Evaluation of the reproducibility of responses to nasal allergen challenge and effects of inhaled nasal corticosteroids.

BACKGROUND: Similar immune responses in the nasal and bronchial mucosa implies that nasal allergen challenge (NAC) is a suitable early phase experimental model for drug development targeting allergic rhinitis (AR) and asthma. We assessed NAC reproducibility and the effects of intranasal corticosteroids (INCS) on symptoms, physiology, and inflammatory mediators. METHODS: 20 participants with mild atopic asthma and AR underwent three single blinded nasal challenges each separated by three weeks (NCT03431961). Cohort A (n = 10) underwent a control saline challenge, followed by two allergen challenges. Cohort B (n = 10) underwent a NAC with no treatment intervention, followed by NAC with 14 days pre-treatment with saline nasal spray (placebo), then NAC with 14 days pre-treatment with INCS (220 µg triamcinolone acetonide twice daily). Nasosorption, nasal lavage, blood samples, forced expiratory volume 1 (FEV1), total nasal symptom score (TNSS), peak nasal inspiratory flow (PNIF) were collected up to 24 h after NAC. Total and active tryptase were measured as early-phase allergy biomarkers (≤30 min) and IL-13 and eosinophil cell counts as late-phase allergy biomarkers (3-7 h) in serum and nasal samples. Period-period reproducibility was assessed by intraclass correlation coefficients (ICC), and sample size estimates were performed using effect sizes measured after INCS. RESULTS: NAC significantly induced acute increases in nasosorption tryptase and TNSS and reduced PNIF, and induced late increases in nasosorption IL-13 with sustained reductions in PNIF. Reproducibility across NACs varied for symptoms and biomarkers, with total tryptase 5 min post NAC having the highest reproducibility (ICC = 0.91). Treatment with INCS inhibited NAC-induced IL-13 while blunting changes in TNSS and PNIF. For a similar crossover study, 7 participants per treatment arm are needed to detect treatment effects comparable to INCS for TNSS. CONCLUSION: NAC-induced biomarkers and symptoms are reproducible and responsive to INCS. NAC is suitable for assessing pharmacodynamic activity and proof of mechanism for drugs targeting allergic inflammation.

Once-daily dolutegravir versus darunavir plus cobicistat in adults at the time of primary HIV-1 infection: the OPTIPRIM2-ANRS 169 randomized, open-label, Phase 3 trial.

BACKGROUND: Whether integrase strand transfer inhibitors (INSTIs) can decrease HIV-1 DNA levels more rapidly than boosted PIs during primary HIV-1 infection (PHI) is unknown. We hypothesized that once-daily dolutegravir/tenofovir/emtricitabine could reduce the viral reservoir through rapid viral replication control further than once-daily darunavir/cobicistat/tenofovir/emtricitabine. METHODS: The OPTIPRIM2-ANRS 169 study was a randomized (1:1), open-label, multicentre trial in adults with ≤5 or ≤3 HIV antibodies detected, respectively, by western blot or immunoblot in the last 10 days. The primary endpoint was total HIV-1 DNA levels in PBMCs at Week 48 (W48) adjusted for baseline levels. The main secondary endpoint was HIV-1 RNA level decrease. RESULTS: Between April 2017 and August 2018, 101 patients were included from 31 hospitals. Most patients were men (93%), the median age was 36 years and 17% were Fiebig stage ≤3. The median (IQR) plasma HIV-1 RNA and DNA levels were, respectively, 5.8 (5.0-6.6) and 3.87 (3.52-4.15) log10 copies/million PBMCs. The median (IQR) decreases in HIV-1 DNA levels at W48 were -1.48 (-1.74 to -1.06) and -1.39 (-1.55 to -0.98) log10 copies/million PBMCs in the dolutegravir and darunavir/cobicistat groups, respectively (P = 0.52). Plasma HIV-1 RNA levels were <50 copies/mL in 24% versus 0% of patients in the dolutegravir and darunavir/cobicistat groups at W4, 55% versus 2% at W8, 67% versus 17% at W12, and 94% versus 90% at W48, respectively. CONCLUSIONS: Dolutegravir-based and darunavir-based regimens initiated during PHI strongly and similarly decreased the blood reservoir size. Considering the rapid viral suppression during a period of high HIV-1 transmission risk, dolutegravir-based regimens are a major first-line option.

