Novel and unique rheumatoid factors cross-react with viral epitopes in COVID-19.

Rheumatoid factors (RFs), polyreactive antibodies canonically known to bind two conformational epitopes of IgG Fc, are a hallmark of rheumatoid arthritis but also can arise in other inflammatory conditions and infections. Also, infections may contribute to the development of rheumatoid arthritis and other autoimmune diseases. Recently, RFs only in rheumatoid arthritis were found to bind novel linear IgG epitopes as well as thousands of other rheumatoid arthritis autoantigens. Specific epitopes recognized by infection-induced polyreactive RFs remain undefined but could provide insights into loss of immune tolerance. Here, we identified novel linear IgG epitopes bound by RFs in COVID-19 but not rheumatoid arthritis or other conditions. The main COVID-19 RF was polyreactive, binding two IgG and multiple viral peptides with a tripeptide motif, as well as IgG Fc and SARS-CoV-2 spike proteins. In contrast, a rheumatoid arthritis-specific RF recognized IgG Fc, but not tripeptide motif-containing peptides or spike. Thus, RFs have disease-specific IgG reactivity and distinct polyreactivities that reflect the broader immune response. Moreover, the polyreactivity of a virus-induced RF appears to be attributable to a very short peptide motif. These findings refine our understanding of RFs and provide new insights into how viral infections may contribute to autoimmunity.

Chronic alcohol use primes bronchial cells for altered inflammatory response and barrier dysfunction during SARS-CoV-2 infection.

Alcohol use disorder (AUD) is a significant public health concern and people with AUD are more likely to develop severe acute respiratory distress syndrome (ARDS) in response to respiratory infections. To examine whether AUD was a risk factor for more severe outcome in response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we examined early responses to infection using cultured differentiated bronchial epithelial cells derived from brushings obtained from people with AUD or without AUD. RNA-seq analysis of uninfected cells determined that AUD cells were enriched for expression of epidermal genes as compared with non-AUD cells. Bronchial epithelial cells from patients with AUD showed a significant decrease in barrier function 72 h postinfection, as determined by transepithelial electrical resistance. In contrast, barrier function of non-AUD cells was enhanced 72 h after SARS-CoV-2 infection. AUD cells showed claudin-7 that did not colocalize with zonula occludens-1 (ZO-1), indicative of disorganized tight junctions. However, both AUD and non-AUD cells showed decreased ß-catenin expression following SARS-CoV-2 infection. To determine the impact of AUD on the inflammatory response to SARS-CoV-2 infection, cytokine secretion was measured by multiplex analysis. SARS-CoV-2-infected AUD bronchial cells had enhanced secretion of multiple proinflammatory cytokines including TNFα, IL-1ß, and IFNγ as opposed to non-AUD cells. In contrast, secretion of the barrier-protective cytokines epidermal growth factor (EGF) and granulocyte macrophage-colony stimulating factor (GM-CSF) was enhanced for non-AUD bronchial cells. Taken together, these data support the hypothesis that AUD is a risk factor for COVID-19, where alcohol primes airway epithelial cells for increased inflammation and increased barrier dysfunction and increased inflammation in response to infection by SARS-CoV-2.NEW & NOTEWORTHY Alcohol use disorder (AUD) is a significant risk factor for severe acute respiratory distress syndrome. We found that AUD causes a phenotypic shift in gene expression in human bronchial epithelial cells, enhancing expression of epidermal genes. AUD cells infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had higher levels of proinflammatory cytokine secretion and barrier dysfunction not present in infected non-AUD cells, consistent with increased early COVID-19 severity due to AUD.

Measurement of the ν_{e}-Nucleus Charged-Current Double-Differential Cross Section at ⟨E_{ν}⟩=2.4 GeV Using NOvA.

