https://nova.newcastle.edu.au/vital/access/ /manager/Index en-au 5 https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:50302 Wed 28 Feb 2024 15:06:11 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:34932 Wed 24 Nov 2021 15:51:46 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:37433 Wed 24 Nov 2021 15:50:40 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:48068 Wed 22 Feb 2023 16:37:56 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:34320 Wed 19 Jan 2022 15:15:22 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:32103 Wed 17 Nov 2021 16:28:21 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:47108 Wed 14 Dec 2022 10:05:30 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:42641 Wed 13 Mar 2024 14:03:28 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:36947 Pseudomonas aeruginosa (P. aeruginosa) in the lungs of cystic fibrosis patients makes eradication of infections with antibiotic therapy very difficult. The lipopeptide antibiotics polymyxin B and colistin are currently the last-resort therapies for infections caused by multidrug-resistant P. aeruginosa. In the present study, we investigated the antibacterial activity of a series of polymyxin lipopeptides (polymyxin B, colistin, FADDI-003, octapeptin A₃, and polymyxin A₂) against a panel of polymyxin-susceptible and polymyxin-resistant P. aeruginosa cystic fibrosis isolates grown under planktonic or biofilm conditions in artificial sputum and their interactions with sputum component biomolecules. In sputum media under planktonic conditions, the lipopeptides FADDI-003 and octapeptin A₃ displayed very promising activity against the polymyxin-resistant isolate FADDI-PA066 (polymyxin B minimum inhibitory concentration (MIC) = 32 mg/L), while retaining their activity against the polymyxin-sensitive strains FADDI-PA021 (polymyxin B MIC = 1 mg/L) and FADDI-PA020 (polymyxin B MIC = 2 mg/L). Polymyxin A₂ was only effective against the polymyxin-sensitive isolates. However, under biofilm growth conditions, the hydrophobic lipopeptide FADDI-003 was inactive compared to the more hydrophilic lipopeptides, octapeptin A₃, polymyxin A₂, polymyxin B, and colistin. Transmission electron micrographs revealed octapeptin A₃ caused reduction in the cell numbers in biofilm as well as biofilm disruption/“antibiofilm” activity. We therefore assessed the interactions of the lipopeptides with the component sputum biomolecules, mucin, deoxyribonucleic acid (DNA), surfactant, F-actin, lipopolysaccharide, and phospholipids. We observed the general trend that sputum biomolecules reduce lipopeptide antibacterial activity. Collectively, our data suggests that, in the airways, lipopeptide binding to component sputum biomolecules may reduce antibacterial efficacy and is dependent on the physicochemical properties of the lipopeptide.]]> Wed 09 Mar 2022 15:59:20 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:34188 Tue 19 Feb 2019 12:58:02 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:46348 Tue 15 Nov 2022 14:13:02 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:45975 Is there evidence of clinically important treatment effects for non-pharmacological therapies in cough treatment for patients with bronchiectasis?" Populations selected were all patients with bronchiectasis due to CF or non-CF bronchiectasis. The interventions explored were the non-pharmacological airway clearance therapies. The comparison populations included those receiving standard therapy and/or placebo. Clinically important outcomes that were explored were exacerbation rates, quality of life, hospitalizations, and mortality. Results: In both CF and non-CF bronchiectasis, there were systematic reviews and overviews of systematic reviews identified. Despite these findings, there were no large randomized controlled trials that explored the impact of airway clearance on exacerbation rates, quality of life, hospitalizations, or mortality. Conclusions: Although the cough panel was not able to make recommendations, they have made consensus-based suggestions and provided direction for future studies to fill the gaps in knowledge.]]