HIV-1-RNA and total HIV-1-DNA loads in the genital compartment in men receiving dolutegravir- versus darunavir-based combined ART (cART) regimens during primary HIV infection.

BACKGROUND: Dolutegravir is a widespread integrase strand-transfer inhibitor (INSTI) recommended for treatment of primary HIV infection (PHI). PHI is a high-risk stage for sexual transmission because of the high viral load in semen. Yet dolutegravir concentrations in semen are lower than in blood during chronic treatment. OBJECTIVES: To compare the kinetics of HIV-RNA and total HIV-DNA in the genital compartment in subjects receiving either tenofovir/emtricitabine/dolutegravir or tenofovir/emtricitabine/darunavir/cobicistat as a first-line combined ART (cART) at the time of PHI. PATIENTS AND METHODS: Eighteen subjects receiving tenofovir/emtricitabine/dolutegravir and 19 receiving tenofovir/emtricitabine/darunavir/cobicistat enrolled in the ANRS169 OPTIPRIM-2 trial participated in the genital substudy. RESULTS: Between week (W) 0 and W2 HIV-RNA in seminal plasma (SP) decreased by 1 log10 copies/mL. Undetectable SP HIV-RNA was achieved in similar proportions between the two regimens at each timepoint. Overall, eight patients still presented detectable HIV-RNA or HIV-DNA in semen at W48; 15.4% and 28.6% presented detectable HIV-RNA and 9.1% and 14.3% presented detectable HIV-DNA in dolutegravir- and darunavir-based cART groups, respectively, with no significant difference. CONCLUSIONS: For the first time, to the best of our knowledge, we showed that a dolutegravir-based regimen initiated as soon as PHI reduces HIV-RNA and HIV-DNA with no difference compared with a control group receiving a darunavir-based regimen. Although the viral purge in semen seems longer after treatment in PHI than CHI, due to high viral loads, early dolutegravir-based treatment initiation permits a major decay of both viral particles and infected cells in semen, efficiently reducing the high risk of transmission during PHI.

LC-HRMS screening of per- and polyfluorinated alkyl substances (PFAS) in impregnated paper samples and contaminated soils.

High per- and polyfluorinated alkyl substance (PFAS) concentrations have been detected in agricultural soils in Southwest Germany. Discharges of PFAS-contaminated paper sludge and compost are suspected to be the cause of the contamination. Perfluorinated carboxylic acids (PFCAs) have been detected also in groundwater, drinking water, and plants in this area. Recently, previously unknown compounds have been identified by high-resolution mass spectrometry (HRMS). Major contaminants were polyfluorinated dialkylated phosphate esters (diPAPs) and N-ethyl perfluorooctane sulfonamide ethanol-based phosphate diester (diSAmPAP). In this study, HRMS screening for PFAS was applied to 14 soil samples from the contaminated area and 14 impregnated paper samples which were from a similar period than the contamination. The paper samples were characterized by diPAPs (from 4:2/6:2 to 12:2/12:2), fluorotelomer mercapto alkyl phosphates (FTMAPs; 6:2/6:2 to 10:2/10:2), and diSAmPAP. In soil samples, diPAPs and their transformation products (TPs) were the major contaminants, but also FTMAPs, diSAmPAP, and their TPs occurred. The distribution patterns of the carbon chain lengths of the precursor PFAS in soil samples were shown to resemble those in paper samples. This supports the hypothesis that paper sludge is a major source of contamination. The presence of major degradation products like PFCAs, FTSAs, or PFOS and their distribution of carbon chain lengths indicate the activity of biotic or abiotic degradation processes and selective leaching processes from the upper soil horizons.

