Search

E-cigarette use has rapidly increased as an alternative means of nicotine delivery by heated aerosolization. Recent studies demonstrate nicotine-containing e-cigarette aerosols can have immunosuppressive and pro-inflammatory effects, but it remains unclear how e-cigarettes and the constituents of e-liquids may impact acute lung injury and the development of acute respiratory distress syndrome caused by viral pneumonia. Therefore, in these studies, mice were exposed one hour per day over nine consecutive days to aerosol generated by the clinically-relevant tank-style Aspire Nautilus aerosolizing e-liquid containing a mixture of vegetable glycerin and propylene glycol (VG/PG) with or without nicotine. Exposure to the nicotine-containing aerosol resulted in clinically-relevant levels of plasma cotinine, a nicotine-derived metabolite, and an increase in the pro-inflammatory cytokines IL-17A, CXCL1, and MCP-1 in the distal airspaces. Following the e-cigarette exposure, mice were intranasally inoculated with influenza A virus (H1N1 PR8 strain). Exposure to aerosols generated from VG/PG with and without nicotine caused greater influenza-induced production in the distal airspaces of the pro-inflammatory cytokines IFN-γ, TNFα, IL-1β, IL-6, IL-17A, and MCP-1 at 7 days post inoculation (dpi). Compared to the aerosolized carrier VG/PG, in mice exposed to aerosolized nicotine there was a significantly lower amount of Mucin 5 subtype AC (MUC5AC) in the distal airspaces and significantly higher lung permeability to protein and viral load in lungs at 7 dpi with influenza. Additionally, nicotine caused relative downregulation of genes associated with ciliary function and fluid clearance and an increased expression of pro-inflammatory pathways at 7 dpi. These results show that (1) the e-liquid carrier VG/PG increases the pro-inflammatory immune responses to viral pneumonia and that (2) nicotine in an e-cigarette aerosol alters the transcriptomic response to pathogens, blunts host defense mechanisms, increases lung barrier permeability, and reduces viral clearance during influenza infection. In conclusion, acute exposure to aerosolized nicotine can impair clearance of viral infection and exacerbate lung injury, findings that have implications for the regulation of e-cigarette products.

Rationale: Cigarette smoke exposure is associated with an increased risk of developing acute respiratory distress syndrome (ARDS) in trauma, transfusion, and nonpulmonary sepsis. It is unknown whether this relationship exists in the general sepsis population. Furthermore, it is unknown if patients with ARDS have differences in underlying biology based on smoking status. Objectives: To assess the relationship between cigarette smoke exposure and ARDS in sepsis and identify tobacco-related biomarkers of lung injury. Methods: We studied a prospective cohort of 592 patients with sepsis from 2009 to 2017. Plasma cotinine and urine NNAL [urine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol] were measured to categorize smoking status. Plasma biomarkers of inflammation and lung injury were measured, including in a smaller cohort of trauma patients with ARDS to increase generalizability. Measurements and Main Results: Passive and active smoking were associated with increased odds of developing ARDS in patients with sepsis. Among patients with sepsis and ARDS, active cigarette smokers were younger and had lower severity of illness than nonsmokers. Patients with ARDS with cigarette smoke exposure had lower plasma levels of IL-8 (P = 0.01) and sTNFR-1 (soluble tumor necrosis factor 1; P = 0.01) compared with those without exposure. Similar biomarker patterns were observed in blunt trauma patients with ARDS. Conclusions: Passive and active smoking are associated with an increased risk of developing ARDS in patients with pulmonary and nonpulmonary sepsis. Among patients with ARDS, those with cigarette smoke exposure have less systemic inflammation, while active smokers also have lower severity of illness compared with nonsmokers, suggesting that smoking contributes to biological heterogeneity in ARDS.