The inclusive electron neutrino charged-current cross section is measured in the NOvA near detector using 8.02×10^{20} protons-on-target in the NuMI beam. The sample of GeV electron neutrino interactions is the largest analyzed to date and is limited by ≃17% systematic rather than the ≃7.4% statistical uncertainties. The double-differential cross section in final-state electron energy and angle is presented for the first time, together with the single-differential dependence on Q^{2} (squared four-momentum transfer) and energy, in the range 1 GeV≤E_{ν}<6 GeV. Detailed comparisons are made to the predictions of the GENIE, GiBUU, NEUT, and NuWro neutrino event generators. The data do not strongly favor a model over the others consistently across all three cross sections measured, though some models have especially good or poor agreement in the single differential cross section vs Q^{2}.

Anti-membrane Antibodies Persist at Least One Year and Discriminate Between Past Coronavirus Disease 2019 Infection and Vaccination.

BACKGROUND: The consequences of past coronavirus disease 2019 (COVID-19) infection for personal and population health are emerging, but accurately identifying distant infection is a challenge. Anti-spike antibodies rise after both vaccination and infection and anti-nucleocapsid antibodies rapidly decline. METHODS: We evaluated anti-membrane antibodies in COVID-19 naive, vaccinated, and convalescent subjects to determine if they persist and accurately detect distant infection. RESULTS: We found that anti-membrane antibodies persist for at least 1 year and are a sensitive and specific marker of past COVID-19 infection. CONCLUSIONS: Thus, anti-membrane and anti-spike antibodies together can differentiate between COVID-19 convalescent, vaccinated, and naive states to advance public health and research.

Alcohol impairs recognition and uptake of Mycobacterium tuberculosis by suppressing toll-like receptor 2 expression.

BACKGROUND: Alcohol impairs pulmonary innate immune function and is associated with an increased risk of tuberculosis (TB). Toll-like receptor 2 (TLR2) is a pattern recognition receptor on alveolar macrophages that recognizes Mycobacterium tuberculosis (Mtb). The expression of TLR2 depends, in part, on granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling. Given our prior work demonstrating the suppression of GM-CSF signaling following chronic alcohol ingestion, we hypothesized that alcohol impairs TLR2 expression via the suppression of GM-CSF and thereby reduces the ability of the macrophage to recognize and phagocytose Mtb. METHODS: Primary alveolar macrophages were isolated from control-fed and alcohol-fed rats. Prior to cell isolation, some alcohol-fed rats were treated with intranasal GM-CSF and then endotracheally inoculated with an attenuated strain of Mtb. Primary macrophages were then isolated and immunofluorescence was used to determine phagocytic efficiency and TLR2 expression in the presence and absence of GM-CSF treatment and phagocytic efficiency in the presence and absence of TLR2 neutralization. RESULTS: TLR2 expression and phagocytosis of Mtb were significantly lower in the alveolar macrophages of alcohol-fed rats than control-fed rats. In parallel, blocking TLR2 signaling recapitulated this decreased phagocytosis of Mtb. In contrast, intranasal GM-CSF treatment restored TLR2 expression and Mtb phagocytosis in the alveolar macrophages of alcohol-fed rats to levels comparable to those of control-fed rats. CONCLUSIONS: Chronic alcohol ingestion reduces TLR2 protein expression and phagocytosis of Mtb, likely due to impaired GM-CSF signaling. GM-CSF restores membrane-bound TLR2 expression and phagocytic function.

Search for Active-Sterile Antineutrino Mixing Using Neutral-Current Interactions with the NOvA Experiment.

This Letter reports results from the first long-baseline search for sterile antineutrinos mixing in an accelerator-based antineutrino-dominated beam. The rate of neutral-current interactions in the two NOvA detectors, at distances of 1 and 810 km from the beam source, is analyzed using an exposure of 12.51×10^{20} protons-on-target from the NuMI beam at Fermilab running in antineutrino mode. A total of 121 of neutral-current candidates are observed at the far detector, compared to a prediction of 122±11(stat.)±15(syst.) assuming mixing only between three active flavors. No evidence for ν[over ¯]_{µ}→ν[over ¯]_{s} oscillation is observed. Interpreting this result within a 3+1 model, constraints are placed on the mixing angles θ_{24}<25° and θ_{34}<32° at the 90% C.L. for 0.05 eV^{2}≤Δm_{41}^{2}≤0.5 eV^{2}, the range of mass splittings that produces no significant oscillations at the near detector. These are the first 3+1 confidence limits set using long-baseline accelerator antineutrinos.

