Characterisation of burden of illness measures associated with human (Fluoro)quinolone-resistant Campylobacter spp. infections - a scoping review.

Campylobacter spp. are one of the most common causes of bacterial gastroenteritis in Canada and worldwide. Fluoroquinolones are often used to treat complicated human campylobacteriosis and strains of Campylobacter spp. resistant to these drugs are emerging along the food chain. A scoping review was conducted to summarise how human (fluoro)quinolone-resistant (FQR; quinolones including fluoroquinolones) Campylobacter spp. infections are characterised in the literature by describing how burden of illness (BOI) associated with FQR is measured and reported, describing the variability in reporting of study characteristics, and providing a narrative review of literature that compare BOI measures of FQR Campylobacter spp. infections to those with susceptible infections. The review identified 26 studies that yielded many case reports, a lack of recent literature and a lack of Canadian data. Studies reported 26 different BOI measures and the most common were hospitalisation, diarrhoea, fever and duration of illness. There were mixed results as BOI measures reported in literature were inconsistently defined and there were limited comparisons between resistant and susceptible infections. This presents a challenge when attempting to assess the magnitude of the BOI due to FQR Campylobacter spp., highlighting the need for more research in this area.

Evaluation of the health and healthcare system burden due to antimicrobial-resistant Escherichia coli infections in humans: a systematic review and meta-analysis.

BACKGROUND: Assessment of the burden of disease due to antimicrobial-resistant Escherichia coli infections facilitates understanding the scale of the problem and potential impacts, and comparison to other diseases, which allows prioritization of research, surveillance, and funding. Using systematic review and meta-analysis methodology, the objectives were to evaluate whether humans with antimicrobial-resistant E. coli infections experience increases in measures of health or healthcare system burden when compared to susceptible E. coli infections. METHODS: Comprehensive literature searches were performed in four primary and seven grey literature databases. Analytic observational studies of human E. coli infections that assessed the impact of resistance to third/fourth/fifth-generation cephalosporins, resistance to quinolones, and/or multidrug resistance on mortality, treatment failure, length of hospital stay and/or healthcare costs were included. Two researchers independently performed screening, data extraction, and risk of bias assessment. When possible, random effect meta-analyses followed by assessment of the confidence in the cumulative evidence were performed for mortality and length of hospital stay outcomes, and narrative syntheses were performed for treatment failure and healthcare costs. RESULTS: Literature searches identified 14,759 de-duplicated records and 76 articles were included. Based on 30-day and all-cause mortality meta-analyses, regardless of the type of resistance, there was a significant increase in the odds of dying with resistant E. coli infections compared to susceptible infections. A summary mean difference was not presented for total length of hospital stay meta-analyses due to substantial to considerable heterogeneity. Since small numbers of studies contributed to meta-analyses for bacterium-attributable mortality and post-infection length of hospital stay, the summary results should be considered with caution. Studies contributing results for treatment failure and healthcare costs had considerable variability in definitions and reporting. CONCLUSIONS: Overall, resistant E. coli infections were associated with significant 30-day and all-cause mortality burden. More research and/or improved reporting are necessary to facilitate quantitative syntheses of bacterium-attributable mortality, length of hospital stay, and hospital costs. Protocol Registration PROSPERO CRD42018111197.

Cost trajectories for cancer patients.

