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Quorum-sensing (QS) systems of Pseudomonas aeruginosa are involved in the control of biofilm formation and virulence factor production. The current study evaluated the ability of halogenated dihydropyrrol-2-ones (DHP) (Br (4a), Cl (4b), and F (4c)) and a non-halogenated version (4d) to inhibit the QS receptor proteins LasR and PqsR. The DHP molecules exhibited concentration-dependent inhibition of LasR and PqsR receptor proteins. For LasR, all compounds showed similar inhibition levels. However, compound 4a (Br) showed the highest decrease (two-fold) for PqsR, even at the lowest concentration (12.5 µg/mL). Inhibition of QS decreased pyocyanin production amongst P. aeruginosa PAO1, MH602, ATCC 25619, and two clinical isolates (DFU-53 and 364707). In the presence of DHP, P. aeruginosa ATCC 25619 showed the highest decrease in pyocyanin production, whereas clinical isolate DFU-53 showed the lowest decrease. All three halogenated DHPs also reduced biofilm formation by between 31 and 34%. The non-halogenated compound 4d exhibited complete inhibition of LasR and had some inhibition of PqsR, pyocyanin, and biofilm formation, but comparatively less than halogenated DHPs.

Introduction: Urinary tract infections (UTIs) affect more than 150 million individuals annually. A strong correlation exists between bladder epithelia invasion by uropathogenic bacteria and patients with recurrent UTIs. Intracellular bacteria often recolonise epithelial cells post-antibiotic treatment. We investigated whether N-acetylcysteine (NAC) could prevent uropathogenic E. coli and E. faecalis bladder cell invasion, in addition to its effect on uropathogens when used alone or in combination with ciprofloxacin. Methods: An invasion assay was performed in which bacteria were added to bladder epithelial cells (BECs) in presence of NAC and invasion was allowed to occur. Cells were washed with gentamicin, lysed, and plated for enumeration of the intracellular bacterial load. Cytotoxicity was evaluated by exposing BECs to various concentrations of NAC and quantifying the metabolic activity using resazurin at different exposure times. The effect of NAC on the preformed biofilms was also investigated by treating 48 h biofilms for 24 h and enumerating colony counts. Bacteria were stained with propidium iodide (PI) to measure membrane damage. Results: NAC completely inhibited BEC invasion by multiple E. coli and E. faecalis clinical strains in a dose-dependent manner (p < 0.01). This was also evident when bacterial invasion was visualised using GFP-tagged E. coli. NAC displayed no cytotoxicity against BECs despite its intrinsic acidity (pH ~2.6), with >90% cellular viability 48 h post-exposure. NAC also prevented biofilm formation by E. coli and E. faecalis and significantly reduced bacterial loads in 48 h biofilms when combined with ciprofloxacin. NAC visibly damaged E. coli and E. faecalis bacterial membranes, with a threefold increase in propidium iodide-stained cells following treatment (p < 0.05). Conclusions: NAC is a non-toxic, antibiofilm agent in vitro and can prevent cell invasion and IBC formation by uropathogens, thus providing a potentially novel and efficacious treatment for UTIs. When combined with an antibiotic, it may disrupt bacterial biofilms and eliminate residual bacteria.

Cystic fibrosis (CF) is a disorder causing dysfunctional ion transport resulting in the accumulation of viscous mucus. This environment fosters a chronic bacterial biofilm-associated infection in the airways. Achromobacter xylosoxidans, a gram-negative aerobic bacillus, has been increasingly associated with antibiotic resistance and chronic colonisation in CF. In this study, we aimed to create a reproducible model of CF infection using an artificial sputum medium (ASMDM-1) with bronchial (BEAS-2B) and macrophage (THP-1) cells to test A. xylosoxidans infection and treatment toxicity. This study was conducted in three distinct stages. First, the tolerance of BEAS-2B cell lines and two A. xylosoxidans strains against ASMDM-1 was optimised. Secondly, the cytotoxicity of combined therapy (CT) comprising N-acetylcysteine (NAC) and the antibiotics colistin or ciprofloxacin was tested on cells alone in the sputum model in both BEAS-2B and THP-1 cells. Third, the efficacy of CT was assessed in the context of a bacterial infection within the live cell/sputum model. We found that a model using 20% ASMDM-1 in both cell populations tolerated a colistin–NAC-based CT and could significantly reduce bacterial loads in vitro (~2 log10 CFU/mL compared to untreated controls). This pilot study provides the foundation to study other bacterial opportunists that infect the CF lung to observe infection and CT kinetics. This model also acts as a springboard for more complex co-culture models.