HIV and the tuberculosis "set point": how HIV impairs alveolar macrophage responses to tuberculosis and sets the stage for progressive disease.

As HIV has fueled a global resurgence of tuberculosis over the last several decades, there is a growing awareness that HIV-mediated impairments in both innate and adaptive immunity contribute to the heightened risk of tuberculosis in people with HIV. Since early immune responses to Mycobacterium tuberculosis (Mtb) set the stage for subsequent control or progression to active tuberculosis disease, early host-pathogen interactions following Mtb infection can be thought of as establishing a mycobacterial "set point," which we define as the mycobacterial burden at the point of adaptive immune activation. This early immune response is impaired in the context of HIV coinfection, allowing for a higher mycobacterial set point and greater likelihood of progression to active disease with greater bacterial burden. Alveolar macrophages, as the first cells to encounter Mtb in the lungs, play a critical role in containing Mtb growth and establishing the mycobacterial set point. However, a number of key macrophage functions, ranging from pathogen recognition and uptake to phagocytosis and microbial killing, are blunted in HIV coinfection. To date, research evaluating the effects of HIV on the alveolar macrophage response to Mtb has been relatively limited, particularly with regard to the critical early events that help to dictate the mycobacterial set point. A greater understanding of alveolar macrophage functions impacted by HIV coinfection will improve our understanding of protective immunity to Mtb and may reveal novel pathways amenable to intervention to improve both early immune control of Mtb and clinical outcomes for the millions of people worldwide infected with HIV.

Impact of short term oral steroid use for intravenous contrast media hypersensitivity prophylaxis in diabetic patients undergoing nonemergent coronary angiography or interventions.

OBJECTIVES: Oral steroids are routinely administered in the United States for prophylaxis of iodinated contrast media hypersensitivity (ICMH). We studied the impact of short-term steroid use in diabetic patients with ICMH undergoing nonemergent coronary angiography. METHODS: We retrospectively analyzed records of diabetic patients with and without ICMH who underwent nonemergent coronary angiography at our center. Primary study endpoint was 30-day major adverse cardiac events (MACE) and secondary endpoints were pre- and postprocedure fasting blood glucose (FBG), highest in hospital blood glucose, pre- and postprocedure systolic blood pressure (SBP), and use of intravenous insulin and antihypertensive medications. RESULTS: A total of 88 diabetics with ICMH (study group) and 76 diabetics without ICMH (control group) undergoing angiography were enrolled. Demographics and hemoglobin A1c values were similar in both groups. Preprocedural FBG was significantly higher in the study group. The study group had significantly higher post angiography FBG (239.93 + 96.88 mg/dl vs. 156.6 + 59.88 mg/dl) and greater use of intravenous (IV) insulin (67.27% vs. 32.43%). Further, those who received steroids had significantly higher systolic SBP postprocedure (146.16 + 25.35 mmHg vs. 130.8 + 21.59 mmHg), a higher incidence of severe hypertension and use of IV antihypertensive medications (80.95% vs. 19.05%) periprocedurally. There were no differences in 30-day MACE between groups. CONCLUSION: Short-term steroid use for ICMH results in a significant increase in surrogate markers for adverse clinical events after coronary procedures. Study findings highlight the need for better periprocedural management of these patients and to limit steroid prophylaxis to those with only true ICMH.

MiR-144 mediates Nrf2 inhibition and alveolar epithelial dysfunction in HIV-1 transgenic rats.

