Generic protease detection technology for monitoring periodontal disease

Periodontal diseases are inflammatory conditions that affect the supporting tissues of teeth and can lead to destruction of the bone support and ultimately tooth loss if untreated. Progression of periodontitis is usually site specific but not uniform, and currently there are no accurate clinical methods for distinguishing sites where there is active disease progression from sites that are quiescent. Consequently, unnecessary and costly treatment of periodontal sites that are not progressing may occur. Three proteases have been identified as suitable markers for distinguishing sites with active disease progression and quiescent sites: human neutrophil elastase, cathepsin G and MMP8. Generic sensor materials for the detection of these three proteases have been developed based on thin dextran hydrogel films cross-linked with peptides. Degradation of the hydrogel films was monitored using impedance measurements. The target proteases were detected in the clinically relevant range within a time frame of 3 min. Good specificity for different proteases was achieved by choosing appropriate peptide cross-linkers.<br/

Analysing Habitat Connectivity and Home Ranges of Bigmouth Buffalo and Channel Catfish Using a Large-Scale Acoustic Receiver Network

The determination if fish movement of potadromous species is impeded in a river system is often difficult, particularly when timing and extent of movements are unknown. Furthermore, evaluating river connectivity poses additional challenges. Here, we used large-scale, long-term fish movement to study and identify anthropogenic barriers to movements in the Lake Winnipeg basin including the Red, Winnipeg, and Assiniboine rivers. In the frame of the project, 80 Bigmouth Buffalo (Ictiobus cyprinellus) and 161 Channel Catfish (Ictalurus punctatus) were tagged with acoustic transmitters. Individual fish were detected with an acoustic telemetry network. Movements were subsequently analyzed using a continuous-time Markov model (CTMM). The study demonstrated large home ranges in the Lake Winnipeg basin and evidence of frequent transborder movements between Canada and the United States. The study also highlighted successful downstream fish passage at some barriers, whereas some barriers limited or completely blocked upstream movement. This biological knowledge on fish movements in the Lake Winnipeg basin highlights the need for fish passage solutions at different obstructions

Evaluation of a training program for device operators in the Australian Government's Point of Care Testing in General Practice Trial: issues and implications for rural and remote practices

From September 2005 to February 2007 the Australian Government funded the Point of Care Testing (PoCT) in General Practice Trial, a multi-centre, cluster randomised controlled trial to determine the safety, clinical effectiveness, cost-effectiveness and satisfaction of PoCT in General Practice. In total, 53 practices (23 control and 30 intervention) based in urban, rural or remote locations across three states (South Australia [SA], New South Wales [NSW] and Victoria [VIC]) participated in the Trial. Control practices had pathology testing performed by their local laboratory, while intervention practices conducted pathology testing by PoCT. In total, 4968 patients (1958 control and 3010 intervention) participated in the Trial. The point-of-care (PoC) tests performed by intervention practices were: haemoglobin A1c (HbA1c) and urine albumin:creatinine ratio (ACR) on patients with diabetes, total cholesterol, triglyceride and high density lipoprotein (HDL) cholesterol on patients with hyperlipidaemia, and international normalised ratio (INR) on patients on anticoagulant therapy. Three PoCT devices measured these tests: the Siemens DCA 2000 (Siemens HealthCare Diagnostics, Melbourne, VIC, Australia) for HbA1c and urine ACR; Point of Care Diagnostics Cholestech LDX analyser (Point of Care Diagnostics; Sydney, NSW, Australia) for lipids; and the Roche CoaguChek S (Roche Diagnostics; Sydney, NSW, Australia) for INR. Point-of-care testing in the General Practice Trial was underpinned by a quality management framework which included an on-going training and competency program for PoCT device operators. This article describes the design, implementation and results of the training and competency program

Evaluation of acoustic telemetry grids for determining aquatic animal movement and survival