BackgroundLimited studies have functionally evaluated the heterogeneity in early ex vivo immune responses during sepsis. Our aim was to characterize early sepsis ex vivo functional immune response heterogeneity by studying whole blood endotoxin responses and derive a transcriptional metric of ex vivo endotoxin response.MethodsBlood collected within 24 h of hospital presentation from 40 septic patients was divided into two fractions and incubated with media (unstimulated) or endotoxin. Supernatants and cells were isolated, and responses measured using: supernatant cytokines, lung endothelial permeability after supernatant exposure, and RNA expression. A transcriptomic signature was derived in unstimulated cells to predict the ex vivo endotoxin response. The signature was tested in a separate cohort of 191 septic patients to evaluate for association with clinical outcome. Plasma biomarkers were quantified to measure in vivo host inflammation.ResultsEx vivo response to endotoxin varied and was unrelated to immunosuppression, white blood cell count, or the causative pathogen. Thirty-five percent of patients demonstrated a minimal response to endotoxin, suggesting early immunosuppression. High ex vivo cytokine production by stimulated blood cells correlated with increased in vitro pulmonary endothelial cell permeability and was associated with attenuated in vivo host inflammation. A four-gene signature of endotoxin response detectable without the need for a functional assay was identified. When tested in a separate cohort of septic patients, its expression was inversely associated with hospital mortality.ConclusionsAn attenuated ex vivo endotoxin response in early sepsis is associated with greater host in vivo inflammation and a worse clinical outcome.

BackgroundEnrichment strategies improve therapeutic targeting and trial efficiency, but enrichment factors for sepsis trials are lacking. We determined whether concentrations of soluble tumor necrosis factor receptor-1 (sTNFR1), interleukin-8 (IL8), and angiopoietin-2 (Ang2) could identify sepsis patients at higher mortality risk and serve as prognostic enrichment factors.MethodsIn a multicenter prospective cohort study of 400 critically ill septic patients, we derived and validated thresholds for each marker and expressed prognostic enrichment using risk differences (RD) of 30-day mortality as predictive values. We then used decision curve analysis to simulate the prognostic enrichment of each marker and compare different prognostic enrichment strategies.Measurements and main resultsAn admission sTNFR1 concentration > 8861 pg/ml identified patients with increased mortality in both the derivation (RD 21.6%) and validation (RD 17.8%) populations. Among immunocompetent patients, an IL8 concentration > 94 pg/ml identified patients with increased mortality in both the derivation (RD 17.7%) and validation (RD 27.0%) populations. An Ang2 level > 9761 pg/ml identified patients at 21.3% and 12.3% increased risk of mortality in the derivation and validation populations, respectively. Using sTNFR1 or IL8 to select high-risk patients improved clinical trial power and efficiency compared to selecting patients with septic shock. Ang2 did not outperform septic shock as an enrichment factor.ConclusionsThresholds for sTNFR1 and IL8 consistently identified sepsis patients with higher mortality risk and may have utility for prognostic enrichment in sepsis trials.

BackgroundTreatment with bone-marrow-derived mesenchymal stromal cells (MSCs) has shown benefits in preclinical models of acute respiratory distress syndrome (ARDS). Safety has not been established for administration of MSCs in critically ill patients with ARDS. We did a phase 2a trial to assess safety after administration of MSCs to patients with moderate to severe ARDS.MethodsWe did a prospective, double-blind, multicentre, randomised trial to assess treatment with one intravenous dose of MSCs compared with placebo. We recruited ventilated patients with moderate to severe ARDS (ratio of partial pressure of oxygen to fractional inspired oxygen

People with endometriosis use cannabis to manage their symptoms. This study aimed to identify costs, modes of administration, product composition, and self‐reported effectiveness for those accessing medicinal cannabis in Australia. There were 192 survey responses analysed. Most (63.5%) used a 'cannabis clinic' doctor, incurring an initial consultation cost of $100–$200+ (10.2% Medicare bulk‐billed) and median cannabinoid medicine costs of $300AUD per month. Cost was a major barrier to access, necessitating reducing dosage (76.1%) and/or consuming illicit cannabis (42.9%), despite a prescription. Most (77%) medical consumers used two or more cannabis products, with delta‐9‐tetrahydrocannabinol predominant oil and flower products most frequently prescribed. [ABSTRACT FROM AUTHOR]