Chronic HIV infection causes redox stress and increases the risk of acute and chronic lung injury, even when individuals are adherent to antiretroviral therapy. HIV-1 transgene expression in rats inhibits nuclear factor (erythroid-derived 2)-like 2 (Nrf2), which regulates antioxidant defenses and alveolar epithelial cell (AEC) barrier function, but the mechanism is unknown. In this study, we present novel evidence that these pathological effects of HIV are mediated by microRNA-144 (miR-144). HIV-1 transgene expression in vivo increases the expression of miR-144 in the alveolar epithelium, and this can be replicated by direct exposure of naïve primary AECs to either Tat or gp120 ex vivo. Further, treating naïve primary AECs with a miR-144 mimic decreased the expression and activity of Nrf2 and inhibited their barrier formation. In contrast, treatment with a miR-144 antagomir increased the expression and activity of Nrf2 and improved barrier function in primary AECs isolated from HIV-1 transgenic rats. Importantly, either delivering the miR-144 antagomir intratracheally, or directly activating Nrf2 by dietary treatment with PB123, increased Nrf2 expression and barrier formation in HIV-1 transgenic rat AECs. This study provides new experimental evidence that HIV-induced inhibition of Nrf2 and consequent AEC barrier dysfunction are mediated via miR-144, and that these pathophysiological effects can be mitigated in vivo by either directly antagonizing miR-144 or activating Nrf2. Our findings suggest that targeting the inhibition of Nrf2 in individuals living with HIV could enhance their lung health and decrease the lung-specific morbidity and mortality that persists despite antiretroviral therapy.

First measurement of neutrino oscillation parameters using neutrinos and antineutrinos by NOvA.

The NOvA experiment has seen a 4.4σ signal of ν[over ¯]_{e} appearance in a 2 GeV ν[over ¯]_{µ} beam at a distance of 810 km. Using 12.33×10^{20} protons on target delivered to the Fermilab NuMI neutrino beamline, the experiment recorded 27 ν[over ¯]_{µ}→ν[over ¯]_{e} candidates with a background of 10.3 and 102 ν[over ¯]_{µ}→ν[over ¯]_{µ} candidates. This new antineutrino data are combined with neutrino data to measure the parameters |Δm_{32}^{2}|=2.48_{-0.06}^{+0.11}×10^{-3} eV^{2}/c^{4} and sin^{2}θ_{23} in the ranges from (0.53-0.60) and (0.45-0.48) in the normal neutrino mass hierarchy. The data exclude most values near δ_{CP}=π/2 for the inverted mass hierarchy by more than 3σ and favor the normal neutrino mass hierarchy by 1.9σ and θ_{23} values in the upper octant by 1.6σ.

Divergent mechanisms for regulating growth and development after imaginal disc damage in the tobacco hornworm, Manduca sexta.

Holometabolous insects have been able to radiate to vast ecological niches as adults through the evolution of adult-specific structures such as wings, antennae and eyes. These structures arise from imaginal discs that show regenerative capacity when damaged. During imaginal disc regeneration, development has been shown to be delayed in the fruit fly Drosophila melanogaster, but how conserved the delay-inducing mechanisms are across holometabolous insects has not been assessed. The goal of this research was to develop the hornworm Manduca sexta as an alternative model organism to study such damage-induced mechanisms, with the advantage of a larger hemolymph volume enabling access to the hormonal responses to imaginal disc damage. Upon whole-body X-ray exposure, we noted that the imaginal discs were selectively damaged, as assessed by TUNEL and Acridine Orange stains. Moreover, development was delayed, predominantly at the pupal-to-adult transition, with a concomitant delay in the prepupal ecdysteroid peak. The delays to eclosion were dose dependent, with some ability for repair of damaged tissues. We noted a shift in critical weight, as assessed by the point at which starvation no longer impacted developmental timing, without a change in growth rate, which was uncoupled from juvenile hormone clearance in the body. The developmental profile was different from that of D. melanogaster, which suggests species differences may exist in the mechanisms delaying development.