BACKGROUND: Health care spending is known to be highly skewed, with a small subset of the population consuming a disproportionate amount of health care resources. Patients with cancer are high-cost users because of high incremental health care costs for treatment and the growing prevalence of cancer. The objectives of the present study included characterizing cancer-patient trajectories by cost, and identifying the patient and health system characteristics associated with high health system costs after cancer treatment. METHODS: This retrospective cohort study identified Ontario adults newly diagnosed with cancer between 1 April 2009 and 30 September 2010. Costs of health care use before, during, and after cancer episodes were used to develop trajectories of care. Descriptive analyses examined differences between the trajectories in terms of clinical and health system characteristics, and a logistic regression approach identified predictors of being a high-cost user after a cancer episode. RESULTS: Ten trajectories were developed based on whether patients were high- or low-cost users before and after their cancer episode. The most common trajectory represented patients who were low-cost in the year before cancer, survived treatment, and continued to be low-cost in the year after cancer (31.4%); stage ii cancer of the male genital system was the most common diagnosis within that trajectory. Regression analyses identified increases in age and in multimorbidity and low continuity of care as the strongest predictors of high-cost status after cancer. CONCLUSIONS: Findings highlight an opportunity to proactively identify patients who might transition to high-cost status after cancer treatment and to remediate that transition.

A multi-method review of home-based chemotherapy.

This study summarises research- and practice-based evidence on home-based chemotherapy, and explores existing delivery models. A three-pronged investigation was conducted consisting of a literature review and synthesis of 54 papers, a review of seven home-based chemotherapy programmes spanning four countries, and two case studies within the Canadian province of Ontario. The results support the provision of home-based chemotherapy as a safe and patient-centred alternative to hospital- and outpatient-based service. This paper consolidates information on home-based chemotherapy programmes including services and drugs offered, patient eligibility criteria, patient views and experiences, delivery structures and processes, and common challenges. Fourteen recommendations are also provided for improving the delivery of chemotherapy in patients' homes by prioritising patient-centredness, provider training and teamwork, safety and quality of care, and programme management. The results of this study can be used to inform the development of an evidence-informed model for the delivery of chemotherapy and related care, such as symptom management, in patients' homes.

Analysis of stress fractures associated with lameness in Thoroughbred flat racehorses training on different track surfaces undergoing nuclear scintigraphic examination.

REASONS FOR PERFORMING STUDY: There is limited information regarding the impact of training track surface on the occurrence of stress fractures. OBJECTIVES: To evaluate the impact of training track surface on the proportion of long bone and pelvic stress fractures associated with lameness in Thoroughbred horses in flat race training undergoing nuclear scintigraphic examination. STUDY DESIGN: Retrospective study. METHODS: Scintigraphic examinations of Thoroughbred flat racehorses were evaluated from 2 hospitals (hospital A [Toronto Equine Hospital], 2003-2009, and hospital B [George D. Widener Hospital for Large Animals, School of Veterinary Medicine, University of Pennsylvania], 1994-2006). Horses admitted to hospital A trained at a single track, at which the main training surface changed from dirt to synthetic on 27 August 2006. Two distinct populations existed at hospital B: horses that trained on dirt (numerous trainers) and those that trained on turf (single trainer). All scintigraphic images were evaluated by a blinded reviewer. Fisher's exact test and logistic regression were used when appropriate, and significance was set at P<0.05. RESULTS: When reviewing 528 scintigraphic examinations from hospital A (257 dirt and 271 synthetic, numerous trainers), there was a greater proportion of stress fractures detected in scintigraphic examinations from horses training on a synthetic surface (31.7%) in comparison to scintigraphic examinations from horses training on a dirt surface (23.0%) at an earlier point in time (P = 0.03). There was a greater proportion of hindlimb/pelvic and tibial stress fractures diagnosed in horses from the synthetic surface-trained group than from the dirt-trained group at hospital A (P<0.04 and P = 0.03, respectively). CONCLUSIONS: This study provides evidence that training surface may affect the proportion of stress fractures diagnosed, but other factors, such as training philosophy, appear to be important. Future prospective investigations to fully elucidate the relationship between training track surface and the proportion of stress fractures and other nonfatal musculoskeletal injuries are warranted.

The delivery of renal replacement therapy in Scotland--why the geographic variation?

