Infected pancreatic necrosis: outcomes and clinical predictors of mortality. A post hoc analysis of the MANCTRA-1 international study

: The identification of high-risk patients in the early stages of infected pancreatic necrosis (IPN) is critical, because it could help the clinicians to adopt more effective management strategies. We conducted a post hoc analysis of the MANCTRA-1 international study to assess the association between clinical risk factors and mortality among adult patients with IPN. Univariable and multivariable logistic regression models were used to identify prognostic factors of mortality. We identified 247 consecutive patients with IPN hospitalised between January 2019 and December 2020. History of uncontrolled arterial hypertension (p = 0.032; 95% CI 1.135-15.882; aOR 4.245), qSOFA (p = 0.005; 95% CI 1.359-5.879; aOR 2.828), renal failure (p = 0.022; 95% CI 1.138-5.442; aOR 2.489), and haemodynamic failure (p = 0.018; 95% CI 1.184-5.978; aOR 2.661), were identified as independent predictors of mortality in IPN patients. Cholangitis (p = 0.003; 95% CI 1.598-9.930; aOR 3.983), abdominal compartment syndrome (p = 0.032; 95% CI 1.090-6.967; aOR 2.735), and gastrointestinal/intra-abdominal bleeding (p = 0.009; 95% CI 1.286-5.712; aOR 2.710) were independently associated with the risk of mortality. Upfront open surgical necrosectomy was strongly associated with the risk of mortality (p < 0.001; 95% CI 1.912-7.442; aOR 3.772), whereas endoscopic drainage of pancreatic necrosis (p = 0.018; 95% CI 0.138-0.834; aOR 0.339) and enteral nutrition (p = 0.003; 95% CI 0.143-0.716; aOR 0.320) were found as protective factors. Organ failure, acute cholangitis, and upfront open surgical necrosectomy were the most significant predictors of mortality. Our study confirmed that, even in a subgroup of particularly ill patients such as those with IPN, upfront open surgery should be avoided as much as possible. Study protocol registered in ClinicalTrials.Gov (I.D. Number NCT04747990)

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

Background Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.Methods A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.Findings Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3.85 [95% CI 2.58-5.75]; p<0.0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63.0% vs 82.7%; OR 0.35 [0.23-0.53]; p<0.0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.Interpretation Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised

Unlocking the mechanisms of interactions between anti-inflammatories and antibiotics for optimal cystic fibrosis treatment

