ABSTRACT
BACKGROUND: Patients with CKD who are on hemodialysis are hyporesponsive to erythropoiesis-stimulating agents (ESAs) because of anemia of inflammation. Interleukin-6 (IL-6) induced hepcidin expression is a key mediator of such inflammation. METHODS: This phase 1/2, placebo-controlled trial assessed effects of ziltivekimab, a novel anti-IL-6 ligand antibody, in patients on hemodialysis with rs855791, a single nucleotide polymorphism of the TMPRSS6 gene that is hypothesized to heighten susceptibility to IL-6-mediated inflammatory effects. After a screening period documenting stable ESA and iron dosing, we randomized 61 patients with elevated IL-6 (≥4 pg/ml) to receive placebo or ziltivekimab (doses of 2, 6, or 20 mg), administered intravenously every 2 weeks for 12 weeks during hemodialysis. ESA dose adjustments were allowed after 4 weeks. We analyzed safety and effects on inflammation, iron metabolism, serum albumin, and anti-drug antibodies. RESULTS: No patient experienced dose-limiting toxicity. Four patients (two each in the 6- and 20-mg cohorts) died of a treatment-emergent adverse event. Compared with patients receiving placebo, those receiving ziltivekimab experienced significantly greater reductions of high-sensitivity C-reactive protein, serum amyloid A, and fibrinogen from baseline to end of treatment. Median ESA usage decreased by 15,000, 15,000, or 33,000 IU/wk per patient in the 2-, 6-, and 20-mg ziltivekimab cohorts, respectively, compared with no change in the placebo group. We also noted significant dose responses for decreased ESA resistance index and increased serum iron, total iron binding capacity, transferrin saturation, and serum albumin. CONCLUSIONS: Ziltivekimab significantly improved markers of inflammation, reduced ESA requirements, and increased serum albumin in patients on hemodialysis with inflammation and hyporesponsiveness to ESA therapy. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of Multiple Doses of COR-001, NCT02868229.
Subject(s)
Anemia/drug therapy , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Inflammation/drug therapy , Kidney Failure, Chronic/therapy , Renal Dialysis/adverse effects , Adult , Aged , Anemia/complications , Biomarkers/metabolism , Cardiovascular Diseases/metabolism , Double-Blind Method , Female , Hematinics/therapeutic use , Hepcidins/metabolism , Humans , Inflammation/complications , Interleukin-6/antagonists & inhibitors , Kidney Failure, Chronic/complications , Ligands , Male , Middle Aged , Serum Albumin/metabolism , Treatment OutcomeABSTRACT
The timely delivery of the most up-to-date medicines and drug products is essential for patients throughout the world. Successful scaling of the bioreactors used within the biopharmaceutical industry plays a large part in the quality and time to market of these products. Scale and topology differences between vessels add a large degree of complication and uncertainty within the scaling process. Currently, this approach is primarily achieved through extensive experimentation and facile empirical correlations, which can be costly and time consuming while providing limited information. The work undertaken in the current study demonstrates a more robust and complete approach using computational fluid dynamics (CFD) to provide potent multiparameter scalability, which only requires geometric and material properties before a comprehensive and detailed solution can be generated. The CFD model output parameters that can be applied in the scale-up include mass transfer rates, mixing times, shear rates, gas hold-up values, and bubble residence times. The authors examined three bioreactors with variable geometries and were able to validate them based on single-phase and multiphase experiments. Furthermore, leveraging the resulting CFD output information enabled the authors to successfully scale-up from a known 2kL to a novel and disparate 5kL single-use bioreactor in the first attempted cell culture. This multiparameter scaling approach promises to ultimately lead to a reduction in the time to market providing patients with earlier access to the most groundbreaking medicines.