> Tue 08 Nov 2022 14:39:17 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:34845 Thu 28 Oct 2021 12:35:34 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:652 Thu 25 Jul 2013 09:10:28 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:660 Thu 25 Jul 2013 09:10:27 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:34955 Thu 17 Feb 2022 09:32:05 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:25164 Pseudomonas aeruginosa. The in vitro synergistic activity of polymyxin B combined with ivacaftor or lumacaftor was assessed using checkerboard and static time-kill assays against a panel of polymyxin-susceptible and polymyxin-resistant P. aeruginosa isolates from the lungs of CF patients. Polymyxin B, ivacaftor, and lumacaftor were ineffective when used individually against polymyxin-resistant (MIC ≥ 4 mg/L) isolates. However, when used together, the combination of clinically relevant concentrations of polymyxin B (2 mg/L) combined with ivacaftor (8 mg/L) or ivacaftor (8 mg/L) + lumacaftor (8 mg/L) displayed synergistic killing activity against polymyxin-resistant P. aeruginosa isolates as demonstrated by a 100-fold decrease in the bacterial count (CFU/mL) even after 24 h. The combinations also displayed excellent antibacterial activity against P. aeruginosa under CF relevant conditions in a sputum medium assay. The combination of lumacaftor (alone) with polymyxin B showed additivity against P. aeruginosa. The potential antimicrobial mode of action of the combinations against P. aeruginosa was investigated using different methods. Treatment with the combinations induced cytosolic GFP release from P. aeruginosa cells and showed permeabilizing activity in the nitrocefin assay, indicating damage to both the outer and inner Gram-negative cell membranes. Moreover, scanning and transmission electron micrographs revealed that the combinations produce outer membrane damage to P. aeruginosa cells that is distinct from the effect of each compound per se. Ivacaftor was also shown to be a weak inhibitor of the bacterial DNA gyrase and topoisomerase IV with no effect on either human type I or type IIα topoisomerases. Lumacaftor displayed the ability to increase the cellular production of damaging reactive oxygen species. In summary, the combination of polymyxin B with KALYDECO or ORKAMBI exhibited synergistic activity against highly polymyxin-resistant P. aeruginosa CF isolates and can be potentially useful for otherwise untreatable CF lung infections.]]> Thu 04 Nov 2021 10:40:12 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:25955 non-CF and pAEC_CF, respectively) during exposure to physiologically relevant NE. The effect of NE activity on pAEC_CF wound repair was also assessed. We report that viability after 48 hours was significantly decreased by 100 nM NE in pAEC_non-CF and pAEC_CF owing to rapid cellular detachment that was accompanied by inflammatory cytokine release. Furthermore, both phenotypes initiated an apoptotic response to 100 nM NE, whereas ≥50 nM NE activity significantly inhibited the proliferative capacity of cultures. Similar concentrations of NE also significantly inhibited wound repair of pAEC_CF, but this effect was reversed by the addition of α1AT. Collectively, our results demonstrate free NE activity is deleterious for epithelial homeostasis and support the hypothesis that proteases in the airway contribute directly to CF structural lung disease. Our results also highlight the need to investigate antiprotease therapies in early CF disease in more detail.]]> Thu 04 Nov 2021 10:39:27 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:31327 Thu 03 Feb 2022 12:22:23 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:34690 Thu 03 Feb 2022 12:20:07 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:7886 Sat 24 Mar 2018 08:35:09 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:7897 Sat 24 Mar 2018 08:35:09 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:1145 Sat 24 Mar 2018 08:32:05 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:2826 Sat 24 Mar 2018 08:28:24 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:1803 Sat 24 Mar 2018 08:27:33 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:12950 1) between patient cohorts receiving specialised care for different lengths of time. Results: Improved mean height z-score (−0.880 v −0.047) and weight centile (28.3% v 48.1%) for the 10–15 year age group in 1997, who had received continuous lifetime care within the clinic, compared with the same age group in 1993, for whom continuous medical care started at an older age. There was no corresponding improvement in FEV₁, as an indicator of lung function, in this group (81.6% predicted v 89.5% predicted). Conclusions: This study suggests that lifetime continuous care within a specialised CF centre is associated with improved growth but not improved lung function.]]