Cystic fibrosis (CF) is a genetic disorder causing dysfunctional ion transport resulting in accumulation of viscous mucus that fosters chronic bacterial biofilm-associated infection in the airways. Achromobacter xylosoxidans and Stenotrophomonas maltophilia are increasingly prevalent CF pathogens and while Burkholderia cencocepacia is slowly decreasing; all are complicated by multidrug resistance that is enhanced by biofilm formation. This study investigates potential synergy between the antibiotics ciprofloxacin (0.5–128 µg/mL), colistin (0.5–128 µg/mL) and tobramycin (0.5–128 µg/mL) when combined with the neutral pH form of N-Acetylcysteine (NACneutral) (0.5–16.3 mg/mL) against 11 cystic fibrosis strains of Burkholderia, Stenotrophomonas and Achromobacter sp. in planktonic and biofilm cultures. We screened for potential synergism using checkerboard assays from which fraction inhibitory concentration indices (FICI) were calculated. Synergistic (FICI ≤ 0.5) and additive (0.5 > FICI ≥ 1) combinations were tested on irreversibly attached bacteria and 48 h mature biofilms via time-course and colony forming units (CFU/mL) assays. This study suggests that planktonic FICI analysis does not necessarily translate to reduction in bacterial loads in a biofilm model. Future directions include refining synergy testing and determining further mechanisms of action of NAC to understand how it may interact with antibiotics to better predict synergy.

Many unique chemical compounds and nanomaterials are being developed, and each one requires a considerable range of in vitro and/or in vivo toxicity screening in order to evaluate their safety. The current methodology of in vitro toxicological screening on cells is based on well-plate assays that require time-consuming manual handling or expensive automation to gather enough meaningful toxicology data. Cost reduction; access to faster, more comprehensive toxicity data; and a robust platform capable of quantitative testing, will be essential in evaluating the safety of new chemicals and nanomaterials, and, at the same time, in securing the confidence of regulators and end-users. Microfluidic chips offer an alternative platform for toxicity screening that has the potential to transform both the rates and efficiency of nanomaterial testing, as reviewed here. The inherent advantages of microfluidic technologies offer high-throughput screening with small volumes of analytes, parallel analyses, and low-cost fabrication.

Liquid–liquid flow profiles are central to the operation of microfluidic devices in a range of applications. We recently demonstrated a multi-stream solvent extraction (SX) chip that combines high-surface-to-volume ratios and volumetric throughput. Here, we study these flow profiles in detail using numerical simulations, with consideration of different boundary conditions. The two liquids differ in viscosity, modelled on platinum (aqueous) and extractant (organic) phases, and the position of the liquid–liquid interfaces (and therefore surface/volume and phase ratios) can be controlled by adjustment of flow rates. The prediction of the position of the interface requires the solution of the governing equations of fluid mechanics. The volume of fluid (VOF) method was used to simulate the dynamics of the organic and aqueous phases to reveal stable flow profiles. This experimentally validated computational model with the root-mean-square deviation of about 11 µm will be useful for simulation of microfluidic SX design and operation, particularly where process intensification is sought through scale-out.Graphic abstract

Objective  Postoperative pain management following scoliosis surgery has traditionally relied on intravenous opioids. The objective of this study was to evaluate the effect of elastomeric pain pumps. Methods A retrospective chart review of 81 adolescent patients who underwent scoliosis surgery in a seven-year period was performed. Patients were divided into three groups as the practice changed: (1) patient-controlled analgesia group (12 patients) who used intravenous (IV) opioids with oral opioids; (2) elastomeric pain pump group (28 patients) with the added use of bupivacaine; and (3) multimodal pain pump group (41 patients) with the added use of gabapentin and methocarbamol. Endpoints were analyzed for length of stay in the hospital, infection rate, and gastrointestinal retention. Results The length of stay in the elastomeric pain pump group was 3.1 days shorter than in the patient-controlled analgesia group ( = 0.004). The length of stay in the multimodal group was 3.9 days shorter than in the patient-controlled analgesia group ( = 0.001). The incidence of prolonged postoperative bowel retention decreased significantly from 25% to 18% to 2% ( = 0.03). Conclusions To our knowledge, this is the first study on the use of elastomeric pain pumps in conjunction with multimodal pain medication following scoliosis surgery. The use of elastomeric pain pumps was associated with clinically and statistically significant improvements in the postoperative course. The addition of methocarbamol and gabapentin was associated with a trend toward further improvements.