Subject(s)
Bioreactors , Heuristics , Hydrodynamics , Animals , CHO Cells , Cell Culture Techniques/methods , Computer Simulation , Cricetulus , Humans , Models, BiologicalABSTRACT
RATIONALE & OBJECTIVE: Epoetin alfa-epbx is a biosimilar to the reference product, epoetin alfa. We compare the safety of epoetin alfa-epbx versus epoetin alfa based on a pooled analysis of findings from 2 randomized, double-blind, comparative clinical studies, and report new data for the long-term safety of epoetin alfa-epbx. STUDY DESIGN: Pooled analyses of previously conducted studies. SETTING & PARTICIPANTS: Hemodialysis patients with anemia. INTERVENTIONS: Data from patients who received 1 or more subcutaneous or intravenous doses of study drug were integrated across route of administration in combined randomized groups (epoetin alfa-epbx, n = 423; epoetin alfa, n = 426). Data from patients who received 1 or more doses of epoetin alfa-epbx in either open-label extension trial were integrated across route of administration in a combined long-term safety studies group (n = 576). OUTCOMES: Adverse events (AEs), immunogenicity, and other outcomes were assessed. RESULTS: Incidences of treatment-emergent AEs, serious AEs, and discontinuation of study drug treatment because of treatment-emergent AEs were similar between combined randomized epoetin alfa-epbx and epoetin alfa, which had mean treatment durations of 18.1 and 17.7 weeks, respectively. Incidences of treatment-emergent AEs, serious AEs, and discontinuation of study drug treatment because of treatment-emergent AEs were 86.5%, 39.4%, and 6.6%, respectively, for the combined long-term safety studies group, which had a mean treatment duration of 40.0 weeks. In total, 12 patients across the combined randomized groups (epoetin alfa-epbx, n = 5; epoetin alfa, n = 7) and 9 patients in the combined long-term safety studies group tested anti-recombinant human erythropoietin antibody positive in 1 or more visits during study conduct. No patient in any group developed neutralizing antibodies or pure red blood cell aplasia. LIMITATIONS: Epoetin alfa comparator not included in the long-term safety studies, greater cumulative exposure to study drug for epoetin alfa-epbx, shorter follow-up in the randomized studies, and potential for selection bias among patients in the open-label long-term safety studies. CONCLUSIONS: This analysis reinforces previous conclusions of similar safety profiles between epoetin alfa-epbx and epoetin alfa. Furthermore, epoetin alfa-epbx had no unexpected safety signals during long-term treatment. FUNDING: This study was funded by Hospira Inc, which was acquired by Pfizer Inc in September 2015. TRIAL REGISTRATION: ClinicalTrials.gov EPOE-10-13 (NCT01473420); EPOE-10-01 (NCT01473407); EPOE-11-04 (NCT01628120); EPOE-11-03 (NCT01628107).
ABSTRACT
Many diseases and disorders are linked to exposure to endocrine disrupting chemicals (EDCs) that mimic the function of natural estrogen hormones. Here we present a Rapid Adaptable Portable In-vitro Detection biosensor platform (RAPID) for detecting chemicals that interact with the human estrogen receptor ß (hERß). This biosensor consists of an allosteric fusion protein, which is expressed using cell-free protein synthesis technology and is directly assayed by a colorimetric response. The resultant biosensor successfully detected known EDCs of hERß (BPA, E2, and DPN) at similar or better detection range than an analogous cell-based biosensor, but in a fraction of time. We also engineered cell-free protein synthesis reactions with RNAse inhibitors to increase production yields in the presence of human blood and urine. The RAPID biosensor successfully detects EDCs in these human samples in the presence of RNAse inhibitors. Engineered cell-free protein synthesis facilitates the use of protein biosensors in complex sample matrices without cumbersome protein purification.