BACKGROUND: The incidence of patients starting renal replacement therapy (RRT) for established renal failure (ERF) in Scotland has fallen from 2005 to 2011 due to a reduction in older patients starting RRT; there are significant differences between NHS Health board areas. AIM: To understand the apparent inequality in provision of RRT between NHS board areas in Scotland. DESIGN: Retrospective population analysis of Scottish renal registry (SRR) data, population statistics and quality outcomes framework summary statistics. RESULTS: The incidence of patients starting RRT for ERF in Scotland fell from 123 per million population (pmp) in 2005 to 96 pmp in 2011. The incidence of ≥75 year olds fell from 406 to 274 pmp. There are significant differences between NHS board areas when standardized for age and social deprivation. There is no relationship between the population prevalence of CKD as reported by QOF and the incidence of RRT for ERF. Those areas with high incidence rates of ≥75 year olds have higher 90-day [Spearman's rank correlation: coefficient = 0.662; P = 0.03] and 1-year [Spearman's rank correlation: coefficient = 0.776; P = 0.003] mortality rates. CONCLUSION: The significant variation in provision of RRT for ERF between Scottish NHS Board areas is not explained by age or social deprivation. There is evidence of change in practice towards RRT for patients aged ≥75 years but variation between NHS Board areas. This disparity must be further investigated to ensure equity of access to RRT for those who will benefit from it, and to non-dialytic care for those who would not.

The selection landscape of malaria parasites.

Malaria parasites have to survive and transmit within a highly selective and ever-changing host environment. Because immunity to malaria is nonsterilizing and builds up slowly through repeated infections, commonly the parasite invades a host that is immunologically and physiologically different from its previous host. During the course of infection, the parasite must also keep pace with changes in host immune responses and red-blood-cell physiology. Here, we describe the "selection landscape" of the most virulent of the human malaria parasites, Plasmodium falciparum, and the adaptive mechanisms it uses to navigate through that landscape. Taking a cost-benefit view of parasite fitness, we consider the evolutionary outcomes of the most important forces of selection operating on the parasite, namely immunity, host death, drugs, mosquito availability, and coinfection. Given the huge potential for malaria parasite evolution in the context of the recently renewed effort to eradicate malaria, a deeper understanding of P. falciparum adaptation is essential.

Practical barriers to the implementation of early goal directed therapy in the UK: trainee skills and awareness.

The Surviving Sepsis Campaign (SSC) recommends Early Goal Directed Therapy (EGDT) in the treatment of septic shock, which requires key critical care skills and knowledge. This study evaluates the availability of these skills in Specialist Registrars in acute hospital specialities in the UK. A questionnaire was sent to Specialist Registrars in Anaesthetics, General Surgery and General Medicine throughout Scotland. One hundred and eighty five responses were obtained. One hundred percent of anaesthetists, 70% of surgeons and 51% of physicians were aware of EGDT Only 62 trainees (6% of surgeons, 79% of anaesthetists, 19% of physicians) had the full complement of skills and knowledge to implement EGDT. This study demonstrates that non-anaesthetic registrars in the UK lack both knowledge and skills required to provide EGDT. The main deficit was in awareness, demonstrating that knowledge of EGDT is not penetrating into specialities beyond anaesthesia. It is now time for the SSC to specifically target non-anaesthetic specialities.

The use of stable isotopes ((13)C/(12)C and (15)N/(14)N) to trace exposure to oil sands processed material in the Alberta oil sands region.

Various oil sands reclamation strategies incorporate oil sands processed material (OSPM) such as mature fine tailings (MFT), engineered tailings (consolidated tailings, CT), and tailings pond water (TPW) into reclamation components that need to develop into viable aquatic ecosystems. The OSPM will contain elevated salinity and organics such as naphthenic acids (NA) and polycyclic aromatic compounds (PAC) that can be chronically toxic to aquatic organisms depending upon levels and age. Due to the complexity of the chemical mixtures, analysis of these compounds in exposed organisms can be challenging. In this study, the stable carbon and nitrogen isotope signatures of selected invertebrates from various types of oil sands reclamation sites were analyzed to determine whether stable isotopes can be used to trace the exposure of aquatic organisms to organic constituents of OSPM. In a series of experimental reclamation ponds of similar age and size, there were trends of (13)C depletion and (15)N enrichment for benthic invertebrates along a gradient of increased levels of MFT and/or TPW. A survey of 16 sites revealed high delta(15)N values for invertebrates in aquatic systems containing MFT and CT (gypsum-treated mixes of MFT and tailings sand), which was attributed to the presence of NH(4)(+), a process by-product in OSPM. Findings of this study indicate a potential for the use of stable nitrogen isotopes to define exposure of biota to OSPM during environmental effects monitoring programs both in surface waters and in cases where groundwater seepage containing oil sands processed water enters surface receiving environments in the region.