Alcohol-Induced Interleukin-17 Expression Causes Murine Lung Fibroblast-to-Myofibroblast Transdifferentiation via Thy-1 Down-Regulation.

BACKGROUND: Alcohol exposure induces TGFß1 and renders the lung susceptible to injury and disrepair. We determined that TGFß1 regulates myofibroblast differentiation through the loss of Thy-1 expression and consequent induction of α-SMA. TGFß1 is important for T helper 17 (Th17) differentiation and IL-17 secretion, which in turn participates in tissue repair. We hypothesized that alcohol induces Th17 differentiation via TGFß1 and that IL-17 produced by these cells contributes to the development of profibrotic lung myofibroblasts. METHODS: Primary lung fibroblasts (PLFs) were treated with alcohol, TGFß1, and IL-17 and then analyzed for Thy-1 expression and cell morphology. Naïve and Th17-polarized CD4+ T cells were exposed to alcohol and assessed for IL-17 expression. CD4+ T cells from alcohol-fed mice were analyzed for Th17 and IL-17 expression. Lungs of control-fed, bleomycin-treated and alcohol-fed, bleomycin-treated mice were analyzed for IL-17 protein expression. RESULTS: Alcohol-treated PLFs expressed lower levels of Thy-1 than untreated cells. TGFß1 or IL-17 exposure suppressed PLF Thy-1 expression. When administered together, TGFß1 and IL-17 additively down-regulated Thy-1 expression. Exposure of naïve and Th17-polarized CD4+ T cells to alcohol induced the Th17 phenotype and augmented their production of IL-17. CD4+ Th17+ levels are elevated in the peripheral compartment but not in the lungs of alcohol-fed animals. Treatment of the PLFs with IL-17 and alcohol induced α-SMA expression. Induction of α-SMA and myofibroblast morphology by IL-17 occurred selectively in a Thy-1- fibroblast subpopulation. Chronic alcohol ingestion augmented lung-specific IL-17 expression following bleomycin-induced lung injury. CONCLUSIONS: Alcohol exposure skews T cells toward a Th17 immune response that in turn primes the lung for fibroproliferative disrepair through loss of Thy-1 expression and induction of myofibroblast differentiation. These effects suggest that IL-17 and TGFß1 contribute to fibroproliferative disrepair in the lung and targeting these proteins could limit morbidity and mortality following lung injury in alcoholic individuals.

Pulmonary Innate Immune Dysfunction in Human Immunodeficiency Virus.

The advent of antiretroviral therapy has transformed infection by the type 1 human immunodeficiency virus (HIV) from a rapidly fatal disease to a chronic illness with excellent long-term survival rates. Although HIV primarily targets the adaptive arm of host immunity, it simultaneously impacts the innate immune system, and has profound implications for lung health, even when viral suppression is achieved with antiretroviral therapy. The lung has evolved a unique array of innate immune defenses, and the pathophysiological interactions between HIV and the pulmonary innate immune system deserve particular attention. In this review, we discuss work that elucidates how the components of innate immunity both respond to and are perturbed by infection with HIV.

Corticosteroids and occurrence of and mortality from infections in severe alcoholic hepatitis: a meta-analysis of randomized trials.