Subject(s)
Biosensing Techniques/methods , Cell-Free System/metabolism , Endocrine Disruptors/blood , Endocrine Disruptors/urine , Protein Biosynthesis/physiology , Cell-Free System/drug effects , Dose-Response Relationship, Drug , Endocrine Disruptors/pharmacology , Estrogen Receptor beta/antagonists & inhibitors , Estrogen Receptor beta/metabolism , Humans , Protein Biosynthesis/drug effectsABSTRACT
OBJECTIVE: This phase II study investigated the feasibility and potential effectiveness of treadmill training versus normal gait re-education for ambulant and non-ambulant people with sub-acute stroke delivered as part of normal clinical practice. DESIGN: A single-blind, feasibility randomized controlled trial. SETTING: Four hospital-based stroke units. SUBJECTS: Participants within three months of stroke onset. INTERVENTIONS: Participants were randomized to treadmill training (minimum twice weekly) plus normal gait re-education or normal gait re-education only (control) for up to eight weeks. MAIN MEASURES: Measures were taken at baseline, after eight weeks of intervention and at six-month follow-up. The primary outcome was the Rivermead Mobility Index. Other measures included the Functional Ambulation Category, 10-metre walk, 6-minute walk, Barthel Index, Motor Assessment Scale, Stroke Impact Scale and a measure of confidence in walking. RESULTS: In all, 77 patients were randomized, 39 to treadmill and 38 to control. It was feasible to deliver treadmill training to people with sub-acute stroke. Only two adverse events occurred. No statistically significant differences were found between groups. For example, Rivermead Mobility Index, median (interquartile range (IQR)): after eight weeks treadmill 5 (4-9), control 6 (4-11) p = 0.33; or six-month follow-up treadmill 8.5 (3-12), control 8 (6-12.5) p = 0.42. The frequency and intensity of intervention was low. CONCLUSION: Treadmill training in sub-acute stroke patients was feasible but showed no significant difference in outcomes when compared to normal gait re-education. A large definitive randomized trial is now required to explore treadmill training in normal clinical practice.
Subject(s)
Exercise Therapy/methods , Gait Disorders, Neurologic/rehabilitation , Psychomotor Performance/physiology , Stroke Rehabilitation/methods , Stroke/complications , Walking Speed , Aged , Exercise Test , Feasibility Studies , Female , Follow-Up Studies , Gait Disorders, Neurologic/etiology , Gait Disorders, Neurologic/physiopathology , Humans , Male , Middle Aged , Mobility Limitation , Risk Assessment , Single-Blind Method , Stroke/diagnosis , Time Factors , Treatment OutcomeABSTRACT
The effectiveness and economics of polyvinyl sulfonic acid (PVSA) as a ribonuclease inhibitor for in vitro systems is reported. PVSA was shown to inhibit RNA cleavage in the presence of RNase A as well as in the presence of Escherichia coli lysate, suggesting that PVSA can act as a broader ribonuclease inhibitor. In addition, PVSA was shown to improve the integrity of mRNA transcripts by up to 5-fold in vitro as measured by their translational viability. Improved preservation of mRNA transcripts in the presence of PVSA under common RNA storage conditions is also reported. A cost comparison with commercially available RNAse inhibitors indicates the economic practicality of PVSA which is approximately 1,700 times less expensive than commonly used ribonuclease inhibitors. PVSA can also be separated from RNA by alcohol precipitation for applications that may be sensitive to the presence of PVSA.
Subject(s)
Bacterial Proteins/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Polyvinyls/pharmacology , Protein Biosynthesis , RNA, Messenger/metabolism , Ribonucleases/antagonists & inhibitors , Sulfonic Acids/pharmacology , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Enzyme Assays , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/economics , Escherichia coli/enzymology , Escherichia coli/genetics , Kinetics , Polyvinyls/chemistry , Polyvinyls/economics , RNA Stability , RNA, Messenger/chemistry , RNA, Messenger/genetics , Ribonucleases/genetics , Ribonucleases/metabolism , Subcellular Fractions/metabolism , Sulfonic Acids/chemistry , Sulfonic Acids/economics , Transcription, GeneticABSTRACT
Emancipating sense codons toward a minimized genetic code is of significant interest to science and engineering. A key approach toward sense codon emancipation is the targeted in vitro removal of native tRNA. However, challenges remain such as the insufficient depletion of tRNA in lysate-based in vitro systems and the high cost of the purified components system (PURE). Here we used RNase-coated superparamagnetic beads to efficiently degrade E. coli endogenous tRNA. The presented method removes >99% of tRNA in cell lysates, while partially preserving cell-free protein synthesis activity. The resulting tRNA-depleted lysate is compatible with in vitro-transcribed synthetic tRNA for the production of peptides and proteins. Additionally, we directly measured residual tRNA using quantitative real-time PCR. © 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:1401-1407, 2017.