Virulence evolution in response to vaccination: the case of malaria.

One theory of why some pathogens are virulent (i.e., they damage their host) is that they need to extract resources from their host in order to compete for transmission to new hosts, and this resource extraction can damage the host. Here we describe our studies in malaria that test and support this idea. We go on to show that host immunity can exacerbate selection for virulence and therefore that vaccines that reduce pathogen replication may select for more virulent pathogens, eroding the benefits of vaccination and putting the unvaccinated at greater risk. We suggest that in disease contexts where wild-type parasites can be transmitted through vaccinated hosts, evolutionary outcomes need to be considered.

Analytical approaches to characterising fish tainting potential of oil sands process waters.

A three-stage study has been carried out with rainbow trout (Oncorhyncus mykiss) to develop analytical approaches which can provide a fingerprint for tainting by oil sands chemicals from process-affected waters and natural sources. The objective was to find a simpler alternative to sensory evaluation. In the first stage, a set of seven test compounds was added to fish tissue which was analysed by headspace and solvent (dichloromethane, DCM) extraction followed by gas chromatography-mass spectrometry (GC-MS). In the second stage, fingerlings (5-20 g) were exposed for 96 hours to the test compound mixture at 1.0 and 0.5 times the estimated tainting threshold concentrations. In the final stage, fingerlings were exposed for 96 hours to an oil sands process water at 5, 10, 20 and 50% concentrations in clean water. None of the test compounds was identified in DCM extracts of tissue from exposed fish. Two long-chain aldehydes, hexadecanal and 9-octadecenal, were tentatively identified in these extracts by matching of mass spectra with library spectra.

Effects of oil sands process-affected waters and naphthenic acids on yellow perch (Perca flavescens) and Japanese medaka (Orizias latipes) embryonic development.

Syncrude Canada Ltd. is currently developing environmentally acceptable oil sands process-affected water management methods as part of their land reclamation strategy. Surface waters of the "wet landscape" reclamation option characteristically have elevated concentrations of sodium sulphate and naphthenic acids (NAs), with low levels of PAHs. The following experiment compared early-life stage responses of yellow perch (Perca flavescens) to those of Japanese medaka (Oryzias latipes) when exposed to Mildred Lake settling basin (MLSB) surface water and a commercial sodium naphthenate (Na-NA) standard. Perch eggs were fertilized and incubated in: 100%, 50%, 20%, 4%, 0.8%, and 0.16% dilutions of MLSB water, as well as 20, 10, 5, 2.5, and 1.25 mg/l solutions of the commercial standard. Medaka embryos were exposed to the same treatments, post-fertilization. Both species demonstrated an increase in the incidence of deformity, and a decrease in length at hatch as NA concentrations increased. MLSB surface water contained higher levels of NAs than the commercial standard, however, showed consistently higher NA threshold effect concentrations for both species. Significant differences between the MLSB water and the Na-NA standard suggest that they contain NA congeners with different toxicity, or other compounds such as PAHs. Species differences in thresholds could be explained by the difference in developmental stage in which the exposures were initiated.

No evidence for the presence of apolipoprotein epsilon4, interleukin-lalpha allele 2 and interleukin-1beta allele 2 cause an increase in programmed cell death following traumatic brain injury in humans.

