Developing an intervention package to optimise the management of vancomycin therapy using theory informed co-design.

BACKGROUND: Optimising the management of vancomycin by achieving target therapeutic concentrations early during therapy has been associated with reduced mortality and morbidity. Despite the availability of guidelines and training, the management of vancomycin remains suboptimal. OBJECTIVES: The primary outcome was the development of interventions and associated implementation strategies to optimise the management of vancomycin therapy. This paper describes how co-design process was used to build a theory informed intervention package, which was implemented across a wide range of in-patient hospital settings in Queensland, Australia. METHODS: This multiple methods study was conducted in four phases: 1) a baseline audit to identify the nature of the problem and associated determinants informed by stakeholder interviews 2) mapping these findings to the Theoretical Domains Framework (TDF) to identify behavioural correlates and modifiers 3) prioritising the behavioural modifiers and associated implementation strategies to inform a protype of the intervention in a series of co-design sessions and 4) implementing and evaluating the intervention package. The study was conducted across the four teaching hospitals in a large Queensland Hospital and Health Service across multiple healthcare disciplines namely nurses, doctors, and pharmacists. This intervention package was subsequently implemented across Queensland Health with the support of the local champions under the guidance of the steering group. RESULTS: Clinicians identified that a multifaceted intervention package and training which can be tailored to the health-care professional disciplines, would be best suited to shift clinician behaviour to align with guidelines. The findings from the co-design process aligned with theory-informed intervention package. Each of the intervention strategies varied in their frequency and popularity of use. CONCLUSIONS: The use of theory-informed and participatory approach assisted with the intervention development process and aligned the intervention content with the priorities of stakeholders. The TDF provided a structured process for developing intervention content which is both acceptable and useful to stakeholders and may improve the management of vancomycin.

Bone density of the humeral condyle in Labrador retrievers with medial coronoid process disease.

OBJECTIVES: To estimate, using CT imaging, differences in the regional bone density of the humeral condyle in Labrador retriever elbows with and without medial coronoid process disease. MATERIALS AND METHODS: The elbows of Labrador Retrievers that had undergone CT were reviewed. Scans were divided into three categories: elbows without medial coronoid process disease; elbows with medial coronoid process disease involving fragmentation of the radial incisure; elbows with medial coronoid process disease involving fragmentation of the medial coronoid apex. A templating technique was employed to define the weight-bearing regions of the medial and lateral portion of the humeral condyle and estimates of volumetric bone density (defined by Hounsfield unit measurement) were compared across the three groups. RESULTS: CT evaluation was performed on 122 elbows in 81 dogs. There was a higher mean Hounsfield unit measurement in the medial and lateral portions of the humeral condyles in elbows with medial coronoid process disease involving fragmentation of the medial coronoid apex compared with elbows with medial coronoid process disease involving fragmentation of the radial incisure. CLINICAL SIGNIFICANCE: Dogs with apical fragmentation of the medial coronoid process exhibited significantly higher estimated bone mineral density within the medial portion of the humeral condyle when compared to dogs with radial incisure fragmentation. The medial portion of the humeral condyle may be associated with the pathogenesis of apical but not radial incisure medial coronoid process fragmentation in Labrador Retrievers.

Organic waste as a sustainable feedstock for platform chemicals.

Biorefineries have been established since the 1980s for biofuel production, and there has been a switch lately from first to second generation feedstocks in order to avoid the food versus fuel dilemma. To a lesser extent, many opportunities have been investigated for producing chemicals from biomass using by-products of the present biorefineries, simple waste streams. Current facilities apply intensive pre-treatments to deal with single substrate types such as carbohydrates. However, most organic streams such as municipal solid waste or algal blooms present a high complexity and variable mixture of molecules, which makes specific compound production and separation difficult. Here we focus on flexible anaerobic fermentation and hydrothermal processes that can treat complex biomass as a whole to obtain a range of products within an integrated biorefinery concept.

Oncologic doses of zoledronic acid induce site specific suppression of bone modelling in rice rats.