Estimated pill intake with on-demand PrEP with oral TDF/FTC using TFV-DP concentration in dried blood spots in the ANRS IPERGAY trial.

BACKGROUND: Tenofovir diphosphate (TFV-DP) concentration in dried blood spots (DBSs) is a reliable pharmacokinetics biomarker of adherence to tenofovir disoproxil fumarate (TDF). We aimed to use DBSs to estimate pill intake among participants using on-demand pre-exposure prophylaxis (PrEP) and to identify predictive factors associated with higher TFV-DP concentrations. METHODS: DBSs were collected at the last study visit of the open-label phase of the ANRS IPERGAY study, assessing on-demand oral TDF/emtricitabine for PrEP among MSM and transgender female participants. We quantified TFV-DP in DBSs centrally. We assessed correlation between pill count and TFV-DP concentration by Spearman correlation and explored associations between participant demographics, sexual behaviour and PrEP use during sexual intercourse (SI) with TFV-DP concentrations by univariate and multivariate logistic regression models. RESULTS: The median age of the 245 participants included in this study was 40 years, with a median body weight of 73 kg. Median (IQR) TFV-DP concentration reached 517 (128-868) fmol/punch, corresponding to an estimated intake of 8-12 tablets per month (2-3 doses per week). Only 39% of participants had a TFV-DP concentration above 700 fmol/punch. TFV-DP concentrations were moderately correlated with pill count (r: 0.59; P < 0.001). In multivariate analysis, only systematic use of PrEP during SI and more frequent episodes of SI in the past 4 weeks were significantly associated with higher TFV-DP levels [OR (95% CI): 11.30 (3.62-35.33) and 1.46 (1.19-1.79), respectively; P < 0.001]. CONCLUSIONS: Among participants using on-demand PrEP, estimated pill intake reached 8-12 tablets per month and was correlated with frequency and systematic use of PrEP for SI.

Effect of intranasal corticosteroid treatment on allergen-induced changes in group 2 innate lymphoid cells in allergic rhinitis with mild asthma.

BACKGROUND: Allergic rhinitis is characterized by rhinorrhea, nasal congestion, sneezing and nasal pruritus. Group 2 innate lymphoid cells (ILC2s), CD4+ T cells and eosinophils in nasal mucosa are increased significantly after nasal allergen challenge (NAC). Effects of intranasal corticosteroids (INCS) on ILC2s remain to be investigated. METHODS: Subjects (n = 10) with allergic rhinitis and mild asthma were enrolled in a single-blind, placebo-controlled, sequential treatment study and treated twice daily with intranasal triamcinolone acetonide (220 µg) or placebo for 14 days, separated by a 7-day washout period. Following treatment, subjects underwent NAC and upper airway function was assessed. Cells from the nasal mucosa and blood, sampled 24 h post-NAC, underwent flow cytometric enumeration for ILC2s, CD4+ T and eosinophil progenitor (EoPs) levels. Cell differentials and cytokine levels were assessed in nasal lavage. RESULTS: Treatment with INCS significantly attenuated ILC2s, IL-5+ /IL-13+ ILC2s, HLA-DR+ ILC2s and CD4+ T cells in the nasal mucosa, 24 h post-NAC. EoP in nasal mucosa was significantly increased, while mature eosinophils were significantly decreased, 24 h post-NAC in INCS versus placebo treatment arm. Following INCS treatment, IL-2, IL-4, IL-5 and IL-13 were significantly attenuated 24 h post-NAC accompanied by significant improvement in upper airway function. CONCLUSION: Pre-treatment with INCS attenuates allergen-induced increases in ILC2s, CD4+ T cells and terminal differentiation of EoPs in the nasal mucosa of allergic rhinitis patients with mild asthma, with little systemic effect. Attenuation of HLA-DR expression by ILC2s may be an additional mechanism by which steroids modulate adaptive immune responses in the upper airways.

Development of AITC-induced dermal blood flow as a translational in vivo biomarker of TRPA1 activity in human and rodent skin.