BACKGROUND: Brain injury after trauma is an important cause of mortality and morbidity in society. There is evidence in both man and laboratory animals that in addition to necrosis, cell loss may occur as a result of programmed cell death (PCD). The cellular and molecular responses after head injury are partly influenced by genetic polymorphisms of apolipoprotein E and the pro-inflammatory cytokine IL-I. AIM: The principal aim of this study was to determine whether the presence of the ApoE epsilon4, IL- 1 alpha2 or IL- 1beta2 allele types influenced the amounts of PCD after head injury compared with controls. METHODS: Paraffin sections from the hippocampus of 38 patients (32 M : 6 F, aged 15 - 75, mean 38 years, survival 7- 576 hours; mean 36 hours) who died after a head injury were stained by Tunel histochemistry and quantified, and genotyping was undertaken by PCR "blind" to clinical detail. RESULTS: There were more Tunel+ cells (neurons and glia) after head injury than in controls with statistically increased numbers in all sectors of the hippocampus including the dentate fascia. However, there was no correlation between ApoEepsilon4, IL- 1 alpha allele 2 and IL- 1beta allele 2 and the amount of Tunel positivity. CONCLUSION: Given that both the ApoE and IL-1 influence outcome after various forms of acute brain injury, further work will be required to determine the mechanism underlying this relationship.

Degradation of naphthenic acids by sediment micro-organisms.

AIMS: Naphthenic acids (NAs) are naturally occurring, linear and cyclic carboxylic surfactants associated with the acidic fraction of petroleum. NAs account for most of the acute aquatic toxicity of oil sands process-affected water (OSPW). The toxicity of OSPW can be reduced by microbial degradation. The aim of this research was to determine the extent of NA degradation by sediment microbial communities exposed to varying amounts of OSPW. METHODS AND RESULTS: Eleven wetlands, both natural and process-affected, and one tailings settling pond in Northern Alberta were studied. The natural wetlands and process-affected sites fell into two distinct groups based on their water chemistry. The extent of degradation of a 14C-labelled monocyclic NA surrogate [14C-cyclohexane carboxylic acid (CCA)] was relatively uniform in all sediments (approximately 30%) after 14 days. In contrast, degradation of a bicyclic NA surrogate [14C-decahydronaphthoic acid (DHNA)] was significantly lower in non process-affected sediments. Enrichment cultures, obtained from an active tailings settling pond, using commercially available NAs as the sole carbon source, resulted in the isolation of a co-culture containing Pseudomonas putida and Pseudomonas fluorescens. Quantitative GC-MS analysis showed that the co-culture removed >95% of the commercial NAs, and partially degraded the process NAs from OSPW with a resulting NA profile similar to that from 'aged wetlands'. CONCLUSIONS: Exposure to NAs induced and/or selected micro-organisms capable of more effectively degrading bicyclic NAs. Native Pseudomonas spp. extensively degraded fresh, commercial NA. The recalcitrant NAs resembled those found in process-affected wetlands. SIGNIFICANCE AND IMPACT OF THE STUDY: These results suggest that it may be possible to manipulate the existing environmental conditions to select for a microbial community exhibiting higher rates of NA degradation. This will have significant impact on the design of artificial wetlands for water treatment.

Gill and liver histopathological changes in yellow perch (Perca flavescens) and goldfish (Carassius auratus) exposed to oil sands process-affected water.

