $148,664/QALY. If indication-specific pricing was implemented, then the model-estimated BV price reductions of 18% to 38% for the consolidative setting would translate into ICERs of $100,000 and $50,000 per QALY, respectively. These findings were consistent on 1-way and probabilistic sensitivity analyses. CONCLUSIONS: BV as consolidation therapy under current US pricing is unlikely to be cost effective at a willingness-to-pay threshold of $100,000 per QALY. However, indication-specific price reductions for the consolidative setting could reduce ICERs to widely acceptable values. Cancer 2017. © 2017 American Cancer Society. Cancer 2017;123:3763-3771. © 2017 American Cancer Society.

Role of macrophage receptor with collagenous structure in innate immune tolerance.

Macrophages play a key role in host defense against microbes, in part, through phagocytosis. Macrophage receptor with collagenous structure (MARCO) is a scavenger receptor on the cell surface of macrophages that mediates opsonin-independent phagocytosis. The goal of our study is to investigate the role of MARCO in LPS or lipotechoic acid-induced macrophage tolerance. Although it has been established that expression of MARCO and phagocytosis is increased in tolerant macrophages, the transcriptional regulation and biological role of MARCO in tolerant macrophages have not been investigated. In this study, we confirm that tolerized mouse bone marrow-derived macrophages (BMDM) selectively increase expression of MARCO (both transcript and cell surface receptor) and increase phagocytosis. We found that H3K4me3 dynamic modification of a promoter site of MARCO was increased in tolerized BMDM. Blocking methylation by treatment with 5-aza-2'-deoxycytidine resulted in reduced H3K4me3 binding in the promoter of MARCO, decreased expression of MARCO, and impaired phagocytosis in tolerized BMDM. However, 5-aza-2'-deoxycytidine had no effect on the inflammatory component of innate immune tolerance. In aggregate, we found that histone methylation was critical to MARCO expression and phagocytosis in tolerized macrophages, but did not affect the inflammatory component of innate immune tolerance.

Ozone enhances pulmonary innate immune response to a Toll-like receptor-2 agonist.

Previous work demonstrated that pre-exposure to ozone primes innate immunity and increases Toll-like receptor-4 (TLR4)-mediated responses to subsequent stimulation with LPS. To explore the pulmonary innate immune response to ozone exposure further, we investigated the effects of ozone in combination with Pam3CYS, a synthetic TLR2/TLR1 agonist. Whole-lung lavage (WLL) and lung tissue were harvested from C57BL/6 mice after exposure to ozone or filtered air, followed by saline or Pam3CYS 24 hours later. Cells and cytokines in the WLL, the surface expression of TLRs on macrophages, and lung RNA genomic expression profiles were examined. We demonstrated an increased WLL cell influx, increased IL-6 and chemokine KC (Cxcl1), and decreased macrophage inflammatory protein (MIP)-1α and TNF-α in response to Pam3CYS as a result of ozone pre-exposure. We also observed the increased cell surface expression of TLR4, TLR2, and TLR1 on macrophages as a result of ozone alone or in combination with Pam3CYS. Gene expression analysis of lung tissue revealed a significant increase in the expression of genes related to injury repair and the cell cycle as a result of ozone alone or in combination with Pam3CYS. Our results extend previous findings with ozone/LPS to other TLR ligands, and suggest that the ozone priming of innate immunity is a general mechanism. Gene expression profiling of lung tissue identified transcriptional networks and genes that contribute to the priming of innate immunity at the molecular level.

Compassion fatigue in healthcare providers during the COVID-19 pandemic: a scoping review protocol.

INTRODUCTION: The COVID-19 pandemic has negatively impacted the psychological health and well-being of healthcare providers. An amplification in chronic stressors, workload and fatalities may have increased the risk of compassion fatigue and disrupted the quality of patient care. Although current studies have explored the general psychological status of healthcare providers during the COVID-19 pandemic, few have focused on compassion fatigue. The purpose of this review is to explore the impacts of the COVID-19 pandemic on compassion fatigue in healthcare providers and the repercussions of compassion fatigue on patient care. METHODS AND ANALYSIS: This scoping review will follow Joanna Briggs Institute and Arksey and O'Malley scoping review methodology. Comprehensive searches will be conducted in the following relevant databases: MEDLINE (Ovid), PsycINFO (Ovid), Embase (Ovid), CINAHL, Scopus, Web of Science. To expand the search, reference lists of included studies will be handsearched for additional relevant studies. Included studies must report on the impact of COVID-19 pandemic on compassion fatigue in healthcare providers and have been published in English since January 2020. ETHICS AND DISSEMINATION: This review does not require research ethics board approval. By examining the impacts of the COVID-19 pandemic on compassion fatigue in healthcare providers, this scoping review can offer important insight into the possible risks, protective factors and strategies to support healthcare providers' psychological health and patient care amidst persisting stressful conditions.