BACKGROUND & AIMS: Prednisolone is the first-line therapy for severe alcoholic hepatitis (AH). Patients with severe alcoholic hepatitis often develop severe infections that negatively impact short-term prognosis. METHODS: We performed this meta-analysis to assess the effect of corticosteroids on the occurrence of and mortality from infections in patients with severe alcoholic hepatitis. Randomized controlled trials examining the use of corticosteroids in severe alcoholic hepatitis and reporting data on infection rates and mortality were included. Random effects model was used to pool the data comparing arms with and without steroids for the occurrence of infection, 28-day mortality and cause specific mortality. RESULTS: Of 1062 patients (528 steroids treated) without infection at baseline from 12 studies, infection was reported in 213 (113 steroids treated) patients without differences comparing arms with and without steroids (OR: 0.98; CI: 0.49-1.94). However, frequency was higher for occurrence of fungal infections among steroid-treated patients (eight of 528 vs. one of 534; P = 0.02). Steroids provided mortality benefit at 28 days (OR: 0.55; CI: 0.34-0.90) mainly for liver failure-related death (OR: 0.46; CI: 0.24-0.87) without differences on mortality from infection (OR: 1.19; CI: 0.38-3.73) or gastrointestinal bleeding (OR: 0.90; CI: 0.43-1.87). Three of nine patients with fungal infections died, all in corticosteroid arm. CONCLUSIONS: Corticosteroids do not increase occurrence of or mortality from bacterial infections in patients with severe alcoholic hepatitis. Further studies are needed to develop strategies of reducing the risk of fungal infection with use of steroids for patients with severe alcoholic hepatitis.

Study on Neurological Consequence of Eclampsia.

The present study was carried out in the Department of Obstetrics and Gynecology at Mymensingh Medical College Hospital, Mymensingh, Bangladesh for a period of one year from 1st June 2009 to 30th June 2010 to see the Neurological Consequence of Eclampsia. A total number of 37 patients were enrolled in this study. Among 37 patients majority are in the age group of 21-30 years which is 19(51.4%) cases followed by less than or equal to 20 years and more than 30 years which are 13(35.1%) cases and 5(13.5%) cases respectively. Knee jerk is present in 28(75.7%) cases and absent in 8(21.6%) cases. The exaggerated knee jerk is present in only in 1(2.7%) case. The rate of Glasgow coma scale is less than 5 in 21(56.8%) cases, 14(37.8%) cases in 5-10 and 2(5.4%) cases is in more than 10. Focal sign is absent in 22(59.5%) cases and present in 15(40.5%) cases. Majority of the patients is presented with absence of neck stiffness which is 35(94.6%) cases and the rest 2(5.4%) cases are presented with neck stiffness. Flexor planter response is found in 20(54.1%) cases which is the highest in number followed by extensor which is 15(40.5%) cases. In only 2(5.4%) cases the planter reflex is not elicitable. Presence of infarct is found in 15(40.5%) cases which is the highest number. Cerebral edema and Presence of haemorrhage is found in 3(8.1%) cases in each. Leuko-encephalopathy is found in 2(5.4%) cases. Encephalopathy and Both infarct & haemorrhage is found in 1(2.7%) case of each. Normal CT scan findings of brain are found in 12(32.4%) cases.

TGF-ß1 epigenetically modifies Thy-1 expression in primary lung fibroblasts.

Idiopathic pulmonary fibrosis is a progressive lung disease that increases in incidence with age. We identified a profibrotic lung phenotype in aging mice characterized by an increase in the number of fibroblasts lacking the expression of thymocyte differentiation antigen 1 (Thy-1) and an increase in transforming growth factor (TGF)-ß1 expression. It has been shown that Thy-1 expression can be epigenetically modified. Lung fibroblasts (PLFs) were treated with TGF-ß1 ± DNA methyltransferase (DNMT) inhibitor 5-aza-2'-deoxycytidine (5-AZA) and analyzed for Thy-1 gene and protein expression, DNMT protein expression, and activity. α-Smooth muscle actin (α-SMA) and collagen type 1 (Col1A1) gene and protein expression was assessed. PLFs were transfected with DNMT1 silencing RNA ± TGF-ß1. TGF-ß1 inhibited Thy-1 gene and protein expression in PLFs, and cotreatment with 5-AZA ameliorated this effect and appeared to inhibit DNMT1 activation. TGF-ß1 induced Thy-1 promoter methylation as assessed by quantitative methyl PCR. Treatment with 5-AZA attenuated TGF-ß1-induced Col1A1 gene and protein expression and α-SMA gene expression (but not α-SMA protein expression). Inhibiting DNMT1 with silencing RNA attenuated TGF-ß1-induced DNMT activity and its downstream suppression of Thy-1 mRNA and protein expression as well as inhibited α-SMA mRNA and Col1A1 mRNA and protein expression, and showed a decreased trend in Thy-1 promoter methylation. Immunofluorescence for α-SMA suggested that 5-AZA inhibited stress fiber formation. These findings suggest that TGF-ß1 epigenetically regulates lung fibroblast phenotype through methylation of the Thy-1 promoter. Targeted inhibition of DNMT in the right clinical context might prevent fibroblast to myofibroblast transdifferentiation and collagen deposition, which in turn could prevent fibrogenesis in the lung and other organs.