The extraction of bitumen from the Athabasca oil sands (Alberta, Canada) produces significant volumes of process-affected water containing elevated levels of naphthenic acids (NAs), ions, and polycyclic aromatic hydrocarbons (PAHs). The sublethal response of aquatic organisms exposed to oil sands constituents in experimental aquatic environments that represent possible reclamation options has been studied. In this study, the effects of process-affected waters on gill and liver tissues in yellow perch (Perca flavescens) and caged goldfish (Carassius auratus) held in several reclamation ponds at Syncrude's Mildred Lake site have been assessed. Following a 3-week exposure, significant gill (epithelial cell necrosis, mucous cell proliferation) and liver (hepatocellular degeneration, inflammatory cell infiltration) histopathological changes were noted in fish held in waters containing high levels of oil sands process-affected water. In addition, measurements of gill dimensions (gill morphometrical indices) proved sensitive and provided evidence of a physiological disturbance (gas exchange) with exposure to oil sands materials. Due to the complexity of oil sands process-affected water, the cause of the alterations could not be attributed to specific oil sands constituents. However, the histopathological parameters were strong indicators of exposure to oil sands process-affected water and morphometrical data were sensitive indicators of pathological response, which can be used to identify the interactive effects of ionic content, NAs, and PAHs in future laboratory studies.

The effects of salinity on naphthenic acid toxicity to yellow perch: gill and liver histopathology.

Naphthenic acids (NAs) are naturally occurring saturated linear and cyclic carboxylic acids found in petroleum, including the bitumen contained in the Athabasca Oil Sands deposit in Alberta, Canada. The processing of these oil sands leads to elevated concentrations of NAs, as well as increased salinity from produced waters as a result of ions leaching from the ores, the process aids, and the water associated with the deeper aquifers. These changes can result in waters that challenge reclamation of impacted waters associated with oil sands development. Laboratory tests examined the effects of salinity on NA toxicity using local young-of-the-year yellow perch exposed to a commercially available mixture of NAs (CNA) and an NA mixture that was extracted from oil sands process-affected water (ENA), with and without the addition of sodium sulfate (Na(2)SO(4)). Gill and liver histopathological changes were evaluated in the surviving fish after 3 weeks of exposure. At 6.8 mg/L ENA and 3.6 mg/L CNA, 100% mortality was observed, both with and without the addition of salt. Exposure of yellow perch to 25% of the NA required to give an LC100 (0.9 mg/L CNA; 1. 7 mg/L ENA) resulted in high levels of gill proliferative (epithelial, mucous, and chloride cell) changes, a response that was increased with the addition of 1g/L salt (Na2SO4) for the ENA. The significance of these changes was a reduced gill surface area, which likely caused a reduction in both the transport of NAs within the fish and the exchange of vital respiratory gases. While the gills were affected, no liver alterations were identified following NA or NA+salt exposures. Differences in the chemical composition of the NAs tested may explain the differences in the lethality and histopathology of yellow perch.

Drug resistance models for malaria.

The main factors affecting the evolution of drug resistance in malaria according to theoretical models are reviewed here. The overwhelming influence on the emergence and rate of spread of drug resistance is the proportion of infected hosts that are treated with drugs. A second important effect is drug efficacy in killing parasites. Factors such as average transmission rate, recombination, the biological cost of resistance, and the mode of gene action also influence the rate of spread but have relatively minor impacts. A simple population dynamics model that captures the epidemiological effects of drug treatment and resistance, as opposed to a population genetics model that does not, is presented in order to illustrate the main conclusions.

The effects of mosquito transmission and population bottlenecking on virulence, multiplication rate and rosetting in rodent malaria.

Malaria parasites vary in virulence, but the effects of mosquito transmission on virulence phenotypes have not been systematically analysed. Using six lines of malaria parasite that varied widely in virulence, three of which had been serially blood-stage passaged many times, we found that mosquito transmission led to a general reduction in malaria virulence. Despite that, the between-line variation in virulence remained. Forcing serially passaged lines through extreme population bottlenecks (<5 parasites) reduced virulence in only one of two lines. That reduction was to a level intermediate between that of the virulent parental and avirulent ancestral line. Mosquito transmission did not reverse the increased parasite replication rates that had accrued during serial passage, but it did increase rosetting frequencies. Re-setting of asexual stage genes during the sexual stages of the life cycle, coupled with stochastic sampling of parasites with variable virulence during population bottlenecks, could account for the virulence reductions and increased rosetting induced by mosquito transmission.