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Amidst growing global acceptance of medicinal cannabinoids as a potential therapeutic interest in cannabidiol (CBD) is increasing. In Australia in 2020, a government inquiry examined the barriers that the public are experiencing in accessing medicinal cannabis. A number of recommendations to improve access were made. In response to these recommendations, the Australian therapeutics regulatory authority down-scheduled CBD from Prescription Only (Schedule 4) to Pharmacist Only (Schedule 3). As a group of early to mid-career researchers of the Australian Centre for Cannabinoid Clinical and Research Excellence (ACRE), we propose some considerations in relation to over-the-counter availability of CBD and opportunities to improve knowledge about its potential therapeutic benefits alongside its increased uptake.

Background In patients with bronchiectasis, airway clearance techniques (ACTs) are important management strategies. Research Question What are the differences in patients with bronchiectasis and a productive cough who used ACTs and those who did not? What was the assessment of bronchiectasis exacerbation frequency and change in pulmonary function at 1-year follow up? Study Design and Methods Adult patients with bronchiectasis and a productive cough in the United States Bronchiectasis and NTM Research Registry were included in the analyses. ACTs included the use of instrumental devices and manual techniques. Stratified analyses of demographic and clinical characteristics were performed by use of ACTs at baseline and follow up. The association between ACT use and clinical outcomes was assessed with the use of unadjusted and adjusted multinomial logistic regression models. Results Of the overall study population (n = 905), 59% used ACTs at baseline. A greater proportion of patients who used ACTs at baseline and follow up continuously had Pseudomonas aeruginosa (47% vs 36%; P = .021) and experienced an exacerbation (81% vs 59%; P Interpretation In patients with bronchiectasis and a productive cough, ACTs are used more often if the patients have experienced a prior exacerbation, hospitalization for pulmonary illness, or had P aeruginosa. There is a significant reduction in the use of ACTs at 1-year follow up. The odds of the development of a bronchiectasis exacerbation are higher in those patients who use ACTs continuously, which suggests more frequent use in an ill bronchiectasis population.

Nerve infiltration in the tumor microenvironment is emerging as a promoter of cancer progression that could be targeted in therapies, but the mechanisms initiating tumor innervation remain to be elucidated. Here we report that endoplasmic reticulum (ER) stress in cancer cells is transmitted to neuronal cells, resulting in neurite outgrowth and tumor innervation. In vitro, the induction of ER stress in various human cancer cells resulted in the synthesis and release of the precursor for brain-derived neurotrophic factor (proBDNF) through a mechanism dependent on the transcription factor X-box binding protein 1 (XBP1). Cancer cell-released proBDNF was found to mediate the transmission of ER stress to neurons, resulting in the stimulation of neurite outgrowth. Next-generation sequencing indicated the increased expression of the Egl-9 family hypoxia inducible factor 3 (EGLN3) that was mediated by c-MYC and necessary to neurite outgrowth induced by proBDNF. In orthotopic tumor xenograft, ER stress stimulated XBP1 and proBDNF expression as well as tumor innervation. Anti-proBDNF antibody inhibited both tumor innervation and cancer progression induced by ER stress. Interestingly, the chemotherapeutic drug 5-Fluorouracil (5-FU) was found to induce ER stress and tumor innervation, and this effect was inhibited by anti-proBDNF antibody. Finally, in human tumors, cancer tissues with nerve infiltration expressed high XBP1 and proBDNF while EGLN3 was upregulated in infiltrated nerves. This study reveals that ER stress participates in tumor innervation through the release of proBDNF and that targeting this pathway could be used in future therapies.

The safety of electronic cigarettes (e-cigarettes) is a major topic of discussion. The key goals of this study were to examine the contents of e-cigarette vapor and determine if nicotine altered inflammatory responses against respiratory syncytial virus (RSV) infection. E-cigarette vapor was passed through a hollow 3D-model of an adult lung, and gas chromatography detected over 50 compounds passed through the 3D model, including nicotine, propylene glycol (PG), ethanol, methanol, and diacetyl. The murine alveolar macrophage cell line MH-S cells were exposed to nicotine and e-cigarette vapor with and without nicotine. Nicotine significantly induced the expression of matrix metalloprotease (Mmp) 12 and reduced expression of Ifn&beta, and Tnf&alpha, To examine the role of nicotine in lung defense against RSV infection, A/J mice were exposed to PBS, e-cigarette vapor with and without nicotine for 2 months before RSV infection. E-cigarette vapor did not influence RSV infection-induced animal weight loss, RSV infectivity, airway hyperresponsiveness during methacholine challenge, or immune cell infiltration into the lungs. However, e-cigarette vapor containing nicotine enhanced obstruction and induced secretion of MMP12 and reduced levels of Ifn&beta, and TNF&alpha, In conclusion, nicotine in vaping products modulates immune responses that may impact the lungs during a respiratory infection.

Background: Increasing numbers of patients are being diagnosed with bronchiectasis, yet much remains to be elucidated about this heterogeneous patient population. We sought to determine the relationship between nutrition and health outcomes in non-cystic fibrosis (non-CF) bronchiectasis, using data from the U.S. Bronchiectasis Nontuberculous Mycobacterial Research Registry (U.S. BRR). Methods: This was a retrospective, observational, longitudinal study using 5-year follow-up data from the BRR. Bronchiectasis was confirmed on computed tomography (CT). We stratified patients into nutrition categories using body mass index (BMI), and correlated BMI to markers of disease severity. Results: Overall, n = 496 patients (mean age 64.6­ ± 13 years; 83.3% female) were included. At baseline 12.3% (n = 61) were underweight (BMI < 18.5kg/m(2)), 63.9% (n = 317) had normal weight (BMI ≥ 18.5kg/m(2) and

