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ImportanceThere is limited evidence for therapeutic options for pediatric COVID-19 outside of multisystem inflammatory syndrome in children (MIS-C).ObjectiveTo determine whether the use of steroids within 2 days of admission for non–MIS-C COVID-19 in children is associated with hospital length of stay (LOS). The secondary objective was to determine their association with intensive care unit (ICU) LOS, inflammation, and fever defervescence.Design, Setting, and ParticipantsThis cohort study analyzed data retrospectively for children (<18 years) who required hospitalization for non–MIS-C COVID-19. Data from March 2020 through September 2021 were provided by 58 hospitals in 7 countries who participate in the Society of Critical Care Medicine Discovery Viral Infection and Respiratory Illness Universal Study (VIRUS) COVID-19 registry.ExposureAdministration of steroids within 2 days of admission.Main Outcomes and MeasuresLength of stay in the hospital and ICU. Adjustment for confounders was done by mixed linear regression and propensity score matching.ResultsA total of 1163 patients met inclusion criteria and had a median (IQR) age of 7 years (0.9-14.3). Almost half of all patients (601/1163, 51.7%) were male, 33.8% (392/1163) were non-Hispanic White, and 27.9% (324/1163) were Hispanic. Of the study population, 184 patients (15.8%) received steroids within 2 days of admission, and 979 (84.2%) did not receive steroids within the first 2 days. Among 1163 patients, 658 (56.5%) required respiratory support during hospitalization. Overall, patients in the steroids group were older and had greater severity of illness, and a larger proportion required respiratory and vasoactive support. On multivariable linear regression, after controlling for treatment with remdesivir within 2 days, country, race and ethnicity, obesity and comorbidity, number of abnormal inflammatory mediators, age, bacterial or viral coinfection, and disease severity according to ICU admission within first 2 days or World Health Organization ordinal scale of 4 or higher on admission, with a random intercept for the site, early steroid treatment was not significantly associated with hospital LOS (exponentiated coefficient, 0.94; 95% CI, 0.81-1.09; P = .42). Separate analyses for patients with an LOS of 2 days or longer (n = 729), those receiving respiratory support at admission (n = 286), and propensity score–matched patients also showed no significant association between steroids and LOS. Early steroid treatment was not associated with ICU LOS, fever defervescence by day 3, or normalization of inflammatory mediators.Conclusions and RelevanceSteroid treatment within 2 days of hospital admission in a heterogeneous cohort of pediatric patients hospitalized for COVID-19 without MIS-C did not have a statistically significant association with hospital LOS.

Background: Scattered tubular-like cells (STCs) are dedifferentiated renal tubular cells endowed with progenitor-like characteristics to repair injured parenchymal cells. STCs may be damaged and rendered ineffective by renal artery stenosis (RAS), but the underlying processes remain unclear. We hypothesized that RAS alters the epigenetic landscape on DNA and the ensuing gene transcriptional profile of swine STCs. Methods: CD24+/CD133+ STCs were isolated from pig kidneys after 10 weeks of RAS or sham (n = 3 each) and their whole 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) profiles were examined by 5mC and 5hmC immunoprecipitation sequencing (MeDIP-/hMeDIP-seq, respectively). A subsequent integrated (MeDIP/hMeDIP-seq/mRNA-seq) analysis was performed by comparing all online available gene sets using Gene Set Enrichment Analysis. Apoptosis, proteolysis, and mitochondrial structure and function were subsequently evaluated in vitro. Results: Differential expression (DE) analysis revealed 239 genes with higher and 236 with lower 5mC levels and 275 genes with higher and 315 with lower 5hmC levels in RAS-STCs compared to Normal-STCs (fold change ≥1.4 or ≤0.7, p ≤ 0.05). Integrated MeDIP-/hMeDIP-seq/mRNA-seq analysis identified several overlapping (DE-5mC/mRNA and DE-5hmC/mRNA levels) genes primarily implicated in apoptosis, proteolysis, and mitochondrial functions. Furthermore, RAS-STCs exhibited decreased apoptosis, mitochondrial matrix density, and ATP production, and increased intracellular amino acid concentration and ubiquitin expression. Conclusions: Renal ischemia induces epigenetic changes in apoptosis-, proteolysis-, and mitochondria-related genes, which correlate with alterations in the transcriptomic profile and corresponding function of swine STCs. These observations may contribute to developing novel targeted interventions to preserve the reparative potency of STCs in renal disease.