Nrf2 regulates PU.1 expression and activity in the alveolar macrophage.

Alveolar macrophage (AM) immune function depends on the activation of the transcription factor PU.1 by granulocyte macrophage colony-stimulating factor. We have determined that chronic alcohol ingestion dampens PU.1 signaling via an unknown zinc-dependent mechanism; specifically, although PU.1 is not known to be a zinc-dependent transcription factor, zinc treatment reversed alcohol-mediated dampening of PU.1 signaling. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a zinc-dependent basic leucine zipper protein essential for antioxidant defenses, is also impaired by chronic alcohol ingestion and enhanced by zinc treatment. We hypothesized that the response of PU.1 to zinc treatment may result from the action of Nrf2 on PU.1. We first performed Nrf2/PU.1 protein coimmunoprecipitation on a rat AM cell line (NR8383) and found no evidence of protein-protein interactions. We then found evidence of increased Nrf2 binding to the PU.1 promoter region by chromatin immunoprecipitation. We next activated Nrf2 using either sulforaphane or an overexpression vector and inhibited Nrf2 with silencing RNA to determine whether Nrf2 could actively regulate PU.1. Nrf2 activation increased protein expression of both factors as well as gene expression of their respective downstream effectors, NAD(P)H dehydrogenase[quinone] 1 (NQO1) and cluster of differentiation antigen-14 (CD14). In contrast, Nrf2 silencing decreased the expression of both proteins, as well as gene expression of their effectors. Activating and inhibiting Nrf2 in primary rat AMs resulted in similar effects. Taken together, these findings suggest that Nrf2 regulates the expression and activity of PU.1 and that antioxidant response and immune activation are coordinately regulated within the AM.

Long-term follow-up in AV junction ablation via the SVC in patients undergoing concurrent device implantation: a single center experience.

BACKGROUND: Ablation of the atrioventricular junction (AVJ) combined with pacemaker implantation (the "ablate and pace" approach) has been an effective treatment strategy for patients with atrial fibrillation (AF) when rate control is the goal of therapy and when rapid ventricular rates during AF is refractory to pharmacologic therapy. OBJECTIVE: This report describes the feasibility and safety of catheter ablation of AVJ via a superior vena cava (SVC) approach performed during concurrent pacemaker or defibrillator implantation. METHODS: A total of 170 consecutive patients with drug-refractory AF underwent combined AVJ ablation and pacemaker or defibrillator implantation using the axillary or subclavian venous approach. The acute and long-term success of achieving complete atrioventricular (AV) block, the impact of the ablation procedure on the total procedure time and fluoroscopy duration, and procedural complications were evaluated. RESULTS: A dual-chamber device in 61% of patients and biventricular device in 39% patients. Catheter ablation of the AVJ was acutely successful in 166 patients (97.6%). The mean procedure time of the AVJ ablation was 7.0 ± 3.3 minutes and the mean fluoroscopy time during the ablation procedure was 3.1 ± 3.2 minutes. The average duration of RF energy application required to achieve complete AV block was 129 ± 65 seconds. Procedural complications were observed in seven patients. Complete AV block persisted in 96% of patients during a mean follow-up of 26 ± 16 months. CONCLUSION: Catheter ablation of the AVJ can be performed successfully and safely using the SVC approach in patients undergoing concurrent device implantation, and it may offer several advantages over the conventional femoral approach.