Growth of unrepaired hypoplastic proximal aortic arch and reintervention rate after aortic coarctation repair.

BACKGROUND: Treatment of tubular hypoplasia of the aortic arch (THAA) associated with aortic coarctation (CoA) remains controversial. We aimed to evaluate growth of unrepaired hypoplastic proximal aortic arches (PAAs) after surgical repair for CoA. METHODS: Preoperative and follow-up echocardiographic images of 139 patients who underwent CoA repairs from 2005 to 2012 were reviewed. THAA was defined as PAA z-score <-3 and non-THAA group z-score ≥-3. Reintervention rates due to aortic obstruction were assessed using competing risk models and diameters of the aorta were compared with Mann-Whitney U tests. RESULTS: Fifty patients (36%) had THAA and 89 (64%) had non-THAA. The survival rate was 94% at 10 years. The overall reintervention rate at 10 years was 9% in the THAA group and 16% in the non-THAA group (P = .54). The catheter reintervention rate at ten years was 2% in the THAA group and 16% in the non-THAA group (P = .031). The surgical reintervention rate at ten years was 7% in the THAA group and 0% in the non-THAA group (P = .016). All 4 patients who required surgical reintervention were in the THAA group and 3 patients with PAA obstruction had preoperative PAA z-scores -3.6, -4.2, and -4.3. Follow-up echocardiograms showed PAA catch-up growth in the THAA group compared with the non-THAA group (preoperative z-score of -3.6 vs -2.3, and at 7 years of -1.1 vs -1.2; P < .001). CONCLUSIONS: Unrepaired PAA hypoplasia grows after CoA repair. Reintervention rates were comparable between groups but those with THAA had higher surgical reintervention rates.

The Impact of Image Processing Algorithms on Optical Coherence Tomography Angiography Metrics and Study Conclusions in Diabetic Retinopathy.

Purpose: The purpose of this study was to evaluate the impact of image processing on quantitative metrics in optical coherence tomography angiography (OCTA) images and study conclusions in patients with diabetes. Methods: This was a single center, retrospective cross-sectional study. OCTA imaging with the Cirrus HD-OCT 5000 AngioPlex of patients with diabetes was performed. The 8 × 8 mm superficial slab images underwent 4 different preprocessing methods (none, background subtraction [BGS], foveal avascular zone brightness adjustment, and contrast limited adaptive histogram equalization [CLAHE]) followed by 4 different binarization algorithms (global Huang, global Otsu, local Niblack, and local Phansalkar) in ImageJ. Vessel density (VD), skeletonized VD (SVD), and fractal dimension (FD) were calculated. Mixed-effect multivariate linear regressions were performed. Results: Two hundred eleven scans from 104 patients were included. Of these scans, 67 (31.8%) had no diabetic retinopathy (DR), 99 (46.9%) had nonproliferative DR (NPDR), and 45 (21.3%) had proliferative DR (PDR). Forty-eight of 211 (22.7%) scans had diabetic macular edema (DME). The image processing method used significantly impacted values of VD, SVD, and FD (all P -values < 0.001). On multivariate analysis, the image processing method changed the clinical variables significantly associated with VD, SVD, and FD. However, BGS and CLAHE yielded more consistent significant covariates across multiple binarization algorithms. Conclusions: The image processing method can impact the conclusions of any given study analyzing quantitative OCTA metrics. Thus, caution is urged in the interpretation of such studies. Background subtraction or CLAHE may play a role in the standardization of image processing. Translational Relevance: This work proposes strategies to achieve robust and consistent analysis of OCTA imaging, which is especially important for clinical trials.

Desynchronization of the molecular clock contributes to the heterogeneity of the inflammatory response.

Heterogeneity in the behavior of genetically and developmentally equivalent cells is becoming increasingly appreciated. There are several sources of cellular heterogeneity, including both intrinsic and extrinsic noise. We found that some aspects of heterogeneity in the response of macrophages to bacterial lipopolysaccharide (LPS) were due to intercellular desynchronization of the molecular clock, a cell-intrinsic oscillator. We found that the ratio of the relative expression of two clock genes, Nfil3 and Dbp, expressed in opposite phases of the clock, determined the fraction of cells that produced the cytokine IL-12p40 in response to LPS. The clock can be entrained by various environmental stimuli, making it a mechanism by which population-level heterogeneity and the inflammatory response can be regulated.