Abstract Renovascular disease (RVD) remains a common etiology of secondary hypertension. Recent clinical trials revealed unsatisfactory therapeutic outcomes of renal revascularization, leading to extensive investigation to unravel key pathophysiological mechanisms underlying irreversible functional loss and structural damage in the chronically ischemic kidney. Research studies identified complex interactions among various players, including inflammation, fibrosis, mitochondrial injury, cellular senescence, and microvascular remodeling. This interplay resulted in a shift of our understanding of RVD from a mere hemodynamic disorder to a pro-inflammatory and pro-fibrotic pathology strongly influenced by systemic diseases like metabolic syndrome (MetS), hypertension, diabetes mellitus, and hyperlipidemia. Novel diagnostic approaches have been tested for early detection and follow-up of RVD progression, using new imaging techniques and biochemical markers of renal injury and dysfunction. Therapies targeting some of the pathological pathways governing the development of RVD have shown promising results in animal models, and a few have moved from bench to clinical research. This review summarizes evolving understanding in chronic ischemic kidney injury.

Aims Despite the common occurrence of coronary artery disease (CAD) and heart failure (HF) with preserved ejection fraction (HFpEF), there is limited evidence to guide revascularization. Methods and Results We investigated the long‐term outcomes of coronary artery bypass grafting (CABG) in patients with HF and significant CAD across the spectrum of ejection fraction, using a large national cohort of patients from the Veteran Affairs (VA) Medical Centers in the US. Patients with HF were stratified into groups, HFpEF, HF with mid‐range ejection fraction (HFmrEF), and HF with reduced ejection fraction (HFrEF) and compared to patients with no preoperative HF. We analysed 10 396 patients. Despite an increased hazard in the first year following revascularization, the long‐term survival (median follow‐up 6.6 years; interquartile range 3.7–10.1) of HFpEF post‐CABG was similar to controls (hazard ratio 0.85, 95% confidence interval 0.68‐1.06), but survival progressively declined with HFmrEF and HFrEF. Similar trends were seen with recurrent HF hospitalization with lower risk with baseline HFpEF (43.9 ± 6.9/100 patient‐years) compared to HFmrEF (65.9 ± 3.8/100 patient‐years) and HFrEF (93.4 ± 4.8/100 patient‐years). Although HFpEF patients had lower mortality and HF hospitalization post‐CABG compared to patients with a lower ejection fraction, they experienced the highest rates of future myocardial infarction. Conclusion Although HFpEF patients with CAD have greater short‐term risk post‐CABG, their long‐term survival is comparable to controls. However, they are at increased risk for HF hospitalizations and myocardial infarction. These data support the safety of CABG in HFpEF patients and suggest continuum of mortality risk for ischaemic HF when stratified by baseline ejection fraction before revascularization.