Macrophage extracellular traps require peptidylarginine deiminase 2 and 4 and are a source of citrullinated antigens bound by rheumatoid arthritis autoantibodies.

Introduction: Anti-citrullinated protein antibodies (ACPAs) are a hallmark of rheumatoid arthritis, but the sources of citrullinated antigens as well as which peptidylarginine deiminases (PADs) are required for their production remain incompletely defined. Here, we investigated if macrophage extracellular traps (METs) could be a source of citrullinated proteins bound by APCAs, and if their formation requires PAD2 or PAD4. Methods: Thioglycolate-induced peritoneal macrophages from wild-type, PAD2-/-, and PAD4-/- mice or human peripheral blood-derived M1 macrophages were activated with a variety of stimulants, then fixed and stained with DAPI and either anti-citrullinated histone H4 (citH4) antibody or sera from ACPA+ or ACPA- rheumatoid arthritis subjects. METs were visualized by immunofluorescence, confirmed to be extracellular using DNase, and quantified. Results: We found that ionomycin and monosodium urate crystals reliably induced murine citH4+ METs, which were reduced in the absence of PAD2 and lost in the absence of PAD4. Also, IgG from ACPA+, but not ACPA-, rheumatoid arthritis sera bound to murine METs, and in the absence of PAD2 or PAD4, ACPA-bound METs were lost. Finally, ionomycin induced human METs that are citH4+ and ACPA-bound. Discussion: Thus, METs may contribute to the pool of citrullinated antigens bound by ACPAs in a PAD2- and PAD4-dependent manner, providing new insights into the targets of immune tolerance loss in rheumatoid arthritis.

Pediatric mental health emergency department visits from 2017 to 2022: A multicenter study.

BACKGROUND: The COVID-19 pandemic adversely affected children's mental health (MH) and changed patterns of MH emergency department (ED) utilization. Our objective was to assess how pediatric MH ED visits during the COVID-19 pandemic differed from expected prepandemic trends. METHODS: We retrospectively studied MH ED visits by children 5 to <18 years old at nine U.S. hospitals participating in the Pediatric Emergency Care Applied Research Network Registry from 2017 to 2022. We described visit length by time period: prepandemic (January 2017-February 2020), early pandemic (March 2020-December 2020), midpandemic (2021), and late pandemic (2022). We estimated expected visit rates from prepandemic data using multivariable Poisson regression models. We calculated rate ratios (RRs) of observed to expected visits per 30 days during each pandemic time period, overall and by sociodemographic and clinical characteristics. RESULTS: We identified 175,979 pediatric MH ED visits. Visit length exceeded 12 h for 7.3% prepandemic, 8.4% early pandemic, 15.0% midpandemic, and 19.2% late pandemic visits. During the early pandemic, observed visits per 30 days decreased relative to expected rates (RR 0.80, 95% confidence interval [CI] 0.78-0.84), were similar to expected rates during the midpandemic (RR 1.01, 95% CI 0.96-1.07), and then decreased below expected rates during the late pandemic (RR 0.92, 95% CI 0.86-0.98). During the late pandemic, visit rates were higher than expected for females (RR 1.10, 95% CI 1.02-1.20) and for bipolar disorders (RR 1.83, 95% CI 1.38-2.75), schizophrenia spectrum disorders (RR 1.55, 95% CI 1.10-2.59), and substance-related and addictive disorders (RR 1.50, 95% CI 1.18-2.05). CONCLUSIONS: During the late pandemic, pediatric MH ED visits decreased below expected rates; however, visits by females and for specific conditions remained elevated, indicating a need for increased attention to these groups. Prolonged ED visit lengths may reflect inadequate availability of MH services.