OBJECTIVES: To examine the effect of zoledronic acid (ZOL) on cortical bone modelling and healing of extraction sockets in the jaw bones of a rodent model. We hypothesized ZOL suppresses both the bone formation in the modelling mode in the jaw bones and alters the extraction site healing. MATERIAL & METHODS: Rice rats were administered saline solution and two dose regimens of ZOL: 0.1 mg/kg, twice a week, for 4 weeks (n=17, saline=8 & ZOL=9) and a higher dose of 0.4 mg/kg, weekly, for 9 weeks (n=30, saline=15 & ZOL=15). Two pairs of fluorochrome bone labels were administered. Extraction of maxillary teeth was performed in maxilla. Mineral apposition rate, mineralizing surface and bone formation rate (BFR) were quantified on periodontal (PDL), alveolar and basal bone surfaces, and in the trabecular bone of proximal tibia. Bone volume (BV) was evaluated at extraction sockets. Multivariate Gaussian models were used to account for repeated measurements, and analyzes were conducted in SAS V9.3. RESULTS: ZOL suppressed bone modelling (BFR/BS) at the PDL surfaces in the mandible (P<.05), but its effect was not significant at the periosteal surfaces of both jaws. BV for the healing sockets of ZOL treated animals was not significantly different (P=.07) compared to the saline group. ZOL suppressive effect was higher in the tibia compared to the jaws. CONCLUSION: ZOL severely suppresses coupled remodelling in the tibia, and the suppression of bone formation in the modelling mode in the jaws demonstrates the site specific effects of ZOL in rice rats.

Standardization of a Videofluoroscopic Swallow Study Protocol to Investigate Dysphagia in Dogs.

BACKGROUND: Videofluoroscopic swallow study (VFSS) is the gold standard for diagnosis of dysphagia in veterinary medicine but lacks standardized protocols that emulate physiologic feeding practices. Age impacts swallow function in humans but has not been evaluated by VFSS in dogs. HYPOTHESIS/OBJECTIVES: To develop a protocol with custom kennels designed to allow free-feeding of 3 optimized formulations of contrast media and diets that address limitations of current VFSS protocols. We hypothesized that dogs evaluated by a free-feeding VFSS protocol would show differences in objective swallow metrics based on age. ANIMALS: Healthy juvenile, adult, and geriatric dogs (n = 24). METHODS: Prospective, experimental study. Custom kennels were developed to maintain natural feeding behaviors during VFSS. Three food consistencies (thin liquid, pureed food, and dry kibble) were formulated with either iohexol or barium to maximize palatability and voluntary prehension. Dogs were evaluated by 16 swallow metrics and compared across age groups. RESULTS: Development of a standardized VFSS protocol resulted in successful collection of swallow data in healthy dogs. No significant differences in swallow metrics were observed among age groups. Substantial variability was observed in healthy dogs when evaluated under these physiologic conditions. Features typically attributed to pathologic states, such as gastric reflux, were seen in healthy dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: Development of a VFSS protocol that reflects natural feeding practices may allow emulation of physiology resulting in clinical signs of dysphagia. Age did not result in significant changes in swallow metrics, but additional studies are needed, particularly in light of substantial normal variation.

An EMG-driven biomechanical model of the canine cervical spine.

Due to the frequency of cervical spine injuries in canines, the purpose of this effort was to develop an EMG-driven dynamic model of the canine cervical spine to assess a biomechanical understanding that enables one to investigate the risk of neck disorders. A canine subject was recruited in this investigation in order to collect subject specific data. Reflective markers and a motion capture system were used for kinematic measurement; surface electrodes were used to record electromyography signals, and with the aid of force plate kinetics were recorded. A 3D model of the canine subject was reconstructed from an MRI dataset. Muscles lines of action were defined through a new technique with the aid of 3D white light scanner. The model performed well with a 0.73 weighted R2 value in all three planes. The weighted average absolute error of the predicted moment was less than 10% of the external moment. The proposed model is a canine specific forward-dynamics model that precisely tracks the canine subject head and neck motion, calculates the muscle force generated from the twelve major moment producing muscles, and estimates resulting loads on specific spinal tissues.