CHAPTER 1 This chapter comprises a literature review exploring the potential role of inhaled anti-inflammatory drugs as an effective treatment option for cystic fibrosis (CF) patients, in comparison with current oral delivery is presented. Specifically, the focus is on ibuprofen (IBU), the only non-steroidal anti-inflammatory drug approved for chronic use in CF. The need for inhalation therapy and the various delivery platforms for inhalation has also been highlighted with an insight into the reasons and challenges associated with developing an inhalation therapy of non-steroidal anti-inflammatory drugs (NSAIDs). This chapter has been published in Expert Opinion on Orphan Drugs, 2018. 6 (1): 69 - 84 under the title “Is there a role for inhaled anti-inflammatory drugs in cystic fibrosis treatment?” Authors: Z. Sheikh, H.X. Ong, M. Pozzoli, P.M. Young, D. Traini CHAPTER 2 This chapter focused on understanding the mechanisms of interactions between the anti-inflammatory drug ibuprofen (IBU) with each of the CF-approved inhaled antibiotics (Tobramycin/TOBI, Colistin/COL or the Colistin prodrug Tadim), including anti-bacterial and anti-inflammatory effects. Chemical interactions of the IBU: antibiotic combinations were elucidated using High-Resolution Mass-Spectrometry (HRMS) and 1H NMR. HRMS showed pairing of IBU and TOBI, further confirmed by 1H NMR, whilst no pairing was observed for either IBU: COL or IBU: Tadim. The anti-bacterial activity of the combinations against Pseudomonas aeruginosa (PAO) showed that neither paired nor non-paired IBU: antibiotic therapies altered the anti-bacterial activity. The anti-inflammatory efficacy of the combination therapies was then determined at two different concentrations (Low and High) using in vitro models of NuLi-1 (healthy) and CuFi-1 (CF) cell lines. Differential response in the anti-inflammatory efficacy of IBU: TOBI was observed between the two concentrations due to changes in the structural conformation of the paired IBU: TOBI complex at High concentration, confirmed by 1H NMR. In contrast, the non-pairing of the IBU: COL and IBU: Tadim combinations showed a significant decrease in IL-8 secretion at both the concentrations tested. Importantly, all antibiotics alone showed anti-inflammatory properties, highlighting the inherent anti-inflammatory properties of these antibiotics. These findings have significant implications for the delivery of combination treatments of IBU and the antibiotics and possible drug-drug interactions at the cellular level. This chapter is currently under review in European Journal of Pharmacology, 2020 under the title “Tobramycin and Colistin display anti-inflammatory properties in CuFi-1 cystic fibrosis cell line’’. Authors: Z. Sheikh, P. Bradbury, T.A. Reekie, M. Pozzoli, P.D. Robinson, M. Kassiou, P.M. Young, H.X. Ong, D. Traini CHAPTER 3 Following on from Chapter 2, Chapter 3 was aimed at developing an in vitro model with characteristic features of the CF airways for assessing drug transport of inhaled therapies used in CF treatment. Novel inhalable drug therapies require an in vitro CF model that appropriately mimics the in vivo CF lung environment to better understand drug delivery and transport across the CF epithelium, and predict drug therapeutic efficacy. In this context, an air-liquid interface (ALI) culture method of the CuFi-1 (CF cell line) was optimised and compared to the NuLi-1 (healthy cell line) cells concerning media composition, culture period and epithelial differentiation. Furthermore, drug transport on both CuFi-1 and NuLi-1 was investigated to determine whether these cell lines could be used to study the transport of drugs in CF treatment, using Ibuprofen as a model drug. Differentiating characteristics specific to airway epithelia such as mucus production, inflammatory response and tight junction formation at two seeding densities (Low and High) were assessed throughout an 8-week ALI culture period. This study demonstrated that both the NuLi-1 and CuFi-1 cell lines fully differentiate in ALI culture with significant mucus secretion, pro-inflammatory cytokines IL-6 and IL-8 production, and functional tight junctions at week 8. For the first time, this study identified that ibuprofen is transported via the paracellular pathway in ALI models of NuLi-1 and CuFi-1 cell lines. Overall, these findings highlighted NuLi-1 and CuFi-1 as promising in vitro ALI models to investigate the transport properties of novel inhalable drug therapies for CF treatment. This chapter has been published in European Journal of Pharmaceutics and Biopharmaceutics, 2020. 