BACKGROUND AND PURPOSE: Develop a translational assay of Transient Receptor Potential Ankyrin 1 (TRPA1) activity for use as a preclinical and clinical biomarker. EXPERIMENTAL APPROACH: Allyl isothiocyanate (AITC), capsaicin or citric acid were applied to ears of wildtype and Trpa1-knock out (Trpa1 KO) rats, and changes in dermal blood flow (DBF) were measured by laser speckle contrast imaging. In humans, the DBF, pain and itch responses to 5-20% AITC applied to the forearm were measured and safety was evaluated. Reproducibility of the DBF, pain and itch responses to topically applied 10% and 15% AITC were assessed at two visits separated by 13-15 days. DBF changes were summarized at 5-minute intervals as areas under the curve (AUC) and maxima. Intraclass correlation coefficient (ICC) was calculated to assess arm-arm and period-period reproducibility. KEY RESULTS: AITC- and citric acid-induced DBF were significantly reduced in Trpa1 KO rats compared to wildtype (90 ± 2% and 65 ± 11% reduction, respectively), whereas capsaicin response did not differ. In humans, each AITC concentration significantly increased DBF compared to vehicle with the maximal increase occurring 5 minutes post application. Ten percent and 15% AITC were selected as safe and effective stimuli. AUC from 0 to 5 minutes was the most reproducible metric of AITC-induced DBF across arms (ICC = 0.92) and periods (ICC = 0.85). Subject-reported pain was more reproducible than itch across visits (ICC = 0.76 vs 0.17, respectively). CONCLUSION AND IMPLICATIONS: AITC-induced DBF is a suitable target engagement biomarker of TRPA1 activity for preclinical and clinical studies of TRPA1 antagonists.

Intraoperative Management of Adult Patients on Extracorporeal Membrane Oxygenation: An Expert Consensus Statement From the Society of Cardiovascular Anesthesiologists-Part I, Technical Aspects of Extracorporeal Membrane Oxygenation.

Extracorporeal membrane oxygenation (ECMO) is used to support patients with refractory cardiopulmonary failure. Given ECMO's increased use in adults and the fact that many ECMO patients are cared for by anesthesiologists, the Society of Cardiovascular Anesthesiologists ECMO working group created an expert consensus statement that is intended to help anesthesiologists manage adult ECMO patients who are cared for in the operating room. In the first part of this 2-part series, technical aspects of ECMO are discussed, and related expert consensus statements are provided.

Intraoperative Management of Adult Patients on Extracorporeal Membrane Oxygenation: An Expert Consensus Statement From the Society of Cardiovascular Anesthesiologists-Part II, Intraoperative Management and Troubleshooting.

In the second part of the Society of Cardiovascular Anesthesiologists Extracorporeal Membrane Oxygenation (ECMO) working group expert consensus statement, venoarterial (VA) and venovenous (VV) ECMO management and troubleshooting in the operating room are discussed. Expert consensus statements are provided about intraoperative monitoring, anesthetic drug dosing, and management of intraoperative problems in VA and VV ECMO patients.

Intraoperative Management of Adult Patients on Extracorporeal Membrane Oxygenation: an Expert Consensus Statement From the Society of Cardiovascular Anesthesiologists-Part I, Technical Aspects of Extracorporeal Membrane Oxygenation.

Extracorporeal membrane oxygenation (ECMO) is used to support patients with refractory cardiopulmonary failure. Given ECMO's increased use in adults and the fact that many ECMO patients are cared for by anesthesiologists, the Society of Cardiovascular Anesthesiologists ECMO working group created an expert consensus statement that is intended to help anesthesiologists manage adult ECMO patients who are cared for in the operating room. In the first part of this 2-part series, technical aspects of ECMO are discussed, and related expert consensus statements are provided.

Coverage of Sex Acts by Event-Driven Pre-exposure Prophylaxis: A Sub-Study of the ANRS IPERGAY Trial.