MRI cross sectional atlas of normal canine cervical musculoskeletal structure.

Although magnetic resonance imaging (MRI) has been increasingly used as a diagnostic tool for cervical spine injuries in canines, a comprehensive normal MRI anatomy of the canine cervical spine muscles is lacking. Therefore, the purpose of this study was to build a magnetic resonance imaging atlas of the normal cross sectional anatomy of the muscles of the canine cervical spine. MRI scans were performed on a canine cadaver using a combination of T1 and T2-weighted images in the transverse, sagittal and dorsal planes acquired at a slice thickness of 1mm. Muscle contours were traced manually in each slice, using local osseous structures as reference points for muscle identification. Twenty-two muscles were traced in 401 slices in the cervical region. A three dimensional surface model of all the contoured muscles was created to illustrate the complex geometrical arrangement of canine neck muscles. The cross-sectional area of the muscles was measured at the mid-level of each vertebra. The accuracy of the location of the mapped muscles was verified by comparing the sagittal view of the 3D model of muscles with still photographs obtained from anatomic canine cadaver dissection. We believe that this information will provide a unique and valuable resource for veterinary researchers, clinicians and surgeons who wish to evaluate MRI images of the cervical spine. It will also serve as the foundation for ongoing work to develop a computational model of the canine cervical spine in which anatomical information is combined with electromyographic, kinematic and kinetic data.

Ewing's sarcoma of bone tumor cells produces MCSF that stimulates monocyte proliferation in a novel mouse model of Ewing's sarcoma of bone.

Ewing's sarcoma of bone is a primary childhood malignancy of bone that is treated with X-radiation therapy in combination with surgical excision and chemotherapy. To better study Ewing's sarcoma of bone we developed a novel model of primary Ewing's sarcoma of bone and then treated animals with X-radiation therapy. We identified that uncontrolled tumor resulted in lytic bone destruction while X-radiation therapy decreased lytic bone destruction and increased limb-length asymmetry, a common, crippling complication of X-radiation therapy. Osteoclasts were indentified adjacent to the tumor, however, we were unable to detect RANK-ligand in the Ewing's tumor cells in vitro, which lead us to investigate alternate mechanisms for osteoclast formation. Ewing's sarcoma tumor cells and archival Ewing's sarcoma of bone tumor biopsy samples were shown to express MCSF, which could promote osteoclast formation. Increased monocyte numbers were detected in peripheral blood and spleen in animals with untreated Ewing's sarcoma tumor while monocyte number in animals treated with x-radiation had normal numbers of monocytes. Our data suggest that our Ewing's sarcoma of bone model will be useful in the study Ewing's sarcoma tumor progression in parallel with the effects of chemotherapy and X-radiation therapy.

Dental unit water treatment with hydrogen peroxide and monovalent silver ions artificially contaminated with freshly isolated pathogens.

BACKGROUND: Dental unit water (DUW) could be contaminated by human pathogens coming from biological fluids penetrated during patient treatment and by opportunistic pathogens detached from aquatic biofilm. These microorganisms could be spread to following patients. We tested the disinfectant activity of hydrogen peroxide and monovalent silver ions (H(2)O(2)-Ag(+)) into DUW artificially contaminated with freshly isolated pathogens. METHODS: The tested microorganisms were Staphylococcus aureus, Enterococcus faecalis, Candida albicans, Pseudomonas aeruginosa, Legionella pneumophila, Mycobacterium chelonae, non-pathogenic Bacillus clausii spores. Bacterial suspensions were inoculated into the waterlines of pre-sterilized dental turbines. The test-turbines were connected to DUW and contaminated water was treated for 10 minutes with H(2)O(2)-Ag(+)-based disinfectant (H(2)O(2) 3% v/v, Ag(+) 0.001% w/v). The control-turbines were left untreated. Turbines were washed with sterile hard water used to assess the residual bacterial loads (expressed in colony forming units -cfu). Each strain was tested five times and the mean log loads were assessed. Following the European Standardization Committee, the disinfectant activity was evaluated as mean log load reduction, that is, the difference between the mean log load detected on the control-turbines and the mean log load detected on the test-turbines. RESULTS: Mean bacterial loads detected on the control-turbines ranged between 105-107 cfu. The mean log load reductions resulted 7.5 log cfu for S. aureus, E. faecalis, P. aeruginosa, 6.3 for C. albicans, 5.4 for L. pneumophila, 5.3 for M. chelonae, 2.9 for B. clausii spores. CONCLUSIONS: DUW disinfection with H(2)O(2)-Ag(+) could help minimize the risk that planktonic pathogens are spread to patients during dental treatment.