Subject(s)
Cell Extracts/chemistry , Escherichia coli/metabolism , RNA, Transfer/metabolism , Ribonuclease, Pancreatic/metabolism , Synthetic Biology/methods , Animals , Cattle , Cell-Free System/metabolism , Codon/genetics , Enzymes, Immobilized/metabolism , Escherichia coli/genetics , Protein Biosynthesis , RNA, Transfer/analysisABSTRACT
BACKGROUND: Therapeutic options for the treatment of anemia secondary to chronic kidney disease (CKD) remain limited. Vadadustat (AKB-6548) is an oral hypoxia-inducible factor prolyl-hydroxylase domain (HIF-PHD) inhibitor that is being investigated for the treatment of anemia secondary to CKD. METHODS: A phase 2a, multicenter, randomized, double-blind, placebo-controlled, dose-ranging trial (NCT01381094) was undertaken in adults with anemia secondary to CKD stage 3 or 4. Eligible subjects were evenly randomized to 5 groups: 240, 370, 500, or 630 mg of once-daily oral vadadustat or placebo for 6 weeks. All subjects received low-dose supplemental oral iron (50 mg daily). The primary endpoint was the mean absolute change in hemoglobin (Hb) from baseline to the end of treatment. Secondary endpoints included iron indices, safety, and tolerability. RESULTS: Ninety-three subjects were randomized. Compared with placebo, vadadustat significantly increased Hb after 6 weeks in a dose-dependent manner (analysis of variance; p < 0.0001). Vadadustat increased the total iron-binding capacity and decreased concentrations of ferritin and hepcidin. The proportion of subjects with at least 1 treatment-emergent adverse event was similar between vadadustat- and placebo-treated groups. No significant changes in blood pressure, vascular endothelial growth factor, C-reactive protein, or total cholesterol were observed. Limitations of this study included its small sample size and short treatment duration. CONCLUSIONS: Vadadustat increased Hb levels and improved biomarkers of iron mobilization and utilization in patients with anemia secondary to stage 3 or 4 CKD. Global multicenter, randomized phase 3 trials are ongoing in non-dialysis-dependent and dialysis-dependent patients.
Subject(s)
Anemia/drug therapy , Glycine/analogs & derivatives , Hypoxia-Inducible Factor-Proline Dioxygenases/antagonists & inhibitors , Picolinic Acids/therapeutic use , Renal Insufficiency, Chronic/drug therapy , Adult , Aged , Anemia/blood , Anemia/etiology , Biomarkers/blood , C-Reactive Protein/analysis , Cholesterol/blood , Dose-Response Relationship, Drug , Double-Blind Method , Erythropoietin/blood , Female , Ferritins/blood , Ferritins/metabolism , Glycine/pharmacology , Glycine/therapeutic use , Hemoglobins/analysis , Hepcidins/blood , Hepcidins/metabolism , Humans , Male , Middle Aged , Picolinic Acids/pharmacology , Renal Insufficiency, Chronic/blood , Renal Insufficiency, Chronic/complications , Vascular Endothelial Growth Factor A/bloodABSTRACT
Here we introduce a Rapid Adaptable Portable In vitro Detection biosensor platform (RAPID) for detecting ligands that interact with nuclear hormone receptors (NHRs). The RAPID platform can be adapted for field use, allowing rapid evaluation of endocrine disrupting chemicals (EDCs) presence or absence in environmental samples, and can also be applied for drug screening. The biosensor is based on an engineered, allosterically activated fusion protein, which contains the ligand binding domain from a target NHR (human thyroid receptor ß in this work). In vitro expression of this protein using cell-free protein synthesis (CFPS) technology in the presence of an EDC leads to activation of a reporter enzyme, reported through a straightforward colorimetric assay output. In this work, we demonstrate the potential of this biosensor platform to be used in a portable "just-add-sample" format for near real-time detection. We also demonstrate the robust nature of the cell-free protein synthesis component in the presence of a variety of environmental and human samples, including sewage, blood, and urine. The presented RAPID biosensor platform is significantly faster and less labor intensive than commonly available technologies, making it a promising tool for detecting environmental EDC contamination and screening potential NHR-targeted pharmaceuticals.