Background Cannabidiol (CBD) confers therapeutic effects in some neurological disorders via modulation of inflammatory, oxidative and cell-signalling pathways. However, CBD is lipophilic and highly photooxidative with low oral bioavailability in plasma and brain. In this study, we aimed to design and test a CBD microencapsulation method as a drug delivery strategy to improve the absorption of CBD. Additionally, we evaluated the brain uptake of CBD capsules when administered alongside capsules containing a permeation-modifying bile acid, deoxycholic acid (DCA). Methods Microcapsules containing either CBD or DCA were formed using the ionic gelation method with 1.5% sodium alginate formulations and 100 mM calcium chloride. C57BL/6J wild type mice randomly assigned to three treatment groups (3–4 mice per group) were administered CBD in the following preparations: 1) CBD capsules, 2) CBD capsules + DCA capsules and 3) naked CBD oil (control). To assess the short-term bioavailability of CBD, plasma and brain samples were collected at 0.3, 1 and 3 hours post administration and CBD levels were analysed with liquid chromatography mass spectrometer. Results We produced spherical capsules at 400 ± 50 μm in size. The CBD capsules were calculated to have a drug loading of 2% and an encapsulation efficiency of 23%. Mice that received CBD capsules + DCA capsules showed a 40% and 47% increase in CBD plasma concentration compared to mice on CBD capsules and naked CBD oil, respectively. Furthermore, the CBD capsules + DCA capsules group showed a 48% and 25% increase in CBD brain concentration compared to mice on CBD capsules and naked CBD oil, respectively. In mice treated with CBD capsules + DCA capsules, the brain CBD concentration peaked at 0.3 hours with a 300% increased availability compared to CBD capsules and naked CBD oil groups, which peaked at 1 hour after administration. Conclusions The microencapsulation method combined with a permeation enhancer, DCA increased the short-term bioavailability of CBD in plasma and brain.

Excessive neutrophil degranulation is a common feature of many inflammatory disorders, including alpha-1 antitrypsin (AAT) deficiency. Our group has demonstrated that phospholipid transfer protein (PLTP) prevents neutrophil degranulation but serine proteases, which AAT inhibits, cleave PLTP in diseased airways. We propose to identify if airway PLTP activity can be restored by AAT augmentation therapy and how PLTP subdues degranulation of neutrophils in AAT deficient subjects. Airway PLTP activity was lower in AAT deficient patients but elevated in the airways of patients on augmentation therapy. Functional AAT protein (from PiMM homozygotes) prevented PLTP cleavage unlike its mutated ZZ variant (PiZZ). PLTP lowered leukotriene B4 induced degranulation of primary, secondary and tertiary granules from neutrophils from both groups (n = 14/group). Neutrophils isolated from Pltp knockout mice have enhance neutrophil degranulation. Both AAT and PLTP reduced neutrophil degranulation and superoxide production, possibly though their inhibition of the Src tyrosine kinase, Hck. Src kinase inhibitors saracatinib and dasatinib reduced neutrophil degranulation and superoxide production. Therefore, AAT protects PLTP from proteolytic cleavage and both AAT and PLTP mediate degranulation, possibly via Hck tyrosine kinase inhibition. Deficiency of AAT could contribute to reduced lung PLTP activity and elevated neutrophil signaling associated with lung disease.

Rationale: Staphylococcus aureus is commonly cultured from the sputum of patients with bronchiectasis; however, little is known about the prevalence of the organism in these patients, the character...

Background Non-cystic fibrosis bronchiectasis ("bronchiectasis") is a chronic inflammatory lung disease often associated with nontuberculous mycobacteria (NTM) infection. Very little data exist to guide bronchiectasis management decisions. We sought to describe patterns of inhaled corticosteroid (ICS) and antibiotic therapy in the United States. Methods We invited 2,000 patients through NTM Info & Research (NTMir) to complete an anonymous electronic survey. We separately queried baseline clinical and laboratory data from the US Bronchiectasis and NTM Research Registry (BRR). Results Among 511 NTMir survey responders with bronchiectasis, whose median age was 67 years, 85 (17%) reported asthma and 99 (19%) reported COPD. History of ICS use was reported by 282 (55%), 171 (61%) of whom were treated 1 year or longer, and 150 (53%) were currently taking ICSs. Fewer reported ever taking azithromycin for non-NTM bronchiectasis (203 responders [40%]) or inhaled tobramycin (78 responders [15%]). The median age of 1,912 BRR patients was 69 years; 528 (28%) had asthma and 360 (19%) had COPD. Among 740 patients (42%) without NTM, 314 were taking ICSs at baseline. Among patients without NTM who were taking ICSs, only 178 (57%) had a concurrent diagnosis of COPD or asthma that could explain ICS use. Fewer were taking suppressive macrolides (96 patients [13%]), and of the 70 patients (10%) taking inhaled suppressive antibiotics, 48 (68%) had chronic Pseudomonas aeruginosa infection. Conclusions ICS use was common in two national samples of patients with bronchiectasis, with relatively few patients taking suppressive antibiotic therapies. Further research is needed to clarify the safety and effectiveness of these therapies in patients with bronchiectasis.

Objectives We sought to describe the characteristics of adult patients with bronchiectasis enrolled in the US Bronchiectasis Research Registry (BRR). Methods The BRR is a database of patients with non-cystic-fibrosis bronchiectasis (NCFB) enrolled at 13 sites in the United States. Baseline demographic, spirometric, imaging, microbiological, and therapeutic data were entered into a central Internet-based database. Patients were subsequently analyzed by the presence of NTM. Results We enrolled 1,826 patients between 2008 and 2014. Patients were predominantly women (79%), white (89%), and never smokers (60%), with a mean age of 64 ± 14 years. Sixty-three percent of the patients had a history of NTM disease or NTM isolated at baseline evaluation for entry into the BRR. Patients with NTM were older, predominantly women, and had bronchiectasis diagnosed at a later age than those without NTM. Gastroesophageal reflux disease (GERD) was more common in those with NTM, whereas asthma, primary immunodeficiency, and primary ciliary dyskinesia were more common in those without NTM. Fifty-one percent of patients had spirometric evidence of airflow obstruction. Patients with NTM were more likely to have diffusely dilated airways and tree-in-bud abnormalities. Pseudomonas and Staphylococcus aureus isolates were cultured less commonly in patients with NTM. Bronchial hygiene measures were used more often in those with NTM, whereas antibiotics used for exacerbations, rotating oral antibiotics, steroid use, and inhaled bronchodilators were more commonly used in those without NTM. Conclusions Adult patients with bronchiectasis enrolled in the US BRR are described, with differences noted in demographic, radiographic, microbiological, and treatment variables based on stratification of the presence of NTM.

In patients with bronchiectasis, airway clearance techniques (ACTs) are important management strategies.What are the differences in patients with bronchiectasis and a productive cough who used ACTs and those who did not? What was the assessment of bronchiectasis exacerbation frequency and change in pulmonary function at 1-year follow up?Adult patients with bronchiectasis and a productive cough in the United States Bronchiectasis and NTM Research Registry were included in the analyses. ACTs included the use of instrumental devices and manual techniques. Stratified analyses of demographic and clinical characteristics were performed by use of ACTs at baseline and follow up. The association between ACT use and clinical outcomes was assessed with the use of unadjusted and adjusted multinomial logistic regression models.Of the overall study population (n = 905), 59% used ACTs at baseline. A greater proportion of patients who used ACTs at baseline and follow up continuously had Pseudomonas aeruginosa (47% vs 36%; P = .021) and experienced an exacerbation (81% vs 59%; P .0001) or hospitalization for pulmonary illness (32% vs 22%; P = .001) in the prior two years, compared with those patients who did not use ACTs. Fifty-eight percent of patients who used ACTs at baseline did not use ACTs at 1-year follow up. There was no significant change in pulmonary function for those who used ACTs at follow up, compared with baseline. Patients who used ACTs at baseline and follow up had greater odds for experiencing exacerbations at follow up compared with those patients who did not use ACTs.In patients with bronchiectasis and a productive cough, ACTs are used more often if the patients have experienced a prior exacerbation, hospitalization for pulmonary illness, or had P aeruginosa. There is a significant reduction in the use of ACTs at 1-year follow up. The odds of the development of a bronchiectasis exacerbation are higher in those patients who use ACTs continuously, which suggests more frequent use in an ill bronchiectasis population.

Objective: This study compares and contrasts the clinical features of non-cystic fibrosis bronchiectasis with 3 uncommon disorders known to be associated with bronchiectasis but with distinctly different underlying defined pathophysiologic derangements, namely severe alpha-1 antitrypsin deficiency (AATD), common variable immunodeficiency (CVI) and primary ciliary dyskinesia (PCD). Methods: The Bronchiectasis Research Registry provides a central database for studying patients with non-cystic fibrosis bronchiectasis. This report consists of information from 13 U.S. sites pertaining to the 3 study diagnoses. Patients with AATD (SZ and ZZ phenotypes only), CVI (patients with IgG≤500), PCD (history of physician diagnosed Kartagener’s syndrome or PCD), and patients with confirmed absence of the above 3 diagnoses (idiopathic control group) were included in the study. Descriptive statistics were computed for the main demographic and clinical characteristics of the sample stratified by group. Values between the groups were compared using Kruskal-Wallis test, and Chi-squared/ Fisher’s exact tests respectively. The significance level was set at 0.05. Software SAS 9.4 was used to perform the statistical analyses. Results: Of the 2170 participants in the database enrolled as of January 2017, 615 respondents had sufficient data and were included in the analyses. Patients with PCD (n=79, mean age 41.9 years [standard deviation (SD)=14.5]) were significantly younger than patients with AATD (n=58, mean age 66.9 [SD=10.7]), CVI (n=18, mean age 66.7 years [SD=10.5]) or the idiopathic group (n=460, mean age 64.2 [SD=15.9]), p

Non-cystic fibrosis bronchiectasis (NCFB) is characterized by dilated bronchi, poor mucus clearance and susceptibility to bacterial infection. Pseudomonas aeruginosa (PA) is one of the most frequently isolated pathogens in patients with NCFB. The purpose of this study was to evaluate the association between presence of PA and disease severity in patients within the US Bronchiectasis and Nontuberculous mycobacteria (NTM) Research Registry (BRR).Baseline US BRR data from adult patients with NCFB collected between 2008 and 2018 was used for this study. The presence of PA was defined as one or more positive PA cultures within two years prior to enrollment. Modified Bronchiectasis Severity Index (m-BSI) and modified FACED (m-FACED) were computed to evaluate severity of bronchiectasis. Unadjusted and multivariable multinomial regression models were used to assess the association between presence of PA and severity of bronchiectasis.Average age of the study participants (n = 1831) was 63.7 years (SD = 14.1), 91.5% white, and 78.8% female. Presence of PA was identified in 25.4% of the patients. Patients with presence of PA had significantly lower mean pre-bronchodilator FEV1% predicted compared to those without PA (62.8% vs. 73.7%, p .0001). In multivariate analyses, patients with presence of PA had significantly greater odds for having high (ORThe presence of PA is common in patients with NCFB within the Bronchiectasis and NTM Research Registry. Severity of bronchiectasis is significantly greater in patients with PA which emphasizes high burden of the disease.

Protein tyrosine phosphatase 1B (PTP1B) has anti-inflammatory potential but PTP1B responses are desensitized in the lung by prolonged cigarette smoke exposure. Here we investigate whether PTP1B expression affects lung disease severity during respiratory syncytial viral (RSV) exacerbations of chronic obstructive pulmonary disease (COPD). Ptp1b(-/-) mice infected with RSV exhibit exaggerated immune cell infiltration, damaged epithelial cell barriers, cytokine production, and increased apoptosis. Elevated expression of S100A9, a damage-associated molecular pattern molecule, was observed in the lungs of Ptp1b(-/-) mice during RSV infection. Utilizing a neutralizing anti-S100A9 IgG antibody, it was determined that extracellular S100A9 signaling significantly affects lung damage during RSV infection. Preexposure to cigarette smoke desensitized PTP1B activity that coincided with enhanced S100A9 secretion and inflammation in wild-type animals during RSV infection. S100A9 levels in human bronchoalveolar lavage fluid had an inverse relationship with lung function in healthy subjects, smokers, and COPD subjects. Fully differentiated human bronchial epithelial cells isolated from COPD donors cultured at the air liquid interface secreted more S100A9 than cells from healthy donors or smokers following RSV infection. Together, these findings show that reduced PTP1B responses contribute to disease symptoms in part by enhancing S100A9 expression during viral-associated COPD exacerbations.

Background The use of electronic (e)-cigarettes is increasing rapidly, but their lung health effects are not established. Clinical studies examining the potential long-term impact of e-cigarette use on lung health will take decades. To address this gap in knowledge, this study investigated the effects of exposure to aerosolised nicotine-free and nicotine-containing e-cigarette fluid on mouse lungs and normal human airway epithelial cells. Methods Mice were exposed to aerosolised phosphate-buffered saline, nicotine-free or nicotine-containing e-cigarette solution, 1-hour daily for 4 months. Normal human bronchial epithelial (NHBE) cells cultured at an air-liquid interface were exposed to e-cigarette vapours or nicotine solutions using a Vitrocell smoke exposure robot. Results Inhalation of nicotine-containing e-cigarettes increased airway hyper-reactivity, distal airspace enlargement, mucin production, cytokine and protease expression. Exposure to nicotine-free e-cigarettes did not affect these lung parameters. NHBE cells exposed to nicotine-containing e-cigarette vapour showed impaired ciliary beat frequency, airway surface liquid volume, cystic fibrosis transmembrane regulator and ATP-stimulated K+ ion conductance and decreased expression of FOXJ1 and KCNMA1. Exposure of NHBE cells to nicotine for 5 days increased interleukin (IL)-6 and IL-8 secretion. Conclusions Exposure to inhaled nicotine-containing e-cigarette fluids triggered effects normally associated with the development of COPD including cytokine expression, airway hyper-reactivity and lung tissue destruction. These effects were nicotine-dependent both in the mouse lung and in human airway cells, suggesting that inhaled nicotine contributes to airway and lung disease in addition to its addictive properties. Thus, these findings highlight the potential dangers of nicotine inhalation during e-cigarette use.

The expression of Toll-like receptor (TLR)-9, a pathogen recognition receptor that recognizes unmethylated CpG sequences in microbial DNA molecules, is linked to the pathogenesis of several lung diseases. TLR9 expression and signaling was investigated in animal and cell models of chronic obstructive pulmonary disease (COPD). We observed enhanced TLR9 expression in mouse lungs following exposure to cigarette smoke. Tlr9−/− mice were resistant to cigarette smoke-induced loss of lung function as determined by mean linear intercept, total lung capacity, lung compliance, and tissue elastance analysis. Tlr9 expression also regulated smoke-mediated immune cell recruitment to the lung; apoptosis; expression of granulocyte-colony stimulating factor (G-CSF), the CXCL5 protein, and matrix metalloproteinase-2 (MMP-2); and protein tyrosine phosphatase 1B (PTP1B) activity in the lung. PTP1B, a phosphatase with anti-inflammatory abilities, was identified as binding to TLR9. In vivo delivery of a TLR9 agonist enhanced TLR9 binding to PTP1B, which inactivated PTP1B. Ptp1b−/− mice had elevated lung concentrations of G-CSF, CXCL5, and MMP-2, and tissue expression of type-1 interferon following TLR9 agonist administration, compared with wild-type mice. TLR9 responses were further determined in fully differentiated normal human bronchial epithelial (NHBE) cells isolated from nonsmoker, smoker, and COPD donors, and then cultured at air liquid interface. NHBE cells from smokers and patients with COPD expressed more TLR9 and secreted greater levels of G-CSF, IL-6, CXCL5, IL-1β, and MMP-2 upon TLR9 ligand stimulation compared with cells from nonsmoker donors. Although TLR9 combats infection, our results indicate that TLR9 induction can affect lung function by inactivating PTP1B and upregulating expression of proinflammatory cytokines.

Multi-component supramolecular systems could be used to prepare exciting new functional materials, but it is often challenging to control the assembly across multiple length scales. Here, we report a simple approach to forming patterned, spatially resolved multi-component supramolecular hydrogels. A multi-component gel is first formed from two low-molecular-weight gelators that consists of two types of fibers, each formed by only one gelator. One type of fibres of this 'self-sorted network' is then selectively removed by a light-triggered gel-to-sol transition. We show that the remaining network has the same mechanical properties as it would if it were initially formed alone. The selective irradiation of sections of the gel through a mask leads to the formation of patterned multi-component networks, in which either one or two networks can be present at a particular position, which a high degree of spatial control.

BACKGROUND: Diaphragm muscle weakness and atrophy are consequences of prolonged mechanical ventilation. Our purpose was to determine whether thickness of the diaphragm (TDI) changes over time after intubation and whether the degree of change affects clinical outcome. METHODS: For this prospective, longitudinal observational study, we identified subjects who required mechanical ventilation and measured their TDI by ultrasonography. TDI was measured at baseline and repeated 72 h later and then weekly until the subject was either liberated from mechanical ventilation, was referred for tracheostomy, or died. The analysis was designed to determine whether baseline TDI and change in TDI affect extubation outcome. RESULTS: Of the 57 subjects who underwent both diaphragm measurements at 72 h, 16 died, 33 were extubated, and 8 underwent tracheostomy. Only 14 subjects received mechanical ventilation for 1 week, and 2 subjects received mechanical ventilation for 2 and 3 weeks. Females had significantly thinner baseline TDI (P = .008). At 72 h, TDI had decreased in 84% of subjects. We found no significant association between the rate of thinning and sex (P = .68), diagnosis of COPD (P = .36), current smoking (P = .85), or pleural effusion (P = .83). Lower baseline TDI was associated with higher likelihood of extubation: 12.5% higher for every 0.01-cm decrease in TDI (hazard ratio 0.875, 95% CI 0.80–0.96, P = .003). For every 0.01-cm decrease in TDI at 72 h, the likelihood of extubation increased by 17% (hazard ratio 0.83, 95% CI 0.70–0.99, P = .041). CONCLUSIONS: Although most of the subjects showed evidence of diaphragm thinning, we were unable to find a correlation with outcome of extubation failure. In fact, the thinner the diaphragm at baseline and the greater the extent of diaphragm thinning at 72 h, the greater the likelihood of extubation. Thickening ratio or other measurement may be a more reliable indicator of diaphragm dysfunction and should be explored.

Porous liquids are a new class of material that could have applications in areas such as gas separation and homogeneous catalysis. Here we use a combination of measurement techniques, molecular simulations, and control experiments to advance the quantitative understanding of these liquids. In particular, we show that the cage cavities remain unoccupied in the absence of a suitable guest, and that the liquids can adsorb large quantities of gas, with gas occupancy in the cages as high as 72% and 74% for Xe and SF6, respectively. Gases can be reversibly loaded and released by using non-chemical triggers such as sonication, suggesting potential for gas separation schemes. Diffusion NMR experiments show that gases are in dynamic equilibrium between a bound and unbound state in the cage cavities, in agreement with recent simulations for related porous liquids. Comparison with gas adsorption in porous organic cage solids suggests that porous liquids have similar gas binding affinities, and that the physical properties of the cage molecule are translated into the liquid state. By contrast, some physical properties are different: for example, solid homochiral porous cages show enantioselectivity for chiral aromatic alcohols, whereas the equivalent homochiral porous liquids do not. This can be attributed to a loss of supramolecular organisation in the isotropic porous liquid.

Rationale: α1-Antitrypsin (A1AT) was identified as a plasma protease inhibitor; however, it is now recognized as a multifunctional protein that modulates immunity, inflammation, proteostasis, apoptosis, and cellular senescence. Like A1AT, protein phosphatase 2A (PP2A), a major serine-threonine phosphatase, regulates similar biologic processes and plays a key role in chronic obstructive pulmonary disease. Objectives: Given their common effects, this study investigated whether A1AT acts via PP2A to alter tumor necrosis factor (TNF) signaling, inflammation, and proteolytic responses in this disease. Methods: PP2A activity was measured in peripheral blood neutrophils from A1AT-deficient (PiZZ) and healthy (PiMM) individuals and in alveolar macrophages from normal (60 mg/kg) and high-dose (120 mg/kg) A1AT-treated PiZZ subjects. PP2A activation was assessed in human neutrophils, airway epithelial cells, and peripheral blood monocytes treated with plasma purified A1AT protein. Similarly, lung PP2A activity was measured in mice administered intranasal A1AT. PP2A was silenced in lung epithelial cells treated with A1AT and matrix metalloproteinase and cytokine production was then measured following TNF-α stimulation. Measurements and Main Results: PP2A was significantly lower in neutrophils isolated from PiZZ compared with PiMM subjects. A1AT protein activated PP2A in human alveolar macrophages, monocytes, neutrophils, airway epithelial cells, and in mouse lungs. This activation required functionally active A1AT protein and protein tyrosine phosphatase 1B expression. A1AT treatment acted via PP2A to prevent p38 and IκBα phosphorylation and matrix metalloproteinase and cytokine induction in TNF-α–stimulated epithelial cells. Conclusions: Together, these data indicate that A1AT modulates PP2A to counter inflammatory and proteolytic responses induced by TNF signaling in the lung.

Background:Exercise improves sleep quality, yet people with untreated obstructive sleep apnea (OSA) may engage in less physical activity (PA) due to fatigue and daytime sleepiness. We examined changes in PA and sleep quality before and after treatment with continuous positive airway pressure (CPAP) in OSA patients.Methods:In this prospective longitudinal study, persons with a primary diagnosis of OSA were enrolled at a community-based hospital in New York City. At 3 time intervals pre- and post-CPAP (3–8 months), we measured sleep quality using validated questionnaires, perceived PA using the International Physical Activity Questionnaire (IPAQ), and actual PA using pedometer steps per day. We sought to investigate how CPAP use and changes in sleep quality impacted the number of steps taken, as recorded in pedometer steps.Results:In total, 62 patients were enrolled in the study from March 2012 to July 2014. In all, patients averaged 53 years of age, and 26 patients (42%) were female. Among all participants, 86% of persons had moderate to severe sleep apnea (AHI ≥15). Approximately 73% of participants were compliant with CPAP use. Poor sleep quality correlated with lower actual PA (P = .004) at baseline. At 3 and 7 months, there was significant improvement in sleep quality (Δ –2.63 ± 3.4 and Δ –3.5 ± 3.8; P < .001) and actual PA (Δ 840 ± 1313 and Δ 1431 ± 1419 steps/day, P < .001) compared with baseline. On multivariate analyses, participants with a higher waist circumference had a significantly greater increase in actual PA (P = .018).Conclusion:Treatment of OSA with CPAP had a progressive incremental improvement in sleep quality and actual PA.

Background Approximately 40% of patients in medical ICUs require mechanical ventilation (MV). Approximately 20% to 25% of these patients will encounter difficulties in discontinuing MV. Multiple studies have suggested that MV has an unloading effect on the respiratory muscles that leads to diaphragmatic atrophy and dysfunction, a process called ventilator-induced diaphragmatic dysfunction (VIDD). VIDD may be an important factor affecting when and if MV can be discontinued. A sensitive and specific diagnostic test for VIDD could provide the physician with valuable information that might influence decisions regarding extubation or tracheostomy. The purpose of this study was to quantify, using daily sonographic assessments, the rate and degree of diaphragm thinning during MV. Methods Seven intubated patients receiving MV during acute care were included. Using sonography, diaphragm muscle thickness was measured daily from the day of intubation until the patient underwent extubation or tracheostomy or died. We analyzed our data using standard descriptive statistics, linear regression, and mixed-model effects. Results The overall rate of decrease in the diaphragm thickness of all seven patients over time averaged 6% per day of MV, which differed significantly from zero. Similarly, the diaphragm thickness decreased for each patient over time. Conclusion Sonographic assessment of the diaphragm provides noninvasive measurement of diaphragmatic thickness and the degree of diaphragm thinning in patients receiving MV. Our data show that diaphragm muscle thinning starts within 48 h after initiation of MV. However, it is unclear if diaphragmatic thinning correlates with diaphragmatic atrophy or pulmonary function. The relationship between diaphragm thinning and diaphragm strength remains to be elucidated.

Alpha-1 antitrypsin (AAT) deficiency and tobacco smoking are confirmed risk factors for Chronic Obstructive Pulmonary Disease. We hypothesized that variable DNA methylation would be associated with smoking and inflammation, as reflected by the level of C-Reactive Protein (CRP) in AAT-deficient subjects. Methylation levels of 1,411 autosomal CpG sites from the Illumina GoldenGate Methylation Cancer Panel I were analyzed in 316 subjects. Associations of five smoking behaviors and CRP levels with individual CpG sites and average methylation levels were assessed using non-parametric testing, linear regression and linear mixed effect models, with and without adjustment for age and gender. Univariate linear regression analysis revealed that methylation levels of 16 CpG sites significantly associated with ever-smoking status. A CpG site in the TGFBI gene was the only site associated with ever-smoking after adjustment for age and gender. No highly significant associations existed between age at smoking initiation, pack-years smoked, duration of smoking, and time since quitting smoking as predictors of individual CpG site methylation levels. However, ever-smoking and younger age at smoking initiation associated with lower methylation level averaged across all sites. DNA methylation at CpG sites in the RUNX3, JAK3 and KRT1 genes associated with CRP levels. The most significantly associated CpG sites with gender and age mapped to the CASP6 and FZD9 genes, respectively. In summary, this study identified multiple potential candidate CpG sites associated with ever-smoking and CRP level in AAT-deficient subjects. Phenotypic variability in Mendelian diseases may be due to epigenetic factors.