Force plate gait analysis in Doberman Pinschers with and without cervical spondylomyelopathy.

BACKGROUND: The most accepted means of evaluating the response of a patient with cervical spondylomyelopathy (CSM) to treatment is subjective and based on the owner and clinician's perception of the gait. OBJECTIVE: To establish and compare kinetic parameters based on force plate gait analysis between normal and CSM-affected Dobermans. ANIMALS: Nineteen Doberman Pinschers: 10 clinically normal and 9 with CSM. METHODS: Force plate analysis was prospectively performed in all dogs. At least 4 runs of ipsilateral limbs were collected from each dog. Eight force platform parameters were evaluated, including peak vertical force (PVF) and peak vertical impulse (PVI), peak mediolateral force (PMLF) and peak mediolateral impulse, peak braking force and peak braking impulse, and peak propulsive force (PPF) and peak propulsive impulse. In addition, the coefficient of variation (CV) for each limb was calculated for each parameter. Data analysis was performed by a repeated measures approach. RESULTS: PMLF (P = .0062), PVI (P = .0225), and PPF (P = .0408) were found to be lower in CSM-affected dogs compared with normal dogs. Analysis by CV as the outcome indicated more variability in PVF in CSM-affected dogs (P = 0.0045). The largest difference in the CV of PVF was seen in the thoracic limbs of affected dogs when compared with the thoracic limbs of normal dogs (P = 0.0019). CONCLUSIONS AND CLINICAL IMPORTANCE: The CV of PVF in all 4 limbs, especially the thoracic limbs, distinguished clinically normal Dobermans from those with CSM. Other kinetic parameters less reliably distinguished CSM-affected from clinically normal Dobermans.

Genomic sequence and analysis of EhV-99B1, a new coccolithovirus from the Norwegian fjords.

Coccolithoviruses are giant dsDNA viruses that infect Emiliania huxleyi, the most ubiquitous marine microalga. Here, we present the genome of the latest coccolithovirus strain to be sequenced, EhV-99B1, and compare it with two other coccolithovirus genomes (EhV-86 and EhV-163). EhV-99B1 shares a pairwise nucleotide identity of 98% with EhV-163 (the two strains were isolated from the same Norwegian fjord but in different years), and just 96.5% with EhV-86 (isolated in the same spring as EhV-99B1 but in the English Channel). We confirmed and extended the list of relevant genomic differences between these EhVs from the Norwegian fjord and EhVs from the English Channel, namely the removal/insertions of: a phosphate permease, an endonuclease, a transposase, and two specific tRNAs. As a whole, this study provided new clues and insights into the diversity and mechanisms driving the evolution of these large oceanic viruses, in particular those processes involving selfish genetic elements.

Advances in total joint replacement in small animals.

Total joint replacement is now considered a routine surgical option for small animals with advanced joint disease. This review highlights the current state of the art in total hip, elbow and knee replacement in small animals, as well as the potential for application to other joints such as the intervertebral discs, hock and shoulder. Advances in cementless fixation, the use of less-invasive, bone-sparing procedures, and the development of custom implant options for revision surgery and oncologic reconstruction will be discussed. As growth in this field continues, it is important that future developments in total joint replacement are built on a foundation of detailed laboratory evaluation of new implant designs and surgical techniques, objective assessment of clinical outcomes, and a comprehensive, coordinated retrieval program that evaluates both well-functioning and failed joint replacements.

The dog as a preclinical model to evaluate interface morphology and micro-motion in cemented total knee replacement.