Subject(s)
Biosensing Techniques , Endocrine Disruptors/analysis , Recombinant Fusion Proteins/chemical synthesis , Thyroid Hormone Receptors beta/chemistry , Drug Evaluation, Preclinical , Humans , Ligands , Recombinant Fusion Proteins/chemistryABSTRACT
Patients on dialysis require phosphorus binders to prevent hyperphosphatemia and are iron deficient. We studied ferric citrate as a phosphorus binder and iron source. In this sequential, randomized trial, 441 subjects on dialysis were randomized to ferric citrate or active control in a 52-week active control period followed by a 4-week placebo control period, in which subjects on ferric citrate who completed the active control period were rerandomized to ferric citrate or placebo. The primary analysis compared the mean change in phosphorus between ferric citrate and placebo during the placebo control period. A sequential gatekeeping strategy controlled study-wise type 1 error for serum ferritin, transferrin saturation, and intravenous iron and erythropoietin-stimulating agent usage as prespecified secondary outcomes in the active control period. Ferric citrate controlled phosphorus compared with placebo, with a mean treatment difference of -2.2±0.2 mg/dl (mean±SEM) (P<0.001). Active control period phosphorus was similar between ferric citrate and active control, with comparable safety profiles. Subjects on ferric citrate achieved higher mean iron parameters (ferritin=899±488 ng/ml [mean±SD]; transferrin saturation=39%±17%) versus subjects on active control (ferritin=628±367 ng/ml [mean±SD]; transferrin saturation=30%±12%; P<0.001 for both). Subjects on ferric citrate received less intravenous elemental iron (median=12.95 mg/wk ferric citrate; 26.88 mg/wk active control; P<0.001) and less erythropoietin-stimulating agent (median epoetin-equivalent units per week: 5306 units/wk ferric citrate; 6951 units/wk active control; P=0.04). Hemoglobin levels were statistically higher on ferric citrate. Thus, ferric citrate is an efficacious and safe phosphate binder that increases iron stores and reduces intravenous iron and erythropoietin-stimulating agent use while maintaining hemoglobin.
Subject(s)
Ferric Compounds/therapeutic use , Iron/metabolism , Kidney Failure, Chronic/metabolism , Kidney Failure, Chronic/therapy , Phosphorus/metabolism , Renal Dialysis , Anemia, Iron-Deficiency/metabolism , Anemia, Iron-Deficiency/prevention & control , Dose-Response Relationship, Drug , Female , Humans , Hyperphosphatemia/metabolism , Hyperphosphatemia/prevention & control , Israel , Male , Middle Aged , Outcome Assessment, Health Care , Treatment Outcome , United StatesABSTRACT
Foot-and-mouth disease (FMD) is a highly-contagious livestock disease with global socioeconomic ramifications. The disease negatively impacts both individual farmers through reduced herd viability and nations through trade restrictions of animals and animal derivatives. Vaccines for FMD prevention have existed for over 70 years, yet the disease remains enzootic in a large percentage of the globe. FMD persistence is due in part to technical limitations of historic and current vaccine technologies. There also exist many socioeconomic and political barriers to global FMD eradication. Here we highlight the barriers to eradication and discuss potential avenues toward FMD eradication.