Objectives: The aims of this study were to determine predictors of survival after hospital discharge and to describe the impact of intensive care unit admission on health-related quality of life at 6 months after hospital discharge in older adults admitted to intensive care units. Design: Prospective longitudinal observational study with administered questionnaire. Settings and Patients: Patients 65 yrs of age and older who were admitted to the medical, surgical, and coronary intensive care units for >24 hrs in a large urban teaching hospital system from August 2007 to May 2008 with a follow-up period ending April 2009. Interventions: Administered questionnaire to patients or proxies. Measurements and Main Results: Four hundred eighty-four patients 65 yrs old and older were enrolled. Data were collected on demographics, comorbidities, intensive care unit admission diagnoses, Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment score, Glasgow Coma Scale score at intensive care unit admission, intensive care unit interventions, and disposition after hospital discharge. A health-related quality of life survey was administered to patients, their proxies, or caregivers at intensive care unit admission, and to hospital survivors at 6 months after hospital discharge. Three hundred sixty-seven (75.8%) and 318 (65.7%) of enrolled patients were alive at hospital discharge and at 6 months, respectively. Mean age of survivors was 77.8 ± 8.5. Independent predictors of death at 6 months were: number of days during the 30 days before hospitalization that the patient felt their "physical health was not good" on the health-related quality of life survey [odds ratio = 1.08; confidence interval 1.04-1.12], a higher Acute Physiology and Chronic Health Evaluation II score [odds ratio = 1.09; 95% confidence interval 1.06-1.12], and chronic pulmonary disease as a comorbidity [odds ratio = 2.22; 95% confidence interval 1.04-4.78]. Of the 318 survivors at 6 months after hospital discharge, 297 (93.4%) completed the health-related quality of life questionnaire. When assessing whether changes in health-related quality of life over time were affected by age in our study cohort of 65 yrs old and older, we found that the oldest survivors, age 86.3 yrs old and older, had worse health-related quality of life over time, including more days spent with poor physical health (p < .004) and mental health (p < .001), while the youngest survivors, age 65-69.3 yrs old, showed improvement in health-related quality of life with fewer days spent with poor physical health (p < .004) and mental health (p < .001) at follow-up compared to baseline. These differences remained after adjusting for severity of illness and other potential confounders. Conclusions: One-third of adults 65 yrs old and older admitted to the intensive care unit die within 6 months of hospital discharge. Among survivors at 6 months, health-related quality of life has significantly worsened over time in the oldest patients but improved in the youngest. Our study in a large cohort of mixed intensive care unit patients identifies additional prognostic factors and significant quality of life information in intensive care unit survivors well after hospital discharge. This additional information may guide clinicians in their discussions with patients, families, and other providers as they decide on what treatments and interventions to pursue.

Background Catheter-related bloodstream infection (CRBSI) is a preventable cause of a potentially lethal ICU infection. The optimal method to teach health-care providers correct sterile techniques during central vein catheterization (CVC) remains unclear. Methods We randomly assigned second- and third-year internal medicine residents trained by a traditional apprenticeship model to simulation-based plus video training or video training alone from December 2007 to January 2008, with a follow-up period to examine CRBSI ending in July 2009. During the follow-up period, a simulation-based training program in sterile techniques during CVC was implemented in the medical ICU (MICU). A surgical ICU (SICU) where no residents received study interventions was used for comparison. The primary outcome measures were median residents' scores in sterile techniques and rates of CRBSI per 1,000 catheter-days. Results Of the 47 enrolled residents, 24 were randomly assigned to the simulation-based plus video training group and 23 to the video training group. Median baseline scores in both groups were equally poor: 12.5 to 13 (52%-54%) out of maximum score of 24 ( P = .95; median difference, 0; 95% CI, 0.2-2.0). After training, median score was significantly higher for the simulation-based plus video training group: 22 (92%) vs 18 (75%) for the video training group ( P P = .03). The incidence rate ratio derived from the Poisson regression (0.30; 95% CI, 0.10-0.91) indicated there was a 70% reduction in the incidence of CRBSI in the postintervention MICU compared with the preintervention MICU and the postintervention SICU. Conclusions Simulation-based training in sterile techniques during CVC is superior to traditional training or video training alone and is associated with decreased rate of CRBSI. Simulation-based training in CVC should be routinely used to reduce iatrogenic risk. Trial Registry ClinicalTrials.gov; No.: NCT00612131; URL: clinicaltrials.gov.

This review summarizes the current information on the relationship between severe alpha-1 antitrypsin deficiency (AATD), asthma and COPD. AATD is a genetic predisposition to the development of early COPD in susceptible individuals and reduction in known factors that enhance lung function loss is the paramount aim of management. Asthma is one controllable condition that leads to the accelerated decline in lung function. Current literature indicates that asthma signs and symptoms are common in those AATD with or without COPD and that bronchodilator response is a risk factor for FEV(1) decline. Furthermore AATD itself predisposes to airway hyper responsiveness, an essential ingredient for reversible airflow obstruction. In the absence of well-characterized markers to distinguish COPD from asthma, clinical diagnosis leads to a delay in the recognition that asthma symptoms such as wheezing can be an early manifestation of COPD in AATD. In addition failure to appreciate asthma overlap in AATD may lead to inadequate suppression of airway inflammation leading to the development of airflow obstruction. The implications of this are discussed as are potential approaches and recommendations for treatment.