We assessed the coverage of sex acts by event-driven pre-exposure prophylaxis (ED-PrEP) over a 2-month period in 54 participants in the open label phase of the ANRS Ipergay trial. Participants received an electronic monitoring system device to record bottle openings. Self-questionnaires collected daily information on PrEP intake and sexual behavior. Intake was also estimated through returned pill counts. Full coverage of sex acts was defined as at least one pill taken both within 24 h before and within 48 h following sex. There was a strong correlation (r = - 0.92) between the number of bottle openings and returned pill counts. During the study, 42 participants (78%) practiced ED-PrEP and 12 (22%) daily PrEP with bottle openings at least 5 days/week whatever their sexual activity. Out of the 154 reported receptive anal sex acts, 81% were condomless: among them, PrEP coverage was hight: 97% among those practicing daily PrEP and 82% among those using ED-PrEP.

Ozone-derived Oxysterols Affect Liver X Receptor (LXR) Signaling: A POTENTIAL ROLE FOR LIPID-PROTEIN ADDUCTS.

When inhaled, ozone (O3) interacts with cholesterols of airway epithelial cell membranes or the lung-lining fluid, generating chemically reactive oxysterols. The mechanism by which O3-derived oxysterols affect molecular function is unknown. Our data show that in vitro exposure of human bronchial epithelial cells to O3 results in the formation of oxysterols, epoxycholesterol-α and -ß and secosterol A and B (Seco A and Seco B), in cell lysates and apical washes. Similarly, bronchoalveolar lavage fluid obtained from human volunteers exposed to O3 contained elevated levels of these oxysterol species. As expected, O3-derived oxysterols have a pro-inflammatory effect and increase NF-κB activity. Interestingly, expression of the cholesterol efflux pump ATP-binding cassette transporter 1 (ABCA1), which is regulated by activation of the liver X receptor (LXR), was suppressed in epithelial cells exposed to O3 Additionally, exposure of LXR knock-out mice to O3 enhanced pro-inflammatory cytokine production in the lung, suggesting LXR inhibits O3-induced inflammation. Using alkynyl surrogates of O3-derived oxysterols, our data demonstrate adduction of LXR with Seco A. Similarly, supplementation of epithelial cells with alkynyl-tagged cholesterol followed by O3 exposure causes observable lipid-LXR adduct formation. Experiments using Seco A and the LXR agonist T0901317 (T09) showed reduced expression of ABCA1 as compared with stimulation with T0901317 alone, indicating that Seco A-LXR protein adduct formation inhibits LXR activation by traditional agonists. Overall, these data demonstrate that O3-derived oxysterols have pro-inflammatory functions and form lipid-protein adducts with LXR, thus leading to suppressed cholesterol regulatory gene expression and providing a biochemical mechanism mediating O3-derived formation of oxidized lipids in the airways and subsequent adverse health effects.

Incidence of Connected Consciousness after Tracheal Intubation: A Prospective, International, Multicenter Cohort Study of the Isolated Forearm Technique.

BACKGROUND: The isolated forearm technique allows assessment of consciousness of the external world (connected consciousness) through a verbal command to move the hand (of a tourniquet-isolated arm) during intended general anesthesia. Previous isolated forearm technique data suggest that the incidence of connected consciousness may approach 37% after a noxious stimulus. The authors conducted an international, multicenter, pragmatic study to establish the incidence of isolated forearm technique responsiveness after intubation in routine practice. METHODS: Two hundred sixty adult patients were recruited at six sites into a prospective cohort study of the isolated forearm technique after intubation. Demographic, anesthetic, and intubation data, plus postoperative questionnaires, were collected. Univariate statistics, followed by bivariate logistic regression models for age plus variable, were conducted. RESULTS: The incidence of isolated forearm technique responsiveness after intubation was 4.6% (12/260); 5 of 12 responders reported pain through a second hand squeeze. Responders were younger than nonresponders (39 ± 17 vs. 51 ± 16 yr old; P = 0.01) with more frequent signs of sympathetic activation (50% vs. 2.4%; P = 0.03). No participant had explicit recall of intraoperative events when questioned after surgery (n = 253). Across groups, depth of anesthesia monitoring values showed a wide range; however, values were higher for responders before (54 ± 20 vs. 42 ± 14; P = 0.02) and after (52 ± 16 vs. 43 ± 16; P = 0.02) intubation. In patients not receiving total intravenous anesthesia, exposure to volatile anesthetics before intubation reduced the odds of responding (odds ratio, 0.2 [0.1 to 0.8]; P = 0.02) after adjustment for age. CONCLUSIONS: Intraoperative connected consciousness occurred frequently, although the rate is up to 10-times lower than anticipated. This should be considered a conservative estimate of intraoperative connected consciousness.