> Sat 24 Mar 2018 08:18:29 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:12951 Sat 24 Mar 2018 08:18:29 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:12952 1) (94.2% ± 16.7 vs 85.9% ± 21.2; P = 0.19) were not significantly different. The averaged annual fall in FEV₁ over 4 years was also not significantly different (3.8% ± 3.8 vs 3.6% ± 3.7; P = 0.82). Weight percentile (Wt%), height percentile (Ht%) and percentage age weight for height (%WFH) were not significantly different between groups in 1993. By 1997, Wt% (36.7% ± 25.1 vs 22.3% ± 19.6; P = 0.04) and Ht% (42.5% ± 29.6 vs 17.6% ± 19.4; P = 0.002) but not %WFH (102% ± 10.0 vs 106% ± 11.2; P > 0.10) were lower in subjects with B. cepacia. Conclusions: In adolescent CF patients, colonization with the Hunter strain of B. cepacia was associated with a deterioration in some nutritional parameters but not with an accelerated decline in FEV₁ over 4 years. As varying pathogenicity of B. cepacia strains may account for differing rates of pulmonary decline, further assessment of the consequences of colonization with certain strains of B. cepacia in CF is needed.]]> Sat 24 Mar 2018 08:18:28 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:5904 Sat 24 Mar 2018 07:47:59 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:5276 Sat 24 Mar 2018 07:46:27 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:28305 97%) to plasma proteins, there is the strong possibility that co-administered CF drugs may compete for the same plasma protein binding sites and impact the free drug concentration. This, in turn, could lead to drastic changes in the in vivo efficacy of ivacaftor and therapeutic outcomes. This biochemical study compares the binding affinity of ivacaftor and co-administered CF drugs for human serum albumin (HSA) and α₁-acid glycoprotein (AGP) using surface plasmon resonance and fluorimetric binding assays that measure the displacement of site-selective probes. Because of their ability to strongly compete for the ivacaftor binding sites on HSA and AGP, drug–drug interactions between ivacaftor are to be expected with ducosate, montelukast, ibuprofen, dicloxacillin, omeprazole, and loratadine. The significance of these plasma protein drug–drug interactions is also interpreted in terms of molecular docking simulations. This in vitro study provides valuable insights into the plasma protein drug–drug interactions of ivacaftor with co-administered CF drugs. The data may prove useful in future clinical trials for a staggered treatment that aims to maximize the effective free drug concentration and clinical efficacy of ivacaftor.]]> Sat 24 Mar 2018 07:27:06 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:28201 Sat 24 Mar 2018 07:23:53 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:4767 Sat 24 Mar 2018 07:20:41 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:22218 Sat 24 Mar 2018 07:17:44 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:22105 Sat 24 Mar 2018 07:10:20 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:46958 40% predicted. We set out to observe the most sensitive clinical measure that would change with treatment in terms of exercise capacity or lung function in adults with severe lung disease as defined by an FEV1 < 40% predicted when clinically stable. Methods: 10 adults homozygous for the Phe508del received LUM/IVA. We assessed; six minute walk test (6MWT), spirometry, gas transfer (DLCO), plethysmography, and nitrogen multiple breath washout (MBW) at baseline, 4, 12, 24 and 52 weeks. Comparison was made with 10 matched historical controls that had been observed over 12 months. Results: There was a significant improvement in 6MWT by 4 weeks of treatment; with a mean increase of 78 m (SD 62.3) and this increased to 118.1 m (SD 80.9) (ANOVA p = 0.006) by 52 weeks. Significant improvements were also seen in the resting heart rate and the oxygen saturation (SaO2) after 6 min walking. A significant improvement was not seen in FEV1 though until 24 weeks, though this was maintained at 52 weeks (ANOVA, p = 0.0004). There were no significant differences seen in the MBW or DLCO. After 12 months treatment with LUM/IVA, in comparison to historical controls; the 6MWT increased by 118 m (SD 80.9), but fell in the controls - 61.3 m (SD 31.1). FEV1; LUM/IVA led to an increase of 0.398 L/min, compared to a fall in the controls - 0.18 (SD 0.2). Conclusion: In adults homozygous for Phe508del with severe disease, treatment with LUM/IVA results in a clinically significant improvement in 6MWT that was evident at 4 weeks and maintained at 52 weeks. Improvement in exercise tolerance is an important outcome to consider in those with more severe airways disease. Trial registration: This was an observational trial conducted on individuals who became eligible to receive LUM/IVA. All investigations were carried out as part of routine clinical care. The trial was registered in retrospect on the 13/5/2019 on the Australian New Zealand Clinical Trials registry; ACTRN12619000708156.]]