OBJECTIVES: This study investigated cemented fixation of the tibial component from a canine total knee replacement preclinical model. The objective was to determine the local morphology at the material interfaces (implant, cement, bone) and the local relative micro- motion due to functional loading following in vivo service. METHODS: Five skeletally mature research dogs underwent unilateral total knee replacement using a cemented implant system with a polyethylene (PE) monobloc tibial component. Use of the implanted limb was assessed by pressure-sensitive walkway analysis. At 60 weeks post-surgery, the animals were euthanatized and the tibia sectioned en bloc in the sagittal plane to create medial and lateral specimens. High resolution imaging was used to quantify the morphology under the tray and along the keel. Specimens were loaded to 50% body weight and micro- motions at the PE-cement and cement-bone interfaces were quantified. RESULTS: There was significantly (p = 0.002) more cement-bone apposition and interdigitation along the central keel compared to the regions under the tray. Cavitary defects were associated with the perimeters of the implant (60 ± 25%). Interdigitation fraction was negatively correlated with cavitary defect fraction, cement crack fraction, and total micro-motion. CLINICAL SIGNIFICANCE: Achieving good interdigitation of cement into subchondral bone beneath the tibial tray is associated with improved interface morphology and reduced micro-motion; features that could result in a reduced incidence of aseptic loosening. Multiple drill holes distributed over the cut tibial surface and adequate pressurization of the cement into the subchondral bone should improve fixation and reduce interface micromotion and cavitary defects.

Chronic exertional compartment syndrome of the forearm: a case series of 12 patients treated with fasciotomy.

Chronic exertional compartment syndrome of the forearm is rare in the published literature. We report the outcome of a series of 12 patients treated with fasciotomy over a 14 year period. All patients underwent dynamic intra-compartmental pressure testing using a slit catheter technique before surgery. Raised intra-compartmental pressures on exercise, typical symptoms and the absence of other diagnoses were criteria for offering surgical intervention. The superficial flexor, deep flexor and extensor compartments were released. Median follow-up was 9.5 years (range 7 months to 12 years). Median patient-reported percentage improvement after surgery was 88% (range 0%-100%). Median time to return to full activity was 9 weeks. Eleven out of 12 patients were satisfied, very satisfied or extremely satisfied with the outcome of surgery. Fasciotomy can be an effective treatment for chronic exertional compartment syndrome of the forearm.

Dietary restriction delays aging, but not neuronal dysfunction, in Drosophila models of Alzheimer's disease.

Dietary restriction (DR) extends lifespan in diverse organisms and, in animal and cellular models, can delay a range of aging-related diseases including Alzheimer's disease (AD). A better understanding of the mechanisms mediating these interactions, however, may reveal novel pathways involved in AD pathogenesis, and potential targets for disease-modifying treatments and biomarkers for disease progression. Drosophila models of AD have recently been developed and, due to their short lifespan and susceptibility to genetic manipulation, we have used the fly to investigate the molecular connections among diet, aging and AD pathology. DR extended lifespan in both Arctic mutant Aß42 and WT 4R tau over-expressing flies, but the underlying molecular pathology was not altered and neuronal dysfunction was not prevented by dietary manipulation. Our data suggest that DR may alter aging through generalised mechanisms independent of the specific pathways underlying AD pathogenesis in the fly, and hence that lifespan-extending manipulations may have varying effects on aging and functional declines in aging-related diseases. Alternatively, our analysis of the specific effects of DR on neuronal toxicity downstream of Aß and tau pathologies with negative results may simply confirm that the neuro-protective effects of DR are upstream of the initiating events involved in the pathogenesis of AD.

Micromorphometry and cellular characteristics of the canine cervical intervertebral discs.