The future of biologics: applications for food allergy.

Allergic diseases affect millions worldwide, with growing evidence of an increase in allergy occurrence over the past few decades. Current treatments for allergy include corticosteroids to reduce inflammation and allergen immunotherapy; however, some subjects experience treatment-resistant inflammation or adverse reactions to these treatments, and there are currently no approved therapeutics for the treatment of food allergy. There is a dire need for new therapeutic approaches for patients with poorly controlled atopic diseases and a need to improve the safety and effectiveness of allergen immunotherapy. Improved understanding of allergy through animal models and clinical trials has unveiled potential targets for new therapies, leading to the development of several biologics to treat allergic diseases. This review focuses on the mechanisms that contribute to allergy, with an emphasis on future targets for biologics for the treatment of food allergy. These biologics include immunotherapy with novel anti-IgE antibodies and analogs, small-molecule inhibitors of cell signaling, anti-type 2 cytokine mAbs, and TH1-promoting adjuvants.

Interaction with epithelial cells modifies airway macrophage response to ozone.

The initial innate immune response to ozone (O3) in the lung is orchestrated by structural cells, such as epithelial cells, and resident immune cells, such as airway macrophages (Macs). We developed an epithelial cell-Mac coculture model to investigate how epithelial cell-derived signals affect Mac response to O3. Macs from the bronchoalveolar lavage (BAL) of healthy volunteers were cocultured with the human bronchial epithelial (16HBE) or alveolar (A549) epithelial cell lines. Cocultures, Mac monocultures, and epithelial cell monocultures were exposed to O3 or air, and Mac immunophenotype, phagocytosis, and cytotoxicity were assessed. Quantities of hyaluronic acid (HA) and IL-8 were compared across cultures and in BAL fluid from healthy volunteers exposed to O3 or air for in vivo confirmation. We show that Macs in coculture had increased markers of alternative activation, enhanced cytotoxicity, and reduced phagocytosis compared with Macs in monoculture that differed based on coculture with A549 or 16HBE. Production of HA by epithelial cell monocultures was not affected by O3, but quantities of HA in the in vitro coculture and BAL fluid from volunteers exposed in vivo were increased with O3 exposure, indicating that O3 exposure impairs Mac regulation of HA. Together, we show epithelial cell-Mac coculture models that have many similarities to the in vivo responses to O3, and demonstrate that epithelial cell-derived signals are important determinants of Mac immunophenotype and response to O3.

Regulation and activity of secretory leukoprotease inhibitor (SLPI) is altered in smokers.

A hallmark of cigarette smoking is a shift in the protease/antiprotease balance, in favor of protease activity. However, it has recently been shown that smokers have increased expression of a key antiprotease, secretory leukoprotease inhibitor (SLPI), yet the mechanisms involved in SLPI transcriptional regulation and functional activity of SLPI remain unclear. We examined SLPI mRNA and protein secretion in differentiated nasal epithelial cells (NECs) and nasal lavage fluid (NLF) from nonsmokers and smokers and demonstrated that SLPI expression is increased in NECs and NLF from smokers. Transcriptional regulation of SLPI expression was confirmed using SLPI promoter reporter assays followed by chromatin immunoprecipitation. The role of STAT1 in regulating SLPI expression was further elucidated using WT and stat1(-/-) mice. Our data demonstrate that STAT1 regulates SLPI transcription in epithelial cells and slpi protein in the lungs of mice. Additionally, we reveal that NECs from smokers have increased STAT1 mRNA/protein expression. Finally, we demonstrate that SLPI contained in the nasal mucosa of smokers is proteolytically cleaved but retains functional activity against neutrophil elastase. These results demonstrate that smoking enhances expression of SLPI in NECs in vitro and in vivo, and that this response is regulated by STAT1. In addition, despite posttranslational cleavage of SLPI, antiprotease activity against neutrophil elastase is enhanced in smokers. Together, our findings show that SLPI regulation and activity is altered in the nasal mucosa of smokers, which could have broad implications in the context of respiratory inflammation and infection.