> Mon 12 Dec 2022 10:01:33 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:52281 Mon 09 Oct 2023 10:04:55 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:49260 Mon 08 May 2023 11:03:18 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:36544 Pseudomonas aeruginosa may be an effective adjunctive for conventional antibiotic treatment against biofilm-dwelling P. aeruginosa. We, therefore, assessed the anti-biofilm activity of N,N’-bis (2-hydroxybenzyl) ethylenediamine-N,N’-diacetic acid (HBED), which is a synthetic hexadentate iron chelator. The effect of HBED was studied using short-term (microtitre plate) and longer-term (flow-cell) biofilm models, under aerobic, anaerobic, and microaerobic (flow-cell) conditions and in combination with the polymyxin antibiotic colistimethate sodium (colistin). HBED was assessed against strains of P. aeruginosa from patients with cystic fibrosis and the reference strain PAO1. HBED inhibited growth and biofilm formation of all clinical strains under aerobic and anaerobic conditions, but inhibitory effects against PAO1 were predominantly exerted under anaerobic conditions. PA605, which is a clinical strain with a robust biofilm-forming phenotype, was selected for flow-cell studies. HBED significantly reduced biomass and surface coverage of PA605, and, combined with colistin, HBED significantly enhanced the microcolony killing effects of colistin to result in almost complete removal of the biofilm. HBED combined with colistin is highly effective in vitro against biofilms formed by clinical strains of P. aeruginosa.]]> Mon 01 Jun 2020 17:28:29 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:40051 40%. There is limited safety or efficacy data in patients with ppFEV1 < 40%. We determined whether LUM/IVA in patients with ppFEV1 < 40 would reduce the rate of pul- monary exacerbations. Methods: This was a case control study performed on patients > 12 years, homozygous for Phe508del CFTR mutation and with ppFEV1 < 40%. Control subjects were matched for age, sex and ppFEV1, and had mutations ineligible for LUM/IVA. We assessed the rate of pulmonary exacerbations requiring intravenous antibiotics, the mean rate of change in ppFEV1 over 12 months and all adverse events. Results: Data was collected from 7 Australian CF centres on 105 patients; 72 on LUM/IVA and 33 controls. LUM/IVA demonstrated a large reduction in exacerbations with an incident rate ratio of 0.455 (95%CI; 0.306 –0.676), p < 0.001 after adjusting for the number of exacerbations in the previous 12 months. LUM/IVA prolonged the time to first exacerbation and reduced the rate of decline in ppFEV1 over 12 months. Adverse events were common; chest tightness or dyspnoea was experienced by 55% and resulted in cessation of treatment in 32%. Conclusions: Treatment with LUM/IVA resulted in a substantially lower rate of pulmonary exacerbations, prolonged time to first exacerbation and slowed the rate of decline of ppFEV1 in participants with severe lung disease. Adverse reactions to LUM/IVA however were unacceptably frequent, and resulted in a very high discontinuation rate.]]> Fri 22 Jul 2022 13:27:19 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:40893 Streptococcus pneumoniae, non-typeable Haemophilus influenzae, Mycobacterium tuberculosis, Aspergillus fumigatus, etc., have the ability to elicit pro-oxidant pathways in the respiratory tract. Also, these pathogens are equipped with enzymatic and non-enzymatic mechanisms to neutralize host-associated oxidative molecules that facilitate the persistence of these pathogens in the lungs. We will discuss the CRD/pathogen-triggered oxidative stress in the lungs. We will also discuss the microbial mechanisms that may further increase oxidative stress in patients with CRDs that potentially results in the heightened inflammatory response in the lungs. Finally, we will discuss the current treatment strategies to limit the oxidative response-associated lung pathologies.]]> Fri 22 Jul 2022 10:38:45 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:51754 Fri 15 Sep 2023 18:27:57 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:41784 Fri 12 Aug 2022 12:10:18 AEST ]]>