156: 121 – 130 under the title “An in vitro model for assessing drug transport in cystic fibrosis treatment: Characterisation of the CuFi-1 cell line”. Authors: Z. Sheikh, P. Bradbury, M. Pozzoli, P.M. Young, H.X. Ong, D. Traini CHAPTER 4 Once established that the ALI models of NuLi-1 and CuFi-1 are suitable cell culture models to study drug transport of inhaled therapies in Chapter 3, Chapter 4 focused on exploring diclofenac (DICLO) as an anti-inflammatory option for CF treatment using these in vitro ALI models of NuLi-1 and CuFi-1. As anti-inflammatory treatment options for CF are limited, there is a need to develop new anti-inflammatory agents. Therefore, a novel pressurized metered dose inhalation (pMDI) formulation of DICLO was successfully developed with the subsequent characterization of the in vitro aerosol performance, transport properties and anti-inflammatory activity across the NuLi-1 and CuFi-1 ALI models. A significantly higher amount of DICLO was transported across the ALI cultures for simulated inhaled delivery in comparison to simulated oral delivery, suggesting the potential of using the inhaled route for targeted delivery of DICLO to the lungs. Consequently, two DICLO pMDI formulations were developed to allow targeted DICLO delivery to CF airways: a Low dose formulation (delivering 150 µg of DICLO per dose) and a High dose formulation (delivering 430 µg of DICLO per dose) and characterized to determine the optimum formulation. The Low dose pMDI DICLO formulation showed a significantly smaller particle size diameter with uniform distribution resulting in a greater aerosol performance when compared to High dose formulation. Importantly, the Low dose DICLO pMDI was efficiently transported across the ALI models and displayed anti-inflammatory activity in both healthy and CF in vitro models, overall highlighting the potential of an aerosolized low-dose DICLO formulation as a promising inhaled anti-inflammatory therapy for CF treatment. This chapter is currently under review for publication in International Journal of Pharmaceutics, 2020 with the title “Development and in vitro characterization of a novel pMDI diclofenac formulation as an inhalable anti-inflammatory therapy for cystic fibrosis”. Authors: Z. Sheikh, L.G. Dos Reis, P. Bradbury, G. Meneguzzo, S. Scalia, P.M. Young, H.X. Ong, D. Traini CHAPTER 5 Ultimately, Chapter 5 summarizes the overall findings presented in this thesis including prospects. The inhaled route allows targeted drug delivery to the lungs at low doses, overcoming decreased bioavailability issues and other systemic side-effects associated with high oral doses. Owing to these numerous advantages of inhaled delivery, the role of potential inhaled anti-inflammatory drugs used in CF treatment with a particular focus on ibuprofen has been investigated. The mechanisms of interactions between the two primary modalities of CF treatment – anti-inflammatory drugs (ibuprofen) and antibiotics was further elucidated to determine if a combination therapy could be more beneficial. Surprisingly, ibuprofen in combination with the antibiotics did not significantly decrease inflammation in a CF model when compared to the drugs alone, suggesting that new anti-inflammatory drugs must be explored to identify a more effective combination treatment. However, to study the drug delivery of novel therapies, an in vitro model simulating the CF lung and suitable to assess drug transport is required. Hence, an in vitro CF bronchial epithelium model to study drug transport was developed and characterized to recapitulate the CF airways and compared to a healthy epithelial model. Finally, a low dose inhalation formulation of novel anti-inflammatory drug diclofenac was successfully developed and characterized in terms of transport and anti-inflammatory activity using these established models. Future studies will focus on investigating the interactions of diclofenac with the CF-approved antibiotics on the developed models and correlate these findings in vivo to comprehend its clinical relevance to optimize CF treatment and reduce treatment burden of CF patients