BACKGROUND: Dogs have a high prevalence of disc-associated cervical spinal cord disorders. Despite this, there are no descriptions of the micromorphometry or cellular characteristics of canine cervical intervertebral discs. HYPOTHESIS/OBJECTIVES: To compare micromorphometric and cellular characteristics at 4 disc regions (outer annulus [OA], inner annulus [IA], transitional zone [TZ], nucleus pulposus [NP]). We hypothesized that measurements would differ between chondrodystrophic (CH) and nonchondrodystrophic (NCH) dogs. ANIMALS: Six CH dogs and 6 NCH dogs, under 3 years old. METHODS: Histologic sections of all cervical discs from each dog were examined. Micromorphometric variables included relative ratio of ventral to dorsal annulus fibrosus (AF), number and mean width of AF fibers, and relative percentage of NP. Cellular variables included cell density, morphology, and grouping. RESULTS: The NP from CH dogs was smaller, more rounded, and more dorsally located compared with that from NCH dogs. The NP occupied a greater proportion of the disc in NCH dogs compared with CH dogs (27.7 versus 15.8%; P<.001). The ratio of ventral to dorsal AF was approximately 3:1 in the CH group and 2:1 in the NCH group. Cellular variables were region dependent. Cell density was 2.4-fold higher in the OA compared with the NP. Approximately 50 of NP cells and 4.5% of OA cells occurred in groups. CONCLUSIONS AND CLINICAL IMPORTANCE: Micromorphometric variables differed by CH status. Cellular variables differed by disc region. Our findings potentially can explain the high incidence of intervertebral disc extrusions in CH dogs compared with NCH dogs.

The Phycodnaviridae: the story of how tiny giants rule the world.

The family Phycodnaviridae encompasses a diverse and rapidly expanding collection of large icosahedral, dsDNA viruses that infect algae. These lytic and lysogenic viruses have genomes ranging from 160 to 560 kb. The family consists of six genera based initially on host range and supported by sequence comparisons. The family is monophyletic with branches for each genus, but the phycodnaviruses have evolutionary roots that connect them with several other families of large DNA viruses, referred to as the nucleocytoplasmic large DNA viruses (NCLDV). The phycodnaviruses have diverse genome structures, some with large regions of noncoding sequence and others with regions of ssDNA. The genomes of members in three genera in the Phycodnaviridae have been sequenced. The genome analyses have revealed more than 1000 unique genes, with only 14 homologous genes in common among the three genera of phycodnaviruses sequenced to date. Thus, their gene diversity far exceeds the number of so-called core genes. Not much is known about the replication of these viruses, but the consequences of these infections on phytoplankton have global affects, including influencing geochemical cycling and weather patterns.

The effect of warming local anaesthetic on the pain of injection during sub-Tenon's anaesthesia for cataract surgery.

In a double blind, randomised controlled trial, we examined the effect of warming local anaesthetic solutions on the pain experienced by patients undergoing a sub-Tenon's block for cataract surgery. In all, 140 patients were randomly allocated to receive either local anaesthetic stored at room temperature (control group) or local anaesthetic warmed to 37 degrees C (study group). Pain scores were assessed using a verbal analogue scale from 0 to 10. There was no significant difference in pain scores between the two groups. We conclude that the practice of warming local anaesthetic prior to performing a sub-Tenon's block does not significantly reduce the amount of pain experienced by patients.

Analysis of two P-element enhancer-trap insertion lines that show expression in the giant fibre neuron of Drosophila melanogaster.

The giant fibre system (GFS) of Drosophila is a simple neural circuit that mediates escape responses in adult flies. Here we report the initial characterization of two genes that are preferentially expressed in the GFS. Two P-element insertion lines, carrying the GAL4 transcriptional activator, were identified that exhibited pronounced expression in elements of the GFS and relatively low levels elsewhere within the adult central nervous system. Genomic DNA flanking the P-element insertion site was recovered from each of these lines, sequenced, and nearby transcripts identified and confirmed to exhibit GFS expression by in situ hybridization. This analysis revealed that these P-elements were in previously characterized genes. Line P[GAL4]-A307 has an insert in the gene short stop for which we have identified a novel transcript, while line P[GAL4]-141 has an insert in the transcription factor ken and barbie. Here we show that ken and barbie mutants have defects in escape behaviour, behavioural responses to visual stimuli and synaptic functions in the GFS. We have therefore revealed a neural role for a transcription factor that previously had no implicated neural function.