Abstract Mutations in chromatin regulator ASXL1 are frequently identified in myeloid malignancies, in particular ∼40% of patients with chronic myelomonocytic leukemia (CMML). ASXL1 mutations are associated with poor prognosis in CMML and significantly co-occur with NRAS mutations. Here, we show that concurrent ASXL1 and NRAS mutations defined a population of CMML patients who had shorter leukemia-free survival than those with ASXL1 mutation only. Corroborating this human data, Asxl1−/− accelerated CMML progression and promoted CMML transformation to acute myeloid leukemia (AML) in NrasG12D/+ mice. NrasG12D/+;Asxl1−/− (NA) leukemia cells displayed hyperactivation of MEK/ERK signaling, increased global levels of H3K27ac, upregulation of Flt3. Moreover, we find that NA-AML cells overexpressed all the major inhibitory immune checkpoint ligands: programmed death-ligand 1 (PD-L1)/PD-L2, CD155, and CD80/CD86. Among them, overexpression of PD-L1 and CD86 correlated with upregulation of AP-1 transcription factors (TFs) in NA-AML cells. An AP-1 inhibitor or short hairpin RNAs against AP-1 TF Jun decreased PD-L1 and CD86 expression in NA-AML cells. Once NA-AML cells were transplanted into syngeneic recipients, NA-derived T cells were not detectable. Host-derived wild-type T cells overexpressed programmed cell death protein 1 (PD-1) and T-cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT) receptors, leading to a predominant exhausted T-cell phenotype. Combined inhibition of MEK and BET resulted in downregulation of Flt3 and AP-1 expression, partial restoration of the immune microenvironment, enhancement of CD8 T-cell cytotoxicity, and prolonged survival in NA-AML mice. Our study suggests that combined targeted therapy and immunotherapy may be beneficial for treating secondary AML with concurrent ASXL1 and NRAS mutations.

Background— The Bypass Angioplasty Revascularization Investigation trial demonstrated that symptomatic diabetics with multivessel coronary artery disease had a survival advantage with initial coronary artery bypass grafting (CABG) versus percutaneous coronary intervention (PCI). No published study has examined different treatments and outcome in asymptomatic diabetics. Methods and Results— This study group consisted of 826 asymptomatic diabetics (age 62±12 years; 76% men) without known coronary artery disease who had abnormal myocardial perfusion during stress single photon emission computed tomography (SPECT). SPECT images were classified as low-, intermediate-, and high-risk. Early revascularization (CABG or PCI ≤4 months after SPECT) was performed in 76 patients. Survival (follow-up, 5.3±3.3 years) was compared in patients treated with CABG, PCI, or medical therapy. Revascularization (CABG or PCI) was performed in 54 of 261 patients with high-risk scans and was independently associated with improved survival (χ 2 =4.55; P =0.03 after multivariate adjustment). Subset analysis demonstrated that the survival advantage was confined to patients treated with CABG (n =39), with a 5-year survival CABG at 85%, PCI at 72%, and medical therapy at 67% ( P =0.02 for 3 groups). Although CABG was associated with better survival, mortality remained high (3% per year). There was no survival advantage by treatment for patients with less-severe SPECT abnormalities. Conclusions— These nonrandomized data suggest that CABG improves survival in asymptomatic diabetic patients with high-risk SPECT, although revascularization was performed infrequently in these patients. These results parallel those of the Bypass Angioplasty Revascularization Investigation trial in symptomatic diabetic patients.

To understand the role of regulatory T cells in staphylococcal enterotoxin B‐induced toxic shock syndrome (TSS), we performed gene expression profiling in HLA‐DR3 transgenic mice using microarrays. We observed that at 3 hours after systemic exposure to SEB (10 μg), the splenic expression of FoxP3, a hall mark of regulatory T cells, was increased by 5 folds (p<0.005). In addition, other genes that regulate FoxP3 + Tregs were also significantly modulated by SEB. These include IL‐2R (27‐fold), IL‐2 (234‐fold), IL‐6 (689‐fold), IL‐21 (21‐fold), TGF‐B1 (0.7‐fold), IL‐17 (5.5‐fold) and IL‐22 (98‐fold). To further characterize the homeostasis of Tregs cells during superantigen‐induced TSS in vivo, HLA‐DR3 transgenic mice were first challenged with SEB and were administered BrdU in drinking water for 3 days. Mice were killed 3 days later and splenocytes analyzed by flow cytometry. We observed that in addition to FoxP3‐TCR Vβ8 + T cells, FoxP3 + TCR Vβ8 + T cells also significantly expanded in vivo as evident from their BrdU staining patterns. This indicated that SEB is able to activate Tregs as well. Depletion of Tregs using anti‐CD25 antibodies (clone PC‐61, 500 ug/mouse) 2 days prior to SEB challenge did not significantly alter serum cytokine levels as compared to control mice treated with rat IgG and SEB. Thus, T regulatory cells have a minimal role in SEB‐induced TSS.