BACKGROUND: Life-threatening status asthmaticus (SA) requiring intensive care is a major concern given the rising prevalence of asthma. We examined episodes of SA requiring admission to the medical intensive care unit (MICU) of an urban hospital center. METHODOLOGY: The charts of patients admitted to the MICU of an urban hospital center with a diagnosis of SA during the 5-year period 2002–2006 were reviewed retrospectively. These results were compared with those of a previously published experience at our institution from 1995 to 1999. RESULTS: The medical records of 84 MICU admissions for SA were reviewed. There were 61 women (5 pregnant). The mean age was 44 years. Use of cigarettes or illicit drugs was found in 51% and 30%, respectively. Mechanical ventilation (MV) was required in 76% of admissions. Noninvasive ventilation was used in 10 patients. Neuromuscular blockade (NMB) was needed in 9% of admissions. The highest average PaCO2 during the first 24 hours was 67 mm Hg. Median duration of MV was 4.4 days. Six patients died, 3 of whom sustained prehospital cardiac arrest. Compared with the patients in the preceding 5-year period, the more recent patients had greater use of illicit drug and cigarettes. Patients presented with more severe asthma, as reflected by a higher PaCO2 and an increased duration of MV. CONCLUSIONS: During the recent 5-year period, we found a trend toward increasing severity of SA, as indicated by the degree of respiratory acidosis, need for NMB, and longer duration of MV. Access to medical care and cigarette and illicit drug use remain potential targets of primary intervention. Journal of Hospital Medicine 2008;3:206–211. © 2008 Society of Hospital Medicine.

Severe alpha(1)-antitrypsin (AAT) deficiency is a proven genetic risk factor for chronic obstructive pulmonary disease (COPD), especially in individuals who smoke. There is marked variability in the development of lung disease in individuals homozygous (PI ZZ) for this autosomal recessive condition, suggesting that modifier genes could be important. We hypothesized that genetic determinants of obstructive lung disease may be modifiers of airflow obstruction in individuals with severe AAT deficiency. To identify modifier genes, we performed family-based association analyses for 10 genes previously associated with asthma and/or COPD, including IL10, TNF, GSTP1, NOS1, NOS3, SERPINA3, SERPINE2, SFTPB, TGFB1, and EPHX1. All analyses were performed in a cohort of 378 PI ZZ individuals from 167 families. Quantitative spirometric phenotypes included forced expiratory volume in one second (FEV(1)) and the ratio of FEV(1)/forced vital capacity (FVC). A qualitative phenotype of moderate-to-severe COPD was defined for individuals with FEV(1)

In a study comparing low-dose theophylline to montelukast in poorly controlled asthmatics, 285 subjects consented to be screened for alpha-1 antitrypsin deficiency. Of the 284 for which complete data was available, 10.5% carried a deficiency gene and 2.4% were mildly deficient with an alpha-1 antitrypsin serum level of less than 20 mu M. In the non-African-American cohort, an abnormal phenotype occurred in 12% and 2.9% were mildly deficient. Baseline pulmonary function and asthma scores were not significantly different between those with normal and abnormal AAT phenotype. However those with the deficiency tended to show a greater bronchodilator response.

Introduction: Cigarette smoke negates the anti-inflammatory effects of protein tyrosine phosphatase 1B (PTP1B). Additionally, respiratory syncytial viral (RSV), a cause of chronic obstructive pulmonary disease (COPD) exacerbations, also reduces airway PTP1B activity. Reduced PTP1B correlates with COPD severity in smoked RSV infected mice. However the exact role of PTP1B in virus-associated COPD exacerbations is unknown. To determine the impact of PTP1B in RSV infection, Ptp1b knockout (-/-) animals were investigated in RSV-induced COPD exacerbations models. Methods: Ptp1b -/- mice (FVB.129S4(B6)-Ptpn1 tm1Bbk /Mmjax) and wild-type littermates were exposed to 4 months of cigarette smoke or room air and subsequently infected with RSV or a mock control. RSV exposures were also performed in epithelial cells from healthy and COPD donors. Airway cytokine production, apoptosis and remodeling were investigated. Results: Loss of PTP1B expression enhanced smoke-induced airway enlargements. RSV infection caused greater airway damage in Ptp1b -/- mice, with exaggerated inflammation, damaged epithelium and increased apoptosis compared to wild-type littermates. There was increased gene expression of S100A9, a damage-associated molecular patterns molecule, in the airways of Ptp1b -/- mice during RSV infection. Treatment with neutralizing anti-S100A9 IgG reduced RSV-pathology with reduced airspace protein, immune cell recruitment, cytokine production and apoptosis. Conclusions: Loss of PTP1B activity in the airways may contribute to the enhanced disease progression during viral-associated COPD exacerbations. Indeed, PTP1B regulation of S100A9 may play a key role in lung injury.

Introduction: Inflammation is central in pathogenesis of lung disease in alpha-1 antitrypsin (A1AT) deficiency. Phospholipid transfer protein (PLTP) prevents airway inflammation; however, in chronic obstructive pulmonary disease (COPD), serine proteases cleave PLTP. We propose that A1AT augmentation therapy exerts novel anti-inflammatory effects by enhancing PLTP activity in the airways. Methods: PLTP activity was measured in bronchoalveolar fluid (BALF) and plasma of healthy non-smokers, healthy smokers, non-A1AT COPD patients (all PiMM) and A1AT deficient COPD patients (all PiZZ). PLTP levels were also determined in BALF and plasma of individuals receiving normal (60 mg/kg) and high-dose (120 mg/kg) A1AT augmentation. A1AT protein isolated from the plasma of PiMM and PiZZ subjects as incubated with COPD BALF prior to combination with recombinant PLTP. PLTP cleavage was investigated. Results: PLTP activity was comparable in the plasma of healthy non-smokers, smokers, PiMM and PiZZ COPD patients. However, BALF PLTP activity was significantly reduced in both COPD cohorts and smokers as compared to healthy individuals. A1AT isolated from plasma of PiMM individuals protected PLTP from proteolytic cleavage while A1AT from plasma of PiZZ individuals did not have the same protective effect. Weekly administration of 120 mg/kg A1AT significantly enhanced PLTP activity levels in BALF of A1AT deficient patients, which coincided with reduced inflammation. Conclusions: A1AT therapy prevents PLTP cleavage and preserves its activity thereby enhancing its anti-inflammatory activity. Enhancing airway PLTP activity could have therapeutic potential in A1AT deficiency.

