Assessment and reduction of the impacts of large freight vehicles on urban traffic corridor performance

Increasing demand for road freight has lead to a widespread adoption of more-productive large freight vehicles (LFVs), such as B-Doubles, by Australia's road freight industry. Individual LFVs have a greater potential to impact traffic efficiency through their greater length and poorer longitudinal performance. However, this is offset to an extent as fewer vehicles are required to perform a given freight task on a tonne-km basis. This research has developed a means of characterising the effects that large freight vehicles have on the performance of an urban arterial corridor managed by signalised intersections. A corridor-level microsimulation model was developed from first principles, which modelled the longitudinal performance of individual vehicles to a greater accuracy than most existing traffic simulation software does. The model was calibrated from traffic counts and GPS-equipped chase car surveys conducted on an urban arterial corridor in Brisbane's southern suburbs. The model was applied to various freight policy and traffic management scenarios, including freight vehicle mode choice, lane utilisation and traffic signal settings; as well as the effectiveness of green time extension for approaching heavy vehicles. Benefits were able to be quantified in terms of reduced travel times and stop rates for both heavy and light vehicles in urban arterial corridors

The review of Melbourne’s Principal Public Transport Network

The integrated transport and land use strategy, Melbourne 2030, defined a Principal Public Transport Network (PPTN) in 2002 intended to provide a high quality and direct public transport connection between the activity centres. The PPTN was recently revised by the Department of Transport in response to growth in Melbourne‟s population, introduction of new services to support that growth, and release of several strategies to supplement the original Melbourne 2030.This paper summarises the process undertaken in reviewing the PPTN. It re-examines the original definition, emphasising connection to activity centres rather than between them, sets out a list of objectives of the network and the criteria used to select the individual links that form the network.Examples of proposed revisions to the network are presented, which would improve accessibility to activity centres, and improve both the catchment and coverage by public transport services. Relations to other defined transport networks are examined, particularly the Principal Freight Network and the Principal Bicycle Network, as is the implementation of the PPTN as both a land use planning tool and within VicRoads‟ network operating plans

Nanomedicines : exploring the past, present and future

Nanoparticles, and liposomes in particular, are growing in popularity as drug delivery vehicles for anti-cancer agents and inflammatory disease therapies, as well as forming the basis of a new class of vaccines. They offer a number of advantages in terms of stability, efficacy and off-target effects, but traditional manufacturing methods are labour-intensive, hard to reproduce and difficult to scale up. This has contributed to a widely-held perception in the pharmaceutical industry that nanomedicines are far from clinically practical. A new generation of microfluidic systems is helping to overcome these issues, allowing the rapid development and seamless scale-up of novel nanoparticles. This technology is transforming the development and manufacture of a range of nanoparticle formulations from a hit-and-miss affair into a standardised process, accelerating novel nanomedicines from the bench to the clinic

Poor outcomes in patients with sepsis undergoing emergency laparotomy and laparoscopy are attenuated by faster time to care measures

ACKNOWLEDGEMENTS NE received the University of Aberdeen Innes Will Endowed Research Scholarship 2022 to carry out the research. FUNDING INFORMATION The Emergency Laparotomy and Laparoscopic Scottish Audit (ELLSA) is a Scottish Government initiative supported via the Modernising Patient Pathways Programme (MPPP).Peer reviewedPublisher PD

Liposomal irinotecan: formulation development and therapeutic assessment in murine xenograft models of colorectal cancer

ABSTRACT Purpose: The purpose is to demonstrate whether an appropriately designed liposomal formulation of irinotecan is effective in treating mice with liver-localized colorectal carcinomas. Experimental Design: Irinotecan was encapsulated in 1,2-distearoyl-sn-glycero-3-phosphocholine/cholesterol (55:45 molar ratio) liposomes using an ionophore (A23187)-generated transmembrane proton gradient. This formulation was evaluated in vivo by measuring plasma elimination of liposomal lipid and drug after i.v. administration. Therapeutic activity was determined in SCID/Rag-2M mice bearing s.c. LS180 tumors or orthotopic LS174T colorectal metastases. Results: Drug elimination from the plasma was significantly reduced when irinotecan was administered in the liposomal formulation. At 1 hour after i.v. administration, circulating levels of the liposomal drug were 100-fold greater than that of irinotecan given at the same dose. High-performance liquid chromatographic analysis of plasma samples indicated that liposomal irinotecan was protected from inactivating hydrolysis to the carboxylate form. This formulation exhibited substantially improved therapeutic effects. For the LS180 solid tumor model, it was shown that after a single injection of liposomal irinotecan at 50 mg/kg, the time to progress to a 400-mg tumor was 34 days (as compared with 22 days for animals treated with free drug at an equivalent dose). In the model of colorectal liver metastases (LS174T), a median survival time of 79 days was observed after treatment with liposomal irinotecan (50 mg/kg, given every 4 days for a total of three doses). Saline and free drug treated mice survived for 34 and 53 days, respectively. Conclusions: These results illustrate that liposomal encapsulation can substantially enhance the therapeutic activity of irinotecan and emphasize the potential for using liposomal irinotecan to treat liver metastases

Genomic and molecular analyses identify molecular subtypes of pancreatic cancer recurrence