1. Acoustic telemetry studies have frequently prioritized linear configurations of hydrophone receivers, such as perpendicular from shorelines or across rivers, to detect the presence of tagged aquatic animals. This approach introduces unknown bias when receivers are stationed for convenience at geographic bottlenecks (e.g. at the mouth of an embayment or between islands) as opposed to deployments following a statistical sampling design. 2. We evaluated two-dimensional acoustic receiver arrays (grids: receivers spread uniformly across space) as an alternative approach to provide estimates of survival, movement and habitat use. Performance of variably spaced receiver grids (5–25 km spacing) was evaluated by simulating (1) animal tracks as correlated random walks (speed: 0.1–0.9 m/s; turning angle SD: 5–30°); (2) variable tag transmission intervals along each track (nominal delay: 15–300 s); and (3) probability of detection of each transmission based on logistic detection range curves (midpoint: 200–1,500 m). From simulations, we quantified (i) time between successive detections on any receiver (detection time), (ii) time between successive detections on different receivers (transit time), and (iii) distance between successive detections on different receivers (transit distance). 3. In the most restrictive detection range scenario (200 m), the 95th percentile of transit time was 3.2 days at 5 km, 5.7 days at 7 km and 15.2 days at 25 km grid spacing; for the 1,500 m detection range scenario, it was 0.1 days at 5 km, 0.5 days at 7 km and 10.8 days at 25 km. These values represented upper bounds on the expected maximum time that an animal could go undetected. Comparison of the simulations with pilot studies on three fishes (walleye Sander vitreus, common carp Cyprinus carpio and channel catfish Ictalurus punctatus) from two independent large lake ecosystems (lakes Erie and Winnipeg) revealed shorter detection and transit times than what simulations predicted. 4. By spreading effort uniformly across space, grids can improve understanding of fish migration over the commonly employed receiver line approach, but at increased time cost for maintaining grids

Evaluation of acoustic telemetry grids for determining aquatic animal movement and survival

1. Acoustic telemetry studies have frequently prioritized linear configurations of hydrophone receivers, such as perpendicular from shorelines or across rivers, to detect the presence of tagged aquatic animals. This approach introduces unknown bias when receivers are stationed for convenience at geographic bottlenecks (e.g. at the mouth of an embayment or between islands) as opposed to deployments following a statistical sampling design. 2. We evaluated two-dimensional acoustic receiver arrays (grids: receivers spread uniformly across space) as an alternative approach to provide estimates of survival, movement and habitat use. Performance of variably spaced receiver grids (5–25 km spacing) was evaluated by simulating (1) animal tracks as correlated random walks (speed: 0.1–0.9 m/s; turning angle SD: 5–30°); (2) variable tag transmission intervals along each track (nominal delay: 15–300 s); and (3) probability of detection of each transmission based on logistic detection range curves (midpoint: 200–1,500 m). From simulations, we quantified (i) time between successive detections on any receiver (detection time), (ii) time between successive detections on different receivers (transit time), and (iii) distance between successive detections on different receivers (transit distance). 3. In the most restrictive detection range scenario (200 m), the 95th percentile of transit time was 3.2 days at 5 km, 5.7 days at 7 km and 15.2 days at 25 km grid spacing; for the 1,500 m detection range scenario, it was 0.1 days at 5 km, 0.5 days at 7 km and 10.8 days at 25 km. These values represented upper bounds on the expected maximum time that an animal could go undetected. Comparison of the simulations with pilot studies on three fishes (walleye Sander vitreus, common carp Cyprinus carpio and channel catfish Ictalurus punctatus) from two independent large lake ecosystems (lakes Erie and Winnipeg) revealed shorter detection and transit times than what simulations predicted. 4. By spreading effort uniformly across space, grids can improve understanding of fish migration over the commonly employed receiver line approach, but at increased time cost for maintaining grids

Palliative radiotherapy in addition to self-expanding metal stent for improving dysphagia and survival in advanced oesophageal cancer (ROCS: Radiotherapy after Oesophageal Cancer Stenting):study protocol for a randomized controlled trial