Delayed diagnosis is common in patients with pulmonary arterial hypertension (PAH). Right-sided heart catheterization, the gold standard for diagnosis, is invasive and cannot be applied for routine screening. Some biomarkers have been looked into; however, due to the lack of a clear pathological mechanism linking the marker to PAH, the search for an ideal one is still ongoing. Elastin is a significant structural constituent of blood vessels. Its synthesis involves cross-linking of monomers by 2 amino acids, desmosine and isodesmosine (DI). Being extremely stable, elastin undergoes little metabolic turnover in healthy individuals resulting in very low levels of DI amino acids in the human plasma, urine, or sputum. We hypothesized that in PAH patients, the elastin turnover is high; which in turn should result in elevated levels of DI in plasma and urine. Using mass spectrometry, plasma and urine levels of DI were measured in 20 consecutive patients with PAH confirmed by cardiac catheterization. The levels were compared with 13 healthy controls. The mean level of total plasma DI in patients with PAH was 0.47 ng/mL and in controls was 0.19 ng/mL (P = 0.001). The mean levels of total DI in the urine of PAH patients was 20.55 mg/g creatinine and in controls was 12.78 mg/g creatinine (P = 0.005). The mean level of free DI in the urine of PAH patients was 10.34 mg/g creatinine and in controls was 2.52 mg/g creatinine (P0.001). This is the first study highlighting that the serum and urine DI has a potential to be a novel screening biomarker for patients with PAH. It paves the way for larger studies to analyze its role in assessing for disease severity and response to treatment.

Increased lung levels of matrix metalloproteinase 9 (MMP9) are frequently observed during respiratory syncytial virus (RSV) infection and elevated MMP9 concentrations are associated with severe disease. However little is known of the functional role of MMP9 during lung infection with RSV. To determine whether MMP9 exerted direct antiviral potential, active MMP9 was incubated with RSV, which showed that MMP9 directly prevented RSV infectivity to airway epithelial cells. Using knockout mice the effect of the loss of Mmp9 expression was examined during RSV infection to demonstrate MMP9’s role in viral clearance and disease progression. Seven days following RSV infection, Mmp9 -/- mice displayed substantial weight loss, increased RSV-induced airway hyperresponsiveness (AHR) and reduced clearance of RSV from the lungs compared to wild type mice. Although total bronchoalveolar lavage fluid (BALF) cell counts were similar in both groups, neutrophil recruitment to the lungs during RSV infection was significantly reduced in Mmp9 -/- mice. Reduced neutrophil recruitment coincided with diminished RANTES, IL-1β, SCF, G-CSF expression and p38 phosphorylation. Induction of p38 signaling was required for RANTES and G-CSF expression during RSV infection in airway epithelial cells. Therefore, MMP9 in RSV lung infection significantly enhances neutrophil recruitment, cytokine production and viral clearance while reducing AHR.

SummaryThis study was designed to determine the prevalence of asthma and atopy, in a large group of subjects with alpha-1 antitrypsin deficiency (AATD) participating in the Alpha-1 Foundation Research Registry. A survey was mailed to all Registry participants (N=2418) and results were collated by AATD phenotype. Participants with PiZZ deficiency were compared to PiMZ and other phenotypes by nonparametric statistics. Responses were collected from 757 participants (31%). Overall 44.6% (N=338) reported MD diagnosed asthma. Wheezing was reported in 76% with respiratory infections, activity and exposure to dusts, fumes, and allergens as common triggers. Across the three groups reported asthma with a history of allergies was reported from 20% to 25%. Wheezing symptoms were significantly less common in the PiMZ group compared with other groups. Of those reporting asthma, 83% of the PiZZ group (n=192) also reported another chronic obstructive pulmonary disease (COPD) diagnosis compared to 48% of the PiMZ group (n=24). Asthma as the only reported diagnosis was three times more prevalent in the PiMZ group compared with the PiZZ group. Although asthma diagnosis is imprecise in the presence of COPD, the high prevalence of wheezing to allergen and irritant exposures with symptoms of atopy suggests that asthma is common in AATD but usually associated with COPD. Those with AATD who are susceptible to asthma require allergy evaluation and aggressive anti-inflammatory strategies as part of their management.

Study objectives To describe asthma features in a cohort with α 1 -antitrypsin (AAT) deficiency, and determine the impact of asthma on FEV 1 decline. Background Asthma may be common in those with AAT deficiency, and may lead to accelerated airflow obstruction. Design Analysis of data obtained from a 5-year, prospective National Heart, Lung, and Blood Institute registry. Setting A multicenter registry consisting of 37 clinical centers, a central phenotyping laboratory, and a data analysis center. Participants A cohort of 1,052 subjects with AAT deficiency. Measurements and results Asthma was defined as reversible airflow obstruction, recurrent attacks of wheezing, and a reported diagnosis of asthma or allergy with or without an elevated serum IgE level. FEV 1 decline was calculated by least-square means with adjustments for covariables. Asthma was present in 21% of the cohort and in 12.5% of those with a normal FEV 1 . Attacks of wheezing were reported in 66%, the first attack occurring at a mean ± SD age of 31 ± 16 years. Allergy and asthma was reported in 29% and 38%, respectively. An elevated IgE level occurred in 17% and was significantly associated with signs and symptoms of asthma and an allergy history. Unadjusted FEV 1 decline was less in the group without asthma and a normal IgE level (− 48.5 mL/yr) vs the groups with asthma features (≥ 64 mL/yr) [p = 0.002]. Multivariable analysis showed that bronchodilator response, age, and smoking were significant predictors for FEV 1 decline but not asthma. Conclusions Symptoms and signs of asthma are common in AAT deficiency and may start at the age of most rapid FEV 1 loss. Adjusting for other risk factors such as bronchodilator response, asthma as defined does not lead to an accelerated FEV 1 decline. In AAT deficiency, augmentation therapy is not more effective in preventing the loss of lung function in those with asthma compared to those without.

Self-sorting in low molecular weight hydrogels can be achieved using a pH triggered approach. We show here that this method can be used to prepare gels with different types of mechanical properties. Cooperative, disruptive or orthogonal assembled systems can be produced. Gels with interesting behaviour can be also prepared, for example self-sorted gels where delayed switch-on of gelation occurs. By careful choice of gelator, co-assembled structures can also be generated, which leads to synergistic strengthening of the mechanical properties.