Pancreatic cancer (PC) remains a highly lethal malignancy, and most patients with localized disease that undergo surgical resection still succumb to recurrent disease. Pattern of recurrence after pancreatectomy is heterogenous, with some studies illustrating that site of recurrence can be associated with prognosis.1 Another study suggested that tumors that develop local and distant recurrence can be regarded as a homogenous disease with similar outcomes.2 Here we investigate novel molecular determinants of recurrence pattern after pancreatectomy for PC

Liposomes in Biology and Medicine

Drug delivery systems (DDS) have become important tools for the specific delivery of a large number of drug molecules. Since their discovery in the 1960s liposomes were recognized as models to study biological membranes and as versatile DDS of both hydrophilic and lipophilic molecules. Liposomes--nanosized unilamellar phospholipid bilayer vesicles--undoubtedly represent the most extensively studied and advanced drug delivery vehicles. After a long period of research and development efforts, liposome-formulated drugs have now entered the clinics to treat cancer and systemic or local fungal infections, mainly because they are biologically inert and biocompatible and practically do not cause unwanted toxic or antigenic reactions. A novel, up-coming and promising therapy approach for the treatment of solid tumors is the depletion of macrophages, particularly tumor associated macrophages with bisphosphonate-containing liposomes. In the advent of the use of genetic material as therapeutic molecules the development of delivery systems to target such novel drug molecules to cells or to target organs becomes increasingly important. Liposomes, in particular lipid-DNA complexes termed lipoplexes, compete successfully with viral gene transfection systems in this field of application. Future DDS will mostly be based on protein, peptide and DNA therapeutics and their next generation analogs and derivatives. Due to their versatility and vast body of known properties liposome-based formulations will continue to occupy a leading role among the large selection of emerging DDS

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Background and aims: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress and novel therapeutic response in PC to develop a biomarker driven therapeutic strategy targeting DDR and replication stress in PC. Methods: We interrogated the transcriptome, genome, proteome and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient derived xenografts and human PC organoids. Results: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, co-segregates with response to platinum (P < 0.001) and PARP inhibitor therapy (P < 0.001) in vitro and in vivo. We generated a novel signature of replication stress with which predicts response to ATR (P < 0.018) and WEE1 inhibitor (P < 0.029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P < 0.001) but not associated with DDR deficiency. Conclusions: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR proficient PC, and post-platinum therapy

Prognostic value of estimated glomerular filtration rate in hospitalised older patients (over 65) with COVID-19: a multicentre, European, observational cohort study

Background: The reduced renal function has prognostic significance in COVID-19 and it has been linked to mortality in the general population. Reduced renal function is prevalent in older age and thus we set out to better understand its effect on mortality. Methods: Patient clinical and demographic data was taken from the COVID-19 in Older People (COPE) study during two periods (February–June 2020 and October 2020–March 2021, respectively). Kidney function on admission was measured using estimated glomerular filtration rate (eGFR). The primary outcomes were time to mortality and 28-day mortality. Secondary outcome was length of hospital stay. Data were analysed with multilevel Cox proportional hazards regression, and multilevel logistic regression and adjusted for individual patient clinical and demographic characteristics. Results: One thousand eight hundred two patients (55.0% male; median [IQR] 80 [73–86] years) were included in the study. 28-day mortality was 42.3% (n = 742). 48% (n = 801) had evidence of renal impairment on admission. Using a time-to-event analysis, reduced renal function was associated with increased in-hospital mortality (compared to eGFR ≥ 60 [Stage 1&2]): eGFR 45–59 [Stage 3a] aHR = 1.26 (95%CI 1.02–1.55); eGFR 30–44 [Stage 3b] aHR = 1.41 (95%CI 1.14–1.73); eGFR 1–29 [Stage 4&5] aHR = 1.42 (95%CI 1.13–1.80). In the co-primary outcome of 28-day mortality, mortality was associated with: Stage 3a adjusted odds ratio (aOR) = 1.18 (95%CI 0.88–1.58), Stage 3b aOR = 1.40 (95%CI 1.03–1.89); and Stage 4&5 aOR = 1.65 (95%CI 1.16–2.35). Conclusion: eGFR on admission is a good independent predictor of mortality in hospitalised older patients with COVID-19 population. We found evidence of a dose-response between reduced renal function and increased mortality

Management of Competing Demands on Urban Freight Corridors

This paper compares the performance under various scenarios of an urban traffic corridor section subjected to a range of vehicle types. A micro-simulation-based model of the corridor was developed from first principles to stochastically assign characteristics and headways for each vehicle and then to track each vehicle as it moved along the corridor. Kinematic behaviour of the different vehicle types (ranging from passenger cars through to B-doubles) were obtained from GPS data collected during a series of chase car surveys on an urban arterial freight route in suburban Brisbane. Corridor performance was reported in terms of intersection capacity and delays as well as travel speeds and stop rates for each vehicle type. The performance of the corridor was found to be sensitive to traffic control measures including the speed limit and traffic signal controller settings such as cycle time and progression design speed. A range of freight policy scenarios were examined, including the effects of increasing freight volumes, choice of freight vehicles used, and vehicle type-specific lane restrictions. Some policies having the potential to improve corridor traffic performance and freight efficiency were able to be identified