Aim: Uterus transplantation (UTx) is an emerging treatment option for women with uterine factor infertility (UFI) or the absence of a functional uterus. This is the study protocol for the first human UTx clinical trial in Australia. Materials and Methods: This protocol outlines the approved training program used to plan, diagnose, screen, and treat patients who may be eligible for UTx using living and deceased donors. This multi‐site clinical research study includes three tertiary hospital sites within New South Wales (NSW), Australia – Prince of Wales, Royal Hospital for Women and Westmead Hospitals. Our UTx protocol is based on that used by our collaborative partner, the inaugural UTx team in Gothenburg, Sweden. The Swedish UTx team provides ongoing preceptorship for the Australian UTx team. Ethics approval for six UTx procedures using living or deceased donors (Western Sydney Local Health District Human Research Ethics Committee: 2019/ETH138038) was granted in 2020. Results: Results from surgeries and live births will be published. Data will be prospectively entered into the registry of the International Society of Uterus Transplantation (ISUTx), a sub‐section of The Transplantation Society (TTS). Trial Id: ACTRN12622000917730. Discussion: A multidisciplinary research team has been formed between three tertiary hospitals in Sydney – The Royal Hospital for Women, Prince of Wales and Westmead Hospitals; and with the Swedish UTx, University of Gothenburg. The Swedish team pioneered animal and human UTx studies since 1998, including publishing the first live birth after UTx. (1) This Australian trial commenced in January 2023. Conclusion: Uterus transplantation gives women with UFI the opportunity to be gestational and genetic mothers. It is a complex procedure for both the donor and recipient, with medical and surgical risks. An extensive multidisciplinary approach is required to optimise patient safety and graft outcomes. This protocol outlines our Australian UTx team strategy for screening, recruitment, surgical approach, and clinical management of UTx recipients and donors. [ABSTRACT FROM AUTHOR]

Background: Microvascular scarring compromises the functionality of the endometrium, and vascular flow at the junctional zone (JZ) may be the key to understanding poor reproductive outcomes in women with Asherman syndrome (AS). Aims: To investigate whether vascular perfusion of the uterus, measured by dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) is impaired in women with intrauterine adhesions (IUA) and AS. Materials and Methods: A prospective observational cohort pilot study of 23 women with IUA treated with hysteroscopic synecholysis and a control group of two patients with cervix cancer were subject to DCE‐MRI with gadolinium to assess uterine vascularity. Twelve regions of interest (ROIs) were allocated on the DCE‐MRI image incorporating the JZ, with control ROI placed at the psoas muscle. Individual ROIs were compared to the mean total perfusion (TP) in the same uterus. Pre‐ and post‐operative perfusion analyses were performed on five women. Receiver operator curves (ROC) were used to analyse MRI as a predictor of IUA. Results: There was no significant difference in perfusion; a trend toward reduced perfusion was observed in women with IUA compared to the controls. The ROC was predictive of higher‐grade and inoperable IUA. Conclusions: Reduced perfusion on DCE‐MRI as assessed by ROC predicted higher‐stage AS. The results of this study support further investigation of DCE‐MRI as a prognostic tool for AS prior to surgical intervention to assist in providing prognostic guidance for women suffering from AS. [ABSTRACT FROM AUTHOR]