Air toxics and epigenetic effects: ozone altered microRNAs in the sputum of human subjects.

Ozone (O3) is a criteria air pollutant that is associated with numerous adverse health effects, including altered respiratory immune responses. Despite its deleterious health effects, possible epigenetic mechanisms underlying O3-induced health effects remain understudied. MicroRNAs (miRNAs) are epigenetic regulators of genomic response to environmental insults and unstudied in relationship to O3 inhalation exposure. Our objective was to test whether O3 inhalation exposure significantly alters miRNA expression profiles within the human bronchial airways. Twenty healthy adult human volunteers were exposed to 0.4 ppm O3 for 2 h. Induced sputum samples were collected from each subject 48 h preexposure and 6 h postexposure for evaluation of miRNA expression and markers of inflammation in the airways. Genomewide miRNA expression profiles were evaluated by microarray analysis, and in silico predicted mRNA targets of the O3-responsive miRNAs were identified and validated against previously measured O3-induced changes in mRNA targets. Biological network analysis was performed on the O3-associated miRNAs and mRNA targets to reveal potential associated response signaling and functional enrichment. Expression analysis of the sputum samples revealed that O3 exposure significantly increased the expression levels of 10 miRNAs, namely miR-132, miR-143, miR-145, miR-199a*, miR-199b-5p, miR-222, miR-223, miR-25, miR-424, and miR-582-5p. The miRNAs and their predicted targets were associated with a diverse range of biological functions and disease signatures, noted among them inflammation and immune-related disease. The present study shows that O3 inhalation exposure disrupts select miRNA expression profiles that are associated with inflammatory and immune response signaling. These findings provide novel insight into epigenetic regulation of responses to O3 exposure.

Subarachnoid extension of primary intracerebral hemorrhage is associated with fevers.

BACKGROUND: Extension of hemorrhage into the subarachnoid space in primary intracerebral hemorrhage (ICH) has recently been associated with poor outcomes, although the mechanisms underlying that association are uncertain. The objectives of this study are to confirm the association between fever and poor outcomes after ICH, and to determine whether subarachnoid hemorrhage extension (SAHE) is associated with fevers. METHODS: Patients with primary ICH were enrolled into a prospective registry between December 2006 and July 2012. SAHE was identified on imaging by blinded expert reviewers. Patient temperature was recorded hourly, and we defined febrile as any recorded temperature >38 °C within the first 14 days. Regression models were developed to test whether fever was associated with poor outcome and whether the occurrence of SAHE was a predictor of fever. RESULTS: Of the 235 patients studied, 39.7 % had SAHE and 58 % had fever. Fever was associated with higher modified Rankin scores at 3 months (odds ratio, OR 1.8 [1.04-3.12], p = 0.04) after adjustment for ICH score. SAHE was a predictor of fevers (OR 1.82 [95 % confidence interval 1.02-3.24], p = 0.04) after adjustment for ICH score, and remained significant after adjustment for other confounders like pneumonia identified in the univariate analysis. CONCLUSIONS: Our data confirm the deleterious effect of fever on the outcome of patients with ICH and show that SAHE is an independent predictor of fever after ICH. SAHE may provoke dysfunctional thermoregulation similar to what is observed after aneurysmal subarachnoid hemorrhage, creating mechanistic pathway between SAHE and poor functional outcomes.