Subject(s)
Disease Eradication , Foot-and-Mouth Disease/prevention & control , Viral Vaccines , Animals , Disease Outbreaks/prevention & control , Disease Outbreaks/veterinary , Foot-and-Mouth Disease Virus , International Cooperation , LivestockABSTRACT
BACKGROUND: Iron-deficiency anemia in non-dialysis-dependent chronic kidney disease (NDD-CKD) frequently requires parenteral iron replacement, but existing therapies often require multiple administrations. We evaluated the efficacy and cardiovascular safety of ferric carboxymaltose (FCM), a non-dextran parenteral iron permitting large single-dose infusions, versus iron sucrose in patients with iron-deficiency anemia and NDD-CKD. METHODS: A total of 2584 participants were randomized to two doses of FCM 750 mg in one week, or iron sucrose 200 mg administered in up to five infusions in 14 days. The primary efficacy endpoint was the mean change to highest hemoglobin from baseline to Day 56. The primary composite safety endpoint included all-cause mortality, nonfatal myocardial infarction, nonfatal stroke, unstable angina, congestive heart failure, arrhythmias and hyper- and hypotensive events. RESULTS: The mean hemoglobin increase was 1.13 g/dL in the FCM group and 0.92 g/dL in the iron sucrose group (95% CI, 0.13-0.28). Similar results were observed across all subgroups, except Stage 2 CKD. More subjects in the FCM group achieved a hemoglobin increase of ≥ 1.0 g/dL between baseline and Day 56 (48.6 versus 41.0%; 95% CI, 3.6-11.6%). There was no significant difference between FCM and iron sucrose recipients with respect to the primary composite safety endpoint, including the major adverse cardiac events of death, myocardial infarction, or stroke. A significant difference in the number of protocol-defined, predominantly transient hypertensive episodes was observed in the FCM group. CONCLUSIONS: Two 750-mg infusions of FCM are a safe and effective alternative to multiple lower dose iron sucrose infusions in NDD-CKD patients with iron-deficiency anemia.
Subject(s)
Anemia, Iron-Deficiency/therapy , Ferric Compounds/administration & dosage , Glomerular Filtration Rate/physiology , Glucaric Acid/administration & dosage , Iron/blood , Maltose/analogs & derivatives , Renal Insufficiency, Chronic/physiopathology , Aged , Anemia, Iron-Deficiency/blood , Anemia, Iron-Deficiency/etiology , Dose-Response Relationship, Drug , Drug Therapy, Combination , Female , Ferric Oxide, Saccharated , Hematinics/administration & dosage , Hemoglobins/metabolism , Humans , Infusions, Intravenous , Male , Maltose/administration & dosage , Middle Aged , Renal Dialysis , Renal Insufficiency, Chronic/blood , Renal Insufficiency, Chronic/complications , Treatment OutcomeABSTRACT
Bioconjugating protein to nonbiological surfaces is an essential component of many promising biotechnologies impacting diverse applications such as medical diagnostics, biocatalysis, biohazard detection, and proteomics. However, to enable the widespread economical use of immobilized-protein technologies, long-term stability, and reusability is essential. To enhance protein stability in harsh conditions, herein we report a minimally invasive and covalent bioconjugation that enables precise control of the immobilization location at potentially any surface-accessible location where the incorporated unnatural amino acid does not impact protein structure and function. Specifically, the PRECISE system is introduced where a uniquely reactive unnatural amino acid was incorporated site-specifically at a prespecified location in GFP using cell-free protein synthesis. The GFP was then directly and covalently attached to superparamagnetic beads by the unnatural amino acid in a single click reaction. The immobilized GFP was probed for retained activity and stability under harsh conditions including freeze-thaw cycling and incubation in urea at elevated temperatures. The immobilized GFP was more stable compared to unattached protein in all cases and for all durations observed. The enhanced stability of the immobilized protein is a promising step towards long-term protein stability for biocatalysis and other immobilized-protein applications.
Subject(s)
Amino Acids/chemistry , Green Fluorescent Proteins/chemistry , Green Fluorescent Proteins/biosynthesis , Models, Molecular , Protein Stability , Surface PropertiesABSTRACT
Virus-like particles (VLPs) have been employed for a number of nanometric applications because they self-assemble, exhibit a high degree of symmetry, and can be genetically and chemically modified. However, high symmetry does not allow for a single unique modification site on the VLP. Here, we demonstrate the co-expression of the cytotoxic A2 protein and the coat protein of the bacteriophage Qß to form a nearly monodispersed population of novel VLPs. Cell-free protein synthesis allows for direct access and optimization of protein-synthesis and VLP-assembly. The A2 is shown to be incorporated at high efficiency, approaching a theoretical maximum of one A2 per VLP. This work demonstrates de novo production of a novel VLP, which contains a unique site that has the potential for future nanometric engineering applications.