Optimizing oral drug delivery using lipid based formulations

This article was published in International Research Journal of Pharmacy [© 2014 International Research Journal of Pharmacy] and the definite version is available at: https://goo.gl/TTYiEn The Article's website is at: www.irjponline.comA great challenge facing the pharmaceutical scientists is transforming the new pharmacologically active lipophilic compounds that are poorly water soluble into orally administered medications with sufficient bioavailability. Lipid-based drug delivery systems has shown a great potential in the oral delivery of poorly water-soluble drugs, primarily for lipophilic drugs, with several successfully marketed products. Oral lipid-based formulations comprises of a broad range of oils, surfactants, and co-solvents. This review provides a comprehensive summary of the development, characterization, and utilization of oral lipid- based formulations, from both physicochemical and biopharmaceutical perspectives. The properties of the various lipid excipients are discussed and the criteria for selection of excipients for lipid-based formulations are identified. Finally the future prospects of this technique have been addressed to expand the utility of lipid based drug delivery systems.Publishe

Development of Inhalable Spray Dried Nitrofurantoin Formulations for the Treatment of Emphysema

A central characteristic of emphysematous progression is the continuous destruction of the lung extracellular matrix (ECM). Current treatments for emphysema have only addressed symptoms rather than preventing or reversing the loss of lung ECM. Nitrofurantoin (NF) is an antibiotic that has the potential to induce lung fibrosis as a side effect upon oral administration. Our study aims to repurpose NF as an inhalable therapeutic strategy to upregulate ECM expression, thereby reversing the disease progression within the emphysematous lung. Spray-dried (SD) formulations of NF were prepared in conjunction with a two-fluid nozzle (2FN) and three-fluid nozzle (3FN) using hydroxypropyl methylcellulose (HPMC) and NF at 1:1 w/w. The formulations were characterized for their physicochemical properties (particle size, morphology, solid-state characteristics, aerodynamic behaviour, and dissolution properties) and characterized in vitro with efficacy studies on human lung fibroblasts. The 2FN formulation displayed a mass mean aerodynamic diameter (MMAD) of 1.8 ± 0.05 µm and fine particle fraction (FPF) of 87.4 ± 2.8% with significantly greater deposition predicted in the lower lung region compared to the 3FN formulation (MMAD: 4.4 ± 0.4 µm; FPF: 40 ± 5.8%). Furthermore, drug dissolution studies showed that NF released from the 2FN formulation after 3 h was significantly higher (55.7%) as compared to the 3FN formulation (42.4%). Importantly, efficacy studies in human lung fibroblasts showed that the 2FN formulation induced significantly enhanced ECM protein expression levels of periostin and Type IV Collagen (203.2% and 84.2% increase, respectively) compared to untreated cells, while 3FN formulations induced only a 172.5% increase in periostin and a 38.1% increase in type IV collagen. In conclusion, our study highlights the influence of nozzle choice in inhalable spray-dried formulations and supports the feasibility of using SD NF prepared using 2FN as a potential inhalable therapeutic agent to upregulate ECM protein production

The development of a 3D-printed in vitro integrated oro-pharyngeal air-liquid interface cellular throat model for drug transport

To simulate the deposition of drugs in the oro-pharynx region, several in vitro models are available such as the United States Pharmacopeia-Induction Port (USP-IP) throat and the Virginia Commonwealth University (VCU) models. However, currently, there is no such in vitro model that incorporates a biological barrier to elucidate drug transport across the pharyngeal cells. Cellular models such as in vitro air-liquid interface (ALI) models of human respiratory epithelial cell lines are extensively used to study drug transport. To date, no studies have yet been performed to optimise the ALI culture conditions of the human pharyngeal cell line Detroit 562 and determine whether it could be used for drug transport. Therefore, this study aimed to develop a novel 3D-printed throat model integrated with an ALI cellular model of Detroit 562 cells and optimise the culture conditions to investigate whether the combined model could be used to study drug transport, using Lidocaine as a model drug. Differentiating characteristics specific to airway epithelia were assessed using 3 seeding densities (30,000, 60,000, and 80,000 cells/well (c/w), respectively) over 21 days. The results showed that Detroit 562 cells completely differentiates on day 18 of ALI for both 60,000 and 80,000 c/w with significant mucus production, showing response to bacterial and viral stimuli and development of functional tight junctions and Lidocaine transport with no significant differences observed between the ALI models with the 2 cell seeding densities. Results showed the suitability of the Low density (60,000 c/w or 1.8 × 105 cells/cm2) ALI model to study drug transport. Importantly, the developed novel 3D-printed throat model integrated with our optimised in vitro Detroit 562 ALI model showed transport of Lidocaine throat spray. Overall, the study highlights the potential of the novel 3D-printed bio-throat integrated model as a promising in vitro system to investigate the transport of inhalable drug therapies targeted at the oro-pharyngeal region

IXD for the Planet: Interaction Design projects in sustainability and the environment

This selection of projects and assignments shows how QUT Interaction Design (IXD) students and staff are leveraging discipline methods to engage with the critical concerns around sustainability and the environment. The work is from IXD first, second and third year students, PhD and Masters students, and IXD academics - many also active in QUT's 'More than Human' research group. Demonstrated here are the design processes to ideate and come up with designs and new understandings, through to creating prototypes and final outcomes. From programming to theory to studio practice, these designers and researchers create experiences to educate and engage in the environment ; and propose solutions for more sustainable futures.A celebration of QUT's inaugural sustainability week, this selection of projects was shown at the QUT Cube visualisation facility in Brisbane city