The application of microfluidic devices to industrial processing is relatively scarce due to the high volumetric throughputs that are generally required. One approach to increasing throughput is massive parallelisation (‘numbering-up’ or ‘scale-out’), which involves the use of many microfluidic devices working in parallel to multiply the overall throughput. Numbering-up is attractive because it is modular and eliminates traditional ‘scale-up’ stages on the path towards full-scale processing. However, numbering-up presents other challenges, some of which are addressed here for liquid–liquid extraction using Y–Y chips. The theoretical limits were explored using the extraction of hexachloroplatinate(IV) ions as an industry-relevant system (extraction using a secondary amine). Experimental numbering-up from one channel to five, and then ten, in an extraction module is demonstrated, with extraction performance unchanged with increasing throughput. Calculations suggest that further numbering-up to at least a 1000-channel module could be facilitated by minor modifications to the present circuit.

Summary We performed a randomised controlled trial (RCT) to determine whether risedronate 35 mg once weekly prevents bone loss following an 8-week reducing course of prednisolone given for an exacerbation of inflammatory bowel disease (IBD). The greatest change in bone mineral density (BMD) was at Ward's triangle (WT), which fell by 2.2% in the placebo group, compared with a reduction of 0.8% in the risedronate group. Introduction Whether bisphosphonates can prevent bone loss associated with intermittent glucocorticoid (GC) therapy is unknown, reflecting the difficulty in performing RCTs in this context. Method To explore the feasibility of RCTs to examine this question, lumbar spine (LS; L2-4) and hip dual X-ray absorptiometry (DXA) scans were performed in 78 patients commencing a GC therapy course for a relapse of IBD. They were then randomised to receive placebo or risedronate 35 mg weekly for 8 weeks, after which the DXA scan was repeated. Results For LS BMD, there was no change in the placebo group (0.1 ± 0.4, p = 0.9), but there was an increase after risedronate (0.8 ± 0.4, p = 0.04; mean% ± SEM by paired Student's t test). There were small decreases in both groups at the total hip (−0.5 ± 0.3, p = 0.04; −0.5 ± 0.3, p < 0.05, placebo and risedronate, respectively). At WT, BMD fell after placebo (−2.2 ± 0.5, p = 0.001) but not risedronate (−0.8 ± 0.5, p = 0.09; p = 0.05 for between-group comparison). Conclusion RCTs can be used to examine whether bisphosphonates prevent bone loss associated with intermittent GC therapy, providing metabolically active sites such as WT are employed as the primary outcome.

Cystic fibrosis (CF) is a disorder causing dysfunctional ion transport resulting in the accumulation of viscous mucus. This environment fosters a chronic bacterial biofilm-associated infection in the airways. Achromobacter xylosoxidans, a gram-negative aerobic bacillus, has been increasingly associated with antibiotic resistance and chronic colonisation in CF. In this study, we aimed to create a reproducible model of CF infection using an artificial sputum medium (ASMDM-1) with bronchial (BEAS-2B) and macrophage (THP-1) cells to test A. xylosoxidans infection and treatment toxicity. This study was conducted in three distinct stages. First, the tolerance of BEAS-2B cell lines and two A. xylosoxidans strains against ASMDM-1 was optimised. Secondly, the cytotoxicity of combined therapy (CT) comprising N-acetylcysteine (NAC) and the antibiotics colistin or ciprofloxacin was tested on cells alone in the sputum model in both BEAS-2B and THP-1 cells. Third, the efficacy of CT was assessed in the context of a bacterial infection within the live cell/sputum model. We found that a model using 20% ASMDM-1 in both cell populations tolerated a colistin–NAC-based CT and could significantly reduce bacterial loads in vitro (~2 log[sub.10] CFU/mL compared to untreated controls). This pilot study provides the foundation to study other bacterial opportunists that infect the CF lung to observe infection and CT kinetics. This model also acts as a springboard for more complex co-culture models.