Subject(s)
Bacteriophages/metabolism , Protein Biosynthesis , Viral Proteins/metabolism , Virion/metabolism , Virology/methods , Bacteriophages/genetics , Cell Fractionation , Escherichia coli/chemistry , Escherichia coli/genetics , Escherichia coli/metabolism , Viral Proteins/genetics , Virion/geneticsABSTRACT
While new approaches to chemical localization have been proposed, animals are still widely used for locating landmines and illegal substances. Existing electronic noses still do not have the necessary sensitivity and accuracy. By modeling a cell's chemical detection system, we can gain insight into the basic "olfactory" system. We use an inspiration from chemotaxis and Hebbian learning to enhance localization and tracking of gradient sources, which can be applied to both chemicals and heat. The eukaryotic receptor clustering model shows improvement over previous prokaryotic chemotaxis-inspired methods that do not take into account receptor clustering. Receptor clustering essentially adapts receptors spatio-temporally. For a mobile simulation, our method locates the source in less convergence time than the other chemotaxis algorithms and insignificantly less time compared to no spatio-temporal filtering (e.g. a single-sensor memoryless case). We then show that local regions of receptor cooperation have the best performance reflecting observations of receptor behavior in biology. To demonstrate the performance of this system in real-time, a stationary 4/8-sensor version of the array is implemented, and the algorithm improves the convergence time, mean, and variance of the Direction-of-Arrival calculation in diffusive, turbulent, and noisy environments.
Subject(s)
Biomimetics/methods , Chemoreceptor Cells/chemistry , Chemoreceptor Cells/physiology , Chemotactic Factors/chemistry , Chemotaxis/physiology , Models, Neurological , Smell/physiology , Animals , Chemotactic Factors/pharmacology , Computer Simulation , Diffusion , Humans , Smell/drug effectsABSTRACT
UNLABELLED: Baer GD, Smith MT, Rowe PJ, Masterton L. Establishing the reliability of mobility milestones as an outcome measure for stroke. Arch Phys Med Rehabil 2003;84:977-81. OBJECTIVE: To establish intrarater, interrater, and test-retest reliability of a standardized measure of mobility, "mobility milestones," incorporating sitting balance, standing balance, and walking ability. DESIGN: Repeated-measures reliability study by using video data of patients with stroke. SETTING: Physiotherapy and rehabilitation departments in Scotland. PARTICIPANTS: Forty physiotherapists recruited from within the Lothian region: 20 senior physiotherapists with at least 3 years of experience working with neurologic patients and 20 staff grade physiotherapists with less than 12 months of experience working with neurologic patients. INTERVENTION: Videotape comprising 40 clips (36 original clips, 4 repeated clips) of stroke patients of differing levels of ability attempting the mobility milestones was produced. After a short training session in the interpretation and application of the mobility milestones, each physiotherapist viewed the tape separately and scored whether the milestone had been achieved or not. This was repeated at a separate test session 2 weeks later. MAIN OUTCOME MEASURE: Score for each mobility milestone. RESULTS: Kappa statistics were used to determine interrater reliability and showed good (.61-.80) to very good (.81-1.0) reliability for 3 of 4 milestones. Intraclass correlation coefficients (ICCs) were used to determine intrarater reliability of the 4 repeated clips and showed 75% of all subjects had high (ICC(2,1)=.91-1.0) reliability. The ICC(2,1) for test-retest reliability showed a similar pattern, with 70% of subjects showing good (.81-.90) or high (.91-1.0) reliability. CONCLUSIONS: The mobility milestones showed favorable levels of reliability when used by experienced or novice physiotherapists. The milestones can be adopted as a simple clinical outcome measure for use with stroke. Further research is required to establish reliability levels when the measure is used by different rehabilitation professionals.