Evidence is accumulating that exposure to cigarette smoke (CS) increases the risk of developing acute respiratory distress syndrome (ARDS). Streptococcus pneumoniae is the most common cause of bacterial pneumonia, which in turn is the leading cause of ARDS. Chronic smokers have increased rates of pneumococcal colonization and develop more severe pneumococcal pneumonia than nonsmokers; yet mechanistic connections between CS exposure, bacterial pneumonia, and ARDS pathogenesis remain relatively unexplored. We exposed mice to 3 wk of moderate whole body CS or air, followed by intranasal inoculation with an invasive serotype of S. pneumoniae. CS exposure alone caused no detectable lung injury or bronchoalveolar lavage (BAL) inflammation. During pneumococcal infection, CS-exposed mice had greater survival than air-exposed mice, in association with reduced systemic spread of bacteria from the lungs. However, when mice were treated with antibiotics after infection to improve clinical relevance, the survival benefit was lost, and CS-exposed mice had more pulmonary edema, increased numbers of BAL monocytes, and elevated monocyte and lymphocyte chemokines. CS-exposed antibiotic-treated mice also had higher serum surfactant protein D and angiopoietin-2, consistent with more severe lung epithelial and endothelial injury. The results indicate that acute CS exposure enhances the recruitment of immune cells to the lung during bacterial pneumonia, an effect that may provide microbiological benefit but simultaneously exposes the mice to more severe inflammatory lung injury. The inclusion of antibiotic treatment in preclinical studies of acute lung injury in bacterial pneumonia may enhance clinical relevance, particularly for future studies of current or emerging tobacco products.

IntroductionCigarette smoking (CS) remains a major public health concern and has recently been associated with an increased risk of developing acute respiratory distress syndrome (ARDS). Bronchoalveolar lavage (BAL) experiments in human volunteers have demonstrated that active smokers develop increased alveolar-epithelial barrier permeability to protein after inhaling lipopolysaccharide (LPS). Here we tested the hypothesis that short-term whole-body CS exposure would increase LPS-induced lung edema in mice.MethodsAdult mice were exposed in a Teague TE-10 machine to CS from 3R4F cigarettes at 100 mg/m3 total suspended particulates for 12 days, then given LPS or saline intratracheally. Control mice were housed in the same room without CS exposure. Post-mortem measurements included gravimetric lung water and BAL protein, cell counts, and lung histology. Cytokines were measured in lung homogenate by ELISA and in plasma by Luminex and ELISA.ResultsIn CS-exposed mice, intratracheal LPS caused greater increases in pulmonary edema by gravimetric measurement and histologic scoring. CS-exposed mice also had an increase in BAL neutrophilia, lung IL-6, and plasma CXCL9, a T-cell chemoattractant. Intratracheal LPS concentrated blood hemoglobin to a greater degree in CS-exposed mice, consistent with an increase in systemic vascular permeability.ConclusionsThese results demonstrate that CS exposure in endotoxin injured mice increases the severity of acute lung injury. The increased lung IL-6 in CS-exposed LPS-injured mice indicates that this potent cytokine, previously shown to predict mortality in patients with ARDS, may play a role in exacerbating lung injury in smokers and may have utility as a biomarker of tobacco-related lung injury.ImplicationsOur results suggest that short-term CS exposure at levels that cause no overt lung injury may still prime the lung for acute inflammatory damage from a "second hit", a finding that mirrors the increased risk of developing ARDS in patients who smoke. This model may be useful for evaluating the acute pulmonary toxicity of existing and/or novel tobacco products and identifying biomarkers of tobacco-related lung injury.

RationaleCigarette smoke exposure is associated with an increased risk of the acute respiratory distress syndrome (ARDS); however, the mechanisms underlying this relationship remain largely unknown.ObjectiveTo assess pathways of lung injury and inflammation in smokers and non-smokers with and without lipopolysaccharide (LPS) inhalation using established biomarkers.MethodsWe measured plasma and bronchoalveolar lavage (BAL) biomarkers of inflammation and lung injury in smokers and non-smokers in two distinct cohorts of healthy volunteers, one unstimulated (n=20) and one undergoing 50 μg LPS inhalation (n=30).Measurements and main resultsAfter LPS inhalation, cigarette smokers had increased alveolar-capillary membrane permeability as measured by BAL total protein, compared with non-smokers (median 274 vs 208 μg/mL, p=0.04). Smokers had exaggerated inflammation compared with non-smokers, with increased BAL interleukin-1β (p=0.002), neutrophils (p=0.02), plasma interleukin-8 (p=0.003), and plasma matrix metalloproteinase-8 (p=0.006). Alveolar epithelial injury after LPS was more severe in smokers than non-smokers, with increased plasma (p=0.04) and decreased BAL (p=0.02) surfactant protein D. Finally, smokers had decreased BAL vascular endothelial growth factor (VEGF) (p

Background: Laparoscopic reverse submucosal dissection (LRSD) is a standardised surgical technique for removal of rectosigmoid endometriosis which optimises the anatomical dissection plane for excision of endometriotic nodules. Aim: This cohort study assesses the outcomes of the first cohort of women treated by LRSD, for deeply infiltrating rectosigmoid endometriosis. Materials and Methods: Primary outcomes assessed were complication rate as defined by the Clavien–Dindo system, and completion of the planned LRSD. Secondary outcomes include mucosal breach, specimen margin involvement, length of hospital admission, and a comparison of pre‐operative and post‐operative pain, bowel function and quality of life surveys. These included the Endometriosis Health Profile Questionnaire (EHP‐30), the Knowles‐Eccersley‐Scott Symptom Questionnaire (KESS) and the Wexner scale. Results: Of 19 patients treated, one required a segmental resection. The median length of hospital admission was two days (range 1–5) and no post‐operative complications occurred. Median pain visual analogue scales (scale 0–10) were higher prior to surgery (dysmenorrhoea 9.0, dyspareunia 7.5, dyschezia 9.0, pelvic pain 6.0) compared to post‐surgical median scores (dysmenorrhoea 5.0, dyspareunia 4.0, dyschezia 2.0, pelvic pain 4.0) at a median of six months (range 4–32). Quality of life studies suggested improvement following surgery with pre‐operative median EHP‐30 and KESS scores (EHP‐30: 85 (5–106), KESS score 9 (0–20)) higher than post‐operative scores (EHP‐30: 48.5 (0–80), KESS score: 3 (0–19)). Conclusion: This series highlights the feasibility of LRSD with low associated morbidity as a progression of partial thickness discoid excision (rectal shaving) for the treatment of rectosigmoid deep infiltrating endometriosis. [ABSTRACT FROM AUTHOR]

To determine the effectiveness of multimodal physiotherapy in an interdisciplinary setting for the treatment of women with persistent pelvic pain (PPP) who have concomitant pelvic floor tension myalgia (PFTM). Prospective cohort study with 2-year follow-up at an interdisciplinary tertiary referral centre for PPP and endometriosis. Thirty-four women with PPP of gynaecological origin >6 months duration and PFTM on examination underwent individualised physiotherapy. Outcome measures were pain, measured by Visual Analogue Scale (VAS) on a scale of 0–100, quality of life assessed by AQoL-6D score range 0.0–1.0 and sexual function measured by the Female Sexual Function Index (FSFI). Participants attended a median of 4 physiotherapy sessions (range 1–11) with the median treatment duration 7 weeks (range: 1–16 weeks). Results at 3 months demonstrated a significant decrease in VAS scores for dysmenorrhoea (72.5 vs. 52, p=.015), low back pain (55 vs. 47.5, p=.004), dyschezia (45 vs. 30.5, p=.031), abdominal pain (52 vs. 36.5, p=.049) and non-menstrual pain (53 vs. 41, p=.018) with a non-significant decrease in dyspareunia (57 vs. 50, p=.365). At 2 years, improvements in dysmenorrhoea persisted (72.5 vs. 60, p=.002) and dyspareunia was significantly improved (57 vs. 36, p=.033). For the 11/24 (46%) women who had no medical or surgical co-intervention throughout the study duration, quality of life score was improved at 2 years compared with baseline (0.72 vs. 0.84, p=.002). Physiotherapy may improve certain pain outcomes in the short and long term. It offers an additional treatment option for women with PPP. [ABSTRACT FROM AUTHOR]