Background: The single most distressing symptom for patients with advanced esophageal cancer is dysphagia. Amongst the more effective treatments for relief of dysphagia is insertion of a self-expanding metal stent (SEMS). It is possible that the addition of a palliative dose of external beam radiotherapy may prolong the relief of dysphagia and provide additional survival benefit. The ROCS trial will assess the effect of adding palliative radiotherapy after esophageal stent insertion. Methods/Design: The study is a randomized multicenter phase III trial, with an internal pilot phase, comparing stent alone versus stent plus palliative radiotherapy in patients with incurable esophageal cancer. Eligible participants are those with advanced esophageal cancer who are in need of stent insertion for primary management of dysphagia. Radiotherapy will be administered as 20 Gray (Gy) in five fractions over one week or 30 Gy in 10 fractions over two weeks, within four weeks of stent insertion. The internal pilot will assess rates and methods of recruitment; pre-agreed criteria will determine progression to the main trial. In total, 496 patients will be randomized in a 1:1 ratio with follow up until death. The primary outcome is time to progression of patient-reported dysphagia. Secondary outcomes include survival, toxicity, health resource utilization, and quality of life. An embedded qualitative study will explore the feasibility of patient recruitment by examining patients’ motivations for involvement and their experiences of consent and recruitment, including reasons for not consenting. It will also explore patients’ experiences of each trial arm. Discussion: The ROCS study will be a challenging trial studying palliation in patients with a poor prognosis. The internal pilot design will optimize methods for recruitment and data collection to ensure that the main trial is completed on time. As a pragmatic trial, study strengths include collection of all follow-up data in the usual place of care, and a focus on patient-reported, rather than disease-orientated, outcomes. Exploration of patient experience and health economic analyses will be integral to the assessment of benefit for patients and the NHS

Identifying Canadian Freshwater Fishes through DNA Barcodes

BACKGROUND: DNA barcoding aims to provide an efficient method for species-level identifications using an array of species specific molecular tags derived from the 5' region of the mitochondrial cytochrome c oxidase I (COI) gene. The efficiency of the method hinges on the degree of sequence divergence among species and species-level identifications are relatively straightforward when the average genetic distance among individuals within a species does not exceed the average genetic distance between sister species. Fishes constitute a highly diverse group of vertebrates that exhibit deep phenotypic changes during development. In this context, the identification of fish species is challenging and DNA barcoding provide new perspectives in ecology and systematics of fishes. Here we examined the degree to which DNA barcoding discriminate freshwater fish species from the well-known Canadian fauna, which currently encompasses nearly 200 species, some which are of high economic value like salmons and sturgeons. METHODOLOGY/PRINCIPAL FINDINGS: We bi-directionally sequenced the standard 652 bp "barcode" region of COI for 1360 individuals belonging to 190 of the 203 Canadian freshwater fish species (95%). Most species were represented by multiple individuals (7.6 on average), the majority of which were retained as voucher specimens. The average genetic distance was 27 fold higher between species than within species, as K2P distance estimates averaged 8.3% among congeners and only 0.3% among concpecifics. However, shared polymorphism between sister-species was detected in 15 species (8% of the cases). The distribution of K2P distance between individuals and species overlapped and identifications were only possible to species group using DNA barcodes in these cases. Conversely, deep hidden genetic divergence was revealed within two species, suggesting the presence of cryptic species. CONCLUSIONS/SIGNIFICANCE: The present study evidenced that freshwater fish species can be efficiently identified through the use of DNA barcoding, especially the species complex of small-sized species, and that the present COI library can be used for subsequent applications in ecology and systematics

TRIM21 and the Function of Antibodies inside Cells

Therapeutic antibodies targeting disease-associated antigens are key tools in the treatment of cancer and autoimmunity. So far, therapeutic antibodies have targeted antigens that are, or are presumed to be, extracellular. A largely overlooked property of antibodies is their functional activity inside cells. The diverse literature dealing with intracellular antibodies emerged historically from studies of the properties of some autoantibodies. The identification of tripartite motif (TRIM) 21 as an intracellular Fc receptor linking cytosolic antibody recognition to the ubiquitin proteasome system brings this research into sharper focus. We review critically the research related to intracellular antibodies, link this to the TRIM21 effector mechanism, and highlight how this work is exposing the previously restricted intracellular space to the potential of therapeutic antibodies

Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial.

BACKGROUND: Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months. METHODS: We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed. FINDINGS: Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed. INTERPRETATION: Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI. FUNDING: British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden